Dr James Schaller
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LEVAQUIN TREATMENT DISASTERS:
THE CASUAL USE OF A SERIOUS MEDICATION

As physicians are asked to do more and more under massive demands and pressures unknown outside the medical guild, they are sometimes not able to discuss the side effects of medications. Indeed, this is the norm in insurance based medical care.

Most prescriptions come with no education or warnings of side effects because such a talk takes a good deal of time and therefore some medical boards, lawyers acting as "medical knowing" medical board prosecutors, insurance companies and malpractice lawyers have made it so PAPER DOCUMENTATION COMES BEFORE PEOPLE.

When it comes to one medication, you should be aware of the tendon risks. So the next time your health care worker offers Levaquin or Cipro, consider these articles:

Related Articles, Links

[Fluorquinolone associated tendon rupture]

[Article in German]

Bravo AR, Stoll R, Bürr P, Haschke M.

Klinische Pharmakologie and Toxikologie, Departement Innere Medizin, Universitätsspital Basel, Basel. raetza@uhbs.ch

We report the case of a 38-year-old patient with a rupture of the right Achilles tendon after physical exercise. A few days before he had been treated with ciprofloxacine 500mg bid for chlamydial urethritis. We discuss know risk factors for Achilles tendon ruptures and the possible contribution of ciprofloxacin and fluorquinolones in this case.

Publication Types:
PMID: 18979434 [PubMed - indexed for MEDLINE]

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[Severe course of a rare non-tuberculous Mycobacteriosis (M. haemophilum) of the hand - case report and strategic comments]

[Article in German]

Schumacher O, Dabernig J, Nenadic I, Ingianni G, Cedidi C.

Die Institutsangaben sind am Ende des Beitrags gelistet. oschum@yahoo.de

INTRODUCTION: Mycobacterium haemophilum belongs to the group of atypical mycobacteria and is rarely reported as a cause of upper extremity and hand infections. It is of low virulence. The bacterium seems to be ubiquitous. Sources and mechanism of infection are poorly defined. CASE REPORT: A 48-year-old female patient was admitted with chronic flexor tendon synovitis of the left palm and distal forearm site. Three debridements were carried out and wound swabs were taken. No proof of bacterial colonisation was found. Histologically a granulomatous infection with Langerhans cells was revealed. Effectively calculated monotherapy with ciprofloxacin was begun. Six weeks postoperatively Mycobacterium haemophilum was cultivated in a colaboration with the National Reference Centre for Mycobacteria in Borstel. Medication was changed to triple therapy with clarithromycin, ethambutol and rifabutin. The patient could carry out her daytime job three months postoperatively. One year after first admission functional impairment needed to be treated by scar excision and radical flexor tendon tendolysis. The palmar defect was resurfaced by using a transmetacarpal DMCA 2 flap at the same time. An almost full range of motion was achieved with intensive hand and physiotherapy after a total treatment period of 15 months. DISCUSSION: Patients with upper extremity infections caused by atypical Mycobacteria need qualified hand-surgical care. The decision about need and kind of medicamentous treatment is based on germ differentiation and should be made in cooperation with the National Reference Centre for Mycobacteria in Borstel. To shorten the diagnostic gap between first admission and detection of Mycobacteria in hand infections with a non-typical course of disease we suggest a standardised approach.

Publication Types:
PMID: 18726875 [PubMed - indexed for MEDLINE]

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Musculoskeletal adverse drug reactions: a review of literature and data from ADR spontaneous reporting databases.

Conforti A, Chiamulera C, Moretti U, Colcera S, Fumagalli G, Leone R.

Department of Medicine and Public Health, Section of Pharmacology, University of Verona, Italy.

The musculoskeletal system can be a target organ for adverse drug reactions (ADRs). Drug-induced muscle, bone or connective tissue injuries may be due to, i), primary direct drug action, or, ii), undirected consequence of generalized drug-induced disease. Musculoskeletal ADRs may be only temporarily disabling, such as muscle cramps, as well as in other cases may be serious and life-threatening, such as rhabdomyolysis. In the last few years there has been an increasing awareness of musculoskeletal ADRs. Some recent drug safety issues dealt with serious or uncommon musculoskeletal reactions like rhabdomyolysis associated to statins and tendon rupture associated to fluoroquinolones. In this review, we firstly selected those drug classes having a significantly high percentage of musculoskeletal disorder reports in the WHO adverse drug reaction database, maintained by the Uppsala Monitoring Centre. Secondly, the different musculoskeletal ADRs were closely analyzed through the data obtained from an Italian interregional ADRs spontaneous reporting database. The findings on drugs associated to different musculoskeletal disorders, have been integrated with a review of the epidemiological data available in the literature. For the most involved drugs (HMG-CoA reductase inhibitors, fluoroquinolones, corticosteroids, bisphosphonates, retinoids) the underlying musculoskeletal ADR mechanisms were also reviewed and discussed.

Publication Types:
PMID: 18690950 [PubMed - indexed for MEDLINE]

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Ciprofloxacin-induced urticaria and tenosynovitis: a case report.

Kayabas U, Yetkin F, Firat AK, Ozcan H, Bayindir Y.

Department of Infectious Disease and Clinical Microbiology, Medical Faculty, Inonu University, Malatya, Turkey. ukayabas@inonu.edu.tr

BACKGROUND: Tendon disorders are rare events associated with fluoroquinolone congestion. Skin reactions are more frequent than tendon disorders. We reported this case as the combination of ciprofloxacin-induced urticaria and tenosynovitis has been unreported in young women. CASE: A 28-year-old woman without underlying disease developed urticarias and tendinopathy 4 days after the initiation of ciprofloxacin treatment for urinary infection. MRI of the left foot revealed increased synovial fluid surrounding the tendon of the flexor hallucis longus muscle representing tenosynovitis. Ciprofloxacin was ceased due to the possibility of ciprofloxacin-induced tendinopathy and urticaria. Complete resolution of her symptoms and findings occurred 3 days after discontinuation of ciprofloxacin without any additional treatment. CONCLUSION: Early discontinuation of fluoroquinolone therapy when tendinopathy is suspected is the basis of therapy. So, it should be kept in mind that fluoroquinolone-induced tendinopathy may occur in an otherwise healthy young patient with no risk factors and in a site other than the Achilles tendon. (c) 2008 S. Karger AG, Basel.

Publication Types:
PMID: 18667819 [PubMed - indexed for MEDLINE]

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Ciprofloxacin-mediated cell proliferation inhibition and G2/M cell cycle arrest in rat tendon cells.

Tsai WC, Hsu CC, Tang FT, Wong AM, Chen YC, Pang JH.

Chang Gung Memorial Hospital Department of Physical Medicine and Rehabilitation, Chang Gung University College of Medicine, Taoyuan, Taiwan.

OBJECTIVE: To investigate the effect of ciprofloxacin on the proliferation and cell cycle progression of tendon cells, and to explore the potential molecular mechanism of ciprofloxacin-associated tendinopathy by analyzing the expression of cell cycle-related cyclin and cyclin-dependent kinase (CDK). METHODS: Rat Achilles tendon cells were treated with ciprofloxacin and then assessed by MTT assay, flow cytometric analysis, and fluorescence confocal microscopy. Levels of messenger RNA (mRNA) for CDK-1 and cyclin B were determined by reverse transcriptase-polymerase chain reaction. Protein expression of CDK-1, cyclin B, checkpoint kinase 1 (CHK-1), and polo-like kinase 1 (PLK-1) was determined by Western blot analysis. RESULTS: Ciprofloxacin inhibited tendon cell proliferation and caused cell cycle arrest at the G2/M phase. Confocal microscopy revealed that chromosomes in ciprofloxacin-treated cells neither properly aligned along the equatorial planes nor segregated successfully during metaphase. Mitotic arrest, misaligned chromosomes, and poor bipolar spindle formation were observed in ciprofloxacin-treated cells. CDK-1 and cyclin B protein and mRNA were both down-regulated. CHK-1 protein expression was also suppressed, but PLK-1 protein expression was up-regulated by ciprofloxacin. CONCLUSION: Our findings suggest a possible mechanism of ciprofloxacin-associated tendinopathy. Down-regulation of CHK-1 and up-regulation of PLK-1 may account for mitotic arrest observed in ciprofloxacin-treated cells.

Publication Types:
PMID: 18512786 [PubMed - indexed for MEDLINE]

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Bilateral ankle pain and quinolone use: a case of tendon rupture secondary to quinolone use.

Panigrahi R, Longcroft-Wheaton G, Laji K.

St. Richard's Hospital, Chichester PO19 6SE.

Publication Types:
PMID: 18422228 [PubMed - indexed for MEDLINE]

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[Fluoroquinolone-induced Achilles tendon rupture]

[Article in German]

Maurin N.

Internist/Nephrologie, Intensivmedizin, Bonn. maurin@t-online.de

HISTORY AND ADMISSION FINDINGS: A 72-year-old female dialysis patient with insulin-dependent diabetes mellitus who was under long-term medication with oral prednisolone due to chronic obstructive pulmonary disease was given levofloxacin for one week to treat an acute bronchitis (one 500 mg dose on the first day, 125 mg/day orally from second day onwards). One day after the end of levofloxacin treatment, the patient complained about a constant dragging pain above the right heel that receded under local application of diclofenac ointment and inactivity of the right foot. Twelve days after ending administration of levofloxacin, strong pains in the right calf were suddenly felt during normal walking, and active plantar flexion was lost. Palpation showed the right calf to be soft; a distinct gap was found in the middle third of the Achilles tendon. The Thompson test was positive, and the patient was unable to stand on her right toes. INVESTIGATIONS AND DIAGNOSIS: Ultrasonography showed a discontinuity of the right Achilles tendon. A spontaneous Achilles tendon rupture after taking fluoroquinolone was diagnosed. TREATMENT AND COURSE: Conservative treatment was applied due to the reduced general condition. Initial treatment involved a below-knee plaster cast in equinus position; the cast was replaced on the fourth day by a pneumatic walker, which was also worn during mobilisation by physiotherapy. CONCLUSION: A typical feature of fluoroquinolone-induced tendinopathy (FIT) is a considerable latency period in some cases between the commencement of treatment with a fluoroquinolone and the onset of FIT symptoms. In addition to fluoroquinolone intake, there are three other predisposing risk factors for tendinopathy: age over 60 years, long-term treatment with systemic glucocorticoids, and chronic kidney disease. The patient showed a combination of all the aforementioned risk factors. In patients with these risk factors, especially among people with a combination of said risk factors - which is frequently the case with nephrologic and dialysis patients, especially -, fluoroquinolones should be administered only after critical evaluation and with a dosage that is adapted to renal function.

Publication Types:
PMID: 18236349 [PubMed - indexed for MEDLINE]

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Quinolone-related Achilles tendinopathy in heart transplant patients: incidence and risk factors.

Barge-Caballero E, Crespo-Leiro MG, Paniagua-Martín MJ, Muñiz J, Naya C, Bouzas-Mosquera A, Piñón-Esteban P, Marzoa-Rivas R, Pazos-López P, Cursack GC, Cuenca-Castillo JJ, Castro-Beiras A.

Heart Transplant Unit, Complejo Hospitalario Universitario Juan Canalejo, La Coruña, Spain. blargesbueno@hotmail.com

BACKGROUND: A high incidence of Achilles tendinopathy--tendinitis or rupture--has been observed after quinolone treatment in lung and kidney transplant patients. In the absence of relevant published data, we aimed to determine its incidence, clinical features, risk factors and outcome among heart graft recipients. METHODS: We studied the clinical records of all adult heart transplant patients who were prescribed quinolones at our center between August 1995 and September 2006. Achilles tendinopathy had been diagnosed clinically, with ultrasound assessment when necessary. In all cases, quinolone treatment had been terminated upon diagnosis of tendinopathy. RESULTS: During this period, quinolones had been given on 242 occasions to 149 heart transplant patients (33 women, 116 men). Achilles tendinopathy developed on 14 occasions (5.8%; 95% confidence interval: 2.8% to 8.7%), affecting 13 men and 1 woman (mean age: 62 years). Three cases involved tendon rupture, and bilateral tendinopathy was present in 8 cases. The median time between the start of treatment and onset of symptoms was 2.5 days, with 12 patients being asymptomatic 2 months after drug withdrawal. Independent risk factors for tendinopathy were renal dysfunction (p = 0.03) and increased time between transplantation and treatment (p = 0.005). Incidence was not influenced by the type, dose or previous administration of quinolones, or by the immunosuppressive regimen. CONCLUSIONS: Quinolone-related Achilles tendinopathy is frequent among heart transplant patients, especially in the presence of renal dysfunction or lengthy post-transplantation survival. If no alternative anti-bacterial therapy is available for high-risk patients, close clinical surveillance should be warranted.

Publication Types:
PMID: 18187086 [PubMed - indexed for MEDLINE]

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Achilles tendon rupture associated with combination therapy of levofloxacin and steroid in four patients and a review of the literature.

Parmar C, Meda KP.

5 Goodwood Drive, Moreton, Wirral, Merseyside, UK. chetan.parmar@rediffmail.com

Publication Types:
PMID: 18173993 [PubMed - indexed for MEDLINE]

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[Bilateral achilles tendon disorders secondary to levofloxacin]

[Article in Spanish]

Rodríguez EF, Páramo de Vega M, Cabarcos A, Touceda A, Cigarrán B, Torre JA.

Publication Types:
PMID: 18035654 [PubMed - indexed for MEDLINE]

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The effects of enrofloxacin on canine tendon cells and chondrocytes proliferation in vitro.

Lim S, Hossain MA, Park J, Choi SH, Kim G.

Laboratory of Veterinary Surgery, College of Veterinary Medicine, Chungbuk National University, Cheongju 361-763, South Korea.

Enrofloxacin, a fluoroquinolone antibiotic has been used widely in humans and domestic animals, including dogs, because of its broad-spectrum activity and relative safety. The side effects of fluoroquinolone, induced tendinopathy, tendonitis, spontaneous tendon rupture and cartilage damage, remain incompletely understood. In the present study, we investigated the in vitro effects of enrofloxacin on cell proliferation and induction of apoptosis in canine Achilles tendon cells and chondrocytes. Cell growth and proliferation after treating with enrofloxacin for 2-6 days was quantified by a colorimetric 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxyanilide inner salt (XTT) assay. The results showed that enrofloxacin could inhibit the proliferation of canine tendon cells and chondrocytes at increasing concentrations (10-200 microg/ml). The inhibition of proliferation of canine tendon cells and chondrocytes after exposure to enrofloxacin were associated with induction of apoptosis, as evidenced by the typical nuclear apoptotic condensed nuclei found using Hoechst 33258 staining. It was demonstrated that canine tendon cells and chondrocytes treated with 200 microg/ml enrofloxacin for 4 days exhibited apoptotic features and fragmentation of DNA. Enrofloxacin also increased the apoptosis of canine tendon cells and chondrocytes in a dose and time-dependent manner. The results indicate that enrofloxacin inhibits cell proliferation, induces apoptosis and DNA fragmentation, which might explain enrofloxacin-induced tendinopathy and cartilage damage.

Publication Types:
PMID: 18027099 [PubMed - indexed for MEDLINE]

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Images in clinical medicine. Quinolone-associated rupture of the Achilles' tendon.

Vyas H, Krishnaswamy G.

Wake Forest University School of Medicine, Winston-Salem, NC 27157-1082, USA. dr_harshavyas@yahoo.com

Publication Types:
PMID: 18003963 [PubMed - indexed for MEDLINE]

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Devastating femoral osteomyelitis after anterior cruciate ligament reconstruction.

Frank M, Schmucker U, David S, Matthes G, Ekkernkamp A, Seifert J.

Department of Trauma and Orthopedic Surgery, Center for Clinical Research, Unfallkrankenhaus, Berlin, Germany. matthias.frank@uni-greifswald.de

Osteomyelitis following arthroscopic assisted anterior cruciate ligament (ACL) reconstruction has not been reported in literature. We describe an aggressive progression of septic arthritis and osteomyelitis leading to the complete destruction of the condylar region in a young non-immunosuppressed patient after reconstruction of the ACL. In addition we discuss the steps in diagnostics and our salvage procedures.

Publication Types:
PMID: 17924094 [PubMed - indexed for MEDLINE]

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Safety concerns with fluoroquinolones.

Mehlhorn AJ, Brown DA.

Department of Pharmacy Practice and Administration, Lloyd L Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, FL 33416, USA. allana_mehlhorn@pba.edu

OBJECTIVE: To review the chemistry, pharmacology, and safety of fluoroquinolones. DATA SOURCES: A MEDLINE search (1966-July 2007) was conducted using the key words fluoroquinolones or quinolones with safety, adverse effects, hypoglycemia, hyperglycemia, dysglycemia, QTc prolongation, torsades, seizures, phototoxicity, tendon rupture, Clostridium difficile, and pseudomembranous colitis for articles published in the English language. STUDY SELECTION AND DATA EXTRACTION: Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the chemistry, pharmacology, and safety of each fluoroquinolone. Clinical trials were reviewed and included to compare the safety of systemic fluoroquinolones on the market. Literature on the pathology of serious adverse effects was also reviewed. DATA SYNTHESIS: Gatifloxacin has been shown to increase the risk of hospitalization for dysglycemia in patients with and without diabetes. Hyperglycemia may occur with any fluoroquinolone, especially if not properly dose adjusted. Hypoglycemia may occur with any fluoroquinolone and has a higher frequency in patients receiving concomitant oral hypoglycemic drugs or insulin. Use of any fluoroquinolone should be avoided in patients with risk factors for QTc interval prolongation or tendinopathy. All fluoroquinolones should be used with caution in patients with a history of seizure disorders and may cause phototoxicity or C. difficile-associated diarrhea (CDAD). CONCLUSIONS: Clinicians should be aware of possible alterations in blood glucose, QTc interval prolongation, seizures, phototoxicity, tendinopathy, or CDAD with the use of any fluoroquinolone, especially in patients with other risk factors for these conditions. Clinicians should closely monitor for these adverse effects and appropriately adjust doses to minimize these risks. To provide safe treatment for patients needing antibiotic therapy, an assessment of the risk-benefit ratio may be warranted in the decision to use a fluoroquinolone.

Publication Types:
PMID: 17911203 [PubMed - indexed for MEDLINE]

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[Fluoroquinolone-induced tendon diseases]

[Article in Spanish]

Medrano San Ildefonso M, Mauri Llerda JA, Bruscas Izu C.

Sección de Reumatología, Hospital Universitario Miguel Servet, Zaragoza. mmedrano@unizar.es

Tendinitis and tendon ruptures induced by fluoroquinolones, while uncommon, have been documented in the literature since 1983. We report five cases of tendinitis induced by fluoroquinolones, three caused by levofloxacin and two by ciprofloxacin. We revise actual knowledge of this association and we insist on how important is an early detection to prevent tendon rupture.

Publication Types:
PMID: 17907887 [PubMed - indexed for MEDLINE]

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"Ciprofloxacin-induced" bilateral rectus femoris tendon rupture.

Karistinos A, Paulos LE.

Department of Orthopaedic Surgery, Baylor College of Medicine, Houston, Texas, USA. tasoskaristinos@yahoo.com

Publication Types:
PMID: 17873557 [PubMed - indexed for MEDLINE]

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Septic arthritis with Staphylococcus lugdunensis following arthroscopic ACL revision with BPTB allograft.

Mei-Dan O, Mann G, Steinbacher G, Ballester SJ, Cugat RB, Alvarez PD.

Orthopedic and Sports Division, Meir University Hospital, Tchernichovsky Street, Kfar-Saba, Israel. omer@extremegate.com

Septic arthritis following anterior cruciate ligament reconstruction is an uncommon but a serious complication resulting in six times greater hospital costs than that of uncomplicated ACL surgery and an inferior postoperative activity level. Promptly initiating a specific antibiotic therapy is the most critical treatment, followed by open or arthroscopic joint decompression, debridement and lavage. Staphylococcus lugdunensis is a coagulase-negative staphylococcus predominantly infecting the skin and soft tissue. The few reported cases of bone and joint infections by S. lugdunensis indicate that the clinical manifestations were severe, the diagnosis elusive, and the treatment difficult. If the microbiology laboratory does not use the tube coagulase (long) test to confirm the slide coagulase test result, the organism might be misidentified as Staphylococcus aureus. S. lugdunensis is more virulent than other coagulase-negative staphylococcus; in many clinical situations it behaves like S. aureus, further increasing the confusion and worsening the expected outcome. S. lugdunensis is known to cause infective endocarditis with a worse outcome, septicemia, deep tissue infection, vascular and joint prosthesis infection, osteomyelitis, discitis, breast abscess, urine tract infections, toxic shock and osteitis pubis. We present the first case report in the literature of septic arthritis with S. lugdunensis following arthroscopic ACL revision with bone-patellar-tendon-bone allograft.

Publication Types:
PMID: 17684731 [PubMed - indexed for MEDLINE]

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Chronic alcohol consumption as a predisposing factor for multiple tendon ruptures in unusual sites in a patient with rheumatoid arthritis.

Bourikas LA, Kritikos HD, Papakostantinou OG, Katsikas GA, Boumpas DT, Sidiropoulos PI.

Department of Rheumatology, Allergy and Clinical Immunology, University Hospital of Heraklion Crete, Greece.

Simultaneous bilateral patellar tendon ruptures are a rare complication of rheumatoid arthritis (RA). Systemic inflammatory diseases (RA, systemic lupus erythematosus (SLE), chronic renal failure, primary and secondary hyperparathyroidism, diabetes mellitus, obesity, sports activity, older age (>50) and drugs (prolonged use of high doses of steroids, local steroid injections and quinolones) are considered as potent predisposing factors for tendon rupture. We report a case of an alcoholic patient with RA and bilateral spontaneous tendon ruptures of the knees. Circumstantial evidence suggest that in this patient, chronic alcohol consumption, a very frequent cause of toxicity to striated and cardiac muscle, contributed to the injury.

Publication Types:
PMID: 17631746 [PubMed - indexed for MEDLINE]

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Pulmonary embolism associated with spontaneous bilateral Achilles tendon rupture.

Ramirez MA, Richardson LC.

Harvard Medical School, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA. miguel_ramirez@hms.harvard.edu

Bilateral Achillies tendon ruptures are a rare occurrence that usually occur in patients with chronic systemic disease. Many cases are also associated with corticosteroid or fluoroquinolone use. Nonoperative treatment is generally indicated in this patient population, as the patients are often considered poor surgical candidates. Nonoperative immobilization, however, conveys the risk of developing deep venous thrombosis and pulmonary embolism. Such risks are even greater in patients displaying bilateral Achilles tendon ruptures. In this report, we illustrate the case of a near-fatal pulmonary embolism as associated with bilateral spontaneous Achilles tendon ruptures. We also review the current literature and make recommendations for prophylaxis and treatment of these potentially devastating complications.

Publication Types:
PMID: 17586442 [PubMed - indexed for MEDLINE]

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Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature.

Muzi F, Gravante G, Tati E, Tati G.

Department of Oncologic Urology, S. Eugenio Hospital, Rome, Italy.

Fluoroquinolones are an important class of synthetic antibiotics and their use recently expanded with a new activity against Gram positive and anaerobics. In the literature many side effects were documented and, among them, tendinitis and subsequent tendon rupture are important causes of morbidity. The incidence is 0.14% to 0.4% but, in the kidney recipient population, the phenomenon is even more common (incidence, 12.2%-15.6%). Advanced age seems to be the most significant risk factor. Long period of hemodialysis, diabetes mellitus, hyperparathyroidism, rheumatic diseases, gout, and corticosteroids are the other predisposing factors in kidney recipients, even if they are still under discussion. All of these risk factors can create a synergistic toxicity or at least an additive effect. A case of tendinitis and a case of bilateral Achilles tendon ruptures in 2 kidney recipients are described and a brief discussion of the literature is presented.

Publication Types:
PMID: 17580216 [PubMed - indexed for MEDLINE]

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Pathogenesis of tendon rupture secondary to fluoroquinolone therapy.

Childs SG.

Adult/Acute Care Nurse Practitioner, Baltimore, MD, USA.

Tendon rupture related to trauma and corticosteroid injection, in and about tendon insertion sites, is well documented in the literature. Rupture of tendon after fluoroquinolone therapy has been identified in the recent past. Both short- and long-term courses of antibiotic treatment with fluoroquinolone may precipitate alteration in tendon matrix leading to tendinopathy with subsequent rupture. The pathogenesis of tendon rupture secondary to fluoroquinolone therapy is presented.

Publication Types:
PMID: 17538473 [PubMed - indexed for MEDLINE]

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Management of bilateral Achilles tendon rupture associated with ciprofloxacin: a review and case presentation.

Akali AU, Niranjan NS.

Department of Plastic & Reconstructive surgery, St Andrews' Center for Burns and Plastic Surgery, Broomfield Hospital, Chelmsford, Essex, UK. auakali@dsl.pipex.com

Fluoroquinolone antibiotics are increasingly being recognized as a cause of Achilles tendinitis and rupture. We report the case of a 62-year old man who developed bilateral Achilles tendon rupture six days following commencement of ciprofloxacin. Tendon exploration and repair was accomplished with the use of a prosthetic substitute (Leeds-Keio ligament) but healing was complicated by left wound breakdown that was successfully repaired with a perforator-based fasciocutaneous flap. A review of the current literature on fluoroquinolone associated achilles ruptures and the various methods of tendon and soft tissue management of the primary or complicated injuries are discussed.

Publication Types:
PMID: 17409040 [PubMed - indexed for MEDLINE]

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Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study.

Sode J, Obel N, Hallas J, Lassen A.

Department of Infectious Medicine, Odense University Hospital, 5000, Odense C, Denmark.

OBJECTIVE: Several case-control studies have reported that the use of fluoroquinolone increases the risk of rupture of the Achilles tendon. Our aim was to estimate this risk by means of a population-based cohort approach. SETTING: Data on Achilles tendon ruptures and fluoroquinolone use were retrieved from three population-based databases that include information on residents of Funen County (population: 470,000) in primary and secondary care during the period 1991-1999. A study cohort of all 28,262 first-time users of fluoroquinolone and all incident cases of Achilles tendon ruptures were identified. MAIN OUTCOME MEASURES: The incidence rate of Achilles tendon ruptures among users and non-users of fluoroquinolones and the standardised incidence rate ratio associating fluoroquinolon use with Achilles tendon rupture were the main outcome measures. RESULTS: Between 1991 and 2002 the incidence of Achilles tendon rupture increased from 22.1 to 32.6/100,000 person-years. Between 1991 and 1999 the incidence of fluoroquinolone users was 722/100,000 person-years, with no apparent trend over time. Within 90 days of their first use of fluoroquinolone, five individuals had a rupture of the Achilles tendon; the expected number was 1.6, yielding an age- and sex-standardised incidence ratio of 3.1 [(95% confidence interval (95%CI): 1.0-7.3). The 90-day cumulative incidence of Achilles tendon ruptures among fluoroquinolone users was 17.7/100,000 (95%CI: 5.7-41.3), which is an increase of 12.0/100,000 (95%CI: 0.0-35.6) compared to the background population. CONCLUSION: Fluoroquinolone use triples the risk of Achilles tendon rupture, but the incidence among users is low.

PMID: 17334751 [PubMed - indexed for MEDLINE]

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Post-marketing surveillance of the safety of levofloxacin in Japan.

Yamaguchi H, Kawai H, Matsumoto T, Yokoyama H, Nakayasu T, Komiya M, Shimada J.

Product Lifecycle Management Department, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. yamagb0n@daiichipharm.co.jp

BACKGROUND: Central nervous system reactions to new quinolones, such as convulsions due to interaction with nonsteroidal anti-inflammatory drugs (NSAIDS), have attracted increased attention in Japan. METHODS: The safety of levofloxacin (LVX) was investigated in Japan by post-marketing surveillance and reviewing spontaneous reports. RESULTS: Post-marketing surveillance was performed in 16,117 patients between 1994 and 1996. The incidence of adverse reactions was 1.3% (203/16,117), being comparable with that for ofloxacin or that shown by phase II/III studies. Among 4,977 patients receiving concomitant NSAID treatment, the overall incidence of adverse reactions and the incidence of neurological reactions (including convulsions) did not significantly differ from those in patients without anti-inflammatory therapy. Review of the spontaneous reports on convulsions showed that patients with nephropathy, patients over 75 years and patients with a history of convulsive diseases were more likely to develop convulsions during LVX therapy. CONCLUSION: LVX should be used cautiously in patients with the above risk factors. Copyright 2007 S. Karger AG, Basel.

PMID: 17259709 [PubMed - indexed for MEDLINE]

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Tendinitis: the Achilles heel of quinolones!

Shortt P, Wilson R, Erskine I.

Craigavon Area Hospital, Portadown, Co Armagh, Northern, Ireland, UK. petershortt475@hotmail.com

We present a case series of two patients who presented to the emergency department with spontaneous bilateral Achilles tendon rupture associated with the use of ciprofloxacin. Tendinitis and tendon rupture are now well recognised but rare complications of treatment with quinolone antimicrobials. The emergency department is an important setting for both surveillance and detection of adverse events associated with drug treatment.

Publication Types:
PMID: 17130584 [PubMed - indexed for MEDLINE]

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Rupture of the Achilles tendon associated with ciprofloxacin.

Palin SL, Gough SC.

Publication Types:
PMID: 17116195 [PubMed - indexed for MEDLINE]

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[Spontaneous bilateral rupture of the Achilles tendon in an elderly woman undergoing prednisone pulse therapy with a history of polymyalgia rheumatica]

[Article in Dutch]

de Wolf MM, van der Krans A, Frijns CJ.

Universitair Medisch Centrum Utrecht, Postbus 85.500, 3508 GA Utrecht.

An 83-year-old woman presented at the neurology out-patient clinic with acute bilateral weakness of the calf muscles that had lasted for a few weeks. Ultrasound and MRI evaluation of the Achilles tendons revealed bilateral ruptures. Possible predisposing factors included treatment with prednisone pulse therapy for obstructive pulmonary disease and prior polymyalgia rheumatica. Surgical reconstruction of the tendons resulted in a major clinical improvement. Rupture of the Achilles tendons can occur spontaneously, and sometimes bilaterally. A predisposing factor is present in nearly every case of spontaneous bilateral rupture of the Achilles tendons. As in spontaneous unilateral ruptures, the most frequently described predisposing factor is the use of corticosteroids or quinolones.

Publication Types:
PMID: 17059091 [PubMed - indexed for MEDLINE]

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Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study.

Corrao G, Zambon A, Bertù L, Mauri A, Paleari V, Rossi C, Venegoni M.

Unit of Biostatistics and Epidemiology, Department of Statistics, University of Milan-Bicocca, Milan, Italy. giovanni.corrao@unimib.it

OBJECTIVE: To investigate the association between the use of fluoroquinolone agents and the risk of tendinitis in a large population-based case-control study. METHODS: The study was performed by linking automated health databases from the Region of Lombardia, Italy. Cases were patients aged > or =18 years who had a hospital discharge diagnosis of non-traumatic tendinitis in 2002-3. For each case, up to five controls were randomly selected among those eligible for inclusion in the study. A conditional logistic regression model was used to estimate the odds ratio of tendinitis associated with the current, recent and past use of fluoroquinolones. Odds ratios were adjusted for exposure to other antibacterials and other drugs. RESULTS: 22,194 cases and 104,906 controls met the inclusion criteria. Current use of fluoroquinolones significantly increased the risk of tendon disorders as a whole (odds ratio [OR] = 1.7; 95% CI 1.4, 2.0), tendon rupture (OR = 1.3; 95% CI 1.0, 1.8) and rupture of the Achilles' tendon (OR = 4.1; 95% CI 1.8, 9.6). Concomitant use of corticosteroids and fluoroquinolones increased the risk of both tendon rupture (OR = 3.1; 95% CI 1.5, 6.3) and rupture of the Achilles' tendon (OR = 43.2; 95% CI 5.5, 341.1). DISCUSSION: Evidence that exposure to fluoroquinolones is associated with the sudden occurrence of tendinitis is supported by this large population-based study. We can estimate that a single case of rupture of the Achilles' tendon would occur for every 5958 persons treated with fluoroquinolones (95% CI 2148, 23,085). The corresponding number needed to harm is 979 (95% CI 122, 9172) for patients who concomitantly use corticosteroids and 1638 (95% CI 351, 8843) for those aged >60 years. CONCLUSION: Clinicians should be aware of this adverse effect, and the increased risk for fluoroquinolone-associated tendinitis in elderly patients with corticosteroid use must be considered when these agents are prescribed.

Publication Types:
PMID: 16970512 [PubMed - indexed for MEDLINE]

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[Achilles tendon rupture during ofloxacin treatment and a short course of prednisolone]

[Article in French]

Vaucher N, Mosquet B, Levast M.

Publication Types:
PMID: 16969318 [PubMed - indexed for MEDLINE]

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Serial sonographic evaluation of Achilles tendons in patients taking fluoroquinolone antibiotics.

Roberts JR, Hudson JA, Lindell KK, Finger DR.

Tripler Army Medical Center Honolulu, HI 96859, USA.

We performed a prospective study to determine if subclinical tendinopathy occurs in asymptomatic adults treated with fluoroquinolone antibiotics. Thirty-eight adults were enrolled. Serial ultrasounds of the Achilles tendons were performed. A board certified musculoskeletal radiologist interpreted the images in a blinded fashion. No changes were identified. Subclinical tendinopathy does not appear to exist in asymptomatic adults treated with fluoroquinolone antibiotics.

PMID: 16773852 [PubMed - indexed for MEDLINE]

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Effects of sparfloxacin on CNS functions and urinary hydroxyproline in mice.

Bharal N, Pillai KK, Vohora D.

Department of Pharmacology, Faculty of Pharmacy, Hamdard University, New Delhi 110062, India.

Sparfloxacin is a widely prescribed drug for various infections. In the present study, sparfloxacin, at two doses, 25 and 50 mg kg(-1) was screened on seven neurological and neurobehavioural parameters in mice. In addition, a chronic study was performed to measure the grip strength of the animal to simulate tendon damage and corresponding hydroxyproline levels were determined in mice urine. Increasing current electroshock test (ICES), pentylenetetrazole (PTZ)-induced seizures, forced swim test (FST), passive avoidance response (PAR), spontaneous alternation behaviour (SAB) and elevated plus maze (EPM) were used for studying the acute effects of sparfloxacin while ICES, grip strength test (GST) and urinary hydroxyproline estimations were done for studying its chronic effects. The results indicate a proconvulsive potential of sparfloxacin on the ICES test (when administered for 21 days) and on PTZ when administered for 4 days. Further sparfloxacin (50 mg kg(-1)x4 days) exhibited anxiety like effects on EPM while mood and memory remained unaffected. Sparfloxacin 50 mg kg(-1) reduced the grip strength of mice after 2 weeks while both 25 and 50 mg kg(-1) reduced the same after 3 weeks. On urinary hydroxyproline, sparfloxacin 25 mg kg(-1) significantly increased the levels after 3 weeks of treatment. At 50 mg kg(-1), an elevation was evident from the first week onwards. In conclusion, sparfloxacin produced proconvulsant and anxiogenic effects in mice and was devoid of effects on mood and memory. On chronic treatment, it reduced grip strength and caused an elevation in urinary hydroxyproline levels.

Publication Types:
PMID: 16701999 [PubMed - indexed for MEDLINE]

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[Levofloxacin-induced tendon rupture with fatal outcome]

[Article in Spanish]

Sánchez Muñoz LA, Sanjuán Portugal FJ, Naya Machado J, Castiella Herrero J.

Publication Types:
PMID: 16680864 [PubMed - indexed for MEDLINE]

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Ultrastructural changes of the gemifloxacin on Achilles tendon in immature rats: comparison with those of ciproxacin and ofloxacin.

Bae CS, Oh DM, Bae JG, Kim JC, Kim SH, Kim SG, Jeong MJ, Kim YS, Lim SC.

College of Veterinary Medicine, Biotechnology Research Institute, Chonnam National University, Gwangju 500-757, Korea.

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent that exhibits potent activity against most Gram-negative and Gram-positive organisms, and has a comparatively low chondrotoxic potential in immature animals. This study examined the effects of gemifloxacin on the Achilles tendons in immature Sprague-Dawley rats treated by oral intubation once daily for 5 consecutive days from postnatal week 4 onward at doses of 0 (vehicle), and 600 mg/kg body weight. Ofloxacin or ciprofloxacin were used for comparison. The Achilles tendon specimens were examined by electron microscopy. In comparison with the vehicle-treated controls, there were ultrastructural changes in all samples from the gemifloxacin-, ofloxacin-, and ciprofloxacin-treated rats. Degenerative changes were observed in the tenocytes, and the cells that detached from the extracellular matrix were recognizable. The degree of degenerative changes and the number of degenerated cells in the Achilles tendon were significantly higher in the treated group than in the control group. Moreover, among the quinolone-treated groups, these findings were most significant in the ofloxacin-treated group, and least significant in the gemifloxacin-treated group. It is unclear what these findings mean with respect to the possible risk in juvenile patients treated with gemifloxacin or other quinolones. However, these results show that gemifloxacin causes less changes in the connective tissue structures.

Publication Types:
PMID: 16623866 [PubMed - indexed for MEDLINE]

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Age-dependent effects on redox status, oxidative stress, mitochondrial activity and toxicity induced by fluoroquinolones on primary cultures of rabbit tendon cells.

Pouzaud F, Dutot M, Martin C, Debray M, Warnet JM, Rat P.

Laboratoratoire de Toxicologie, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes-Paris5, France.

The age-related difference in fluoroquinolone-induced tendon toxicity was investigated. In vitro tendon cells from juvenile and young adult rabbits, respectively, were incubated with quinolone (nalidixic acid, NA) or fluoroquinolone (ofloxacin, OFX or pefloxacin, PEF) at 0.01 microM to 1 mM for 72 h. Redox status, glutathione (GSH), reactive oxygen species (ROS), and mitochondrial activity were assessed using intracellular fluorescent probes. Fluorescence signal was detected on living adherent tenocytes in microplates using cold-light cytofluorometry. Tendon toxicity differed significantly between the two cell groups and the difference was greatest with highest dose (1 mM). For 72 h, significant (p < 0.001) differences between immature and young adult primary tenocytes were observed for redox status decrease, GSH decrease, and ROS production increase. Mitochondrial activity remained unaltered in immature tenocytes. We confirm two groups of intrinsic tendon toxicity (OFX/NA vs. PEF) associated to oxidative stress (GSH decrease). Our in vitro experimental model confirms the clinical observations of age dependent tenotoxicity. First group (NA, OFX) showed greater intrinsic tenotoxicity for young adult than immature tenocytes, second group (PEF) was highly toxic for immature and young adult cells. The three quinolones do not altered mitochondrial activity in immature tenocytes whereas alteration was observed in young adult tenocytes.

Publication Types:
PMID: 16574493 [PubMed - indexed for MEDLINE]

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Rupture of adductor longus tendon due to ciprofloxacin.

Mouzopoulos G, Stamatakos M, Vasiliadis G, Skandalakis P.

Sparta Hospital, Sparta and Laiko Hospital, Athens, Greece. gmouzopoulos@yahoo.gr

We present a rare case of spontaneous rupture of the adductor longus tendon induced by ciprofloxacin. A 35-year-old man was diagnosed with pneumonia and was recommended ciprofloxacin 500 mg iv twice a day for 7 days. Three days after receiving the initial dose, he developed discomfort in his left medial thigh, and pain and swelling in the same area followed ten days later. He consulted us when he noted a palpable mass on the medial side of his left thigh, and MRI study revealed adductor longus tendon rupture. There was no obvious underlying disease or other factor causing fragility of his adductor longus tendon. We review the pathophysiological mechanisms leading to fluoroquinolone-related tendon rupture as well as the risk factors and discuss proper management.

Publication Types:
PMID: 16459870 [PubMed - indexed for MEDLINE]

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Achilles tendon rupture and its association with fluoroquinolone antibiotics and other potential risk factors in a managed care population.

Seeger JD, West WA, Fife D, Noel GJ, Johnson LN, Walker AM.

i3 Drug Safety, Auburndale, MA, USA. jseeger@epidemiology.com

BACKGROUND: Case reports and observational studies have implicated fluoroquinolone antibiotic exposure as a risk factor for Achilles tendon rupture (ATR), an uncommon condition for which there are few formal studies. We sought to quantify the strength of association between exposure to fluoroquinolone antibiotics and the occurrence of ATR, accounting for other risk factors. METHODS: This was a case-control study nested within a health insurer cohort. Cases of ATR were identified and confirmed using patterns of health insurance claims that were validated through sampled medical record review. Information on risk factors, including fluoroquinolone exposure, came from health insurance claims. RESULTS: There were 947 cases of ATR and 18 940 controls. A dispensing of a fluoroquinolone antibiotic in the past 6 months was more common among ATR cases than controls, although not significantly so (odds ratio (OR) = 1.2; 95% confidence interval (CI) = 0.9-1.7), and exposure to a higher cumulative fluoroquinolone dose was more strongly associated (OR = 1.5, 95%CI = 1.0-2.3). Other risk factors for ATR were trauma (OR = 17.2, 95%CI = 14.0-20.2), male sex (OR = 3.0, 95%CI = 2.6-3.5), injected corticosteroid administration (OR = 2.2, 95%CI = 1.6-2.9), obesity (OR = 2.0, 95%CI = 1.2-3.1), rheumatoid arthritis (OR = 1.9, 95%CI = 1.0-3.7), skin or soft tissue infections (OR = 1.5, 95%CI = 0.9-2.3), oral corticosteroids (OR = 1.4, 95%CI = 1.0-1.8), and non-fluoroquinolone antibiotics (OR = 1.2, 95%CI = 1.1-1.5). CONCLUSIONS: The elevation in ATR risk associated with fluoroquinolones was similar in magnitude to that associated with oral corticosteroids or non-fluoroquinolone antibiotics. Trauma and male sex were more strongly associated with ATR, as were obesity and injected corticosteroids.

Publication Types:
PMID: 16456878 [PubMed - indexed for MEDLINE]

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[Tendinitis associated with levofloxacin]

[Article in Spanish]

Alvarez Luque I, Gomariz Santacecilia M, Villamor Baliarda E, Rando Matos Y, García Fernández Y.

Publication Types:
PMID: 16194501 [PubMed - indexed for MEDLINE]

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Achilles tendinopathy after treatment with fluoroquinolone.

Yu C, Giuffre B.

Department of Radiology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. cyu@nsccahs.health.nsw.gov.au

Fluoroquinolone antibiotic therapy is a recognized but poorly understood cause for Achilles tendinopathy. We report here a patient who developed bilateral partial Achilles tendon tears as a result of fluoroquinolone therapy. Ultrasound and MRI were both useful in identifying and distinguishing between Achilles tendinosis and tendon rupture. The current published literature on this problem was also reviewed.

Publication Types:
PMID: 16174181 [PubMed - indexed for MEDLINE]

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Fluoroquinolone-induced arthralgia and myalgia in the treatment of sinusitis.

O-Lee T, Stewart CE 4th, Seery L, Church CA.

Division of Otolaryngology-Head and Neck Surgery, Loma Linda University School of Medicine, Loma Linda, California, USA.

BACKGROUND: Because of their broad-spectrum coverage, fluoroquinolone antibiotics are widely used in the treatment of acute sinusitis and acute exacerbations of chronic sinusitis. Generally, they are well tolerated, and adverse effects are usually mild. In our experience with quinolones, patients have frequently complained of arthralgias and/or myalgias. Although tendon rupture has been described as one of the more severe side effects, there are few published reports of arthralgias and/or myalgias associated with these drugs. METHODS: A retrospective review of fluoroquinolone prescriptions in a tertiary rhinology clinic was completed. Patients treated with oral levofloxacin for sinusitis over a 12-month period were contacted by mail and asked to complete an anonymous survey regarding adverse effects. Of 81 patients identified, 36 responses were received. RESULTS: Among respondents, the incidence of arthralgias and/or myalgias was 25%, which was more than twice the incidence of any other adverse effect reported. Occurrence of arthralgias and/or myalgias did not appear to be influenced by respondent age, course length, concurrent use of oral steroids, or a history of arthritis. Among those reporting arthralgia or myalgia, symptoms began after an average of 3 days of therapy and resolved an average of 7.5 days after cessation of treatment. Fourteen percent of respondents were unable to complete their course of therapy because of arthralgias and/or myalgias. CONCLUSION: Although effective and generally well tolerated in the treatment of sinusitis, fluoroquinolone antibiotics may produce adverse effects of arthralgia and/or myalgia.

PMID: 16171175 [PubMed - indexed for MEDLINE]

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Contrasting effects of fluoroquinolone antibiotics on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, in human tendon-derived cells.

Corps AN, Harrall RL, Curry VA, Hazleman BL, Riley GP.

Rheumatology Research Unit, Box 194, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. anc@mole.bio.cam.ac.uk

OBJECTIVES: Fluoroquinolone antibiotics may cause tendon pain and rupture. We reported previously that the fluoroquinolone ciprofloxacin potentiated interleukin (IL)-1beta-stimulated expression of matrix metalloproteinases (MMP)-3 and MMP-1 in human tendon-derived cells. We have now tested additional fluoroquinolones and investigated whether they have a similar effect on expression of MMP-13. METHODS: Tendon cells were incubated for two periods of 48 h with or without fluoroquinolones and IL-1beta. Total ribonucleic acid (RNA) was assayed for MMP messenger RNA by relative quantitative reverse transcriptase polymerase chain reaction, with normalization for glyceraldehyde-3-phosphate dehydrogenase mRNA. Samples of supernatant medium were assayed for MMP output by activity assays. RESULTS: MMP-13 was expressed by tendon cells at lower levels than MMP-1, and was stimulated typically 10- to 100-fold by IL-1beta. Ciprofloxacin, norfloxacin and ofloxacin each reduced both basal and stimulated expression of MMP-13 mRNA. In contrast, ciprofloxacin and norfloxacin increased basal and IL-1beta-stimulated MMP-1 mRNA expression. Both the inhibition of MMP-13 and the potentiation of MMP-1 expression by fluoroquinolones were accompanied by corresponding changes in IL-1beta-stimulated MMP output. The non-fluorinated quinolone nalidixic acid had lesser or no effects. CONCLUSIONS: Fluoroquinolones show contrasting effects on the expression of the two collagenases MMP-1 and MMP-13, indicating specific effects on MMP gene regulation.

Publication Types:
PMID: 16148020 [PubMed - indexed for MEDLINE]

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Musculoskeletal injury associated with fluoroquinolone antibiotics.

Khaliq Y, Zhanel GG.

Department of Pharmacy, Ottawa Hospital General Campus, Ottawa, Ontario K1H 8L6, Canada.

With the expanded use of fluoroquinolones and increasing number of reports of tendon injury linked to these agents, clinicians must be aware of the frequency and strength of this association. In the past, pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury is reported with most fluoroquinolones. As many as half of patients with fluoroquinolone-associated tendinopathy experience tendon rupture, and almost one third have received long-term corticosteroids. Tendon injury is mostly reported in the lower extremities, but injury in the upper extremities, including the hand, has also been reported. Management is similar regardless of the location of the injury. Use of fluoroquinolones requires careful patient assessment and follow-up in view of this complication with potential for sequelae.

Publication Types:
PMID: 16139623 [PubMed - indexed for MEDLINE]

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[Drug tendon disorders]

[Article in French]

Daghfous R, El Aidli S, Gheni R, Belkahia C.

Centre National de Pharmacovigilance, Sis Hôpital Charles Nicolle, Tunis.

Tendinitis is a rare adverse reaction described after drugs use. It's described with drug belonging to the same class. Physiopathology is still unknown. Fluoroquinolones especially pefloxacine, were the most incriminated. This drug induced tendinitis in older people aged more than 60 years. Approximatively one case out of five leads to tendon breaking off. The others lead to a favourable outcome after drug withdrawal. In three cases, tendinitis was described with statines, and concerned 2 men and 1 woman, aged more than 50 years. Simvastatine was suspected in two cases and the outcome was favourable in all cases after drug withdrawal. Other drugs, like corticosteroids, can exceptionally induce this side effect that can be serious. Consequences of drug tendinitis can then be dangerous and prescription of this class, and especially fluoroquinolones, must be cautions.

Publication Types:
PMID: 16044896 [PubMed - indexed for MEDLINE]

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Antimicrobial safety: focus on fluoroquinolones.

Owens RC Jr, Ambrose PG.

Division of Infectious Diseases, Department of Clinical Pharmacy Services, Maine Medical Center, Portland, Maine 04102, USA. Owensr@mmc.org

BACKGROUND/PURPOSE: Infrequent toxicities associated with certain drugs and drug classes have recently gained much attention from different health-care perspectives. To protect the patient, continued surveillance of safety and tolerability data is essential. Data from preclinical testing, phase 1-3 trials, and postmarketing surveillance may be used to objectively assess the risks associated with a specific drug or family of compounds. This review summarizes safety and tolerability data for the quinolones. MAIN FINDINGS: The most common adverse events associated with the quinolone class involve the gastrointestinal tract (nausea and diarrhea) and central nervous system (CNS) (headache and dizziness). These adverse events are usually mild and do not require discontinuation of therapy. Uncommon and potentially serious quinolone-related adverse events involve the cardiovascular system (rate-corrected electrocardiographic QT interval prolongation), musculoskeletal system (tendinitis and tendon rupture), endocrine system (glucose homeostasis dysregulation), renal system (crystalluria, interstitial nephritis, and acute renal failure), and the CNS (seizures). Severe idiosyncratic adverse events are specific to individual agents that may share some structural congruity, such as the 1-(2,4)-difluorophenyl group shared by trovafloxacin (associated with hepatitis), temafloxacin (associated with hemolytic-uremic syndrome), and tosufloxacin (associated with eosinophilic pneumonitis). Overall, discontinuation rates from clinical trials were <4% for the currently marketed quinolones. Quinolones with higher discontinuation rates, such as trovafloxacin (7.0%) and grepafloxacin (6.4%), are no longer available for general use. CONCLUSIONS: The currently marketed quinolones are well tolerated, with safety profiles similar to those of other antimicrobial classes. Although adverse effects are unusual, some, including tendinitis and CNS-related effects, are more common with quinolones than with other antimicrobial classes. Rare adverse effects attributed to some members of the quinolone family (e.g., Torsades de Pointes, hepatotoxicity, and dysglycemias) are more likely to occur in select "susceptible" populations. These adverse events can often be circumvented by avoiding exposure to the specific quinolone. In some cases, the therapeutic value offered by a quinolone may outweigh its potential risks.

Publication Types:
PMID: 15942881 [PubMed - indexed for MEDLINE]

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Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells.

Sendzik J, Shakibaei M, Schäfer-Korting M, Stahlmann R.

Institute of Clinical Pharmacology and Toxicology, Department of Toxicology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Garystr. 5, 14195 Berlin, Germany.

Antimicrobial therapy with fluoroquinolones can be associated with tendinitis and other tendon disorders as an adverse reaction associated with this class of antimicrobials. Here we investigated aspects of the mechanism of quinolone-induced tendotoxicity in human tenocytes focussing mainly on the question whether fluoroquinolones may induce apoptosis. Monolayers of human tenocytes were incubated with ciprofloxacin or levofloxacin at different concentrations (0, 3, 10, 30 and 100mg/L medium) for up to 4 days. Ultrastructural changes were studied by electron microscopy, and alterations in synthesis of specific proteins were determined using immunoblotting. At concentrations, which are achievable during quinolone therapy, 3mg ciprofloxacin/L medium significantly decreased type I collagen; similar changes were observed with 3mg ciprofloxacin or 10mg levofloxacin/L medium for the beta(1)- integrin receptors. Effects were intensified at higher concentrations and longer incubation periods. Cytoskeletal and signalling proteins, such as activated shc or erk 1/2, were significantly reduced by both fluoroquinolones already at 3mg/L. Furthermore, time- and concentration-dependent increases of matrix metalloproteinases as well as of the apoptosis marker activated caspase-3 were found. Apoptotic changes were confirmed by electron microscopy: both fluoroquinolones caused typical alterations like condensed material in the nucleus, swollen cell organelles, apoptotic bodies and bleb formation at the cell membrane. Our results provide evidence that besides changes in receptor and signalling proteins apoptosis has to be considered as a final event in the pathogenesis of fluoroquinolone-induced tendopathies.

Publication Types:
PMID: 15890441 [PubMed - indexed for MEDLINE]

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Fluoroquinolones and tendon disorders.

Melhus A.

Lund University, Department of Medical Microbiology, Malmö University Hospital, S-205 02 Malmö, Sweden. asa.melhus@mikrobiol.mas.lu.se

Fluoroquinolones are the most potent oral antibiotics in clinical use today. Increasingly, these drugs are being prescribed for relatively benign infections and for new categories of patients, including paediatric patients. As their use becomes more frequent, so will the adverse events. This review focuses on a rare but debilitating adverse reaction, the fluoroquinolone-associated tendinopathy. Despite many published case reports and approximately 3500 cases reported to the World Health Organization Collaborating Centre for Drug Monitoring, little is known about the mechanisms behind this fluoroquinolone-specific toxicity. Data on chemical properties, mode of action, pharmacokinetic features, clinical presentation and risk factors in relation to tendon toxicity are discussed and the literature reviewed. As long as the musculoskeletal toxicity cannot be predicted by in vitro or in vivo models and this class of antibiotics is one of the most commonly linked to selection of resistant bacteria, a more prudent use of fluoroquinolones is warranted.

Publication Types:
PMID: 15794721 [PubMed - indexed for MEDLINE]

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[Ofloxacin-induced achilles tendinitis in the absence of a predisposition]

[Article in French]

Aouam K, El Aïdli S, Daghfous R, Kastalli S, Lakhal M, Loueslati MH, Belkahia C.

Publication Types:
PMID: 15789832 [PubMed - indexed for MEDLINE]

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[Partial bilateral rupture of the Achilles tendon associated to levofloxacin]

[Article in Spanish]

Lado Lado FL, Rodríguez Moreno C, Velasco González M, Durán Parrondo C, Moar Calvo B.

Servicio de Medicina Interna, Departamento de Medicina, Hospital Clínico Universitario, Santiago de Compostela, A Coruña. flladol@usc.es

Fluoroquinolones-associated tendonitis and tendon rupture are well described in the literature but these are not frequently observed and related to the new agents of this group, as levofloxacin. This is probably due to the recent introduction and expansion. Although epidemiological studies are needed to know the frequency of that levofloxacin-induced tendinopathies, case-report could alert to the physicians about this possible severe adverse reaction. We present a case of bilateral Achilles tendonitis with partial spontaneous rupture probably associated to levofloxacin.

Publication Types:
PMID: 15777120 [PubMed - indexed for MEDLINE]

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Missed Achilles tendon rupture due to oral levofloxacin: surgical treatment and result.

Lüthje P, Nurmi I, Nyyssönen T.

Department of Orthopaedics and Traumatology, Kuusankoski Regional Hospital, 45750, Kuusankoski, Finland. peter.luthje@pp.inet.fi

We describe a case of a 60-year-old male patient who was treated with oral levofloxacin. The patient sustained a total subcutaneous rupture of the left Achilles tendon which was not diagnosed for at least 5 months. Surgical treatment was successful.

Publication Types:
PMID: 15645269 [PubMed - indexed for MEDLINE]

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Rupture of multiple tendons after levofloxacin therapy.

Braun D, Petitpain N, Cosserat F, Loeuille D, Bitar S, Gillet P, Trechot P.

Pneumology Department, Maillot Hospital, 54150 Briey, France.

An 80-year-old man treated by levofloxacin developed multiple tendon ruptures. His symptoms resolved over 9 months after levofloxacin discontinuation. Nasal corticosteroid therapy, aging and chronic respiratory insufficiency were probably predisposing factors in this patient.

Publication Types:
PMID: 15589446 [PubMed - indexed for MEDLINE]

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Recurrent tendinitis after treatment with two different fluoroquinolones.

Burkhardt O, Köhnlein T, Pap T, Welte T.

Department of Pulmonary and Critical Care Medicine, University Otto-von-Guericke, Magdeburg, Germany. olaf.burkhardt@medizin.uni-magdeburg.de

Tendinopathies with and without tendon rupture are rare adverse events, occurring mainly following older fluoroquinolones, but recently also to an increasing extent following levofloxacin. We report the first case of tendinitis after treatment with moxifloxacin, and of recurrent tendinitis after treatment with 2 different fluoroquinolones. From these findings we conclude hitherto unexplained class effect of fluoroquinolones in respect of the development of tendinitis.

Publication Types:
PMID: 15198194 [PubMed - indexed for MEDLINE]

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[The rupture of both Achilles tendons as a complication from fluoroquinolone treatment]

[Article in Finnish]

Pohjola-Sintonen S, Kannisto M.

HYKS, Peijaksen sairaala Sairaalakatu 1 01400 Vantaa. sinikka.pohjola-sintonen@hus.fi

Publication Types:
PMID: 15185511 [PubMed - indexed for MEDLINE]

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Bilateral simultaneous spontaneous rupture of the Achilles tendon.

Mehra A, Maheshwari R, Case R, Croucher C.

Weston General Hospital, Weston Super Mare.

Publication Types:
PMID: 15176150 [PubMed - indexed for MEDLINE]

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The effects of enrofloxacin on decorin and glycosaminoglycans in avian tendon cell cultures.

Yoon JH, Brooks RL Jr, Zhao JZ, Isaacs D, Halper J.

Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA.

Tendonitis and tendon rupture have been reported to occur during or following therapy with fluoroquinolone antibiotics. Though the pathogenesis is unknown, several studies suggest that fluoroquinolone antibiotics alter proteoglycan content in soft tissues, including tendons, and thereby alter collagen fibrillogenesis. To better understand the mechanism of action of fluoroquinolones, we studied the effects of enrofloxacin, a widely used fluoroquinolone in veterinary medicine, on avian tendon cell cultures established from gastrocnemius tendons from 18-day-old chicken embryos. We found that cell proliferation was progressively inhibited with increasing concentrations of enrofloxacin. This was accompanied by changes in morphology, extracellular matrix content and collagen fibril formation as detected by electron microscopy. We also observed a 35% decrease in the content of total monosaccharides in enrofloxacin-treated cells. The ratio of individual monosaccharides was also altered in enrofloxacin-treated cells. Enrofloxacin also induced the synthesis of small amounts of keratan sulfate in tendon cells. Moreover we observed enrofloxacin-induced changes in glycosylation of decorin, the most abundant tendon proteoglycan, resulting in the emergence of multiple lower molecular bands that were identifiable as decorin after chondroitinase ABC and N-glycanase treatment of extracts from enrofloxacin-treated cells. Medium conditioned by enrofloxacin-treated cells contained less decorin than did medium conditioned by control cells. We hypothesize that enrofloxacin induces either changes in the number of N-linked oligosaccharides attached to the core protein of decorin or changes in decorin degradation process. In conclusion, our data suggest that enrofloxacin affects cell proliferation and extracellular matrix through changes in glycosylation.

Publication Types:
PMID: 15148565 [PubMed - indexed for MEDLINE]

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The effect of enrofloxacin on cell proliferation and proteoglycans in horse tendon cells.

Yoon JH, Brooks RL Jr, Khan A, Pan H, Bryan J, Zhang J, Budsberg SC, Mueller PO, Halper J.

The Soft Tissue Center, Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388, USA.

Fluoroquinolone antibiotics have been used widely in humans and domestic animals, including horses, because of their broad-spectrum bactericidal activity, and relative safety. The use of fluoroquinolones, however, is not without risk. Tendonitis and spontaneous tendon rupture have been reported in people during or following therapy with fluoroquinolones. We have studied the effects of enrofloxacin, a fluoroquinolone antibiotic used commonly in domestic animals, on tendon cell cultures established from equine superficial digital flexor tendons. Effects on cell proliferation and morphology were studied using cell counting and scanning electron microscopy. Monosaccharide content and composition was determined by gas chromatography-mass spectrometry analysis. Western and Northern blot analyses were utilized to evaluate the synthesis and expression of two proteoglycans, biglycan and decorin. Our data demonstrate that enrofloxacin inhibits cell proliferation, induces morphological changes, decreases total monosacharide content and alters small proteoglycan synthesis at the glycosylation level in equine tendon cell cultures. These effects are more pronounced in juvenile tendon cells than in adult equine tendon cells. We hypothesize that morphological changes and inhibition of cell proliferation are a result of impaired production of biglycan and decorin, proteoglycans involved in fibrillogenesis of collagen, the most important structural component of the tendon of enrofloxacin-treated tendon cells. Our findings suggest that fluoroquinolones should be used with caution in horses, especially in foals.

Publication Types:
PMID: 15119847 [PubMed - indexed for MEDLINE]

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A 57-year-old male retired colonel with acute ankle swelling.

McKinley BT, Oglesby RJ.

Department of Medicine and Rheumatology Service, Walter Reed Army Medical Center, Building 2, Ward 77, Washington, DC 20307-5001, USA.

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PMID: 15080249 [PubMed - indexed for MEDLINE]

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Levofloxacin-induced bilateral Achilles tendon rupture: a case report and review of the literature.

Kowatari K, Nakashima K, Ono A, Yoshihara M, Amano M, Toh S.

Department of Orthopaedic Surgery, Aomori Rosai Hospital, 1 Minamigaoka, Shirogane-machi, Hachinohe 031-8551, Japan.

We present a rare case of spontaneous bilateral Achilles tendon rupture induced by levofloxacin, one of the fluoroquinolone antibiotics. A 76-year-old man was diagnosed with acute appendicitis and was commenced on oral levofloxacin 300 mg/day for 2 weeks. Seven days afterward he developed pain in both Achilles tendons, and at 14 days he developed swelling in the tendons. Four days later he felt a sharp, painful snap in both Achilles tendons while changing trousers. Both Achilles tendons ruptured completely at the mid-portion. There was no obvious underlying disease or pathophysiological factor causing fragility of his Achilles tendons. Despite the relatively large volume of case-based evidence, the pathophysiology of fluoroquinolone-induced tendinitis and tendon rupture is unclear. When tendinitis develops during fluoroquinolone therapy, the physician should consider the possible association between the fluoroquinolone and tendon rupture.

Publication Types:
PMID: 15045551 [PubMed - indexed for MEDLINE]

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[Achilles bilateral tendonitis and levofloxacin]

[Article in Spanish]

Gómez Rodríguez N, Ibáñez Ruán J, González Pérez M.

Publication Types:
PMID: 15043504 [PubMed - indexed for MEDLINE]

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[Muscle and tendon problems as a side-effect of levofloxacine: review of a case]

[Article in Spanish]

Vergara Fernández I.

Publication Types:
PMID: 15023326 [PubMed - indexed for MEDLINE]

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[Levofloxacin and Achilles tendon involvement in hemodialysis patients]

[Article in Spanish]

Gutiérrez E, Morales E, García Rubiales MA, Valentín MO.

Publication Types:
PMID: 15002793 [PubMed - indexed for MEDLINE]

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[Levofloxacin-induced bilateral rupture of the Achilles tendon: clinical and sonographic findings]

[Article in Italian]

Filippucci E, Farina A, Bartolucci F, Spallacci C, Busilacchi P, Grassi W.

Clinica Reumatologica--Università Politecnica delle Marche, Italia. emilio_filippucci@yahoo.it

The fluoroquinolones are antibiotics widely used in the clinical practice. The concomitant use of corticosteroids and fluoroquinolones in elderly patients is recognised as a risk factor for developing clinically relevant tendon lesions. Fluoroquinolone-induced tendinopathy is underreported in the literature. A 67-year-old man, came to our observation complaining of 5 days history of bilateral heel pain. The patient had a medical history of sarcoidosis and was treated with a daily dose of 5 mg of prednisone. He was initially given oral levofloxacin (500 mg/die) for 10 days, because of an acute respiratory infection. Two days before the end of the antibiotic therapy, he developed bilateral heel pain. He denied any history of trauma. Physical examination revealed swelling and marked tenderness with mild palpation of the Achilles tendons at the calcaneal insertion. The ultrasound evaluation of the Achilles tendons revealed the following main abnormalities: diffuse thickening, loss of the "fibrillar" echotexture, blurred margins, and bilateral partial tendon tears. Bilateral Achilles tendon pain and rupture has been described as a rare adverse effect of fluoroquinolone treatment. Most of the fluoroquinolone-induced tendinopathies of the Achilles tendon are due to ciprofloxacin. To the best of our knowledge, this is the first description of bilateral Achilles tendon rupture due to levofloxacin. The risk/benefit ratio of the fluoroquinolones should be carefully considered and these drugs should be prescribed cautiously in elderly patients treated with corticosteroids. This case can be regarded as a representative example of the potential clinical efficacy of sonography in daily rheumatological practise.

Publication Types:
PMID: 14872227 [PubMed - indexed for MEDLINE]

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[A rapid development of Achilles tendon rupture following quinolone treatment]

[Article in Swedish]

Kahn F, Christensson B.

Universitetssjukhuset i Lund. fredrik.kahn@skane.se

Publication Types:
PMID: 14763088 [PubMed - indexed for MEDLINE]

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Antibiotics: Achilles' heel of the Achilles' tendon.

[No authors listed]

Publication Types:
PMID: 14734287 [PubMed - indexed for MEDLINE]

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[The myo-tendinopathy caused by levofloxacin]

[Article in French]

Othmani S, Battikh R, Ben Abdallah N.

Publication Types:
PMID: 14682197 [PubMed - indexed for MEDLINE]

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Ciprofloxacin and Achilles' tendon rupture: a causal relationship.

Ozaras R, Mert A, Tahan V, Uraz S, Ozaydin I, Yilmaz MH, Ozaras N.

Publication Types:
PMID: 14677043 [PubMed - indexed for MEDLINE]

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Levofloxacin-induced tendon rupture: a case report and review of the literature.

Gold L, Igra H.

Departments of Internal Medicine and Dermatology, Mount Sinai Medical Center, Miami Beach, Florida, USA.

Publication Types:
PMID: 14645337 [PubMed - indexed for MEDLINE]

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Levofloxacin-associated Achilles tendon rupture and tendinopathy.

Melhus A, Apelqvist J, Larsson J, Eneroth M.

Department of Medical Microbiology, Malmö University Hospital, Malmö, Sweden. asa.melhus@mikrobiol.mas.lu.se

Fluoroquinolones have a documented ability to induce Achilles tendinopathy. Hitherto, few published reports have implicated levofloxacin. This article reports 5 cases of Achilles tendon disorders, including 3 complicated by rupture of the tendon, during levofloxacin treatment of patients with chronic obstructive pulmonary disease.

Publication Types:
PMID: 14606622 [PubMed - indexed for MEDLINE]

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Bilateral Achilles tendinitis with spontaneous rupture induced by levofloxacin in a patient with systemic sclerosis.

de La Red G, Mejía JC, Cervera R, Lladó A, Mensa J, Font J.

Publication Types:
PMID: 14579169 [PubMed - indexed for MEDLINE]

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In vitro discrimination of fluoroquinolones toxicity on tendon cells: involvement of oxidative stress.

Pouzaud F, Bernard-Beaubois K, Thevenin M, Warnet JM, Hayem G, Rat P.

Laboratoire de Toxicologie, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris, Paris, France.

Tendinopathy are classic side effects observed with fluoroquinolones antibiotics. A previously validated model based on a spontaneously immortalized rabbit tendon cell line (Teno cell line) was used to evaluate cellular responses to the fluoroquinolones pefloxacin (PEF), ofloxacin (OFX), levofloxacin (LVX), and ciprofloxacin (CIP), in various concentrations. Cell viability, redox status changes, reduced glutathione content, and reactive oxygen species production were assessed using neutral red, Alamar blue, monobromobimane and 2,7-dichlorofluorescindiacetate fluorescent probes, respectively. Living adherent tenocytes were analyzed using a cold light cytofluorometer adapted to 96-well microplates. All fluoroquinolones showed moderate cytotoxicity after 24 h and more severe, significant toxicity after 72 h on tendon cells. Moreover, two groups of fluoroquinolones may be differentiated: intrinsic toxicity for tendon cells was high with ciprofloxacin and pefloxacin [redox status decrease was 80 and 62% (*p < 0.05) for PEF and CIP at 1 mM for 72 h, respectively], but moderate with ofloxacin and levofloxacin LVX [redox status decrease was 30 and 22% (*p < 0.05) for OFX and LVX at 1 mM during 72 h, respectively]. Our model supports a role for early oxidative stress in the development of fluoroquinolone-induced tendinopathy. Moreover, our study indicates that intrinsic toxicity to tendon cells varies across fluoroquinolones. The Teno cell line may be a useful model for detecting and evaluating tendon toxicity of new fluoroquinolones and other drugs associated with tendinopathy.

Publication Types:
PMID: 14569066 [PubMed - indexed for MEDLINE]

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[Do tendon lesions occur during quinolone administration?]

[Article in German]

Shah P.

Medizinische Klinik III, Universitätsklinikum, Frankfurt.

Publication Types:
PMID: 14562223 [PubMed - indexed for MEDLINE]

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[Advances in treatment of Achilles tendon injury]

[Article in Chinese]

Yu LP, Luo YX.

Department of Orthopedics, Tongji Hospital, Tongji Medical Collage, Huazhong Science and Technology University, Wuhan, Hubei, P. R. China, 430030. yulipeng@hotmail.com

OBJECTIVE: To review the anatomy, etiology, therapy strategy of Achilles tendon injury and its related advances in recent years. METHODS: The related articles in recent years were extensively reviewed. RESULTS: There still were many arguments about the effect of corticosteroid on the treatment of tendon disease. Fluoqmnolone was found to be related with Achilles tendon injury. Acute rupture of Achilles tendon could be treated with open operation, percutaneous repair, or conservative therapy. For old rupture, many kinds of operations could be selected. CONCLUSION: The growth factors found in recent years provide us with new prospect for future treatment of Achilles tendon injury.

Publication Types:
PMID: 12920733 [PubMed - indexed for MEDLINE]

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Comment in:
Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids.

van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH.

Pharmacoepidemiology Unit, Department of Epidemiology & Biostatistics and Internal Medicine, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands.

BACKGROUND: In several case reports, the occurrence of Achilles tendon rupture has been attributed to the use of quinolones, but the epidemiologic evidence for this association is scanty. METHODS: We conducted a population-based case-control study in the General Practice Research Database in the United Kingdom during the period 1988 through 1998. Cases were defined as all persons who had a first-time recording of an Achilles tendon rupture, and who had at least 18 months of valid history before the index date. As a control group, we randomly sampled 50 000 patients with at least 18 months of valid history who were assigned a random date as index date. RESULTS: We identified 1367 cases that met the inclusion criteria. The adjusted odds ratio (OR) for Achilles tendon rupture was 4.3 (95% confidence interval [CI], 2.4-7.8) for current exposure to quinolones, 2.4 (95% CI, 1.5-3.7) for recent exposure, and 1.4 (95% CI, 0.9-2.1) for past exposure. The OR of Achilles tendon rupture was 6.4 (95% CI, 3.0-13.7) in patients aged 60 to 79 years and 20.4 (95% CI, 4.6-90.1) in patients aged 80 years or older. In persons aged 60 years and older, the OR was 28.4 (95% CI, 7.0-115.3) for current exposure to ofloxacin, while the ORs were 3.6 (95% CI, 1.4-9.1) and 14.2 (95% CI, 1.6-128.6) for ciprofloxacin and norfloxacin, respectively. Approximately 2% to 6% of all Achilles tendon ruptures in people older than 60 years can be attributed to quinolones. CONCLUSIONS: Current exposure to quinolones increased the risk of Achilles tendon rupture. The risk is highest among elderly patients who were concomitantly treated with corticosteroids.

PMID: 12912715 [PubMed - indexed for MEDLINE]

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Fluoroquinolone therapy and Achilles tendon rupture.

Vanek D, Saxena A, Boggs JM.

California School of Podiatric Medicine, San Francisco, CA, USA.

Fluoroquinolones have been associated with tendinopathies. The authors present three cases of Achilles tendinopathy in which the patients' symptoms were preceded by treatment for unrelated bacterial infections with ciprofloxacin. Although the exact mechanism of the relationship is not understood, those who engage in sports or exercise should be advised of the risk of quinolone-induced tendinopathy.

Publication Types:
PMID: 12869605 [PubMed - indexed for MEDLINE]

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Levofloxacin-associated Achilles tendon rupture.

Mathis AS, Chan V, Gryszkiewicz M, Adamson RT, Friedman GS.

Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. smathis@sbhcs.com

OBJECTIVE: To describe a case of levofloxacin-induced partial Achilles tendon rupture; this occurred in the presence of known risk factors and acute renal failure. CASE SUMMARY: A 79-year-old white man received levofloxacin for presumed pneumonia, developed acute renal failure in the setting of dehydration, and began having ankle pain on the 12th day of admission. Levofloxacin was discontinued, and magnetic resonance imaging revealed a 6-cm partial tear and degenerative changes. DISCUSSION: The Naranjo probability scale indicates a possible association between levofloxacin and tendon rupture because the event occurred in the setting of known risk factors such as steroid use, renal failure, older age, and male gender. CONCLUSIONS: Levofloxacin, like other fluoroquinolones, may cause Achilles tendon rupture, and this may be particularly likely with known risk factors.

Publication Types:
PMID: 12841810 [PubMed - indexed for MEDLINE]

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Ultrastructural changes induced by the des-F(6)-quinolone garenoxacin (BMS-284756) and two fluoroquinolones in Achilles tendon from immature rats.

Shakibaei M, Stahlmann R.

Institute of Anatomy, Benjamin Franklin Medical Center, Freie Universität Berlin, 14195 Berlin, Germany.

Garenoxacin is a des-(6)-fluoroquinolone exhibiting a comparatively low chondrotoxic potential in juvenile animals. We studied the effects of the drug on Achilles tendons in immature Wistar rats treated by oral intubation once daily (1) for 5 consecutive days from postnatal week 4 onward at doses of 0 (vehicle), 200 and 600 mg/kg body weight (b wt), and (2) for 21 consecutive days from postnatal day 4 onward at doses of 0 (vehicle), 80, 240 or 300 mg/kg b wt; ofloxacin or ciprofloxacin were used as comparators. Achilles tendon specimens were studied by electron microscopy. In comparison with vehicle-treated controls, ultrastructural changes were detectable in all samples from the garenoxacin-, ofloxacin-, or ciprofloxacin-treated rats (one animal per group). We found degenerative changes such as multiple vacuoles and large vesicles in the cytoplasm of tenocytes that resulted from swelling and dilatation of cell organelles (mitochondria, endoplasmic reticulum), densified nuclei and clumped chromatin; furthermore, cells that detached from the extracellular matrix, a general decrease of the fibril diameter and an increase in the distance between the collagenous fibrils were recognizable. The degree of changes increased with increasing doses. It remains unclear what these findings mean with respect to a possible risk in juvenile patients treated with garenoxacin or the other quinolones, but our results underline the fact that, in principle, this des-(6)-fluoroquinolone also has the potential to cause changes in connective tissue structures.

Publication Types:
PMID: 12811465 [PubMed - indexed for MEDLINE]

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Ciprofloxacin reduces the stimulation of prostaglandin E(2) output by interleukin-1beta in human tendon-derived cells.

Corps AN, Curry VA, Harrall RL, Dutt D, Hazleman BL, Riley GP.

Addenbrooke's Hospital, Cambridge, UK.

OBJECTIVE: Fluoroquinolone antibiotics such as ciprofloxacin can induce tendon pathology and have various effects on tendon-derived cells in culture. We are investigating whether ciprofloxacin modifies signalling responses in tendon cells. METHODS: Human Achilles tendon-derived cells were preincubated with or without ciprofloxacin (50 mug/ml) and were then challenged with interleukin-1beta (IL-1beta, 1 ng/ml) for up to 48 h. Prostaglandin E2 (PGE2) output was assayed by ELISA. The expression of cyclooxygenase-2 (COX-2) was examined by Western blotting. RESULTS: IL-1beta stimulated a substantial and prolonged increase in the output of PGE2. Preincubation with ciprofloxacin reduced IL-1beta-induced PGE2 output at all times tested; the reduction at 48 h was 69% (99% confidence interval 59-79%; 15 experiments). Norfloxacin and ofloxacin also reduced PGE2 output. However, ciprofloxacin did not affect the induction of COX-2 by IL-1beta, measured at 4 or 48 h. CONCLUSIONS: Ciprofloxacin reduces IL-1beta-induced PGE2 output in tendon-derived cells. The reduction in PGE2 output could modulate various cellular activities of IL-1beta, and may be implicated in fluoroquinolone-induced tendinopathy.

Publication Types:
PMID: 12810931 [PubMed - indexed for MEDLINE]

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Fluoroquinolone-associated tendinopathy: a critical review of the literature.

Khaliq Y, Zhanel GG.

Department of Pharmacy, Ottawa Hospital General Campus, Ottawa, Canada.

With the expanded use of fluoroquinolones for the treatment of community-acquired respiratory infections and reports of tendon injury linked to the use of these agents, we reviewed the literature to investigate the frequency and strength of this association. Ninety-eight case reports were available for review. The incidence of tendon injury associated with fluoroquinolone use is low in a healthy population but increases in patients who have renal dysfunction, who are undergoing hemodialysis, or who have received renal transplants. Pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury was reported with most fluoroquinolones. The median duration of fluoroquinolone treatment before the onset of tendon injury was 8 days, although symptoms occurred as early as 2 hours after the first dose and as late as 6 months after treatment was stopped. Up to one-half of patients experienced tendon rupture, and almost one-third received long-term corticosteroid therapy. Tendon injury associated with fluoroquinolone use is significant, and risk factors such as renal disease or concurrent corticosteroid use must be considered when these agents are prescribed.

Publication Types:
PMID: 12766835 [PubMed - indexed for MEDLINE]

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Reoccurrence of levofloxacin-induced tendinitis by phenoxymethylpenicillin therapy after 6 months: a rare complication of fluoroquinolone therapy?

Schindler C, Pittrow D, Kirch W.

Institute of Clinical Pharmacology, Medical Faculty of the Dresden University of Technology, Dresden, Germany. christoph.schindler@mailbox.tu-dresden.de

Publication Types:
PMID: 12756981 [PubMed - indexed for MEDLINE]

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Fluoroquinolones in the elderly: safety considerations.

Stahlmann R, Lode H.

Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany. ralf.stahlmann@medizin.fu-berlin.de

Fluoroquinolones such as ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin are widely used for the treatment of bacterial infections. Fluoroquinolone-induced adverse effects have not been reported to occur with increased frequency in the elderly, but large trials comparing the tolerability in aged and young individuals are not available. Renal function declines consistently with age and recommendations for dosage changes of renally eliminated fluoroquinolones (ofloxacin, levofloxacin, gatifloxacin) are related to changes in kidney function rather than to age per se. However, during routine clinical work, creatinine clearance data are usually not available; thus it seems more practical to recommend dosage adjustment for elderly individuals in whom low creatinine clearance values can be expected. Reactions of the gastrointestinal tract are the most often observed adverse effects during therapy with fluoroquinolones; however, compared with many other antibacterials, fluoroquinolones are less frequently associated with diarrhoea. Similarly, hypersensitivity reactions, as observed during therapy with penicillins and other beta-lactam agents, occur more rarely during fluoroquinolone therapy. Adverse reactions of the CNS are of particular concern for the elderly population. Elderly patients with impairments of the CNS (e.g. epilepsy, pronounced arteriosclerosis) should be treated with fluoroquinolones only under close supervision. Probably, many signs of possible adverse reactions such as confusion, weakness, loss of appetite, tremor or depression are often mistakenly attributed to old age and remain unreported. Fluoroquinolones can cause QT interval prolongation. Therefore, they should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalaemia or hypomagnesaemia and patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents. Chondrotoxicity of fluoroquinolones, as observed in immature animals, has led to restricted use in paediatric patients, but there is no indication that similar effects could occur in joint cartilage of adults. Tendinitis and tendon ruptures have occurred in rare cases as late as several months after treatment with some fluoroquinolones. Chronic renal diseases, concomitant use of corticosteroids and age over 60 years have been recognised as risk factors for fluoroquinolone-induced tendon disorders. Overall, the widely used fluoroquinolones discussed in this review are generally well tolerated. Nevertheless, as with all drugs, their specific adverse effect profiles must be considered when they are chosen for treatment of bacterial infections. Because of physiological changes in renal function and in case of certain comorbidities, some special considerations are necessary when fluoroquinolones are used to treat elderly patients.

Publication Types:
PMID: 12641485 [PubMed - indexed for MEDLINE]

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Ultrasonography of non-traumatic rupture of the Achilles tendon secondary to levofloxacin.

Cebrian P, Manjon P, Caba P.

Departamento de Radiodiagnóstico, Hospital Universitario 12 de Octubre, Madrid, Spain. pcvbb@yahoo.es

Rupture of Achilles tendon (AT) is an uncommon complication of treatment with fluoroquinolones. We describe a case of bilateral tendinosis and rupture of the right AT in a patient who began levofloxacin treatment for community acquired pneumonia. Sonography showed thickening and hypoecogenicity of both AT and complete rupture and separation of the right Achilles tendon.

Publication Types:
PMID: 12627618 [PubMed - indexed for MEDLINE]

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Spontaneous Achilles tendon rupture in patients treated with levofloxacin.

Haddow LJ, Chandra Sekhar M, Hajela V, Gopal Rao G.

Publication Types:
PMID: 12615887 [PubMed - indexed for MEDLINE]

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Fluoroquinolones in ambulatory ENT and respiratory tract infections: rarely appropriate.

[No authors listed]

(1) The risk-benefit ratio of antibiotic therapy in exacerbations of chronic bronchitis is uncertain. If an antibiotic is considered, fluoroquinolones are at best second-line options, after betalactam agents such as amoxicillin, and macrolides. (2) For community-acquired pneumonia the first-line antibiotics are betalactam agents such as amoxicillin, and macrolides. Patients with severe disease should receive combination therapy with a betalactam and a macrolide or a fluoroquinolone. (3) Acute sinusitis generally resolves spontaneously. If an antibiotic is prescribed, fluoroquinolones are at best second-line options, after betalactam agents such as amoxicillin, and macrolides. The value of systemic antibiotic therapy is also controversial in chronic sinusitis and chronic otitis media; once again, fluoroquinolones are not agents of first choice. (4) Fluoroquinolones share many adverse effects, especially neuropsychiatric, cutaneous, tendon, and cardiac involvement. They can also damage cartilage in children. They are contraindicated in pregnant women. They potentiate oral anticoagulants.

PMID: 12602405 [PubMed - indexed for MEDLINE]

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Tendon abnormalities and hypersensitivity of levofloxacin.

[No authors listed]

PMID: 12602391 [PubMed - indexed for MEDLINE]

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[Achilles tendinitis associated to levofloxacin: report of 4 cases]

[Article in Spanish]

Aros C, Flores C, Mezzano S.

Laboratorio de Nefrología, Instituto y Servicio de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.

Fluoroquinolone-associated tendinitis are well described in the literature, but these are not frequently observed and usually are related to the oldest fluoroquinolones. Levofloxacin is a recently introduced fluoroquinolone. In this paper we report four cases (three female, aged 39 to 70 years old) of Achilles tendinitis occurring in a period of few months. Two patients on chronic dialysis, one kidney transplant recipient, and one patient with chronic vasculitis, both with normal renal function. All were chronically using corticosteroids. In the four cases, tendinitis had an acute onset with bilateral involvement and was invalidating. In 3 cases the onset of tendinitis was early during levofloxacin treatment and in 1 case, it began 10 days after the end of the treatment. All patients were treated with rest and physiotherapy, two were treated with non-steroidal anti-inflammatory drugs. All patients had a complete recovery alter 3-8 weeks.

Publication Types:
PMID: 12587511 [PubMed - indexed for MEDLINE]

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Comment on:
[Levofloxacin and bilateral spontaneous Achilles tendon rupture]

[Article in Spanish]

Bernácer L, Artigues A, Serrano A.

Publication Types:
PMID: 12570920 [PubMed - indexed for MEDLINE]

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Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions.

Leone R, Venegoni M, Motola D, Moretti U, Piazzetta V, Cocci A, Resi D, Mozzo F, Velo G, Burzilleri L, Montanaro N, Conforti A.

Clinical Pharmacology Unit, WHO Reference Centre for Education and Communication in International Drug Monitoring, University of Verona, Italy. rleone@sfm.univr.it

OBJECTIVE: To analyse and compare with one another and with other antibacterial drugs the adverse drug reactions (ADRs) of the different fluoroquinolones currently used in Italy, spontaneously reported from doctors in three northern Italian regions. METHODS: The data on fluoroquinolones and other antibacterials were obtained from the spontaneous reporting system database of Emilia Romagna, Lombardy and the Veneto, which are the principal contributors to the Italian spontaneous surveillance system. The fluoroquinolone ADRs with a causality assessment of certain, probable or possible (according to WHO criteria), reported between January 1999 and December 2001, were selected and toxicity profiles of individual drugs were described and compared with one another. The reports were also correlated with sex and age of patients and with regional prescription data to estimate individual fluoroquinolone reporting rate of adverse events. RESULTS: During the study period, 10 011 reports were received by the system (a mean annual reporting rate of approximately 185 per million inhabitants): 1920 referred to systemic antimicrobials, of which 432 (22.5%) involved fluoroquinolones. Pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin (221) and lomefloxacin (196). The most frequently reported reactions to fluoroquinolones involved the skin, but their percentage (25%) was significantly lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas the percentages of reactions involving the central nervous (12.2 vs 3.6%), musculoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were significantly higher (p < 0.01). We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05). Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin. CONCLUSIONS: The differences in the safety profiles should be taken into account when prescribing a fluoroquinolone to individual patients.

Publication Types:
PMID: 12534327 [PubMed - indexed for MEDLINE]

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[Rupture of the Achilles' tendon secondary to levofloxacin]

[Article in Spanish]

Tomás ME, Pérez Carreras M, Morillasa JD, Castellano G, Solís JA.

Publication Types:
PMID: 12525331 [PubMed - indexed for MEDLINE]

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[Tenotoxic potential of fluoroquinolones in the choice of surgical antibiotic prophylaxis in ophthalmology]

[Article in French]

Pouzaud F, Rat P, Cambourieu C, Nourry H, Warnet JM.

Unité de Pharmaco-Toxicologie Cellulaire, CHNO des XV-XX, 28, rue de Charenton, 75571 Paris cedex 12, France.

PURPOSE: Fluoroquinolones are mainly used in ophthalmic antibiotic prophylaxis because of their broad spectrum activity and good ocular diffusion. But a single oral dose of fluoroquinolones can result in a serious source of tendinopathy and tendon rupture, especially in patients 60 years and older. It seems very important to investigate tendon toxicity of fluoroquinolones to improve the risk-benefit ratio in ophthalmologic antibiotic prophylaxis. MATERIAL: and methods: The intrinsic tenotoxic potential of four fluoroquinolones (pefloxacin, ofloxacin, ciprofloxacin, levofloxacin) was directly evaluated on living adherent tendon cells in microplates. Cell viability and reactive oxygen species production was evaluated using neutral red, alamar blue, and dichlorofluorescin diacetate tests. RESULTS: Results showed a loss of viability associated with free radical production depending on fluoroquinolone molecules. Pefloxacin appeared more tenotoxic but no study has confirmed its efficacy in surgical antibiotic prophylaxis and its use in the patient who is 60 years and older could be disputed. Ciprofloxacin is highly toxic with a low ocular diffusion and seems to be inappropriate for antibiotic prophylaxis. Ofloxacin and levofloxacin are less cytotoxic, associated with good ocular diffusion and a broad antibacterial spectrum. CONCLUSION: Ofloxacin and levofloxacin seem to be good alternatives for improving the risk-benefit ratio in surgical antibiotic prophylaxis in patients 60 years and older.

Publication Types:
PMID: 12515937 [PubMed - indexed for MEDLINE]

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Children as a special population at risk--quinolones as an example for xenobiotics exhibiting skeletal toxicity.

Stahlmann R.

Department of Toxicology, Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, Garystrasse 5, 14195 Berlin, Germany. ralf.stahlmann@medizin.fu-berlin.de

The sensitivity of the immature skeletal system during postnatal mammalian development was discussed during the workshop "Children as a Sensitive Subgroup and their Role in Regulatory Toxicology" (Schwenk et al. 2002, Arch Toxicol, in press). As a typical example of xenobiotics exhibiting this extraordinary type of toxicity, the quinolone-induced effects on cartilage, bone growth, and tendons were considered in depth. Animal experiments indicate that chondrotoxicity of quinolones can affect articular cartilage depending on the developmental stage. Results from studies with pipemidic acid in dogs at various developmental stages from 1 week old to 17 months old showed pronounced effects in the most sensitive age groups: 3- to 6-month-old dogs exhibited gait alterations and lameness, but signs of toxicity were not observed in 12- or 17-month-old dogs. Similarly, experiments performed in rats indicate that they exhibit the highest sensitivity for articular cartilage defects at a certain stage of development between 3 and 6 weeks postnatally; mature articular cartilage does not seem to be a target for quinolone-induced toxicity. Some very limited data indicate that in animals at an early developmental phase the epiphyseal growth plate can also be damaged by quinolones, and that these effects are associated with irreversible bone damage and growth inhibition. Another manifestation of toxic effects of quinolones on connective tissue structures are tendopathies. For this effect, it is not quite clear whether juveniles are more susceptible than adults because clinical and experimental data seem to point in different directions. Pathogenesis of both effects can probably be explained by the magnesium-chelating properties of these drugs, leading to a deficit of functionally available magnesium and, subsequently, to radical formation and irreversible connective tissue lesions. However, unequivocal explanations for the phase-dependency of the effects are lacking.

Publication Types:
PMID: 12491034 [PubMed - indexed for MEDLINE]

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Comment on:
"Ciprofloxacin: a warning for clinicians".

Breck RW.

Publication Types:
PMID: 12448217 [PubMed - indexed for MEDLINE]

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Comment in:
Physical therapist management of fluoroquinolone-induced Achilles tendinopathy.

Greene BL.

Department of Rehabilitation Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA. bgree02@emory.edu

BACKGROUND AND PURPOSE: Use of fluoroquinolone antibiotics is reported to be a cause of adverse musculoskeletal effects, such as tendinopathies and tendon ruptures. The purpose of this case report is to describe the management and outcomes of a patient with bilateral Achilles tendinopathy secondary to fluoroquinolone antibiotic use. CASE DESCRIPTION: The patient was a 41-year-old man who developed bilateral Achilles tendon pain on the third day of levofloxacin use. The physical therapy intervention consisted of an initial phase to reduce stress on the tendon through the use of crutches and orthoses and a second phase to progressively stress the tendon through exercise and functional activities. OUTCOMES: After 11 weeks of physical therapy (14 treatments), the patient's pain decreased from 3/10 to 1/10 on a visual analog scale and his Lower Extremity Functional Scale score increased from 28/80 to 71/80. DISCUSSION: An overlapping 2-phased intervention approach based on connective tissue remodeling principles may be effective in elimination of pain and restoration of function following fluoroquinolone-induced Achilles tendinopathy.

Publication Types:
PMID: 12444881 [PubMed - indexed for MEDLINE]

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Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy.

Corps AN, Harrall RL, Curry VA, Fenwick SA, Hazleman BL, Riley GP.

Addenbrooke's Hospital, Cambridge, UK. Rheumatology Research Unit, Box 194, Unit E6, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. anc@mole.bio.cam.ac.uk

OBJECTIVE: To determine whether the fluoroquinolone antibiotic ciprofloxacin, which can cause tendon pain and rupture in a proportion of treated patients, affects the expression of matrix metalloproteinases (MMPs) in human tendon-derived cells in culture. METHODS: Cell cultures were derived from 6 separate tendon explants, and were incubated in 6-well culture plates for 2 periods of 48 hours each, with ciprofloxacin (or DMSO in controls) and interleukin-1beta (IL-1beta), alone and in combination. Samples of supernatant medium from the second 48-hour incubation were assayed for MMPs 1, 2, and 3 by Western blotting. RNA was extracted from the cells and assayed for MMP messenger RNA (mRNA) by semiquantitative reverse transcription-polymerase chain reaction, with normalization for GAPDH mRNA. RESULTS: Unstimulated tendon cells expressed low or undetectable levels of MMP-1 and MMP-3, and substantial levels of MMP-2. IL-1beta induced a substantial output of both MMP-1 and MMP-3 into cell supernatants, reflecting increases (typically 100-fold) in MMP mRNA, but had only minor effects on MMP-2 expression. Ciprofloxacin had no detectable effect on MMP output in unstimulated cells. Preincubation with ciprofloxacin potentiated IL-1beta-stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression. Ciprofloxacin also potentiated IL-1beta-stimulated MMP-1 mRNA expression, but did not potentiate the output of MMP-1, and had no significant effects on MMP-2 mRNA expression or output. CONCLUSION: Ciprofloxacin can selectively enhance MMP expression in tendon-derived cells. Such effects might compromise tendon microstructure and integrity.

Publication Types:
PMID: 12428247 [PubMed - indexed for MEDLINE]

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Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin.

Yee CL, Duffy C, Gerbino PG, Stryker S, Noel GJ.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ 08869, USA.

BACKGROUND: Fluoroquinolones (FQs) have been infrequently used in children, largely because of concern that these agents can cause lesions of the cartilage in juvenile animals. However, the relevance of this laboratory observation to children treated with FQs is unknown. A retrospective, observational study was conducted to assess the incidence and relative risk of tendon or joint disorders (TJDs) that occur after use of selected FQs compared with azithromycin (AZ), a drug with no known effect on cartilage or tendons in humans or animals. METHODS: An automated database was searched to identify patients younger than 19 years who had been prescribed ofloxacin (OFX), levofloxacin, ciprofloxacin (CPX), or AZ. Potential cases of TJD occurring within 60 days of a prescription of one of the study drugs were identified based on assignment of a claims diagnosis consistent with a TJD within this period. Verified cases were identified by a blinded review of abstracts of medical records from subjects identified as potential cases. RESULTS: The incidence of verified TJD was 0.82% for OFX (13 of 1593) and CPX (37 of 4531) and was 0.78% for AZ (118 of 15,073). The relative risk of TJD for OFX and CPX compared with AZ was 1.04 (95% confidence interval, 0.55 to 1.84) and 1.04 (95% confidence interval, 0.72 to 1.51), respectively. The distributions of claims diagnoses and time to onset of TJD were comparable for all groups. The most frequently reported category of TJD involved the joint followed by tendon, cartilage and gait disorder. CONCLUSIONS: In this observational study involving more than 6000 FQ-treated children, the incidence of TJD associated with selected FQ use in children was <1% and was comparable with that of the reference group, children treated with AZ.

Publication Types:
PMID: 12182376 [PubMed - indexed for MEDLINE]

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Quinolone-associated tendonitis: a potential problem in COPD?

Butler MW, Griffin JF, Quinlan WR, McDonnell TJ.

Department of Respiratory Medicine, St Vincent's University Hospital, Dublin, Ireland.

BACKGROUND: Quinolones have traditionally had limited application in the area of community-acquired respiratory tract infections due to poor cover against Streptococcus pneumoniae. This trend is changing with the broader spectrum of newer fluoroquinolones. A rare serious side effect of fluoroquinolones is tendinopathy. AIMS: This study describes two cases of levofloxacin-associated tendinopathy in patients with severe chronic obstructive pulmonary disease (COPD) and the implications and mechanisms involved are discussed. CONCLUSIONS: The finding of two cases of levofloxacin-induced tendinopathy in our patients suggests that the problem may be more frequent than previously considered. Patients with COPD treated with fluoroquinolones may have other risk factors for tendinopathy such as advanced age, corticosteroid use and renal impairment and merit vigilance for signs of tendonitis.

Publication Types:
PMID: 12120977 [PubMed - indexed for MEDLINE]

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Clinical toxicological aspects of fluoroquinolones.

Stahlmann R.

Institute of Clinical Pharmacology and Toxicology, Freie Universität Berlin, Garystrasse 5, 14195, Germany. stahl@medizin.fu-berlin.de

Reactions of the gastrointestinal tract and the central nervous system are the most often observed adverse effects during therapy with fluoroquinolones. Pathogenesis of the neurotoxic effects of fluoroquinolones could be related to the activation of the NMDA receptor. Animal experiments as well as clinical experience show that the cardiotoxic potentials of sparfloxacin and grepafloxacin are higher than those of the other fluoroquinolones: they cause QT prolongation at rather low doses thus increasing the risk for severe arrhythmia (torsades de pointes). Phototoxicity has been described for all quinolones, but derivatives with a halogen atom at position 8 show the highest potential for such reactions (e.g. clinafloxacin). Chondrotoxicity of quinolones can affect the articular cartilage and the epiphyseal growth plate in immature animals; the use of these drugs in pediatrics should be restricted to carefully selected indications (such as the use of ciprofloxacin in cystic fibrosis). Tendinitis and tendon ruptures can also be induced by quinolones. Overall, quinolones are as well tolerated as most other anti-microbial agents. However, their specific toxic potentials have to be considered when they are chosen for treatment of bacterial infections.

PMID: 12052667 [PubMed - indexed for MEDLINE]

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Fluoroquinolones and risk of Achilles tendon disorders: case-control study.

van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH.

Department of Epidemiology & Biostatistics and Internal Medicine, Erasmus Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

Publication Types:
PMID: 12039823 [PubMed - indexed for MEDLINE]

PMCID: PMC113766


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Achilles tendon disease in lung transplant recipients: association with ciprofloxacin.

Chhajed PN, Plit ML, Hopkins PM, Malouf MA, Glanville AR.

Heart Lung Transplant Unit, St. Vincent's Hospital, Sydney, NSW, Australia. chhajed@hotmail.com

Achilles tendonitis or rupture are uncommon complications following the use of fluoroquinolones, with a reported incidence in the general population of 0.4%. The aims of the current study were to determine the incidence of Achilles tendon disease (ATD) in lung transplant recipients (LTR) and to identify risk factors. Questionnaires were sent to 150 LTR of whom 101 responded (67%). Twenty-two LTR (21.8%) experienced ATD (tendonitis 16, rupture six). The mean age of LTR who developed ATD was 52.9+/-6.1 yrs (range: 19-63.5 yrs). Only the use of ciprofloxacin was significantly associated with ATD (p<0.05). Age, sex, underlying disease necessitating transplantation, serum creatinine and cyclosporine levels were not associated with ATD. The association between ciprofloxacin and ATD was not dose related. Of the 72 LTR who had received ciprofloxacin, 20 (28%) developed ATD (tendonitis 15, rupture five). In patients receiving ciprofloxacin, there was no association between the mean cumulative dose of prednisolone and ATD. Tendon rupture occurred with a lower ciprofloxacin dosage than tendonitis and the mean recovery duration was significantly longer. To conclude, lung transplant recipients receiving ciprofloxacin are at significant risk of developing Achilles tendon disease. The association between ciprofloxacin and Achilles tendon disease appears to be idiosyncratic rather than dose-related.

Publication Types:
PMID: 11936524 [PubMed - indexed for MEDLINE]

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[Skin nodules and ulcers of the limbs in a patient with rheumatoid arthritis]

[Article in German]

Böcher W, Galle PR, Märker-Hermann E.

I. Medizinische Klinik und Poliklinik der Johannes Gutenberg-Universität Mainz, Germany.

CASE HISTORY: While being treated with corticosteroids and methotrexate for rheumatoid arthritis, a 63-year-old man developed livid nodules on his lower arms, hands and feet, as well as fever, necrotizing skin ulcers and rupture of a finger extensor tendon. INVESTIGATIONS: No vasculitis was found in a biopsy of one of the nodules on the lower arm. Fast growing mycobacteria, classified as M. marinum by PCR, were cultured from wound swabs. Treatment and course: The lesions healed on administration of ciprofloxacin, ethambutol and clarithromycin as well as local treatment. CONCLUSION: Cutaneous lesions of an atypical mycobacterial infection are often misdiagnosed. This is especially so in immunocompromised patients and in the differential diagnosis of vasculitis.

Publication Types:
PMID: 11935470 [PubMed - indexed for MEDLINE]

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[Tendinopathy associated with fluoroquinolones: individuals at risk, incriminated physiopathologic mechanisms, therapeutic management]

[Article in French]

Saint F, Salomon L, Cicco A, de la Taille A, Chopin D, Abbou CC.

Service d'Urologie, Hôpital Henri Mondor, 51, avenue du Maréchal de Lattre de Tassigny, 94010 Créteil. saintf@wanadoo.fr

The use of fluoroquinolones in urology has grown considerably over recent years. Unfortunately, although these molecules are not associated with severe life-threatening complications, they have nevertheless been associated with tendon lesions responsible for functional disability. The frequency of these complications is probably underestimated. There is a variable lag-time (3 to 5 days) between introduction of the antibacterial and onset of pain. The symptom most frequently reported is pain over the tendon affected and the tendons most frequently affected are those submitted to high constraints. Bilateral lesions are present in 66% of cases. Although Pefloxacin is associated with the highest frequency of tendon complications (2.7% versus 0.2-0.3% for other fluoroquinolones), the duration of treatment appears to be important in every case, with a peak frequency after a fortnight of treatment. Although these complications were considered for a long time to be associated with patients presenting certain risk factors (age, steroid therapy, renal failure), they can also occur suddenly, in young adult sportsmen or non-sportsmen, with no known tendon disease. Several hypotheses have been proposed to explain the development of these cases of tendinopathy: immuno-allergic mechanisms, direct toxicity of the molecule on collagen fibres, cell-mediated oxidative aggression, or tendon necrosis due to vascular mechanisms. The outcome remains favourable in 75% of cases of tendinitis and in 49% of cases for tendon rupture. Contraindications must therefore be identified and the duration of treatment must be adapted, as the functional handicap can be long and particularly severe.

Publication Types:
PMID: 11859676 [PubMed - indexed for MEDLINE]

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Comment in:
Quinolones: a comprehensive review.

Oliphant CM, Green GM.

University of Wyoming School of Pharmacy, Casper, USA. coliphant@wmcnet.org

With the recent introduction of agents such as gatifloxacin and moxifloxacin, the traditional gram-negative coverage of fluoroquinolones has been expanded to include specific gram-positive organisms. Clinical applications beyond genitourinary tract infections include upper and lower respiratory infections, gastrointestinal infections, gynecologic infections, sexually transmitted diseases, and some skin and soft tissue infections. Most quinolones have excellent oral bioavailability, with serum drug concentrations equivalent to intravenous administration. Quinolones have few adverse effects, most notably nausea, headache, dizziness, and confusion. Less common but more serious adverse events include prolongation of the corrected QT interval, phototoxicity, liver enzyme abnormalities, arthropathy, and cartilage and tendon abnormalities. The new fluoroquinolones are rarely first-line agents and should be employed judiciously. Inappropriate use of agents from this important class of antibiotics will likely worsen current problems with antibiotic resistance. Applications of fluoroquinolones in biologic warfare are also discussed.

Publication Types:
PMID: 11858629 [PubMed - indexed for MEDLINE]

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[Acute osteomyelitis in the child with sickle cell disease in a tropical zone: value of oral fluoroquinolones]

[Article in French]

Gbadoé AD, Dogba A, Dagnra AY, Atakouma Y, Tékou H, Assimadi JK.

Unité d'infectiologie et d'oncohématologie, département de pédiatrie, université du Bénin, BP 8881, Lomé, Togo. adgbadoe@tg.refer.org

AIM: This study was designed to assess the efficacy and the safety of fluoroquinolones in their compassionate use for acute osteomyelitis in children with sickle cell disease in a tropical country. PATIENTS AND METHODS: This study was non comparative, including twelve children (eight SS, three SC and one SEzerothalassemia) treated for acute osteomyelitis with oral ciprofloxacin or ofloxacin because of the following reasons: financial inability to afford conventional parenteral beta-lactams therapy (nine patients), refusal of hospitalization (two patients), and failure of conventional treatment (one patient). RESULTS: The mean age of patients was 9.5 +/- 2.6 years. The long bones were the predominantly site. Salmonella species were present in 75% of cases, followed by other enterobacteriaceae (16.7%), and Staphylococcus aureus (8.3%). Successful outcome occurred in all cases after three to four-weeks of treatment and 45 days of plaster immobilization. Transient bilateral Achilles tendon tendinitis was noted in a five-year-old patient. CONCLUSION: In economically developing countries, oral fluoroquinolones may be a therapeutic alternative for acute osteomyelitis in patients with sickle cell disease particularly in cases of financial hardship or failure with conventional therapy.

Publication Types:
PMID: 11811024 [PubMed - indexed for MEDLINE]

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Ciprofloxacin-associated Achilles tendon rupture in a hemodialysis patient.

Malaguti M, Triolo L, Biagini M.

Publication Types:
PMID: 11730281 [PubMed - indexed for MEDLINE]

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[Achilles pain and functional impotence in a patient with chronic obstructive pulmonary disease with pneumonia. Tendon rupture caused by levofloxacin]

[Article in Spanish]

Nuño Mateo FJ, Noval Menéndez J, Suárez M, Guinea O.

Servicios de Medicina Interna, Hospital de Cabueñes, Gijón.

Publication Types:
PMID: 11692412 [PubMed - indexed for MEDLINE]

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Biochemical changes in Achilles tendon from juvenile dogs after treatment with ciprofloxacin or feeding a magnesium-deficient diet.

Shakibaei M, de Souza P, van Sickle D, Stahlmann R.

Institute of Anatomy, Freie Universität Berlin, Germany. mehshaki@zedat.fu-berlin.de

Quinolones are antibacterial agents that have the potential to induce Achilles tendon disorders - such as tendinitis or even ruptures - in patients treated with these drugs. We studied the effects of ciprofloxacin on several proteins of Achilles tendons from immature dogs, 10- to 11-weeks-old. The dogs were treated orally for 5 days with 30 or 200 mg ciprofloxacin/kg body weight or with the vehicle alone. Since quinolone-like alterations in joint cartilage were observed in magnesium-deficient animals, another group was fed a magnesium-deficient diet for 6 weeks. At necropsy, tendons (n=3 from each group) were frozen and stored until analysis when they were homogenized in a lysis buffer to release a soluble fraction of the tendon proteins. Densitometric analysis of the immunoblots with anticollagen type I, anti-elastin, anti-fibronectin, and antiintegrin antibodies showed a significant reduction of all proteins. For example, collagen type I concentrations (mean +/-SD, arbitrary densitometric units) were 3190+/-217 (controls), 1890+/-468 (30mg/kg), 1695+/-135 (200mg/kg) and 2053+/-491 in the magnesium-deficient dogs. The differences between concentrations in controls and all treated groups were statistically significant (P<0.01, t-test). Similarly, compared with control samples, relative concentrations of other proteins in tendons from ciprofloxacin-treated dogs (30 mg/kg) decreased by 73% (elastin), 88% (fibronectin), and 96% (beta1 integrin) (data from low-dose group only). A very similar pattern of protein alterations was detected in samples from magnesium-deficient dogs. In conclusion, rather low doses of a fluoroquinolone or a diet-induced magnesium deficiency caused similar biochemical alterations in the soluble fraction of proteins from canine tendons. These findings support our hypothesis that quinolone-induced toxic effects on connective tissue structures are due to the magnesium-antagonistic effects of these antibacterial agents. They also indicate that patients with a latent magnesium deficiency could be at an increased risk of quinolone-induced tendon disorders.

Publication Types:
PMID: 11570695 [PubMed - indexed for MEDLINE]

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Latest industry information on the safety profile of levofloxacin in the US.

Kahn JB.

Infectious Disease Research, Ortho-McNeil Pharmaceutical Inc, Raritan, NJ 08869-0602, USA.

This paper reviews the safety data for levofloxacin utilizing reports from clinical and post-marketing surveillance trials. The side effect incidence rates are 1.3% for nausea, 0.1% for anxiety, 0.3% for insomnia, and 0.1% for headache. No levofloxacin-related adverse events were reported at a rate higher than 1.3%, and most were lower. Four clinical trials were reported. Levofloxacin achieved superior clinical and microbiological results compared to ceftriaxone/macrolide combination, and was better tolerated. Results comparing IV azithromycin plus ceftriaxone versus 500 mg levofloxacin in hospitalised CAP demonstrated that levofloxacin performed better, with more adverse events associated with the comparators (levofloxacin 5.3%, comparators 9.3%). High-dose levofloxacin (750 mg) was also evaluated and found to be well tolerated. Surveillance data reported low ADR rates for levofloxacin: nausea 0.8%, rash 0.5%, abdominal pain 0.4%, and diarrhoea, dizziness, and vomiting 0.3%. Worldwide and US surveillance data confirmed that tendon rupture occurred in less than 4 per million prescriptions, taste perversion in less than 3 per million, convulsions in 2 per million, and photosensitivity, hepatitis, hepatic failure, QT prolongation, torsade de pointes or empyema all in less than 1 per million. Copyright 2001 S. Karger AG, Basel

Publication Types:
PMID: 11549787 [PubMed - indexed for MEDLINE]

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Comparison of side effects of levofloxacin versus other fluoroquinolones.

Carbon C.

Internal Medicine Unit, Bichat-Claude Bernard Hospital, Paris, France.

The side-effect profile of levofloxacin was compared with that of other fluoroquinolones based on European and international data from approximately 130 million prescriptions. Levofloxacin was found to be very safe with a low rate of hepatic abnormalities (1/650,000). In contrast, 140 trovafloxacin-treated patients developed hepatic problems, 14 of which were severe, and 8 required transplantation. The main CNS problems associated with fluoroquinolones include dizziness, convulsions, psychosis, and insomnia. Levofloxacin, ofloxacin, and moxifloxacin reportedly have the lowest potential of inducing central nervous system (CNS) adverse events among the fluoroquinolones currently available. Cardiovascular problems were seen in 1/15 million levofloxacin prescriptions compared to 1-3% of sparfloxacin patients having QTc prolongation of greater than 500 msec. Moxifloxacin was also associated with QTc prolongation when compared to non-fluoroquinolone comparators. Nausea, vomiting, and diarrhoea remain the main adverse drug reactions (ADRs) associated with levofloxacin. However, the ADR rate for levofloxacin is still one of the lowest of any fluoroquinolone at 2% (compared to 2-10% for other fluoroquinolones). Ofloxacin and levofloxacin have a very low phototoxic potential, whereas this is a problem for sparfloxacin, enoxacin, and pefloxacin. The tolerance profile of levofloxacin can be considered to be very good, and better than most, if not all of the fluoroquinolones available. Copyright 2001 S. Karger AG, Basel

Publication Types:
PMID: 11549784 [PubMed - indexed for MEDLINE]

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Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands.

van der Linden PD, Nab HW, Simonian S, Stricker BH, Leufkens HG, Herings RM.

Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands. vanderLinden@mi.fgg.eur.nl

INTRODUCTION: Shortly after their introduction, fluoroquinolones were associated with reports of tendinitis and tendon rupture. During the past years, the number of reports has risen, possibly because of an increased use of fluoroquinolones. In this study, we describe the use of fluoroquinolones in the Dutch community and the possible public health effects of an association between fluoroquinolone use and tendon ruptures. METHODS: In the PHARMO drug database we identified all prescriptions for fluoroquinolones in the period 1991-1996. The incidence of fluoroquinolone use was expressed as the number of fluoroquinolone episodes per 1000 inhabitants in one year, and extrapolated to the Dutch population after standardisation on age and gender. The annual incidence of non-traumatic tendon ruptures in the period 1991-1996 was calculated with data from the nation-wide hospital registry. The expected number of fluoroquinolone attributable tendon ruptures was calculated on the basis of the use of fluoroquinolones, the number of non-traumatic tendon ruptures and an assumed relative risk of 1.5-10. RESULTS: In 1996, approximately 251,000 patients experienced 318,000 episodes of fluoroquinolone use in the Netherlands. Females used more often fluoroquinolones than males, and the number of episodes increased exponentially with age. In the period 1991 through 1996, the absolute number of fluoroquinolone episodes increased by 160%, from 122,000 to 318,000. The absolute number of hospitalised tendon ruptures increased with 28%, from 768 in 1991 to 984 in 1996. Assuming a relative risk of 1.5 to 10.0, 1 to 15 tendon ruptures could be attributed to fluoroquinolone use in 1996. Only 7% of the observed increase could be attributed to the increased use of fluoroquinolones. If the total increase of hospitalised non-traumatic tendon ruptures would be attributable to the increase in fluoroquinolone use, this would mean that the risk of non traumatic tendon ruptures to fluoroquinolones would be more than 250 times the risk during non-use. CONCLUSION: In the Netherlands, a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996. Assuming a relative risk of 1.5 to 10.0 for tendon ruptures during fluoroquinolone use, only 0.5 to 7% of the increase in non-traumatic tendon ruptures could be attributed to the increased fluoroquinolone use. The increase in the incidence of non-traumatic hospitalised tendon ruptures in the Netherlands is not likely to be explained solely by the increased use of fluoroquinolones.

Publication Types:
PMID: 11468881 [PubMed - indexed for MEDLINE]

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Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998.

van der Linden PD, van Puijenbroek EP, Feenstra J, Veld BA, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH.

Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.

OBJECTIVE: Fluoroquinolone antibiotics have been associated with tendinitis and tendon rupture. In this paper we report on the followup of 42 spontaneous reports of fluoroquinolone-associated tendon disorders. METHODS: This study is based on cases of fluoroquinolone-associated tendon disorders reported to the Netherlands Pharmacovigilance Foundation Lareb and the Drug Safety Unit of the Inspectorate for Health Care between January 1, 1988, and January 1, 1998. By means of a mailed questionnaire, we collected information on the site of injury, onset of symptoms, treatment, and course of the tendon disorder as well as information on possible risk factors and concomitant medication. RESULTS: Of 50 mailed questionnaires, 42 (84%) were returned. The data concerned 32 patients (76%) with tendinitis and 10 patients (24%) with a tendon rupture. Sixteen cases (38%) were attributed to ofloxacin, 13 (31%) to ciprofloxacin, 8 (19%) to norfloxacin, and 5 (12%) to pefloxacin. There was a male predominance, and the median age of the patients was 68 years. Most of the reports concerned the Achilles tendon, and 24 patients (57%) had bilateral tendinitis. The latency period between the start of treatment and the appearance of the first symptoms ranged from 1 to 510 days with a median of 6 days. Most patients recovered within 2 months after cessation of therapy, but 26% had not yet recovered at followup. CONCLUSION: These reports suggest that fluoroquinolone-associated tendon disorders are more common in patients over 60 years of age. Ofloxacin was implicated most frequently relative to the number of filled prescriptions in the Netherlands.

PMID: 11409663 [PubMed - indexed for MEDLINE]

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Malignant hyperthermia susceptibility revealed by myalgia and rhabdomyolysis during fluoroquinolone treatment.

Guis S, Jouglard J, Kozak-Ribbens G, Figarella-Branger D, Vanuxem D, Pellissier JF, Cozzone PJ.

Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS 6612, Faculté de Médecine, France.

Fluoroquinolones cause myalgia, but this complication is not clearly documented. We describe a patient who developed myalgia and rhabdomyolysis during fluoroquinolone treatment. The patient was a 33-year-old man treated with norfloxacin for common cystitis. He complained of general muscular fatigue, tendon disorders, and articular pain during treatment. When the antimicrobial agent was stopped, symptoms decreased, with persistence of slight myalgia for 10 days. Rhabdomyolysis was detected. Six months later, investigation by 31P magnetic resonance spectroscopy revealed an oxidative disorder and an abnormal abundance of phosphomonoesters. In vitro contracture tests led to a diagnosis of malignant hyperthermia susceptibility. Our case shows that for any subject presenting myalgia with rhabdomyolysis triggered by fluoroquinolone treatment, the presence of a latent myopathy should be investigated.

Publication Types:
PMID: 11409139 [PubMed - indexed for MEDLINE]

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Ultrastructure of Achilles tendon from rats after treatment with fleroxacin.

Shakibaei M, Stahlmann R.

Institute for Anatomy, Benjamin Franklin Medical Center, Freie Universität Berlin, Königin-Luise-Strasse 15, 14195 Berlin, Germany.

Quinolone therapy can be associated with tendon disorders (tendinitis, ruptures), but little is known about possible ultrastructural changes in tendons after exposure to these antimicrobials. We studied the Achilles tendons from fleroxacin-treated adult rats by electron microscopy. Wistar rats were treated orally with single oral doses of 0, 30, 100, 300 or 600 mg fleroxacin/kg body weight (n = 6 per group). The animals were killed 4 weeks after treatment. Achilles tendon samples were collected and tangential sections were made from the distal part of the tendon. Subsequently, tendons were cut crosswise for preparation of ultrathin sections. Samples were fixed by using glutaraldehyde, osmium tetroxide, tannic acid and finally contrasted with uranyl acetate/lead citrate before they were examined by transmission electron microscopy. The rats did not show any general effects such as behavioural changes or body weight changes which could be attributed to the treatment. However, we were able to detect pathological changes even at the lowest dose level (30 mg/kg), which increased in incidence and severity with increasing doses. Tenocytes exhibited degenerative changes such as multiple vacuoles and large vesicles in the cytoplasm that resulted from swelling and dilatation of cell organelles (mitochondria, endoplasmic reticulum). The nucleus became dense and the chromatin had clumped to form rough plaques. The cells detached from the extracellular matrix. Other important findings were a general decrease of the fibril diameter and an increase in the distance between the collagenous fibrils. The finding that these rather low single dose of a fluoroquinolone induce ultrastructural changes in Achilles tendons from rats, which were not associated with clinical symptoms and which were still present 4 weeks after treatment, is of concern. Further toxicological as well as clinical studies are needed to characterize the conditions under which quinolone-induced tendon lesions develop.

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PMID: 11354912 [PubMed - indexed for MEDLINE]

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Comment on:
The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism.

Riley G, Fenwick S, Hazleman B.

Publication Types:
PMID: 11292056 [PubMed - indexed for MEDLINE]

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Fleroxacin uptake in ischaemic limb tissue.

Miglioli PA, Kafka R, Bonatti H, Fraedrich G, Allerberger F, Schoeffel U.

Department of Pharmacology, University of Padua, L.go E. Meneghetti, 2., 35131 Padova, Italy.

Antibiotic application to patients with ischaemia of lower limbs may be indicated to avoid or treat infection of soft tissues. Fleroxacin, a fluoroquinolone, active against various Gram-negative and Gram-positive organisms may be used for this purpose. We evaluated the diffusion of fleroxacin into bone, subcutaneous fat, muscle and tendon tissues of lower limb tissue after a 400 mg i.v. dose. Concentrations in ischaemic tissues were similar to those found in non-ischaemic sites. Since the maximum antibiotic levels found were lower than the MICs of various pathogens relevant for infection, we suggest to increase the dose used for this peri-operative prophylaxis to 800 mg.

PMID: 11233695 [PubMed - indexed for MEDLINE]

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[Aquariums and mycobacterioses]

[Article in French]

Kiesch N.

Service de Dermatologie, C.H.U. Saint Pierre, U.L.B.

Mycobacterium infections are increasingly reported in fish fanciers who keep an aquarium. Inoculation occurs on abraded skin after an incubation period of 2 to 3 weeks. Clinically papulo-nodules, ulcers or verrucous plaques develop. These may progress into sporotrichoid lesions or into deeper infections involving tendons and bone. Cultural identification is obtained by biopsy specimen at low temperature (30-33 degrees C). Faster identification may be performed by polymerase chain reaction. Histopathologic examination is characterized by a nonspecific inflammatory infiltrate in the acute phase. In chronic lesions the histopathologic pattern is a tuberculoidlike granuloma. No absolute consensus has been reached for the treatment but generally it is started with minocycline. Other antibiotics (cotrimoxazole, quinolones, clarithromycine, ethambutol in association) have made their proof.

Publication Types:
PMID: 11068476 [PubMed - indexed for MEDLINE]

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[Rupture of the patellar ligament one month after treatment with fluoroquinolone]

[Article in French]

Saint F, Gueguen G, Biserte J, Fontaine C, Mazeman E.

Service d'Urologie, CHRU et Université de Lille, 59037 Lille Cedex,, France.

Musculoskeletal disorders including arthralgia and myalgia are adverse effect common to all fluoroquinolones. We report a case of spontaneous rupture of the patellar ligament in a 37-year-old man participating in leisure sports which occurred one month after a three-week course of Ciprofloxacine(R). Several cases of tendon ruptures have been reported in the literature, including the patellar tendon. Unusual features in our case were the one-month delay before tendon rupture and the absence of inaugural signs. We reviewed the pathophysiological mechanisms leading to fluoroquinolone-related tendon rupture as well as the risk factors and discussed proper management. Care must be taken when prescribing fluoroquinolones for patients at risk. Close follow-up is most important.

Publication Types:
PMID: 10970974 [PubMed - indexed for MEDLINE]

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Fluoroquinolone-induced tendinopathy: also occurring with levofloxacin.

Fleisch F, Hartmann K, Kuhn M.

Publication Types:
PMID: 10961538 [PubMed - indexed for MEDLINE]

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Comment in:
The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism.

Williams RJ III, Attia E, Wickiewicz TL, Hannafin JA.

Laboratory for Soft Tissue Research, Sports Medicine & Shoulder Service, Hospital for Special Surgery, New York, New York, USA.

The pathologic mechanisms underlying fluoroquinolone-induced tendinopathy are poorly understood. The observed incidence of tendinitis and tendon rupture in patients treated with ciprofloxacin hydrochloride suggests that the fluoroquinolone antibiotics alter tendon fibroblast metabolism. The purpose of this study was to examine the effect of ciprofloxacin on fibroblast metabolism in vitro. Canine Achilles tendon, paratenon, and shoulder capsule specimens were maintained in culture with ciprofloxacin (5, 10, or 50 microg/ml). Fibroblast proliferation, collagen synthesis, proteoglycan synthesis, and matrix-degrading activity were analyzed. Incubation of Achilles tendon, Achilles paratenon, and shoulder capsule fibroblasts with ciprofloxacin resulted in a statistically significant 66% to 68% decrease in cell proliferation compared with control cells at day 3 in culture. Ciprofloxacin caused a statistically significant 36% to 48% decrease in collagen synthesis compared with controls in all fibroblast cultures. Ciprofloxacin caused a statistically significant 14% to 60% decrease in proteoglycan synthesis in all fibroblast cell lines. Compared with unstimulated control fibroblasts, culture media from Achilles tendon, paratenon, and shoulder capsule cells that were exposed to ciprofloxacin demonstrated statistically significant increases in matrix-degrading proteolytic activity after 72 hours in culture. This study demonstrates that ciprofloxacin stimulates matrix-degrading protease activity from fibroblasts and that it exerts an inhibitory effect on fibroblast metabolism. The increase in protease activity and the inhibition of both cell proliferation and the synthesis of matrix ground substance may contribute to the clinically described tendinopathies associated with ciprofloxacin therapy.

PMID: 10843129 [PubMed - indexed for MEDLINE]

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Comment on:
Fluoroquinolones.

Litt JZ.

Publication Types:
PMID: 10832957 [PubMed - indexed for MEDLINE]

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Comment in:
Quinolones and tendon ruptures.

Casparian JM, Luchi M, Moffat RE, Hinthorn D.

Department of Medicine, University of Kansas Medical Center, Kansas City 66160-7319, USA.

We report two cases of tendon rupture associated with ciprofloxacin. One patient had a complete rupture of an Achilles tendon 6 months after taking the medication. The other case involved a partial rupture of the subscapularis tendon. Both ruptures occurred with minimal mechanical stress on the tendons, suggesting that the fluoroquinolone increased the susceptibility to rupture. We also review the literature describing the association between fluoroquinolones and tendon rupture and discuss the mechanisms explaining the heightened risk of tendon rupture associated with these drugs.

Publication Types:
PMID: 10832946 [PubMed - indexed for MEDLINE]

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Pefloxacin-induced achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen.

Simonin MA, Gegout-Pottie P, Minn A, Gillet P, Netter P, Terlain B.

Department of Pharmacology, UMR 7561, CNRS-Université Henri Poincaré-Nancy I "Physiopathologie et Pharmacologie Articulaires," Faculté de Médecine, Vandoeuvre-lès-Nancy, France.

Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.

Publication Types:
PMID: 10722483 [PubMed - indexed for MEDLINE]

PMCID: PMC89784


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Ultrastructure of Achilles tendons of rats treated with ofloxacin and fed a normal or magnesium-deficient diet.

Shakibaei M, Pfister K, Schwabe R, Vormann J, Stahlmann R.

Institute of Anatomy, Benjamin Franklin Medical Center, Freie Universit]at Berlin, 14195 Berlin, Germany.

Fluoroquinolones can cause tendinitis and tendon rupture. However, toxicological as well as clinical information on quinolone-induced tendopathy is scarce. We performed extensive electron microscopic studies with Achilles tendon specimens from ofloxacin-treated rats. The drug was given at a dose of 1,200 mg/kg (body weight) orally. Juvenile Wistar rats received one or three oral doses each of 1,200 mg of ofloxacin/kg (body weight)/day. Three days after treatment, the tenocytes of their Achilles tendons showed degenerative alterations, such as multiple vacuoles and vesicles in the cytoplasm that had developed due to swellings and dilatations of cell organelles. Other indications of cell degradation were the occurrence of cell debris and cell detachment from the extracellular matrix accompanied by a loss of cell-matrix interaction. The tenocytes of juvenile Wistar rats that had been treated at day 36 with a single oral dose of 1,200 mg of ofloxacin/kg (body weight) and sacrificed either 3 or 6 months later exhibited similar degenerative alterations. The number of degenerative alterations of tenocytes after ofloxacin treatment was considerably higher in rats that had received a magnesium-deficient diet than in rats with normal magnesium status. Of the adult rats that had been treated once, 5 times, and 10 times with ofloxacin and killed 1 day later, only those with the 10-times treatment showed a significantly increased number of degeneratively altered tenocytes. In summary, effects observed in tendons show similar pathological features as described earlier in cartilage, indicating that quinolone-induced arthropathy and quinolone-induced tendopathy probably are different clinical manifestations of the same toxic effect on cellular components of connective tissue structures.

Publication Types:
PMID: 10639347 [PubMed - indexed for MEDLINE]

PMCID: PMC89668


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Effect of long-term administration of an injectable enrofloxacin solution on physical and musculoskeletal variables in adult horses.

Bertone AL, Tremaine WH, Macoris DG, Simmons EJ, Ewert KM, Herr LG, Weisbrode SE.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus 43210, USA.

OBJECTIVE: To evaluate clinical safety of administration of injectable enrofloxacin. DESIGN: Randomized controlled clinical trial. ANIMALS: 24 adult horses. PROCEDURES: Healthy horses were randomly allocated into 4 equal groups that received placebo injections (control) or IV administration of enrofloxacin (5 mg/kg [2.3 mg/lb], 15 mg/kg [6.8 mg/lb], or 25 mg/kg [11.4 mg/lb] of body weight, q 24 h) for 21 days. Joint angles, cross-sectional area of superficial and deep digital flexor and calcaneal tendons, carpal or tarsal osteophytes or lucency, and midcarpal and tarsocrural articular cartilage lesions were measured. Physical and lameness examinations were performed daily. Measurements were repeated after day 21, and articular cartilage and bone biopsy specimens were examined. RESULTS: Enrofloxacin did not induce changes in most variables during administration or for 7 days after administration. One horse (dosage, 15 mg/kg) developed lameness and cellulitis around the tarsal plantar ligament during the last week of administration. One horse (dosage, 15 mg/kg) developed mild superficial digital flexor tendinitis, and 1 horse (dosage, 25 mg/kg) developed tarsal sheath effusion without lameness 3 days after the last administration. High doses of enrofloxacin (15 and 25 mg/kg) administered by bolus injection intermittently induced transient neurologic signs that completely resolved within 10 minutes without long-term effects. Slower injection and dilution of the dose ameliorated the neurologic signs. Adverse reactions were not detected with a 5 mg/kg dose administered IV as a bolus. CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin administered IV once daily at the rate of 5 mg/kg for 3 weeks is safe in adult horses.

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PMID: 11128543 [PubMed - indexed for MEDLINE]

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Comparative tolerability of the newer fluoroquinolone antibacterials.

Ball P, Mandell L, Niki Y, Tillotson G.

School of Biomedical Sciences, University of St Andrews, Fife, Scotland. Peterball1@aol.com

The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin and CNS, and are mainly mild and reversible. Of the gastrointestinal events, nausea and vomiting are the most common. Mild hepatic reactions are a class effect, usually presenting as mild transaminase level increases without clinical symptoms. However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin. It is not currently known whether the severe reactions to trovafloxacin are specific to that agent or simply represent an extreme of an emerging class effect. The enormous worldwide usage of, and extensive published adverse effect data on the other fluoroquinolones and naphthyridones suggests the former. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid. CNS reactions vary in severity and include dizziness, convulsions (notably with lomefloxacin) and psychoses. Fluoroquinolones differ in their pro-convulsive activity, relating to their differing potential as gamma-aminobutyric acid antagonists and binding to the N-methyl-D-aspartate receptor. The basis for the increased seizure potential following the coadministration of nonsteroidal anti-inflammatory drugs with certain fluoroquinolones is not fully understood. Fluoroquinolone phototoxicity, caused by the generation of toxic free oxygen species under exposure to UVA radiation, is significantly more common with 8-halogenated compounds. Certain patient groups, e.g. patients with cystic fibrosis, are predisposed to this adverse effect. Murine photocarcinogenicity has been demonstrated with lomefloxacin, but no such effects have been reported in humans. Prolongation of the QTc interval is also a class effect, although cardiac arrhythmias have only been linked with sparfloxacin. Among the newer fluoroquinolones, clinically significant cardiac events are rare or absent but possible interactions in patients receiving other drugs capable of causi ng QT prolongation should be anticipated. Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones, most frequently reported with pefloxacin. Predisposing factors include aging, corticosteroid use, renal disease, haemodialysis and transplantation. Use of fluoroquinolones in paediatric patients remains contentious. However, accruing human data suggest that restrictions on paediatric use imposed because of fluoroquinolone-induced cartilage damage in juvenile animals, may soon be relaxed. Data from over 1700 children in the UK failed to disclose arthropathy and extensive paediatric use of norfloxacin in Japan and ciprofloxacin in developing countries has been free of articular effects.

Publication Types:
PMID: 10554054 [PubMed - indexed for MEDLINE]

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Toxicity of quinolones.

Stahlmann R, Lode H.

Institute of Clinical Pharmacology and Toxicology, Department of Toxicology, University Medical Center Benjamin Franklin, Freie Universität Berlin, Germany.

Reactions of the gastrointestinal tract, the CNS and the skin are the most often observed adverse effects during therapy with fluoroquinolones. At least for some of the newer fluoroquinolones a steep dose-response relationship of adverse effects seems to exist. Pathogenesis of the neurotoxic effects of fluoroquinolones is still unknown. Among the newer drugs, trovafloxacin caused mild CNS reactions such as dizziness and lightheadedness in a considerable proportion of patients. Young females seem to be especially sensitive to this effect, which diminishes during treatment or if taken together with food. Cardiotoxic potentials of sparfloxacin and grepafloxacin are higher than those of other fluoroquinolones, but during therapy no clearcut drug-related serious reactions have been reported, apart from a slight prolongation of the QT interval. However, to avoid risks these drugs should not be prescribed to patients with known prolongation of the QT interval (e.g. patients on antiarrhythmics). Phototoxicity has been described for all quinolones, but derivatives with a halogen atom at position 8 show the highest potential for such reactions. Fleroxacin, sparfloxacin, clinafloxacin and lomefloxacin belong to this group of fluoroquinolones. The phototoxic potential of the other new fluoroquinolones is considerably lower, but extensive exposure to UV light should generally be avoided during therapy with all quinolones. Chondrotoxicity of quinolones, as observed in immature animals, can affect articular cartilage and/or the epiphyseal growth plate, depending on the developmental stage. Pathogenesis of chondrotoxicity can probably be explained by the magnesium-chelating properties of these drugs. As juveniles are especially sensitive, use of these drugs in paediatrics should be restricted to carefully selected indications (such as the use of ciprofloxacin in cystic fibrosis). Another manifestation of the toxic effects of quinolones on connective tissue structures are tendopathies. Tendinitis and tendon ruptures have occurred as late as several months after quinolone treatment. Overall, quinolones are well tolerated drugs. Their specific toxic potentials have to be considered when they are chosen for treatment of bacterial infections.

Publication Types:
PMID: 10553703 [PubMed - indexed for MEDLINE]

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Suspected role of ofloxacin in a case of arthalgia, myalgia, and multiple tendinopathy.

Schwald N, Debray-Meignan S.

Geriatrics Department, Hôtel-Dieu, Paris, France.

A 53-year-old woman on ofloxacin developed myalgia, arthralgia, and tendinopathy. Her symptoms resolved after ofloxacin discontinuation. Although tendinopathy is a well-documented complication of quinolone therapy, there have been few reports of muscle symptoms. Concomitant involvement of the tendons, muscles, and joints has been exceedingly rare. Inhaled glucocorticoid therapy and moderate hypothyroidism were probably precipitating factors in our patient.

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PMID: 10526383 [PubMed - indexed for MEDLINE]

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Achilles tendinitis associated with fluoroquinolones.

van der Linden PD, van de Lei J, Nab HW, Knol A, Stricker BH.

Pharmaco-epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, The Netherlands.

AIMS: To determine whether there is an association between use of fluoroquinolones and tendinitis in a large population under everyday circumstances. METHODS: A retrospective cohort study was carried out in a dynamic population. Data came from the IPCI-database which consists of all data on consultations, morbidity, prescriptions and other interventions, as registered by GPs in a source population of approximately 250 000 persons. For this study data were collected from 41 general practices in the period from January 1st, 1995 through December 31st, 1996. All persons treated with either fluoroquinolones, amoxicillin, trimethoprim, cotrimoxazole or nitrofurantoin were followed from the first day of treatment until the outcome of interest, death, transfer to another practice, or end of the study period, whichever came first. The risk window was defined as the legend duration +1 month. Potential cases were defined as a registration of a tendinitis or tendon rupture. Patients with a history of tendinitis or tendon rupture, preceding trauma or inadequate diagnoses were excluded on the basis of a review of the patient profiles and additional clinical data, blinded as to the exposure status. Results were adjusted for age, gender, concurrent corticosteroid exposure and number of GP visits. RESULTS: There were 1841 users of fluoroquinolones and 9406 users of the other antibacterial drugs with an average duration of 9 and 7 days, respectively. Tendinitis or tendon rupture was registered in 97 profiles, but after review only 22 complied with the case definition. The adjusted relative risk of tendinitis to fluoroquinolones was 3. 7 (95%CI: 0.9-15.1) for Achilles tendinitis and 1.3 (95%CI: 0.4-4.7) for other types of tendinitis. Achilles tendinitis to ofloxacin had a relative risk of 10.1 (95%CI: 2.2-46.0) and an excess risk of 15 cases per 100 000 exposure days. CONCLUSIONS: Although the numbers in our study are small, our results suggest that some fluoroquinolones may increase the risk of Achilles tendinitis, and that this risk increase is highest for ofloxacin.

PMID: 10510157 [PubMed - indexed for MEDLINE]

PMCID: PMC2014320


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Levofloxacin-induced bilateral Achilles tendonitis.

Lewis JR, Gums JG, Dickensheets DL.

College of Pharmacy, University of Florida, Gainesville, USA. lewisjr.alachua@shands.ufl.edu

OBJECTIVE: To report a case of possible levofloxacin-induced bilateral Achilles tendonitis. CASE SUMMARY: An 83-year-old white woman presented to her physician with five days of hemoptysis. She was diagnosed with right lower-lobe pneumonia based on chest X-ray, and levofloxacin 500 mg/d po for 10 days was prescribed. Three days into treatment she began having a variety of adverse effects, including severe nausea, constipation, stomach cramps, and dizziness. Signs of tendonitis began three days after treatment and peaked four days after completion of therapy. Two weeks later, she was treated by her podiatrist with an ankle immobilizer and rest. At her three-week follow-up, she had marked improvement in her pain and bruising; however, her symptoms had not completely resolved. DISCUSSION: Tendonitis and tendon rupture are rare adverse effects of fluoroquinolone antibiotics; there are no reports in the literature of levofloxacin-induced tendonitis. As newer fluoroquinolones become available, the postmarketing studies will become increasingly important to capture the data on rare but serious adverse effects not discovered in the premarketing trials. CONCLUSIONS: To our knowledge, this is the first reported case of tendonitis caused by levofloxacin reported in the literature. Reports have been made, however, to the manufacturer via postmarketing surveillance. As more people are treated with newer fluoroquinolones, the clinical incidence of tendon rupture with these agents may become clearer.

Publication Types:
PMID: 10466906 [PubMed - indexed for MEDLINE]

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Fluoroquinolone-induced tendinopathy: what do we know?

Harrell RM.

Department of Emergency Medicine, Louisiana State University School of Medicine, Shreveport, USA.

Fluoroquinolones are relatively safe, effective antibiotics. As their use becomes more frequent, so will the adverse side effects. I highlight a rare but debilitating adverse reaction-fluoroquinolone-induced tendinopathy. Case reports and letters from 1987 to 1998 were identified by using Grateful Med and PubMed Internet accesses to the National Library of Medicine. Articles were reviewed for clinical practicality. There are few articles on fluoroquinolone-induced tendinopathy in the US literature targeting primary care physicians. This entity has been described in many case reports, but little has been done to isolate the causative agents. Incidence of this side effect is difficult to estimate, since no prospective studies are available for review or calculation of risk. Fluoroquinolone-induced tendinopathy appears more commonly in tendons under high stress. The cause is probably multifactorial. Risk factors for the development of fluoroquinolone-induced tendinopathy are age, renal failure, corticosteroid use, and previous tendinopathy from fluoroquinolones.

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PMID: 10372859 [PubMed - indexed for MEDLINE]

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[Insidious rupture of the Achilles tendon after ciprofloxacin-induced tendopathy. A case report]

[Article in German]

Petersen W, Laprell H.

Lubinusklinik, Klinik für Chirurgie und Orthopädie, Kiel.

A 45 years old female runner developed a bilateral tendinopathy of the Achilles tendon after repeated antimicrobiotical treatment with ciprofloxacin. One month later the right Achilles tendon ruptured without any sudden pain. MRI revealed degenerative changes of the left Achilles tendon; on the right side the tendon was ruptured with a dehiscence of 4 cm between both ends of the tendon. The tendon was reconstructed surgically. The histological analysis showed cystic changes with focal necrosis. This finding differ from findings in non drug induced tendinopathies. After antimicrobiotical treatment with ciprofloxacin the side effect of a tendon disorder must be considered. The impairment of the tendon may be as strong that a tendon rupture may occur at daily living activities without any typical clinical symptoms.

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PMID: 9816984 [PubMed - indexed for MEDLINE]

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[Fluoroquinolones as etiology of tendinopathy]

[Article in German]

Gabutti L, Stoller R, Marti HP.

Departement Innere Medizin, Inselspital Bern.

Tendinopathies as a result of fluoroquinolone therapy represent a new clinical entity. We report on tendinitis and tendon rupture in six fluoroquinolone treated patients of our outpatient and dialysis service between 1995 and 1997. The most important risk factors for tendinopathies were renal failure in all cases, glucocorticosteroid therapy in five patients, secondary hyperparathyroidism in three patients, advanced age in two patients, and diabetes mellitus in another patient. Latency periods of 2 to 60 days between onset of fluoroquinolone therapy and emergence of symptoms suggest significant involvement of these agents and are compatible with previously published case reports. Therefore, care should be used in prescribing fluoroquinolones to older renal transplant or hemodialysis patients with additional risk factors for tendinopathies. These drugs should be stopped when symptoms of tendinitis occur, particularly to prevent tendon rupture. The incidence of fluoroquinolone induced tendinopathies in patients without renal diseases is unknown.

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PMID: 9789471 [PubMed - indexed for MEDLINE]

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Achilles tendinitis and ruptures.

Kahn MF.

Publication Types:
PMID: 9773187 [PubMed - indexed for MEDLINE]

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In vitro study of cytotoxicity of quinolones on rabbit tenocytes.

Bernard-Beaubois K, Hecquet C, Hayem G, Rat P, Adolphe M.

Laboratoire de Pharmacologie Cellulaire de l'Ecole Pratique des Hautes Etudes, Centre de Recherches Biomédicales des Cordeliers, Paris, France.

Tendinitis and tendon rupture complicating fluoroquinolone therapy have been reported recently, especially affecting men over 60 years. These new quinolones are more potent antimicrobial agents than older nonfluorinated compounds like nalidixic acid. We compared the effects of one quinolone (nalidixic acid) and two fluoroquinolones (norfloxacin and pefloxacin) on cultured rabbit Achilles tendon cells. First, we examined their effects on cell viability, mitochondrial succinate dehydrogenase and global activity, mitochondrial activity using microtitration methods. Pefloxacin and norfloxacin were more cytotoxic than nalidixic acid according to IC50 values. These results confirm that mitochondria represent a biological target of fluoroquinolones. Moreover, the extracellular matrix was studied by molecular hybridization. After a 72 h treatment, the level of type I collagen transcripts was not modified with any of the three antimicrobial agents, whereas mRNA encoding decorin was decreased with 10(-4) mol/L pefloxacin only. The decrease of transcripts encoding decorin suggests that this matrix component is another target of pefloxacin and modification of decorin seems to be an early event (before mitochondrion alteration) which may contribute to the explanation of tendon rupture.

Publication Types:
PMID: 9733283 [PubMed - indexed for MEDLINE]

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[Bilateral tendinitis caused by ciprofloxacin]

[Article in Spanish]

Blanco Andrés C, Bravo Toledo R.

Publication Types:
PMID: 9607242 [PubMed - indexed for MEDLINE]

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Fluoroquinolones as a cause of tendon disorders in patients with renal failure/renal transplants.

Marti HP, Stoller R, Frey FJ.

Publication Types:
PMID: 9566681 [PubMed - indexed for MEDLINE]

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Ciprofloxacin, bilateral Achilles tendonitis and unilateral tendon rupture--a case report.

West MB, Gow P.

Publication Types:
PMID: 9484431 [PubMed - indexed for MEDLINE]

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Toxic effects of quinolone antibacterial agents on the musculoskeletal system in juvenile rats.

Kashida Y, Kato M.

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. JDN07402@niftyserve.or.jp

Quinolone antibacterial agents have adverse effects on the musculoskeletal system in humans, consisting mainly of myalgia and arthralgia, and additionally of tendon disorders and rhabdomyolysis. The present study was conducted to examine the toxic effects of quinolones on the musculoskeletal system in juvenile rats using light microscopy, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and electron microscopy. Single oral administration of 900 mg/kg pefloxacin (PFLX) or levofloxacin (LVFX) was found to induce lesions in the muscle + fascia, tendon + sheath, and synovial membrane, in addition to articular cartilage in the fore- and hindlimbs. Articular cartilage lesions were not necessarily associated with changes in the muscle, tendon, and synovial membrane, or the reverse. Among all lesions, the ankle and elbow showed the highest incidence and severity. Changes were more severe in the PFLX than in the LVFX group. Lesions in the muscle + fascia, tendon + sheath, and synovial membrane were similar and characterized by edema and increased number of mononuclear cells, many of which were positively stained with BrdU, as well as vascular endothelial cells in the Achilles tendon sheath and synovial membrane in the ankle. Electron microscopic examination revealed an increased number of fibroblasts and macrophages and collagen deposition in the matrix of the synovial membrane and tendon sheath. Capillary endothelial cells were hypertrophied, increased in number, and stratified. These results suggest that quinolones have toxic potentials in the muscle, tendon, and synovial membrane in addition to articular cartilage, and that local vascular hyperpermeability may contribute to the development of these lesions.

PMID: 9437810 [PubMed - indexed for MEDLINE]

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[Tendon disease caused by ciprofloxacin, an atypical site]

[Article in French]

Peyrade F, Taillan B, Chichmanian RM, Lebrun C, Dujardin P.

Publication Types:
PMID: 9435847 [PubMed - indexed for MEDLINE]

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Comment in:
Subcutaneous rupture of the Achilles tendon: basic science and some aspects of clinical practice.

Waterston SW, Maffulli N, Ewen SW.

Department of Orthopaedic Surgery, University of Aberdeen Medical School, Foresterhill, Scotland.

Publication Types:
PMID: 9429005 [PubMed - indexed for MEDLINE]

PMCID: PMC1332561


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Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds.

Kashida Y, Kato M.

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Edogawa, Tokyo, Japan.

Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.

Publication Types:
PMID: 9371338 [PubMed - indexed for MEDLINE]

PMCID: PMC164133


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Achilles tendon rupture and fluoroquinolones use: report of two cases.

de la Garza Estrada VA, Vázquez Caballero R, Camacho Carranza JL.

Departamento de Medicina Interna, Hospital Angeles del Pedregal, México, D.F.

A report of two cases of fluoroquinolones-associated Achilles tendon rupture in two previously-healthy males is presented. Neither of them had any other predisposing condition for this complication. Both were used to strenuous physical activity. No other cause could be found in relation to their traumatic experience. Emphasis is placed on the necessity of identifying this potential and probably unusual complication of these widely-used antimicrobials.

Publication Types:
PMID: 9291644 [PubMed - indexed for MEDLINE]

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Tendons and fluoroquinolones. Unresolved issues.

Kahn MF, Hayem G.

Publication Types:
PMID: 9338923 [PubMed - indexed for MEDLINE]

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Spontaneous bilateral Achilles tendon rupture associated with ciprofloxacin.

Poon CC, Sundaram NA.

Publication Types:
PMID: 9216589 [PubMed - indexed for MEDLINE]

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Pathology of the Achilles tendon in association with ciprofloxacin treatment.

Movin T, Gad A, Güntner P, Földhazy Z, Rolf C.

Department of Orthopedics, Huddinge University Hospital, Sweden.

Achilles tendon pain or rupture after fluoroquionolone treatment has been described as an uncommon adverse effect. We report two patients with ciprofloxacin-associated Achilles tendon disease, one with histopathological examination. Microscopic evaluation showed irregular collagen fiber arrangement, hypercellularity, and increased interfibrillar glycosaminoglycans. These pathological features are also seen in tendon overuse injuries in athletes.

Publication Types:
PMID: 9167931 [PubMed - indexed for MEDLINE]

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Possible involvement of nitric oxide in the quinolone-induced tendon lesions in rats.

Kashida Y, Kato M.

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.

Quinolone antibacterial agents have been reported to induce adverse effects on the tendon and the musculoskeletal system in humans. We have previously demonstrated that Achilles tendon lesions could be induced in juvenile rats by a single oral administration of quinolones at high doses with simultaneous induction of lesions in the muscle, synovial membrane and articular cartilage. In the present investigation, we examined the involvement of nitric oxide (NO) in pefloxacin (PFLX)-induced lesions of the Achilles tendon in juvenile rats. The incidence of lesions was diminished markedly by co-administration of a potent NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Further, the urinary nitrate/nitrite excretion was decreased significantly by 4 h after administration, unchanged between 4 and 8 h, and significantly increased in the 8- to 24-h samples in the PFLX group, as compared to the control group. In contrast, the serum concentration of nitrate/nitrite was significantly higher in the PFLX group 4 h after administration, but there was no difference from controls was observed at 8 and 24 h. These results suggest that NO is involved in the induction of Achilles tendon lesions in juvenile rats by pefloxacin (PFLX) and may be similar to the tendon disorder of humans receiving quinolones.

PMID: 9403275 [PubMed - indexed for MEDLINE]

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[Repeated rupture of the extensor tendons of the hand due to fluoroquinolones. Apropos of a case]

[Article in French]

Levadoux M, Carli P, Gadea JF, De Mauleon De Bruyere P, Perre C.

Service de chirurgie Orthopédique, Hôpital d'Instruction des Armées, Sainte-Anne, Toulon, Naval.

Fluoroquinolone toxicity on cartilages and tendons has been well known since 1983. Tendon inflammation or rupture has been described. Achilles tendon rupture is the most frequent complication but many other sites of tendon injuries have been reported. This article presents a case of rupture of extensor tendons of the hand in an elderly woman treated by fluoroquinolones. As far as we know, this site of tendon lesion has never been previously described. Histological examination of tendon injuries was possible after surgical treatment. Histological structures were similar to the classical description but had specific features. Like other authors, we think that the mechanism of the disease involves vascular disorders as well as direct toxicity. The histological lesions seem to be different in chronic and acute forms.

Publication Types:
PMID: 9289004 [PubMed - indexed for MEDLINE]

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What is the risk of Achilles tendon rupture with ciprofloxacin?

Shinohara YT, Tasker SA, Wallace MR, Couch KE, Olson PE.

Publication Types:
PMID: 9002057 [PubMed - indexed for MEDLINE]

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Achilles tendon rupture due to ciprofloxacin.

Jagose JT, McGregor DR, Nind GR, Bailey RR.

Publication Types:
PMID: 9006634 [PubMed - indexed for MEDLINE]

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From the Food and Drug Administration.

Nightingale SL.

PMID: 8769577 [PubMed - indexed for MEDLINE]

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Partial Achilles tendon ruptures associated with fluoroquinolone antibiotics: a case report and literature review.

McGarvey WC, Singh D, Trevino SG.

Department of Orthopaedic Surgery, Baylor College of Medicine, Houston, Texas, USA.

Fluoroquinolone antibiotics (such as olprofloxacin, pefloxacin, ofloxacin, norfloxacin, temafloxacin, etc.) have recently been implicated in the etiology of Achilles tendinitis and subsequent tendon rupture. We report on a patient with bilateral partial Achilles tendon ruptures associated with ciprofloxacin therapy and present a review of the current literature on this increasingly recognized complication. Treatment with fluoroquinolones should be discontinued at the first sign of tendon inflammation so as to reduce the risk of subsequent rupture. Magnetic resonance imaging is useful in distinguishing between Achilles tendinitis and partial tendon rupture.

Publication Types:
PMID: 8863030 [PubMed - indexed for MEDLINE]

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Tendon disorders with fluoroquinolones.

Pierfitte C, Royer RJ.

Centre de Pharmacovigilance, CHU de Nancy, France.

PMID: 8953821 [PubMed - indexed for MEDLINE]

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Adverse drug reactions with fluoroquinolones.

Royer RJ.

Pharmacologie Clinique, Hôpital Central-CHU de Nancy, France.

The French system of drug surveillance has analysed the notifications of adverse drug reactions (ADRs) to fluoroquinolones since they were launched. Their frequency ranges from 1/15,000 to 1/208,000 case per days of treatment. Cutaneous diseases and tendon disorders predominate in France whereas cutaneous effects and neuropsychiatric disorders are predominant in the UK; tendon disorders take up only the 5th position. Among the most unexpected ADRs are the following: -shock represents 33 of the anaphylaxis reactions which range from 1/5.6 x 10(6) to 1/4.4 x 10(5) case per days of treatment. -acute renal failure is rare: one case/80,000 patients treated by ciprofloxacin to 1/320,000 by norfloxacin. The pathophysiology is not well known. Tendon ruptures represent 81 cases for 921 notifications of tendon disorders which are related in decreasing order to pefloxacin 1/23,130 case per days of treatment, ofloxacin, norfloxacin and ciprofloxacin 1/779,600 case per days of treatment. Age and corticosteroids increase the risk of tendon rupture.

PMID: 8953819 [PubMed - indexed for MEDLINE]

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[Surgically treated chronic bilateral Achilles tendon disease, without spontaneous rupture, caused by perfloxacin]

[Article in French]

Beuchard J, Rochcongar P, Saillant G, Allain H, Beneton C.

Publication Types:
PMID: 8760630 [PubMed - indexed for MEDLINE]

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Comment on:
Judging by reactions.

Loring SJ.

Publication Types:
PMID: 8710290 [PubMed - indexed for MEDLINE]

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[Rupture of the Achilles tendon after ciproxine therapy]

[Article in Swedish]

Hugo-Persson M.

Infektionskliniken, Helsingborgs lasarett.

Publication Types:
PMID: 8667750 [PubMed - indexed for MEDLINE]

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Click here to read
A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies.

Wilton LV, Pearce GL, Mann RD.

Drug Safety Research Unit, Southampton, UK.

1. The safety in everyday clinical usage of three 4-quinolone antibiotics, (ciprofloxacin, norfloxacin and ofloxacin), was compared with similar data for azithromycin and cefixime, each agent being examined by Prescription-Event Monitoring (PEM) during the early post-marketing period. 2. In PEM the exposure data are derived from general practitioner prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are provided by questionnaires (green forms) on which the prescribing medical practitioner records event data. When necessary, further information is obtained from a number of sources which include follow-up of all pregnancies and the patients' life-time medical record. 3. The main outcome measures were demographic information, including the patient's date of birth and sex; the indication for prescribing the drug being monitored; the reason for stopping treatment; the start and stop dates of treatment and the events recorded during and after treatment. 4. The final cohort for each of the five antibiotics exceeded 11000 patients. The only event significantly related to the use of all five antibiotics was nausea/vomiting. This was also the most frequent adverse event causing treatment to be discontinued with norfloxacin, ofloxacin and azithromycin (relevant information was not requested in the studies of ciprofloxacin and cefixime). Vaginal candidiasis was significantly more frequently associated with the use of the three 4-quinolones than with azithromycin and cefixime but it was frequently delayed until the week or two after the cessation of therapy. Within each event, as recorded in these studies, the highest event rates (the number of events per 1000 patients) in the week following the start of therapy were: 9.2 for diarrhoea with cefixime; 4.9 for nausea/vomiting with ofloxacin; 2.4 for rash with azithromycin; 2.2 for abdominal pain with norfloxacin; 1.5 for headache/migraine with ofloxacin; 1.4 for malaise/lassitude with ofloxacin; 1.2 for dizziness with norfloxacin. Uncommon events (reported in less than 1:1000 patients) included rare cases of allergic phenomena, convulsions and pseudomembranous colitis. There were no reports of tendinitis, tenosynovitis or tendon rupture in children but tendon disorders were reported in the two months following the start of treatment in 20 adults. A total of 307 pregnancies were reported. Thirty-eight of the 55 women who received these drugs during the first trimester of pregnancy gave birth to healthy babies. No congenital abnormalities were reported. Apart from one case of unconfirmed pseudomembranous colitis, none of the other 2468 deaths that occurred in these studies was attributed to the antibiotics. 5. These five antibiotics are acceptably safe antimicrobial agents when used in general medical practice. PEM is an effective method for monitoring the safety of recently introduced antimicrobial agents.

Publication Types:
PMID: 8730972 [PubMed - indexed for MEDLINE]

PMCID: PMC2042595


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Fluoroquinolone induced tendinopathy: report of 6 cases.

Zabraniecki L, Negrier I, Vergne P, Arnaud M, Bonnet C, Bertin P, Treves R.

CHRU Dupuytren, Department of Rheumatology, Limoges, France.

We describe 6 cases of fluoroquinolone induced Achilles tendinitis in 4 women and 2 men, mean age 68.6 years. Patients presented with pain and swelling of sudden onset, which was most often bilateral. Tendon rupture was frequent, accompanied by nodules and ecchymoses. The diagnosis was clinical, occasionally ultrasonography was helpful; the role of magnetic resonance imaging has yet to be defined. Certain risk factors were found, particularly association with longterm steroid therapy, and close surveillance of high risk subjects is mandatory. Although proper dosage and duration of treatment were respected, the principal fluoroquinolones were clearly incriminated. We found no correlation between treatment duration and the degree of involvement. Nevertheless, immediate discontinuation of the antibiotic and placement of both Achilles tendons at rest is essential. Early and appropriate management did not prevent prolonged recovery times and there was always a risk of functional sequelae. This side effect is class related and rare. Its physiopathologic mechanism is poorly understood.

Publication Types:
PMID: 8832995 [PubMed - indexed for MEDLINE]

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Comment in:
Fluoroquinolone antibiotics: tied to tendon ruptures.

Shuster J.

Publication Types:
PMID: 8684697 [PubMed - indexed for MEDLINE]

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[Bilateral Achilles tendon rupture caused by oral fluoroquinolones]

[Article in Finnish]

Mäki T, Heinäsmäki T, Riutta J, Tikkanen T, Laasonen L, Eklund K.

Department of Internal Medicine, Helsinki Central University Hospital, Helsinki, Finland.

Publication Types:
PMID: 10596182 [PubMed - indexed for MEDLINE]

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[Tendinopathy and fluoroquinolones]

[Article in French]

Castagnola C, Suhler A.

Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard-Herriot, Lyon.

Tendinopathies, essentially involving the Achilles tendon, which tendon rupture, can be secondary to treatment with fluoroquinolones, and facilitated by corticosteroid therapy, renal failure and sport. Fluoroquinolone treatment must therefore be prescribed cautiously and patients must be advised to stop treatment at the slightest warning signs of tendinitis.

Publication Types:
PMID: 8766149 [PubMed - indexed for MEDLINE]

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[Rupture of the long biceps tendon following ingestion of fluoroquinolone]

[Article in French]

Guérin B, Grateau G, Quartier G, Durand H.

Publication Types:
PMID: 8763095 [PubMed - indexed for MEDLINE]

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[Ciprofloxacin-associated bilateral acute achilles tendinitis]

[Article in Hebrew]

Mirovsky Y, Pollack L, Arlazoroff A, Halperin N.

Dept. of Orthopedics, Assaf Harofeh Medical Center, Zerifin.

Bilateral achilles tendinitis developed in a 40-year-old man following treatment with Ciprofloxacin, 500 mg twice a day, for prostatis. The signs of tendinitis resolved 6 weeks after cessation of the drug. In recent years very few cases of this rare complication have been reported. In some cases it results in a torn achilles tendon. If diagnosed early, complete recovery usually follows about 6 weeks after cessation of the drug.

Publication Types:
PMID: 8846955 [PubMed - indexed for MEDLINE]

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A reappraisal of quinolone tolerability. The experience of their musculoskeletal adverse effects.

Hayem G, Carbon C.

Clinique de Rhumatologie, CHU Bichat-Claude Bernard, Paris, France.

The experience of the rheumatological adverse effects of fluoroquinolones should be helpful for both toxicologists and epidemiologists. In the case of fluoroquinolone-related arthropathy, the paediatric clinical experience seems to support the possible use of newer derivatives like ciprofloxacin in children who really need it. This therapeutic attitude is still contradictory to the labelling of fluoroquinolones. Inversely, there has been an important time-lag between the first reports of fluoroquinolone-related tendinopathies and the official recognition of this unusual toxic phenomenon. This delay, along with the widespread use of fluoroquinolones, makes it difficult to return to more reasonable prescribing guidelines for these very useful and effective anti-microbial compounds. The reasons why potentially serious adverse effects of fluoroquinolones were not anticipated before their commercialisation may be related to the lack of adequate in vitro and in vivo models, and the unexpectedness of the events. When it occurs, fluoroquinolone-induced arthropathy is most frequently benign, and heals without sequelae. The prognosis is not so favourable in the case of fluoroquinolone-related tendinopathy, which carries an important risk of immediate or secondary tendon rupture. Increasingly, fluoroquinolones are being prescribed for benign infections of the urinary or bronchopulmonary tracts. Sometimes, they are even used for antimicrobial prophylaxis before surgical or endoscopic procedures. We believe that for any prescription, the risk/benefit ratio of the fluoroquinolones should be carefully considered, since better tolerated, less expensive drugs can usually be prescribed. Clear information dedicated both to physicians and patients regarding the cautions for use and possible adverse effects of fluoroquinolones would help reduce the risk and severity of adverse reactions. This is especially important for phototoxicity, tendinopathy and cardiovascular adverse effects. As underlined by Ball and Tillotson in this issue, the future clinical use of the fluoroquinolones will be determined by the balance between the antibacterial efficacy and adverse effects of these agents. The adverse reactions affecting the musculoskeletal system provide a good example of this dilemma. Given the absence of an adequate model of tendinopathy and the poor predictivity of animal manifestations in arthropathy and cartilage lesions in humans, careful monitoring of patients during phase II and III trials and, more importantly, long term pharmacovigilance during the postmarketing period, are still strongly warranted.

PMID: 8652078 [PubMed - indexed for MEDLINE]

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Histological examination on Achilles tendon lesions induced by quinolone antibacterial agents in juvenile rats.

Kato M, Takada S, Kashida Y, Nomura M.

Drug Safety Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.

We examined the effects of the quinolone antibacterial agents pefloxacin (PFLX) and ofloxacin (OFLX) on the Achilles tendon of Sprague-Dawley rats. A single oral administration of PFLX 300 and 900 mg/kg or OFLX 900 mg/kg induced edema with mononuclear cell infiltration mainly in the inner sheath of the inner Achilles tendon just proximal to the tuber calcanei in rats killed on the next day. Cell infiltration was also seen in the adjacent synovial membrane and joint space. With progression of severity, the lesions extended to the surface tendon tissue, wherein irregularly arranged collagen bundles were detached from each other and nuclei of fibroblasts were pyknotic and fragmented. After 2-wk repeated administration, these lesions were replaced by fibrotic foci with regenerated tendon fibroblasts, and the incidence and severity were reduced in the OFLX but not PFLX groups. Coadministration of cyclosporin A with OFLX 300 mg/kg induced these lesions despite the fact that neither induced lesions alone. The tendon lesions were induced in juvenile rats (4 wk of age) but not in young adults (12 wk). The articular cartilage of juvenile rats showed focal degeneration and/or cavitation in the tarsal joints after a single and 2-wk administration of PFLX or OFLX. Hydrocortisone slightly increased the incidence of OFLX-induced lesions in both the tendon and cartilage after a 2-wk administration. The occurrence of the tendon lesions is different from that of the Achilles tendon disorders reported in older humans, but they are thought to be a useful model for them.

PMID: 7659960 [PubMed - indexed for MEDLINE]

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Click here to read
Epicondylitis after treatment with fluoroquinolone antibiotics.

Le Huec JC, Schaeverbeke T, Chauveaux D, Rivel J, Dehais J, Le Rebeller A.

University of Bordeaux II, Hôpital Pellegrin, France.

We report two cases of epicondylitis of the elbow occurring after treatment with fluoroquinolone antibiotics. Both patients had intense pain which appeared very shortly after the first dose of the drug and was not relieved by conservative treatment. Ultrasonography revealed extensive inflammatory lesions with pseudonecrotic areas. MRI confirmed the lesions and also showed a subclinical abnormality of the adjoining tendons. The persistent nature of the pain was the indication for surgical release of the extensor mechanism. After operation pain disappeared completely and the patients were able to return to their normal activities. Lesions of the tendo Achillis are a well-known side-effect of treatment with fluoroquinolone. Our two cases show that such lesions may occur elsewhere. They also indicate the need for caution when prescribing these antibiotics to patients at risk of tendon lesions, such as top-level sportsmen or patients on dialysis or steroid treatment.

Publication Types:
PMID: 7706350 [PubMed - indexed for MEDLINE]

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Comment on:
More on fluoroquinolone antibiotics and tendon rupture.

Szarfman A, Chen M, Blum MD.

Publication Types:
PMID: 7800023 [PubMed - indexed for MEDLINE]

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Comment on:
More on fluoroquinolone antibiotics and tendon rupture.

Pierfitte C, Gillet P, Royer RJ.

Publication Types:
PMID: 7800022 [PubMed - indexed for MEDLINE]

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[Tendinopathies and fluoroquinolones: a public health problem? Value of drug monitoring studies]

[Article in French]

Pierfitte C.

Centre de Pharmacovigilance de Lorraine, Nancy.

PMID: 8665625 [PubMed - indexed for MEDLINE]

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Magnetic resonance imaging may be an asset to diagnose and classify fluoroquinolone-associated Achilles tendinitis.

Gillet P, Blum A, Hestin D, Pourel J, Pierfitte C, Mainard D, Kessler M, Netter P.

Department of Pharmacology, URA CNRS, Vandoeuvre-lès-Nancy, France.

The aim of this study was to document the accuracy of magnetic resonance imaging (MRI) during fluoroquinolone-associated Achilles tendinitis. Fourteen Achilles tendons were examined by MRI (T1 and T2 or T2*-weighted sequences) in nine patients with typical tendinopathy (13 cases of tendinitis and 1 rupture) during fluoroquinolone therapy. Tendinous involvement was classified according to the prominence of intra- or peritendinous changes. The most typical feature was the presence of intratendinous changes, longitudinal or transversal, detected on T1 or T2-weighted sequences. Peritendinitis was most visible in two cases and nodular involvement in three cases. It was concluded that MRI appears a helpful and accurate method in identifying and classifying such iatrogenic tendinitis. In addition, MRI indicates orthopedic management when detecting risk of rupture.

PMID: 7768488 [PubMed - indexed for MEDLINE]

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Mycobacterium phlei infection of the foot: a case report.

Spiegl PV, Feiner CM.

A case of Mycobacterium phlei infection in the flexor digitorum longus and posterior tibialis tendon of an otherwise healthy adult male is reported. To our knowledge, this is the second reported case in the English literature of human infection by M. phlei. Diagnosis and treatment of nontuberculous mycobacterial infection are discussed. The clinician is encouraged to include this infection in the differential diagnosis of pain and swelling in the extremity.

Publication Types:
PMID: 7894643 [PubMed - indexed for MEDLINE]

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[Epicondylitis induced by fluoroquinolones in athletes. Apropos of 2 cases]

[Article in French]

Le Huec JC, Schaeverbeke T, Chauveaux D, Moinard M, Rivel J, Le Rebeller A.

Service de Rhumatologie, CHU Pellegrin, Université de Bordeaux II.

Epicondylitis occurred in two leisure athletes who were taking fluoroquinolones. No similar cases have been reported in the literature. In both cases, pain occurred early after initiating drug therapy. Pain was intense and was not controlled by usual care. Echography demonstrated major inflammatory lesions with pseudo-necrosis. Magnetic resonance imaging confirmed the lesions and gave evidence of infraclinical lesions of the adjacent tendons. Surgical disinsertion of the epicondyles with biopsy was indicated due to the persistent pain. Histological examination revealed unspecific lesions of hyalin degeneration and a few giant cells in one case. Pain disappeared after surgery and the patients were able to return to their work, but neither was able to continue his sports activity. Lesions of the Achilles tendon have been observed in patients taking fluoroquinolone and the two cases reported here confirm the possibility of other localizations. Care must therefore be taken when prescribing these antibiotics in patients at risk (dialysis patients, those on corticosteroids, high-performance athletes).

Publication Types:
PMID: 7860672 [PubMed - indexed for MEDLINE]

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Fluoroquinolones and Achilles tendinopathy in renal transplant recipients.

Donck JB, Segaert MF, Vanrenterghem YF.

Department of Nephrology, University Hospital Gasthuisberg, Leuven, Belgium.

PMID: 7940700 [PubMed - indexed for MEDLINE]

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Comment in:
Achilles tendinitis and tendon rupture due to fluoroquinolone antibiotics.

Huston KA.

Publication Types:
PMID: 8058092 [PubMed - indexed for MEDLINE]

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[Tendinitis due to fluoroquinolones. Description of 2 cases]

[Article in Spanish]

Hernández MV, Peris P, Sierra J, Collado A, Muñoz-Gómez J.

Servicios de Reumatología, Hospital Clínic i Provincial, Barcelona.

Two patients with tendinitis by ciprofloxacin are described. In both patients isolated involvement of the Aquilles tendon was produced. The symptoms initiated at 2 to 4 weeks of the beginning of treatment. The two patients had undergone chemotherapy and bone marrow transplantation due to chronic myeloid leukemia and acute promyelocytic leukemia, respectively with no data on recurrence of leukemia being obtained at the time of the tendinitis. Suppression of ciprofloxacin achieved disappearance of the symptomatology.

Publication Types:
PMID: 7934295 [PubMed - indexed for MEDLINE]

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[Tendinitis of the Achilles tendon caused by pefloxacin and other fluoroquinolone derivatives]

[Article in Dutch]

Dekens-Konter JA, Knol A, Olsson S, Meyboom RH, de Koning GH.

Registratie Evaluatie Bijwerkingen, Apotheek AZG, Groningen.

Four cases were reported to the Netherlands Pharmacovigilance Foundation LAREB of Achilles tendinitis, as a suspected adverse reaction to pefloxacin; the patients were two men of 64 years old, one of 33 and one of 76 years old. More than twenty cases of tendinitis have previously been described in the literature in association with pefloxacin and various other fluoroquinolone derivatives; tendon rupture was a frequent complication. In the data base of the WHO Collaborating Centre for International Drug Monitoring tendon disorders are a very rare reaction, with the exception of fluoroquinolone derivatives. More information is needed with regard to the frequency of tendinopathy during the use of pefloxacin and the other drugs in this group. Achilles tendon rupture is an serious condition, often requiring surgical treatment. Patients using a fluoroquinolone derivative should be informed of the risk of developing tendinitis and tendon rupture.

Publication Types:
PMID: 8139714 [PubMed - indexed for MEDLINE]

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[What is your diagnosis? Bilateral Achilles tendinitis associated with quinolone treatment]

[Article in German]

Van Linthoudt D, D'Oro A, Ott H.

Service de rhumatologie, Hôpital communal La Chaux-de-Fonds.

Publication Types:
PMID: 8134743 [PubMed - indexed for MEDLINE]

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Features of tendon disorders with fluoroquinolones.

Royer RJ, Pierfitte C, Netter P.

Service de Pharmacologie Clinique, CHU Nancy CO 34.

PMID: 8091374 [PubMed - indexed for MEDLINE]

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[Spontaneous ruptures of the Achilles tendon after kidney transplantation: use of fluoroquinolones]

[Article in French]

Leray H, Mourad G, Chong G, Marcelli C, Borderie P, Mion C.

Publication Types:
PMID: 8309916 [PubMed - indexed for MEDLINE]

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[Tendinopathy caused by ciprofloxacin with possible partial rupture of Achilles tendon]

[Article in French]

Boulay I, Farge D, Haddad A, Bourrier P, Chanu B, Rouffy J.

Publication Types:
PMID: 8141519 [PubMed - indexed for MEDLINE]

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Ciprofloxacin associated bilateral achilles tendon rupture.

Lee WT, Collins JF.

Department of Medicine, Auckland Hospital, New Zealand.

Publication Types:
PMID: 1445042 [PubMed - indexed for MEDLINE]

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Seven Achilles tendinitis including 3 complicated by rupture during fluoroquinolone therapy.

Ribard P, Audisio F, Kahn MF, De Bandt M, Jorgensen C, Hayem G, Meyer O, Palazzo E.

Department of Rheumatology, Medical School Xavier-Bichat, Hôpital Bichat, Paris, France.

We describe 7 Achilles tendinitis occurring during fluoroquinolone treatment. Antibiotic agents used were pefloxacin and ofloxacin. In 3 cases the course was complicated by rupture of the tendon, one of which is histologically documented. The toxic effects of quinolones on tendon is discussed.

PMID: 1433021 [PubMed - indexed for MEDLINE]

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Ciprofloxacin in the treatment of Mycobacterium fortuitum infection of the peroneal tendons. A case report.

Binning TA, Karlin JM, Klein D, Scurran BL, Cooke RA.

Department of Podiatric Surgery, Kaiser Permanente Medical Center, Oakland, CA 94611-5693.

In the case reported, M. fortuitum was sensitive in vitro to amikacin, erythromycin, tobramycin, and ciprofloxacin. Because the patient did not respond to long-term therapy with amikacin and erythromycin, an experimental antibiotic, ciprofloxacin, was tried. Only after extensive surgical debridement and 2 1/2 months of oral ciprofloxacin therapy was the infection eradicated and wound healing obtained. The authors conclude that a wound that has reopened, but remains indolent, exudes a clear, serous drainage and responds poorly to antibiotics should suggest a possible mycobacterial infection. Combination antibiotic therapy is recommended because of the high rate of relapse and development of resistance to drugs. Extensive surgical debridement of all infected tissue remains the primary treatment. The therapeutic value of ciprofloxacin and other newer antibiotics in the treatment of mycobacterial infection is promising.

Publication Types:
PMID: 1432657 [PubMed - indexed for MEDLINE]

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[Tendon rupture and fluoro-quinolones: an undesirable effect of drug selection]

[Article in French]

Chaslerie A, Bannwarth B, Landreau JM, Yver L, Begaud B.

Publication Types:
PMID: 1496284 [PubMed - indexed for MEDLINE]

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[3 cases of Achilles tendinitis caused by pefloxacin, 2 of them with tendon rupture]

[Article in French]

Perrot S, Kaplan G, Ziza JM.

Publication Types:
PMID: 1604233 [PubMed - indexed for MEDLINE]

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[Achilles tendinitis induced by pefloxacin. Apropos of 2 cases]

[Article in French]

Blanche P, Sereni D, Sicard D, Christoforov B.

Publication Types:
PMID: 1482040 [PubMed - indexed for MEDLINE]

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[Achilles tendon rupture in 2 adults treated with pefloxacin, one of the cases with bilateral involvement]

[Article in French]

Franck JL, Bouteiller G, Chagnaud P, Sapene M, Gautier D.

Publication Types:
PMID: 1780680 [PubMed - indexed for MEDLINE]

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[Arthropathy with achilles tendon involvement induced by pefloxacin. Apropos of a case]

[Article in French]

Jorgensen C, Anaya JM, Didry C, Canovas F, Serre I, Baldet P, Ribard P, Kahn MF, Sany J.

Service d'Immuno-Rhumatologie, Centre Gui-de-Chauliac, Montpellier.

Publication Types:
PMID: 1775911 [PubMed - indexed for MEDLINE]

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[Ciprofloxacin in the prevention and treatment of surgical infections]

[Article in Russian]

Iakovlev VP, Blatun LA, Khlebnikov EP, Makarenkova RV, Elagina LV, Puchkova LS, Kutsidi EV.

A clinico-laboratory study on ciprofloxacin made by Bayer (Germany) was applied to patients with extended posttraumatic wounds and performed with the aim of preventing postoperative purulent complications in patients operated on the organs of the gastrointestinal tract. In the both groups ciprofloxacin was administered orally in doses of 500 and 1000 mg and intravenously in a dose of 200 mg. The results of the assay on ciprofloxacin sensitivity of the isolates from the wound excretion and urine showed that they were more sensitive to ciprofloxacin than to aminoglycosides and cephalosporins. 15 minutes after the intravenous administration the serum concentration of ciprofloxacin amounted to 7.5 +/- 0.9 micrograms/ml and in 6 hours it was equal to 0.45 +/- 0.45 micrograms/ml, the mean concentrations of ciprofloxacin being attained in the bile (8.7 +/- +/- 3.9 micrograms/ml), gallbladder wall (5.5 +/- 3.8 micrograms/g), liver (0.73 micrograms/g), muscles (1.93 micrograms/g) and tendon (0.15 microgram/g). After the oral administration in a dose of 500 mg ciprofloxacin was detected in the blood serum in an amount of 2.0 +/- 0.7 micrograms/ml in 1 hour and in an amount of 0.9 +/- 0.13 micrograms/ml in 6 hours. After the drug oral administration in a dose of 1000 mg the maximum concentrations were: 6.34 +/- 4.2 micrograms/ml on the average and 2.1 +/- 0.8 micrograms/ml in 6 hours (0.4 micrograms/g in the muscles, 1.4 micrograms/g in the skin and 0.34 micrograms/g in the bones). The study showed that ciprofloxacin was a highly efficient antimicrobial agent in the treatment of the complicated wound infections and the prophylaxis of the purulent complications during the postoperative period in the patients operated on gastrointestinal organs.

Publication Types:
PMID: 1781714 [PubMed - indexed for MEDLINE]

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[Article in French]

Perrot S, Ziza JM, De Bourran-Cauet G, Desplaces N, Lachand AT.

Publication Types:
PMID: 1831902 [PubMed - indexed for MEDLINE]

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