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Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for Usage in the Athletic Population
Abstract
Fluoroquinolone antibiotics are associated with a wide spectrum of musculoskeletal complications that involve not only tendon but also cartilage, bone, and muscle. Insights into the pathoetiology of fluoroquinolone toxicity on musculoskeletal tissues have been evolving over recent years. Although the pathoetiology is certainly multifactorial, alterations in cell signaling proteins and direct toxic effects on musculoskeletal tissues have been strongly implicated. Increasing age and concomitant systemic corticosteroid use appear to significantly increase the risk of adverse events. The purpose of this article is to review the musculoskeletal complications associated with use of fluoroquinolone antibiotics by adults; identify risk factors associated with fluoroquinolone toxicity; explore the possible pathoetiology of fluoroquinolone toxicity on tendon, cartilage, bone, and muscle; and offer recommendations regarding evaluation and treatment of fluoroquinolone-associated musculoskeletal complications. In addition, this review will provide recommendations regarding fluoroquinolone use in athletes and return to play after fluoroquinolone exposure.
... Fluoroquinolone. Fluoroquinolone antibiotics are employed to manage a series of infections, such as those of the urinary, respiratory, and gastrointestinal tracts, as well as those of the skin, bones, and joints [30]. Despite the fact that the etiology of fluoroquinoloneassociated muscle disorders is yet to be completely clarified, there is evidence of an interplay between latent myopathy disorders and the fluorine atom in fluoroquinolones [30]. ...
... Fluoroquinolone antibiotics are employed to manage a series of infections, such as those of the urinary, respiratory, and gastrointestinal tracts, as well as those of the skin, bones, and joints [30]. Despite the fact that the etiology of fluoroquinoloneassociated muscle disorders is yet to be completely clarified, there is evidence of an interplay between latent myopathy disorders and the fluorine atom in fluoroquinolones [30]. ...
... Consistent with this view, myalgia represents the most common adverse effect of fluoroquinolone administration [30]. Symptoms, which typically consist of diffuse muscle pain with or without weakness [30] with perhaps a preference for proximal muscle groups [30], appearing within 1 week of fluoroquinolone treatment [30] and often resolving within 1-4 weeks of the discontinuation of the drug [30] despite the persistence of symptoms for up to 6 months, have been described [30]. ...
It is widely recognized that athletes consume oral antibiotics almost twice as often as observed in the non-sports population in order to reduce as much as possible the period of inactivity due to bacterial diseases. However, increasing evidences have demonstrated the ability of some classes of antibiotics to induce muscle weakness, pain, and a feeling of fatigue upon resuming physical activity conditions that considerably limit the athletic performance of athletes, ascribable to alterations in the biochemical mechanisms underlying normal musculoskeletal activity, such as mitochondrial respiration. For this reason, tailoring a treatment plan for effective antibiotics that limit an athlete’s risk is paramount to their safety and ability to maintain adequate athletic performance. The present review illustrates and critically analyzes the evidence on the use of antibiotics in sports, deepening the molecular mechanisms underlying the onset and development of muscle–tendon alterations in athletes as well as delineating the pharmacological strategies aimed at counteracting such adverse events.
... To date, several scientific peer reviews on CIP and ENR have been published, including a review of ENR for veterinary use (Trouchon and Lefebvre 2016), a clinical review of musculoskeletal complications of FQs along with guidelines and precautions for usage in athletes (Hall et al. 2011), CIP cardiotoxicity and hepatotoxicity in humans and animals (Adikwu and Brambaifa 2012), a mini-review on toxic tendinopathy (Bolon 2017), an overview of FQs and tendinopathy focused on athletes and sports clinicians (Lewis and Cook 2014) and one on FQ-induced liver injury (Licata et al. 2012). ...
... In animals, quinolone-class drugs have been associated with cartilage erosions in weightbearing joints and other forms of arthropathy in immature animals of various species. Thus, it has been advised to not use ENR either in young and growing animals or with standing cartilage development disorders or musculoskeletal injury around functionally significant joints even at therapeutic doses (Hall et al. 2011;Khazaeil et al. 2012). ...
... Many research articles have concluded that OS-mediated mitochondrial damage is the core of FQ toxicity (Barnhill et al. 2012;Correia et al. 2017;Michalak et al. 2017). ROS contribute to tendon toxicity through direct toxic effects and via MMP induction (Hall et al. 2011). The possible molecular mechanisms related to CIP-associated tendinopathy: (i) cyclin B and cyclin-dependent kinase 1 downregulation and subsequent inhibition of cell proliferation and cell cycle arrest in the G2/M phase; (ii) inhibition of tenocyte migration by downregulation of focal adhesion kinase phosphorylation; and (iii) induction of MMP-2 activity with collagen type I degradation via indirect ROS effect ( Figure 4) (Tsai and Yang 2011;. ...
Ciprofloxacin (CIP) (human use) and enrofloxacin (ENR) (veterinary use) are synthetic anti-infectious medications that belong to the second generation of fluoroquinolones. They have a wide antimicrobial spectrum and strong bactericidal effects at very low concentrations via enzymatic inhibition of DNA gyrase and topoisomerase IV, which are required for DNA replication. They also have high bioavailability, rapid absorption with favorable pharmacokinetics and excellent tissue penetration, including cerebral spinal fluid. These features have made them the most applied antibiotics in both human and veterinary medicine. ENR is marketed exclusively for animal medicine and has been widely used as a therapeutic veterinary antibiotic, resulting in its residue in edible tissues and aquatic environments, as well as the development of resistance and toxicity. Estimation of the risks to humans due to antimicrobial resistance produced by CIP and ENR is important and of great interest. Moreover, in rare cases due to their overdose and/or prolonged administration, the development of CIP and ENR toxicity may occur. The toxicity of these fluoroquinolones antimicrobials is mainly related to reactive oxygen species (ROS) and oxidative stress (OS) generation, besides metabolism-related toxicity. Therefore, CIP is restricted in pregnant and lactating women, pediatrics and elderly similarly ENR do in the veterinary field. This review manuscript aims to identify the toxicity induced by ROS and OS as a common sequel of CIP and ENR. Furthermore, their metabolism and the role of metabolizing enzymes were reported.
... It has been reported that patients receiving fluoroquinolones (FQs) as part of ATT may manifest joint pain/ arthralgias. FQs are known to cause arthralgia, tendonitis, and even tendon rupture [6][7][8][9]. We observed some of these reactions in patients receiving FQs in the form of levofloxacin (Lfx) or moxifloxacin (Mfx). ...
... The exact mechanism of FQ-associated arthralgia is not clear. FQs exert toxic effects on tendons, cartilage, bone, and muscle [9]. In vitro studies have suggested that FQs may contribute to tendinopathies by inhibiting collagen maturation, reducing cell stability, and directly degrading matrix [23]. ...
... In vitro studies have suggested that FQs may contribute to tendinopathies by inhibiting collagen maturation, reducing cell stability, and directly degrading matrix [23]. They also stimulate reactive oxygen species resulting in tendon toxicity along with changes in signaling protein function leading to alterations in cell regulation and repair [9]. These factors may also be spec-ulated to cause arthralgia. ...
Background:
Joint pain is frequently observed in patients on antituberculous treatment, and pyrazinamide is known to be associated with joint pain in patients receiving antituberculous treatment. Fluoroquinolone-associated joint pain and tendon injury have been reported in long-term corticosteroid and transplant recipients, but data are lacking in patients with tuberculosis.
Objectives:
The objective of this study was to examine the incidence of joint pain manifested during administration of antituberculous therapy and their association with fluoroquinolones.
Methods:
Patients diagnosed with tuberculosis attending the outpatient clinic over a period of 1 year were reviewed and divided into 3 groups: group A receiving pyrazinamide, group B receiving a fluoroquinolone, and group C receiving both pyrazinamide and a fluoroquinolone. Latency to onset of joint pain was noted in all 3 groups. Joint pain was initially managed with analgesics, and associated hyperuricemia was treated with allopurinol/febuxostat. Causative drugs were stopped in case of intolerable joint pain.
Results:
260 patients (47% females, aged 38 ± 18 years; mean ± SD) were included [group A (n = 140), group B (n = 81), and group C (n = 39)]. Overall, 76/260 (29%) patients developed joint pain: group A - 24/140 patients (17%), group B - 32/81 patients (40%), and group C - 20/39 patients (51%). The median latency to the onset of joint pain was 83 days (interquartile range, IQR 40-167): 55 days (IQR 32-66) in group A, 138 days (IQR 74-278) in group B, and 88 days (IQR 34-183) in group C. Hyperuricemia was present in 12/24 (50%) patients in group A and 11/20 (55%) patients in group C. Pyrazinamide was stopped in 7/140 (5%) patients in group A, fluoroquinolones in 6/81 (7%) patients in group B, and both pyrazinamide and fluoroquinolones were stopped in 5/39 (13%) patients in group C because of intolerable joint pain. Major joints affected were knees and ankles.
Conclusion:
There is a high incidence of joint pain in patients receiving antituberculous treatment, which is higher when fluoroquinolones or the pyrazinamide-fluoroquinolone combination are administered as compared to pyrazinamide alone.
... Among all possible events associated with FQ treatment, those from the musculoskeletal system are the most commonly discussed in the literature [5]. ...
... Most cases reported in the literature relate to tendon damage -inflammation, degeneration or rupture of the tendons. Several risk factors for tendinopathy have been identified, and the most important include: age over 60 years, long-term glucocorticoid therapy, sport activities, history of rheumatic diseases, diabetes, renal impairment and hemodialysis and organ transplants [5][6][7][8] (Table I). ...
... It is the best known and the easiest test, which was performed in our patient and was positive in the affected area. As many as 50% of reported cases manifested bilateral symptoms, but at the same time up to 50% of tendon rupture cases may not be preceded by any heraldic symptom [5,7]. ...
The authors report a case of a 67-year-old woman with giant cell arteritis with acute Achilles tendon rupture, which occurred after 3 days of levofloxacin therapy introduced because of newly diagnosed erosive gastritis associated with Helicobacter pylori infection. The Achilles tendon rupture was surgically treated and the patient made a complete recovery. In view of the widespread use of levofloxacin in practice, this case report raises important clinical implications. Tendinopathies are a known complication, quite rare in the healthy population, but the risk of rupture significantly increases in the population of patients over 60 years of age, with chronic usage of glucocorticosteroids, impaired renal function and recipients of organ transplants. What needs underlining, there are also described differences between individual fluoroquinolones as a cause of tendon damage in this group.
Considering the widespread use of this group of drugs in patients, knowledge about the risk of adverse events including tendinopathy promotes safe use of fluoroquinolones.
... Relatively, human Achilles tendon has little to no vasculature for itself [13] and is nurtured ultimately by permeation from the peripheral tissues suggesting that once a Fluoroquinolone has reached its peak concentration, it is likely to reside semi-permanently in tendon tissue and be harmful due to its prolonged residency. This may explain the higher prevalence of Achilles tendon incidents in diabetic and aged patients, who also suffer from a decreased circulatory network in Achilles tendon [13][14][15][16][17]. ...
... Levofloxacin-associated tendinopathy, similar to other Fluoroquinolones, is a widely recognized event that eventually led the US Food and Drug Administration to add a black box warning label citing the risk of tendonitis and tendon rupture [15]. Pharmacokinetic studies have Pharmacokinetic Prediction of Levofloxacin Accumulation in Tissue and Its Association to Tendinopathy 128 been studied to address issues such as drug interaction, systemic availability and disposition of Levofloxacin in healthy adults, the elderly and patients with renal impairment [25]. ...
... PP Pharmacokinetic Prediction of Levofloxacin Accumulation in Tissue and Its Association to Tendinopathy 129 in agreement with reported cases of Achilles tendonitis and ruptures, where most of the symptoms were reported when patients were walking or involved in sporting activities. Halting the use of Levofloxacin together with resting alone or resting in combination with supportive treatments can relieve, prevent or reduce the severity of adverse events [7,15,46,48]. In fact, histological studies have observed that the pathological features found in tendon disorders produced by Fluoroquinolones are similar to those seen in excessive exercise injuries in athletes, suggesting that rapid and immense stretching activities may in part play a significant role in the incidents [46,49]. ...
Objectives: We investigated pharmacokinetic tissue distributions of Levofloxacin to explain adverse tendon incidents. Methods: The pharmacokinetic profiles of single and multiple dosing of 500 mg Levofloxacin following oral and IV infusion administration were simulated. Monte Carlo simulation was used to simulate the drug concentration profiles in plasma and tissue after seven dosing regimens while varying the drug's elimination and distribution rates to analyze the effects of changing those rates on Levofloxacin accumulation in tissue. Results: Simulated data following oral and IV administration reflect well the reported data (mean simulated plasma Cmax = 6.59 μg/mL and 5.19 μg/mL for IV and oral versus 6.4 μg/mL and 5.2 μg/mL for observed clinical IV and oral route, respectively). Simulations of seven repetitive doses are also in agreement with reported values. Low elimination rates affect the drug concentration in plasma and tissue significantly with the concentration in plasma rising to 35 μg/mL at day 7. Normal elimination rates together with escalation of distribution rates from plasma to tissue increase tissue concentration after 7 doses to 9.5 µg/mL, a value is more than twice that of normal. Conclusions: Simulation can be used to evaluate drug concentration in different tissues. The unexpectedly high concentrations in some cases may explain the reason for tendinopathy in clinical settings.
... Some fetal skeletal malformations were recorded such as impaired ossification of the skull, absence of sternebrae, absence of digit's bone of fore and hind limb, and absence of some metacarpal and metatarsal bone, reduction or absence of caudal vertebrae. This result agrees with that reported by many investigators [52,53], Also, with the administration of ofloxacin to pregnant female rats and rabbits [35], administration of levofloxacin to rats [15,17], and administration of fluoroquinolones (DW-116) to the pregnant rats and rabbits, respectively [53,54] These results can be explained by the association of fluoroquinolones with a wide range of musculoskeletal complications that include not only tendons but also cartilage, bone, and muscle. [54], and that these effects are associated with irreversible bone damage and growth inhibition. ...
... This result agrees with that reported by many investigators [52,53], Also, with the administration of ofloxacin to pregnant female rats and rabbits [35], administration of levofloxacin to rats [15,17], and administration of fluoroquinolones (DW-116) to the pregnant rats and rabbits, respectively [53,54] These results can be explained by the association of fluoroquinolones with a wide range of musculoskeletal complications that include not only tendons but also cartilage, bone, and muscle. [54], and that these effects are associated with irreversible bone damage and growth inhibition. These effects may 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 [55] also, Arora stated that bone and cartilage damage can be caused by fluoride accumulation with frequent administration of fluoroquinolones [56]. ...
Aim. The present study aims to evaluate the risk of the ciprofloxacin drug on the development of fetuses of the albino rat during pregnancy. Method. Pregnant rats were exposed orally to 206 mg kg-1 of coumatetralyl daily on days 5 through 20 of gestation. Animals were sacrificed on the 20th day of gestation for fetal examination. Results. Ciprofloxacin produced a significant elevation in the percentages of late resorption sites and dead fetuses compared with the control group. The mean fetal weights were significantly reduced. Visceral abnormalities were revealed in the form of dilated brain ventricles, hypertrophy of the heart, hypoplasia of the lung, dilated renal pelvis. Skeletal examination showed wide open fontanel, incomplete ossification of parietal and interparietal bones, incomplete ossification of the sternum, reduction in the number, or even complete absence of phalanges, sacral, and/or caudal vertebrae. Conclusion. The results indicate that ciprofloxacin has a teratogenic effect at lower doses. Therefore, further studies are necessary to evaluate its safety during pregnancy.
... Other risk factors like age, repeated trauma due to sports activities, or steroid therapy may impair the repair process of the tendon, thus, increasing the risk of tendinopathy in this group of patients. 6,14 The tendinopathy usually presents with acute or subacute onset of pain and swelling over the tendon. Together with a history of recent consumption of fluoroquinolones and absence of other obvious causes of the tendinopathy, the diagnosis can be established. ...
... Athletes who are prescribed with fluoroquinolones should be advised to alter their training regimen (reduction in high-intensity and ballistic activities, decrease in total training volume) during the course of the antibiotics. 14 ...
We report a case of Achilles tendinitis after intake of ciprofloxacin for treatment of respiratory tract infection. Fluoroquinolone-induced tendinopathy is an uncommon but increasingly recognised adverse effect of this antibiotic class. Most of the cases occur in the Achilles tendon and may lead to tendon rupture. Possible predisposing risk factors include use of steroid, patients with renal impairment or renal transplant, old age, and being an athlete. The drug should be stopped once this condition is suspected. Symptomatic treatment should be given and orthopaedic referral is desirable if tendon rupture occurs.
... For example, acetylcholine esterase (AChE) activity was severely depressed in muscles of catfish exposed to enorxacin, which suggests a potential neurotoxic effect of enorxacin in fish [5]. Similarly, Hall and coworkers reported that fluoroquinolone antibiotics were associated with a wide array of musculoskeletal complications in tendon, cartilage, bone, and muscle tissues [6]. In detoxification metabolism, DKAs can induce glutathione (GSH) production at the end of the hatching period, as well as inhibit superoxide dismutase (SOD) activities [7]. ...
... DKAs are detected in many environmental matrices where they create a ''pseudo-persistent'' phenomenon due to their large dosages and frequent application [2,3]. Although trace level DKA exposure does not cause direct and acute effects, long-term exposure in aquatic ecosystem leads to chronic toxicological effects on aquatic organism and human health [5,6]. The presence of many DKAs coexisting in the environment poses an especially large threat to organisms throughout the environment. ...
β-Diketone antibiotics (DKAs) can produce chronic toxicity in aquatic ecosystems due to their pseudo-persistent in the environment. In this study, after long-term DKA exposure to zebrafish (Danio rerio), 47 protein spots had greater than 2-fold differential expression as compared to the control; there were 26 positive proteins with 14 up-regulated and 12 down-regulated. The main functions of the differentially expressed proteins were related to signal transduction mechanisms and the cytoskeleton. Of the 26 target genes, 11 genes were consistent between their transcriptional and translational levels. Low dose DKA exposure (4.69 and 9.38 mg/L) stimulated spontaneous movement in zebrafish. Changes in both creatine kinase activity and creatine concentration showed a similar trend to zebrafish activity. There was no obvious change in SV-BA after DKA exposure, while a reduction of heart rate was concomitant with increasing DKA concentrations. DKAs also induced severe histopathological changes in zebrafish heart tissue, such as dissolution of cristae and vacuolation of mitochondria. These results demonstrated that trace-level DKA exposure affects a variety of cellular and biological processes in zebrafish.
... 49,55,56,61 This risk should be discussed with athletes, and alternative antibiotics might be considered if appropriate. 20,57,61 CardIaC arrhyThmIas Cardiac effects from antibiotics may have significant consequences regarding participation and safety. Macrolides are a popular class of antibiotics used for a variety of mild to moderate bacterial infections. ...
... Rates of antibiotic-associated diarrhea from multiple studiesSORT: Strength of Recommendation TaxonomyA: consistent, good-quality patient-oriented evidence B: inconsistent or limited-quality patient-oriented evidence C: consensus, disease-oriented evidence, usual practice, expert opinion, or case series Fluoroquinolones should be discouraged in patients over 60 years on corticosteroids, if appropriate alternatives are available, to reduce risk of tendon injury.12,22,49,55,56,57,61 Fluoroquinolones should be avoided in athletes unless medically necessary.20,57,61 ...
Context:
Antibiotics are the mainstay of treatment for bacterial infections in patients of all ages. Athletes who maximally train are at risk for illness and various infections. Routinely used antibiotics have been linked to tendon injuries, cardiac arrhythmias, diarrhea, photosensitivity, cartilage issues, and decreased performance.
Evidence acquisition:
Relevant articles published from 1989 to 2012 obtained through searching MEDLINE and OVID. Also, the Food and Drug Administration website was utilized.
Study design:
Clinical review.
Level of evidence:
Level 3.
Results:
The team physician should consider alternative medications in place of the "drug of choice" when adverse drug effects are a concern for an athlete's health or performance. If alternative medications cannot be selected, secondary preventative measures, including sunscreen or probiotics, may be needed.
Conclusion:
Physicians choose medications based on a variety of factors to help ensure infection resolution while limiting potential side effects. Extra precautions are indicated when treating athletes with certain antibiotics.
... Medication use should impact therapeutic decision-making by manual therapists. Medication use should affect therapeutic decisions made by manual therapists, such as whether to avoid intense exercise or deep tissue mobilization [96][97][98][99][100][101][102]. ...
... For instance, researchers reported that fluoroquinolones could cause serious tendinopathy via underlying toxic effects on proteoglycan synthesis in tendons (Khaliq & Zhanel, 2005). Hall et al. (2011) reported that fluoroquinolones exerted adverse effects on musculoskeletal tissues by inducing alterations of cell-signaling pathways and its direct toxicity, related to arthralgia, cartilage lesions, myalgia, and rhabdomyolysis, in addition to tendon disorders. ...
Emerging studies have shown that environmental contaminants were related to decreased handgrip strength. Nevertheless, no prior research has investigated the relationship of exposure to environmental antibiotics with grip strength. Thus, we explored the relationship between urinary antibiotic burden and grip strength among the elderly in China. This study consisted of 451 men and 539 women from the baseline survey of a cohort study. Commonly used antibiotics for humans and animals were detected in 990 urine samples through a biomonitoring method. Grip strength was measured by an electronic dynamometer. We examined the associations of antibiotic exposure with low grip strength (LGS), grip strength, and grip strength index, respectively. Results suggested that 34.9% of participants developed LGS, and 93.0% of individuals were exposed to 1–10 antibiotics. Among women, oxytetracycline (Quartile 2: odds ratio: 2.97, 95% confidence interval: 1.36–6.50), florfenicol (Quartile 3: 2.60 [1.28–5.27]), fluoroquinolones (Quartile 4: 1.88 [1.07–3.30]), and chloramphenicols (Quartile 3: 2.73 [1.35–5.51]) could enhance LGS risk. Among men, ofloxacin (Quartile 2: 3.32 [1.45–7.59]) increased LGS risk, whereas tetracycline (Quartile 2: 0.31 [0.11–0.88]) was implicated in reduced LGS risk. In participants < 70 years, ofloxacin (Quartile 2: 3.00 [1.40–6.42]) could increase LGS risk. For participants who were 70 years of age or older, veterinary antibiotics (Quartile 3: 1.73 [1.02–2.94]) were linked to a 73% increased risk of LGS. Our findings suggested that antibiotics mainly pertained to LGS, and there were gender and age disparities in associations between antibiotic exposure and muscle strength indicators in the elderly Chinese population.
... This involves the creation of breaks in the retinal layer with or without separation from its underlying tissues, with the subsequent loss of blood and oxygen supply, which requires urgent medical attention to avoid loss of vision [24,26]. A possible mechanism for quinolone involvement in RD involves their ability to destroy the collagen content of the vitreous, with the resulting separation of the retina from the underlying tissues, a mechanism that resembles their damaging effect on collagen and connective tissues in joints and muscles, which led to a classwarning for possible tendon rupture [24,[27][28][29][30][31][32][33]. ...
Background
Quinolones are popular antibiotics that are known for their potency, broad coverage, and reasonable safety. Concerns have been raised about a possible association between quinolones and retinal detachment (RD).
Methods
We conducted a nested case–control study using electronic health records (EHR) from the Health Facts® Database. The initial cohort included all patients who were admitted between 2000 and 2016, with no history of eye disease, and had a minimum medical history of one year. Eligible cases comprised inpatients who were first admitted with a primary diagnosis of RD between 2010 and 2015. Each eligible case was matched without replacement to five unique controls by sex, race, age, and period-at-risk. We used conditional logistic regression to calculate RD risk, adjusting for exposure to other medications, and major risk factors.
Results
We identified 772 cases and 3860 controls. Whereas our primary analysis of all subjects revealed no quinolone-associated RD risk, elevated but non-significant risks were noted in African Americans (ciprofloxacin and levofloxacin), those aged 56–70 years old (moxifloxacin), and women (ciprofloxacin).
Conclusion
Our study did not identify an elevated RD risk within 30 days following systemic administration of quinolone antibiotics. Suggestions of increased risk observed in some population subgroups warrant further investigation.
... properties, and a higher treatment failure rate when compared to fluoroquinolones. These are contraindicated in pregnancy as well and should not be used in children younger than 12 years of age due to their negative effects on cartilages and tendons (Caspar et al., 2018;Hall et al., 2011;Tezer et al., 2015). Some studies, however, have shown fluoroquinolones to be safe in children (Karli et al., 2018). ...
Although Francisella (F.) tularensis is a well-described and understood zoonotic pathogen, its importance in Central Europe is relatively minor and, as such, tularaemia may be missed in the differential diagnosis. The annual incidence of tularaemia in the Czech Republic is relatively stable with up to 100 reported cases per year, except in the epidemic years 1998 and 1999 with 225 and 222 reported cases, respectively. It is, however, higher in comparison with the neighbouring countries. The common route of transmission in Central Europe is handling infected animals. Tularaemia is not commonly recognized as a tick-borne disease. Here we report two rare cases of a tick bite-associated ulceroglandular form of tularaemia in 2.5-year-old and 6.5-year-old children presenting with cervical lymphadenopathy. The unusual and interesting features of those cases are the young age and relatively uncommon route of transmission suggesting possible changes in the epidemiology of tularaemia in the Czech Republic. Therefore, the infection with F. tularensis should be considered in the differential diagnosis after a tick bite even in infants.
... Левофоксацин ассоциируется высокой частотой развития повреждение сухожилий в сравнении с другими ФХ [13]. Выделены факторы риска тендинитов и разрывов сухожилий на прием ФХ [13,14]. К основным факторам риска относят: возраст старше 60 лет, мужской пол, ХБП, гемодиализ, прием глюкокортикостероидов, ХОБЛ, трансплантация органов, применение ЛФ. ...
Eradication therapy is the mainstay of treatment for H. pylori-associated diseases. A case of the development of tendinitis of the left patellar ligament proper during eradication therapy using a triple regimen with levofoloxacin for 14 days for exacerbation of duodenal ulcer is presented.
... Also, Siddiqui et al. [25] reported that ciprofloxacin reduced the length of long bone extremities in rats. In addition, Hall et al. [26] revealed that fluoroquinolones were associated with a wide spectrum of musculoskeletal complications that involved not only tendon but also cartilage, bone, and muscle. ...
... Limited data, mostly from experimental animal models, suggest that fluoroquinolones also accumulate in cartilage (197). This may have some significance, as fluoroquinolones are associated with arthralgia, myalgia, and joint damage in some studies (198), and mast cell mediators have been shown to weaken tendons (181). In sum, this unusual tissue distribution pattern of fluoroquinolones may result in intense mast cell activation that is both delayed and restricted to certain tissues. ...
Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.
... Also, Siddiqui et al. [25] reported that ciprofloxacin reduced the length of long bone extremities in rats. In addition, Hall et al. [26] revealed that fluoroquinolones were associated with a wide spectrum of musculoskeletal complications that involved not only tendon but also cartilage, bone, and muscle. ...
Objective: To evaluate the effect of norfloxacin on pregnant female rats. Animals: 30 pregnant female rats (170-200 gm of weight and 3.5-4 months age). Design: Randomized controlled study. Procedures: The effect of orally administrated norfloxacin, given twice daily for 10 successive days, on the fetal development in pregnant female rats at therapeutic (35 mg/kg) and double therapeutic (70 mg/kg) doses was investigated in pregnant female rats. At 6 th-15 th day of pregnancy, 30 females were classified, in groups of ten rats, into 3 groups. Group 1 (control group): rats were given distilled water orally. Group 2: rats were given norfloxacin at a dose rate of 35 mg/kg bwt. Group 3: rats were given norfloxacin at a double therapeutic dose of 70 mg/kg bwt. At 20 th day of gestation all pregnant rats were anesthetized to determine the changes; if any; in fetal development (morphological, visceral, skeletal and histopathological examinations) and on treated dams (biochemical parameters of serum and histopathological alterations in placenta, liver and kidney). Results: Administration of norfloxacin, in both doses, to pregnant females decreased the number of viable feti, fetal body weight and crown-rump length, and increased the number of resorbed feti (P< 0.05). It also induced visceral and skeletal abnormalities in feti. Histopathological examination of internal organs to both dams and feti revealed pathological alterations in liver and kidney of both, and placenta of the dam. Administration of norfloxacin at both therapeutic and double therapeutic doses increased maternal serum transferases levels (ALT and AST), decreased serum albumin and total portein levels, and increased serum levels of urea and creatinine (P< 0.05). Conclusion and clinical relevance: High doses of norfloxacin induce fetal defects and abnormalities in early stage of gestation in rats.
... Magnesium is essential in integrin signaling, a protein that plays a role in maintaining the extracellular matrix's integrity in tendons. Thus, by chelating magnesium from tendons, fluoroquinolones can lower integrin levels, leading to reduced MAPK signaling, reduced proliferation of tenocytes, and increased caspase-3, an effector of apoptosis [14]. Animal studies of fluoroquinolone exposure in hypomagnesemic rats and dogs showed a more profound toxic effect on joints and tendons [15]. ...
Fluoroquinolones are antimicrobial agents that inhibit bacterial DNA synthesis by binding to DNA gyrase and DNA topoisomerase IV. Fluoroquinolones have also been associated with the development of tendinopathy, tendon rupture, and arthropathy. The postulated mechanisms for quinolone-associated tendinopathy are alteration of the tendon extracellular matrix, impairment of tenocyte proliferation, and enhanced apoptosis due to the quinolone cation chelation properties. We present a case of a man who developed multiple tears of the rotator cuff after exposure to levofloxacin. Although marketed quinolones are well tolerated, adverse events involving gastrointestinal, cardiovascular, neurological, and tendinopathy and at-risk patient populations should be kept in mind by clinicians.
... Fluoroquinolones have been associated with various muscle-related disorders, including tendinitis, tendinosis, tendon rupture, arthralgia, myalgia and rhabdomyolysis. 6 Fluoroquinolones work by inhibiting DNA gyrase and topoisomerase IV, 2 enzymes essential for DNA replication and transcription within the bacterial cell. 7 The mechanism behind fluoroquinolone-associated muscle disorders is not well understood, but different hypotheses have been postulated. ...
Dermatomyositis is an inflammatory disorder involving muscle and skin. Similar to many other autoimmune diseases, environmental factors appear to trigger the onset of disease in some cases. Many drugs have been reported to be associated with dermatomyositis, and rarely infections have been described as potential triggering agents. Here we are describing a case of dermatomyositis that developed after doxycycline and levofloxacin use, who also had recent Epstein-Barr virus infection. Dermatomyositis associated with doxycycline or levofloxacin use has not yet been described in the literature, while reports of dermatomyositis after Epstein-Barr virus infection have been rare and limited to juvenile dermatomyositis or in association with cancer. It is important for clinicians to be aware of this rare association so that the diagnosis and treatment can be exercised promptly.
... This inorganic phosphorus compound significantly stimulates the growth and osteogenic differentiation of the bone cells (Liu et al., 2009). This cell proliferation increase was absent in presence of A50, this may be due to that the proliferative effect exerted by the phosphate released from solgel degradation would be counteracted by the high moxifloxacin concentration, an fluoroquinolone antibiotic which has been frequently associated with a wide spectrum of musculoskeletal complications that involve not only tendon but also cartilage, bone, and muscle (Hall et al., 2011;Jacobs et al., 2014). Due to the degradation of sol-gel would take place after 48-72 h of surgery, this potential local cytotoxicity would be a assumable and transient complication by taking into account the beneficit of prophylaxis. ...
The aim of this study was to evaluate the effect of a moxifloxacin-loaded organic-inorganic sol-gel with different antibiotic concentration in the in vitro biofilm development and treatment against Staphylococcus aureus, S. epidermidis, and Escherichia coli, cytotoxicity and cell proliferation of MC3T3-E1 osteoblasts; and its efficacy in preventing the prosthetic joint infection (PJI) caused by clinical strains of S. aureus and E. coli using an in vivo murine model. Three bacterial strains, S. epidermidis ATCC 35984, S. aureus 15981, and, E. coli ATCC 25922, were used for microbiological studies. Biofilm formation was induced using tryptic-soy supplemented with glucose for 24 h, and then, adhered and planktonic bacteria were estimated using drop plate method and absorbance, respectively. A 24-h-mature biofilm of each species growth in a 96-well plate was treated for 24 h using a MBECTM biofilm Incubator lid with pegs coated with the different types of sol-gel, after incubation, biofilm viability was estimated using alamrBlue. MC3T3-E1 cellular cytotoxicity and proliferation were evaluated using CytoTox 96 Non-Radioactive Cytotoxicity Assay and alamarBlue, respectively. The microbiological studies showed that sol-gel coatings inhibited the biofilm development and treated to a mature biofilm of three evaluated bacterial species. The cell studies showed that the sol-gel both with and without moxifloxacin were non-cytotoxic and that cell proliferation was inversely proportional to the antibiotic concentration containing by sol-gel. In the in vivo study, mice weight increased over time, except in the E. coli-infected group without coating. The most frequent symptoms associated with infection were limping and piloerection; these symptoms were more frequent in infected groups with non-coated implants than infected groups with coated implants. The response of moxifloxacin-loaded sol-gel to infection was either total or completely absent. No differences in bone mineral density were observed between groups with coated and non-coated implants and macrophage presence lightly increased in the bone grown directly in contact with the antibiotic-loaded sol-gel. In conclusion, moxifloxacin-loaded sol-gel coating is capable of preventing PJI caused by both Gram-positive and Gram-negative species.
... It has the most antibacterial activity against Gramnegative bacteria and better safety profile and good effectiveness against resistant pathogenic bacteria as compared to other antibiotics [10,11]. Ciprofloxacin is used in the urinary and respiratory tract, skin, bone, and joint infections [12].Silver and its products have been used in water and air purification, cosmetics, clothing and biomedical applications, including diagnosis, treatment, and drug delivery because of its broad-spectrum antimicrobial features. With the rapid advancement of nanotechnology, the applications of nanoscale materials has also been expanded. ...
Introduction: Nowadays, antibiotic resistance is rising at an alarming rate. Essentially, one of the important ways for bacteria such as P. aeruginosa to survive in the presence of antibiotics is biofilm formation. In the current report, we have focused on inhibiting the microbial biofilm formation of P. aeruginosa through combining glutathione (GSH) coated silver nanoparticles (AgNPs) and Ciprofloxacin (Cip). Materials and Methods: AgNPs were biosynthesized using Eucalyptus Camaldulensis leaf extracts and surface modification of AgNPs was done, using glutathione. Synthesized nanoparticles were characterized by FTIR, XRD, DLS, SEM, and CHN tests. Then, 50 isolates of P. aeruginosa were originated from different samples of hospitalized patients from Sina hospital and 24 isolates were selected as a strong biofilm producer using microtiter plate method for further studies. Finally, the synergistic effect of GSH-coated AgNPs and Cip was investigated on the biofilm formation of P. aeruginosa. Result: The images of SEM represent the spherical structure of silver nanoparticles with a smooth surface. Also, the results of FTIR, XRD, DLS, SEM, and CHN of AgNPs before and after surface coating confirmed the formation of GSH-coated AgNPs. GSH-coated AgNPs and Cip at a concentration of 1/2 and 1/4 MIC had inhibitory activity on biofilm formation of 87.5% and 83.4% of P. aeruginosa isolates respectively. Conclusion: This study illustrated that the combination of GSH-coated AgNPs and Cip has a synergistic inhibitory activity on P. aeruginosa biofilm formation.
... Specific evidence regarding what measures are most effective is lacking; however, guidelines detailing important considerations and emphasizing close monitoring have been published. 15 Our study has several limitations. First, this study is a retrospective chart review, and as such, we relied on preexisting records, which may have been incomplete or contained incorrect data. ...
Background
Achilles tendon rupture (ATR) is a common injury with increasing incidence. Several risk factors have been identified; however, little is known about seasonal variations in injury prevalence. Previous reports have generated mixed results, with no clear consensus in the literature. The purpose of this investigation was to retrospectively review ATRs seen at a major academic orthopaedic surgery department in New York City to determine whether a statistically significant seasonal pattern of ATRs exists.
Methods
A retrospective chart review was conducted, identifying patients with an acute ATR. Patients were excluded if they had a chronic rupture, laceration, débridement for tendinitis, Haglund deformity, or other nonacute indications for surgery. Date and mechanism of injury were determined from the clinical record.
Results
The highest rate of injury was seen in spring (P = 0.015) and the lowest in fall (P < 0.001), both of which were statistically significant. Overall, no statistically significant difference was noted in summer or winter, although more injuries were seen in summer. When only sports-related injuries are considered, a similar trend is seen, with most injuries occurring in spring (n = 48, P = 0.076) and fewest in fall (n = 25, P = 0.012); however, only the lower number in fall reaches statistical significance. No statistically significant difference was noted between seasons when only non–sports-related injuries were considered.
Conclusion
A statistically significant increase was noted in the incidence of ATRs in spring and a statistically significant decrease in fall. The need for recognition of risk factors and preventive education is increasingly important in the orthopaedic surgery community and for primary care physicians, athletic trainers, coaches, and athletes.
Level of Evidence
Prognostic level IV
... [17][18][19][20] Te fndings parallel reports of FQ-associated NP toxicity in humans. [21][22][23][24][25] With respect to the clinical investigations, voluntary eforts from interested persons were critical. Te study questions and design for the web survey were developed by the Floxed Network and reviewed and commented upon by 2 external pharmacovigilance investigators who have extensive experience with FAERS reports. ...
Background:
The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists.
Objective:
To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability.
Methods:
5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program.
Results:
Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD).
Limitations:
Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin.
Conclusion:
Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.
... [10][11][12] Certain forms of ocular toxicity of fluoroquinolones have also been observed in humans. 13,14 Moreover, the effects of cytotoxic properties on collagen and connective tissue offer a plausible pathophysiologic mechanism for acute fluoroquinoloneassociated rhegmatogenous RD. [15][16][17][18][19][20] Hence, given the controversial epidemiologic results and the widespread use of fluoroquinolones, we assessed the association between RD and fluoroquinolones using the French health care databases. ...
Importance
Several studies have focused on the current use of oral fluoroquinolones and the risk for retinal detachment (RD), but the existence of this association is under debate. Given the widespread fluoroquinolone use, investigation of this association is essential.Objective
To assess the association between oral fluoroquinolone use and the risk for RD, including the rhegmatogenous and exudative types.Design, Setting, and Participants
This case-crossover study included 27 540 adults with RD from French health care databases from July 1, 2010, through December 31, 2013. Patients with a history of RD or retinal break, endophthalmitis, intravitreal injection, choroidal retinal vitreal biopsy, and human immunodeficiency virus infection or those hospitalized within 6 months of RD were excluded. The risk period of primary interest was current use, defined as exposure to fluoroquinolones within 10 days immediately before RD surgery, according to previous findings. Oral fluoroquinolone use was assumed to start on the day the prescription was dispensed.Main Outcomes and Measures
Exposure to fluoroquinolones during the risk period (1-10 days) compared with the control period (61-180 days). The association was also assessed regarding use in the recent (11-30 days) and past (31-60 days) intermediate risk period, type of fluoroquinolone, and type of RD.Results
Of the 27 540 eligible patients (57% men; mean [SD] age, 61.5 [13.6] years), 663 patients with RD were exposed to fluoroquinolones during the observation period, corresponding to 80 cases exposed during the 10-day risk period (≤10 days before RD) and 583 cases exposed during the control period (61-180 days). We found a significant increased risk for RD during the 10-day period after the dispensing of oral fluoroquinolones, with an adjusted odds ratio of 1.46 (95% CI, 1.15-1.87). The risk was significantly increased for rhegmatogenous and exudative RD, with adjusted odds ratios of 1.41 (95% CI, 1.04-1.92) and 2.57 (95% CI, 1.46-4.53), respectively. Recent and past use of fluoroquinolones were not associated with a higher risk for RD, with adjusted odds ratios of 0.94 (95% CI, 0.78-1.14) and 1.06 (95% CI, 0.91-1.24), respectively.Conclusions and Relevance
Current oral fluoroquinolone use was associated with an increased risk for RD, including the rhegmatogenous and exudative types. These findings, along with the available literature, suggest an association between fluoroquinolone use and the risk for RD. The nature of this association should be further investigated in future studies.
... The first Quinolone, nalidixic acid was first isolated as a byproduct of the synthesis of chloroquine in early 1960s (Hall et al., 2011) Later in the 1980s fluorinated derivatives e.g., ciprofloxacin were synthesized (Stahlmann, 2002). Ciprofloxacin is a second generation fluoroquinolone with a broad spectrum of antibacterial activity. ...
Ciprofloxacin is one of the fluoroquinolones with a wide clinical acceptability. Rescently there are increasing reports on Ciprofloxacin induce Chondrotoxicity and Tendinopathy in Animal experiment and clinical experience which is of great clinical concern. A comprehensive survey and review of literaure on reported ciprofloxacin induced Chondrotoxicity and Tendinopathy in Humans and Animals was performed. It was observd that ciprofloxacin is a potential inducer of Chrondrotoxicity and Tendinopathy which could be potentiated by coadministration with corticosteroids.This conditions were reported to be characterised by cartilage lesion, matrix swelling, inhibition of chondrocytes proliferation, secretion of soluble proteoglycan, modification of the metabolism and integrity of extracellular proteins, decrease in epiphyseal growth plate, humerus and femur.The mechanism behind this phenomenon is said to be multifactoral. Ciprofloxacin induced Chrondrotoxicity and Tendinopathy in growing animals is attributed to oxidative stress (lipid peroxidation, Deoxyribonucleic Acid (DNA) oxidative stress). Ciprofloxacin induced cartilage damage may also be attributed to formation of Ciprofloxacin chelates and complexes which possesses the potential to induce a deficiency of functionally available divalent ions resulting in cytoskeletal changes. Animal studies showed that oxidative damage or metabolism of tissues was also found suggesting the involvement of a reactive oxygen species. Administration of magnesium, zinc chloride and vitamin E (α tocopherol) were found to prevent or reverse ciprofloxacin induced Chrondrotoxicity and Tendinopathy. Through excess formation of collagen, increase osteoblastic activity, increase bone growth, inhibition of free oxidation radicals' formation thereby preventing DNA oxidation and oxidative stress. Zinc also directly stimulates DNA synthesis either by enzyme stimulation or altering, the binding of f1 and f3 histones to DNA so as to affect RNA synthesis. Patient medical history should be considered before Ciprofloxacin recommendation. Coadministration with corticosteroid should be done with caution. Further evaluation of antioxidants effect in Ciprofloxacin induce Chonrotoxicity, Tendinopathy in humans could be of clinical importance as observed in Animal studies.
... Fluoroquinolones are associated with a wide spectrum of musculoskeletal complications that involve not only tendon but also cartilage, bone, and muscle 26 . These drugs cause damage to the weight bearing joints in juvenile animals 22 . ...
ENEFITS AND RISKS OF FLUOROQUINOLONES USE IN PEDIATRICS: A REVIEW
Abadi kahsu*, Teshager Aklilu, Birhanetensay Masresh and Wondim Melkam Department of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Ethiopia
ABSTRACT:
Fluoroquinolones are synthetic fluorinated derivatives of nalidixic acid and are an important group of antibacterials along with the beta-lactam and macrolides are used for the treatment of various infectious diseases in adults; however, their use in children has been limited as the result of fluoroquinolone induced musculoskeletal toxicity in animal studies. Those antibiotics are useful in the treatment of cytic fibrosis, urinary tract infections, neutropenia, gastrointestinal infections, meningitis with resistant bacteria, chronic suppurative otitis media, some cases of complicated acute otitis media, conjunctivitis, infections caused by Enterobacteriaceae (including the neonatal period), some mycobacterial infections, prophylaxis of anthrax and sepsis caused by other antibiotic resistant organisms in pediatrics. Most of the available human studies showed the incidence of musculoskeletal adverse event is relatively higher in fluoroquinolones than non fluoroquinolone antibiotics; however, almost all AEs are reversible and transient. Hence, fluoroquinolones can be clinically considered in children when the benefit outweighs the possible risk.
Keywords
: Fluoroquinolones, Pediatrics, Benefits, Risks.
... Thus, we suggest that iron chelation by FQ antibiotics inhibits ␣-KG-dependent collagen prolyl 4-hydroxylase and other dioxygenase enzymes, perhaps explaining FQ side effects, including spontaneous tendon ruptures (44). In addition, FQinduced epigenetic modifications uncovered here may explain aspects of FQ nephrotoxicity. ...
Fluoroquinolones (FQ) are powerful broad-spectrum antibiotics whose side effects include renal damage and, strangely, tendinopathies. The pathological mechanisms underlying these toxicities are poorly understood. Here we show that the FQ drugs Norfloxacin, Ciprofloxacin, and Enrofloxacin are powerful iron chelators comparable to Deferoxamine, a clinically-useful iron chelating agent. We show that iron chelation by FQ leads to epigenetic effects through inhibition of α-ketoglutarate-dependent dioxygenases that require iron as a co-factor. Three dioxygenases were examined in HEK293 cells treated with FQ. At sub-mM concentrations these antibiotics inhibited Jumonji domain histone demethylases, TET DNA demethylases, and collagen prolyl 4-hydroxylases, leading to accumulation of methylated histones and DNA, and inhibition of proline hydroxylation in collagen, respectively. These effects may explain FQ-induced nephrotoxicity and tendinopathy. By the same reasoning, dioxygenase inhibition by FQ was predicted to stabilize transcription factor HIF-1α by inhibition of oxygen-dependent HIF prolylhydroxylation. In dramatic contrast to this prediction, HIF-1α protein was eliminated by FQ treatment. We explored possible mechanisms for this unexpected effect and show that FQ inhibit HIF-1α mRNA translation. Thus, FQ antibiotics induce global epigenetic changes, inhibit collagen maturation, and block HIF-1α accumulation. We suggest that these mechanisms explain the classic renal toxicities and peculiar tendinopathies associated with FQ antibiotics.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
... Please provide details of the citation " Wang et al., 2009" in the reference list or delete the text citation. Similarly, Hall et al. (2011) found that FQs were associated with a wide array of musculoskeletal complications involving tendon, cartilage, bone, and muscle. Further, Ding et al. (2010) showed that lidamycin could inhibit angiogenesis of zebrafish embryo by down-regulation of VEGF expression. ...
Pediatric Achilles tendon injuries requiring surgical treatment are considered rare and have not been well described. A retrospective chart review was conducted from 2010 to 2020 to identify cases of acute Achilles tendon rupture or laceration that required surgical repair in individuals 19 years or younger. A total of 24 individuals with acute Achilles tendon ruptures (n = 8) and lacerations (n = 16) were identified. All spontaneous ruptures occurred in skeletally mature individuals during sports. One subject was on minocycline at the time of injury, while two had a body mass index (BMI) ≥ 99% for age. Another had a history of clubfoot surgery on the injured side. Patients with lacerations were younger (9.9 ± 3.3 vs 16.3 ± 1.6 years) and had lower BMI (17.3 ± 3.8 vs. 28.0 ± 9.4) than those with spontaneous ruptures. The majority of cases had good outcomes with no postoperative complications.
What is known and objective:
The combination of HMG-CoA reductase inhibitors (statins) and fluoroquinolones generally is not considered a significant risk factor for rhabdomyolysis. Rhabdomyolysis is a known risk associated with statin therapy but has seldom been described with fluoroquinolone use. We describe a case of acute rhabdomyolysis involving the co-administration of atorvastatin and levofloxacin.
Case description:
A 65-year-old white male presented with clinical and laboratory evidence of rhabdomyolysis after approximately 19 days of levofloxacin therapy for treatment of a prosthetic joint infection. His symptoms resolved after discontinuation of levofloxacin and atorvastatin therapy and did not recur following reintroduction of atorvastatin therapy.
What is new and conclusion:
Delayed-onset rhabdomyolysis may occur in patients receiving levofloxacin. Weekly complete metabolic panels along with patient education about symptoms of rhabdomyolysis should be considered, particularly in patients on concurrent medications known to cause rhabdomyolysis.
Introduction:
The present systematic review investigates the biological and chemical mechanisms that affect the health and structure of tendons following the use of fluoroquinolones (FQs).
Sources of data:
A total of 12 articles were included, organized, and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Areas of agreement:
Five mechanisms were identified: arrest of proliferation through a decreased activity of cyclin B, CDK-1, CHK-1, and increased PK-1; decrease tenocytes migration through decreased phosphorylation of FAK; decrease type I collagen metabolism through increased MMP-2; chelate effect on ions that influence epigenetics and several enzymes; fluoroquinolones-induced ROS (radical oxygen species) production in mitochondria.
Areas of controversy:
There is no definite structure-damage relationship. The dose-effect relationship is unclear.
Growing points:
Knowing and defining the damage exerted by FQs plays a role in clinical practice, replacing FQs with other antibacterial drugs or using antioxidants to attenuate their pathological effects.
Areas timely for developing research:
Clinical and basic sciences studies for each FQs are necessary.
Clinically identified myopathies can occur with administration of medications such as statins, glucocorticoids, antibiotics, antirheumatics, and retinoids. While the frequency of drug-induced myopathies is unclear, they are an important group of disorders in anyone presenting with muscular symptoms and should be considered in patients with symptoms ranging from mild myalgia or muscle cramping to profound muscle weakness without a known etiology. Certain medications are commonly associated with myopathy and frequently prescribed (glucocorticoids, statins); a few are more likely to occur with exercise, whereas others have myopathy as a rare side effect. Developing a greater understanding of underlying mechanisms and symptoms of drug-induced myopathy can promote enhanced awareness, early recognition, and improved patient care because many drug-induced myopathies are potentially reversible at early stages. Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Background:
Nemonoxacin, a novel nonfluorinated quinolone, has broad-spectrum antibacterial activity, including activity against antibiotic-resistant strains, and was developed for treating community-acquired pneumonia (CAP). This report provides an integrated safety summary of oral nemonoxacin from two phase II and one phase III clinical studies.
Methods:
Patients with mild CAP were randomized for treatment with nemonoxacin 500 mg (NEMO-500MG), nemonoxacin 750 mg (NEMO-750MG), or levofloxacin 500 mg (LEVO), orally, once daily, for 7-10 days. Hematological, gastrointestinal, and hepatic disorders; electrocardiography abnormalities; and reported quinolone-associated clinical concerns were included in this analysis.
Results:
A total of 520, 155, and 320 subjects were assigned to receive NEMO-500MG, NEMO-750MG, and LEVO, respectively. The incidence of adverse events (AEs) was the highest (54.8%) in the NEMO-750MG group (NEMO-500MG, 36.9%; NEMO-750MG, 54.8%; LEVO, 39.7%) and that of drug-related AEs was comparable between the three groups (NEMO-500MG, 22.9%; NEMO-750MG, 31.0%; LEVO, 22.5%). The majority (>80%) of the patients showed mild drug-related AEs and the distribution based on severity was similar between the groups. The most commonly reported drug-related AEs included neutropenia (NEMO-500MG, 2.5%; NEMO-750MG, 8.4%; LEVO, 4.4%), nausea (NEMO-500MG, 2.5%; NEMO-750MG, 7.1%; LEVO, 2.5%), leukopenia (NEMO-500MG, 2.3%; NEMO-750MG, 4.5%; LEVO, 3.1%), and increased alanine aminotransferase level (NEMO-500MG, 4.4%; NEMO-750MG, 0%; LEVO, 2.5%).
Conclusion:
Nemonoxacin was well tolerated and no clinically significant safety concerns were identified, suggesting that it possesses a desirable safety and tolerability profile similar to that of levofloxacin, and may be a suitable alternative to fluoroquinolones for treating patients with CAP.
Aims:
To enhance the antimicrobial and antibiofilm activity of norfloxacin against the planktonic and biofilm mode of growth in ESKAPE pathogens using chemically modified norfloxacin salts.
Methods and results:
Antimicrobial testing, synergy testing and time kill curve analysis, were performed to evaluate antibacterial effect of norfloxacin carboxylic acid salts against ESKAPE pathogens. In vivo efficacy to reduce bacterial bioburden was evaluated in zebrafish infection model. Crystal violet assay and live dead staining were performed to discern antibiofilm effect. Membrane permeability, integrity and molecular docking studies were carried out to ascertain the mechanism of action. The carboxylic acid salts, relative to parent molecule norfloxacin, displayed 2-4 fold reduction in MIC against Staphylococcus aureus and Pseudomonas aeruginosa, in addition to displaying potent bacteriostatic effect against certain members of ESKAPE pathogens. In-vivo treatments revealed that norfloxacin tartrate (SRIN2) reduced MRSA bioburden by greater than 1 log fold relative to parent molecule in the muscle tissue. In silico docking with gyrA of S. aureus showed that increased affinity of SRIN2 towards DNA gyrase. The enhanced antibacterial effect of norfloxacin salts could be partially accounted by altered membrane permeability in S. aureus and perturbed membrane integrity in P. aeruginosa. Antibiofilm studies revealed that SRIN2 (Norfloxacin-tartarate) and SRIN3 (Norfloxacin-benzoate) exerted potent antibiofilm effect particularly/selectively against gram negative ESKAPE pathogens. The impaired colonization of both S. aureus and P. aeruginosa due to improved norfloxacin salts was further supported by live dead imaging.
Conclusion:
Norfloxacin carboxylic acid salts can act as potential alternatives in terms of drug resensitization and reuse.
Significance and impact:
Our study shows that carboxylic acid salts of norfloxacin could be effectively employed to treat both planktonic and biofilm based infections caused by select members of ESKAPE pathogens. This article is protected by copyright. All rights reserved.
The development of tendinitis and tendinopathy is often multifactorial and the result of both intrinsic and extrinsic factors. Intrinsic factors include anatomic factors, age-related factors, and systemic factors, whereas extrinsic factors include mechanical overload and improper form and equipment. Although tendinitis and tendinopathy are often incorrectly used interchangeably, they are in 2 distinct pathologies. Due to their chronicity and high prevalence in tendons about the ankle, including the Achilles tendon, the posterior tibialis tendon, and the peroneal tendons, tendinitis and tendinopathies cause significant morbidity and are important pathologies for physicians to recognize.
Objective
To understand the prevalence and distribution of Chlamydia pneumoniae (CP) and Mycoplasma pneumoniae (MP) in the population and to provide a basis for the prevention and treatment of respiratory tract infection.
Methods
This study included a total of 4500 healthy subjects who were given physical examination in Shenzhen People's Hospital from January to December in 2016. Venous blood was drawn from people to detect the MP- and CP-specific IgG and IgM in the serum using chemiluminescence immunoassay (CLIA). The relationship of MP and CP infections with patient age, seasons, and percentage of infections was analyzed.
Conclusion
CP and MP cause high rate of asymptomatic infection, which may be associated with the high incidence of CP and MP infection, especially in children and the elderly population. Therefore, the implementation of effective and practical prevention measures has become an urgent need. MP culture and drug sensitivity test should be performed as early as possible in patients with manifested MP infections in order to ensure timely and proper treatment and to reduce the emergence of drug-resistant strains.
Purpose
Methicillin-resistant Staphylococcus aureus (MRSA) and other multidrug-resistant organisms (MDROs) are becoming increasingly common in health care and community settings. As the physical therapy profession moves toward complete direct access, knowledge of the microbiology, recognition of these organisms, and prevention of transmission are important for physical therapists. Although health care–acquired MRSA is found in traditional care settings, community-acquired MRSA is found in younger persons, families, and members of sports teams.
Methods
This article uses a review of the literature to explore the transmission of MRSA, as well as to highlight effective prevention methods. Both health care–acquired MRSA and community-acquired MRSA are compared and discussed. Prevalence of other MDROs is also described.
Conclusion
Universal decolonization in intensive care units is one of the few strategies supported by a high level of evidence. Physical therapists must understand the development and transmission of MDROs, so that they can protect themselves, as well as others they come in contact with. Review of the integument, particularly in athletes, is important to identify MRSA lesions early.
Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite the attractive profile as anti-infective agents, their use in children is limited, primarily due to safety concerns. In this review, we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad-spectrum antibiotics resulting in the development of drug resistant bacteria that can be challenging to effectively treat. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults that should be considered at the point of prescribing. This article is protected by copyright. All rights reserved.
We present a case series of four previously healthy, employed adults without significant prior medical history in each of whom symptoms developed while on fluoroquinolones (FQs), with progression that continued following discontinuation evolving to a severe, disabling multisymptom profile variably involving tendinopathy, muscle weakness, peripheral neuropathy, autonomic dysfunction, sleep disorder, cognitive dysfunction and psychiatric disturbance. Physicians and patients should be alert to the potential for FQ-induced severe disabling multisymptom pathology that may persist and progress following FQ use. Known induction by FQs of delayed mitochondrial toxicity provides a compatible mechanism, with symptom profiles (and documented mechanisms of FQ toxicity) compatible with the hypothesis of an exposure-induced mitochondrial neurogastrointestinal encephalomyopathy.
The top 5 running injuries seen in the office are discussed in detail.
An adverse drug reaction (ADR) is a serious concern for practicing veterinarians and other health professionals, and refers to an unintended, undesired and unexpected response to a drug that negatively affects the patient's health. It may be iatrogenic or genetically induced, and may result in death of the affected animal. The ADRs are often complicated and unexpected due to myriad clinical symptoms and multiple mechanisms of drug-host interaction. Toxicity due to commonly used drugs is not uncommon when they are used injudiciously or for a prolonged period. Licosamides, exclusively prescribed against anaerobic pyoderma, often ends with diarrhoea and vomiting in canines. Treatment with Penicillin and ß-lactam antibiotics induces onset of pemphigious vulgare, drug allergy or hypersensitivity. Chloroamphenicol and aminoglycosides causes Gray's baby syndrome and ototoxicity in puppies, respectively. Aminoglycosides are very often associated with nephrotoxicity, ototoxicity and neuromuscular blockage. Injudicious use of fluroquinones induces the onset of arthropathy in pups at the weight bearing joints. The most effective therapeutic measure in managing ADR is to treat the causative mediators, followed by supportive and symptomatic treatment. So, in this prospective review, we attempt to bring forth the commonly occurring adverse drug reactions, their classification, underlying mechanism, epidemiology, treatment and management as gleaned from the literature available till date and the different clinical cases observed by the authors.
Fluoroquinolone use for the treatment of bacterial infections is a common practice for foot and ankle surgeons because of its rather broad-spectrum coverage against common pathogens, good tissue penetration, and high bioavailability. An associated risk of tendinopathy has been reported in published studies, although tendon rupture has been much less frequent. In addition, tendinopathy has been more commonly reported with earlier generations of fluoroquinolones. We present a case of levofloxacin-mediated Achilles rupture that was complicated by the presence of an infected hematoma and abscess and subsequent long-term postoperative follow-up data, with a review of the literature.
Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.
Exposure to fluoroquinolone antibiotics is postulated as a risk factor for subsequent development of type 2 diabetes. It is hypothesized that fluoroquinolones induce an intracellular magnesium deficit that can lead to insulin resistance. A temporal correlation is reported between the rate of outpatient prescription of quinolones and the incidence of diabetes during the period 1980-2011 with a lag of approximately two years (R(2)=0.86, P<10(-9)). The increase in incidence of diabetes after 1990 and the recent decrease in the number of new cases are both reflected in the fluoroquinolone prescription rates. A geographical correlation is reported (adj. R(2)=0.7, P<0.0001) between rates of increase in prevalence of diabetes in each U.S. state and a model using only local rates of outpatient fluoroquinolone prescription, local rates of increase in the prevalence of obesity, and local rates of population growth as predictor variables. Prescription rates of non-quinolone antibiotics correlated less well with the local rates of increase in prevalence of diabetes. The data are consistent with fluoroquinolone exposure predisposing an individual to develop diabetes with a probability that strongly depends upon factors that also lead to an increase in obesity. According to the hypothesis, much of the increase in the incidence of type 2 diabetes in the U.S. from 1990 to the present can be attributed to fluoroquinolone exposure.
Keywords: levofloxacin, tendinopathySir,Levofloxacin is recommended for the management ofcommunity-acquired pneumonia. As its use increases, it isimportant that doctors are aware of its relatively uncommonadverse effects. Achilles tendinitis (incidence: 0.10.01%) –and tendon rupture (incidence: < 0.01%) are well recognizedbut rare adverse effects of levofloxacin and other fluoro-quinolones.
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.
Magnesium (Mg) is the fourth most abundant mineral in the body and the most abundant intracellular divalent cation, with essential roles in many physiological functions. Consequently, the assessment of Mg status is important for the study of diseases associated with chronic deficiency. In spite of intense research activities there is still no simple, rapid, and accurate laboratory test to determine total body Mg status in humans. However, serum Mg < 0.75 mmol/l is a useful measurement for severe deficiency, and for values between 0.75 and 0.85 mmol/l a loading test can identify deficient subjects. The loading test seems to be the gold standard for Mg status, but is unsuitable in patients with disturbed kidney and intestinal functions when administered orally. There is also a need to reach a consensus on a standardized protocol in order to compare results obtained in different clinical units. Other cellular Mg measurements, such as total or ionized Mg, frequently disagree and more research and systematic evaluations are needed. Muscle Mg appears to be a good marker, but biopsies limit its usefulness, as is the case with bone Mg, the most important but heterogeneous Mg compartment. The development of new and non invasive techniques such as nuclear magnetic resonance (NMR) may provide valuable tools for routinely analysing ionized Mg in tissues. With the development of molecular genetics techniques, the recent discovery of Transient Receptor Potential Melastatin channels offers new possibilities for the sensitive and rapid evaluation of Mg status in humans.
The alpha7beta1 integrin is increased in skeletal muscle in response to injury-producing exercise, and transgenic overexpression of this integrin in mice protects against exercise-induced muscle damage. The present study investigates whether the increase in the alpha7beta1 integrin observed in wild-type mice in response to exercise is due to transcriptional regulation and examines whether mobilization of the integrin at the myotendinous junction (MTJ) is a key determinant in its protection against damage. A single bout of downhill running exercise selectively increased transcription of the alpha7 integrin gene in 5-wk-old wild-type mice 3 h postexercise, and an increased alpha7 chain was detected in muscle sarcolemma adjacent to tendinous tissue immediately following exercise. The alpha7B, but not alpha7A isoform, was found concentrated and colocalized with tenascin-C in muscle fibers lining the MTJ. To further validate the importance of the integrin in the protection against muscle damage following exercise, muscle injury was quantified in alpha7(-/-) mice. Muscle damage was extensive in alpha7(-/-) mice in response to both a single and repeated bouts of exercise and was largely restricted to areas of high MTJ concentration and high mechanical force near the Achilles tendon. These results suggest that exercise-induced muscle injury selectively increases transcription of the alpha7 integrin gene and promotes a rapid change in the alpha7beta integrin at the MTJ. These combined molecular and cellular alterations are likely responsible for integrin-mediated attenuation of exercise-induced muscle damage.
We present a case of pefloxacin-induced arthropathy in a 15-year-old patient with brain abscess. Six joints were involved, of which the right elbow joint was most severely affected. Magnetic resonance imaging of the right elbow revealed joint effusion, and bone scintigraphy showed increased tracer uptake which was still present in the follow-up bone scans.
Chondrocyte toxicity and necrosis were seen with electron microscopy after incubation of human adult cartilage biopsy specimens in ciprofloxacin or ofloxacin. In vitro exposure of chondrocytes to fluoroquinolones did not affect apoptosis as determined by flow cytometry. While the immediate clinical significance of this finding remains unclear, the possibility of long-term cartilage damage after fluoroquinolone treatment cannot be excluded.
Twenty-nine children with cystic fibrosis (CF) were investigated for quinolone-induced arthropathy. Magnetic resonance imaging (MRI) was performed in 14/14 children treated with ofloxacin or ciprofloxacin and in 10/15 of those never treated with quinolones. The frequency of pathologic MRI findings, concerning cartilage thickness, careful analysis of the cartilage structure, presence of edema, cartilage-bone borderline and the presence of fluid in joints did not show any difference between both groups. Thus the presence of quinolone-induced arthrotoxicity cannot be confirmed in this study.
Fluoroquinolones are known to cause rhabdomyolysis. Levofloxacin is a recent fluoroquinolone and its muscular toxicity is not well documented. We describe the case of a 77-year-old female patient, who presented with an acute rhabdomyolysis after treatment with levofloxacin. She had a background of serious cardio-pulmonary disease. She received an oral ambulatory treatment with levofloxacin for pulmonary infection. After 6 days, she presented with severe rhabdomyolysis, resulting in complete anuria with hyperkalaemia, complicated with acute liver cytolysis and respiratory failure. The treatment was a daily repeated haemodialysis. She presented with a fatal myocardial infarction 13 days after admission. The medical history inclines us to strongly suspect levofloxacin as the cause of this severe adverse drug reaction. We also reviewed 27 other suspect cases reported in the database provided by the World Health Organization Collaborating Centre for Drug Monitoring (Uppsala, Sweden). We conclude that rhabdomyolysis can be a rare, severe adverse effect of levofloxacin, as well as the other fluoroquinolones.
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.ResultsOf 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.
This report describes a case of acute steroid-induced myopathy following a single dose of oral prednisolone. A 55-year-old man presented with an acute exacerbation of chronic obstructive pulmonary disease (COPD), which was treated with prednisolone 40 mg daily in addition to bronchodilators. He developed features of myopathy the next day. Serum CPK was moderately elevated and electromyogram (EMG) was suggestive of primary muscle disease. He was managed conservatively and improved 10 days after stopping prednisolone. Mechanisms of steroid-induced myopathy and relevant literature have been reviewed.
Glucocorticoids are a well-recognized cause of muscle weakness. The early effects of glucocorticoids on skeletal muscle (SkM) androgen and IGF-1 pathways have not been previously investigated in human subjects.
To determine if administration of the potent glucocorticoid dexamethasone down-regulates SkM androgen receptor and the IGF-1 signalling pathway.
Twenty-four subjects (12 men and 12 women), including 12 with type 2 diabetes and 12 nondiabetics were enrolled. Venous blood sampling and biopsy of vastus lateralis were performed before and after administration of oral dexamethasone 4 mg/day for 4 days.
Changes in plasma testosterone and IGF-1, SkM androgen receptor mRNA, SkM IGF-1mRNA and SkM IGF-1 receptor mRNA by quantitative RT-PCR after dexamethasone.
Relative expression of SkM androgen receptor was similar in male (1.63 +/- 0.37) vs. female (1.57 +/- 0.30) subjects, despite the significant difference in plasma testosterone levels. Plasma IGF-1 and SkM expression of IGF-1 and IGF-1 receptor were also similar between males and females. Following dexamethasone, there was a significant down-regulation of SkM androgen receptor (1.60 +/- 0.23 vs. 1.11 +/- 0.16, P < 0.05) and IGF-1 (1.72 +/- 0.29 vs. 1.06 +/- 0.14, P < 0.05) mRNA, but no change in expression of the IGF-1 receptor. Plasma testosterone fell significantly in both sexes (male: 15.0 +/- 1.3 vs. 11.3 +/- 1.2 nmol/l, P < 0.01, female: 1.8 +/- 0.5 vs. 0.5 +/- 0.1 nmol/l, P < 0.05).
Exogenous steroid excess results in relative androgen deficiency at two levels, reduced circulating testosterone and SkM androgen receptor mRNA, along with reduced SkM IGF-1 mRNA. These defects may contribute to the development of steroid-induced myopathy.
To report a possible association between fluoroquinolones and diplopia.
Database study.
A total of 171 subjects were studied.
Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, World Health Organization, and Food and Drug Administration were collected on fluoroquinolones and diplopia.
Data garnered from the spontaneous reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, other systemic disease, and dechallenge and rechallenge data.
A total of 171 case reports of diplopia associated with fluoroquinolones were reported, including 76 men, 91 women, and 4 case reports in which the gender was not specified. The median age was 51.6 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 9.6 days (range 1 day to 5 months). Seventeen subjects also had concomitant tendinitis, 49 patients were 60 years or older, 1 patient had renal cysts, and 4 patients were taking systemic anti-inflammatory steroids. There were 53 positive dechallenge and 5 positive rechallenge case reports.
According to World Health Organization criteria, the relationship between fluoroquinolone therapy and diplopia is "possible." This causality assessment is based on the time relationship of drug administration and ADR development, the multiple positive dechallenge and rechallenge reports, and the plausible mechanism by which diplopia could occur: possible tendinitis of the extraocular muscles.
Proprietary or commercial disclosure may be found after the references.
The fluoroquinolones are a relatively new class of antimicrobials with an appealing spectrum of activity. Their use in pediatric medicine is limited because of the concern over possible growth inhibition, as published reports have documented articular cartilage damage in animal models after their administration. These data, extrapolated to include the epiphyseal cartilage, suggest that these agents may reduce growth rates, but limited human data are at the least equivocal, if not strictly contradictory to such claims. Specific investigations into the effects of fluoroquinolones on epiphyseal plate cartilage and growth velocity have not been performed.
Gatifloxacin and ciprofloxacin were used as representative agents of the fluoroquinolone class. Each drug was administered to experimental lambs over a 14-day interval at a dose designed to reflect those used in pediatric medicine. Recumbent versus standing intervals were used to monitor for arthropathy. Upon completion of fluoroquinolone administration, lambs underwent double fluorochrome labeling for determination of growth velocity. Gross and microscopic analysis of articular cartilage was performed to assess for pathologic changes. Age- and sex-matched lambs served as controls.
Neither gatifloxacin nor ciprofloxacin negatively affected growth velocity of the proximal tibial growth plate as measured by double fluorochrome labeling. In addition, no difference between experimental and control lambs in regard to recumbent versus standing intervals was noted. Examination of the articular cartilage failed to suggest chondrotoxicity.
Fluoroquinolone antimicrobials do not affect growth velocity in the ovine model when administered along a dosing regimen that closely models that seen in pediatric medicine.
Fluoroquinolones may be acceptable for use in the pediatric population, as concerns over chondrotoxicity and growth inhibition may not be valid. These data suggest that expanded studies in lambs and other species, including humans, with differences in dosing and duration are justified to ultimately demonstrate clinical safety.
Tendinitis and tendon rupture during treatment with fluoroquinolone antibiotics is thought to be mediated via oxidative stress. This study investigated whether ciprofloxacin and moxifloxacin cause oxidative stress and mitochondrial damage in cultured normal human Achilles' tendon cells and whether an antioxidant targeted to mitochondria (MitoQ) would protect against such damage better than a non-mitochondria targeted antioxidant. Human tendon cells from normal Achilles' tendons were exposed to 0-0.3 mM antibiotic for 24 h and 7 days in the presence of 1 microM MitoQ or an untargeted form, idebenone. Both moxifloxacin and ciprofloxacin resulted in up to a 3-fold increase in the rate of oxidation of dichlorodihydrofluorescein, a marker of general oxidative stress in tenocytes (p<0.0001) and loss of mitochondrial membrane permeability (p<0.001). In cells treated with MitoQ the oxidative stress was less and mitochondrial membrane potential was maintained. Mitochondrial damage to tenocytes during fluoroquinolone treatment may be involved in tendinitis and tendon rupture.
Due to their broad-spectrum activity and oral bioavailability, fluoroquinolone antibiotics are commonly prescribed to adults aged >60 years for many common community-acquired infections. The association between fluoroquinolone use and Achilles tendinitis is well established but sometimes missed in clinical practice. Older patients and patients with renal dysfunction are at particularly increased risk for this complication.
We present a case of Achilles tendinitis in a 77-year-old patient with renal dysfunction and a urinary tract infection (UTI) treated with ciprofloxacin 250 mg PO QD. Tendinitis developed within several days of the start of treatment and improved within 2 days of treatment cessation, without the need for intervention. The likelihood of ciprofloxacin having caused this reaction was probable (Naranjo score, 7). Early diagnosis and treatment cessation might have prevented tendon rupture, and the tendinitis resolved completely with subsequent physical therapy.
Based on this outcome in this patient with UTI, fluoroquinolones should be used with caution, particularly in patients with risk factors predisposing to tendinitis, including advanced age and renal dysfunction.
A case report of a ciprofloxacin and simvastatin interaction is presented. The addition of ciprofloxacin to chronic simvastatin therapy led to the development of rhabdomyolysis. As ciprofloxacin is a weak inhibitor of CYP3A4, it is very likely that other mechanisms involving the ATP-binding cassette drug efflux transporter family played a role in this drug interaction.
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.
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.
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.
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.
Twenty-nine children with cystic fibrosis (CF) were investigated for quinolone-induced arthropathy. Magnetic resonance imaging (MRI) was performed in 14/14 children treated with ofloxacin or ciprofloxacin and in 10/15 of those never treated with quinolones. The frequency of pathologic MRI findings, concerning cartilage thickness, careful analysis of the cartilage structure, presence of edema, cartilage-bone borderline and the presence of fluid in joints did not show any difference between both groups. Thus the presence of quinolone-induced arthrotoxicity cannot be confirmed in this study.
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.
Ciprofloxacin is a highly potent antibacterial agent that is used extensively in bone and joint infections. Because of reports of potential chondro-toxicity in animals, the effects of this drug on cells derived from human cartilage were tested in liquid micromass and agarose gel cultures. An inhibition of cell proliferation as indicated by a decrease in [3H]-thymidine uptake and bromodeoxyuridine labeling at ciprofloxacin concentrations of 0.5 and 50 mg/l was found which corresponded to the therapeutic and toxic serum levels. There was no effect on proteoglycan synthesis as indicated by 35SO4 incorporation. Immunocytochemistry showed no changes in morphology or staining patterns for type-I procollagen, type-II collagen, keratan sulfate and unsulfated chondroitin. Because the amount of inhibition of DNA synthesis varied with different ciprofloxacin concentrations, this data suggests that this agent has a differential effect on newly differentiating cells and might be the basis for contraindication in pediatric patients.
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.
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.
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.
To determine whether there is an association between use of fluoroquinolones and tendinitis in a large population under everyday circumstances.
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.
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.
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.
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.
Quinolone-induced chondrotoxicity is possibly associated with the magnesium-chelating properties of quinolones. This toxic effect seems to be restricted to a rather short time period during postnatal development as shown in rats and dogs. We studied developmental changes of the integrin pattern on canine chondrocytes (e.g. the alpha(v)beta(3)- or alpha(5)beta(1)-integrin), because integrin function depends on divalent cations, as well as the matrix composition (e.g., collagen type II, fibronectin), in 11-, 18-, and 55-week-old Beagles (n=8) by immunohistochemistry. We also analyzed the magnesium and calcium content by atomic absorption spectroscopy in cartilage and bone and studied the effects of a magnesium-deficient diet on joint cartilage in four immature Beagles (18 weeks old at necropsy). The dogs were fed the magnesium-deficient diet for 40 to 46 days. All dogs exhibited gait alterations ('limping') after 4 weeks on the magnesium-deficient diet. Male, magnesium-deficient dogs exhibited pronounced weakness in their front legs; in one of these dogs the front legs were hyperextended to a 90 degrees angle. We observed no significant differences in the integrin pattern in samples from dogs at different developmental stages or in magnesium-deficient dogs in comparison to age-matched controls. Localization of fibronectin in the joint cartilage was found to vary with the age of the dogs as well as with the site of collection. In the middle zone of immature joint cartilage, corresponding to the predilective site of quinolone-induced cartilage lesions, we observed a slight increase in staining with the fibronectin antibody in some samples from magnesium-deficient dogs. Electron microscopy revealed alterations in chondrocytes from the magnesium-deficient dogs (e.g., swollen mitochondria and enlarged endoplasmic reticulum) which are also seen after treatment with quinolones. In summary, we found no significant differences of the integrin pattern on chondrocytes from joint cartilage of dogs at various developmental stages. However, magnesium deficiency in immature dogs induced similar clinical symptoms as quinolone treatment as well as distinct alterations in chondrocytic fibronectin staining and their ultrastructure. This corroborates our findings in rats where magnesium chelation is an important event in quinolone-induced chondrotoxicity.
Fluoroquinolones, such as ciprofloxacin, have an adverse effect on growing cartilage and endochondral ossification in children. This study was carried out to determine whether ciprofloxacin also has an adverse effect on the healing of experimental fractures.
Sixty male 300-gram Wistar rats were divided equally into three groups, which received ciprofloxacin, cefazolin, or no treatment for three weeks, beginning seven days after production of a closed, nondisplaced, bilateral femoral fracture. The serum concentrations of the ciprofloxacin and the cefazolin were 2.4 and 146 micrograms per milliliter, respectively. Radiographic, histological, and biomechanical studies were used to evaluate fracture-healing.
Radiographs revealed significantly more advanced healing of the control fractures compared with the fractures in the ciprofloxacin-treated group (average stage, 2.1 compared with 1.5, p = 0.01). The cefazolin-treated group was not different from the controls with respect to radiographic healing (average stage, 1.8 compared with 2.1, p = 0.18). Torsional strength-testing of fracture callus exposed to ciprofloxacin revealed a 16 percent decrease in strength compared with the controls (284 compared with 338 newton-millimeters, p = 0.04) and a 49 percent decrease in stiffness (twenty compared with thirty-nine newton-millimeters per degree, p = 0.001). The biomechanical strength in the cefazolin-treated group was not different from that of the controls. Fracture calluses in the animals treated with ciprofloxacin showed abnormalities in cartilage morphology and endochondral bone formation and a significant decrease in the number of chondrocytes compared with the controls (0.77 x 10(4) compared with 1.3 x 10(4) cells per square millimeter, p = 0.004).
These data suggest that experimental fractures exposed to therapeutic concentrations of ciprofloxacin in serum demonstrate diminished healing during the early stages of fracture repair. The administration of ciprofloxacin during early fracture repair may compromise the clinical course of fracture-healing.
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.
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.
We studied the inhibitory effects of the fluoroquinolones levofloxacin, ciprofloxacin, and trovafloxacin on growth and extracellular matrix mineralization in MC3T3-E1 osteoblast-like cell cultures. Levofloxacin had the least inhibitory effect on cell growth, with a 50% inhibitory concentration of approximately 80 microg/ml at 48 and 72 hours. Ciprofloxacin had an intermediate degree of inhibition, with a 50% inhibitory concentration of 40 microg/ml at 48 and 72 hours. Trovafloxacin exerted a profound inhibitory effect on cell growth, with a 50% inhibitory concentration of 0.5 microg/ml, lower than clinically achievable serum levels. The decreased cell counts with up to 2.5 microg/ml of trovafloxacin and with up to 40 microg/ml of ciprofloxacin were not associated with decreased rates of 5-bromo-2'-deoxyuridine incorporation per cell. Alatrovafloxacin, the L-alanyl-l-alanine prodrug of trovafloxacin, exerted effects on proliferation and 5-bromo-2'-deoxyuridine incorporation similar to those of the parent compound. The quinolones evaluated also inhibited extracellular matrix mineralization by MC3T3-E1 cells. Treatment of confluent cultures with trovafloxacin, ciprofloxacin, or levofloxacin resulted in strong inhibition of calcium deposition, as determined on day 14 by alizarin red staining and biochemical analysis. The effect was apparent with 2.5-5 microg/ml of each of the three antibiotics tested and progressively increased to more than a 90% decline in the calcium/protein ratio with 20-40 microg/ml antibiotic concentration. Further in vivo studies are advocated to evaluate the relevance of the in vitro cytotoxicity reported here to bone healing in orthopaedic patients.
Quinolones and magnesium deficiency cause similar lesions in joint cartilage of young animals. Chondrocytes cultivated in the presence of quinolones and in Mg-free medium show severe alterations in cytoskeleton and decreased ability to adhere to the culture dish. We investigated whether Mg2+ supplementation can prevent quinolone-mediated effects on chondrocytes in vitro. Chondrocytes cultivated in Dulbecco's modified Eagle's medium/HAM's F-12 medium were treated with ciprofloxacin (80 and 160 microg/ml) and enrofloxacin (100 and 150 microg/ml). Mg2+ was added at a concentration of 0.0612 mg/ml (MgCl) and 0.0488 mg/ml (MgSO4) or a triple dose. In addition, cells were cultivated in Mg-free medium and accordingly treated with Mg2+ supplementation. After 5 days in culture, the number of adherent cells per milliliter was determined. The number of chondrocytes in quinolone-treated groups decreased to 12-36% that of the control group within the culture period. With Mg2+ supplementation, the number of attached cells increased to 40-70% that of control cells. The threefold dose of Mg2+ led to better results than did the single dose. Cell proliferation tested by immunohistochemical staining with Ki67 (clone MIB5) decreased from 70% in control groups to 55%, 48%, and 30% in enrofloxacin-treated groups in a concentration dependent manner (50, 100, and 150 microg/ml). Addition of Mg2+ did not increase the rate of cell proliferation. These results suggest that a great part of quinolone-induced damage is due to magnesium complex formation, as Mg2+ supplementation is able to reduce the effects in vitro. However, quinolone effects on cell proliferation seem to be an independent process that is not influenced by magnesium supplementation.