Adverse Effects Of Fluoroquinolones Research Articles

Fluoroquinolone prophylaxis in patients with neutropenia at high risk of serious infections: Exploring pros and cons.

The use of fluoroquinolones to prevent infections in neutropenic patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT) is a controversial issue, with international guidelines providing conflicting recommendations. Although potential benefits are clear, concerns revolve around efficacy, potential harms, and antimicrobial resistance (AMR) implications. Fluoroquinolone prophylaxis reduces neutropenic fever (NF) bloodstream infections and other serious bacterial infections, based on evidence from systematic reviews, randomized controlled trials, and observational studies in adults and children. Fluoroquinolone prophylaxis may also reduce infection-related morbidity and healthcare costs; however, evidence is conflicting. Adverse effects of fluoroquinolones are well recognized in the general population; however, studies in the cancer cohort where it is used for a defined period of neutropenia have not reflected this. The largest concern for routine use of fluoroquinolone prophylaxis remains AMR, as many, but not all, observational studies have found that fluoroquinolone prophylaxis might increase the risk of AMR, and some studies have suggested negative impacts on patient outcomes as a result. The debate surrounding fluoroquinolone prophylaxis calls for individualized risk assessment based on patient characteristics and local AMR patterns, and prophylaxis should be restricted to patients at the highest risk of serious infection during the highest risk periods to ensure that the risk-benefit analysis is in favor of individual and community benefit. More research is needed to address important unanswered questions about fluoroquinolone prophylaxis in neutropenic patients with cancer or receiving HSCT.

CLINICAL PHARMACOLOGY OF FLOROCHINOLONS: A FOCUS ON SAFETY. Review

Fluoroquinolones are effective in the treatment of infections of almost any localization (upper and lower respiratory tract, urinary system, skin and soft tissues, bones and joints, liver and bile ducts, gastrointestinal tract, female genital tract, central nervous system, intra-abdominal), sexually transmitted infections. Resistance is slowly formed to fluoroquinolones. Among the benefits of certain fluoroquinolones are that they can be administered either orally or intravenously. Fluoroquinolones can also be combined with antibacterial agents of other groups. Levofloxacin (the left-turning isomer of ofloxacin) has now become one of the most commonly used antibiotics. This is because the drug exhibits high tissue penetration, creating in the alveolar macrophages, the mucous membranes of the bronchi and fluid lining the respiratory epithelium, a concentration that is significantly higher than the MIC to respiratory pathogens. The literature review presents current insights on the pharmacokinetics, pharmacodynamics, and adverse effects of fluoroquinolones. The risks of tendinitis, tendon ruptures, aortic aneurysm / dissection, QT prolongation, recurrence of C.difficile antibiotic-associated diarrhea, hypo- and hyperglycemic conditions are emphasized. The clinical role of fluoroquinolones inhibitory effect on cytochrome P450 isoenzymes CYP1A2 and CYP2C9 activities, which metabolize many drugs with low therapeutic index (derivatives of sulfonylureas, warfarin, phenytoin, and theophylline etc). Therefore, when deciding on the prescription of fluoroquinolones, especially for elderly patients, the doctor should collect a detailed anamnesis, in particular regarding the administration of drugs with a small therapeutic index, and conduct therapeutic drug monitoring, including monitoring blood glucose levels.

Adverse Effects of Fluoroquinolones: A Retrospective Cohort Study in a South Indian Tertiary Healthcare Facility.

The Food and Drug Administration (FDA) safety review revealed that the use of fluoroquinolones (FQs) is linked with disabling and potentially permanent serious adverse effects. These adverse effects compromise the tendons, muscles, joints, nerves, and central nervous system of the human body. The purpose of the study was to investigate the incidence and risk factors for adverse drug reactions (ADRs) caused by FQs in comparison with other antibiotics used. A retrospective cohort study was conducted over seven months in Kasturba Medical College Hospital, Manipal, India. Patients who were prescribed with FQs were selected as the study cohort (SC; n = 482), and those without FQs were the reference cohort (RC; n = 318). The results showed that 8.5% (41) of patients developed ADRs in the SC, whereas 4.1% (13) of patients developed ADRs in the RC. With oral and parenteral routes of administration, almost a similar number of ADRs were observed. Levofloxacin caused the highest number of ADRs reported, especially with the 750-mg dose. Based on a multiple logistic regression model, FQ use (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.18–4.39; p = 0.015) and concomitant steroid use (OR: 3.19; 95% CI: 1.31–7.79; p = 0.011) were identified as independent risk factors for the development of ADRs among antibiotics users, whereas age was found to be protective (OR: 0.98; 95% CI: 0.97–1.00; p = 0.047). The study found a higher incidence of ADRs related to FQs compared to other antibiotics. The study concludes a harmful association between FQ use and the development of ADRs. Moreover, FQs are not safe compared to other antibiotics. Hence, the use of FQs should be limited to the conditions where no other alternatives are available.

Effects of enrofloxacin on antioxidant system, microsomal enzymatic activity, and proteomics in porcine liver.

Enrofloxacin (EF) is a widely used fluoroquinolone, usually regarded as a safe and effective treatment for bacterial infections. Adverse effects of EF have previously been demonstrated in some species, but so far there have been no studies looking specifically at the impact of EF on pigs. In this study, three different doses of EF (5, 25 and 125mgkgbw-1 ) were administrated to Bama pigs. The results showed that lipid peroxidation of pig liver tissue occurred with all EF doses. The 125mgkg dose of EF induced catalase (CAT) and glutathione peroxidase (GSH-px) and increased CYP450 content in pig liver microsomes. The activity of microsomal NADPH-cytochrome C reductase (NCCR) was elevated at both the 25 and 125mgkg doses of EF. Microsomal erythromycin N-demethylase (ERND) and aminopyrin N-demethylase (AND) were inhibited by high doses of EF, while aniline-4-hydroxylase (AH) was unaffected. None of the EF treatments affected superoxide dismutase (SOD) or cytochrome b5 content. Antioxidases and microsomal enzymes may work together to resist the adverse effects of EF. Proteomic analysis revealed increased protein expression of carboxylesterase (CES) and alpha-enolase (ENO1) in microsomes as a stress response to EF. These results provide new information about the adverse effect of fluoroquinolones and help guide their usage more effectively in the clinic or animal breeding.

Fluoroquinolone Induced Movement Disorders: Case Report and Literature Review

Background: Movement disorders are a very rare adverse effect of fluoroquinolones. The mechanism involves inhibition of GABA-A-receptors as well as activation of the excitatory NMDA receptors. This is thought to induce a hyperexcitable neuronal state. A literature review suggests this is a class effect and occurs shortly after initiation and resolves within a few days of discontinuation. Case Presentation: A 62-year-old man with Campylobacter jejuni was treated with levofloxacin. The patient had normal liver enzymes and serum creatinine. Two hours after the initial dose of levofloxacin it was noted that the patient neck would shake and turn to the left and his right arm would abduct at the shoulder and flex at the elbow. The movements would occur every 1 to 2 minutes. There was muscle fasciculations in the bicep and forearm of the right arm briefly after the neck movement. The patient was given diphenhydramine 25 mg IV x 1 dose and within 20 minutes there was a reduction in the abnormal movements. Within 24 hours the movement disorder had completely resolved. Conclusion: The case presented and literature review summarizes the data on fluoroquinolone induced movement disorders.

The cytotoxic effects of levofloxacin on rat bone marrow mesenchymal stem cells

Objective To study the effects of levofloxacin on rat bone marrow mesenchymal stem cells (BMSCs). Methods Rat BMSCs were treated with levofloxacin at different concentrations (0, 5, 10, 20, 40, 80 μg/ml). Toxic effects of levofloxacin on cell viability was assessed by methyl thiazol tetrazolium (MTT) assay. The cell apoptosis was detected by double staining. Reverse transcription-polymerase chain reaction (RT-PCR) analysis were used to detect the expression of matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-13 (MMP-13), tissue inhibitors of metalloproteinase-1 (TIMP-1) and tissue inhibitors of metalloproteinase-3 (TIMP-3) in the treated cells. Results After being treated with a concentration of levofloxacin (5-80 μg/ml) for 48 h, the cell viabilities were decreased to 92.39%, 88.26%, 84.11%, 78.71%, and 71.90% of that in the control. Levofloxacin, with concentrations ranging from 5 to 80 μg/ml, induced dose-dependent BMSCs apoptosis (vs. control P values were 0.022, 0.013, 0.007, 0.004, 0.002). Moreover, levofloxacin significantly increased the mRNA expression of MMP-3 (vs. control P values were 0.025, 0.021, 0.014, 0.002, 0.001) and MMP-13 (vs. control P values were 0.015, 0.009, 0.004, 0.003, 0.001)and decreased the expression of TIMP-1 (vs. control P values were 0.027, 0.015, 0.007, 0.005, 0.001)in a concentration-dependent manner. Conclusion Levofloxacin has cytotoxic effects on BMSCs characterized, which suggest a potential adverse effect of fluoroquinolones. Key words: Levofloxacin; Bone marrow mesenchymal stem cells; Cytotoxicity; Apoptosis

Systemic use of fluoroquinolone in children

Fluoroquinolones are an important class of antibiotics that are widely used in adult patients because of their broad spectrum of activity, good tissue penetration, and oral bioavailability. However, fluoroquinolone use in children is limited because juvenile animals developed arthropathy in previous experiments on fluoroquinolone use. Indications for fluoroquinolone use in patients younger than 18 years, as stated by the U.S. Food and Drug Administration, include treatment of complicated urinary tract infections and postexposure treatment for inhalation anthrax. In Korea, the systemic use of fluoroquinolones has not been approved in children younger than 18 years. Although concerns remain regarding the adverse musculoskeletal effects of fluoroquinolones in children, their use in the pediatric population has increased in many circumstances. While pediatricians should be aware of the indications and adverse effects of fluoroquinolones, recent studies have shown that the risk for musculoskeletal complications in children did not significantly increase following fluoroquinolone treatment. In addition, fluoroquinolones may be particularly helpful in treating multidrug-resistant infections that have not responded to standard antibiotic therapy in immunocompromised patients. In the present article, we provide an updated review on the safety and current recommendations for using fluoroquinolones in children.

The effects of levofloxacin on rabbit anterior cruciate ligament cells in vitro

Articular cartilage, epiphyseal growth plate and tendons have been recognized as targets of fluoroquinolone-induced connective tissue toxicity. The effects of fluoroquinolones on ligament tissues are still unknown. The aim of this study was to investigate the effects of levofloxacin, a typical fluoroquinolone antibiotic drug, on rabbit anterior cruciate ligament (ACL) cells in vitro. Rabbit ACL cells were treated with levofloxacin at different concentrations (0, 14, 28, 56, 112 and 224 μM) and were assessed to determine the possible cytotoxic effects of levofloxacin on ACL cells. Levofloxacin, with concentrations ranging from 28 to 224 μM, induced dose-dependent ACL cell apoptosis. Characteristic markers of programmed cell death and degenerative changes were identified by electron microscopy in the ACL cells treated with 28 μM of levofloxacin. Moreover, levofloxacin significantly increased the mRNA expression of matrix metalloproteinase 3 (MMP-3) and MMP-13 and decreased the expression of tissue inhibitors of metalloproteinase 1 (TIMP-1) in a concentration-dependent manner; TIMP-3 and collagen type I alpha 1 (Col1A1) mRNA expression was not affected. Immunocytochemical analysis indicated that levofloxacin markedly increased the expression of active caspase-3 within a concentration range of 28 to 224 μM, whereas a clear-cut decrease in Col1A1 expression was found with levofloxacin treatment concentrations of 112 and 224 μM, compared to controls. Our data suggest that levofloxacin has cytotoxic effects on ACL cells characterized by enhanced apoptosis and decreased extracellular matrix, which suggest a potential adverse effect of fluoroquinolones.

Inhibition by fluoroquinolones of K + currents in rat dissociated hippocampal neurons

The effects of four fluoroquinolones (sparfloxacin, fleroxacin, ofloxacin and levofloxacin) on K + currents were investigated in pyramidal neurons acutely isolated from rat hippocampus, to evaluate their relative potencies for inhibiting these channels. Using patch-clamp electrophysiological techniques, we found that all four compounds inhibited the delayed rectifier K + current ( I K), but with different potencies. Sparfloxacin was the most potent compound, displaying an IC 50 value of 6.44×10 −4 M, followed by fleroxacin, ofloxacin and levofloxacin, their IC 50 values being 7.09×10 −3, 8.42×10 −3 and 1.10×10 −2 M, respectively. In contrast, the fast transient K + current ( I A) was blocked only by sparfloxacin (IC 50=2.86×10 −3 M) and fleroxacin (IC 50=4.38×10 −3 M), but not by ofloxacin and levofloxacin even at concentrations up to 1 mM. The K + current inhibition was reversible after washout of the compounds. Further study is needed to clarify the possible involvement of this novel action in the adverse effects of fluoroquinolones in the central nervous system (CNS).

Quinolones in the aged.

Pharmacokinetic studies of fluoroquinolone antibacterials generally demonstrate some quantitative alterations in elderly compared with younger populations. The most common observations are an increased maximal plasma drug concentration and area under the concentration-time curve, which are primarily attributable to the 10 to 15% decrease in lean body mass in the elderly. For quinolones excreted primarily by the renal route, there is a prolongation in elimination half-life correlated with the aging-associated decline in creatinine clearance. Quinolones with major routes of nonrenal clearance will not usually show a prolongation in half-life because of compensatory relative increases in nonrenal mechanisms. Alterations directly attributable to aging alone, however, are minor, and vary between different quinolones. They do not justify a consistent need for dosage alterations on the basis of age alone. Agents with primarily renal excretion, such as ofloxacin or levofloxacin, may require dosage adjustment in the very elderly or the frail elderly, if significant decreases in creatinine clearance are present. No age-related differences in adverse effects of fluoroquinolones have been reported. Studies in both community-dwelling and institutionalised elderly populations have consistently shown quinolones to be as effective as comparative parenteral or oral therapy. While elderly populations may be at greater risk of adverse effects because of comorbidities and concurrent therapies, an increased occurrence of adverse events in elderly populations receiving quinolone antimicrobials relative to younger populations has not been reported.

A Reappraisal of Quinolone Tolerability The Experience of their Musculoskeletal Adverse Effects

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

The adverse effects of fluoroquinolones.

The adverse effects of fluoroquinolones.