ArticleLiterature Review

Safety issues and drug–drug interactions with commonly used quinolones

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Abstract

Introduction: Quinolones are widely used antimicrobials with good efficacy and favourable safety. Recently, forms of quinolone toxicity such as peripheral neuropathy, retinal detachment or QTc-prolongation have attracted attention. Areas covered: Data on different aspects of direct quinolone toxicity are reviewed and consider risk factors and predisposing structural properties. Indirect forms of quinolone toxicity such as Clostridium difficile infections or adverse reactions associated with drug-drug interactions are also discussed. Finally, the role of transporters in the pharmacokinetics of these antimicrobials and their utilisation in critically ill patients are illustrated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2014 was completed using the terms: quinolone, quinolone-induced toxicity, quinolone pharmacokinetics, quinolone and critically ill, drug-drug interactions. Expert opinion: Quinolones exhibit an important component of the antibiotic arsenal. Although several adverse events have been associated with their use, taking into consideration risk factors, contraindications and potential drug-drug interactions can drastically reduce the respective risks.

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... Neuropathy is defined as any disease that affects peripheral nerves (excluding the brain and spinal cord) [56]. It gives many various signs and symptoms, but in the case of fluoroquinolone-induced neuropathy, the most characteristic is weakness, numbness, changes in pain and temperature sensitivity [57], hyperesthesia, hypoesthesia, allodynia, or even peripheral paresis [58]. There are also some reports indicating the possibility of optic nerve neuropathy related to the use of fluoroquinolones [59] that manifests with reduced visual acuity, reduced visual field, and color vision disturbances that resolve completely after discontinuation of the therapy. ...
... The drawback of this proposed mechanism is the fact that it was established in rats and investigated innervated organs were salivary glands, so the direct transfer to some symptoms in humans could not be certain. Some clinical and neurophysiological findings suggest a small fiber neuropathy pattern of toxicity [58,64], which is consistent with the work previously cited. Furthermore, axonal degeneration and demyelination patterns were also observed [65]. ...
... In conclusion, fluoroquinolone-induced neuropathy manifests itself as various symptoms that affect both sensory and motor neurons [57,58]. There are several hypotheses explaining the possible pathophysiology of this AE [62,63,65], but none of them is certain, and probably more than one mechanism is responsible for the full spectrum of observed neuropathies. ...
... Como en todos los fármacos orales, las alteraciones gastrointestinales (dispepsia, náuseas, vómitos y diarrea) son los EA más comunes de las fluoroquinolonas, llegando a suponer hasta el 20% [45]. glóbulo rojo en presencia del antibiótico causando hemólisis intravascular y otros sin él, generalmente IgG, que producen hemólisis extravascular [12,14]. ...
... Las interacciones medicamentosas de las fluoroquinolonas con repercusión clínica se producen cuando se administran conjuntamente con antiácidos que llevan magnesio y aluminio con los que forman complejos y reducen su biodisponibilidad oral. Puede evitarse si los antiácidos se toman al menos dos horas después [45,86]. También son consecuencia de la inhibición de algunos citocromos por ciprofloxacino: 1) CYP1A2 que altera el aclaramiento de algunos fármacos como olanzapina, haloperidol, amitriptilina, imipramina, duloxetina, verapamilo, propanolol, teofilina y cafeína; y 2) CYP3A4 que da lugar a un síndrome serotoninérgico. ...
... Es dosis dependiente y más frecuente en pacientes con más de 60 años. La probabilidad de fototosensibilidad entre las fluoroquinolonas disponibles sigue este orden creciente: ciprofloxacino > levofloxacino > moxifloxacino [45,61]. ...
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RESUMEN Los antibióticos orales son uno de los fármacos más utilizados en la comunidad. Sus efectos adversos son generalmente poco frecuentes y leves, e incluyen toxicidad e interacciones medicamentosas. El mecanismo de producción es variado y no siempre bien conocido. El conocimiento de los efectos adversos con relevancia clínica puede permitir hacer un uso más juicioso de los antibióticos basados en el principio primero no hacer daño, primun non nocere. En esta revisión exploramos los principales efectos adversos de los antibióticos orales con énfasis en los β-lactámicos, macrólidos y fluoroquinolonas.
... Los EA más frecuentes de las fluoroquinolonas son los digestivos: dispepsia, náuseas, vómitos y diarrea. Las náuseas y vómitos también pueden ser de origen central por neurotoxicidad [92]. Las alteraciones hepáticas consisten habitualmente en elevaciones leves de las transaminasas [66,92]. ...
... Las náuseas y vómitos también pueden ser de origen central por neurotoxicidad [92]. Las alteraciones hepáticas consisten habitualmente en elevaciones leves de las transaminasas [66,92]. Las fluoroquinolonas, como otros antibióticos, también son un factor de riesgo para la aparición de diarrea asociada a C. difficile [62]. ...
... Neurológicos. Los EA localizados en el sistema nervioso periféricos suponen < 1%, su espectro clínico es muy amplio e incluye hipoestesia, hiperestesia, alodinia, paresia, síndrome de Guillain Barré y polineuropatía periférica aguda [92]. La afectación del sistema nervioso central puede llegar hasta el 2% y también es muy variada: ansiedad, inquietud, nerviosismo, euforia, alucinaciones, delirio, manía, psicosis, encefalopatía, disquinesia orofacial, mioclonía, ataxia, disartria, corea, mareo y convulsiones [92]. ...
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Exacerbation of chronic obstructive pulmonary disease and community-acquired pneumonia are the most frequent infections of the lower respiratory tract in daily clinical practice. Antibiotic selection is a crucial component in its treatment and, in most cases, it is performed empirically. Scientific societies make therapeutic recommendations based on scientific evidence and / or expert recommendations that are of great help to clinicians. Beta-lactams, fluoroquinolones and macrolides are the most commonly used drugs for oral administration. From a practical point of view, there are three keys to the appropriate choice of oral antibiotic treatment, which are the effectiveness, safety and the ecological impact on the patient's microbiota, including the development of resistance, which will be assessed in depth in this review. ©The Author 2019. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).
... The most common associated CNS adverse reactions are anxiety, restlessness, nervousness, euphoria, and dizziness with an incidence of up to 2%. 16 QT interval prolongation is also a notable adverse reaction to quinolones. 17 Other rare serious adverse events such as Clostridium difficile-associated diarrhea and hepatitis have also been observed with varying degrees of causation evidence. ...
... Ciprofloxacin, levofloxacin, and moxifloxacin are the most widely used quinolones. 16 AEs commonly associated with fluoroquinolones include gastrointestinal and CNS toxicity (headache and dizziness). ECG abnormalities (such as QT interval prolongation), disrupted glucose metabolism, phototoxicity, tendon and joint disorders, hypersensitivity and skin disorders, peripheral neuropathy, retinal detachment, and hepatic toxicity were also reported. ...
... ECG abnormalities (such as QT interval prolongation), disrupted glucose metabolism, phototoxicity, tendon and joint disorders, hypersensitivity and skin disorders, peripheral neuropathy, retinal detachment, and hepatic toxicity were also reported. 16,17 This report presents the safety profile of nemonoxacin by integrating the data of two phase II and one phase III clinical study data. In general, nemonoxacin taken orally once daily was found to be safe and well tolerated in patients with CAP. ...
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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.
... Previously, it was also investigated in a clinical phase II study as a treatment for enteric infection, including that caused by C. difficile [23,24]. In addition, OPS-2071 has low systemic absorption in humans after oral administration, similar to rodents, so its efficacy may be exerted in the gastrointestinal tract alone, and it may be possible to avoid known quinolone side effects such as QTc prolongation, dysglycemia, and adverse central nervous system reactions [23,25,26]. In fact, severe side effects were not observed in the phase I clinical trial designed to evaluate the safety and tolerability of single and multiple ascending oral doses of OPS-2071 in healthy individuals [26]. ...
... Therefore, it is not expected that other fluoroquinolones will exert an immunosuppressive effect in vivo at clinical dose levels. In addition, even if other fluoroquinolones have similar immunosuppressive effects, it is difficult to increase their dose to achieve similar immunosuppressive effects in colonic mucosa due to their higher bioavailability and the risk of systemic side effects that are peculiar to quinolones [25]. Because of its immunosuppressive activity and low absorption, OPS-2071 may be the first fluoroquinolone to exert a functional immunosuppressive effect solely in the gastrointestinal tract. ...
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Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although many types of drug are used, clinical outcomes are still unsatisfactory. Previous studies have suggested that intestinal bacteria are involved in the pathogenesis of IBD. Accordingly, in an IBD model we evaluated the therapeutic effects of OPS-2071, a low-absorption quinolone antibacterial agent indicated for intestinal infection, and investigated its mechanism of action.Methods The therapeutic effects of OPS-2071 and comparison therapies were evaluated using naive CD4 + T cell-transfer IBD model mice. In vitro inhibition of LPS-induced TNF-α production and inhibitory effects on T cell responses stimulated using anti-CD3/CD28 antibody-loaded beads were evaluated using mouse splenocytes and human peripheral blood mononuclear cells. In addition, in vitro activities against bacteria implicated in IBD pathogenesis were tested.ResultsOPS-2071 dose-dependently decreased both colonic weight/length ratio and the colitis histological score as compared with the vehicle group. The therapeutic effect of OPS-2071 was equivalent to that of anti-IL-12/23 (p40) antibody. In vitro, OPS-2071 suppressed TNF-α production induced by LPS stimulation and T cell responses in a dose-dependent manner. At high concentrations, these effects were comparable to those of existing immunosuppressive agents, such as prednisolone, in both mouse and human cells. OPS-2071 also showed antibacterial activity against IBD-related bacteria.Conclusions Our results suggest that OPS-2071 had both immunosuppressive and antibacterial effects. This dual effect makes OPS-2071 a unique and promising candidate for IBD.
... clozapine, theophylline) have been observed. [237] Concomitant oral administration of enoxacin (400 mg twice daily for 6 days) with theophylline (250 mg twice daily for 11 days) resulted in a reduction in total clearance of theophylline by 74% in six healthy subjects, [238] while ciprofloxacin (500 mg twice daily for two and a half days) reduced theophylline's total clearance by 19% after a single oral dose of theophylline syrup (3.4 mg/kg) in nine healthy subjects. [239] In contrast, concomitant administration of norfloxacin (400 mg twice daily for 4 days) with theophylline (200 mg three times daily for 4 days) had no significant effect on theophylline's total clearance in 10 healthy subjects. ...
... [240] For more detailed information, the reader is referred to several review articles. [233,237,241] Anti-inflammatory drugs for inflammatory bowel disease ...
... Zu beachten ist, dass Fluorchinolone nicht zusammen (Mindestabstand 2 h) mit Milch und Milchprodukten, mineralischen Antazida oder anderen Arzneimitteln mit zwei-oder dreiwertigen Ionen (wie Eisen, Zink, Calcium oder Aluminium) eingenommen werden sollen [197]. Einige Medikamente der Nicht-Standardtherapie erreichen höhere Serumspiegel, wenn sie mit der Nahrung aufgenommen werden (z. ...
... Enterale Komplexbindung mit di-oder trivalenten Kationen, wie Eisen, Magnesium, Calcium, Zink, Aluminium, Sucralfat, dadurch starke Verminderung der Resorption. Die gleichzeitige Gabe der genannten Medikamente oder Nahrungsmittel, die hohe Konzentrationen von mehrwertigen Kationen aufweisen, muss daher unterbleiben oder es muss ein mehrstündiger Abstand eingehalten werden [197]. Wichtige unerwünschte Arzneimittelwirkungen*: Störungen des Zentralnervensystems (Kopfschmerzen, Schlaflosigkeit, schlechte Träume), in seltenen Fällen kann es zu epileptischen Anfällen kommen, gastrointestinale Reaktionen (Übelkeit, Erbrechen, Diarrhö), Sehnenentzündungen und Sehnenrupturen (Risiko erhöht bei gleichzeitiger Gabe von Kortikosteroiden), periphere Neuropathie, QT-Zeit-Verlängerung, Herzrhythmusstörungen. ...
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Zusammenfassung In Deutschland ist seit 2015 ein deutlicher Anstieg der gemeldeten Tuberkulosefälle zu verzeichnen. Zurückzuführen ist dieser vor allem auf die aktuell vermehrte Migration. Durch die niedrige Inzidenz in den vorhergehenden Jahren konzentriert sich die Erfahrung im Umgang mit Tuberkulose immer mehr auf spezialisierte Zentren. Pneumologen wie auch andere Fachbereiche sind nun aber wieder häufiger an der Behandlung einer Tuberkulose beteiligt, sodass Fachwissen zur Standardtherapie wie auch zu selteneren Therapiesituationen benötigt wird. Die aktuelle Leitlinie zur Diagnostik und Therapie, einschließlich Chemoprävention und -prophylaxe im Erwachsenenalter fasst den derzeitigen Wissensstand zusammen und passt die Empfehlungen an die Situation in Deutschland an. Realisiert wurde die AWMF S2k-Leitlinie durch das Deutsche Zentralkomitee zur Bekämpfung der Tuberkulose e. V. (DZK) im Auftrag der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V. (DGP). Zur Behandlung der Tuberkulose im pädiatrischen Bereich wird in Kürze eine eigenständige Leitlinie der entsprechenden Fachgesellschaften veröffentlicht. Im Vergleich zu den Empfehlungen von 2012 sind eigenständige Kapitel zur Labordiagnostik und zum therapeutischen Medikamentenmanagement entstanden. Die Kapitel Mehrfachresistenzen gegen Medikamente der Standardtherapie, HIV-Koinfektion und die Übersicht der Arzneimittel wurden erweitert. Die umfangreiche Überarbeitung der Empfehlungen soll Ärzten und auch anderen Beschäftigten im Gesundheitswesen helfen, den aktuellen Herausforderungen im Umgang mit dem selten gewordenen Tuberkuloseerreger zu begegnen.
... When phosphate-binders are administered concomitantly with a quinolone, reduced absorption occurs due to chelation caused by phosphate binders, demonstrated by a reduction of the Cmax and AUC. This likely results in decreased therapeutic efficacy of quinolone therapy [60]. ...
Article
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Antimicrobial agents are widely used, and drug interactions are challenging due to increased risk of adverse effects or reduced efficacy. Among the interactions, the most important are those affecting metabolism, although those involving drug transporters are becoming increasingly known. To make clinical decisions, it is key to know the intensity of the interaction, as well as its duration and time-dependent recovery after discontinuation of the causative agents. It is not only important to be aware of all patient treatments, but also of supplements and natural medications that may also interact. Although they can have serious consequences, most interactions can be adequately managed with a good understanding of them. Especially in patients with polipharmacy it is compulsory to check them with an electronic clinical decision support database. This article aims to conduct a narrative review focusing on the major clinically significant pharmacokinetic drug-drug interactions that can be seen in patients receiving treatment for bacterial infections.
... However, their use has been associated with safety concerns, including connective tissue disorders, adverse cardiovascular outcomes, and neuropathies. 1 Another safety concern is hypoglycaemia, which has led to the withdrawal of gatifloxacin and class-wide safety warnings by regulatory agencies. [2][3][4] The link between fluoroquinolones and hypoglycaemia is supported by pharmacovigilance analyses 5 and observational studies. 2 The underlying pharmacologic mechanism involves the inhibition of K + channels in pancreatic beta-cells and a subsequent increase in insulin secretion. ...
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Aim: Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. Materials and methods: Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. Results: Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. Conclusions: In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible.
... Fluoroquinolones are commonly used antibiotic agents that are effective for a variety of infections among the patients being treated for cancer. Nevertheless, cardiac side effects such as an amplified risk of QT interval prolongation and TdP have also been observed in patients using fluoroquinolones [22,23] . Among reported cases with antibiotic-induced QT prolongation, drug interactions are the most common acquired risk factor for TdP [24] . ...
Preprint
Aims: Tyrosine kinase inhibitors (TKIs) improve patient outcomes, but the prevalence of clinically significant TKI-associated drug–drug interaction (DDI) is unknown. We aim to assess the risk prevalence between TKIs and other drugs in cancer patients. Methods: This was a retrospective cross-sectional study conducted in three tertiary care hospitals. All medical data were collected in the computer-based medication prescription system from January 2020 to December 2020. The hazardous DDIs identification has been performed using US Food and Drug Administration-approved labels. Descriptive statistics and univariate and multivariate logistic regression analyses were applied to identify risk factors associated with potential hazardous interactions. Results: A total of 2754 patients were included in our study. 413 hazardous DDIs were identified and 387 (14.1%) patients experienced at least one DDI. Proton pump inhibitor, dexamethasone and fluoroquinolones were most frequently implicated in clinically relevant DDIs with TKIs. In a multivariate analysis, younger age, the number of drugs and lung cancer had a higher risk for the occurrence of hazardous DDIs. Conclusions: The prevalence of hazardous DDIs is relatively high in the cancer patient population receiving TKIs treatment. The awareness of potential clinically relevant DDIs can help patients reduce the probability of adverse event of drugs.
... Quinolones are generally well tolerated agents, but they may sometimes cause adverse drug reactions (ADRs). In general, the central nervous system (CNS) side effects are few (1% and less) (1,2). The most common side effects are on the gastrointestinal system (approximately 20%) (2). ...
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Introduction: Moxifloxacin is an antibiotic used orally or parenterally in the emergency department (ED) for the treatment of various infections, especially acute exacerbation of chronic bronchitis and community-acquired pneumonia. The side effects of the drug are mainly on the gastrointestinal system, while the central nervous system side effects are rare. Case report: Herein, we present an elderly patient who had altered mental status associated with the use of moxifloxacin. Upon discontinuation of the drug, the patient quickly returned to baseline neurologic status. In the evaluation of altered mental status in elderly patients in the ED, much of the effort should be spent primarily on ruling out more complex diagnoses. However, this approach requires more invasive and advanced testing. Conclusion: Considering drug side effects among these more complicated diagnoses may increase noninvasive and radiation-free options for the patient and physician.
... Wegen enteraler Komplexbindung mit di-oder trivalenten Kationen wird empfohlen, Milchprodukte und Zubereitungen, die 2-wertige oder 3-wertige Kationen enthalten, wie bspw. Eisen-oder Zinksalze oder Magnesium-oder Aluminium-haltige Antazida, 2 Stunden vor bis 2 Stunden nach der Anwendung nicht einzunehmen [397]. ...
Article
Zusammenfassung Die Tuberkulose ist in Deutschland eine seltene, überwiegend gut behandelbare Erkrankung. Weltweit ist sie eine der häufigsten Infektionserkrankungen mit ca. 10 Millionen Neuerkrankungen/Jahr. Auch bei einer niedrigen Inzidenz in Deutschland bleibt Tuberkulose insbesondere aufgrund der internationalen Entwicklungen und Migrationsbewegungen eine wichtige Differenzialdiagnose. In Deutschland besteht, aufgrund der niedrigen Prävalenz der Erkrankung und der damit verbundenen abnehmenden klinischen Erfahrung, ein Informationsbedarf zu allen Aspekten der Tuberkulose und ihrer Kontrolle. Diese Leitlinie umfasst die mikrobiologische Diagnostik, die Grundprinzipien der Standardtherapie, die Behandlung verschiedener Organmanifestationen, den Umgang mit typischen unerwünschten Arzneimittelwirkungen, die Besonderheiten in der Diagnostik und Therapie resistenter Tuberkulose sowie die Behandlung bei TB-HIV-Koinfektion. Sie geht darüber hinaus auf Versorgungsaspekte und gesetzliche Regelungen wie auch auf die Diagnosestellung und präventive Therapie einer latenten tuberkulösen Infektion ein. Es wird ausgeführt, wann es der Behandlung durch spezialisierte Zentren bedarf. Die Aktualisierung der S2k-Leitlinie „Tuberkulose im Erwachsenenalter“ soll allen in der Tuberkuloseversorgung Tätigen als Richtschnur für die Prävention, die Diagnose und die Therapie der Tuberkulose dienen und helfen, den heutigen Herausforderungen im Umgang mit Tuberkulose in Deutschland gewachsen zu sein.
... Due to their strong potency, wide range of activity, excellent absorption, practical formulations, high serum concentrations, and comparatively low frequency of side effects, quinolones have been favored as antibiotics for more than five decades. Quinolones are frequently given for a variety of human infections; however, they have some modest adverse effects as well as gastrointestinal and CNS responses, genotoxicity, and phototoxicity (Douros et al., 2015). ...
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Typhoid fever is a febrile illness caused by Salmonella species (Enterica serovars typhi). Typhoid fever is primarily transmitted through contaminated water or food. Quinolones are one of the most commonly prescribed antibacterial classes used for the treatment of different bacterial infections in humans including typhoid fever. Due to the widespread use of these drugs, the number of quinolone-resistant bacterial strains are increasing all the time. Salmonella resistance mechanisms to the quinolone antibiotic class have become increasingly complex, attracting global attention. Studies on Salmonella resistance to the quinolone class of antibiotics are not well reported in Nigeria. This information is scanty or completely not covered the Northern parts of Nigeria in the available literature. As a result, this review discusses previous and current research on Salmonella resistance to a class of quinolone antimicrobial drugs in Nigeria.
... Lack of activity against β-lactams for some intracellular atypical respiratory pathogens and poor tolerability of fluoroquinolones among children and elderly patients limit their use as first-line drugs in community settings. 12 Thus, while countries such as China are experiencing the need of new respiratory antibiotics, the paradox is that, globally, the discovery efforts in this therapeutic area have been relatively curtailed. Failure to successfully develop an outpatient and hospital-use commensurate CABP antibiotic in recent years underlines the enormous discovery and development challenges in optimising oral and IV PK, and gaining monotherapy-appropriate pathogen spectrum coverage. ...
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Background: Widespread MDR Streptococcus pneumoniae in China translates clinically into a substantial pneumococcal disease burden and related morbidity and mortality, particularly in the elderly and children. Nafithromycin (WCK 4873), a novel lactone ketolide class of antibiotic designed with a 3 day, once-daily regimen is highly active against resistant pneumococci and other community respiratory pathogens. It is currently in clinical development for the treatment of community-acquired bacterial pneumonia (CABP). Objectives: To determine the in vitro activity of nafithromycin against clinical S. pneumoniae isolates collected during 2015-21 from three hospitals in mainland China. Methods: A total of 920 clinical isolates (one isolate per patient), which predominantly with the macrolide- and clindamycin-resistant phenotype were included in this study. The MICs of nafithromycin and other antibiotics tested were determined using the reference broth microdilution method. Results: Clinical S. pneumoniae isolates used in this study showed high macrolide and clindamycin resistance (>95% against erythromycin and azithromycin and 80% against clindamycin) for which nafithromycin showed potent activity (MIC50/90; 0.03/0.06 mg/L) with 100% susceptibility at a proposed pharmacokinetics/pharmacodynamics (PK/PD) breakpoint of 0.25 mg/L. Among other classes of antibiotics tested, moxifloxacin also showed good activity while amoxicillin/clavulanate and ceftriaxone showed lower susceptibility. Conclusions: Nafithromycin exhibited therapeutically relevant in vitro antibacterial activity against contemporary highly resistant pneumococci collected from mainland China. This study supports the clinical development of nafithromycin for the management of CABP caused by pneumococci in China.
... (dabigatran, apixaban and rivaroxaban) are presented in Table 3 which are substrates for these enzymes. 11,12,29,30 In addition, Dethlefsen et al reported that the time to return to normal intestinal flora after ciprofloxacin administration was about 2-5 months. 26 clarithromycin on hospitalization for major bleeding. ...
Article
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Fluoroquinolones and macrolides may, due to a potential drug‐drug interaction, increase the concentration of any concomitantly administered direct oral anticoagulant (DOAC) and thereby increase the risk of severe bleeding. However, clinical evidence for such an effect is scarce. The present study aimed to evaluate the association between the use of fluoroquinolones or macrolides and bleeding events in patients with concomitant DOAC use. This was a nationwide cohort study including 19 288 users of DOACs in 2008‐2018 using information from Swedish national health registers. We compared the incidence of bleeding events associated with use of fluoroquinolones or macrolides using doxycycline as a negative control. Cox regression was used to calculate crude and adjusted hazard ratios (aHRs) in time windows of various length of follow‐up after the start of antibiotic use. The incidence rates for fluoroquinolones and macrolides ranged from 12 to 24 and from 12 to 53 bleeding events per 100 000 patients in the investigated time windows. The aHRs (95% confidence interval) for use of fluoroquinolones and macrolides were 1.29 (0.69‐2.44) and 2.60 (0.74‐9.08) at the concomitant window, 1.31 (0.84‐2.03) and 1.79 (0.75‐4.29) at 30 days, and 1.34 (0.99‐1.82) and 1.28 (0.62‐2.65) at 150 days, respectively. With regard to fluoroquinolones, the present study suggests that the risk of bleeding when combined with DOACs, if any, is small. Codispensation of macrolides in patients on DOACs was not associated with an increased risk of bleeding. However, due to the small number of macrolide users, the results must be interpreted with caution.
... Many epidemiologic studies have examined quinoloneassociated RD risk, with conflicting results [24,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. In 2013, the US FDA 1 flagged a safety signal for quinoloneassociated RD risk based on spontaneous reports to FAERS 2 [38,50]. ...
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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.
... Fluoroquinolones and domperidone are commonly used to treat cancer patients with infections, nausea or vomiting. However, cardiac adverse events such as QTc prolongation and amplified risk of torsades de pointes (TdP) have also been observed in patients taking fluoroquinolones or domperidone (Rossi and Giorgi, 2010;Douros et al., 2015). Although the incidence of cardiac events is low with the use of fluoroquinolones or domperidone alone, the concurrent use of drugs that potentially prolong the QTc interval may markedly increase the risk of pro-arrhythmic effects (Haverkamp et al., 2012;Biewenga et al., 2015;Ehrenpreis et al., 2017;Brunetti et al., 2019). ...
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Background: Oral administration increases the risk of interactions, because most oral antineoplastic agents (OAAs) are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Potential drug–drug interactions (DDIs) are commonly observed in patients with cancer, while the extent to which OAAs related hazardous DDIs remains unclear. Methods: We studied the contraindication patterns between oral antineoplastic agents and other medications among cancer patients in two tertiary care teaching hospitals in China. A total of 20 clinically significant hazardous DDI pairs that involved 30 OAAs were identified based on the predetermined criteria. Patient medications were checked for DDIs by using the US Food and Drug Administration approved labeling. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. Results: In this study, 13,917 patients were included and a total of 297 DDIs were identified. The results revealed that proton pump inhibitors (PPIs), dexamethasone and fluoroquinolones were the most often involved hazardous DDIs with OAAs. The most prevalent contraindication is the simultaneous use of certain molecular targeted agents and PPIs. In the result of the multivariate analysis, younger age (0–20 group), increasing number of drugs and patient treated with targeted therapy had a higher risk for DDIs. Conclusion: The prevalence of OAAs related hazardous DDIs appears to be low in the cancer patients. However, physicians and clinical pharmacologists should be aware of the potential hazardous DDIs when prescribing OAAs, especially certain pH-dependent molecular targeted agents and potential QTc prolonging drugs.
... Widely used for both prophylaxis and the therapy of various infections [1,2], due to their high antibacterial activity [1,3], broad spectra (against respiratory, genitourinary, gastrointestinal, bone, and ophthalmic infections), and favorable pharmacokinetics [3], fluoroquinolones (FQs) are generally well tolerated [2,[4][5][6], reportedly possessing a favorable safety profile [7]. Nevertheless, serious, disabling, and potentially permanent side effects associated with the class and affecting muscles, joints, and the nervous system, triggered safety reviews by both the U.S. Food and Drug Administration (FDA) (2016) [8] and the European Medicines Agency (EMA) (2019) [9]. ...
Article
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Background: Recent drug safety concerns described fluoroquinolone (FQ)-induced peripheral nervous system reactions. The objective of this study was to characterize such reports from VigiBase. Methods: The analysis included FQ-induced peripheral nervous system disorder adverse drug reaction (ADR) reports (up to July 2019). We looked into the disproportionality data in terms of proportional reporting ratio (PRR) and information component (IC) values, and descriptive analysis was performed for FQ-ADRs positive associations (ADRs, suspected FQs, potential risk factors, such as associated therapy and underlying disease). Results: Disproportionality analysis revealed 4374 reports (3531 serious) with peripheral nervous system ADRs associated with at least three FQs (neuropathy peripheral, 5492; neuralgia, 481; polyneuropathy, 220; sensory loss, 99; peripheral sensorimotor neuropathy, 39). Among these, both time-to-onset and duration of reaction were mostly between 1-7 days and ≥30 days. Most of the ADRs were not recovered/resolved at the time of reporting. Conclusion: The results augment the existing data on FQ safety concerns, specifically their potential effect on the nervous system.
... There are significant interactions between FQs and multivalent cations (calcium, aluminum, zinc). [98] FQs can increase the level of warfarin, cyclosporine, sirolimus, and digoxin. [99] However, in a clinical setting, the extent of drug interaction may vary under fast and fed conditions. ...
Article
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COVID-19 is a pandemic viral pneumonia caused by β-coronavirus SARS-CoV-2. It is associated with many complications including extreme systemic inflammatory response which eventually causes acute respiratory distress syndrome (ARDS), hypercoagulability, cytokine storm, failure of vital organs, and a high incidence of death. Bacterial secondary infection is possibly involved, in such cases, the role of antibiotics is justified. However, some antibiotics may have a role beyond the management of secondary infection. The current review discussed the potential antiviral effects of certain Fluoroquinolones (FQs) against SARS CoV-2 viruses. Several mechanisms such as targeting Main proteases and acting as zinc ionophore are discussed. Also explained their unique features, good access to lung tissues for suppression of inflammatory response via modulation of matrix metallopeptidases (MMPs) are explored. Their role in secondary infections, pharmacokinetics, and safety issues was briefly explored‎. The promising favorable features of FQs along with their efficacy in the management of secondary infections, highlights the need to consider these important antibiotics for more research as well as clinical trials in the management of COVID-19
... It is easy to understand why. Members of this group have proved themselves to be systemic drugs [1][2][3], very effective in treating acute infectious inflammatory diseases [4], they share such mechanism of action in which the bacterial DNA gyrase (the key bacterial enzyme) is inhibited [5]. Fluoroquinolones target two elements in bacterial cells, two enzymes, responsible for transforming spatial configuration of DNA [6][7][8][9]. ...
Article
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In the present research we study the changes in ratio of different kinds of leucocytes in chickens of Hisex Brown cross following the application of fluoroquinolone antibiotic drugs. In the study we used Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Enrofloxacin. The control set was given pure drinking water throughout the experiment; each of the experimental groups was given water with one of the above-mentioned antibacterial fluoroquinolone drugs, the dosage being 200 mg/L. The leukogram contains the total number of leucocytes and the content of separate cell types and their total numbers. The study reveals significant and valid changes concerning the number of lymphocytes. On the seventh and the ninth days after the drug withdrawal all the fluoroquinolones except Ofloxacin caused lymphopenia. The valid changes in the number of pseudoeosinophils do not show clear tendencies, such changes are observed once under the influence of each drug on different days of the research. Levofloxacin, Enrofloxacin, Ofloxacin cause refractory basophilia. The application of antimicrobial fluoroquinolone drugs in the course of ten days results in changes in the ratio of different kinds of leucocytes in chicken blood, but at the conclusion of the experiment every value in the leukogram returns to physiological standard.
... Analysis of treatment protocols for infectious diseases at poultry farms shows a noteworthy trend in use of fluoroquinolone medicines. Such situation can be explained by the fact that by now medicines of this pharmacological group have solidly proven to be effective chemotherapeutic drugs which have systemic action [1][2][3] and are highly effective in management of severe infectious and inflammatory diseases [4], which share a common mechanism of action inhibiting the key enzyme (DNA-gyrase) of bacterial cells [5]. Fluoroquinolones affect two targets in a microbial cellenzymes responsible for transformation of spatial configuration of DNA [6][7][8][9]. ...
Article
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This study was aimed at evaluation of white blood cells of domestic birds over time using a broad-spectrum chemotherapeutic drug Ciprofloxacin. Ciprofloxacin more actively inhibits gram-negative bacteria. In order to evaluate the dynamics, three groups of chickens were formed (1st group – control; 2nd and 3rd groups – experimental ones), which consisted of Hisex Brown cross-bred cockerels. Within the framework of this experiment chickens in the 2nd and 3rd groups were contaminated with Escherichia coli . A day before and for four days after the contamination chickens in the 3rd group received 200 mg/L of ciprofloxacin with water. Blood samples were drawn from all experimental chickens at Day 1, 5, 10, 15 and 20 after the contamination. White blood cell differential count was performed. Analysis of the data obtained showed significant changes in some blood cell parameters in the 2nd and 3rd groups in comparison to the control group. Inflammatory response was detected, which was characterized by significant increase in absolute count and percentage of pseudoeosinophils, monocytes and basophils in the 2nd and 3rd group in comparison to the control group. Nevertheless, white blood cells differential count in the 3rd group was relatively closer to analogous count in the control group.
... However, a large quantity of quinolones were emitted into the environment through human and animals' excrement, causing environmental pollution because of their bacterial resistance, allergy, and toxicity (Junza et al. 2014;Hou et al. 2014). Therefore, extensive use of quinolones will pose harmful effect on ecological environment and human health (Moreno-González et al. 2014;Douros et al. 2015). Among quinolone antibiotics, fleroxacin (FLRX), enoxacin (EN), norfloxacin (NOR), ciprofloxacin (CIP), enrofloxacin (ENRO), and lomefloxacin hydrochloride (LOME) were often detected in environment waters (Lang et al. 2018;Zhang and Cheng, 2019). ...
Article
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Rapid separation and analysis of trace quinolones (fleroxacin (FLRX), enoxacin (EN), norfloxacin (NOR), ciprofloxacin (CIP), enrofloxacin (ENRO), and lomefloxacin hydrochloride (LOME)) in real water samples were achieved by using a multi-templates molecularly imprinted polymer (MIP) based solid phase extraction (SPE) coupled with dispersive liquid-liquid microextraction (DLLME) followed by high performance liquid chromatography (HPLC). The MIP was prepared via surface molecular imprinting, using the selected quinolones as the templates and mesoporous silica modified magnetic graphene oxide as the carrier. The preparation and adsorption conditions were optimized. The MIP presented high adsorption capacity and wonderful selective recognition for the quinolones, with the adsorption capacities of 20.15, 20.88, 18.01, 20.01, 16.98, and 17.09 mg/g for FLRX, EN, NOR, CIP, ENRO, and LOME, respectively. Meanwhile, a SPE-DLLME-HPLC method for trace detection of FLRX, EN, NOR, CIP, ENRO, and LOME in real water samples was developed and showed outstanding applicability. The spiked recoveries and relative standard deviations (RSDs) were 89.67–100.5%, and 3.59–7.12%, respectively.
... Long-term or high-dose antibiotic administration may cause varying degrees of toxicity to bodily tissues and organs [3]. For example, the incorrect use of quinolone antibiotics can cause serious adverse reactions in the tendons, muscles, joints and nervous system [4,5] and may lead to systemic multiorgan toxicity in severe cases. Additionally, the extensive use of antibiotics promotes the emergence of drug-resistant bacteria, which are a serious threat to human health. ...
Article
Conventionally used antibiotics are present in low concentrations at the infection site and require multiple administrations to sustain a continuous bactericidal effect, which not only increases their systemic toxicity but also results in bacterial drug resistance. In this study, we first identified an interesting drug resistance mechanism mediated by bacterial outer membrane vesicles (OMVs) and then designed novel antibiotic-loaded OMVs using this mechanism. We show that these antibiotic-loaded OMVs can effectively enter and kill pathogenic bacteria in vitro. In a mouse model of intestinal bacterial infection, one low-dose oral administration of antibiotic-loaded OMVs showed that the drug was retained in the intestine for 36 h, and no systemic spread was detected 12 h after drug administration. The antibiotic-loaded OMVs significantly reduced the bacterial load in the small intestine and feces of infected mice. Safety experiments confirmed that the antibiotic-loaded OMVs had excellent biocompatibility. This study extends the application range of OMVs and provides new ideas for the development of antibacterial drugs.
... As experience with the class has grown, AEs associated with the class have been well defined and have become a prospective part of the development process of more current FQs [1,15]. However, not all FQs have the same AE profile. ...
Article
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Background Through improved understanding of the structure-activity relationship attributes of fluoroquinolones, molecule development has improved efficacy, safety, and tolerability of the class. Adverse events (AEs) associated with the fluoroquinolones are well defined and a prospective part of the development process. However, not all fluoroquinolones have the same AE profile with different substitutions on the core molecule resulting in differences in side effects and spectrum of activity. Unique structural attributes of delafloxacin (DLX) may differentiate its AE profile compared to other fluoroquinolones. This analysis compared the incidence of AEs between DLX and vancomycin/aztreonam across two phase 3 ABSSSI studies in order to provide a broader overview of DLX safety. Methods Safety events occurring in all subjects in the pivotal phase 3 trials were pooled to provide a broad overview of DLX safety. Results DLX was safe and well-tolerated in the pooled phase 3 ABSSSI trial population of 741 subjects. Treatment-emergent AEs (TEAEs) were seen in the DLX group versus the comparator group at 45.1% and 47.7%, respectively. Most were mild or moderate in severity. Treatment-related TEAEs were reported in the DLX group versus the comparator group at rates of 22.1% and 26.1%, respectively. Conclusions Available data show DLX is well tolerated in both intravenous and oral formulation for the treatment of ABSSSI and does not appear to be associated with increased risk of AEs associated with other fluoroquinolones. It remains important to monitor for potential AEs that have been observed with other fluoroquinolones.
... Because of its good efficacy and favorable safety profile, moxifloxacin is extensively used to treat respiratory tract, skin, soft tissue, intra-abdominal, urinary, and gastrointestinal system infections. 1 Gastrointestinal system-related adverse drug reactions (ADRs) are the most common (2%-20%) ADRs of fluoroquinolones followed by central nerve system (CNS)-related ADRs (CNS-ADRs) with an incidence of 1% to 2%. 2 Pharmacovigilance studies revealed that moxifloxacin treatment is uncommonly (1% or less) associated with CNS-ADRs compared to those associated with second-generation quinolones. 3 Moreover, among these CNS-ADRs, moxifloxacin-induced visual hallucinations are very rarely seen (<0.1%). 4 We report a 66-year-old woman treated with moxifloxacin for lobar pneumonia who developed unexpected ADRs. ...
Article
Visual hallucinations are sensory perceptions that occur without external stimuli. Moxifloxacin-induced visual hallucinations are very rarely reported (<0.1%). We describe a 66-year-old woman, without any known neuropsychiatric disorder or illicit drug abuse, who experienced complex visual hallucinations, mood, and behavioral alterations secondary to peroral 1 dose of moxifloxacin treatment that persisted for approximately 36 hours. In addition, a sudden increase in her blood glucose level was noted which also improved a few days after discontinuation of moxifloxacin treatment. Although very rare, it should be kept in mind that moxifloxacin may coincidentally induce neuropsychiatric adverse effects and hyperglycemia. Clinicians should be alert to recognize such uncommon offending adverse drug reactions.
... Recently, FQ was reported to be associated with tendinopathy [23,32,33]. The pathophysiology of tendinopathy associated with FQ administration can be explained by FQ-associated collagen toxicity [34]. ...
Article
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Purpose To investigate the association between oral fluoroquinolones (FQ) and the risk of rhegmatogenous retinal detachment (RRD) using a nationwide population-based study in Korea, designed to control for time-related bias. Methods As a nested case-control study within a cohort, the KNHIS-NSC 2002–2013 (Korean National Health Insurance Service National Sample Cohort) data used for the investigation. The subjects who visited an ophthalmologist were included in a cohort. Subjects with infectious ocular diseases, severe ocular trauma, and congenital diseases were excluded. Within the cohort, subjects who underwent surgery for RRD were defined as cases, and controls were matched by age group, sex, and cohort entry date using an incidence density sampling method. After investigating the exposure to oral FQ, the odds ratio was calculated by the FQ exposure rate of both groups and adjusted by the confounding factors of demography, health service utilization, and comorbidities. Results A total of 1,151 subjects in the case group and 11,470 subjects in the control group were included. There were intergroup differences in household income, numbers of ophthalmologic visits and drug prescriptions, events of intraocular surgeries, and prevalence of diabetes and degenerative myopia (all P’s<0.05). The crude odds ratio of the total group was 1.06 (P = 0.53, 95% CI 0.88–1.28), and the odds ratio adjusted for all pre-defined confounders was 1.00 (P = 0.99, 95% CI 0.81–1.24). The crude and adjusted odds ratios were not showed statistical significance (all P’s>0.05). Conclusions By the nested case-control design, this study showed that oral administration of FQ was not associated with the increased risk of development of RRD.
... Las interacciones farmacodinámicas involucran alteraciones del efecto de un medicamento sobre otro. Al igual que otros antimicrobianos, las quinolonas pueden aumentar el efecto de los anticoagulantes orales warfarina y acenocumarol 44 . Se ha postulado desplazamiento del anticoagulante de la unión a proteínas plasmáticas, inhibición de citocromo y disrupción de la microbiota intestinal que sintetiza vitamina K; por lo que su mecanismo involucra interacción farmacocinética y farmacodinámica 46 . ...
Article
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Quinolones are a group of widely used antimicrobials. Although they are considered safe for patients, knowledge of the safety profile is necessary so that professionals become aware of what is necessary to monitor. At the musculoskeletal level, quinolones have the potential to damage cartilage, causing even tendon rupture in infrequent cases. Hypoglycemia / hyperglycemia has been observed at the endocrine level, thus, careful monitoring of glycemia in patients with quinolone is recommended in diabetic patients. At the cardiovascular level, arrhythmias induced by these antimicrobials are rare but severe. At the level of the nervous system, the appearance of alterations of the central nervous system and the peripheral neuropathy are emphasized. When assessing the safety of quinolones, it is important to consider potential interactions with other substances (medical products). In children it is preferred not to use fluoroquinolones because of the potential risk of cartilage damage and growth, effects that do not seem to be so dramatic in the face of new evidence. Despite optimism, the safety of the treatment of these antimicrobials should be evaluated in every pediatric patient.
... These agents can lower the seizure threshold [14] and therefore be unsuitable for some patients with epilepsy. They may also prolong the QTc interval [15], which may render them unsafe for patients on certain antiarrhythmic agents or in those who already have a prolonged QTc interval. ...
Article
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Epididymo-orchitis is a common urological condition in men of all ages, causing a unilateral or bilateral swelling of the epididymis and/or testis. It is frequently caused by sexually transmitted infections, Chlamydia trachomatis and Neisseria gonorrheae, as well as common enteric organisms implicated in urinary tract infections. Men over 35 years old may develop epididymo-orchitis associated with enteric organisms, often associated with functional bladder outlet problems such as benign prostatic hyperplasia or urethral stricture disease. Fluoroquinolones, especially ciprofloxacin, have long been the mainstay of treatment for these infections; however, rising resistance to ciprofloxacin in E. coli isolates in Europe and the USA means that there is an unprecedented necessity for alternative antimicrobials with adequate penetration into genital tissues (epididymis and testes) to allow appropriate and comprehensive treatment of epididymo-orchitis in this group of patients.
... Fluoroquinolones are one of the most promising and intensively studied drugs of day-to-day antiinfective therapy. Ciprofloxacin is the most widely used second-generation quinolone among them [1,2]. It exhibits broad spectrum antimicrobial activity against both, gram-positive and gram-negative bacteria [3,4] and it can be delivered through all the possible routes of drug administration routes, such as parental, topical and oral [5]. ...
Article
A sensitive, specific and reproducible liquid chromatography coupled to tandem mass spectrometric method was developed and validated for the estimation of ciprofloxacin, an extensively used second-generation quinolone antibiotics, in human plasma. A liquid-liquid extraction of ciprofloxacin and the internal standard, ofloxacin, has been approached from the biological matrix using chloroform. Chromatographic separation was achieved in positive ion modes, isocratically on a 3.5 μm C18 analytical column (75 mm×4.6 mm, i.d.) with 0.2% formic acid solution in water: methanol (10:90, v/v) as mobile phase, at a flow rate of 0.5 mL.min(-1). The MS/MS ion transitions were monitored as 332.0→231.3 for ciprofloxacin and 362.2→261.0 for IS. The method showed good linearity in the range of 0.01-5.00 μg.mL(-1) (r(2) >0.99) with a good precision (3.37-12.60%) and accuracy (87.25-114%). At the same time, ciprofloxacin was found to be stable during stability studies viz. bench-top, auto-sampler, freeze-thaw cycle and long-term. The developed and validated method was successfully applied to measure plasma ciprofloxacin concentrations in a single dose bioequivalence study.
... According to pharmacovigilance studies moxifloxacin along with levofloxacin, are quinolones that have less central nervous system (CNS) adverse effects (1% or less of the overall rate). [1] Most of the reported cases of CNS adverse effects of quinolones are of second-generation (ciprofloxacin, norfloxacin, and ofloxacin). ...
Article
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Third generation quinolones are extensively used to treat a variety of common bacterial infections. Due to their extensive use in clinical practice, an increase in neuropsychiatric events has been reported. We report the case of psychotic symptoms occurs after three doses of moxifloxacin in a healthy adult male with no underlying risk factors. After the discontinuation of moxifloxacin treatment, there was a complete resolution of patient's symptoms. The case draws attention to a rare side effect of a commonly use drug and alert the clinicians to be cautious in those patients that have a baseline risk factors which makes the patient more susceptible to such adverse drug effect.
... Fluoroquinolones carry risks to the patient that may be uncomfortable to patients near the end of life, including neurotoxicity, dysglycemia, antibiotic-associated diarrhea, skin reactions, and Clostridium difficile infection. 11 Intravenous vancomycin requires close monitoring, which may negatively impact comfort. The use of these broad-spectrum agents also has implications beyond the individual patient as follows: transmission of drug-resistant microorganisms may have catastrophic consequences for other hospitalized patients. ...
Article
Background: Antimicrobials are commonly used in patients near the end of life, but the percentage and predictors of patients prescribed antibiotics while hospitalized on a comfort care protocol are unknown. Objective: To determine how often patients in the acute care setting are continued on antimicrobials when they are transitioned to comfort-focused care and to describe patient characteristics correlated with antimicrobial use. Design: Retrospective cohort study conducted from June 2012 to August 2014. Setting: Two interrelated academic medical centers. Patients: Inpatients >18 years old transitioned to a comfort care protocol. Measurements: Administration of antimicrobials to patients on the comfort care protocol. Analysis: We generated descriptive statistics and used a modified Poisson regression to estimate unadjusted and adjusted associations along with 95% confidence intervals (CIs) and p-values. Results: There were 1881 patients included in the study; 77% of patients ultimately transitioned to a comfort care protocol received antimicrobials during their admission and 82% died in hospital. Of the 711 alive at ≥24 hours after comfort care orders, 111 (15.6%) were still on antimicrobials. After adjusting for age, a documented infection was positively associated with being on antibiotics (adjusted relative risk [ARR] = 1.46, 95% CI: 1.00-2.12, p = 0.05). Patients in the medical and surgical intensive care units (ICUs) were less likely than those on medicine to receive antimicrobials (MICU ARR = 0.32, 95% CI: 0.14-0.72, p = 0.01; SICU/Neuro ARR = 0.32, 95% CI: 0.12-0.85, p = 0.02). Conclusions: Antimicrobial use is relatively high in hospitalized patients near the end of life, even when the goal is comfort.
Article
Quinolones and their derivatives of the second to fourth generation (fluoroquinolones) are highly active antimicrobial agents. This research examines pharmacokinetic properties of fluoroquinolones in comparative aspect of their effect on pathogenic. Microflora of conjunctival cavity in children diagnosed with conjunctivitis and dacryocystitis. The study was carried out in 2020 in Ophthalmologic Polyclinics No. 1 (Moscow, the Russian Federation). The group comprised 200 children aged six years who were diagnosed with bacterial conjunctivitis and dacryocystitis. The composition of pathogenic microflora species and the effect of moxifloxacin and other fluoroquinolones on the sensitivity and resistance of microorganisms were analyzed using conjunctival scrapings. The presence of eight species of pathogenic microorganisms in the scrapings has been established. The majority of bacteria detected were gram-positive: St. epidermidis (59%) and St. aureus (21%), p ≤ 0.05. Other types of microorganisms, including gram-negative E. coli, K. pneumonia, and St. saprophycus, were discovered 20 times (p≤0.001 relative to St. epidermidis), 18 times (p ≤ 0.001), and 15 times (p ≤ 0.01) less frequently, accordingly. The levels of bacterial resistance were 13% for moxifloxacin, 16% for levofloxacin, and 21% for ciprofloxacin. Moxifloxacin monotherapy showed a 100% result. After five days of treatment, all patients demonstrated minimal values (0.5 and 0.1 points vs. 3.8 and 4.4 points at the beginning of treatment, p ≤ 0.01) for two parameters (conjunctival hyperemia and sticky eye), the other three parameters were zero. Fourth-generation fluoroquinolone (moxifloxacin) has been shown to be highly effective against gram-positive Staphylococcus aureus bacteria.
Article
Background Enteric infections are a major public health issue in developing countries. Antimicrobial resistance is also a problem for enteric infection. OPS-2071 is a novel quinolone antibiotic with low oral absorption and potent antibacterial activity against Clostridioides difficile. Objectives This study was conducted to confirm the antimicrobial activity of OPS-2071 against major enteropathogenic bacteria and to evaluate the risk of emergence of drug resistance. Methods The antibacterial activity was evaluated by the agar dilution method. The inhibitory activity against DNA gyrase and topoisomerase IV was determined by supercoiling assay and decatenation assay, respectively. The mutant prevention concentration and frequency of spontaneous resistance were determined by inoculation on drug-containing agar. Results Compared with the reference drugs, the antibacterial activity of OPS-2071 was more potent against Gram-positive bacteria and Campylobacter jejuni, including quinolone-resistant strains. Against other Gram-negative bacteria, OPS-2071 was comparable to existing quinolones. The inhibitory activities against DNA gyrase with quinolone-resistant mutations closely correlated with the antibacterial activity. Spontaneous resistance to OPS-2071 was not observed in Staphylococcus aureus and Escherichia coli and was lower than that of existing quinolones and higher than that of azithromycin in C. jejuni. The mutant prevention concentration of OPS-2071 was lower than that of tested compounds in S. aureus and C. jejuni and slightly higher than that of existing quinolones in E. coli. Conclusions The broad and potent in vitro antibacterial activity and lower risk of drug resistance suggested that OPS-2071 may be useful for enteric infections caused by major pathogens including quinolone-resistant Campylobacter.
Chapter
The quinolones are a diverse class of antimicrobial agents which target the two essential bacterial type II topoisomerases, DNA gyrase and topoisomerase IV which inhibit DNA synthesis. The molecular structure of the quinolones has been altered over time with the naphthyridine nucleus being the base for a series of more active compounds, most importantly the fluorination at the 6-position giving the fluoroquinolones. These changes have changed the antibacterial spectrum of activity which was initially predominantly Gram negative bacteria but now includes Gram positive, anaerobes and mycobacteria. This class remain the best oral option for treating infections due to Pseudomonas aeruginosa. There has been a corresponding increase in the list of indications, which now includes urinary tract infections, sexually transmitted infections, ophthalmic infections, gastrointestinal infections, respiratory infections, skin and soft tissue infections, bone and joint infections and tuberculosis. This wider use has led to increasing concerns regarding the emergence of resistance. Resistance can be the result of mutations in chromosomal genes or plasmid-mediated. Important side effects include tendinopathy, aortic dissection, reduced seizure threshold (leading to increased chances of seizures), prolonged QT interval and diarrhea due to C. difficile infection. Care must be exercised to reduce the risk of emerging resistance if they are to remain as useful as they are now.
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Background: The goal of our study is the comparative analysis of the effect of fluoroquinolones on the chicken leukogram. Materials and methods: In the study we used Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Enrofloxacin. For the study we made seven groups, thirty-five chickens in each group. The control set was given pure drinking water throughout the experiment; each of the experimental groups was given water with one of the above-mentioned antibacterial fluoroquinolone drugs, the dosage being 200 mg per liter. The blood samples were collected with cardiac punctures on the first, third, fifth, seventh and ninth days after the withdrawal of the drug. The leukogram contains the total number of leucocytes and the content of separate cell types and their total numbers. Results: The valid changes in the number of pseudoeosinophils do not show clear tendencies, such changes are observed once under the influence of each drug on different days of the research. On the seventh and the ninth days after the drug withdrawal all the fluoroquinolones except Ofloxacin caused lymphopenia. Ciprofloxacin is the only tested drug, the usage of which does not cause valid changes in the number of monocytes. Those groups that receive Enrofloxacin or Ofloxacin have a short period of eosinophilia. Levofloxacin, Enrofloxacin, Ofloxacin cause refractory basophilia. Conclusion: The application of antimicrobial fluoroquinolone drugs in the course of ten days results in changes in the ratio of different kinds of leucocytes in chicken blood, but at the conclusion of the experiment every value in the leukogram returns to physiological standard.
Article
It is important to see the role of metabolism in drug toxicity as one component of the bigger picture of all adverse reactions suffered by patients during drug therapy. Drug‐adverse effects are classified as either predictable (type A) or unpredictable (type B). Type A predictable effects can be reversible concerning pharmacological effects, but the effects from an overdose could well be irreversible as well as predictable. Type B unpredictable effects could be reversible or, if they are very severe, irreversible. Type A describes the vast majority of adverse effects and patients experience these in direct proportionality to the quantity of the drug and/or its metabolites in their tissues. These effects are sometimes described as toxic, but these are not usually irreversible effects. Serious advances in understanding type B‐drug hypersensitivity reactions have been made over the past decade.
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Drugs are tested at the preclinical stage in animal populations that are usually inbred and display little variation from animal to animal. Data from animal studies in one country are usually comparable with that of another, provided the animal species and strain are the same. This chapter discusses some of the major factors related to patient genetic identity and how they live their lives, on drug metabolism and how these factors affect the goal of maintaining drug levels within the patient's therapeutic window. The factors discussed in the chapter are the effects of age, diet, disease, gender, ethanol, and smoking. Genetic diversity manifests in differences in single DNA nucleotides and/or whole genes that code for particular proteins. The chapter discusses genetic polymorphisms in Cytochrome P450 systems and nonconjugative systems, conjugative polymorphisms such as acetylation, methylation, uridine diphosphate glucuronosyl transferase 1A1, and sulphonation, and transporter polymorphisms.
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Der Einsatz von Fluorchinolon- und Chinolonantibiotika wurde am 11.03.2019 von der Europäischen Kommission gesetzlich bindend eingeschränkt. Bereits seit 2008 wurden in den USA schrittweise Warnungen zum Einsatz von dieser Antibiotikagruppe ausgegeben aufgrund der zunehmend entdeckten erheblichen und teils irreversiblen Nebenwirkungen dieser Substanzen. Hierzu zählen u. a. Sehnenrupturen, psychiatrische Beschwerden, Hypoglykämien und Aortenaneurysmen; auch ein Fatiguesyndrom kann sich nach dem Einsatz der (Fluor-)Chinolone entwickeln. Diese Antibiotikagruppe wirkt durch eine Hemmung der bakteriellen Topoisomerasen. Jedoch ist diese Hemmung nicht spezifisch genug, sodass auch humane Topoisomerasen gehemmt werden, und insbesondere die mitochondriale DNA beeinflusst wird. Ein Gebrauch ausserhalb der neuen Empfehlung gilt als off label. Für die Urologie bedeuten die Regularien insbesondere, dass Alternativen zur antibiotischen Prophylaxe bei Prostatabiopsien eingesetzt werden müssen. Davon abgesehen werden keine Änderungen in den Leitlinien der European Association of Urology erfolgen. Abschliessend sollten Empfehlungen eingehalten und der Einsatz von antibiotischen Prophylaxen und Therapien auf ein nötiges Minimum reduziert werden.
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Introduction: Prosthetic joint infections are an increasingly important problem among patients undergoing arthroplasty procedures, and are associated with significant morbidity, reduced quality of life, substantial healthcare costs, and even mortality. Arthroplasties are performed with increasing frequency in elderly patients, who present specific problems. Areas covered: Surgical therapy is clearly influenced by the clinical status of the patient, which in some case can contraindicate surgery. Antibiotic selection is also affected by comorbidities and underlying diseases, which in some cases reduce therapeutic options. The authors review this together with the changes in pharmacokinetics and pharmacodynamics in the elderly population and the prospects for future research on prevention and treatment. Expert opinion: The management of PJI in the elderly makes multidisciplinary teams even more mandatory than in other patients, because the complexity of these patients. A frequent scenario is that in which surgery is contraindicated with long-term suppressive treatment as the only available option. Treating physicians must consider the presence of multiple comorbidities, interactions with other treatments and secondary effects when choosing antibiotic treatment. An in-depth knowledge of the alterations in pharmacokinetics and pharmacodynamics in elderly patients is key for a proper treatment selection.
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Understanding the basic mechanisms of drug interactions allows researchers and clinicians to best interpret and apply drug interaction data and make predictions about patient-specific interactions. Drug interactions can occur during the absorption, distribution, metabolism, and excretion phases of drug distribution (pharmacokinetic interactions) and at the site of action (pharmacodynamic interactions). The consequences of unintended interactions can be extremely harmful and potentially fatal, such as those leading to cardiac conduction abnormalities. Knowledge of the mechanisms of drug interactions has also identified useful interactions with therapeutic benefits, such as in the development of feasible dosing regimens for protease inhibitors in the treatment of HIV and hepatitis C infection. This chapter describes the mechanisms of drug interactions for each of the aforementioned pharmacokinetic processes. The cytochrome P450 family of enzymes, the P-glycoprotein drug transporter, and their mechanisms for inhibition, induction, and suppression are reviewed. Preclinical and clinical methods used to study cytochrome P450 are discussed.
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Localized photo-polymerization was ingeniously applied to prepare a multifunctional molecularly imprinted polymer (MIP) fluorescent probe using the “layer-by-layer” assembly of MIP and Fe3O4 nanoparticles on NaYF4: Yb³⁺, Er³⁺ upconversion particles ([email protected]). Enrofloxacin was used as the template and chosen as the target molecular during the investigation of the adsorption property. This ternary probe has magnetic and broad-spectrum molecular recognition capability, fast response, and upconversion fluorescence. The results of the fluorescence quenching analysis showed good linear ranges of 1.03 nmol/L to 0.28 μmol/L for enrofloxacin, 1.69 nmol/L to 0.22 μmol/L for fleroxacin, 6.92 nmol/L to 0.28 μmol/L for levofloxacin, 7.54 nmol/L to 0.30 μmol/L for ciprofloxacin, and 3.90 nmol/L to 0.25 μmol/L for enoxacin. This probe was further used to determine five quinolones in fish tissues and the recoveries ranging from 90.33% to 108.43% were obtained with relative standard deviation below 5.53%. This work offers a new and general strategy to synthesize a [email protected] upconversion fluorescence probe with magnetic and selective molecular recognition capability for rapid and accurate sensing of multiple chemical residues in the environment and agri-food products.
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TNF Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimised, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four ten-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reversephase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-kB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.
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Background: Antipsychotic drugs could be nephrotoxic in schizophrenia patients.Methods: The present study investigated the protective effect of oil from black seed on kidney dysfunctions using several biological approaches in adult rats. The animals were divided into six groups (n = 10): normal control rats; haloperidol (HAL)-induced rats: induced rats were pre-,co- and post-treated with black seed oil (BSO), respectively,and the last group was treated with the oil only. The treatment was done through oral administration, and the experiment lasted 14 days.Results: Therapeutic administration of HAL to rats caused reduction in both enzymatic and non-enzymatic proteins mediated by stable OH˙ and DPPH free radicals. K+, Na+ and MDA contents as well as 51 nucleotidase, aldose-reductase activities were increased with corresponding decrease in the activity of lactate dehydrogenase (LDH) in HAL-induced toxicity rats. Contrariwise, differential treatments with BSO prevented and reversed the nephrotoxicity by depleting K+, Na+, MDA contents and aldose-reductase activity, and AMP hydrolysis with increased adenosine triphosphate (ATP) in the PMFs of rat kidney. The cytotoxicity of HAL elicited on both inner renal cortex and outer medulla was equally alleviated by combined active molecules of oil from black seed (OBS). However, pre-, co- and post-treatment demonstrate significant approaches in averting nephrotoxicity of neuroleptic drug (HAL) via several biological mechanisms. Conclusions: This study therefore validates the use of black seed oil as therapy particularly for individuals with renal dysfunctions
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Prescribing medications, recognizing and managing medication side effects and drug interactions, and avoiding polypharmacy are all essential skills in the care of older adults in primary care. Important side effects of medications commonly prescribed in older adults (statins, proton pump inhibitors, trimethoprim-sulfamethoxazole and fluoroquinolone antibiotics, zolpidem, nonsteroidal antiinflammatory drugs, selective serotonin reuptake inhibitors, dipeptidyl peptidase 4 inhibitors) were reviewed. Important drug interactions with four agents or classes (statins, warfarin, factor Xa inhibitors, and calcium channel blockers) are discussed.
Article
Prostate specific antigen (PSA) levels are often evaluated in an attempt to detect early prostate cancer, however false positive PSA tests are common.1 A strategy to limit false positives, surrounding concerns that prostatitis may increase PSA, has been to defer biopsy decisions until after a course of antibiotics and repeat PSA measurement. This strategy has been evaluated in prior studies, including several small randomized trials, with differing conclusions regarding its benefit.2–4 The authors report a prospective, randomized trial investigating the impact of six weeks of fluoroquinolone antibiotics on PSA levels in asymptomatic men with an elevated PSA. This single-institution study randomized 150 of 1,151 eligible patients with a PSA between 4.0 and 20.0 ng/mL to 6 weeks of fluoroquinolone therapy (ciprofloxacin, but due to formulary changes a proportion received levofloxacin) or 6 weeks of observation. The primary endpoint was change in PSA 8 weeks after randomization. Rate of cancer diagnosis was a secondary outcome for patients who received a biopsy. A near significant difference in the change in PSA across groups was reported (−0.68 vs. 0.01 ng/mL for treatment and observation groups, respectively, p=0.052). 62% of treatment patients and 72% of observation patients underwent biopsy with no difference in cancer detection rate (63% vs. 52%, respectively, p=0.60). The authors conclude that asymptomatic patients with elevated PSA should not receive antibiotics prior to determining if a prostate biopsy is warranted. While the authors are commended for completing a prospective randomized trial to inform the debate on this urological practice, one limitation of this study is the lack of a pre-trial power calculation to plan enrollment. Despite this limitation, the post-intervention median PSA levels in both the treatment and observation groups were above most accepted biopsy thresholds (5.1 ng/mL and 5.0 ng/mL, respectively), indicating that even if the study had found a statistically significant difference, it may not have been clinically relevant. Also, as shown in this study, a decrease in PSA does not indicate an absence of prostate cancer. Given this trial and others on the topic have not provided convincing evidence of this practice, the authors are correct in concluding evidence does not support this management strategy. The risks and costs associated with unnecessary antibiotics are not trivial.5 When hospitalizations after transrectal prostate biopsy were assessed in the Michigan Urological Surgery Improvement Collaborative (MUSIC), 95% of hospital admissions were for infectious complications, and the majority of cultures identified fluoroquinolone resistant organisms.6 With rising antibiotic resistance7 and in an era increasingly focused on quality care and appropriate healthcare utilization, we do not recommend antibiotic therapy prior to making decisions about prostate biopsy in asymptomatic men with elevated PSA. This practice is also highlighted within the American Board of Internal Medicine and American Urological Association’s Choosing Wisely campaign as something that physicians and patients should question.8
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Background: Safety concerns for fluoroquinolones exist from animal studies demonstrating cartilage injury in weight-bearing joints, dependent on dose and duration of therapy. For children treated with levofloxacin or comparator in randomized, prospective, comparative studies for acute otitis media and community-acquired pneumonia, this 5-year follow-up safety study was designed to assess the presence/absence of cartilage injury. Methods: Children enrolled in treatment studies were also enrolled in a 1-year follow-up safety study, which; focused on musculoskeletal adverse events (MSAE). Those with persisting MSAEs, protocol-defined musculoskeletal disorders, or of concern to the Data Safety and Monitoring Committee were requested to enroll in four additional years of follow-up, the subject of this report. Results: Of the 2233 subjects participating in the 12-month follow-up study, 124 of 1340 (9%) of the levofloxacin subjects, and 83 of 893 (9%) of the comparator subjects were continued for 5-year posttreatment assessment. From children identified with an MSAE during years 2 through 5 posttreatment, the number that were "possibly related" to drug therapy was equal for both arms: 1 of 1340 for levofloxacin and 1 of 893 for comparator. Of all cases of MSAE assessed by the Data Safety and Monitoring Committee at 5 years' posttreatment, no case was assessed as "likely related" to study drug. Conclusions: With no clinically detectable difference between levofloxacin- and comparator-treated children in MSAEs presenting between 1 and 5 years in these safety studies, risks of cartilage injury with levofloxacin appear to be uncommon, are clinically undetectable during 5 years, or are reversible.
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A study reported a significant association between oral fluoroquinolones and the development of retinal detachment among current users of oral fluoroquinolones (Etminan M, Forooghian F, Brophy JM et al. JAMA 2012; 307: 1414-9). However, other published studies have discordant results. This study aimed to investigate this association and to estimate the absolute risk of developing retinal detachment in patients exposed to oral fluoroquinolones. A self-controlled case series study was conducted with data retrieved from the Hong Kong Clinical Data Analysis and Reporting System database and the Taiwan National Health Insurance Research Database. Hong Kong and Taiwanese patients who had prescriptions for oral fluoroquinolones and a procedure for retinal detachment between 2001 and 2012 and between 2000 and 2010, respectively, were defined as cases and included in the analysis. A total of 9 events were found during the fluoroquinolone-exposed period and 1407 events were found during the non-exposed period. The adjusted incidence rate ratio in the combined model was 1.26 (0.65-2.47). The crude absolute risk of experiencing retinal detachment whilst on oral fluoroquinolones was ∼1.3 per 200 000 prescriptions. Our study does not support the association between the use of fluoroquinolones and the development of retinal detachment and our findings are strikingly similar to that of the study conducted in Denmark. Doubt is cast on the association between the use of fluoroquinolones and the development of retinal detachment. Therefore, the use of fluoroquinolones should not be precluded based on the current evidence on the risk of retinal detachment. The impact of different ethnicities on the response to fluoroquinolones should also be investigated.
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A recent Canadian case-control study reported a 4.5-fold increased risk of retinal detachment (RD) during oral fluoroquinolone use. Of the fluoroquinolone-exposed cases, 83 % were exposed to ciprofloxacin. We sought to replicate this finding, and assess whether it applied to all fluoroquinolones. In two large US healthcare databases, we performed three case-control analyses: one replicating the recent study; one addressing additional potential confounders; and one that increased sample size by dropping the Canadian study's requirement for a prior ophthalmologist visit. We also performed a self-controlled case-series (SCCS) analysis in which each subject served as his or her own comparator. In the replication case-control analyses, the adjusted odds ratios (ORs) for any exposure to fluoroquinolones or ciprofloxacin were approximately 1.2 in both databases, and were statistically significant, and the ORs for current exposure were modestly above 1 in one database, modestly below 1 in the other, and not statistically significant. In the other case-control analyses, the ORs were close to 1. In a post hoc age-stratified case-control analysis, we observed an association of RD with fluoroquinolone exposure among older subjects in one of the two databases. All estimates from the SCCS analyses were below 1.2 and none was statistically significant. The present study does not confirm the recent Canadian study's finding of a strong relationship between RD and current exposure to fluoroquinolones. Instead, it found a modest association between RD and current or any exposure to fluoroquinolones in the case-control analyses, and no association in the SCCS analyses.
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Purpose: Peripheral neuropathy (PN) is an identified risk of systemic antibacterial therapy with fluoroquinolones. The risk and its severity, including the development of Guillain-Barré syndrome (GBS) between individual agents is uncertain. This study examines the association between fluoroquinolones and PN and GBS in cases spontaneously reported to the FDA Adverse Event Reporting System. Methods: Cases reported to FDA Adverse Event Reporting System between 1997 and 2012 were retrieved. The Medical Dictionary for Regulatory Activities Preferred Term was used to define PN and GBS. Individual fluoroquinolones were identified by generic names and route of administration. Empirical Bayes Geometric Mean (EBGM) with 95% confidence interval (EB05-EB95) was calculated as disproportionality measure. Safety signals with EB05 2 or more was considered a significant disproportional increase in the event reporting of at least twice times higher than that expected. Results: There were 539 PN reports out of 46,257 adverse event reports submitted for fluoroquinolones. Nine percent of PN reports were for GBS. Significant disproportionality of PN (EBGM 2.70; EB05-EB95 2.51-2.90) and GBS (EBGM 3.22; EB05-EB95 2.55-4.02) was identified for fluoroquinolones. Signals of PN were detected for ciprofloxacin (EBGM 3.24; EB05-EB95 2.87-3.66) and levofloxacin (EBGM 3.36; EB05-EB95 3.02-3.72). A GBS signal was detected for ciprofloxacin (EBGM 4.15; EB05-EB95 2.94-5.74). GBS and PN, respectively, ranked 6th and 8th among reported neurologic events. Conclusions: This study re-emphasizes the link between fluoroquinolones and PN and shows the potential association with more severe forms of nerve damage, for example, GBS. Unless the benefit of fluoroquinolone therapy (e.g., overwhelming infection or development of bacterial resistance) outweighs PN risk, treatment with alternative antibacterial agents is recommended.
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Results of a pharmacoepidemiologic evaluation of fluoroquinolone-associated hepatotoxicity using national hospital admissions data on Veterans Affairs (VA) patients are reported. In a retrospective case-control study, all adults with a primary diagnosis of hepatotoxicity on admission to a VA facility during a 6.5-year period (January 2002-June 2008) were identified. After the exclusion of patients whose records indicated known causes of hepatotoxicity or a history of liver disease, a subgroup of 7,862 patients with exposure to fluoroquinolone antibiotics in the six months prior to hospital admission were matched with nonexposed controls (n = 45,512). Conditional logistic regression was used to assess the overall and drug-specific risks of hepatotoxicity in the case group, controlling for comorbidities, concomitant use of known hepatotoxic medications, and other variables. After adjusting for confounders, logistic regression analysis indicated a significantly higher overall risk of hepatotoxicity development among fluoroquinolone users relative to controls (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.04-1.38). Drug-specific risk analyses focused on three fluoroquinolone agents (ciprofloxacin, levofloxacin, and moxifloxacin) indicated a significant association between ciprofloxacin use and an increased risk of hepatotoxicity (OR, 1.29; 95% CI, 1.05-1.58); when considered as independent variables, levofloxacin use and moxifloxacin use were not significantly associated with hepatotoxicity risk. The findings of a national VA safety study suggested an increased hepatotoxicity risk asssociated with fluoroquinolone exposure in the study population.
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To update the evidence for associations between antibiotic classes and hospital-acquired Clostridium difficile infection (HA-CDI). Electronic databases of journal articles, scholarly theses and conference proceedings using subject headings and keywords related to CDI and antibiotic exposure were searched. Observational epidemiological studies measuring associations between antibiotic classes and HA-CDI were eligible for inclusion. Pooled ORs and 95% CIs were calculated using a random effects model. Study factors identified a priori were examined as sources of heterogeneity. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Of 569 citations identified, 13 case-control and 1 cohort study (15 938 patients) were included. The strongest associations were found for third-generation cephalosporins (OR = 3.20, 95% CI = 1.80-5.71; n = 6 studies; I(2) = 79.2%), clindamycin (2.86, 2.04-4.02; n = 6; I(2) = 28.5%), second-generation cephalosporins (2.23, 1.47-3.37; n = 6; I(2) = 48.4%), fourth-generation cephalosporins (2.14, 1.30-3.52; n = 2; I(2) = 0.0%), carbapenems (1.84, 1.26-2.68; n = 6; I(2) = 0.0%), trimethoprim/sulphonamides (1.78, 1.04-3.05; n = 5; I(2) = 70%), fluoroquinolones (1.66, 1.17-2.35; n = 10; I(2) = 64%) and penicillin combinations (1.45, 1.05-2.02; n = 6; I(2) = 54%). The study population and the timing of measurement of antibiotic exposure were the most common sources of heterogeneity. Study quality scored high for seven studies, moderate for six studies and low for one study. The risk of HA-CDI remains greatest for cephalosporins and clindamycin, and their importance as inciting agents should not be minimized. The importance of fluoroquinolones should not be overemphasized, particularly if fluoroquinolone-resistant epidemic strains of C. difficile are absent.
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Bacterial resistance to antibiotics is growing up day by day in both community and hospital setting, with a significant impact on the mortality and morbidity rates and the financial burden that is associated. In the last two decades multi drug resistant microorganisms (both hospital- and community-acquired) challenged the scientific groups into developing new antimicrobial compounds that can provide safety in use according to the new regulation, good efficacy patterns, and low resistance profile. In this review we made an evaluation of present data regarding the new classes and the new molecules from already existing classes of antibiotics and the ongoing trends in antimicrobial development. Infectious Diseases Society of America (IDSA) supported a proGram, called "the [prime]10 x 20[prime] initiative", to develop ten new systemic antibacterial drugs within 2020. The microorganisms mainly involved in the resistance process, so called the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) were the main targets. In the era of antimicrobial resistance the new antimicrobial agents like fifth generation cephalosporins, carbapenems, monobactams, beta-lactamases inhibitors, aminoglycosides, quinolones, oxazolidones, glycopeptides, and tetracyclines active against Gram-positive pathogens, like vancomycin-resistant S. aureus (VRSA) and MRSA, penicillin-resistant streptococci, and vancomycin resistant Enterococcus (VRE) but also against highly resistant Gram-negative organisms are more than welcome. Of these compounds some are already approved by official agencies, some are still in study, but the need of new antibiotics still does not cover the increasing prevalence of antibiotic-resistant bacterial infections. Therefore the management of antimicrobial resistance should also include fostering coordinated actions by all stakeholders, creating policy guidance, support for surveillance and technical assistance.
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Background: Observational studies and fatal case reports raise concern about the safety of severe dysglycemia associated with fluoroquinolone use. The objective of this study was to assess the risk of severe dysglycemia among diabetic patients who received different fluoroquinolones. Methods: In a population-based inception cohort study of diabetic patients covering the period from January 2006 to November 2007, outpatient new users of levofloxacin, ciprofloxacin, moxifloxacin, cephalosporins, and macrolides orally were identified. Study events were defined as emergency department visits or hospitalization for dysglycemia within 30 days following the initiation of antibiotic therapy. Results were analyzed with adjusted multinomial propensity score. Results: A total of 78 433 diabetic patients receiving the antibiotics of interest were included in the study. The absolute risk of hyperglycemia per 1000 persons was 6.9 for moxifloxacin and 1.6 for macrolides. In contrast, the risk of hypoglycemia was 10.0 for moxifloxacin and 3.7 for macrolides. The adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of levofloxacin, ciprofloxacin, and moxifloxacin compared with macrolides were 1.75 (1.12-2.73), 1.87 (1.20-2.93), and 2.48 (1.50-4.12), respectively, for hyperglycemia and 1.79 (1.33-2.42), 1.46 (1.07-2.00), and 2.13 (1.44-3.14), respectively, for hypoglycemia. Patients taking moxifloxacin faced a significantly higher risk of hypoglycemia than those receiving ciprofloxacin. A significant increase in the risk of hypoglycemia was also observed among patients receiving moxifloxacin concomitantly with insulin (AOR, 2.28; 95% CI, 1.22-4.24). Conclusions: Diabetics using oral fluoroquinolones faced greater risk of severe dysglycemia. The risk of hypoglycemia varied according to the type of fluoroquinolone administered, and was most commonly associated with moxifloxacin.
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Although quinolones are the most commonly prescribed antibacterials, their use is threatened by an increasing prevalence of resistance. The most common causes of quinolone resistance are mutations of a specific serine or acidic residue in the A subunit of gyrase or topoisomerase IV. These amino acids are proposed to serve as a critical enzyme-quinolone interaction site by anchoring a water-metal ion bridge that coordinates drug binding. To probe the role of the proposed water-metal ion bridge, we characterized wild-type, GrlAE85K, GrlAS81F/E85K, GrlAE85A, GrlAS81F/E85A and GrlAS81F Bacillus anthracis topoisomerase IV, their sensitivity to quinolones and related drugs and their use of metal ions. Mutations increased the Mg2+ concentration required to produce maximal quinolone-induced DNA cleavage and restricted the divalent metal ions that could support quinolone activity. Individual mutation of Ser81 or Glu85 partially disrupted bridge function, whereas simultaneous mutation of both residues abrogated protein–quinolone interactions. Results provide functional evidence for the existence of the water-metal ion bridge, confirm that the serine and glutamic acid residues anchor the bridge, demonstrate that the bridge is the primary conduit for interactions between clinically relevant quinolones and topoisomerase IV and provide a likely mechanism for the most common causes of quinolone resistance.
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Background: Although fluoroquinolones are sometimes associated with mild, transient elevations in aminotransferase levels, serious acute liver injury is uncommon. Regulatory warnings have identified moxifloxacin as presenting a particular risk of hepatotoxicity. Thus, we examined the risk of idiosyncratic acute liver injury associated with the use of moxifloxacin relative to other selected antibiotic agents. Methods: We conducted a population-based, nested, case-control study using health care data from Ontario for the period April 2002 to March 2011. We identified cases as outpatients aged 66 years or older with no history of liver disease, and who were admitted to hospital for acute liver injury within 30 days of receiving a prescription for 1 of 5 broad-spectrum antibiotic agents: moxifloxacin, levofloxacin, ciprofloxacin, cefuroxime axetil or clarithromycin. For each case, we selected up to 10 age- and sex-matched controls from among patients who had received a study antibiotic, but who were not admitted to hospital for acute liver injury. We calculated odds ratios (ORs) to determine the association between admission to hospital and previous exposure to an antibiotic agent, using clarithromycin as the reference. Results: A total of 144 patients were admitted to hospital for acute liver injury within 30 days of receiving a prescription for one of the identified drugs. Of these patients, 88 (61.1%) died while in hospital. After multivariable adjustment, use of either moxifloxacin (adjusted OR 2.20, 95% confidence interval [CI] 1.21-3.98) or levofloxacin (adjusted OR 1.85, 95% CI 1.01-3.39) was associated with an increase in risk of acute liver injury relative to the use of clarithromycin. We saw no such risk associated with the use of either ciprofloxacin or cefuroxime axetil. Interpretation: Among older outpatients with no evidence of liver disease, moxifloxacin and levofloxacin were associated with an increased risk of acute liver injury relative to clarithromycin.
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Cardiac safety was compared in patients receiving moxifloxacin and other antimicrobials in a large patient population from Phase II-IV randomized active-controlled clinical trials. Moxifloxacin 400 mg once-daily monotherapy was administered orally (PO) or sequentially (intravenous/oral, IV/PO). Across 64 trials, 21,298 patients received PO therapy (10,613 moxifloxacin, 10,685 comparators) while 6846 received sequential IV/PO therapy (3431 moxifloxacin, 3415 comparators). Treatment-emergent cardiac adverse event (AE) rates were similar for moxifloxacin and comparators in PO (6.6% vs 5.8%) and IV/PO (11.0% vs 12.0%) trials. Treatment-emergent cardiac adverse drug reactions were rare in PO (moxifloxacin 3.2% vs comparators 2.4%) and IV/PO (moxifloxacin 1.4% vs comparators 1.5%) patients. There were five (<0.02%) treatment-emergent drug-related deaths due to cardiac events out of 28,144 patients; one PO patient died treated with comparators, one patient died treated with IV/PO moxifloxacin, and three patients died after treatment with IV/PO comparators. Only one case of treatment-related non-fatal torsade de pointes occurred in the comparator arm. Incidence rates of cardiac AEs remained low in populations at elevated risk of cardiac events predisposed to QTc prolongation (i.e. community-acquired pneumonia patients admitted to the intensive care unit and/or mechanical ventilation, patients with documented prolongation of baseline QTc interval, women, and patients ≥ 65 years old). There was no evidence of unexpected cardiac events. After moxifloxacin treatment, an expected small prolongation in QTcB and QTcF was found. This analysis of numerous clinical trials shows the favorable cardiac safety profile of moxifloxacin, when used appropriately and according to its label, versus other antibiotics.
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Fluoroquinolones are commonly prescribed classes of antibiotics. Despite numerous case reports of ocular toxicity, a pharmacoepidemiological study of their ocular safety, particularly retinal detachment, has not been performed. To examine the association between use of oral fluoroquinolones and the risk of developing a retinal detachment. Nested case-control study of a cohort of patients in British Columbia, Canada, who had visited an ophthalmologist between January 2000 and December 2007. Retinal detachment cases were defined as a procedure code for retinal repair surgery within 14 days of a physician service code. Ten controls were selected for each case using risk-set sampling, matching on age and the month and year of cohort entry. The association between retinal detachment and current, recent, or past use of an oral fluoroquinolone. From a cohort of 989,591 patients, 4384 cases of retinal detachment and 43,840 controls were identified. Current use of fluoroquinolones was associated with a higher risk of developing a retinal detachment (3.3% of cases vs 0.6% of controls; adjusted rate ratio [ARR], 4.50 [95% CI, 3.56-5.70]). Neither recent use (0.3% of cases vs 0.2% of controls; ARR, 0.92 [95% CI, 0.45-1.87]) nor past use (6.6% of cases vs 6.1% of controls; ARR, 1.03 [95% CI, 0.89-1.19]) was associated with a retinal detachment. The absolute increase in the risk of a retinal detachment was 4 per 10,000 person-years (number needed to harm = 2500 computed for any use of fluoroquinolones). There was no evidence of an association between development of a retinal detachment and β-lactam antibiotics (ARR, 0.74 [95% CI, 0.35-1.57]) or short-acting β-agonists (ARR, 0.95 [95% CI, 0.68-1.33]). Patients taking oral fluoroquinolones were at a higher risk of developing a retinal detachment compared with nonusers, although the absolute risk for this condition was small.
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Clostridium difficile infection (CDI) is a common hospital-acquired infection with increasing incidence, severity, recurrence, and associated morbidity and mortality. There are emerging data on the occurrence of CDI in nonhospitalized patients. However, there is a relative lack of community-based CDI studies, as most of the existing studies are hospital based, potentially influencing the results by referral or hospitalization bias by missing cases of community-acquired CDI. To better understand the epidemiology of community-acquired C. difficile infection, a population-based study was conducted in Olmsted County, Minnesota, using the resources of the Rochester Epidemiology Project. Data regarding severity, treatment response, and outcomes were compared in community-acquired vs. hospital-acquired cohorts, and changes in these parameters, as well as in incidence, were assessed over the study period. Community-acquired CDI cases accounted for 41% of 385 definite CDI cases. The incidence of both community-acquired and hospital-acquired CDI increased significantly over the study period. Compared with those with hospital-acquired infection, patients with community-acquired infection were younger (median age 50 years compared with 72 years), more likely to be female (76% vs. 60%), had lower comorbidity scores, and were less likely to have severe infection (20% vs. 31%) or have been exposed to antibiotics (78% vs. 94%). There were no differences in the rates of complicated or recurrent infection in patients with community-acquired compared with hospital-acquired infection. In this population-based cohort, a significant proportion of cases of CDI occurred in the community. These patients were younger and had less severe infection than those with hospital-acquired infection. Thus, reports of CDI in hospitalized patients likely underestimate the burden of disease and overestimate severity.
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Since their introduction in the mid-1980s, the fluoroquinolones have been administered to more than 100 million patients. Generally, adverse effects reported in association with the fluoroquinolones have been those that could have been predicted by previous experience with non-fluorinated derivatives and by animal toxicity studies. Examples of such adverse events are CNS-related toxicity, upper gastrointestinal tract reactions and phototoxicity. Some adverse experiences in animals, notably cartilage toxicity, have been of minimal clinical importance. This should lead to a re-evaluation of the possible paediatric indications for the fluoroquinolones. With temafloxacin, which was withdrawn from clinical use in June 1992, new and serious adverse events were reported at a frequency of about 1 per 3500 patients treated. This frequency of adverse events is too low to be detected even in very careful analyses of phase III registration studies. Anaphylaxis, haemolytic anaemia and renal failure were the most striking adverse events reported with temafloxacin, and, in addition, hypoglycaemia and hepatic failure were reported. These reactions may be attributable to an immunological reaction in some patients. Because of the rarity of these reactions, they can be detected only by studies encompassing thousands of patients, usually during postmarketing surveillance. Safety monitoring of each new fluoroquinolone during its early clinical use is therefore recommended.
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Background and objective: Ciprofloxacin is a broad-spectrum, synthetic antibacterial used for the treatment of various bacterial infections. In multidrug therapy, ciprofloxacin is commonly prescribed with analgesics for the management of infection, pain and inflammation. The objective of this study was to evaluate the pharmacokinetic properties of ciprofloxacin tablets with concurrent administration of diclofenac tablets in healthy adult human volunteers. Methods and design: The disposition pharmacokinetics of a single oral dose of ciprofloxacin 500 mg alone and with co-administration of a diclofenac 50 mg tablet in 12 healthy male volunteers was investigated using a two-period, crossover design. The blood samples were collected at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after administration of the drugs and the concentration of ciprofloxacin in serum was determined using reversed phase high-performance liquid chromatography. The pharmacokinetic parameters were calculated using a noncompartmental model and a two-compartment model. Results: The maximum plasma concentration (Cmax) of ciprofloxacin increased from 2.48±0.33 mg/mL when administered alone to 3.91±0.8 mg/mL with co-administration of diclofenac. Time to reach Cmax (tmax) with ciprofloxacin reduced from 2.02±0.3 hours when administered alone to 1.49±0.2 h with co-administration of diclofenac. Significant increases in ciprofloxacin area under the serum concentration-time curve (AUC) and elimination half-life, together with a significant decrease in total body clearance of ciprofloxacin, were observed with concurrent administration of diclofenac. Conclusion: Oral co-administration of ciprofloxacin tablets with diclofenac tablets increased ciprofloxacin AUC and Cmax, and reduced ciprofloxacin tmax and total body clearance.
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Moxifloxacin, a fluoroquinolone with potent activity against respiratory pathogens, is approved and considered as an alternative to β-lactams and macrolides for the treatment of acute bacterial sinusitis and lower respiratory tract infections. In this review, we critically examine its safety profile in comparison with other fluoroquinolones and other antibacterial classes sharing similar indications. Data were extracted from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects. Global analysis did not reveal significantly higher incidences of drug-related adverse effects than for comparators. Tendon rupture was infrequent with moxifloxacin, including when used in elderly patients with chronic obstructive pulmonary disease. Severe toxic cutaneous reactions and allergies were very rare. Phototoxicity and CNS adverse effects were less common than with other fluoroquinolones. Although causing a 4–7 msec corrected QT interval prolongation, severe cardiac toxicity was neither seen in large cohorts or clinical trials nor reported to pharmacovigilance systems. Hepatotoxicity was not different from what was observed for other fluoroquinolones (excluding trovafloxacin) and less frequent than reported for amoxicillin-clavulanic acid or telithromycin. The data show that using moxifloxacin, in its accepted indications and following the corresponding guidelines, should not be associated with an excessive incidence of drug-related adverse reactions, provided the clinician takes care in identifying patients with known risk factors and pays due attention to the contraindications and warnings mentioned in the labelling.
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Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water-metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water-metal ion bridge is a general mechanism of quinolone-topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water-metal ion bridge is essential for quinolone activity against E. coli topoisomerase IV. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase IV. The water-metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase IV. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase IV proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates.
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Objective: Both over-the-counter medicine, such as antacids or alginates, and proton pump inhibitors (PPI) are used for treating acid-related disorders. We sought to describe what characterizes users of these different medicines, including long-term PPI users within the general population. Method: A cross-sectional survey was conducted in an internet panel representative of the Danish adult population in 2012. Data queried included antacid/alginate and PPI use, reason for therapy, co-medication, and presence of upper gastrointestinal symptoms. Long-term PPI use was defined as using PPI ≥1/3 of the last year (∼120 days). Risk of long-term PPI use was estimated by logistic regression. Results: A total of 18,223 people received the questionnaire, of which 52% (9390) responded. Antacid/alginate use was reported by 23%; 16% reported use of only antacid/alginate. PPI use was reported by 13.6%; 6.2% were defined as long-term PPI users. Antacid/alginate users were younger, used less co-medication, had most often started on therapy because of reflux symptoms, and had less often ongoing symptoms. Risk of long-term PPI use appeared to be increased in male gender, by renewing PPI prescription by phone/e-mail, using co-medication, and having started on PPI for several reasons. Combination of antacid/alginate and PPI was reported by approximately 50% of those on therapy with weekly or daily symptoms. Conclusion: 23% of Danish adults were using antacids or alginates and 14% were using PPI, of which one-half were on long-term therapy. Prescription renewal by phone or e-mail and use of other prescription medication were associated with long-term PPI use, indicating a behavioral pattern, in which unnecessary PPI therapy may be maintained.
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Quinolone and fluoroquinolone antibiotics are potent, broad-spectrum agents commonly used to treat a range of infections. Resistance to these agents is multifactorial and can be via one or a combination of target-site gene mutations, increased production of multidrug-resistance (MDR) efflux pumps, modifying enzymes, and/or target-protection proteins. Fluoroquinolone-resistant clinical isolates of bacteria have emerged readily and recent data have shown that resistance to this class of antibiotics can have diverse, species-dependent impacts on host-strain fitness. Here we outline the impacts of quinolone-resistance mutations in relation to the fitness and evolutionary success of mutant strains.
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Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN. This article is protected by copyright. All rights reserved.
Article
Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.
Article
Purpose: The aim of this study is to determine if oral fluoroquinolone exposure is associated with an increased hazard for having a retinal tear or detachment. Methods: A retrospective cohort study was performed using individuals who met inclusion criteria from The Health Improvement Network database. Cohorts were created for individuals who had a prescription written for either an oral fluoroquinolone or an oral β-lactam antibiotic (comparison group). Subjects were excluded if they had a previous diagnosis of a retinal tear or detachment (hereafter retinal break (RB)), or a procedure code to treat an RB, where in the practice for less than 365 days, had a previous prescription for either antibiotic within 365 days of the index date or had intraocular surgery or a diagnosis of endophthalmitis within 90 days prior to the antibiotic prescription. Covariates of interest were age, gender, diabetes, and year of index. The primary outcome measure of interest was the hazard ratio (HR) of undergoing a procedure to treat an RB within 7, 30, 90, or 365 days after exposure to an oral fluoroquinolone prescription versus an oral β-lactam prescription. Results: After exclusions, 6,604,423 prescriptions (290,393 fluoroquinolone; 6,314,030 β-lactam) from 3,413,498 patients (247,073 fluoroquinolone; 3,303,641 β-lactam) and 2685 RB procedures were eligible for analysis (661 retinal tears and 2024 retinal detachments). For fluoroquinolones, 0, 1, 5, and 23 RBs occurred at the 7-, 30-, 90-, and 365-day time points, respectively. For β-lactam prescriptions, 7, 28, 87, and 373 RBs occurred at the 7-, 30-, 90-, and 365-day time points, respectively. Because of zero events occurring in the fluoroquinolone cohort during the 7-day observation period, an unadjusted or an adjusted HR (and subsequent p-value or confidence intervals) was unable to be calculated. Univariate and multivariate analyses demonstrated that fluoroquinolones were not significantly associated with RB in the 30-, 90-, or 365-day observation periods (30-day HR = 0.78, p = 0.80, 95%CI: 0.11, 5.71; 90-day HR = 1.25, p = 0.63, 95%CI: 0.51, 3.08; and 365-day HR = 1.35, p = 0.16, 95%CI: 0.89, 2.06). Conclusions: Our results do not support an association between oral fluoroquinolone use and subsequent procedures to treat an RB.
Article
Self-controlled observational study designs, such as the case-crossover design and the self-controlled case series, are reviewed, and their respective rationale, strengths and limitations are compared. Although no single design is generally superior to the others, they share the trait of being robust towards confounders that are stable over time. The self-controlled designs can be particularly useful when using secondary health care data for pharmacoepidemiological research and might be useful in screening for adverse drug effects. The main limitations of self-controlled designs are that they are amenable only to transient effects; some may be inefficient with long-term exposure; and they may be sensitive towards trends in exposure. This article is protected by copyright. All rights reserved.
Article
To examine whether oral fluoroquinolone antibiotics are associated with an increase in subsequent rhegmatogenous retinal detachment and symptomatic retinal breaks in a large population-based cohort. Population-based cohort study. Adult residents of Olmsted County, Minnesota, who were prescribed oral fluoroquinolone medications from January 1, 2003, to June 30, 2011. Comparison cohorts consisted of patients prescribed oral macrolide and β-lactam antibiotics during the study period. Procedure codes were used to identify retinal detachment repair and prophylaxis procedures occurring within 1 year of prescription dates. Travel clinic, pro re nata, and self-treatment prescriptions were excluded. Patients with tractional retinal detachment, previous retinal detachment repair, endophthalmitis, and necrotizing retinitis were excluded, as were those with intraocular surgery or severe head/eye trauma ≤90 days before the procedure. Rates of retinal detachment repair and prophylaxis procedures within 7, 30, 90, and 365 days of the first prescription were calculated and compared between antibiotic prescription cohorts using chi-square tests. Retinal detachment repair rates also were compared with the expected Olmsted County, Minnesota, rates using the one-sample log-rank test. Oral fluoroquinolones were prescribed for 38 046 patients (macrolide n = 48 074, β-lactam n = 69 079) during the study period. Retinal detachment repair procedures were performed within 365 days of the first prescription in 0.03% (95% confidence interval [CI], 0.01-0.06) of the fluoroquinolone cohort, 0.02% (95% CI, 0.01-0.03) of the macrolide cohort, and 0.03% (95% CI, 0.02-0.05) of the β-lactam cohort (P > 0.05). Retinal detachment prophylaxis procedures for symptomatic retinal breaks were performed within 365 days of the first prescription in 0.01% (95% CI, 0.00-0.03) of the fluoroquinolone cohort, 0.02% (95% CI, 0.01-0.04) of the macrolide cohort, and 0.02% (95% CI, 0.01-0.04) of the β-lactam cohort (P > 0.05). Similar comparisons of treatment rates within 7, 30, and 90 days of the first prescription were all nonsignificant between cohorts. Post-fluoroquinolone retinal detachment repair rates were similar to expected rates (36.8 per 100 000/year vs. 28.8 per 100 000/year for age- and sex-matched historical rates, P = 0.35). Oral fluoroquinolone use was not associated with an increased risk of rhegmatogenous retinal detachment or symptomatic retinal breaks in this population-based study.
Article
This review aims to clarify the underlying risk of arrhythmia associated with the use of macrolides and fluoroquinolones antibiotics. Torsades de pointes (TdP) is a rare potential side effect of fluoroquinolones and macrolide antibiotics. However, the widespread use of these antibiotics compounds the problem. These antibiotics prolong the phase 3 of the action potential and cause early after depolarization and dispersion of repolarization that precipitate TdP. The potency of these drugs, as potassium channel blockers, is very low, and differences between them are minimal. Underlying impaired cardiac repolarization is a prerequisite for arrhythmia induction. Impaired cardiac repolarization can be congenital in the young or acquired in adults. The most important risk factors are a prolonged baseline QTc interval or a combination with class III antiarrhythmic drugs. Modifiable risk factors, including hypokalemia, hypomagnesemia, drug interactions, and bradycardia, should be corrected. In the absence of a major risk factor, the incidence of TdP is very low. The use of these drugs in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high-risk factors.
Article
A recent study of ophthalmologic patients found a strong association between fluoroquinolone use and retinal detachment. Given the prevalent use of fluoroquinolones, this could, if confirmed in the general population, translate to many excess cases of retinal detachment that are potentially preventable. To investigate if oral fluoroquinolone use is associated with an increased risk of retinal detachment. A nationwide, register-based cohort study in Denmark from 1997 through 2011, using linked data on participant characteristics, filled prescriptions, and cases of retinal detachment with surgical treatment (scleral buckling, vitrectomy, or pneumatic retinopexy). The cohort included 748,792 episodes of fluoroquinolone use (660,572 [88%] ciprofloxacin) and 5,520,446 control episodes of nonuse. Poisson regression was used to estimate rate ratios (RRs) for incident retinal detachment, adjusting for a propensity score that included a total of 21 variables. The risk windows were classified as current use (days 1-10 from start of treatment), recent use (days 11-30), past use (days 31-60), and distant use (days 61-180). A total of 566 cases of retinal detachment occurred, of which 465 (82%) were rhegmatogenous detachments; 72 in fluoroquinolone users and 494 in control nonusers. The crude incidence rate was 25.3 cases per 100,000 person-years in current users, 18.9 in recent users, 26.8 in past users, and 24.8 in distant users compared with 19.0 in nonusers. Compared with nonuse, fluoroquinolone use was not associated with a significantly increased risk of retinal detachment: the adjusted RRs were 1.29 (95% CI, 0.53 to 3.13) for current use; 0.97 (95% CI, 0.46 to 2.05) for recent use; 1.37 (95% CI, 0.80 to 2.35) for past use; and 1.27 (95% CI, 0.93 to 1.75) for distant use. The absolute risk difference, estimated as the adjusted number of retinal detachment cases per 1,000,000 treatment episodes, was 1.5 (95% CI, -2.4 to 11.1) for current use. In this cohort study based on the general Danish population, oral fluoroquinolone use was not associated with increased risk of retinal detachment. Given its limited power, this study can only rule out more than a 3-fold increase in the relative risk associated with current fluoroquinolone use; however, any differences in absolute risk are likely to be of minor, if any, clinical significance.
Article
Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications-most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug-drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.
Article
Background: An association between use of oral fluoroquinolones (FQs) and retinal detachment remains controversial. This study was to determine the association of recent use of oral FQs and rhegmatogenous retinal detachment (RRD) after adjustment for confounding factors known to be associated with RRD. Methods: This retrospective population-based cohort study with parallel groups included adults treated with an oral FQ (FQ cohort = 178 179 prescriptions) and propensity score-matched adults treated with oral amoxicillin (amoxicillin cohort = 178 179 prescriptions). The data were extracted from the Taiwan National Health Insurance Research Database from 1998 to 2010. Interaction terms were used to identify populations at risk. RRD was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Results: During the 90-day follow-up period, 96 patients (0.054%) in the FQ cohort developed RRD compared to 46 (0.026%) among the matched amoxicillin cohort. The overall adjusted hazard ratio (HR) for FQ use and RRD was 2.07 (95% confidence interval [CI], 1.45-2.96). The interval between use of oral FQs and onset of RRD was 35.5 days (interquartile range, 14-57 days). Interaction terms were not significant for age, sex, diabetes, indications for antimicrobials, or underlying ophthalmic conditions. The adjusted HRs differed for specific FQs. These were 10.68 (95% CI, 3.28-34.82) for ciprofloxacin, 2.41 (95% CI, .76-7.68) for levofloxacin, 2.00 (95% CI, 1.06-3.79) for norfloxacin, and 1.17 (95% CI, .59-2.31) for ofloxacin. Conclusions: The use of oral FQs was associated with the subsequent occurrence of RRD. The FQ risk was independent of age, sex, diabetes, indications for antimicrobials, and underlying ophthalmic conditions. Certain FQs carried higher risk of RRD.
Article
Quinolones are a class of antibacterial agents for the treatment of several infectious diseases (e.g. urinary and respiratory tract infections). They are used worldwide due to their broad spectrum of activity, high bioavailability and good safety profile. The safety profile varies from quinolone to quinolone. The aim of this article was to review the neurological and psychiatric adverse drug reaction (ADR) profile of quinolones, using a literature search strategy designed to identify case reports and case series. A literature search using PubMed/MEDLINE (from inception to 31 October 2010) was performed to identify case reports and case series related to quinolone-associated neurological and psychiatric ADRs. The search was conducted in two phases: the first phase was the literature search and in the second phase relevant articles were identified through review of the references of the selected articles. Relevant articles were defined as articles referring to adverse events/ reactions associated with the use of any quinolone. Abstracts referring to animal studies, clinical trials and observational studies were excluded. Identified case reports were analysed by age group, sex, active substances, dosage, concomitant medication, ambulatory or hospital-based event and seriousness, after Medical Dictionary for Regulatory Activities (MedDRA®) coding. From a total of 828 articles, 83 were identified as referring to nervous system and/or psychiatric disorders induced by quinolones. 145 individual case reports were extracted from the 83 articles. 40.7% of the individual case reports belonged to psychiatric disorders only, whereas 46.9% related to neurological disorders only. Eight (5.5%) individual case reports presented both neurological and psychiatric ADRs. Ciprofloxacin, ofloxacin and pefloxacin were the quinolones with more neurological and psychiatric ADRs reported in the literature. Ciprofloxacin has been extensively used worldwide, which may explain the higher number of reports, while for ofloxacin and pefloxacin, the number of reports may be over-representative. A total of 232 ADRs were identified from the selected articles, with 206 of these related to psychiatric and/or neurological ADRs. The other 26 were related to other body systems but were reported together with the reactions of interest. Mania, insomnia, acute psychosis and delirium were the most frequently reported psychiatric adverse events; grand mal convulsion, confusional state, convulsions and myoclonus were the most frequently reported neurological adverse events. Several aspects should be taken into account in the development of CNS adverse effects, such as the pharmacokinetics of quinolones, chemical structure and quinolone uptake in the brain. These events may affect not only susceptible patients but also ’healthy’ patients.
Article
There has been dramatic change in the epidemiology of Clostridium difficile infection (CDI) since the turn of the 21st century noted by a marked increase in incidence and severity, occurring at a disproportionately higher frequency in older patients. Historically considered a nosocomial infection associated with antibiotic exposure, CDI has now also emerged in the community in populations previously considered low risk. Emerging risk factors and disease recurrence represent continued challenges in the management of CDI. The increased incidence and severity associated with CDI has coincided with the emergence and rapid spread of a previously rare strain, ribotype 027. Recent data from the United States and Europe suggest that the incidence of CDI may have reached a crescendo in the recent years and is perhaps beginning to plateau. The acute care direct costs of CDI were estimated to be US$4.8 billion in 2008. However, nearly all the published studies have focused on CDI diagnosed and treated in the acute care hospital setting and fail to measure the burden outside the hospital, including recently discharged patients, outpatients, and those in long-term care facilities. Enhanced surveillance methods are needed to monitor the incidence, to identify populations at risk, and to characterize the molecular epidemiology of strains causing CDI.
Article
Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disruptin