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Third and Fourth Generation Fluoroquinolone Antibacterials: A Systematic Review of Safety and Toxicity Profiles
Abstract
In the last decade, several third- and fourth-generation fluoroquinolones (FQs) have been approved for clinical use. These new agents exhibit a more potent and broader-spectrum antibacterial activity and improved pharmacokinetic properties in comparison to the earlier FQs. Although new FQs are generally safe and well tolerated, moderate-to-severe toxicity events have been reported for some of them, leading to their restriction, suspension or even withdrawal from the market. The most common FQ-related adverse effects (AEs) are usually mild and involve the gastrointestinal tract (e.g. nausea and diarrhea) and the central nervous system (e.g. headache and dizziness). Uncommon, but severe AEs (e.g. arthropathy, QTc interval prolongation, dysglycaemia and phototoxicity) and idiosyncratic reactions (e.g. hepatitis and hemolytic anemia) have also been reported and will be discussed throughout this paper. The evidence currently available suggests that AEs can be inherent to the FQ class or can be associated with a particular chemical moiety of the molecular structure of each FQ, thus varying in frequency, severity and nature.The main goal of this review is to provide a systematic evaluation of safety and tolerability data of the newer FQs with emphasis on those currently marketed.
... Many fluoroquinolones have either achieved the status of advanced research chemical tools or have been approved for clinical use, which allows for classifying them into four generations [8]. Among the periphery elements that vary in different fluoroquinolones, the amine substituent in position 7 is of particular importance [9]. ...
... Among the periphery elements that vary in different fluoroquinolones, the amine substituent in position 7 is of particular importance [9]. Notable examples illustrating the 7-amino group's variations in fluoroquinolones, in combination with altering the aromatic ring substituents, include moxifloxacin [10], ciprofloxacin [11], sparfloxacin [12], four generations [8]. Among the periphery elements that vary in different fluoroquinolones, the amine substituent in position 7 is of particular importance [9]. ...
... four generations [8]. Among the periphery elements that vary in different fluoroquinolones, the amine substituent in position 7 is of particular importance [9]. ...
The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin. However, the spectrum of antibacterial activity was quite different, as the new compounds showed no activity against Pseudomonas aeruginosa. Among the prepared and tested compounds, the broadest range of activity (five pathogens of the six in the ESKAPE panel) and the highest level of activity were demonstrated by 1-yclopropyl-7-[8-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-azaspiro[3.4]oct-6-yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the lead compound nominated for further characterization and development.
... nausea, vomiting and anorexia) and nervous in less than 5% (e.g. mild headache, dizziness and mood alterations) (Anad on and Mart ınez-Larrañaga, 1992 Kamath 2013; Sousa et al. 2014;Golomb et al. 2015;Michalak et al. 2017). On the other side, some rarer AEs were recorded including arthropathy and tendinopathies ; Anad on and Mart ınez-Larrañaga 1992; Baboldashti et al. 2011;Hori et al. 2012;Sousa et al. 2014;Michalak et al. 2017), hepatic toxicity (Alan et al. 2011;Adikwu and Brambaifa 2012;Unger and Al-Jashaami 2016;Baloch et al. 2017), nephrotoxicity (Bird et al. 2013;Khan et al. 2015a), cardiac toxicity (Arce et al. 2010;Adikwu and Brambaifa 2012;Niedrig et al. 2016;Michalak et al. 2017), genotoxicity (Nunes et al. 2018) and chromosomal aberrations in human lymphocytes (Gorla et al. 1999). ...
... mild headache, dizziness and mood alterations) (Anad on and Mart ınez-Larrañaga, 1992 Kamath 2013; Sousa et al. 2014;Golomb et al. 2015;Michalak et al. 2017). On the other side, some rarer AEs were recorded including arthropathy and tendinopathies ; Anad on and Mart ınez-Larrañaga 1992; Baboldashti et al. 2011;Hori et al. 2012;Sousa et al. 2014;Michalak et al. 2017), hepatic toxicity (Alan et al. 2011;Adikwu and Brambaifa 2012;Unger and Al-Jashaami 2016;Baloch et al. 2017), nephrotoxicity (Bird et al. 2013;Khan et al. 2015a), cardiac toxicity (Arce et al. 2010;Adikwu and Brambaifa 2012;Niedrig et al. 2016;Michalak et al. 2017), genotoxicity (Nunes et al. 2018) and chromosomal aberrations in human lymphocytes (Gorla et al. 1999). In addition, peripheral neuropathy (LaSalvia et al. 2010;Ahmed et al. 2011;Ali 2014;Francis and Higgins 2014;Michalak et al. 2017) and toxic optic neuropathy (Samarakoon et al. 2007;Thompson 2007;Kuo et al. 2014;Grzybowski et al. 2015) were reported, In 2018, risks of hypoglycemia and mental health problems were added. ...
... So, these antibiotics should be avoided in patients with convulsive or other central nervous system (CNS) disorders. Furthermore, CIP is contraindicated in pregnant, lactating women and children because of the great risk of cartilage and bone damage that enhances growth retardation ( Figure 3) (Barnhill et al. 2012;Sousa et al. 2014). The concern of CIP in pediatrics is because studies in juvenile animals developed arthropathy (Adefurin et al. 2011). ...
Ciprofloxacin (CIP) (human use) and enrofloxacin (ENR) (veterinary use) are synthetic anti-infectious medications that belong to the second generation of fluoroquinolones. They have a wide antimicrobial spectrum and strong bactericidal effects at very low concentrations via enzymatic inhibition of DNA gyrase and topoisomerase IV, which are required for DNA replication. They also have high bioavailability, rapid absorption with favorable pharmacokinetics and excellent tissue penetration, including cerebral spinal fluid. These features have made them the most applied antibiotics in both human and veterinary medicine. ENR is marketed exclusively for animal medicine and has been widely used as a therapeutic veterinary antibiotic, resulting in its residue in edible tissues and aquatic environments, as well as the development of resistance and toxicity. Estimation of the risks to humans due to antimicrobial resistance produced by CIP and ENR is important and of great interest. Moreover, in rare cases due to their overdose and/or prolonged administration, the development of CIP and ENR toxicity may occur. The toxicity of these fluoroquinolones antimicrobials is mainly related to reactive oxygen species (ROS) and oxidative stress (OS) generation, besides metabolism-related toxicity. Therefore, CIP is restricted in pregnant and lactating women, pediatrics and elderly similarly ENR do in the veterinary field. This review manuscript aims to identify the toxicity induced by ROS and OS as a common sequel of CIP and ENR. Furthermore, their metabolism and the role of metabolizing enzymes were reported.
... The majority of literature regarding to these aspects refers to fluoroquinolones and sulfonamides. Central nervous system events have been reported in 1-3.3% of patients taking a fluoroquinolone [91,96], with confusion (51%), hallucinations (27%), agitation (13%), and delusion being the most frequently psychiatric effects observed [96]. Samyde et al. [97] also found 608 reports of suicidal behavior correlated with fluoroquinolones therapy, 97 of which completed the suicide. ...
... The majority of literature regarding to these aspects refers to fluoroquinolones and sulfonamides. Central nervous system events have been reported in 1-3.3% of patients taking a fluoroquinolone [91,96], with confusion (51%), hallucinations (27%), agitation (13%), and delusion being the most frequently psychiatric effects observed [96]. Samyde et al. [97] also found 608 reports of suicidal behavior correlated with fluoroquinolones therapy, 97 of which completed the suicide. ...
... As above mentioned, old antibiotics (vancomycin, daptomycin, and linezolid) have limitations because of toxicity [96,97], tolerance [103,104], drug resistance [81], and drug-drug interactions [83]. Moreover, intravenous administration requires an intravenous line, and oral administration of linezolid also presents a potential problem of compliance [111]. ...
Purpose of review:
Previous studies suggest an association between depression and increased risk of various type of infections, including acute bacterial skin and skin structure infections (ABSSSI). Here, we review the latest advancement in our understanding of immunity in patients with depression and its relevance to disease management and diagnosis, with a special focus on patients suffering from ABSSSI.
Recent findings:
Recent studies have highlighted the role of hypothalamic-pituitary-adrenal axis, neuro-endocrine stress signaling pathways and behavioral attitudes (substance abuse and homelessness) in the pathogenesis of infections in depressed patients. Furthermore, acute bacterial infections, in turn, have emerged as a possible risk for depression development because of different mechanisms including antibiotic-driven changes in the microbiota.
Summary:
Recent evidences have emphasized the threat that comanagement of depression and infection pose to infectious disease physician and psychiatrist. Depressed patients with ABSSSI must be closely monitored for drug side-effects, drug-drug interactions, toxicity, and adequate compliance. New management strategies including new long-acting antibiotics (e.g., dalbavancin) are welcome.
... This is thought to induce a hyperexcitable neuronal state resulting in the development of a movement disorder (10,15,19,20,25). There is a similarity between the structure of certain substituents at position 7 of the fluoroquinolone nucleus and the neurotransmitter GABA (29). It is hypothesized that fluoroquinolones may compete with and displace GABA from its receptor sites in the CNS leading to stimulation of the CNS (29). ...
... There is a similarity between the structure of certain substituents at position 7 of the fluoroquinolone nucleus and the neurotransmitter GABA (29). It is hypothesized that fluoroquinolones may compete with and displace GABA from its receptor sites in the CNS leading to stimulation of the CNS (29). Other mechanisms that have been suggested include the interaction of fluoroquinolones with opioid, dopamine and glutamate receptors (29). ...
... It is hypothesized that fluoroquinolones may compete with and displace GABA from its receptor sites in the CNS leading to stimulation of the CNS (29). Other mechanisms that have been suggested include the interaction of fluoroquinolones with opioid, dopamine and glutamate receptors (29). Ulutas Med J 2018;4(1):53-63 (30). ...
... Fluoroquinolones (FQs), which are synthesized by addition of a fluorine atom at position C-6 of the bicyclic ring structure of quinolone, 1,2 are commonly used in treatment of various infections, 3−6 although some of the compounds, for example, grepafloxacin, sparfloxacin, and gatifloxacin, etc., have been withdrawn from the European and U.S. markets. 1 They exert bactericidal effects by inhibiting DNA gyrase and topoisomerase IV and interfering replication of bacterial DNA. Despite restricted FDA-approved pediatric indications due to safety concerns, some FQs were used to treat a variety of infections in children due to their excellent pharmacokinetic and pharmacodynamics properties. ...
... 13 Moreover, gastrointestinal AEs, such as nausea and vomiting, are caused by a CNS-mediated mechanism in combination with direct irritation of the gastrointestinal tract. 1 Studies of the relationship between drug adverse reactions and drug structure contribute to structural modifications and an understanding of adverse reaction mechanisms. 2 The neurotoxicity mechanism of FQs is not fully understood, 14 but studies have shown that it is closely related to FQ structure. 2,15 The possible interaction sites of FQs include antagonizing γaminobutyric acid (GABA) receptors, activating N-methyl-Daspartic acid (NMDA) receptors, decreasing serotonin levels, altering microRNA expression, and so on. ...
... From the combined data of several studies, it appears that the R7 side chain substituent has the strongest influence on the GABA binding inhibition. 1,17,49,50 The findings suggest that not only the piperazinyl group at the C-7 side chain may play a vital role in the binding with the residue GLU 402 of GABA receptor, but steric hindrance of the compounds was influenced upon the binding. ...
Central nervous system (CNS) side effects are one of the most frequently reported adverse reactions of fluoroquinolones (FQs). However, the mechanism is not fully understood. In this study, zebrafish (Danio rerio) were used as a model system. We quantified neurobehavior by recording indicators with automated video-tracking and used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect drug absorption in vivo. We studied embryotoxicity and effects on zebrafish locomotor activity of 17 typical FQs. In addition, we calculated the stable conformation of typical FQs in aqueous conditions. The relationships between structure, neurotoxicity, and embryotoxicity were analyzed. The results indicate: (1) The effects of FQs on zebrafish neurobehavior can be divided into four categories. Type Ⅰ has no significant influence on locomotor activity. Type Ⅱ suppresses locomotor activity. Type Ⅲ inhibits at low concentration and stimulates at high concentration. Type Ⅳ stimulates and then suppresses (biphasic response). (2) Structural modifications of FQs can change toxicity properties in zebrafish. Cleavage of the C-7 piperazinyl structure decreases neurotoxicity but enhances embryotoxicity. The C-3 decarboxyl formation and 5-NH2 derivatives might enhance embryotoxicity and neurotoxicity. (3) There are two toxic functional groups. The piperazinyl structure at position C-7 (toxic functional group I) can cause primary reactions which may be by the inhibition of γ-aminobutyric acid (GABA) receptors, and the nucleus containing a carboxyl group at position 3 (toxic functional group II) might cause a reaction secondary to the effect of toxic functional group I and reverse its effects.
... The addition of a halogen (fluorine or chlorine) at position 8 leads to third-generation quinolones -levofloxacin and gatifloxacin -, which have greater activity against Pseudomonas aeruginosa, gram-positive bacteria, and anaerobes. Finally, the fourth generationmoxifloxacin, gemifloxacin, and trovafloxacin -is more potent against gram-positive bacteria and anaerobes and less active against P. aeruginosa, due to a double ring derived from the pyrrolidone ring at position 7 and a methoxy group at position 8. 3,4 Bactericidal activity of quinolones targets the bacterial enzymes DNA gyrase and DNA topoisomerase IV, inhibiting microorganism replication. 1,4,5 Currently, these antibiotics are widely used in the treatment of gram-positive and gram-negative bacteria affecting the urinary, respiratory, digestive, and cutaneous tracts, in addition to sexually transmitted infections, prostatitis, and tuberculosis. ...
... Finally, the fourth generationmoxifloxacin, gemifloxacin, and trovafloxacin -is more potent against gram-positive bacteria and anaerobes and less active against P. aeruginosa, due to a double ring derived from the pyrrolidone ring at position 7 and a methoxy group at position 8. 3,4 Bactericidal activity of quinolones targets the bacterial enzymes DNA gyrase and DNA topoisomerase IV, inhibiting microorganism replication. 1,4,5 Currently, these antibiotics are widely used in the treatment of gram-positive and gram-negative bacteria affecting the urinary, respiratory, digestive, and cutaneous tracts, in addition to sexually transmitted infections, prostatitis, and tuberculosis. 5 Due to the widespread use of quinolones, adverse events related to the use of these drugs have been described. ...
... It was observed that the halogen (fluorine/chlorine atom) substitution in the C8 position led to an increased risk of phototoxicity. The 8-fluorine substituent proved to have more phototoxic potential than 8-chlorine [5,37,195,287]. Additionally, an amino substituent at the C5 position and a fluorine/chlorine substituent at the C8 position can increase the phototoxic potential of FQs [8]. Some halogenated FQs have been withdrawn due to their phototoxic potential, such as clinafloxacin (8-chloro derivative), and fleroxacin, lomefloxacin, and sparfloxacin (8-fluoro derivatives) (Table 3) [2,44]. ...
... The usual FQs are rarely associated with severe liver damage with increased transaminase levels (estimation of 1:100,000 patients who received treatment with FQs). However, some FQs were withdrawn as a result of serious side-effects, including hepatotoxicity (e.g., temafloxacin, trovafloxacin, and gatifloxacin (Table 3)) [287,[358][359][360][361]. ...
Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European Medicine Agency (EMA) and regulatory authorities from other countries. Severe AEs associated with some FQs have been reported, leading to their withdrawal from the market. New systemic FQs have been recently approved. The FDA and EMA approved delafloxacin. Additionally, lascufloxacin, levonadifloxacin, nemonoxacin, sitafloxacin, and zabofloxacin were approved in their origin countries. The relevant AEs of FQs and their mechanisms of occurrence have been approached. New systemic FQs present potent antibacterial activity against many resistant bacteria (including resistance to FQs). Generally, in clinical studies, the new FQs were well-tolerated with mild or moderate AEs. All the new FQs approved in the origin countries require more clinical studies to meet FDA or EMA requirements. Post-marketing surveillance will confirm or infirm the known safety profile of these new antibacterial drugs. The main AEs of the FQs class were addressed, highlighting the existing data for the recently approved ones. In addition, the general management of AEs when they occur and the rational use and caution of modern FQs were outlined.
... They have a fast bactericidal and dose-dependent activity. Structurally, quinolones are composed of the 4oxo-1,4-dihydroquinoleine ring core with a nitrogen atom at position 1, a carbonyl at position 4, and a carboxyl at position 3. Since the beginning of its synthetization [18], several structural changes have been introduced, improving antimicrobial effectiveness and the broadening of the antibacterial spectrum of quinolones, with better bioavailability, greater tissue penetration and, consequently, long half-life [19]. Therefore, quinolones have been classified into four different groups, based on their chemical structure and their antibacterial spectra [19][20][21] ( Figure 1). ...
... Structurally, quinolones are composed of the 4oxo-1,4-dihydroquinoleine ring core with a nitrogen atom at position 1, a carbonyl at position 4, and a carboxyl at position 3. Since the beginning of its synthetization [18], several structural changes have been introduced, improving antimicrobial effectiveness and the broadening of the antibacterial spectrum of quinolones, with better bioavailability, greater tissue penetration and, consequently, long half-life [19]. Therefore, quinolones have been classified into four different groups, based on their chemical structure and their antibacterial spectra [19][20][21] ( Figure 1). The first generation quinolones (oxolinic acic, nalidixic acid, cinoxacin, and pipemidic acid) have activity against enterobacteria and some Gram-negative. ...
Over recent years, the consumption of quinolones as first-line treatment has increased, leading to a growth in incidence of hypersensitivity reactions (HSRs) to this group of antibiotics. Both diagnosis and management of HSRs to quinolones are complex and controversial. These practical guidelines aim to provide recommendations for an effective clinical practice. With this purpose, an expert panel reviewed the literature regarding HSRs to quinolones and analyzed controversies in this area. Most HSRs to these drugs are immediate and severe, being the risk for HSR higher in subjects who reported allergy to betalactams, moxifloxacin-induced anaphylaxis and immediate reactions (IRs) compared with patients who reported reactions to quinolones inducing other symptoms. Regarding diagnosis of HSRs to quinolones, the usefulness of skin tests is controversial, with sensitivity and specificity varying among studies. Most in vitro tests are produced in-house, with no validated commercial ones and basophil activation test being useful for diagnosing IRs although with diverse results regarding sensitivity. Drug provocation test is nowadays the gold standard for confirming or excluding the diagnosis as well as to find safe alternatives, although contraindicated for severe reactions. Cross-reactivity among quinolones is controversial among different studies, with the lowest cross-reactivity for levofloxacin. Desensitization may be considered in allergy to quinolones when no other alternative exist.
... Fluoroquinolones have been widely used in clinical practice for over 20 years because of their broad-spectrum antibacterial activity and excellent bioavailability. 1 Despite their effectiveness, fluoroquinolones are also associated with several rare but serious adverse reactions, including arthropathy, QT interval prolongation, neurological events, phototoxicity and retinal detachment. In addition, idiosyncratic reactions related to fluoroquinolones, especially hepatotoxicity, have become an increasing concern. ...
... In addition, idiosyncratic reactions related to fluoroquinolones, especially hepatotoxicity, have become an increasing concern. [1][2][3][4] Moxifloxacin is a relatively new antibacterial agent with improved activity against gram-positive bacteria and anaerobes and has equal or higher bioavailability and a longer elimination half-life than the previous fluoroquinolones. 5,6 However, moxifloxacin is not exempt from safety concerns, especially the potential risk of hepatotoxicity. ...
Background
Fluoroquinolone-related hepatotoxicity is rare but serious and is attracting increasing attention. We explored the incidence, clinical features and risk factors of acute liver injury associated with fluoroquinolone use.
Materials and methods
Based on the Adverse Drug Events Active Surveillance and Assessment System that we developed, we carried out a case-control study by enrolling patients who were hospitalized and received fluoroquinolones to treat or prevent infections at the Chinese People’s Liberation Army General Hospital from Jan 2016 to Dec 2017. The incidence of fluoroquinolone-induced acute liver injury was estimated, and logistic regression was used to reveal the risk factors of this adverse reaction.
Results
We found that 17,822 patients received fluoroquinolones, and 13,678 of them met the inclusion criteria. A total of 91 patients developed acute liver injury after receiving the medication, and 369 controls were matched to these patients. The overall incidence of fluoroquinolone-induced acute liver injury in the Chinese population is approximately 6–7 cases per 1,000 individuals annually. Multivariate logistic regression analysis showed that older age slightly decreased the risk of hepatotoxicity (OR, 0.98; 95% CI, 0.96–0.99). The male sex (OR, 2.19; 95% CI, 1.07–4.48), alcohol abuse (OR, 2.91; 95% CI, 1.39–6.11) and hepatitis B carrier status (OR, 2.38; 95% CI, 1.04–5.48) increased the risk of liver injury. Concurrent use of cephalosporins or carbapenems was also associated with an increased risk.
Conclusion
Increased risk of fluoroquinolone-related hepatotoxicity may be associated with youth, the male sex, alcohol abuse, hepatitis B carrier status and the concurrent use of cephalosporins or carbapenems.
... This generation has emerged from an attempt to expand antibacterial activity spectrum and also improve pharmacokinetic properties. LEV is one of the outstanding representatives of the third-generation of the quinolone class, evidencing a broad spectrum of antibacterial activity against most aerobic gram-negative and gram-positive bacteria and demonstrating a moderate activity against anaerobes (1)(2)(3)(4)(5). Chronic rhinosinusitis (CRS) is one of the most common chronic diseases with continued increasing prevalence despite the evolution of conventional antibiotic therapy, which is one of the most prescribed medication by physicians for the treatment of this medical condition. ...
... The three mean plasma concentration values attained with the lower topical dose were much lower than those obtained after IV delivery, confirming that systemic exposure of LEV following the IN dose of 0.24 mg/ kg is minimal when compared to the IV administered dose. Therefore, IN delivery will guarantee a reduced LEV distribution to other organs, having the important advantage of minimizing or even avoiding the development of adverse effects; this is an important issue for CRS patients that often require multiple courses of antibiotics and the concomitant use of corticosteroids, a therapy that increases the risk of development of tendinitis and tendon rupture (4,30). ...
Purpose:
To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection.
Methods:
Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used.
Results:
Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points.
Conclusion:
The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.
... The residual or zero CIP concentration mean values obtained in plasma after this IN administration and the lower C max /dose parameter compared to that of IV administration demonstrate that IN delivery has the important advantage of avoiding or minimizing CIP distribution to other organs and thus the development of adverse effects. This is particularly relevant for patients with CRS because fluoroquinolones are associated with increased risk for tendinitis and tendon rupture which is more pronounced with the concurrent use of corticosteroids, making these patients a more susceptible population to this musculoskeletal disorder, due to the simultaneous implementation of the two types of drug in CRS therapy (Sousa et al., 2014;Stahlmann and Lode, 2013). ...
... The unique anatomical connection between nose and brain has drawn our attention to assess CIP in olfactory bulb for the evaluation of its potential to develop central nervous system adverse effects, which are the second most commonly reported for fluoroquinolones (Sousa et al., 2014). The higher IN dose-normalized value found for mean C max compared to the corresponding IV value may suggest a direct transport of the drug from nasal cavity through olfactory epithelium to brain. ...
Intranasal administration of antibiotics is an alternative and attractive delivery approach in the treatment of local infections such as chronic rhinosinusitis. This topical route has the advantage of delivering high drug concentrations directly to the site of infection when trying to eradicate the highly resistant bacterial biofilms. The purpose of this study was to assess and compare the pharmacokinetic parameters of ciprofloxacin following intranasal and intravenous administrations to rats in plasma, olfactory bulb and nasal mucosa of two different nasal regions. For intranasal administration a thermoreversible in-situ gel was used to increase drug residence time in nasal cavity. Ciprofloxacin concentration time-profile in nasal mucosa of the studied anterior region (at naso- and maxilloturbinates level) was markedly higher after intranasal administration (0.24 mg/kg) than that following intravenous administration (10 mg/kg), while in nasal mucosa of the more posterior region (at ethmoidal turbinates level) ciprofloxacin concentrations were found to be higher after intranasal administration when the different dose administered by both routes is taken into account. A plateau in ciprofloxacin concentration was observed in nasal mucosa of both studied regions after intranasal administration, suggesting a slow delivery of the drug over a period of time using the nasal gel formulation. In plasma and olfactory bulb, concentration of ciprofloxacin was residual after intranasal administration, which demonstrates this is a safe administration route by preventing systemic and particularly central nervous system adverse effects. Dose-normalized pharmacokinetic parameters of ciprofloxacin exposure to nasal mucosa revealed higher values after intranasal delivery not only in the anterior region but also in the posterior nasal region. In conclusion, topical intranasal administration appears to be advantageous for delivering ciprofloxacin to the biophase, with negligible systemic and brain exposure using a 41.7-fold lower dose than intravenous administration. Therefore, it may represent a promising approach in the drug management of chronic rhinosinusitis.
... The fluoroquinolones are generally well tolerated, however a variety of central nervous system (CNS) adverse effects have been reported. 1,2 We describe a case of probable levofloxacin-associated secondary intracranial hypertension in a child treated for drug-resistant tuberculosis. ...
... 3 The fluoroquinolones are known to interact with the neurotransmitter GABA, opioid, dopamine and glutamate receptors, but these mechanisms are mostly ascribed to epileptogenic and depressive adverse effects; the mechanism for causing intracranial hypertension is not well described. 1 Efforts were made to exclude other etiologicl factors known to be associated with intracranial hypertension in children. 3,4 Our patient was a well-nourished, non-obese child with no associated endocrine disorders. ...
Fluoroquinolones are a key component of multidrug-resistant tuberculosis treatment. We describe the first reported case of probable levofloxacin-associated intracranial hypertension in a 6-year-old girl with pulmonary multidrug-resistant tuberculosis. The case highlights the potential risk of secondary intracranial hypertension in multidrug-resistant tuberculosis patients who require prolonged fluoroquinolone therapy and the need for ophthalmologic screening in children with suggestive signs and symptoms.
... A adição de um halogênio (flúor ou cloro) à posição 8 levou às quinolonas de terceira geração -levofloxacino e gatifloxacino -com maior atividade contra Pseudomonas aeruginosa, bactérias gram-positivas e anaeróbias. Por fim, a quarta geração -moxifloxacino, gemifloxacino e trovafloxacino -é mais potente contra bactérias gram-positivas e anaeróbias, com menor ação contra P. aeruginosa devido a presença de um anel duplo derivado do anel de pirrolidona na posição 7, e um grupo metoxi na posição 8 3,4 . ...
... Diphenoxylate have some unpleasant side effects like tachycardia, dry mouth, nausea, changes in mood, numbness in arms & legs, loss of appetite and blurring of vision etc [6]. Norfloxacin is used for the treatment of diarrhea and have side effects such as seizures, photosensitivity, rashes, depression, anxiety, hypoglycemia, hypoglycemia, dizziness muscle spasm, headache and confusion [7]. ...
Plant extract and its anti-diarrhoeal activity
... The pathophysiological mechanism of neurotoxicity induced by fluoroquinolones is not fully understood. FQNs are structurally related to the neurotransmitter GABA due to the similarity between the structure of particular substituents at position seven of the FQN nucleus [72]. Thus, FQNs may compete and displace GABA from its receptor sites, possibly leading to overstimulation [73]. ...
Background:
Fluoroquinolones (FQNs) are related to several central nervous system side effects. This review aims to evaluate the clinical-epidemiological profile, pathophysiological mechanisms, and management of FQNs-associated movement disorders (MDs).
Methods:
Two reviewers identified and assessed relevant reports in six databases without language restriction between 1988 and 2022.
Results:
A total of 45 reports containing 51 cases who developed MDs secondary to FQNs were reported. The MDs included 25 myoclonus, 13 dyskinesias, 7 dystonias, 2 cerebellar syndromes, 1 ataxia, 1 tic, and 2 undefined cases. The FQNs reported were ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin, levofloxacin, gemifloxacin, and pefloxacin. The mean and median age were 64.54 (SD: 15.45) and 67 years (range: 25-87 years). The predominant sex was male (54.16%). The mean and median time of MD onset were 6.02 (SD: 10.87) and 3 days (range: 1-68 days). The mean and median recovery time after MD treatment was 5.71 (SD: 9.01) and 3 days (range: 1-56 days). A complete recovery was achieved within one week of drug withdrawal in 80.95% of the patients. Overall, 95.83% of the individuals fully recovered after management.
Conclusions:
Future cases need to describe the long-term follow-up of the individuals. Additionally, FQN-induced myoclonus should include electrodiagnostic studies.
... Moreover, the structure-activity relationship (SAR) and the broadspectrum of activity of uoroquinolone antibiotics are wellknown. 78,79 Pokrovskaya et al. reported that neomycin B-ciprooxacin hybrid compounds were covalently bound via different linkers in order to achieve the optimum linker length and physicochemical properties required for the best activity. 80 Neomycin B-ciprooxacin hybrids, with an aromatic triazole linker and aliphatic triazole linker (Fig. 17), exhibited more antibacterial activity than (free) neomycin B, but not cipro-oxacin. ...
Hybrid compounds (L1–L2) possess potential advantages over mixtures used in combination therapies.
... Os efeitos adversos mais comuns relacionados às fluoroquinolonas são geralmente leves e envolvem o trato gastrointestinal e o sistema nervoso central. As evidências disponíveis sugerem que os efeitos adversos podem ser próprios da classe das fluoroquinolonas, ou podem estar associados a uma porção química particular da estrutura molecular de cada fluoroquinolona, variando assim em frequência, severidade e natureza (Sousa, et al., 2014), ou podem também ocorrer devido a maiores concentrações plasmáticas e aumento da penetração tecidual, como reflexo do maior volume de distribuição (Eshar, et al., 2018). ...
As fluoroquinolonas são drogas sintéticas que evoluíram ao longo do tempo, sendo formadas por um grupo de antibióticos desenvolvido a partir do ácido nalidíxico, contendo assim, quatro gerações com diferenças estruturais que alteram o espectro de atividade. As fluroquinolonas são utilizadas em todo o mundo no tratamento de infecções de origem bacteriana. Este estudo teve como objetivo reunir informações sobre o uso das fluoroquinolonas em cães e gatos domésticos. Para a realização desta revisão bibliográfica, foram coletados os dados do período de 2006 a 2019 na literatura disponível no Portal da Capes, no Google Acadêmico e em livros, utilizando-se os seguintes descritores: fluroquinolones in dogs e fluroquinolones in cats, também sendo empregadas estas palavras em português. A partir desta busca pode-se verificar que as fluroquinolonas são indicadas em terapias humanas e veterinárias, e possuem, atualmente, atividade antimicrobiana bastante satisfatória, boa disponibilidade através da via oral, boa difusão para os tecidos, meia-vida prolongada e toxicidade significativamente reduzida. A resistência a este antibiótico pode ser atribuída a fatores como: uso indiscriminado e abusivo, facilidade de acesso, uso errôneo em tratamentos não-infecciosos, entre outros fatores. São indicadas principalmente para cães e gatos com infecções bacterianas de organismos Gram-negativos, Gram-positivos e bactérias anaeróbias. Conclui-se que os antimicrobianos do grupo das quinolonas evoluíram ao longo do tempo, com a intenção de criar antimicrobianos eficazes, de ampla ação, mínimos efeitos adversos e preço acessível.
... Also, the exceptionally high rate of FQ resistance is reported in this country due to their poorly controlled use (Zhang et al., 2014), raising concerns about the compromised efficacy of MDR-TB therapy by the emergence of FQ resistance. To overcome the drug resistance, modification and optimization of the current FQs are necessary (Sousa et al., 2014). ...
Objective:
WFQ-228 is a novel developed fluoroquinolone (FQ) displaying potent antimicrobial activity against various clinical isolates of pathogens, including FQ-resistant isolates. The aim was to comparatively analyse in vitro susceptibilities of WFQ-228, levofloxacin (LFX) and moxifloxacin (MFX) against Mycobacterium tuberculosis (MTB) isolates, especially with gyrA mutations.
Methods:
We selected a panel of 75 MTB isolates, consisting of 25 FQ-susceptible and 50 FQ-resistant isolates determined by conventional drug susceptibility testing. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of FQs to MTB isolates were assessed.
Results:
MFX exhibited the most potent activity against FQ-susceptible MTB, demonstrating a MIC50 of 0.031 mg/L, which was lower than that of LFX and WFQ-228. Against FQ-resistant MTB isolates, the MIC50 of WFQ-228 was higher than that of MFX, but lower than that of LFX. For WFQ-228, there was significant overlap existing in the MIC distributions between probable susceptible (PS) and probable resistant (PR) group. Six out of 50 PR isolates were classified as susceptible based on a proposed critical concentration (CC) of 0.5 mg/L, yielding a poor sensitivity of 88.0%. These discordant isolates had GyrA substitution in Ala90Val, Ser91Pro and Asp94Tyr. Additionally, MFX exhibited bactericidal activity against of MTB isolates without gyrA mutations, which was significantly higher than that of isolates with gyrA mutations.
Conclusion:
WFQ-228 is more efficacious than LFX in isolates with specific mutations conferring low-level FQ resistance. The bactericidal effect is noted more frequently in FQ-susceptible isolates than FQ-resistant isolates for MFX.
... Grepafloxacin (1999) and sparfloxacin (2001) were withdrawn from the market due to adverse cardiac reaction (Abo-Salem et al., 2014;Briasoulis et al., 2011). In general, the common side effects of quinolone drugs are mild; however, rare cases of more severe effects, such as life-threatening cardiac events, have been reported (Sousa et al., 2014). According to animal and clinical trials, the cardiotoxicity of sparfloxacin and grepafloxacin is significantly higher than that of other quinolones. ...
Quinolones are ranked as the second most commonly used class of antibiotics in China, despite their adverse clinical and environmental effects. However, information on their cardiac developmental toxicity to zebrafish is limited. This study investigates the relationships between different quinolone structures and toxicity in zebrafish embryos using in vivo and in silico methods. All of the experimentally tested quinolones show cardiac developmental toxicity potential and present mortality and teratogenic effects in a dose-dependent manner. Theoretically, the acute toxicity values predicted using quantitative structure−toxicity relationship (QSTR) modeling based on previously reported LC50 values are in good agreement with the in vivo results. Further investigation demonstrates that the hormetic concentration response of some quinolones may be related to methylation on the piperazine ring at the C-7 position. The amino group at the C-5 position, the methylated or ethylated piperazine group at the C-7 position, halogens at the C-8 position and a cyclopropyl ring at N1 position may be responsible for cardiac developmental toxicity. In terms of survival (key ecological endpoint), the naridine ring is more toxic than the quinoline ring. This combined approach can predict the acute and cardiac developmental toxicity of other quinolones and impurities.
... The proportions of fluoroquinolones (such as OFX, MFX, and levofloxacin) were identified to be higher than our previous investigation in adult TB cases in Sichuan. [36] Though various adverse effects have been reported, [37,38] fluoroquinolones are still considered as key components of current MDR-TB regimens. [39] The certain numbers of resistance to fluoroquinolones among new child TB cases are likely from the MDR-TB patients with fluoroquinolones treatment, which should be concerned for their impact on the circulation patterns of DR-TB strains in this area. ...
The aim of this study was to investigate the epidemiological characteristics and profile of drug-resistant tuberculosis (DR-TB) among children with TB in Sichuan province of China.
From January 2015 to December 2018, microbiological culture-confirmed child TB cases (aged <15 years old) were enrolled retrospectively. Epidemiological and clinical information from these cases, and the drug susceptibility testing results of the isolates were collected and analyzed.
Of 317 culture-confirmed child TB cases, 16.7% (53/317) were aged under 5 years old. 54.9% were Tibetans, and 31.9% had clear history of contact with TB patients. More than half (53.9%) were not vaccinated by Calmette–Guérin bacillus (BCG). Thirty percent (n = 95) were diagnosed as severe TB, and 92.4% (n = 293) were new cases. The ratio of severe TB in BCG vaccinated group was significant lower than that observed in unvaccinated group (P < .01). Significantly higher proportion of severe TB among Tibetans than Han child TB cases was observed in BCG unvaccinated group (P < .01). The overall rate of DR-TB in this study was 24.3% (77/317) and 17 multidrug-resistant tuberculosis (MDR-TB) cases were identified with rate of MDR-TB at 5.4% (17/317). No extensively drug-resistant case was found. Thirteen out of 17 MDR-TB cases (76.4%) were Tibetan children. The ratio of any resistance to 4 first-line drugs identified were: isoniazid (INH), 15.5%; rifampicin (RIF), 9.1%; ethambutol, 0.6% and streptomycin, 6.0%, respectively. More than half of MDR patterns were resistant to INH + RIF (9/17), followed by at least resistance to INH + RIF + streptomycin (n = 7).
This was the first investigation on the epidemiological characteristics and profiles of DR-TB among child TB cases in Southwest of China. Our findings indicated a potentially high risk of TB infection to Tibetan children in the concentrated Tibetan communities of Sichuan.
... However, antibacterial use has also been associated with medication toxicities, increased rates of Clostridioides (former Clostridium) difficile (C. difficile) colitis, and the potential for fostering drugresistant pathogens [16][17][18][19][20][21]. ...
Acute myeloid leukemia (AML) patients undergoing consolidation chemotherapy with intermediate or high-dose cytarabine (IDAC/HiDAC) are often placed on prophylactic antibacterials. This practice is largely based on the benefits of prophylaxis (PPX) during induction chemotherapy. However, recent concerns regarding antibacterial prophylaxis have emerged including risk of Clostridioides difficile colitis, medication toxicities, and the potential for fostering multidrug-resistant pathogens. We therefore retrospectively explored whether antibacterial PPX is beneficial during cytarabine consolidation. Adult AML patients who received IDAC/HiDAC at our institution from January 2007 to March 2018 were evaluated for receipt of antibacterial PPX. The primary endpoint was rate of febrile neutropenia (FN); secondary endpoints were rates of unplanned hospitalization, bacteremia, infection from resistant organisms, C. difficile colitis, and death from infection. One hundred twenty patients with data from 229 IDAC/HiDAC cycles were included. Patients who received antibacterial PPX were more often hospitalized during cytarabine cycle 1 (C1) than those who received no PPX. Patients who received PPX had significantly more episodes of bacteremia, in addition to infections from resistant, predominantly Gram-positive organisms during cycle 1 of consolidation than those without PPX. Antibacterial PPX during IDAC/HiDAC consolidation treatment at our institution did not decrease the rates of FN, hospitalization, or bacteremia and was associated with higher risk of infection from drug-resistant bacteria in C1. Prospective studies examining antibacterial prophylaxis during cytarabine consolidation for AML patients are necessary, with strong consideration made for institution-specific protocols.
... The proportions of uoroquinolones (such as OFX, MFX and LFX) were identi ed to be higher than our previous investigation in adult TB cases in Sichuan [36]. Though various adverse effects have been reported [37,38], uoroquinolones are still considered as key components of current MDR-TB regimens [39]. The certain numbers of resistance to uoroquinolones among new child TB cases are likely from the MDR-TB patients with uoroquinolones treatment, which should be concerned for their impact on the circulation patterns of DR-TB strains in this area. ...
Background: The aim of this study was to investigate the epidemiological characteristics and profile of drug-resistant tuberculosis (DR-TB) among children with TB in Sichuan province of China.
Methods: From January 2015 to December 2018, microbiological culture-confirmed child TB cases (aged<15 years old) were enrolled retrospectively. Epidemiological and clinical information from these cases, and the drug susceptibility testing (DST) results of the isolates were collected and analyzed.
Results: Of 317 culture-confirmed child TB cases, 16.7% (53/317) were aged under 5 years old. 54.9% were Tibetans, and 31.9% had clear history of contact with TB patients. More than half (53.9%) weren’t vaccinated by Calmette–Guérin bacillus (BCG). 30% (n=95) were diagnosed as severe TB, and 92.4% (n=293) were new cases. The ratio of severe TB in BCG vaccinated group was significant lower than that observed in unvaccinated group (p<0.01). Significantly higher proportion of severe TB among Tibetans than Han child TB cases was observed in BCG unvaccinated group (p<0.01). The overall rate of DR-TB in this study was 24.3% (77/317) and 17 multidrug-resistant tuberculosis (MDR-TB) cases were identified with rate of MDR-TB at 5.4% (17/317). No XDR case was found. 13 out of 17 MDR-TB cases (76.4%) were Tibetan children. The ratio of any resistance to four first-line drugs identified were: INH, 15.5%; RIF, 9.1%; EMB, 0.6% and SM, 6.0%, respectively. More than half of MDR patterns were resistant to INH+RIF (9/17), followed by at least resistance to INH+RIF+SM (n=7).
Conclusions: This was the first investigation on the epidemiological characteristics and profiles of DR-TB among child TB cases in Southwest of China. Our findings indicated a potentially high risk of TB infection to Tibetan children in the concentrated Tibetan communities of Sichuan.
... Some fluoroquinolones have been associated with electrocardiogram QT prolongation leading to cardiac arrhythmia or torsades de pointes, which has resulted in the withdrawal of at least two of these drugs, sparfloxacin and grepafloxacin, from the market. 70 QT prolongation in humans correlates with binding to the hERG K + channel in a preclinical assay. In this assay, zoliflodacin showed high IC 50 values against a variety of ion channels associated with the action potential in cardiac cells including hERG, indicating a low likelihood for inducing cardiac arrhythmia. ...
The CDC and World Health Organization have issued a list of priority pathogens for which there are dwindling therapeutic options, including antibiotic-resistant N. gonorrhoeae, for which novel, oral agents are urgently needed. Zoliflodacin, the first in a new class of antibacterial agents called the spiropyrimidinetriones, is being developed for the treatment of gonorrhea. It has a unique mode-of-inhibition against bacterial type II topoisomerases with binding sites in bacterial gyrase that are distinct from those of the fluoroquinolones. Zoliflodacin is bactericidal, with a low frequency of resistance and potent antibacterial activity against N. gonorrhoeae, including multi-drug resistant strains (MICs ranging from ≤0.002 - 0.25 µg/mL). Although being developed for the treatment of gonorrhea, zoliflodacin also has activity against Gram-positive, fastidious Gram-negative and atypical pathogens. A hollow-fiber infection model using S. aureus showed that that pharmacokinetic/pharmacodynamic (PK/PD) index of fAUC/MIC best correlated with efficacy in in vivo neutropenic thigh models in mice. This data and unbound exposure magnitudes derived from the thigh models were subsequently utilized in a surrogate pathogen approach to establish dose ranges for clinical development with N. gonorrhoeae. In preclinical studies, a wide safety margin supported progression to Phase 1 studies in healthy volunteers, which showed linear pharmacokinetics, good oral bioavailability and no significant safety findings. In a Phase 2 study, zoliflodacin was effective in treating gonococcal urogenital and rectal infections. In partnership with GARDP, zoliflodacin is currently being studied in a global Phase 3 clinical trial. Zoliflodacin represents a promising new therapy for drug resistant infections caused by N. gonorrhoeae.
... Systemic fluoroquinolones remain commonly prescribed broadspectrum antibiotics, both in hospital and outpatient settings, despite rising resistance rates [1][2][3][4][5][6][7]. Since their approval, fluoroquinolones were associated with serious adverse events (AEs), such as Clostridium difficile infection, fatal arrhythmia due to QT prolongation, hepatotoxicity, severe haemolytic-uremic syndrome and dysglycemia, leading to the market withdrawal of some compounds (temafloxacin, trovafloxacin, grepafloxacin and gatifloxacin) [8][9][10][11][12][13]. ...
Background:
Regulatory agencies warned against fluoroquinolones for the management of minor infections because of the risk of emerging adverse events (collagen-associated adverse events, neuropsychiatric toxicity and long-term disability). We aimed to assess quality and credibility of evidence as well as causality regarding these putative associations.
Methods:
MEDLINE, Scopus, Web of Science and PROSPERO were searched, from inception to August 2019, for systematic reviews with meta-analyses investigating emerging adverse events. Two investigators extracted data to grade quality (through validated AMSTAR-2 tool), rank credibility of the evidence (convincing, highly suggestive, suggestive, weak) through adapted criteria including E-value calculation, and assess causality (Hill's criteria).
Results:
Seven systematic reviews of observational studies providing 16 risk estimates [seven, five and four, respectively, for aortic aneurysm/dissection (AAD), retinal detachment (RD) and any tendon disorders (ATD)] met inclusion criteria. No systematic reviews with meta-analysis investigating the risk of neuropsychiatric toxicity or long-term disability were found. The associations between fluoroquinolones and AAD/ATD showed highly suggestive credibility and were supported by strong evidence of causality (double increased risk, especially within first 2 months of treatment). Conflicting data concerning the emergence of RD were retrieved, resulting in weak evidence of causality. Quality of the evidence ranged from high to low for AAD, from moderate to critically low for RD, and it was moderate for ATD.
Conclusion:
Our analysis supports credible, plausible and highly suggestive associations with AAD (rare occurrence but strong causality) and ATD. Limitations of both umbrella reviews and observational evidence should be considered.
... Negative side effects of the most frequently used PIMs according to the STOPP/START criteria are as follows. Antibiotics like gyrase inhibitors and diuretics increase the risk of dizziness [23][24][25], although a use was observed in less than 10% of the patients treated with CTC. Benzodiazepines and opioids are frequently used in the pre-and postoperative stage and of undisputed benefit for anxiety and pain relief, yet they should be stopped as soon as possible because of their large potential to induce falls and therefore their impact on mortality [26][27][28]. ...
Background
Multimorbidity and polypharmacy are common challenges in the treatment of older trauma patients. Therefore, various integrated care models were developed over the last few years, merging the expertise of geriatricians and trauma surgeons. The aim of this study was to evaluate, if the number of prescriptions of potentially inappropriate medication (PIM) could be reduced in these patients by an interdisciplinary co-managed concept compared to conventional trauma care.
Methods
We conducted a retrospective, dual-center cohort study, including all patients aged 70 years and older admitted with a fracture of the hip or the proximal humerus within the study period. Patients were treated in the universities department of trauma surgery with two different hospital sites, one with conventional trauma care (CTC) and the other one with a certified orthogeriatric trauma unit (OGC). Based on the STOPP/START criteria by O´Mahony et al., PIMs were defined, which should be avoided in (ortho)geriatric patients. Medical records of each patient were analyzed at discharge. Besides patients basic information, all prescribed drugs, changes in the medication plan and who carried out these changes were collected. For statistical analysis based on the data quality and distribution, the t test, Mann–Whitney U test and the Chi-square test were used.
Results
A total of 95 patients were included, 73 of them females, with an average age of 82.59 years (SD ± 6.96). Mean length of hospital stay was 12.98 at CTC and 13.36 days at OGC (p = 0.536). Among conventional care (41 patients), prescription of one or more PIMs was found in 85.4% of the patients, whereas at the orthogeriatric ward (54 patients) only in 22.2% (p < 0.001). Besides that, changes in medication were made for 48.1% of the patients during their stay on the orthogeriatric ward.
Conclusions
Our findings show that an integrated care concept can reduce the number of prescriptions of PIMs significantly and potentially avoids adverse drug reactions and additional burdens in older trauma patients.
... Chinfloxacin is a new member of the quinolone class of antibiotics and is currently under clinical development in China. Although the quinolone class of antibiotics is widely used and generally safe, several quinolones have been withdrawn from the market due to phototoxicity, risky QT interval prolongation, glucose homeostasis dysregulation, and/or hepatotoxicity (5). Due to the unique properties of the fluorine atom, chinfloxacin has much improved pharmacological properties compared to those of its parent, moxifloxacin, in preclinical studies. ...
Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single ascending dose study to assess safety and tolerability of chinfloxacin. The single dose pharmacokinetic study, food effect study and a multiple dose pharmacokinetics study was conducted in Part B, Part C and Part D, respectively. Part E was a randomized, placebo- and positive-controlled single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/QTc interval. The results suggest that single and multiple oral administration of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to C max (T max ) was about 2 h and T 1/2 was 14-16 h. Food slightly affected the drug’s rate and extent of absorption, increasing the T max from 1.60 to 2.59 h and reducing the C max by 13.6% and AUC by 8.95%, respectively. Chinfloxacin 400 mg had no effect on prolongation of QT/QTc intervals. Although chinfloxacin 600 mg caused mild effect on prolongation of QT/QTc interval, the effect was less pronounced than that of the positive control, moxifloxacin 400 mg. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at ChiCTR.org.cn. Identifier of Part A to Part D: ChiCTR-TRC-10001619; Identifier of the Part E: ChiCTR1800015906.)
... Comentario: las fluoroquinolonas son un grupo de antibióticos ampliamente utilizados para tratar diferentes infecciones bacterianas. Sus efectos adversos más comunes descritos son cefalea, vómito, diarrea, mareo o náuseas, pero pueden ocurrir algunos más graves como tendinitis, rotura tendinosa o hasta psicosis (18). En 2013 la FDA (Foods and Drugs Administration) incluyó en la lista de efectos adversos de las fluoroquinolonas la neuropatía periférica permanente (19), riesgo que se ha confirmado en estudios publicados posteriormente (20, 21) -uno de los cuales analizamos en una Ronda Clínica y Epidemiológica anterior (22)-, ante lo cual en 2016 esta misma entidad emitió una alerta de seguridad sugiriendo evitar la prescripción estos medicamentos para condiciones como bronquitis, sinusitis o infección de vías urinarias no complicada, dado que el riesgo de eventos adversos graves sobrepasa el beneficio ofrecido (23). ...
In this new edition of the Clinical and Epidemiological Round, the reader will be able to find four articles that we consider of special interest for current clinical practice. Abuzaid A., et al, performed a systematic review and meta-analysis comparing the outcomes of oxygen therapy vs. no-oxygen therapy in post-acute myocardial infarction settings. Freund Y., et al, present a non-inferiority cluster clinical trial in which they seek to prospectively validate the safety of a strategy based on clinical criteria to rule out pulmonary embolism. Also, using a retrospective cohort with propensity score
matching study, Pasternak et al intend to investigate whether the use of oral fluoroquinolone is associated with an increased risk of aortic aneurysm or dissection. Finally, the SMART investigators group assess, through a pragmatic randomized clinical trial in critically ill patients, the impact of balanced crystalloids versus saline in the risk of developing major renal events.
... 5,6 In descending order, the rank of fluoroquinolone antibiotics (FQ) related to their phototoxic potential is as follows; lomefloxacin, fleroxacin, clinafloxacin, sparfloxacin, sitafloxacin, enoxacin pefloxacin, ciprofloxacin grepafloxacin, gemifloxacin, levofloxacin, norfloxacin, ofloxacin, trovafloxacin. 3,[7][8][9][10][11][12][13] Gatifloxacin and moxifloxacin have not been linked to phototoxic events. 14,15 It had been easy to correlate the presence of a halogen at position 8 of the quinolone nucleus with phototoxic events. ...
Aims:
Delafloxacin is a fluoroquinolone antibiotic recently approved by the FDA for treatment of acute bacterial skin and skin structure infections (ABSSSI). Delafloxacin was assessed for phototoxicity potential compared with a known phototoxic fluoroquinolone.
Methods:
A Phase 1, investigator-blind, placebo/active-controlled, randomized, parallel-group study was conducted in 52 healthy male and female volunteers who received 200 or 400 mg of oral delafloxacin, 400 mg oral lomefloxacin or placebo once daily for 6 days. This study evaluated the photosensitizing potential and possible wavelength dependency of delafloxacin by comparing the response of the skin to ultraviolet A (UVA), ultraviolet B (UVB) and visible radiation prior to and during administration of delafloxacin, lomefloxacin as a positive control, or placebo. Adverse events were monitored throughout the study.
Results:
Forty-seven subjects completed six days of dosing, and no evidence of phototoxicity was seen with delafloxacin. Delafloxacin at 200 and 400 mg day-1 and placebo did not demonstrate differences in percent change from baseline in minimal erythema dose at all tested wavelengths (295-430 nm) by monochromator and solar simulator. Lomefloxacin, the positive control, had statistically significant differences (p < 0.05) at UVA wavelengths of 335 and 365 ± 30 nm 24 hours after radiation exposure (maximum response). The phototoxic index results were significantly higher for lomefloxacin at 335 nm and 365 nm compared to placebo and delafloxacin.
Conclusions:
200 and 400 mg of delafloxacin administered for 6 days were well tolerated in healthy adult volunteers. Delafloxacin and placebo failed to demonstrate a phototoxic effect but lomefloxacin, the positive control, demonstrated moderate phototoxicity.
... Synthetically, it may be easier to append fluoroquinolones to other therapeutic agents than, for example, -lactams with narrow windows of chemical stability. Moreover, the well-elucidated structure-activity relationship of fluoroquinolone antibiotics and their broad-spectrum of activity make them an attractive class of antibiotics (208)(209)(210). ...
The global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-negative bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clinical evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-negative bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-negative pathogens and/or expand the usefulness of our current antibiotic arsenal.
... Both are frequently administered for the treatment of urinary tract infections, bronchitis and other infections of the nose, throat, eye etc. [14][15][16][17][18]. Inspite of their frequent use both the drugs are known to pose severe harmful effects to humans. LMF, a fluoroquinolone not only results in some mild side effects like nausea, diarrhea, headache, dizziness etc., but it also undergoes serious phototoxic reactions in melanin containing tissues resulting in severe allergies, retinal degeneration, and toxic dermatitis and in some adverse conditions may end up in mitochondrial and DNA damage [19][20][21][22]. LMF has also been reported to induce cardiotoxicity [20], Central nervous system (CNS) disorders [21] etc. ...
A gold-palladium nanoparticles decorated electrochemically reduced graphene oxide (AuNP-PdNP-ErGO) modified, glassy carbon sensor has been developed for the individual and simultaneous determination of lomefloxacin (LMF) and amoxicillin (AMX). A new sensing platform exploiting the beneficial interaction of gold, palladium and ErGO has been prepared involving a one-step electrochemical process, and is characterized using Field Emission Scanning Electron Microscopy, elemental mapping, Transmission Electron Microscopy, Raman, X-ray diffraction and Electrochemical Impedance Spectroscopy. The calibration curves for LMF and AMX have been constructed using square wave voltammetry and exhibited a linear response in the concentration range of 4–500 μM and 30–350 μM respectively. The sensitivity and limit of detection were 0.0773 μA/μM and 81 nM, 0.0376 μA/μM and 9 μM for LMF and AMX respectively. The proposed protocol was successfully applied for testing the presence of LMF and AMX in the complex matrix like urine and in the solutions containing excess of potentially interfering substances like ascorbic acid, uric acid, hypoxanthine etc.
... -wydłużenie odcinka QT, po gatifloksacynie i klinafloksacynie -zaburzenia w gospodarce glukozy, z kolei hemolizę obserwowano po temafloksacynie, a hepatotoksyczność po zastosowaniu trowafloksacyny [12]. ...
... Despite the fact that numerous fluoroquinolone agents have been produced in the last decades, only a few of them are marketed, and some of them have been withdrawn or restricted because of their toxicity [7]. The most frequent reasons for withdrawal included tendinitis after treatment with pefloxacin; rashes appeared after sparfloxacin and clinafloxacin therapy; electrocardiogram disorders such as QTc prolongation occured during grepafloxacin administration; gatifloxacain and clinafloxacin therapy led to dysglycemia; hemolysis occured during temafloxacin administration; hepatotoxicity was found in trovafloxacin treatment [2,7,9]. The pharmacokinetic properties of quinolones are listed in Table 1. ...
Quinolones are potent antimicrobial agents with a basic chemical structure of bicyclic ring. Fluorine atom at position C-6 and various substitutions on the basic quinolone structure yielded fluoroquinolones, namely norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin and numerous other agents. The target molecules of quinolones and fluoroquinolones are bacterial gyrase and topoisomerase IV enzymes. Broad-spectrum and excellent tissue penetration make fluoroquinolones potent agents but their toxic side effects and increasing number of resistant pathogens set limits on their use. This review focuses on recent advances concerning quinolones and fluoroquinolones, we will be summarising chemical structure, mode of action, pharmacokinetic properties and toxicity. We will be describing fluoroquinolones introduced in clinical trials, namely avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and non-fluorinated nemonoxacin. These agents have been proved to have enhanced antibacterial effect even against ciprofloxacin resistant pathogens, and found to be well tolerated in both oral and parenteral administrations. These features are going to make them potential antimicrobial agents in the future.
... The first generation includes 1-alkyl-4-quinolone-carboxilic acid structures and their corresponding 1,8-naphthyridine derivatives, such as nalidixic acid and cinoxacin (Gram-negative spectrum). The addition of fluorine at position 6 and the dialkylamino chain at position C7 of the quinolone structure yield the second, third, and fourth generations, with a broader antimicrobial spectrum (extended from Gram-negative to Gram-positive bacteria coverage) and improved pharmacokinetic properties [4,5]. Moxifloxacin, a fourth-generation FQ, is widely used due to its Gram-positive activity [3], lower resistance rate than levofloxacin and lower phototoxicity and risk of adverse effects [6,7]. ...
Opinion statement
Fluoroquinolones (FQs) are important antibiotics for the treatment of a wide range of infectious diseases. However, while FQs are generally well-tolerated, both IgE and T cell-mediated hypersensitivity reactions can occur. Moreover, there has been an increase in the prevalence of these reactions in recent decades, probably due to higher levels of consumption. The diagnosis of allergy to FQs is complex and is based on clinical history, skin tests (STs), and determination of the drug-specific IgE using both immunoassays and basophil activation tests (BATs). However, these approaches have sub-optimal sensitivity and specificity: clinical history can be unreliable and overestimate the incidence of reactions, STs show a high rate of false positives, and in vitro tests have low sensitivity. Therefore, drug provocation testing is currently the best method to establish diagnosis; however, it carries certain risks and should be avoided for cases with a history of severe reactions. In order to improve the sensitivity and specificity of in vivo and in vitro methods, it is crucial to fully characterize the FQ antigenic determinants that are recognized by the immunological system. Current data indicate that groups at the C2–C6 positions of their chemical structure may form part of the antigenic determinant recognized by IgE. Moreover, their photostability can affect protein reactivity and therefore the formation of the hapten-carrier. All of these factors influence IgE and T cell recognition, the clinical response, and cross-reactivity and are the key for improving diagnostic methods. Additionally, a previous diagnosis of hypersensitivity to β-lactams has been reported to be a risk factor for FQ hypersensitivity, and this significantly decreases the therapeutic options for treating infectious diseases. Therefore, further studies are needed to obtain an accurate diagnosis, taking into account cross-reactivity, and to find alternative treatments.
... Newer FQs are more potent and active across a broader spectrum, have improved pharmacokinetic properties, and, if they receive FDA approval, are likely to be prescribed in place of levofoxacin, ciprofoxacin, or moxifoxacin to cancer patients for prevention or treatment of bacterial infections. 3 FQs are associated with a range of toxicities. As is the case with many other medications administered to cancer patients, some FQ toxicities have not been fully characterized even though they have been in use since 1987, when ciprofoxacin 4 was approved for use in the United States. ...
Background:
The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists.
Objective:
To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability.
Methods:
5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program.
Results:
Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD).
Limitations:
Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin.
Conclusion:
Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.
... Modifications to the quinolone structure, particularly the addition of fluorine(s) at key positions, have provided compounds with increased potency, broader spectrum of activity, and acceptable safety profiles. However, safety has been problematic in fluoroquinolone development (4)(5)(6). Several potent compounds have either been determined to be unsuitable for human use due to unacceptable toxicities, have required black box warnings on their labels, have been restricted to topical applications, or have resulted in removal from the market (7)(8)(9). Resistance development to fluoroquinolones is also becoming a significant concern among several Gram-positive and Gramnegative pathogens, including Staphylococcus aureus, Escherichia coli, and Neisseria gonorrhoeae. ...
AZD0914, a new spiropyrimidinetrione bacterial DNA gyrase inhibitor with a novel mode of inhibition, has activity against bacterial species commonly cultured from patient infections, including fluoroquinolone-resistant isolates. This study assessed the in vitro activity of AZD0914 against key Gram-positive and fastidious Gram-negative clinical isolates collected globally in 2013. AZD0914 demonstrated potent activity with MIC90 values for AZD0914 of 0.25 mg/L against Staphylococcus aureus (n=11680), coagulase-negative staphylococci (n=1923), streptococci (n=4380), and Moraxella catarrhalis (n=145), 0.5 mg/L against Staphylococcus lugdensis (n= 120) and Haemophilus influenzae (n=352), 1 mg/L against Enterococcus faecalis (n=1241), and 2 mg/L against H. parainfluenzae (n=70). Activity against E. faecium was more limited (MIC90 = 8 mg/L). The spectrum and potency of AZD0914 included fluoroquinolone-resistant isolates in each species group including methicillin-resistant staphylococci, penicillin-resistant streptococci, vancomycin-resistant enterococci, and β-lactamase-producing Haemophilus spp. and M. catarrhalis. Based on these in vitro findings, AZD0914 warrants further investigation for its utility against a variety of Gram-positive and fastidious Gram-negative bacterial species.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Infection risk during high-dose cytarabine (HiDAC) consolidation following induction therapy for acute myeloid leukemia (AML) is not well understood complicating decisions regarding antimicrobial prophylaxis during this period. We performed a retrospective chart review of adult patients with AML undergoing HiDAC consolidation between June 2016 and November 2021 at our institution. The primary endpoint was microbiologically confirmed infection within 30 days of HiDAC administration. This study included 111 patients who received a total of 264 cycles of HiDAC therapy. 36% of patients undergoing HiDAC consolidation had at least 1 infection over the course of their consolidation therapy. Infection complicated 18% of HiDAC cycles. The majority of infections were bacterial (81%), primarily caused by gram-negative organisms. Fluoroquinolone prophylaxis was associated with a lower hazard of bacterial infection (HR 0.46, 95% CI 0.24, 0.88). However, 26% of bacterial infections broke through antibiotic therapy with multiple cases concerning for fluoroquinolone resistance. Viral and fungal infections were rare (14% and 3% of infections respectively).
Antibiotics discovery has always played an important role in curing several outpacing resistances. Effective treatments for many of the common infectious diseases have now been possible. The question came up with the nature of infectious diseases, which lead to the discovery of antibiotics and setting up levels along with the discovery of synthetic models. The discoveries in the field of antibiotics have increased the average life expectancy of humans. However, the antibiotic resistance developed by microorganisms is still a matter of concern. The sensitivity and resistivity of bacteria is the most important factor to be discussed while talking about antibiotics. In this review, the era of antibiotic discovery along with recent advances in discovery/development and manufacturing, mechanism of action, and cellular targets of antibiotics along with the major components like sensitivity and antibiotic resistance have been discussed.
Past researches indicate that some types of antibiotics, apart from their antimicrobial effects, have some other important effects which indirectly are exerted by modulating and regulating the immune system’s mediators. Among the compounds with antimicrobial effects, fluoroquinolones (FQs) are known as synthetic antibiotics, which exhibit the property of decomposing of DNA and prevent bacterial growth by inactivating the enzymes involved in DNA twisting, including topoisomerase II (DNA gyrase) and IV. Interestingly, immune responses are indirectly modulated by FQs through suppressing pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and super-inducing IL-2, which tend to increase both the growth and activity of T and B lymphocytes. In addition, they affect the development of immune responses by influencing of expression of other cytokines and mediators. This study aims to review past research on the immunomodulatory effects of FQs on the expression of cytokines, especially IL-2 and to discuss controversial investigations.
Background
Pulmonary infections are an increasing problem in individuals and current therapies are lacking. Liposomes are spherical lipidic vesicles composed of phospholipid and cholesterol. Liposomes have numerous advantages, such as biodegradability, biocompatibility, non-immunogenicity, lack of toxicity, controlled release properties and high stability. Objective: This work was carried out to construct a novel liposomal moxifloxacin formulation and examine its antimicrobial effects against Pseudomonas aeruginosa and Staphylococcus aureus.
Methods
The liposomal moxifloxacin formulation was prepared by the thin film hydration method. The bilayer was composed of cholesterol and phospholipid at 30:70 molar ratio. To prepare cationic liposomes 5% cationic agent (CTAB) was added. The liposomes were sized down with bath sonication technique. The liposomal characterizations were tested regarding vesicle size, surface charge and drug encapsulation efficacy. Microdilution method was used to determine the Minimum Inhibitory Concentration (MIC) for Pseudomonas aeruginosa and Staphylococcus aureus of free drug, neutral and cationic moxifloxacin liposomes.
Results
The size of liposomes was 50-70 nm. The zeta potential of neutral and cationic vesicles was ~ 0 and +22 mV. The MIC values to Pseudomonas aeruginosa of free drug, neutral and cationic moxifloxacin liposomes were 10, 5 and 2.5, respectively. The MICs against Staphylococcus aureus of free drug, neutral and cationic moxifloxacin liposomes were 1, 1 and 0.5, respectively.
Conclusion
This study demonstrates that the encapsulation of moxifloxacin into liposomes (especially cationic vesicles) could enhance antimicrobial properties.
IntroductionFluoroquinolones are widely used to treat bacterial infections. Many in vitro and in vivo studies have established a chemical relationship between fluoroquinolones’ particular chemical structure and photosensitivity. The aim of this study was to establish a relationship between the chemical structure of fluoroquinolones and the risk of photosensitivity adverse effects from real-world data.Methods
All the Individual Case Safety Reports (ICSRs) related to fluoroquinolones and registered in the World Health Organization global database (VigiBase®) up to December 31, 2017 were collected. A disproportionality analysis was performed in order to quantify the photosensitivity risk for each fluoroquinolone by calculating their reporting odds ratio (ROR).ResultsUp to December 31, 2017, 282,805 ICSRs related to fluoroquinolones were selected, of which 1647 were photosensitivity adverse event cases. Sparfloxacin had the highest adjusted ROR of 161.10 (95% confidence interval [CI] 133.66–194.02) followed by grepafloxacin (40.30 [26.30–59.60]) closely followed by lomefloxacin (32.61 [28.61–37.07]), then enoxacin (11.04 [8.33–14.32]) and fleroxacin (8.22 [5.06–12.56]).Conclusion
This study confirms the high reporting rate of photosensitivity adverse effects for sparfloxacin from real-world data. Moreover, our data suggest more photosensitivity adverse effects reporting for fluoroquinolones with a halogen at their 8th position.
Lomefloxacin may be more likely than other fluoroquinolones to cause photosensitivity. However, the rate of photosensitivity is variable and a meta-analysis has yet to be performed. The aim of this meta-analysis is to compare the rate of photosensitivity between outpatients who received lomefloxacin and those who received other fluoroquinolones. PubMed, EMBASE, Cochrane Library databases and trial registries were searched for randomized controlled trials (RCTs) of outpatients through June 12, 2019. The study outcome was the rate of photosensitivity based on the intention-to-treat principle, estimated by risk difference (RD) as the primary analysis and Peto odds ratio (Peto OR) as the secondary analysis, with 95% confidence intervals (CIs) using random-effects models. Four RCTs (total of 2295 patients) were included in this meta-analysis. A statistically higher risk of photosensitivity was found with lomefloxacin than with other fluoroquinolones (RD, 3.4%; 95% CI, 0.7%-6.2%; P-value = 0.013; I2 = 10.9%). The odds of photosensitivity was also significantly higher with lomefloxacin (Peto OR, 5.81; 95% CI, 3.34 to 10.11; P-value <0.001; I2 = 0%). This meta-analysis of RCTs found significantly higher photosensitivity with lomefloxacin compared to other fluoroquinolones. Considering this finding and given its lack of additional efficacy compared to other fluoroquinolones, lomefloxacin as a fluoroquinolone option should potentially be reconsidered.
The review analyzes publications devoted to the frequency of renal adverse reactions during tuberculosis chemotherapy. The most significant pathophysiological mechanisms causing development of drug-induced nephrotoxicity are presented. The article describes the specific features of nephrotoxic effect of aminoglycosides, capreomycin, rifampicin, pyrazinamide, fluoroquinolones, and linezolid. The authors concluded that it was necessary to perform clinical and laboratory monitoring of kidney function for the timely detection of nephrotoxic reactions.
In view of the wide application of fluoroquinolones (FQs), a group of broad-spectrum synthetic antibacterial agents, and their large ingress into the environment, the toxic effects on non-target organisms caused by FQs have received great attention. In this study, we used zebrafish embryo as a model, measured the general toxic effects of norfloxacin, a commonly used FQs, and investigated the effects of norfloxacin on the neurodevelopment of zebrafish embryos. Our data showed that norfloxacin significantly inhibited the hatching rate of zebrafish embryos, and increased the mortality and malformation rate of the embryos. To discuss the developmental neurotoxicity of norfloxacin, we measured the expression of several stem cell and neuron lineage markers in the zebrafish embryos. We found that norfloxacin exposure inhibited the expression of GFAP (glial cell marker), and enhanced the expression of Sox 2 (stem cell marker) and Eno2 (mature neuron marker). By measuring the level of active Caspase 3 and the expression ratio of Bax to Bcl2, we discovered that norfloxacin induced obvious cell apoptosis in the brain of zebrafish embryos. To explore the mechanism of the developmental neurotoxic effects of norfloxacin, we applied MK-801, a non-competitive NMDA receptors antagonist, to block the actions of NMDA receptors. The results indicated that MK-801 could rescue the upregulated cell apoptosis and disrupted balance of neuro-glial differentiation induced by norfloxacin in the brain of zebrafish embryos. Our results suggest that the activation of NMDA receptors mediates the developmental neurotoxicity of norfloxacin.
Background
Fluoroquinolones (FQ) have been widely used for a variety of Gram-positive and Gram-negative infections, and by 2002 had become the most commonly prescribed class of antibiotics for adults in the US. With widespread use, the class has become associated with a range of adverse events. Delafloxacin is a fluoroquinolone approved in the US for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI). Delafloxacin is differentiated from other fluoroquinolones due to structural differences and in its activity against MRSA including quinolone resistant strains. This paper reviews the safety profile of delafloxacin across clinical studies with emphasis on the incidence of adverse events of special interest that are associated with fluoroquinolones.
Methods
Data from two completed Phase 3 studies of delafloxacin for the treatment of ABSSSI were pooled and are the primary focus of this paper. Additional support from the full safety analysis set (30 completed phase 1 to phase 3 clinical studies) is included where applicable.
Results
Fewer patients in the pooled delafloxacin group had AESIs than in the comparator group (7.0% vs 9.2%, respectively). Delafloxacin had a low rate of discontinuations due to treatment-related adverse events (<1%). Serious adverse events occurred at similar rates in patients treated with delafloxacin versus comparators.
Conclusions
Serious adverse events occurred at similar rates in patients treated with delafloxacin versus non-quinolone comparators used to treat ABSSSIs.
Trial registration
Clinicaltrials.gov identifier: NCT01984684 and NCT01811732.
Quinolones represent an important category of antibiotics that are generally safe and well tolerated. However, in the last 12 years, there has been an increase in the incidence of hypersensitivity reactions to these antibiotics. Allergic reactions to quinolones can be classified as either immediate or delayed reactions. A precise diagnosis can be difficult as history is often unreliable and test reagents are not standardized; therefore drug provocation testing is generally accepted as the gold standard. There are currently no commercial in vitro tests for the evaluation of quinolones allergy, although determination of specific IgE, basophil activation test, and lymphocyte transformation test have been shown to be useful for in vitro evaluation. Patients with a diagnosis of hypersensitivity to quinolones must avoid the culprit drug; however, when it is the only therapeutic option available, drug desensitization may be required.
Background
Low effectiveness of anti-melanoma therapies makes it necessary to search for new drugs that could improve or replace the standard chemotherapy. Fluoroquinolones are a group of synthetic antibiotics, used in the treatment of wide range of bacterial infections. Moreover, this class of antibiotics has shown promising anti-tumor activity in several cancer cell lines. The aim of this study was to examine the effect of ciprofloxacin on cell viability, apoptosis and cell cycle distribution in COLO829 melanoma cells.
Methods
Cell viability was evaluated by the WST-1 assay. Cell cycle distribution and apoptosis in cells exposed to ciprofloxacin was analyzed by the use of fluorescence image cytometer NucleoCounter NC-3000.
Results
Ciprofloxacin decreased the cell viability in a dose- and time-dependent manner. For COLO829 cells treated with ciprofloxacin for 24 h, 48 h and 72 h the values of IC50 were found to be 0.74 mM, 0.17 mM and 0.10 mM, respectively. The oligonucleosomal DNA fragmentation was observed when the cells were exposed to ciprofloxacin in concentration of 1.0 mM for 48 h and 72 h. At lower ciprofloxacin concentrations (0.01 mM and 0.1 mM) cells were arrested in S-phase suggesting a mechanism related to topoisomerase II inhibition. Moreover, it was demonstrated that ciprofloxacin induced apoptosis as a result of mitochondrial membrane breakdown.
Conclusions
The obtained results for COLO 829 melanoma cells were compared with data for normal dark pigmented melanocytes and the use of ciprofloxacin as a potential anticancer drug for the treatment of melanoma in vivo was considered.
Four classes of antibacterial agents that operate by inhibition of the Type II topoisomerases, DNA gyrase and Topoisomerase IV, have progressed at least through Phase 2 clinical trials. Compounds from each of the four classes are not cross-resistant to one another as determined by analyses with laboratory and clinical resistant bacterial strains. Hence, they are defined herein as sharing a mode of action, in that they inhibit the same targets, but differing in mode of inhibition, in that they obstruct enzyme activity via divergent binding modes. Two of the classes, fluoroquinolones and aminocoumarins, were long ago approved for clinical use, though the use of the latter has been limited. Two newer classes, spiropyrimidinetriones and quinolines, are represented by the advanced drug candidates zoliflodacin and gepotidacin, each featuring a novel scaffold and a distinct binding motif. X-ray crystallography has shown fluoroquinolone and spiropyrimidinetrione binding at DNA cleavage sites of the topoisomerases. However, the two differ by their dependence on [Mg2+] for binding serving in part to explain the lack of cross-resistance. Quinolines bind to DNA-topoisomerase complexes offset from the cleavage sites as ascertained by X-ray crystallography. Novobiocin, the only aminocoumarin to receive regulatory ap
proval, competes with ATP binding at a site quite remote from the DNA-binding domain. As novobiocin has been withdrawn from the clinic, considerable drug discovery efforts have focused on alternative ATP site binders (ATPase inhibitors). With widespread use of fluoroquinolones leading to resistance, the importance of developing novel antibiotics that would not be cross-resistant is clear. Reviewed herein are the current understandings of the respective mechanisms of inhibition and the respective topoisomerase binding modes for the four classes of antibacterials now with clinical proof of concept.
Introduction:
Increasing numbers of children with drug-resistant tuberculosis are accessing second-line antituberculosis drugs; these drugs are more toxic than first-line drugs. Little is known about the safety of new antituberculosis drugs in children. Knowledge of adverse effects, and how to assess and manage these, is important to ensure good adherence and treatment outcomes.
Areas covered:
A Pubmed search was performed to identify articles addressing adverse effects of second-line antituberculosis drugs; a general search was done for the new drugs delamanid and bedaquiline. This review discusses adverse effects associated with oral second-line antituberculosis drugs, including delamanid and bedaquiline. The spectrum of adverse effects caused by antituberculosis drugs is wide; the majority are mild or moderate, but even these are important to manage as it could lead to non-adherence to treatment. Adverse effects may be more common in HIV-infected than in HIV-uninfected children.
Expert opinion:
Although children may experience fewer adverse effects from oral second-line antituberculosis drugs than adults, evidence from prospective studies of the incidence of adverse events in children is still limited. Higher doses of second-line drugs, new antituberculosis drugs, and new drug regimens are being evaluated in children: these call for strict pharmacovigilance in children treated in the near future, as adverse effect profiles may change.
In this edition of the clinical and epidemiological round, we analyze four articles relevant for clinical practice, namely: the adverse effects of some antimicrobials are studied by Etminan et al., looking for a possible association between the use of oral fluoroquinolones and the risk of peripheral neuropathy (1). Fralick et al., studied the risk of sudden death after the use of trimethoprim-sulfamethoxazole (2). Bakker and collaborators make an interesting contribution about the need of nasoyeyunal catheter in patients suffering from acute pancreatitis (3). Finally, Kanegaye et al., look for the best diagnostic test for urinary infections in infants (4).
Background:
A growing body of evidence suggests that glutamatergic system, especially the abnormalities of glutamate and N-methyl-D-aspartate (NMDA) receptors contribute to the pathophysiology of major depressive disorders. An imbalance in glutamatergic neurotransmission may contribute to increased levels of NMDA agonism, thereby enhancing excitatory activity in most brain circuits involved in major depression. Although NMDA receptor antagonists have been demonstrated to possess antidepressant-like activity, the molecular changes underlying abnormal glutamatergic signaling still remain poorly understood. Therefore, we aimed to review the current literature focusing on the main pharmacological properties and the impact of glutamatergic drugs targeting NMDA receptors in major depression.
Methods:
A detailed literature search in PubMed/Medline and ScienceDirect databases using the terms glutamate, depression and major depressive disorder has been performed.
Results:
Most drugs acting at glutamatergic receptors showed biochemical effects indicative of antidepressant activity in both clinical and preclinical studies. Recent neuroimaging and genetic contributions also confirm the antidepressant properties of these medications. However, human studies including NMDA receptor antagonists provided mixed results. In overall, glutamatergic receptor modulation may facilitate neuronal stem cell enhancement (neurogenesis) as well as the release of neurotransmitters associated with treatment response to depression in humans.
Limitations:
Cognitive side effects and psychotomimetic properties complicate the application and the development of clinically useful agents.
Conclusions:
Glutamatergic system represents a target for effective intervention in major depression. Specifically, those glutamatergic medications targeting NMDA receptors by inhibiting the release of neurotransmitters or modulating its post-synaptic responses may serve as molecule modulators with specific antidepressant properties.
Background:
Quinolone antibiotics are associated with increased risk of tendinopathy. Identifying at-risk individuals has important clinical implications. We examined whether age, sex, glucocorticoid use, obesity, diabetes, and renal failure/dialysis predispose individuals to the adverse effects of quinolones.
Methods:
Among 6.4 million patients in The Health Improvement Network (THIN) database, 28,907 cases of Achilles tendonitis and 7685 cases of tendon rupture were identified in a case-crossover study. For each participant, we ascertained whether there was a prescription of a quinolone and comparison antibiotic within 30 days before the diagnosis of tendon disorder (case period) and a prescription of the same medications within 30 days 1 year before disease diagnosis (control period).
Results:
Use of quinolones was strongly associated with an increased risk of Achilles tendonitis (odds ratio [OR], 4.3; 95% confidence interval [CI], 3.2-5.7) and tendon rupture (OR, 2.0; 95% CI, 1.2-3.3). No association was found between the use of other antibiotics and either outcome. The association with Achilles tendonitis was stronger among participants who were aged more than 60 years (OR, 8.3 vs 1.6), who were nonobese (OR, 7.7 vs 2.4), and who used oral glucocorticoids (OR, 9.1 vs 3.2). The association was nonsignificantly stronger in women (OR, 5.0 vs 3.6), diabetic persons (OR, 7.0 vs 4.1), and those in renal failure or receiving dialysis (OR, 20.0 vs 3.9). The effect for tendon rupture was stronger in women, with borderline significance in glucocorticoid users and nonobese persons.
Conclusion:
Quinolone-associated tendinopathy is more pronounced among elderly persons, nonobese persons, and individuals with concurrent use of glucocorticoids.
Background:
Fluoroquinolones have been suspected to cause cardiac arrhythmia but data are lacking, particularly for the individual fluoroquinolones. We assessed the risk of serious arrhythmia, defined as ventricular arrhythmia or sudden/unattended death identified in hospital discharge diagnoses, related to fluoroquinolones as a class as well as for each individual molecule.
Methods:
We used a cohort of patients treated for respiratory conditions from 1 January 1990 to 31 December 2005, identified using the healthcare databases from the province of Quebec (Canada), with follow-up until 31 March 2007. A nested case-control analysis was performed within this cohort, with all cases of serious arrhythmia occurring during follow-up identified from hospitalization records. These cases were matched with up to 20 controls. Conditional logistic regression was used to compute adjusted rate ratios (RRs) of serious arrhythmia associated with fluoroquinolone use.
Results:
Within the cohort of 605127 subjects, 1838 cases were identified (incidence rate=4.7/10000 person-years). The rate of serious arrhythmia was elevated with current fluoroquinolone use (RR=1.76; 95% confidence interval [CI], 1.19-2.59), in particular with new current use (RR=2.23; 95% CI, 1.31-3.80). Gatifloxacin use was associated with the highest rate (RR=7.38; 95% CI, 2.30-23.70); moxifloxacin and ciprofloxacin were also associated with elevated rates of serious arrhythmia (RR=3.30; 95% CI, 1.47-7.37 and RR=2.15; 95% CI, 1.34-3.46, respectively).
Conclusions:
The use fluoroquinolones is associated with an elevated risk of serious arrhythmia, with some differences among molecules. Given that the individual fluoroquinolones share various indications, the relative risks of serious arrhythmia could inform the choice of different molecules in high-risk patients.
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.
Fluoroquinolones are one of the most promising and intensively studied drugs of contemporary anti-infective chemotherapy. New fluoroquinolone antibacterials with improved pharmacokinetic properties and a broad spectrum of activity have been developed, opening new windows of opportunity for clinical use. To our knowledge, no comprehensive and critical review of the analytical methods for the determination of these agents, which correspond to the third- and fourth-generation quinolones, has yet been published. This work summarizes for the first time most of the liquid chromatographic methods reported in the literature for the separation and quantification of the new fluoroquinolones in biological matrices and pharmaceutical formulations. A systematic and detailed survey of physicochemical properties, sample preparation procedures, and chromatographic and detection conditions is presented herein. In the course of this review several liquid chromatographic methods are discussed: reversed-phase high-performance liquid chromatography (RP-HPLC), ion-exchange high-performance liquid chromatography (IEX-HPLC), hydrophilic interaction liquid chromatography (HILIC), high-performance thin-layer chromatography (HPTLC) and other chiral chromatographic methods. Their advantages, applicability and limitations are also examined.
Figure
Liquid chromatographic methods for determination of new fluoroquinolones in biological matrices and pharmaceutical formulations.
The present study aimed to develop an effective screening strategy to predict in vivo phototoxicity of multiple compounds by combined use of in vitro phototoxicity assessments and cassette dosing pharmacokinetic (PK) studies. Photochemical properties of six fluoroquinolones (FQs) were evaluated by UV spectral and reactive oxygen species (ROS) assays, and phototoxic potentials of FQs were also assessed using 3T3 neutral red uptake phototoxicity test (3T3 NRU PT) and intercalator-based photogenotoxicity (IBP) assay. Cassette dosing pharmacokinetics on FQs was conducted for calculating PK parameters and dermal distribution. All the FQs exhibited potent UV/VIS absorption and ROS generation under light exposure, suggesting potent photosensitivity of FQs. In vitro phototoxic risks of some FQs were also elucidated by 3T3 NRU PT and IBP assay. Decision matrix for phototoxicity prediction was built upon these in vitro data, taken together with outcomes from cassette dosing PK studies. According to the decision matrix, most FQs were deduced to be phototoxic, although gatifloxacin was found to be less phototoxic. These findings were in agreement with clinical observations. Combined use of in vitro photobiochemical and cassette dosing PK data will be useful for predicting in vivo phototoxic potentials of drug candidates with high productivity and reliability.
Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre-clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co-trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome-wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity.
Idiosyncratic adverse drug reactions (IADRs) occur in a minority of patients yet account for the majority of postmarketing use restrictions by the Food and Drug Administration. Despite the impact of these toxicities, the underlying mechanisms are still poorly understood. Animal models of IADRs would be beneficial in understanding mechanisms and in developing assays with predictive potential. Recent work exploring the interactions between inflammatory stress and drugs associated with human idiosyncratic drug-induced liver injury (IDILI) has led to the development of the first animal models that apply to a range of drugs. Here, we discuss hypotheses for the mechanisms of IDILI and focus on a murine model of trovafloxacin-induced hepatotoxicity as an example related to the inflammatory stress hypothesis.
Mitochondria play key roles in aerobic life and in cell death. Thus, interference of normal mitochondrial function impairs cellular energy and lipid metabolism and leads to the unleashing of mediators of cell death. The role of mitochondria in cell death due to drug hepatotoxicity has been receiving renewed attention and it is therefore timely to assess the current status of this area.
Limited evidence suggests there may be a link between fluoroquinolone use and Clostridium difficile-associated diarrhea (CDAD), but such an association remains unclear due to conflicting data.
To determine the relationship between inpatient fluoroquinolone use and CDAD; secondary objectives included the relationship between CDAD and fluoroquinolone selection, duration of therapy, and route of administration, as well as the association between fluoroquinolones and CDAD complications.
We conducted a retrospective, case-control study of adult inpatients diagnosed with CDAD during the period of July 2007-July 2008. In total, 174 case patients were matched on a 1:1 basis with controls. A thorough assessment of all inpatient antibiotic use was conducted, including regimens administered at our institution within the previous 8 weeks. Odds ratios were calculated using univariate logistic-regression analysis.
Use of fluoroquinolones was not significantly different between patients with CDAD and matching controls (OR 1.36; 95% CI 0.09 to 2.10; p = 0.16). No relationship was found between CDAD and the individual fluoroquinolones: ciprofloxacin (OR 1.36; 95% CI 0.87 to 2.12; p = 0.18), levofloxacin (OR 1.17; 95% CI 0.62 to 2.22; p = 0.63), and moxifloxacin (OR 1.34; 95% CI 0.81 to 2.20; p = 0.25). Fluoroquinolone route of administration did not differ significantly between groups for patients receiving intravenous (OR 1.20; 95% CI 0.74 to 1.94; p = 0.46) or oral (OR 0.79; 95% CI 0.44 to 1.44; p = 0.45) therapy. Complications from CDAD were not significantly increased by fluoroquinolone use (OR 1.37; 95% CI 0.72 to 2.61; p = 0.35).
Inpatient administration of fluoroquinolones was not associated with CDAD at our institution. Fluoroquinolone use in patients who developed CDAD was not related to higher incidences of CDAD-related complications.
Fluoroquinolones are one of the most promising and vigorously pursued areas of contemporary antiinfective chemotherapy depicting broad spectrum and potent activity. They have a relatively simple molecular nucleus, which is amenable to many structural modifications. These agents have several favorable properties such as excellent bioavailability, good tissue penetrability and a relatively low incidence of adverse and toxic effects. They have been found effective in treatment of various infectious diseases. This paper is an attempt to review the therapeutic prospects of fluoroquinolone antibacterials with an updated account on their development and usage.
A wide range of drugs can cause mental status changes.Fluoroquinolones are one among them and are underrecognised.The CNS side effects of levofloxacin like headache, dizziness, restlessness, tremor, insomnia, hallucinations, convulsions, anxiety and depression are well documented. We report a rare case of middle aged diabetic male admitted to hospital with multiple infections who developed acute psychosis following levofloxacin administration.
Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean +/- standard deviation) was 0.18 +/- 0.05 mmol/liter (control on normal diet, 0.82 +/- 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 +/- 10.5 and 14.3 +/- 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.
The 'antioxidant hypothesis' proposes that vitamin C, vitamin E, carotenoids, and other antioxidants occurring in fruit and vegetables afford protection against heart disease and cancer by preventing oxidative damage to lipids and to DNA, respectively. To test elements of this hypothesis, we have measured blood levels of dietary antioxidants, and 8-oxodeoxyguanosine (8-oxo-dG) concentrations in lymphocyte DNA, in healthy men and women from five European countries: France, Ireland, The Netherlands, Spain, and the U.K. Volunteers, aged 25 45, all nonsmokers, gave blood samples before and after a 12-wk carotenoid supplementation regime. Vitamin C was measured in plasma and vitamin E and carotenoids were measured in serum by high-performance liquid chromatography (HPLC). 8-oxo-dG was assayed by HPLC (with coulometric detection) in DNA isolated from lymphocytes from the same blood samples. Mean values were calculated for groups of volunteers at each sampling time according to country, sex, and supplementation (between 9 and 24 individual samples contributing to each mean). We found that 8-oxo-dG levels in lymphocyte DNA vary significantly according to sex and country. A low mean 8-oxo-dG concentration is seen in DNA of women from all five countries, and of men from France and Spain. 8-oxo-dG is significantly higher (up to about threefold) in lymphocyte DNA from men in Ireland and the U.K. Oxidative DNA damage is not significantly affected by carotenoid supplementation; nor is there any association with mean baseline levels of antioxidants, which are generally similar in the five countries. The five countries sampled lie on an axis from northern to southern Europe with a steep gradient in terms of premature heart disease. There is a strong association between premature coronary heart disease mortality in men and the mean levels of 8-oxo-dG for the five countries (r = 0.95, P < 0.01). Women have low coronary heart disease mortality rates, which do not correlate with 8-oxo-dG. In terms of cancer deaths, only colorectal cancer in men shows a significant positive correlation (r = 0.91, P < 0.05), and stomach cancer in women is negatively correlated with DNA oxidation (r = -0.92, P = 0.01).
Moxifloxacin, a broad-spectrum fluoroquinolone with the methoxy group at position 8 of the quinolone structure that is believed to confer reduced phototoxicity, was investigated in 32 healthy human male volunteers by a randomized double-blind placebo and positive control (lomefloxacin) phototest technique. A comparison of pre- and on-drug photosensitivity levels tested with an irradiation monochromator using relevant sunlight wavelengths, failed to demonstrate phototoxicity after administration of either placebo or moxifloxacin (200 mg or 400 mg/day) for 7 days. As expected, lomefloxacin (400 mg/day) phototoxicity was revealed at the UVA wavebands 335 +/- 30 nm and 365 +/- 30 nm (maximal at 24 h), with a phototoxic index of 3-4. The susceptibility to this effect rapidly normalized within 48 h of stopping the drug. No special protection from UVA wavelengths is necessary for those taking moxifloxacin.
Objective: To analyse and compare with one another and with other antibacterial drugs the adverse drug reactions (ADRs) of the different fluoroquinolones currently used in Italy, spontaneously reported from doctors in three northern Italian regions.
Methods: The data on fluoroquinolones and other antibacterials were obtained from the spontaneous reporting system database of Emilia Romagna, Lombardy and the Veneto, which are the principal contributors to the Italian spontaneous surveillance system. The fluoroquinolone ADRs with a causality assessment of certain, probable or possible (according to WHO criteria), reported between January 1999 and December 2001, were selected and toxicity profiles of individual drugs were described and compared with one another. The reports were also correlated with sex and age of patients and with regional prescription data to estimate individual fluoroquinolone reporting rate of adverse events.
Results: During the study period, 10 011 reports were received by the system (a mean annual reporting rate of approximately 185 per million inhabitants): 1920 referred to systemic antimicrobials, of which 432 (22.5%) involved fluoroquinolones.
Pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin (221) and lomefloxacin (196). The most frequently reported reactions to fluoroquinolones involved the skin, but their percentage (25%) was significantly lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas the percentages of reactions involving the central nervous (12.2 vs 3.6%), musculoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were significantly higher (p < 0.01). We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05). Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin.
Conclusions: The differences in the safety profiles should be taken into account when prescribing a fluoroquinolone to individual patients.
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.
This paper presents a general survey of the mechanisms involved in drug phototoxicity. Moreover, a list of 174 currently used clinical drugs inducing photosensitization is provided in addition to some others from which phototoxic effects are suspected. Likewise, some aspects related to the mechanisms involved in the phototoxicity of fluoroquinolones and non steroidal-antiinflammatory drugs have been reviewed. Finally, a possible role of the arenediazonium ions as photosensitisers is discussed
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.
Introduction:
Quinolones are among the most often prescribed antimicrobial agents. Some types of toxicity observed during therapy with these drugs have gained much attention.
Areas covered:
Here, we review the potential of the most widely used fluoroquinolones, ciprofloxacin, levofloxacin and moxifloxacin for adverse reactions. The rates of adverse events are similar for quinolones and other antibacterial agents. However, quinolone therapy can be associated with specific risks, which must be weighed against their benefit. In some studies, use of quinolones was associated with Clostridium difficile-associated diarrhea. Patients with impairments of the CNS (e.g., epilepsy or arteriosclerosis) should not be treated with quinolones. They should be avoided in patients with known prolongation of the QT interval or other risk factors for tachyarrhythmia. The risk for quinolone-associated tendinopathy is more pronounced among elderly persons, non-obese patients and individuals with concurrent use of glucocorticoids or chronic renal diseases. Quinolones are contraindicated in children because they cause destruction of the immature joint cartilage in animals. The use in paediatrics is restricted to life-threatening infections.
Expert opinion:
Changes in the resistance situation and newly recognized adverse reactions require a continuing adjustment of therapeutic recommendations and constant educational efforts in the field of antimicrobial therapy.
These broad-spectrum antibiotics--notable for combatting pathogens resistant to other drugs--have a small but noteworthy potential for adverse effects. This review and patient handout highlight signs and symptoms to watch for.
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.
Photochemical properties and phototoxicity of Pazufloxacin (PAX) were systematically investigated in aqueous solutions using UV-Vis, fluorescence, laser flash photolysis, pulse radiolysis and SDS-PAGE gel electrophoresis techniques. PAX triplet-state ((3)PAX(∗)) absorption spectra (λ(max)=570nm) was determined. (3)PAX(∗) was quenched by PAX and O(2), with rate constants of 6.9×10(8) and 3.2×10(8)dm(3)mol(-1)s(-1), respectively. The pK(a) values (5.7 and 8.6) for the protonation equilibrium were determined by UV-Vis and fluorescence techniques. The PAX triplet energy (E(T)=260.3kJ/mol) was obtained using energy transfer method. The reaction of electron transfer from tryptophan (TrpH) and dGMP to (3)PAX(∗) was found with rate constants of 8.8×10(7) and 8.7×10(6)dm(3)mol(-1)s(-1), respectively. The rate constants for reactions of ()OH, SO(4)(-) and hydrated electron with PAX were found to be 5.8×10(8), 2.1×10(9) and 9×10(9)dm(3)mol(-1)s(-1), respectively. Based on the results obtained, a rational scheme for dGMP, TrpH and lysozyme photodamage induced by PAX was proposed.
The central nervous system (CNS) toxicity of fluoroquinolones is well known but usually occurs benign. In the literature, there are a few number of severe CNS toxicity cases related to fluoroquinolones. Levofloxacin is a third-generation fluorinated quinolone antibiotic, is the active levo stereoisomer of ofloxacin, and has one of the most favorable adverse reaction profiles. We describe a case of delirium associated with levofloxacin in a 55-year-old man who was hospitalized in our medical clinic for pneumonia.
Fluoroquinolones are popular and widely used in primary care and hospital settings. Premarketing studies showed a favourable side-effect profile. However, significant morbidity and the need for liver transplantation for acute liver failure have been reported. We reviewed the available data on liver damage linked to fluoroquinolones.
A systematic search of case reports on the MEDLINE database encompassing the years 2000-2011 was carried out. Additional references were found by a manual search of the retrieved paper. We also describe three new cases of hepatotoxicity attributable to fluoroquinolones seen at our Unit.
Thirty-five cases were retrieved from MEDLINE (51.4% male). According to the RUCAM scale, liver injury was classified as hepatocellular (51.4%), cholestatic (28.6%) or mixed (20.0%). Older age (≥ 65 years) was present in 42.8%. The time between initiation of treatment and hepatic injury ranged from 1 to 39 days (median 8 days). According to the RUCAM score, our cases were classified to be "highly probable" or "probable". Only one patient underwent liver biopsy, which showed the features of liver damage linked to drug exposure. Liver enzymes from all patients return to normal range within 4 weeks of withdrawal. Only one patient showed a renal failure, associated with liver injury, with a need for haemodialysis for 3 weeks.
Fluoroquinolones are substantially safe antibiotics. Although fluoroquinolone-related hepatic injury occurs infrequently, its consequences can be severe. Patients should also be cautioned to avoid re-exposure to other members of the fluoroquinolone class.