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the (282), and (178), fluoroquinolones (77), for (71), with (62), doi (58), pmid (57), are (56), from (53), quinolones (45), antibiotics (41), #generation (39), drug (38), use (36), fluoroquinolone (33), quinolone (32), may (31), other (31), edit (31), fda (29), pdf (28), that (27), risk (27), effects (27), safety (26), july (25), infections (25), dna (24), acid (24), archived (24), drugs (23), original (22), journal (22), antibiotic (21), associated (21), treatment (21), have (21), retrieved (19), ciprofloxacin (19), antimicrobial (19), acute (19), adverse (19), first (19), bacterial (17), such (17), clinical (16), related (16), levofloxacin (16), march (16), their (16), not (16), these (16), class (16), children (16), only (16), side (15), can (15), but (15), this (14), nalidixic (14), agents (14), activity (14), administration (14), 2011 (14), review (14), pmc (14), resistance (14), october (13), april (13), november (13), 2005 (13), 2008 (13), bacteria (13), infectious (13), events 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onditions such as marfan syndrome and ehlers danlos syndrome and the elderly for these people fluoroquinolones should be used only when no other treatment options are available 32 one year after the warning announcement prescribing behaviors were reported to have remained unchanged 28 colitis edit clostridioides difficile colitis may occur in connection with the use of any antibacterial drug especially those with a broad spectrum of activity such as clindamycin cephalosporins and fluoroquinolones fluoroquinoline treatment is associated with risk that is similar to 33 or less than 34 35 that associated with broad spectrum cephalosporins fluoroquinolone administration may be associated with the acquisition and outgrowth of a particularly virulent clostridium strain 36 other edit more generally fluoroquinolones are tolerated with typical drug side effects being mild to moderate 37 common side effects include gastrointestinal effects such as nausea vomiting and diarrhea as well as headache and insomnia postmarketing surveillance has revealed a variety of relatively rare but serious adverse effects associated with all members of the fluoroquinolone antibacterial class among these tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of black box warnings in the united states 38 39 a 2018 eu wide review of fluoroquinolones concluded that they are associated with serious side effects including tendonitis tendon rupture arthralgia pain in extremities gait disturbance neuropathies associated with paraesthesia depression fatigue memory impairment sleep disorders and impaired hearing vision taste and smell tendon damage especially to achilles tendon but also other tendons can occur within 48 hours of starting fluoroquinolone treatment but the damage may be delayed several months after stopping treatment 40 the overall rate of adverse events in people treated with fluoroquinolones is roughly similar to that seen in people treated with other antibiotic classes 34 41 42 43 a u s centers for disease control and prevention study found people treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides but less frequently than those treated with penicillins clindamycin sulfonamides or vancomycin 44 fluoroquinolones prolong the heart s qt interval by blocking voltage gated potassium channels 45 prolongation of the qt interval can lead to torsades de pointes a life threatening arrhythmia but in practice this appears relatively uncommon in part because the most widely prescribed fluoroquinolones ciprofloxacin and levofloxacin only minimally prolong the qt interval 46 in 2019 study by journal of the american college of cardiology it was discovered that fluoroquinolones could increase the risk for heart valve diseases 47 events that may occur in acute overdose are rare and include kidney failure and seizure 48 susceptible groups of patients such as children and the elderly are at greater risk of adverse reactions during therapeutic use 37 49 50 mechanism of toxicity edit the mechanisms of the toxicity of fluoroquinolones have been attributed to their interactions with different receptor complexes such as blockade of the gaba a receptor complex within the central nervous system leading to excitotoxic type effects 39 and oxidative stress 51 interactions edit products containing multivalent cations such as aluminium or magnesium containing antacids and products containing calcium iron or zinc invariably result in marked reduction of oral absorption of fluoroquinolones 52 other drugs that interact with fluoroquinolones include sucralfate probenecid cimetidine theophylline warfarin antiviral agents phenytoin cyclosporine rifampin pyrazinamide and cycloserine 52 administration of quinolone antibiotics to a benzodiazepine dependent individual can precipitate acute benzodiazepine withdrawal symptoms due to quinolones displacing benzodiazepines from their binding sites 53 fluoroquinolones have varying specificity for cytochrome p450 so may have interactions with drugs cleared by those enzymes the order from most p450 inhibitory to least is enoxacin ciprofloxacin norfloxacin ofloxacin levofloxacin trovafloxacin gatifloxacin moxifloxacin 52 contraindications edit quinolones are not recommended in people with epilepsy marfan s syndrome ehlers danlos syndrome 54 qt prolongation pre existing cns lesions or cns inflammation or who have had a stroke 39 they are best avoided in the athlete population 55 safety concerns exist for fluoroquinolone use during pregnancy so they are contraindicated unless no other safe alternative antibiotic exists 56 however one meta analysis looking at the outcome of pregnancies involving quinolone use in the first trimester found no increased risk of malformations 57 they are also contraindicated in children due to the risks of damage to the musculoskeletal system 58 their use in children is not absolutely contraindicated however for certain severe infections where other antibiotics are not an option their use can be justified 59 quinolones should also not be given to people with a known hypersensitivity to the drug class 60 61 the basic pharmacophore or active structure of the fluoroquinolone class is based upon the quinoline ring system 62 the addition of the fluorine atom at c6 distinguishes the successive generation fluoroquinolones from the first generation of quinolones the addition of the c6 fluorine atom has since been demonstrated not to be required for the antibacterial activity of this class circa 1997 63 antibiotic misuse and bacterial resistances edit see also antibiotic misuse and antibiotic resistance because the use of broad spectrum antibiotics encourages the spread of multidrug resistant strains and the development of clostridioides difficile infections treatment guidelines often recommend minimizing the use of fluoroquinolones and other broad spectrum antibiotics in less severe infections and in those in which risk factors for multidrug resistance are not present it has been recommended that fluoroquinolones not be used as a first line agent for community acquired pneumonia 64 instead recommending macrolide or doxycycline as first line agents the drug resistant streptococcus pneumoniae working group recommends fluoroquinolones be used for the ambulatory treatment of community acquired pneumonia only after other antibiotic classes have been tried and failed or in cases with demonstrated drug resistant streptococcus pneumoniae 65 resistance to quinolones can evolve rapidly even during a course of treatment numerous pathogens including escherichia coli commonly exhibit resistance 66 widespread veterinary usage of quinolones in particular in europe has been implicated 67 fluoroquinolones had become the class of antibiotics most commonly prescribed to adults in 2002 nearly half 42 of these prescriptions were for conditions not approved by the u s fda such as acute bronchitis otitis media and acute upper respiratory tract infection according to a study supported in part by the agency for healthcare research and quality 68 69 in addition they are commonly prescribed for medical conditions such as acute respiratory illness that are usually caused by viral infections 70 three mechanisms of resistance are known 71 some types of efflux pumps can act to decrease intracellular quinolone concentration 72 in gram negative bacteria plasmid mediated resistance genes produce proteins that can bind to dna gyrase protecting it from the action of quinolones finally mutations at key sites in dna gyrase or topoisomerase iv can decrease their binding affinity to quinolones decreasing the drugs effectiveness citation needed mechanism of action edit structure of bacterial dna gyrase complexed with dna and two ciprofloxacin molecules green quinolones are chemotherapeutic bactericidal drugs they interfere with dna replication by preventing bacterial dna from unwinding and duplicating 73 specifically they inhibit the ligase activity of the type ii topoisomerases dna gyrase and topoisomerase iv which cut dna to introduce supercoiling while leaving nuclease activity unaffected with the ligase activity disrupted these enzymes release dna with single and double strand breaks that lead to cell death 74 the majority of quinolones in clinical use are fluoroquinolones which have a fluorine atom attached to the central ring system typically at the 6 position or c 8 position most of them are named with the oxacin suffix first and second generation quinolones are largely active against gram negative bacteria whereas third and fourth generation quinolones have increased activity against gram positive and anaerobic bacteria 75 some quinolones containing aromatic substituents at their c 7 positions are highly active against eukaryotic type ii topoisomerase 76 it has also been proposed that quinolone antibiotics cause oxidation of guanine nucleotides in the bacterial nucleotide pool and that this process contributes to the cytotoxicity of these agents 77 the incorporation of oxidized guanine nucleotides into dna could be bactericidal bacterial cytotoxicity could arise from incomplete repair of closely spaced 8 oxo 2 deoxyguanosine in the dna resulting in double strand breaks 77 cellular uptake edit fluoroquinolones can enter in cells easily via porins so are often used to treat intracellular pathogens such as legionella pneumophila and mycoplasma pneumoniae for many gram negative bacteria dna gyrase is the target whereas topoisomerase iv is the target for many gram positive bacteria citation needed eukaryotic cells are not believed to contain dna gyrase or topoisomerase iv however debate exists concerning whether the quinolones still have such an adverse effect on the dna of healthy cells some compounds in this class have been shown to inhibit the synthesis of mitochondrial dna 78 79 80 81 pharmacology edit the basic pharmacophore or active structure of the fluoroquinolone class is based upon the quinoline ring system 82 various substitutions made to the quinoline ring resulted in the development of numerous fluoroquinolone drugs the addition of the fluorine atom at c 6 distinguishes the successive generation fluoroquinolones from the first generation quinolones although examples are known that omit the atom while retaining antibacterial activity 63 pharmacokinetics edit pharmacokinetics of newer fluoroquinolones following a single oral dose 83 drug dosage a mg ba tooltip bioavailability c max μg ml t max h auc tooltip area under the curve pharmacokinetics μg h ml t 1 2 tooltip terminal half life h vd f tooltip volume of distribution l kg protein binding excreted unchanged dose adjustment renal tooltip renal impairment hepatic tooltip hepatic impairment ciprofloxacin 500 750 70 70 2 30 3 00 1 2 1 2 10 1 14 0 3 5 3 5 3 5 3 5 30 30 34 34 yes yes no no garenoxacin 400 600 nd 92 5 0 10 4 nd 1 2 60 96 7 14 2 9 8 nd nd 75 nd 40 nd nd nd nd nd gatifloxacin 400 96 3 86 1 5 33 8 8 0 1 8 20 76 yes no gemifloxacin 320 640 70 70 1 19 2 29 1 2 1 2 7 3 15 9 8 0 8 0 3 5 3 5 60 60 27 27 yes yes no no levofloxacin 500 750 99 99 5 08 7 13 1 7 1 7 48 0 82 0 6 9 6 9 1 1 1 1 31 31 83 83 yes yes nd nd moxifloxacin 200 400 86 86 1 16 3 34 1 7 1 7 15 4 33 8 12 1 12 1 3 3 3 3 47 47 19 19 no no no no a dosage applies only to c max and auc the other parameters an average of the values available in the literature irrespective of dosage history edit nalidixic acid although technically a naphthyridine it is considered the predecessor of all subsequently developed quinolone antibiotics although not formally a quinolone nalidixic acid is considered the first quinolone drug it was introduced in 1962 for treatment of urinary tract infections utis in humans 84 nalidixic acid was discovered by george lesher and coworkers in a distillate during an attempt at chloroquine synthesis 85 nalidixic acid is thus considered to be the predecessor of all members of the quinolone family including the second third and fourth generations commonly known as fluoroquinolones since the introduction of nalidixic acid more than 10 000 analogs have been synthesized but only a handful have found their way into clinical practice the first generation also included other quinolone drugs such as pipemidic acid oxolinic acid and cinoxacin which were introduced in the 1970s they proved to be only marginal improvements over nalidixic acid 86 these drugs were widely used as a first line treatment for many infections including very commons ones such as acute sinusitis acute bronchitis and uncomplicated utis 87 reports of serious adverse events began emerging and the fda first added a black box warning to fluoroquinolones in july 2008 for the increased risk of tendinitis and tendon rupture in february 2011 the risk of worsening symptoms for those with myasthenia gravis was added to the warning in august 2013 the agency required updates to the labels to describe the potential for irreversible peripheral neuropathy serious nerve damage citation needed in november 2015 an fda advisory committee discussed the risks and benefits of fluoroquinolones for the treatment of acute bacterial sinusitis acute bacterial exacerbation of chronic bronchitis and uncomplicated utis based on new safety information the new information focused on two or more side effects occurring at the same time and causing the potential for irreversible impairment the advisory committee concluded that the serious risks associated with the use of fluoroquinolones for these types of uncomplicated infections generally outweighed the benefits for patients with other treatment options 87 88 89 90 91 the 21 member joint committee overwhelmingly recommended stronger label warnings on the containers because of rare but sometimes devastating side effects 92 on 12 may 2016 the fda issued a drug safety communication advising that fluoroquinolones should be reserved for these conditions only when no other options are available due to potentially permanent disabling side effects occurring together the drug safety communication also announced the required labeling updates to reflect this new safety information 87 the fda put out another label change in july 2017 strengthening the warnings about potentially disabling adverse effects and limiting use of these drugs to second line treatments for acute sinusitis acute bronchitis and uncomplicated utis 87 generations edit the first generation of the quinolones began following introduction of the related but structurally distinct naphthyridine family nalidixic acid in 1962 for treatment of utis in humans 93 nalidixic acid was discovered by george lesher and coworkers in a chemical distillate during an attempt at synthesis of the chloroquinoline antimalarial agent chloroquine 94 naphthyridone and quinolone classes of antibiotics prevent bacte...