| Quinolone | |
|---|---|
| Drug class | |
 The second generation fluoroquinolone, ciprofloxacin. The two-ringed nitrogen-containing system with a ketone is called aquinolone. | |
| Class identifiers | |
| Use | Bacterial infection |
| ATC code | J01M |
| Clinical data | |
| Drugs.com | Drug Classes |
| External links | |
| MeSH | D015363 |
| Legal status | |
| In Wikidata | |
Quinolone antibiotics constitute a large group ofbroad-spectrumbacteriocidals that share abicyclic core structure related to the substance4-quinolone.[1] They are used in human and veterinary medicine to treat bacterialinfections, as well as inanimal husbandry, specificallypoultry production.[2]
Quinolone antibiotics are classified into four generations based on their spectrum of activity and chemical modifications.[citation needed] The first-generation quinolones, such as nalidixic acid, primarily target Gram-negative bacteria and are mainly used for urinary tract infections. Second-generation quinolones introduced fluorine atoms into their structure, creatingfluoroquinolones, which significantly expanded their antibacterial activity to include some Gram-positive bacteria. Third-generation fluoroquinolones further improved Gram-positive coverage, while fourth-generation fluoroquinolones offer broad-spectrum activity, including anaerobic bacteria.
Only quinolone antibiotics in generation two and higher are consideredfluoroquinolones, as they contain afluorine atom in their chemical structure and are effective against bothGram-negative andGram-positive bacteria. One example isciprofloxacin, one of the most widely used antibiotics worldwide.[3][4]
Fluoroquinolones are frequently prescribed forgenitourinary tract infections[5] and are widely used in the treatment ofhospital-acquired infections associated withurinary catheters. The FDA published a 2018 safety alert recommending FQs be reserved for use only in patients who have no alternative treatment options for the following indications: uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.Incommunity-acquired infections, they are only recommended when risk factors formultidrug resistance are present or after other antibiotic regimens have failed. However, for serious acute cases ofpyelonephritis or bacterialprostatitis where the person may need to be hospitalised, fluoroquinolones are recommended asfirst-line therapy.[6]
Due to people withsickle-cell disease being at increased risk for developingosteomyelitis fromSalmonella, fluoroquinolones are the "drugs of choice" for this organism due to their ability to enter bone tissue withoutchelating it, astetracyclines are known to do.[citation needed]
Inbiofilm-associated infections, quinolones exhibit a good ability to penetrate the biofilm and target bacteria within it, especially during the early stages of biofilm formation. Their antibiofilm activity is generally higher than that of oldbeta-lactams andglycopeptides but remains lower compared to antibiotics such astetracyclines,daptomycin, andfosfomycin, which demonstrate greater efficacy against biofilms.[7]
Fluoroquinolones are featured prominently in guidelines for the treatment of hospital-acquired pneumonia.[8]
In most countries, fluoroquinolones are only approved for use in children under narrowly defined circumstances, owing in part to the observation of high rates of musculoskeletal adverse events in fluoroquinolone-treated juvenile animals. The use of fluoroquinolones in those 18 years of age and under is only FDA approved for complicated UTI's (pyelonephritis and for postexposure prophylaxis) and treatment of inhalation anthrax. In the UK, the prescribing indications for fluoroquinolones for children are severely restricted. Only inhalationalanthrax andpseudomonal infections incystic fibrosis infections are licensed indications in the UK due to ongoing safety concerns. In a study comparing the safety and efficacy of levofloxacin to that ofazithromycin orceftriaxone in 712 children with community-acquired pneumonia, serious adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these were considered by the treating physician to be unrelated or doubtfully related to the study drug. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the U.S. FDA Adverse Effects Reporting System at the time of the 20 September 2011 U.S.FDA Pediatric Drugs Advisory Committee included musculoskeletal events (39, including five cases oftendon rupture) andcentral nervous system events (19, including five cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.[9]
Meta-analyses conclude that fluoroquinolones pose little or no additional risk to children compared to other antibiotic classes.[10][11][12] Fluoroquinolone use in children may be appropriate when the infection is caused bymultidrug-resistant bacteria, or when alternative treatment options require parenteral administration and oral therapy is preferred.[13][14]
On May 12, 2016 the U.S. Food and Drug Administration advised that the serious, disabling and potentially permanent side effects associated with fluoroquinolone antibiotics (Cipro, Levaquin, Avelox, etc.) generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections. These side effects can involve tendons, muscles, joints, nerves and the central nervous system as well as cardiac, dermatologic and worsening of myasthenia gravis conditions. With fluoroquinolones these effects are sometimes collectively called floxing.[15]
Fluoroquinolones can increase the risk ofpsychiatric symptoms, includingdepression andpsychotic reactions. These may potentially lead to thoughts of suicide or suicide attempts.[16]
For example, recent reports from senior coroners on two suicides show the risks of fluoroquinolones in everyday life. Neither victim had a history of depression or mental health problems. However, both men had been prescribed ciprofloxacin shortly before they killed themselves.[17][18]
In a "Report to Prevent Future Deaths," mandated by UK law, one of the coroners noted that there is no compelling reason why patients should expect to risk becoming suicidal from an antibiotic unless this fact and potential symptoms were brought to their attention by the prescriber.[17]
A 2024 review from the UK'sMedicines & Healthcare Products Regulatory Agency examined the effectiveness of current measures to reduce these identified risks of fluoroquinolones. It concluded, "Systemic fluoroquinolones must now only be prescribed when other commonly recommended antibiotics are inappropriate."[19]
Nervous-system effects includeinsomnia,restlessness, and rarely,seizure,convulsions, and psychosis.[20] Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[21][22][23][24]
In 2008, the U.S. FDA addedblack box warnings on all fluoroquinolones, advising of the increased risk oftendon damage.[25] In 2016, the FDA found that systemic use (by mouth or injection) of fluoroquinolones was associated with "disabling and potentially permanent serious side effects" involving the tendons, muscles, joints, nerves, and central nervous system, concluding that these side effects generally outweigh the benefits for people with acutesinusitis, acutebronchitis, and uncomplicated urinary tract infections when other treatment options are available.[26] Concerns regardinglow blood sugar andmental health problems were added in 2018.[27] In December 2018, the FDA issued a warning regarding an increased risk ofaortic aneurysms andaortic dissections associated with fluoroquinolone use. This warning specifically targeted older adults and patients with conditions such ashypertension,Marfan syndrome,Ehlers-Danlos syndrome,atherosclerosis,peripheral vascular disease, and a history ofaneurysms.[28]
Quinolones are associated with a risk oftendonitis andtendon rupture; a 2013 review found the incidence of tendon injury among those taking fluoroquinolones to be between 0.08 and 0.20%.[29] The risk appears to be higher among people older than 60 and those also taking corticosteroids;[29] the risk also may be higher among people who are male, have a pre-existing joint or tendon issue, have kidney disease, or are highly active.[30] Some experts have advised avoidance of fluoroquinolones in athletes.[30] If tendonitis occurs, it generally appears within one month, and the most common tendon injured appears to be theAchilles tendon.[29] The cause is not well understood.[29]
Fluoroquinolones can increase the rate of rare but serious tears in the aorta by 31% compared to other antibiotics.[31] People at increased risk include those with aortic aneurysm, hypertension, certain genetic conditions such asMarfan syndrome andEhlers-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]
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 virulentClostridium strain.[36]
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 disordermyasthenia 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 withcephalosporins ormacrolides, but less frequently than those treated withpenicillins,clindamycin,sulfonamides, orvancomycin.[44]
Fluoroquinolones prolong the heart'sQT interval by blocking voltage-gated potassium channels.[45] Prolongation of the QT interval can lead totorsades de pointes, a life-threateningarrhythmia, 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 byJournal 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 includekidney 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]
The mechanisms of the toxicity of fluoroquinolones have been attributed to their interactions with different receptor complexes, such as blockade of the GABAA receptor complex within the central nervous system, leading to excitotoxic type effects[39] and oxidative stress.[51]
Products containing multivalentcations, such as aluminium- or magnesium-containingantacids, and products containing calcium, iron, or zinc invariably result in marked reduction of oral absorption of fluoroquinolones.[52] Other drugs that interact with fluoroquinolones includesucralfate,probenecid,cimetidine,theophylline,warfarin,antiviral agents,phenytoin,cyclosporine,rifampin,pyrazinamide, andcycloserine.[52]
Administration of quinolone antibiotics to abenzodiazepine-dependent individual can precipitate acutebenzodiazepine withdrawal symptoms due to quinolones displacing benzodiazepines from their binding sites.[53] Fluoroquinolones have varying specificity forcytochrome 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]
Quinolones are not recommended in people withepilepsy,Marfan's syndrome,Ehlers-Danlos Syndrome,[54]QT prolongation, pre-existing CNS lesions, or CNS inflammation, or who have had astroke.[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 knownhypersensitivity to the drug class.[60][61]
The basicpharmacophore, or active structure, of the fluoroquinolone class is based upon thequinoline ring system.[62] The addition of thefluorineatom 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 theantibacterial activity of this class (circa 1997).[63]
Because the use of broad-spectrum antibiotics encourages the spread of multidrug-resistant strains and the development ofClostridioides 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 recommendingmacrolide or doxycycline as first-line agents. The Drug-ResistantStreptococcus 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-resistantStreptococcus pneumoniae.[65]
Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerouspathogens, includingEscherichia 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 asacute bronchitis,otitis media, and acute upper respiratory tract infection, according to a study supported in part by theAgency 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 ofefflux pumps can act to decrease intracellular quinolone concentration.[72] In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind toDNA gyrase, protecting it from the action of quinolones. Finally,mutations at key sites inDNA gyrase ortopoisomerase IV can decrease their binding affinity to quinolones, decreasing the drugs' effectiveness.[citation needed]
Quinolones are chemotherapeutic bactericidal drugs. They interfere withDNA replication by preventing bacterial DNA from unwinding and duplicating.[73] Specifically, they inhibit the ligase activity of thetype 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 afluorineatom attached to the central ring system, typically at the6-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 intoDNA could be bactericidal. Bacterial cytotoxicity could arise from incomplete repair of closely spaced8-oxo-2'-deoxyguanosine in the DNA resulting in double-strand breaks.[77]
Fluoroquinolones can enter in cells easily viaporins, so are often used to treatintracellularpathogens such asLegionella pneumophila andMycoplasma 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 ofmitochondrial DNA.[78][79][80][81]
The basicpharmacophore, 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 thefluorineatom 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]
| Drug | Dosagea (mg) | BATooltip Bioavailability (%) | Cmax (μg/mL) | tmax (h) | AUCTooltip Area under the curve (pharmacokinetics) (μg • h/mL) | t1/2Tooltip Terminal half-life (h) | Vd/FTooltip Volume of distribution (L/kg) | Protein binding (%) | Excreted unchanged (%) | Dose adjustment | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| RenalTooltip Renal impairment | HepaticTooltip 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 Cmax andAUC. The other parameters an average of the values available in the literature irrespective of dosage. | |||||||||||
Although not formally a quinolone,nalidixic acid is considered the first quinolone drug. It was introduced in 1962 for treatment ofurinary tract infections (UTIs) in humans.[84] Nalidixic acid was discovered by George Lesher and coworkers in adistillate during an attempt atchloroquine 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 10,000analogs have been synthesized, but only a handful have found their way into clinical practice. The first generation also included other quinolone drugs, such aspipemidic acid,oxolinic acid, andcinoxacin, 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]
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 chemicaldistillate during an attempt at synthesis of the chloroquinoline antimalarial agent,chloroquine.[94] Naphthyridone and quinolone classes of antibiotics prevent bacterial DNA replication by inhibition of DNA unwinding events, and can be both bacteriostatic and bacteriocidal.[73] (SeeMechanism of Action earlier.) The majority of quinolones in clinical use belong to the second generation class of "fluoroquinolones", which have a true quinoline framework, maintain the C-3 carboxylic acid group, and add afluorineatom to the all-carbon containing ring, typically at the C-6 or C-8 positions.[75]
Quinolones can be classified into generations based on their antibacterial spectrums.[95][96] The earlier-generation agents are, in general, more narrow-spectrum than the later ones, but no standard is employed to determine which drug belongs to which generation. The only universal standard applied is the grouping of the non-fluorinated drugs found within this class (quinolones) within the first-generation heading. As such, a wide variation exists within the literature dependent upon the methods employed by the authors.[citation needed]
The first generation is rarely used. Frequently prescribed drugs aremoxifloxacin,ciprofloxacin,levofloxacin.
Structurally related first-generation drugs, but formally not 4-quinolones, includecinoxacin,[97]nalidixic acid,[97] andpiromidic acid,pipemidic acid
The second-generation class is sometimes subdivided into "Class 1" and "Class 2".[97]
A structurally related second-generation drug, but formally not a 4-quinolone, isenoxacin.[97]
Unlike the first and second generations, the third generation is active againststreptococci.[97]
A structurally related third-generation drug, but formally not a 4-quinolone, istosufloxacin (Ozex, Tosacin).
Fourth-generation fluoroquinolones act at DNA gyrase and topoisomerase IV.[100] This dual action slows development of resistance.[dubious –discuss]
Two structurally related fourth-generation drugs, but formally not 4-quinolones, aregemifloxacin andtrovafloxacin (removed from clinical use).[97][98]
In development:
Quinolones have been widely used inanimal husbandry, and several agents have veterinary-specific applications.
This article incorporatespublic domain material fromFDA updates warnings for fluoroquinolone antibiotics.United States Department of Health and Human Services.
{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)From 1995 to 2002, inappropriate antibiotic prescribing for acute respiratory infections, which are usually caused by viruses and thus are not responsive to antibiotics, declined from 61 to 49 percent. However, the use of broad-spectrum antibiotics such as the fluoroquinolones, jumped from 41 to 77 percent from 1995 to 2001. Overuse of these antibiotics will eventually render them useless for treating antibiotic-resistant infections, for which broad-spectrum antibiotics are supposed to be reserved.
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