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Quinolone antibiotic

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Quinolone
Drug class
The second generation fluoroquinolone, ciprofloxacin. The two ringed nitrogen containing system with a ketone is called aquinolone.
Class identifiers
UseBacterial infection
ATC codeJ01M
Clinical data
Drugs.comDrug Classes
External links
MeSHD015363
Legal status
In Wikidata

Quinolone antibioticsconstitute a large group ofbroad-spectrumbacteriocidalsthat share abicyclic core structurerelated to the substance4-quinolone.[1]They are used in human and veterinary medicine to treat bacterialinfections,as well as in animal husbandry, specifically poultry production.[2]

Nearly all quinolone antibiotics in use arefluoroquinolones,which contain afluorineatom in their chemical structure and are effective against bothGram-negativeandGram-positivebacteria. One example isciprofloxacin,one of the most widely used antibiotics worldwide.[3][4]

Medical uses

[edit]
Levofloxacin
Trovafloxacin

Fluoroquinolones are often used for genitourinary infections[5]and are widely used in the treatment of hospital-acquired infections associated with urinary catheters. In community-acquired infections, they are recommended only when risk factors for multidrug resistance are present or after other antibiotic regimens have failed. However, for serious acute cases ofpyelonephritisor bacterialprostatitiswhere the person may need to be hospitalised, fluoroquinolones are recommended as first-line therapy.[6]

Due to people withsickle-cell diseasebeing at increased risk for developingosteomyelitisfrom theSalmonella,fluoroquinolones are the "drugs of choice" due to their ability to enter bone tissue without chelating it, astetracyclinesare known to do.[citation needed]

Fluoroquinolones are featured prominently in guidelines for the treatment of hospital-acquired pneumonia.[7]

Children

[edit]

In most countries, fluoroquinolones are approved for use in children only under narrowly defined circumstances, owing in part to the observation of high rates of musculoskeletal adverse events in fluoroquinolone-treated juvenile animals. In the UK, the prescribing indications for fluoroquinolones for children are severely restricted. Only inhalantanthraxandpseudomonalinfections incystic fibrosisinfections are licensed indications in the UK due to ongoing safety concerns. In a study comparing the safety and efficacy of levofloxacin to that ofazithromycinorceftriaxonein 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 of tendon rupture) andcentral nervous systemevents (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.[8]

Meta-analyses conclude that fluoroquinolones pose little or no additional risk to children compared to other antibiotic classes.[9][10][11]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.[12]

Adverse effects

[edit]

While typical drug side effects reactions are mild to moderate, sometimes serious adverse effects occur.

Boxed warnings

[edit]

In 2008, the U.S. FDA addedblack box warningson all fluoroquinolones, advising of the increased risk of tendon damage.[13]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 acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections when other treatment options are available.[14]Concerns regardinglow blood sugarandmental health problemswere added in 2018.[15]

Tendons

[edit]

Quinolones are associated with a small risk of tendonitis and tendon rupture; a 2013 review found the incidence of tendon injury among those taking fluoroquinolones to be between 0.08 and 0.20%.[16]The risk appears to be higher among people older than 60 and those also taking corticosteroids;[16]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.[17]Some experts have advised avoidance of fluoroquinolones in athletes.[17]If tendonitis occurs, it generally appears within one month, and the most common tendon injured appears to be theAchilles tendon.[16]The cause is not well understood.[16]

Nervous system

[edit]

Nervous-system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis.[18]Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[19][20][21][22]

Aortic dissection

[edit]

Fluoroquinolones can increase the rate of rare but serious tears in the aorta by 31% compared to other antibiotics.[23]People at increased risk include those with aortic aneurysm, hypertension, certain genetic conditions such asMarfan syndromeandEhlers-Danlos syndrome,and the elderly. For these people, fluoroquinolones should be used only when no other treatment options are available.[24]

Colitis

[edit]

Clostridium difficilecolitismay 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[25]or less than[26][27]that associated with broad spectrum cephalosporins. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulentClostridiumstrain.[28]

Other

[edit]

More generally, fluoroquinolones are tolerated, with typical drug side effects being mild to moderate.[29]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 gravisare the subject of"black box" warningsin the United States.[30][31]

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.[32]

The overall rate of adverse events in people treated with fluoroquinolones is roughly similar to that seen in people treated with other antibiotic classes.[26][33][34][35]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 withcephalosporinsormacrolides,but less frequently than those treated withpenicillins,clindamycin,sulfonamides,orvancomycin.[36]

Fluoroquinolones prolong the heart'sQT intervalby blocking voltage-gated potassium channels.[37]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.[38]

In 2019 study byJournal of the American College of Cardiologyit was discovered that fluoroquinolones could increase the risk for heart valve diseases.[39]

Events that may occur in acute overdose are rare, and includekidney failureand seizure.[40]Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[29][41][42]

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 GABAAreceptor complex within the central nervous system, leading to excitotoxic type effects[31]and oxidative stress.[43]

Interactions

[edit]

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.[44]Other drugs that interact with fluoroquinolones includesucralfate,probenecid,cimetidine,theophylline,warfarin,antiviral agents,phenytoin,cyclosporine,rifampin,pyrazinamide,andcycloserine.[44]

Administration of quinolone antibiotics to abenzodiazepine-dependentindividual can precipitate acutebenzodiazepine withdrawalsymptoms due to quinolones displacing benzodiazepines from their binding sites.[45]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.[44]

Contraindications

[edit]

Quinolones are not recommended in people withepilepsy,Marfan's syndrome,Ehlers-Danlos Syndrome,[46]QT prolongation,pre-existing CNS lesions, or CNS inflammation, or who have had astroke.[31]They are best avoided in the athlete population.[47]Safety concerns exist for fluoroquinolone use during pregnancy, so they are contraindicated unless no other safe alternative antibiotic exists.[48]However, one meta-analysis looking at the outcome of pregnancies involving quinolone use in the first trimester found no increased risk of malformations.[49]They are also contraindicated in children due to the risks of damage to the musculoskeletal system.[50]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.[51]Quinolones should also not be given to people with a knownhypersensitivityto the drug class.[52][53]

The basicpharmacophore,or active structure, of the fluoroquinolone class is based upon thequinolinering system.[54]The addition of thefluorineatomat 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 theantibacterialactivity of this class (circa1997).[55]

Antibiotic misuse and bacterial resistances

[edit]
See also:Antibiotic misuseandAntibiotic resistance

Because the use of broad-spectrum antibiotics encourages the spread of multidrug-resistant strains and the development ofClostridium difficileinfections, 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,[56]instead recommendingmacrolideor doxycycline as first-line agents. The Drug-ResistantStreptococcus pneumoniaeWorking 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.[57]

Resistanceto quinolones can evolve rapidly, even during a course of treatment. Numerouspathogens,includingEscherichia coli,commonly exhibit resistance.[58]Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.[59]

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.[60][61]In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.[62]

Three mechanisms of resistance are known.[63]Some types ofeffluxpumps can act to decrease intracellular quinolone concentration.[64]In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind toDNA gyrase,protecting it from the action of quinolones. Finally,mutationsat key sites inDNA gyraseortopoisomerase IVcan 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 withDNA replicationby preventing bacterial DNA from unwinding and duplicating.[65]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.[66]The majority of quinolones in clinical use are fluoroquinolones, which have afluorineatomattached to the central ring system, typically at the6-position or C-8 position.Most of them are named with the-oxacinsuffix. 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.[67]Some quinolones containing aromatic substituents at their C-7 positions are highly active against eukaryotic type II topoisomerase.[68]

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.[69]The incorporation of oxidized guanine nucleotides intoDNAcould be bactericidal. Bacterial cytotoxicity could arise from incomplete repair of closely spaced8-oxo-2'-deoxyguanosinein the DNA resulting in double-strand breaks.[69]

Cellular uptake

[edit]

Fluoroquinolones can enter in cells easily viaporins,so are often used to treatintracellularpathogenssuch asLegionella pneumophilaandMycoplasma 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.[70][71][72][73]

Pharmacology

[edit]

The basicpharmacophore,or active structure, of the fluoroquinolone class is based upon the quinoline ring system.[74]Various substitutions made to the quinoline ring resulted in the development of numerous fluoroquinolone drugs. The addition of thefluorineatomat C-6 distinguishes the successive-generation fluoroquinolones from the first-generation quinolones, although examples are known that omit the atom while retaining antibacterial activity.[55]

Pharmacokinetics

[edit]
Pharmacokinetics of newer fluoroquinolones following a single oral dose[75]
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 CmaxandAUC.The other parameters an average of the values available in the literature irrespective of dosage.

History

[edit]
Nalidixic acid. Although technically anaphthyridine,it is considered the predecessor of all subsequently developed quinolone antibiotics.

Although not formally a quinolone,nalidixic acidis considered the first quinolone drug. It was introduced in 1962 for treatment ofurinary tract infections(UTIs) in humans.[76]Nalidixic acid was discovered by George Lesher and coworkers in adistillateduring an attempt atchloroquinesynthesis.[77]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 10,000analogshave 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.[78]

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.[79]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.[79][80][81][82][83]The 21-member joint committee overwhelmingly recommended stronger label warnings on the containers because of rare but sometimes devastating side effects.[84]

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.[79]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.[79]

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.[85]Nalidixic acid was discovered by George Lesher and coworkers in a chemicaldistillateduring an attempt at synthesis of the chloroquinoline antimalarial agent,chloroquine.[86]Naphthyridone and quinolone classes of antibiotics prevent bacterial DNA replication by inhibition of DNA unwinding events, and can be both bacteriostatic and bacteriocidal.[65](SeeMechanism of Actionlater.) 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 afluorineatomto the all-carbon containing ring, typically at the C-6 or C-8 positions.[67]

Sites of substitution in second-generation fluoroquinolone antibiotics: Here, and in following the orientation of the quinolones are flipped with respect to horizontal and vertical axes, relative to earlier images; the nitrogen (N)-containing pyridine ring is now on the left, and the N-1 atom and C-6 carbonyl are at 12 o'clock and 6 o'clock in the pyridine ring. The characteristic 6-fluoro group is shown in red. For instance, in ciprofloxacin, above, the R substituent attached to the N-1 atom is acyclopropylgroup, the R substituent in blue is apiperazinemoiety, and the remaining substitution sites (R groups) are hydrogen atoms.

Quinolones can be classified into generations based on their antibacterial spectrums.[87][88]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-fluorinateddrugs 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.

First generation

[edit]

Structurally related first-generation drugs, but formally not 4-quinolones, includecinoxacin,[89]nalidixic acid,[89]andpiromidic acid,pipemidic acid

Second generation

[edit]

The second-generation class is sometimes subdivided into "Class 1" and "Class 2".[89]

A structurally related second-generation drug, but formally not a 4-quinolone, isenoxacin.[89]

Third generation

[edit]

Unlike the first and second generations, the third generation is active againststreptococci.[89]

A structurally related third-generation drug, but formally not a 4-quinolone, istosufloxacin(Ozex, Tosacin).

Fourth generation

[edit]

Fourth-generation fluoroquinolones act at DNA gyrase and topoisomerase IV.[92]This dual action slows development of resistance.[dubious–discuss]

Two structurally related third-generation drugs, but formally not 4-quinolones, aregemifloxacinandtrovafloxacin(removed from clinical use).[89][90]

In development:

Veterinary use

[edit]

Quinolones have been widely used inanimal husbandry,and several agents have veterinary-specific applications.

References

[edit]

Public DomainThis article incorporatespublic domain materialfromFDA updates warnings for fluoroquinolone antibiotics.United States Department of Health and Human Services.

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