Quinolone antibiotic
Quinolone | |
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J01M | |
Clinical data | |
Drugs.com | Drug Classes |
External links | |
MeSH | D015363 |
Legal status | |
In Wikidata |
Quinolone antibiotics constitute a large group of
Nearly all quinolone antibiotics in use are fluoroquinolones, which contain a
Medical uses
Fluoroquinolones are often used for genitourinary infections 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 of pyelonephritis or bacterial prostatitis where the person may need to be hospitalised, fluoroquinolones are recommended as first-line therapy.[5]
Due to people with
Fluoroquinolones are featured prominently in guidelines for the treatment of hospital-acquired pneumonia.[6]
Children
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 inhalant
Meta-analyses conclude that fluoroquinolones pose little or no additional risk to children compared to other antibiotic classes.[8][9][10] Fluoroquinolone use in children may be appropriate when the infection is caused by multidrug-resistant bacteria, or when alternative treatment options require parenteral administration and oral therapy is preferred.[11]
Adverse effects
While typical drug side effects reactions are mild to moderate, sometimes serious adverse effects occur.
Boxed warnings
In 2008, the U.S. FDA added
Tendons
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%.[15] The risk appears to be higher among people older than 60 and those also taking corticosteroids;[15] 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.[16] Some experts have advised avoidance of fluoroquinolones in athletes.[16] If tendonitis occurs, it generally appears within one month, and the most common tendon injured appears to be the Achilles tendon.[15] The cause is not well understood.[15]
Nervous system
Nervous-system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis.[17] Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[18][19][20][21]
Aortic dissection
Fluoroquinolones can increase the rate of rare but serious tears in the aorta by 31% compared to other antibiotics.
Colitis
Other
More generally, fluoroquinolones are tolerated, with typical drug side effects being mild to moderate.[28] 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.[29][30]
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.[31]
The overall rate of adverse events in people treated with fluoroquinolones is roughly similar to that seen in people treated with other antibiotic classes.[25][32][33][34] 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.[35]
Fluoroquinolones prolong the heart's
In 2019 study by Journal of the American College of Cardiology it was discovered that fluoroquinolones could increase the risk for heart valve diseases.[38]
Events that may occur in acute overdose are rare, and include kidney failure and seizure.[39] Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[28][40][41]
Mechanism of toxicity
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[30] and oxidative stress.[42]
Interactions
Products containing multivalent
Administration of quinolone antibiotics to a
Contraindications
Quinolones are not recommended in people with
The basic
Antibiotic misuse and bacterial resistances
Because the use of broad-spectrum antibiotics encourages the spread of multidrug-resistant strains and the development of
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.[59][60] In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.[61]
Three mechanisms of resistance are known.
Mechanism of action
Quinolones are chemotherapeutic bactericidal drugs. They interfere with DNA replication by preventing bacterial DNA from unwinding and duplicating.[64] 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.[65] 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.[66] Some quinolones containing aromatic substituents at their C-7 positions are highly active against eukaryotic type II topoisomerase.[67]
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.
Cellular uptake
Fluoroquinolones can enter in cells easily via
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.[69][70][71][72]
Pharmacology
The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.[73] 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.[54]
Pharmacokinetics
Drug | Dosagea (mg) |
BA (%) | Cmax (μg/mL) |
tmax (h) |
AUC (μg • h/mL) |
t1/2 (h) |
Vd/F (L/kg) |
Protein binding (%) |
Excreted unchanged (%) |
Dose adjustment | |
---|---|---|---|---|---|---|---|---|---|---|---|
Renal |
Hepatic
| ||||||||||
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 and AUC. The other parameters an average of the values available in the literature irrespective of dosage. |
History
Although not formally a quinolone,
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.[78] 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.[78][79][80][81][82] The 21-member joint committee overwhelmingly recommended stronger label warnings on the containers because of rare but sometimes devastating side effects.[83]
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.[78] 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.[78]
Generations
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.
Quinolones can be classified into generations based on their antibacterial spectrums.[86][87] 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 are moxifloxacin, ciprofloxacin, levofloxacin.
First generation
- flumequine (veterinary use)
- oxolinic acid
- rosoxacin
Structurally related first-generation drugs, but formally not 4-quinolones, include cinoxacin,[88] nalidixic acid,[88] and piromidic acid, pipemidic acid
Second generation
The second-generation class is sometimes subdivided into "Class 1" and "Class 2".[88]
- ciprofloxacin[88][89]
- fleroxacin
- lomefloxacin[88]
- nadifloxacin
- norfloxacin
- ofloxacin[88]
- pefloxacin
- rufloxacin
A structurally related second-generation drug, but formally not a 4-quinolone, is enoxacin.[88]
Third generation
Unlike the first and second generations, the third generation is active against
A structurally related third-generation drug, but formally not a 4-quinolone, is tosufloxacin (Ozex, Tosacin).
Fourth generation
Fourth-generation fluoroquinolones act at DNA gyrase and topoisomerase IV.[91] This dual action slows development of resistance.[dubious ]
- clinafloxacin[89]
- gatifloxacin[92]
- moxifloxacin[88]
- sitafloxacin
- prulifloxacin
- besifloxacin
- delafloxacin
Two structurally related third-generation drugs, but formally not 4-quinolones, are gemifloxacin and trovafloxacin (removed from clinical use).[88][89]
In development:
Veterinary use
Quinolones have been widely used in animal husbandry, and several agents have veterinary-specific applications.
- danofloxacin – 2nd gen, related to ciprofloxacin
- difloxacin – 2nd/3rd gen, related to temafloxacin
- enrofloxacin – 2nd gen, metabolizes into ciprofloxacin
- ibafloxacin – 3rd gen, related to levofloxacin
- marbofloxacin – 3rd gen, related to levofloxacin
- orbifloxacin – 3rd gen, related to sparfloxacin
- sarafloxacin – 2nd/3rd gen, related to difloxacin
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This article incorporates public domain material from FDA updates warnings for fluoroquinolone antibiotics. United States Department of Health and Human Services.
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External links
- Quinolone antibiotic at Curlie
- Healthcare-associated Infections (HAIs)- Quinolones and the Clinical Laboratory CDC
- Information for Healthcare Professionals: Fluoroquinolone Antimicrobial Drugs from the U.S. Food and Drug Administration
- Fluoroquinolones Archived 17 June 2006 at the Wayback Machine "Family Practice Notebook" entry page for Fluoroquinolones
- Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD