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Quinolone

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Not to be confused with quinoline.

Essential structure of all quinolone antibiotics: the blue drawn remainder of R is usually piperazine; if the connection contains fluorine (red), it is a fluoroquinolone.
Nalidixic acid
Ciprofloxacin
Levofloxacin
Trovafloxacin
See also: 2- and 4-Quinolones

The quinolones are a family of synthetic broad-spectrum antibacterial drugs.[1][2][3]

The first generation of quinolones began with the introduction of nalidixic acid in 1962 for treatment of urinary tract infections in humans.[4] Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis.[5] Quinolones exert their antibacterial effect by preventing bacterial DNA from unwinding and duplicating (please see the Mechanism of Action section for details).[6] The majority of quinolones in clinical use belong to the subset fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7 position.

Medical uses

Fluoroquinolones are broad-spectrum antibiotics (effective for both gram negative and gram positive bacteria) that play an important role in treatment of serious bacterial infections, especially hospital-acquired infections and others in which resistance to older antibacterial classes is suspected. Because the use of broad-spectrum antibiotics encourages the spread of multidrug resistant strains and the development of Clostridium difficile infections, treatment guidelines from the Infectious Disease Society of America, the American Thoracic Society, and other professional organizations 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.

Fluoroquinolones are featured prominently in the The American Thoracic Society guidelines for the treatment of hospital-acquired pneumonia.[7] The Society recommends fluoroquinolones not be used as a first-line agent for community-acquired pneumonia,[8] 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 those with demonstrated drug-resistant Streptococcus pneumoniae.[9]

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 patient may need to be hospitalised, fluoroquinolones are recommended as first-line therapy.[10]

Due to sickle-cell disease patients being at increased risk for developing osteomyelitis from the Salmonella genus, fluoroquinolones are the "drugs of choice" due to their ability to enter bone tissue without chelating it as tetracyclines are known to do.

Adverse effects

See also: Adverse effects of fluoroquinolones

In general, fluoroquinolones are well tolerated, with most side effects being mild to moderate.[11] On occasion, serious adverse effects occur.[12]Common side effects include gastrointestinal effects such as nausea, vomiting and diarrhea, as well as headache and insomnia.

The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes.[13][14][15][16] A U.S. Centers for Disease Control study found patients 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.[17]

Post-marketing surveillance has revealed a variety of relatively rare but serious adverse effects that are 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. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients.[18] The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin is has been estimated at 17 per 100,000 treatments.[19][20] Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.[21] Tendon damage may manifest during, as well as up to a year after fluoroquinolone therapy has been completed.[22]

FQs prolong the QT interval by blocking voltage-gated potassium channels.[23] 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.[24]

Clostridium difficile associated diarrhea 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 simlar to[25] or less [26][27] than that associated with broad spectrum cephalosporins.

Studies examining nervous system effects have estimated that neurotoxicity occurs in approximately 1% to 4.4% of patients taking FQs, with serious adverse effects occurring less than 0.5% of the time.[24] The most important of these may be peripheral neuropathy, which can be permanent.[28] Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis[29] Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[30][31][32][33]

Events that may occur in acute overdose are rare, and include renal failure and seizure.[34] Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[11][35][36]

Contraindications

Quinolones are contraindicated if a patient has epilepsy, QT prolongation, pre-existing CNS lesions, CNS inflammation or suffered a stroke.[12] There are safety concerns of fluoroquinolone use during pregnancy and, as a result, are contraindicated except for when no other safe alternative antibiotic exists.[37] However, one meta-analysis looking at the outcome of pregnancies involving Quinolone use in the first trimester found no increased risk of malformations.[38] They are also contraindicated in children due to the risks of damage to the musculoskeletal system.[39] 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.[40] Quinolones should also not be given to people with a known hypersensitivity to the drug.[41][42] Quinolone antibiotics should not be administered to patients who are dependent on benzodiazepines, since they compete directly with benzodiazepines at the GABA-A receptor, acting as a competitive antagonist and thus possibly precipitating a severe acute and potentially fatal withdrawal effect.[43][44][45]

Pharmacology

The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.[46] The addition of the fluorine atom at C6 distinguishes the successive-generation fluoroquinolones from the first-generation quinolones. The addition of the C6 fluorine atom has since been demonstrated to not be required for the antibacterial activity of this class (circa 1997).[47]

Various substitutions made to the quinoline ring resulted in the development of numerous fluoroquinolone drugs available today. Each substitution is associated with a number of specific adverse reactions, as well as increased activity against bacterial infections, whereas the quinoline ring, in and of itself, has been associated with severe and even fatal adverse reactions.[48]

Mechanism of action

Structure of bacterial DNA gyrase complexed with DNA and two ciprofloxacin molecules (green)

Fluoroquinolones inhibit the topoisomerase II ligase domain, leaving the two nuclease domains intact. This modification, coupled with the constant action of the topoisomerase II in the bacterial cell, leads to DNA fragmentation via the nucleasic activity of the intact enzyme domains. Recent evidence has shown eukaryotic topoisomerase II is also a target for a variety of quinolone-based drugs. Thus far, most of the compounds that show high activity against the eukaryotic type II enzyme contain aromatic substituents at their C-7 positions.[49][50]

Fluoroquinolones can enter cells easily via porins and, therefore, 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. Some compounds in this class have been shown to inhibit the synthesis of mitochondrial DNA.[51][52][53][54][55][56][57]

Mechanism of toxicity

The mechanisms of the toxicity of fluoroquinolones has 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[12] and oxidative stress.[58]

Interactions

Theophylline, nonsteroidal anti-inflammatory drugs and corticosteroids enhance the toxicity of fluoroquinolones.[59][60][61]

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.[62] Taking colloidal silver along with several versions of quinolones might decrease how much antibiotic the body absorbs.[63]

Other drugs that interact with fluoroquinolones include antacids, sucralfate, probenecid, cimetidine, warfarin, antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.[61]

Many fluoroquinolones, especially ciprofloxacin, inhibit the cytochrome P450 isoform CYP1A2.[64] This inhibition causes an increased level of drugs that are metabolized by this enzyme. This includes antidepressants such as amitriptyline and imipramine, clozapine (an atypical antipsychotic), caffeine, olanzapine (an atypical antipsychotic), ropivacaine (a local anaesthetic), theophylline (a xanthine), and zolmitriptan (a serotonin receptor agonist).[64]

Antibiotic misuse and bacterial resistances

See also: Antibiotic misuse and Antibiotic resistance

Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[65] Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.[66]

Fluoroquinolones have been recommended to be reserved for the use in patients who are seriously ill and may soon require immediate hospitalization.[67] Though considered to be very important and necessary drugs required to treat severe and life-threatening bacterial infections, the associated antibiotic misuse remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics such as happens with children suffering from otitis media (ear infections) has given rise to a breed of super bacteria that are resistant to antibiotics entirely.[68]

For example, the use of the fluoroquinolones had increased threefold in an emergency room environment in the United States between 1995 and 2002, while the use of safer alternatives, such as macrolides, declined significantly.[69][70] Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the 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.[70][71] In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.[72]

Within a recent study concerning the proper use of this class in the emergency rooms of two academic hospitals, 99% of these prescriptions were revealed to be in error. Out of the 100 total patients studied, 81 received a fluoroquinolone for an inappropriate indication. Out of these cases, 43 (53%) were judged to be inappropriate because another agent was considered first line, 27 (33%) because there was no evidence of a bacterial infection to begin with (based on the documented evaluation), and 11 (14%) because of the need for such therapy was questionable. Of the 19 patients who received a fluoroquinolone for an appropriate indication, only one patient of 100 received both the correct dose and duration of therapy.[73]

Three mechanisms of resistance are known.[74] Some types of efflux pumps can act to decrease intracellular quinolone concentration.[75] 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.

History

Nalidixic acid is considered to be the predecessor of all members of the quinolone family, including the second, third and fourth generations commonly known as fluoroquinolones. This 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.[76] Though it is generally accepted nalidixic acid is to be considered the first quinolone drug, this has been disputed over the years by a few researchers who believe chloroquine, from which nalidixic acid is derived, is to be considered the first quinolone drug, rather than nalidixic acid.

Since the introduction of nalidixic acid in 1962, more than 10,000 analogs have been synthesized, but only a handful have found their way into clinical practice.

  • Advocacy Groups and Regulation:

In August 2013, the U.S. Food and Drug Administration issued a Safety Alert requiring drug labels and for all fluoroquinolone antibacterial drugs "be updated to better describe the serious side effect of peripheral neuropathy. This serious nerve damage potentially caused by fluoroquinolones may occur soon after these drugs are taken and may be permanent." Only those taken by mouth or injection were covered by the alert, while those used topically on the eyes and ears were not.

Several advocacy groups have petitioned the FDA to increase the prominence of adverse effect warnings on the labels of fluroquinolone antibacterials, and to withdraw others from the market.[77][78][79][80][81][82][83]

Current litigation

A significant number of cases are pending before the United States District Court, District of Minnesota, involving the drug Levaquin. On 13 June 2008, a Judicial Panel On Multidistrict Litigation (MDL) granted the Plaintiffs’ motion to centralize individual and class-action lawsuits involving Levaquin in the District of Minnesota over objection of Defendants, Johnson and Johnson / Ortho McNeil.[84]

On 6 July 2009, the New Jersey Supreme Court had also designated litigation over Levaquin as a mass tort and has assigned it to an Atlantic County, N.J., judge. The suits charge the drug has caused Achilles tendon ruptures and other permanent damage.[85] Of a total of about 3400 cases, 845 were recently settled out of court after Johnson and Johnson prevailed in three of the first four cases to go to trial[86][87]

Several class action lawsuits had been filed in regards to the adverse reactions allegedly suffered by those exposed to ciprofloxacin during the anthrax scare of 2001.

Boxed warnings

In the US, the package insert for fluoroquinolone antibiotics includes a boxed warning of increased risk of developing tendonitis and tendon rupture in patients of all ages taking fluoroquinolones for systemic use. This risk is further increased in individuals over 60 years of age, taking corticosteroid drugs, and have received kidney, heart, or lung transplants. Another boxed warning says fluoroquinolones, due to their neuromuscular blocking activity, may exacerbate muscle weakness in persons with myasthenia gravis. Serious adverse events, including deaths and requirement for ventilatory support, have been reported in this group of patients. Avoidance of fluoroquinolones in patients with known history of myasthenia gravis is advised.[88]

A class-action lawsuit was filed on behalf of individuals alleging harm by the use of fluoroquinolones, as well as action by the consumer advocate group, Public Citizen.[89][84] Partly as a result of the efforts of Public Citizen, the FDA ordered boxed warnings on all fluoroquinolones, advising consumers of an enhanced risk of tendon damage.[90]

Generations

Researchers divide the quinolones into generations based on their antibacterial spectrum.[91][92] 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 nonfluorinated 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.

The first generation is rarely used today. Nalidixic acid was added to the OEHHA Prop 65 list as a carcinogen on 15 May 1998.[93] A number of the second-, third-, and fourth-generation drugs have been removed from clinical practice due to severe toxicity issues or discontinued by their manufacturers. The drugs most frequently prescribed today consist of Avelox (moxifloxacin), Cipro (ciprofloxacin), Levaquin (levofloxacin), and, to some extent, their generic equivalents.

First-generation

Second-generation

The second-generation class is sometimes subdivided into "Class 1" and "Class 2".[95]

Third-generation

Unlike the first- and second-generations, the third-generation is active against streptococci.[95]

Fourth-generation

Fourth generation fluoroquinolones act at DNA gyrase and topoisomerase IV.[99] This dual action slows development of resistance.

In development

Veterinary use

The quinolones have been widely used in agriculture, and several agents have veterinary, but not human, applications.

However, the agricultural use of fluoroquinolones in the U.S. has been restricted since 1997, due to concerns over the development of antibiotic resistance.[101]

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