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The quinolones are a family of synthetic broad-spectrum antibacterial drugs. The term quinolone(s) refers to potent synthetic chemotherapeutic antibacterials.[1][2]
The first generation of the quinolones begins with the introduction of nalidixic acid in 1962 for treatment of urinary tract infections in humans.[3] Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis.[4]
They prevent bacterial DNA from unwinding and duplicating.[5] (See Mechanism of Action later.)
Quinolones, in comparison to other antibiotic classes, have among the highest risk of causing colonization with MRSA and Clostridium difficile.[6][7][8] 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.
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Fluoroquinolones are broad-spectrum antibiotics 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.
Debates are still taking place as to whether or not the effectiveness of fluoroquinolones for the treatment of community-acquired respiratory disorders is similar to that of other antibiotic classes.[9][10]
Fluoroquinolone use for pneumonia is increasing, and with it so is bacterial resistance to fluoroquinolones. A Canadian study found the great majority of fluoroquinolone prescriptions for community-acquired pneumonia were inappropriate. Clinical guidelines in Canada recommend fluoroquinolones only for outpatient treatment of pneumonia in a small number of patients, such as those with certain comorbid conditions, e.g., patients with a history of COPD, or those with recent use of antibiotics.[11] For severe forms of community-acquired pneumonia, the fluoroquinolones are associated with reduced hospitalization rates, but with no differences found in mortality between other antibiotic classes.[12]
Fluoroquinolones are not recommended as first-line antibiotics for acute sinusitis, as this condition is usually self-limiting, and the risks outweigh the benefits in comparison to other antibiotic classes.[10][13]
Antibiotics including fluoroquinolones can be effective in some cases of bronchitis. However, only about 5-10% of bronchitis cases are caused by a bacterial infection; most cases of bronchitis are caused by a viral infection and are self-limiting and resolve themselves in a few weeks. It has been recommended that antibiotics are limited in most cases to those whose symptoms fail to resolve on their own.[14]
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.[15] Campbell's Urology, the urologist's most authoritative reference text, identifies only about 5% of all patients with prostatitis as having bacterial prostatitis, which can be "cured" at least in the short term by antibiotics. In other words, 95% of men with prostatitis have little hope for a cure with antibiotics alone, since they do not actually have any identifiable bacterial infection.[16]
Fluoroquinolones are featured prominently in the The American Thoracic Society guidelines for the treatment of hospital-acquired pneumonia. The Society recommends fluoroquinolones not be used as a first-line agent for community-acquired pneumonia, 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. Doctors at the Centers for Disease Control are concerned fluoroquinolones are being used as a "one-size-fits-all" treatment unnecessarily by doctors without considering suitability and differences due to age and other risk factors. Effective interventions have been recommended to reduce the excessive fluoroquinolone prescribing in the United States.[17]
In general, fluoroquinolones are well tolerated, with most side effects being mild to moderate. On occasion, serious adverse effects occur.[18][19] Some of the serious adverse effects that occur more commonly with fluoroquinolones than with other antibiotic drug classes include central nervous system (CNS) and tendon toxicity.[20][21] The currently marketed quinolones have safety profiles similar to those of other antimicrobial classes.[20] Fluoroquinolones are sometimes associated with an QTc interval prolongation and cardiac arrhythmias,[22] convulsions, tendon rupture, torsade de pointes and hypoglycemia.[23]
These adverse reactions are a class effect of all quinolones; however, certain quinolones are more strongly associated with increased toxicity to certain organs. For example, moxifloxacin carries a higher risk of QTc prolongation,[24] and gatifloxacin has been most frequently linked to disturbed blood sugar levels, although all quinolones carry these risks.[25][26] Some quinolones were withdrawn from the market because of these adverse events (for example, sparfloxacin was associated with phototoxicity and QTc prolongation; thrombocytopenia and nephritis were seen with tosufloxacin; and hepatotoxicity with trovafloxacin).[27] Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.[28] The risk of adverse events is further increased if the dosage is not properly adjusted, for example if there is renal insufficiency.[25]
The serious events may occur during therapeutic use at therapeutic dose levels or with acute overdose. At therapeutic doses, they include: CNS toxicity, cardiovascular toxicity, tendon / articular toxicity, and, rarely, hepatic toxicity.[29] Caution is required in patients with liver disease.[30] Events that may occur in acute overdose are rare, and include renal failure and seizure.[29] Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[20][21] Adverse reactions may manifest during, as well as after fluoroquinolone therapy has been completed.[31]
Fluoroquinolones are considered high-risk antibiotics for the development of Clostridium difficile and MRSA infections.[6][32] A previously rare strain of C. difficile that produces a more severe disease with increased levels of toxins is becoming epidemic, and may be connected to the use of fluoroquinolones.[33] Fluoroquinolones are more strongly associated with C. difficile infections than other antibiotics, including clindamycin, third-generation cephalosporins, and beta lactamase inhibitors. One study found fluoroquinolones were responsible for 55% of C. difficile infections.[34] The European Center for Disease Prevention and Control recommends fluoroquinolones and the antibiotic clindamycin should be avoided in clinical practice due to their high association with C. difficile, a potentially life-threatening super-infection.[7]
The CNS is an important target for fluoroquinolone-mediated neurotoxicity. Adverse event reporting in Italy by doctors showed fluoroquinolones among the top three prescribed drugs for causing adverse neurological and psychiatric effects. These neuropsychiatric effects included tremor, confusion, anxiety, insomnia, agitation, and, in severe cases, psychosis. Moxifloxacin came out worst among the quinolones for causing CNS toxicity.[35] Some support and patient advocacy groups refer to these adverse events as "fluoroquinolone toxicity". Some people from these groups claim to have suffered serious long-term harm to their health from using fluoroquinolones. This has led to a class-action lawsuit by those harmed by the use of fluoroquinolones, as well as action by the consumer advocate group, Public Citizen.[36][37] Partly as a result of the efforts of Public Citizen, the FDA ordered black box warnings on all fluoroquinolones, advising consumers of their possible toxic effects on tendons.[38]
Quinolones are contraindicated if a patient has epilepsy, QT prolongation, pre-existing CNS lesions, CNS inflammation or suffered a stroke.[18] There are safety concerns of fluoroquinolone use during pregnancy and, as a result, are contraindicated except for when no other safe alternative antibiotic exists.[39] However, one meta-analysis looking at the outcome of pregnancies involving Quinolone use in the first trimester found no increased risk of malformations.[40] They are also contraindicated in children due to the risks of damage to the musculoskeletal system.[41] 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.[42] Quinolones should also not be given to people with a known hypersensitivity to the drug.[43][44] 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.[45][46][47]
The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.[48] 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).[49]
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,[50] whereas the quinoline ring, in and of itself, has been associated with severe and even fatal adverse reactions.[51]
Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with DNA replication. The other protein synthesis inhibitor antibiotics used today (e.g., tetracyclines, lincomycin, erythromycin, and chloramphenicol) do not interact with components of eukaryotic ribosomal particles and, thus, have not been shown to be toxic to eukaryotes,[52] as opposed to the fluoroquinolone class of drugs. (Selective toxicity) Other drugs used to treat bacterial infections, such as penicillins and cephalosporins, inhibit cell wall biosynthesis, thereby causing bacterial cell death, as opposed to the interference with DNA replication as seen within the fluoroquinolone class of drugs.
Quinolones inhibit the bacterial DNA gyrase or the topoisomerase II enzyme, thereby inhibiting DNA replication and transcription. 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.[53]
Quinolones 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. However, there is debate concerning whether the quinolones still have such an adverse effect on the DNA of healthy cells, in the manner described above, hence contributing to their adverse safety profile. This class has been shown to damage mitochondrial DNA.[54][55][56][57][58][59][60][61]
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[18] and oxidative stress.[62] The severity of oxidative stress generated by fluoroquinolones has been described as 'enormous' by the authors of one research study and they suggested coadministration of antioxidants when using fluoroquinolones to minimise the potential for oxidative-related cellular damage.[63]
Theophylline, nonsteroidal anti-inflammatory drugs and corticosteroids enhance the toxicity of fluoroquinolones.[64][65][66]
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.[67]
Other drugs that interact with fluoroquinolones include antacids, sucralfate, probenecid, cimetidine, warfarin, antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.[66]
Many fluoroquinolones, especially ciprofloxacin, inhibit the cytochrome P450 isoform CYP1A2.[68] This inhibition causes an increased level of, for example, 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).[68]
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.[69] Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.[70]
Fluoroquinolones have been recommended to be reserved for the use in patients who are seriously ill and may soon require immediate hospitalization.[71] 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 has given rise to a breed of super bacteria that are resistant to antibiotics entirely.[72]
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.[17][73] 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.[73][74] In addition, they are commonly prescribed for medical conditions, such as acute respiratory illness, that are usually caused by viral infections.[75]
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.[76]
Three mechanisms of resistance are known.[77] Some types of efflux pumps can act to decrease intracellular quinolone concentration.[78] 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.
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.[79] 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.[50]
Increased hospitalizations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Severe reactions do occur with the fluoroquinolone class and can add significantly to the cost of care. Antibacterial adverse effects account for nearly 25% of all adverse drug reactions among hospitalized patients.[80]
Adverse effects of fluoroquinolones can lead to patients attending hospital emergency rooms. Many of the important adverse effects of fluoroquinolones are widely underappreciated by physicians, and are often misdiagnosed as other medical or psychiatric conditions. Physicians typically fail to enquire about antibiotic use to explain with an acute presentation of new symptoms. The important adverse effects of fluoroquinolones include hypoglycemia or hyperglycemia, QTc prolongation, central nervous system toxicity, gastrointestinal, skin, musculoskeletal, cardiotoxicity, and respiratory effects, phototoxicity, tendinopathy, angioedema, and Clostridium difficile infections. A further factor that leads to misdiagnosis of quinolone adverse effects is some symptoms can persist or occur for the first time quite some time after a course of quinolone has been finished, so inquiring about distant-past use of quinolones has been recommended. Quinolones are probably the worst offending antibiotic for causing C. difficile infections. Some of the adverse effects can present similar to acute dementia, confusion, and psychosis. Quinolones are a common cause of cerebral dysfunction, with neuropsychiatric disturbances being the most common quinolone adverse effects. One study found, of all drug classes prescribed by doctors including psychotropic drugs, fluoroquinolones were the most common cause of neuropsychiatric adverse effects.[81]
Under the George W. Bush administration (2001–2009), patent extension legislation that allowed Bayer AG, as well as other drug companies, a six-month patent extension for testing their products for safety in children was signed into law. It has been estimated that Bayer AG's revenue increased an extra $358 million due to ciprofloxacin's pediatric patent extension. The legislation was drafted after extensive lobbying of numerous members of Congress by Bayer AG and others. One of the four sponsors of this legislation was Chris Dodd (D-CT), who, at the time, ranked as one of the top three beneficiaries of campaign contributions by drug companies. Sen. Edward Kennedy (D-MA), who chaired the committee with jurisdiction over the bill, refused to fight over the language that (if it had been included) would have reduced the drug company's profits due to these patent extensions. The reasons for Sen. Edward Kennedy's decision not to fight for the inclusion of this language were not made known.[82]
The results of these pediatric trials indicated arthropathy occurred more frequently in patients who received ciprofloxacin (within these studies). The affected joints included the knees, elbows, ankles, hips, wrists, and shoulders of the pediatric patients. In one study, at six weeks, arthropathy was seen in 9.3% of ciprofloxacin patients. These rates increased significantly after one year to 13.7% of the ciprofloxacin patients. Such arthropathy occurred more frequently in patients treated with ciprofloxacin than any other control drug, regardless of whether they received IV ciprofloxacin or the oral version of the drug. Ciprofloxacin patients reported more than one event and on more than one occasion when compared to the control patients. The overall incidence of adverse events at six weeks was 41% in those patients being treated with ciprofloxacin. Serious adverse events were seen in 7.5% of these patients and 3% of the patients discontinued the drug due to adverse events. Despite these results the FDA stated "[t]he data support updating the package insert to include safety; and treatment recommendations for pediatric patients between 1 and 17 years of age with complicated urinary tract infection or pyelonephritis."[83]
Within a 2005 memo, the FDA reviewed 17 unique pediatric cases reported to the FDA during the 13-month period after the pediatric exclusivity for ciprofloxacin had been granted. During this period, there was one report of death, two of disability, and four of hospitalization. The disabilities involved the inability to walk (in a 12-year-old female patient) and the inability to run (in a 12-year-old male patient). The hospital admissions were for pseudomembranous colitis, pancytopenia, tendonitis, and Stevens–Johnson syndrome. The female patient received five weeks of ciprofloxacin oral therapy at the recommended doses. Even though ciprofloxacin was discontinued, she could not stand or walk, and required a wheelchair one month later. These 17 unique pediatric cases showed mostly hematological, musculoskeletal, allergic/hypersensitivity, and central nervous system adverse events. It does not appear this executive summary was ever released to the medical community.[84]
The adverse drug reaction profile of ciprofloxacin and other fluoroquinolone drugs has spawned a grass-roots movement of those so affected to lobby for black box warnings and Dear Doctor letters, as well as the petitioning of the FDA for the removal of some fluoroquinolone drugs from clinical practice.[85][86][87][88][89][90][91]
The effectiveness and the proven clinical need for the drugs found within this class have rarely been called into question. They have a proven track record with regard to eradicating bacterial infections and are to be considered an essential tool within the medical community. However, there is controversy concerning the safety profile of quinolones, as well as their proper use.
At present, a significant number of cases are pending before the United States District Court, District of Minnesota, involving the drug Levaquin. On June 13, 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.[37]
Most recently, 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.[92]
Several class action lawsuits had been filed in regards to the adverse reactions suffered by those exposed to ciprofloxacin during the anthrax scare of 2001, as well.
U.S. Boxed Warning: 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.
Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid.[93] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[94] In response to a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."[95]
By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA, prompting the agency to act.[85] Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.[96]
Nine years later, in 2005, the Illinois Attorney General filed a second petition with the FDA again seeking black box warnings and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded it had not yet been able to reach a decision on the matter.[97][98][99] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for black box warnings by filing a third petition requesting such changes be made.[86][97] When the FDA failed to respond to these two petitions as required by law, Public Citizen, in January 2008, filed suit to compel the FDA to respond to their 2006 petition.[100][101] On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients.[102] The package inserts for ciprofloxacin, Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings.[103] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.[104] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.[105] through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.
A review of the FDA website indicated the majority of the generic versions of the fluoroquinolones have not been updated to include this Boxed Warning as of September 2009. In addition, numerous reports claim this information has not been disseminated to pharmacists, the name-brand products continue to contain the previous labels that are absent of this warning, and the Medication Guide has not been made available to pharmicists or physicians for distribution.
In 2011, the FDA has added another boxed warning that 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.[106]
Researchers divide the quinolones into generations based on their antibacterial spectrum.[107][108] 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 May 15, 1998.[109] 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.
The second-generation class is sometimes subdivided into "Class 1" and "Class 2".[111]
Unlike the first- and second-generations, the third-generation is active against streptococci.[111]
Fourth generation fluoroquinolones act at DNA gyrase and topoisomerase IV.[117] This dual action slows development of resistance.
The quinolones have been widely used in agriculture, and several agents having veterinary, but not human, use exist.
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