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Quinolone

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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

The quinolones also referred to as fluoroquinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone(s) refers to potent synthetic chemotherapeutic antibacterials[1][2] the first generation of which was derived from an attempt to create a synthetic form of chloroquine, which was used to treat malaria during World War II. Hans Andersag discovered chloroquine, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. 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] Recent evidence has shown that 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.[6]

Quinolones in comparison to other antibiotic classes have the highest risk of causing colonisation with MRSA and C Difficile. A general avoidance of fluoroquinolones is recommended based on the available evidence and clinical guidelines.[7][8][9] The parent of the quinolone (aka fluoroquinolone) class is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7 position.

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.[10] Though it is generally accepted that nalidixic acid is to be considered the first quinolone drug, this has been disputed over the years by a few researchers who believe that chloroquine, from which nalidixic acid is derived, is to be considered the first quinolone drug rather than nalidixic acid.

This class of synthetic chemotherapeutic agents has a broad spectrum of antimicrobial activity as well as a unique mechanism of action resulting in inhibition of bacterial DNA gyrase and topoisomerase IV. However there is considerable concern that this affects the DNA of healthy cells as well.[11][12][13][14][15][16][17][18]

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.[19]

Indications

The effectiveness of fluoroquinolones for the treatment of respiratory disorders is similar to other antibiotic classes.[20][21]

Fluoroquinolone use for pneumonia is increasing and with it so is bacterial resistance to fluoroquinolones. The majority of the prescribing of fluoroquinolones is inappropriate with less than 4 percent of people prescribed quinolones being appropriate according to clinical guidelines. Clinical guidelines in Canada only recommend fluoroquinolones for outpatient treatment of pneumonia in a small number of patients such as those with certain co-morbid conditions such as patients with a history of COPD, or recent use of antibiotics.[22] For severe forms of community-acquired pneumonia the fluoroquinolones are associated with improved treatment rates, but with no differences found in mortality between other antibiotic classes.[23]

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.[21][24]

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.[25]

Fluoroquinolones are often used for genitourinary infections; in general they are recommended only after other antibiotic regimes 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.[26] Prostatitis has been termed "the waste basket of clinical ignorance" by prominent Stanford University Urologist Dr. Thomas Stamey. 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 don't actually have any identifiable bacterial infection.[27]

The American Thoracic Society recommends that fluoroquinolones are not used as a first line agent, instead recommending macrolide or doxycycline as first line agents. The Drug-Resistant Streptococcus pneumoniae Working Group recommends fluoroquinolones are only used after other antibiotic classes have been tried and failed or in those with demonstrated drug-resistant Streptococcus pneumoniae. The Center for Disease Control are concerned that 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.[28]

Adverse effects

See also: Adverse effects of fluoroquinolones

Fluoroquinolones are generally well tolerated with most side effects being mild to moderate. Occasionally serious adverse effects occur.[29][30] Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity.[31][32] The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes.[31] Fluoroquinolones are sometimes associated with an QTc interva prolongation and cardiac arrhythmias.[33]

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,[34] and gatofloxacin has been most frequently linked to disturbed blood sugar levels, although all quinolones carry these risks.[35][36] 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).[37] Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.[38] The risk of adverse events is further increased if the dosage is not properly adjusted, for example if there is renal insufficiency.[35]

The serious events may occur during therapeutic use at therapeutic dose levels or with acute overdose. At therapeutic doses they include: central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and rarely hepatic toxicity.[39] Caution is required in patients with liver disease.[40] Events that may occur in acute overdose are rare and include: renal failure and seizure.[39] Susceptible groups of patients such as children and the elderly are at greater risk of adverse reactions during therapeutic use.[31][32] Adverse reactions may manifest during, as well as after fluoroquinolone therapy has been completed.[41]

Fluoroquinolones are considered high risk antibiotics for the development of C Difficile and MRSA infections.[42][7] A previoualy rare strain of C Difficile which produces a more severe disease with increased levels of C Difficile toxins is becoming epidemic, may be connected to the use of fluoroquinolones.[43] Fluoroquinolones are more strongly associated with C difficile infections than other antibiotics including clindamycin, 3rd generation cephalosporins beta latamase inhibitors. One study found that fluoroquinolones were responsible for 55% of C difficile infections.[44] The European Center for Disease Prevention and Control recommend that fluoroquinolones and the antibiotic clindamycin are avoided in clinical practice due to their high association with clostridium difficile, a potentially life-threatening super-infection.[45]

The central nervous system is an important target for fluoroquinolone mediated neurotoxicity. Adverse event reporting in Italy by doctors showed fluoroquinolones among the top 3 prescribed drugs for causing adverse neurological and psychiatric adverse effects. These neuropsychiatric effects included tremor, confusion, anxiety, insomnia, agitation and in severe cases psychosis. Moxifloxacin came out worst amongst the quinolones for causing CNS toxicity.[46] 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 people harmed by the use of fluoroquinolones as well as action by the consumer advocate group Public Citizen.[47][48] Partly as a result of the efforts of Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[49]

Contraindications

Quinolones are contraindicated if a patient has epilepsy, QT Prolongation, pre-existing CNS lesions, CNS inflammation or those who have suffered a stroke.[29]

Black box warnings

Black Box 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 who 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.[50] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[51] 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 that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."[52]

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.[53] 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.[54]

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 that it had not yet been able to reach a decision on the matter.[55][56][57] 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.[55][58] 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.[59][60] 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.[61] 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.[62] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.[63] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.[64] through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

A review of the FDA website indicates that the majority of the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of September 2009. Additionally there are numerous reports that this information has not been dessiminated to the pharmacist, 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 the pharmicist or physician for distribution.

Pharmacology

The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system.[65] The addition of the fluorine atom at C6 is what distinguishes the successive generations, fluoroquinolones, from the first generation, quinolones. It has since been demonstrated that the addition of the C6 fluorine atom is not a necessary requirement for the antibacterial activity of this class (circa 1997).[66]

Various substitutions made to the quinoline ring resulted in the development of numerous fluoroquinolone drugs that we see today. Each substitution is associated with a number of specific adverse reactions, as well as increased activity against bacterial infections,[19] where as the quinoline ring, in and of itself, has been associated with severe and even fatal adverse reactions.[67]

Mechanism

Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with DNA replication. The other antibiotics used today, (e.g., tetracyclines, lincomycin, erythromycin, and chloramphenicol) do not interact with components of eukaryotic ribosomal particle and thus have proven not to be toxic to eukaryotes,[68] as opposed to the fluoroquinolone class of drugs. Safer 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 IV enzyme, thereby inhibiting DNA replication and transcription. 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. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV. However, there is considerable 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 rather bizarre adverse safety profile. This class has been shown to damage mitochondrial DNA.[11]

Interactions

Caffeine, Theophylline, non-steroidal anti-inflammatory drugs and corticosteroids enhance the toxicity of fluoroquinolones.[69][70][71]

Other drugs that interact with fluoroquinolones include Antacids, Sucralfate, Probenecid, Cimetidine, Warfarin, Antiviral agents, Phenytoin, Cyclosporine, Rifampin, Pyrazinamide, and Cycloserine.[71]

Antibiotic misuse and bacterial resistance

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.[72] Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.[73]

Fluoroquinolones have been recommended to be reserved for the use in patients who are seriously ill and may soon require immediate hospitalization.[74] Though considered to be a 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 which are resistant to antibiotics entirely.[75]

For example the use of the fluoroquinolones had increased three-fold in an emergency room environment in the United States between 1995 and 2002, while the use of safer alternatives such as macrolides declined significantly.[28][76] 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 that was supported in part by the Agency for Healthcare Research and Quality.[77][76] Additionally they are commonly prescribed for medical conditions such as acute respiratory illness which is usually caused by viral infections.[78]

Within a recent study concerning the proper use of this class in the emergency room it was revealed that 99% of these prescriptions were in error. Out of the one hundred total patients studied, eighty one received a fluoroquinolone for an inappropriate indication. Out of these cases, forty three (53%) were judged to be inappropriate because another agent was considered first line, twenty seven (33%) because there was no evidence of a bacterial infection to begin with (based on the documented evaluation), and eleven (14%) because of the need for such therapy was questionable. Out of the nineteen patients who received a fluoroquinolone for an appropriate indication, only one patient out of one hundred received both the correct dose and duration of therapy.[79]

There are three known mechanisms of resistance.[80] Some types of efflux pumps can act to decrease intracellular quinolone concentration. 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 drug's effectiveness.

Social and economic impact

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 amongst hospitalized patients.[81]

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 which leads to misdiagnosis of quinolone adverse effects is that 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 that of all drug classes prescribed by doctors including psychotropic drugs fluoroquinolones were the most common cause of neuropsychiatric adverse effects.[82]

Patent extensions

Under the George W. Bush administration (2001–2008) patent extension legislation was signed into law that allowed Bayer AG, as well as other drug companies, a six month patent extension for testing their products for safety in children. It has been estimated that Bayer A.G.'s revenue increased an extra $358 million due to ciprofloxacin's pediatric patent extension. The legislation that was signed by President George W Bush, granting Bayer and other drug manufacturers a six month extension on their patents (to conduct pediatric testing), was drafted after extensive lobbying of numerous members of Congress by Bayer A.G. 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-Mass.), 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 to not fight for the inclusion of this language were not made known.[83]

The results of these pediatric trials indicated that 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 that “The 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.”[84]

Within a 2005 memo the FDA reviewed seventeen unique pediatric cases reported to the FDA during the thirteen month period after the pediatric exclusivity for ciprofloxacin had been granted. During this period there was one death, two reports of disability and four of hospitalization. The disabilities involved the inability to walk (in a 12-year 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 5 weeks of ciprofloxacin oral therapy at the recommended doses. Even though ciprofloxacin was discontinued, she could not stand or ambulate and required a wheelchair one month later. These seventeen unique pediatric cases showed mostly hematological, musculoskeletal, allergic/hypersensitivity, and central nervous system adverse events. It does not appear that this executive summary was ever released to the medical community.[85]

  • Economic impact: adverse reactions:

The adverse drug reaction profile of ciprofloxacin and other fluoroquinolone drugs has spawned a grass root 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.[86][87][88][89][90][91][92]

Current litigation

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 in regards 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.

Currently there are a significant number of cases 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.[48]

Most recently on July 6, 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 that the drug has caused Achilles tendon ruptures and other permanent damage.[93]

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.

Generations

The quinolones are divided into generations based on their antibacterial spectrum.[94][95] The earlier generation agents are, in general, more narrow spectrum than the later ones. Generally the quinolones are grouped by generations by researchers. But there is no standard 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 there exist a wide variation within the literature dependant upon the methods employed by the authors. Some researchers group these drugs by patent dates, some by a specific decade (i.e. 60’s 70’s 80’s etc.) and others by the various structural changes.

The first generation is rarely used today. Nalidixic acid was added to the OEHHA Prop 65 list as a carcinogen on May 15, 1998.[96] A number of the 2nd, 3rd and 4th 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.

1st generation

  • cinoxacin (Cinobac) (Removed from clinical use)[97]
  • flumequine (Flubactin) (Genotoxic carcinogen)(Veterinary use)
  • nalidixic acid (NegGam, Wintomylon)[97] (Genotoxic carcinogen)
  • oxolinic acid (Uroxin) (Currently unavailable in the United States)
  • piromidic acid (Panacid) (Currently unavailable in the United States)
  • pipemidic acid (Dolcol) (Currently unavailable in the United States)
  • rosoxacin (Eradacil) (Restricted use, currently unavailable in the United States)

2nd generation

The 2nd generation class is sometimes subdivided into "Class 1" and "Class 2".[98]

3rd generation

Unlike the first and second generation, the third generation is active against streptococci.[98]

4th generation

In development

Veterinary use

The quinolones have been widely used in agriculture and several agents exist which have veterinary but not human use.

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