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Quinolone
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The quinolones are a family of synthetic broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluorine atom attached the central ring system, typically at the 6-position.
The term Quinolone(s) refers to the first generation of the potent and toxic synthetic chemotherapuetic agents derived from Chloroquine used to treat serious, complicated and life threatening bacterial infections.
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The quinolones are a family of synthetic broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluorine atom attached the central ring system, typically at the 6-position.
The term Quinolone(s) refers to the first generation of the potent and toxic synthetic chemotherapuetic agents derived from Chloroquine used to treat serious, complicated and life threatening bacterial infections. 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 kidney infections in humans. This drug was discovered by George Lesher and coworkers in a distillate during chloroquine synthesis.
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.
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 chemotherapuetic 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.
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.
Pharmacology
The pharmcore of the quinolone class is based upon the quinoline ring. 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).
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, where as the quinoline ring, in and of itself, has been associated with severe and even fatal adverse reactions.
Mechanism
Quinolones and fluoroquinolones are chemotherapuetic 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, as opposed to the fluoroquinolone class of drugs. Safer drugs used to treat bacterial infections, such as penicillins and cephalosporins, inhibit protein synthesis 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.
Adverse effects
Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects being rarely. Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity. The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes. Fluoroquinolones are sometimes associated with an QTc interval prolongation and cardiac arrhythmias.
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, and gatofloxacin has been most frequently linked to disturbed blood sugar levels, although all quinolones carry these risks.
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).
Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture. The risk of adverse events is further increased if the dosage is not properly adjusted, for example if there is renal insufficiency.
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. Caution is required in patients with liver disease. Events that may occur in acute overdose are rare and include: renal failure and seizure. Susceptible groups of patients such as children and the elderly are at greater risk of adverse reactions during therapeutic use. Adverse reactions may manifest during, as well as after fluoroquinolone therapy.
Some 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. 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.
Contraindications
Quinolones are contraindicated if a patient has epilepsy, preexisting CNS lesions, CNS inflammation or stroke those who have suffered a stroke.
Interactions
Caffeine, Theophylline, nonsteroidal antiinflamatory drugs, and corticosteroids enhance the toxicity of fluoroquinolones.
Other drugs that interact with fluoroquinolones include Antacids, Sucralfate, Probenecid, Cimetidine, Warfarin, Antiviral agents, Phenytoin, Cyclosporine, Rifampin, Pyrazinamide, and Cycloserine.
Scripting Abuse and Bacterial 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. Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.
It should be reserved for the use in patients who are seriously ill and may soon require immediate hospitalization. Though considered to be a very important and necessary drug required to treat severe and life threatening bacterial infections, the associated scripting abuse 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.
Many researchers believe this to be the direct result of the aggressive and unethical manner in which these drugs have been promoted by the various manufacturers over the years, (both for licensed as well as unlicensed and unapproved uses), combined with their improper use by the treating physicians.
For example the use of the fuoroquinolones 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.
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.. Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin, with such as viral infections, or those to which no proven benefit exist.
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.
There are three known mechanisms of resistance. 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.
Current Litigation involving this class
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 this class, as well as their proper use. (See bacterial resistance)
Currently there are a significant number of cases currently 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.
As a result of this order, product liability attorneys are currently aggressively seeking additional plaintiffs who may have been damaged by this class.
Generations
The quinolones are divided into generations based on their antibacterial spectrum. 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 (Cancer causing agent) May 15, 1998. 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)
- flumequine (Flubactin) (Genotoxic carcinogen)(Veterinary use)
- nalidixic acid (NegGam, Wintomylon) (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".
- ciprofloxacin (Ciprobay, Cipro, Ciproxin)
- enoxacin (Enroxil, Penetrex) (Removed from clinical use)
- fleroxacin (Megalone, Roquinol) (Removed from clinical use)
- lomefloxacin (Maxaquin)
- nadifloxacin (Acuatim, Nadoxin, Nadixa)
- norfloxacin (Lexinor, Noroxin, Quinabic, Janacin)(restricted use)
- ofloxacin (Floxin, Oxaldin, Tarivid)
- pefloxacin (Peflacine) (Currently unavailable in the United States)
- rufloxacin (Uroflox) (Currently unavailable in the United States)
3rd generation
Unlike the first and second generation, the third generation is active against streptococci.
- balofloxacin (Baloxin) (Currently unavailable in the United States)
- gatifloxacin (Tequin) (Zymar) (removed from clinical use) Sometimes reported as 4th generation.
- grepafloxacin (Raxar) (Removed from clinical use)
- levofloxacin (Cravit, Levaquin)
- moxifloxacin (Avelox,Vigamox)(restricted use). Sometimes reported as 4th generation.
- pazufloxacin (Pasil, Pazucross) (Currently unavailable in the United States)
- sparfloxacin (Zagam)(restricted use),
- temafloxacin (Omniflox) (Removed from clinical use)
- tosufloxacin (Ozex, Tosacin) (Currently unavailable in the United States)
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.
External links
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- from the U.S. Food and Drug Administration
- "Family Practice Notebook" entry page for Fluoroquinolones
- "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD
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