Pefloxacine 70458-92-3

History

Pefloxacin was developed in 1979 (German Patent Roger Bellon/Dainippon). It was approved in France for human use in 1985.

Licensed uses

Oral and I. V. fluoroquinolones are not licensed for use in children due to the risk of permanent injury to the musculoskeletal system. At least ten cases of arthropathy occurred in pediatric patients receiving fluoroquinolones; seven of these cases involved pefloxacin. Clinical features included joint swelling or pain in one or more joints. Usually the knees were most oftentimes reported. One patient had evidence of significant joint damage to the right hip and both knees. One study that calculated the risk of such injury had stated that such injury occurred more often with Pefloxacin. However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK. Prescribing a fluoroquinolone to treat an unapproved use within the pediatric (as well as the adult population) exposes the treating physician to the risk of being sued for malpractice should the treating physician fail to both warn the patient of this fact, as well as the risks of any adverse drug reactions the patient may experience. Note: Not recommended for the treatment of infections which can be treated by simple and established antibiotics. In the adult population Pefloxacin is generally limited to the treatment of proven serious and life threatening bacterial infections such as:*Uncomplicated gonococcal urethritis in males. *Bacterial infections in the gastrointestinal system. Pefloxacin has been increasingly used as a veterinary medicine to treat microbial infections. Antibiotics such as Pefloxacin do not improve sinusitis symptoms. When prescribed for Community Acquired Pneumonia, Chronic Bronchitis, and Acute Bacterial Sinusitis the use of the fluoroquinolone class offers no compelling advantages over established treatment Nor does antibiotic treatment help sore throats. The use of antibiotics such as Pefloxacin to treat bronchitis is to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction. Antibiotics' futility against bronchitis had been confirmed in 2002. Since Streptococci and Pneumococci show only intermediate susceptibility to pefloxacin, the drug should not be prescribed as 1st-line treatment in respiratory tract infections, when bacteriological examination has not been carried out. Additionally Pefloxacin and other fluoroquinolones have no effect upon viral infections such as the common head cold. NOTE: Pefloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

Availability

Pefloxacin is available as:*Tablet; Oral Multiple Strengths Prescription *Injectable; Injection Multiple Strengths Prescription *Solution; Oral Prescription See the latest package insert for pefloxacin for additional details.

Trade names

Trade names are being redirected to this article.

Mode of action

Pefloxacin is a broad-spectrum antibiotic that is active against bothGram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, which is an enzyme necessary to separate, replicated DNA, thereby inhibiting cell division. *Mechanism of action:The bactericidal action of pefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited. The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al. ) Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei. As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells. There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non abating adverse reactions experienced by some patients following fluoroquinolone therapy.

Contraindications

*Hypersensitivity (allergy) to pefloxacin or to one of its components or to another member of the quinolones. *Known deficiency in glucose-6 phosphate dehydogenase (a blood red cells enzyme). *Due to growing prevalence of antibiotic resistance to the fluoroquinolones in Southeast Asia, the use of pefloxacin in patients who have been to Southeast Asia is increasingly being contraindicated. *Pefloxacin is also considered to be contraindicated within the pediatric population (due to the risk of arthropathies), pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders. *Precautions::Coadministration of Pefloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug. :Patients should be warned to avoid exposure to direct sunlight or UV light during treatment and until 36 hours after the discontinuation of treatment, because of the risk of phototoxicity reactions (allergic skin rashes). :Tendinitis (inflammation of tendon) may occur and can lead to tendon rupture, particularly in the Achilles tendon and more frequently in elderly patients. Age, past history of tendinitis, vigorous physical exercise and long-term corticoid treatment may predispose a patient to tendinitis and tendon rupture. Therefore, as soon as the treatment with pefloxacin is initiated, it is recommended to look for pain or edema at the level of Achilles tendon, particularly in patients at risk. If such signs are identified therapy should be discontinued immediately. :In patients with a past history of convulsions or with risk factors of convulsions pefloxacin should be used with caution. :In case of myasthenia pefloxacin should be used with caution in these patients. *Pregnancy The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason the Fluroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The Flouroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class. *Pediatric population Fluoroquinolones are not licensed for use in children due to the risk of fatalities as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed in the United States for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure) and Levofloxacin was recently licensed for the treatment of Inhalational Anthrax (post-exposure). However, the Fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK. At least ten cases of arthropathy occurred in pediatric patients receiving fluoroquinolones; seven of these cases involved pefloxacin. Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9. 3%. Pefloxacin is well known to be associated with high incidence of arthropathy in humans because the drug affects articular cartilage and the epiphyseal growth plate. The importance of this toxicity is that it is irreversible and manifest later after the drug is discontinued. Musculoskeletal events tended to be more frequent with pefloxacin. 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. The serious events may occur with therapeutic or with acute overdose. At therapeutic doses they include central nervous system toxicity, cardiovascular toxicity, tendon/ articular toxicity, and rarely hepatic toxicity. Events that may occur in acute overdose are rare and include renal failure and seizure. Adverse reactions may manifest during, as well as after fluoroquinolone therapy. Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people 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 legal action by the consumer advocate group Public Citizen. *Irreversible peripheral neuropathy has been associated with Pefloxacin. Pefloxacin is also reported to be the most potent inducer of photosensitivity in the ultraviolet A(UVA) range, with a higher incidence of skin rash and photosensitization than other quinolones. *Pefloxacin has been associated with thrombocytopenia, which appears to be dose related. *Pefloxacin has also associated with ocular damage when given to animals in high dosages. Manifestations included cataracts, multiple punctate lenticular opacities, retinal morphologic changes, and altered visual acuity. Tendinitis and rupture, usually of the Achilles tendon, are a class-effects of the fluoroquinolones, most frequently reported with pefloxacin. The estimated risk of tendon damage during pefloxacin therapy has been estimated by the French authorities in 2000 to be 1 case per 23,130 treatment days as compared to ciprofloxacin where it has been estimated to be 1 case per 779,600. As early as 1996 E, Voisin MC et al.

Overdose

In the event of acute overdosage, the patient should be kept under close medical supervision and given supportive treatment. Hemodialysis is not effective.

Pharmacology

*Chemical name:1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acidFormula:C17H20FN3O3Pharmacology:Pefloxacin is a fluoroquinolone antibiotic. Flouroquinolones such as pefloxacin possess excellent activity against gram-negative aerobic bacteria such as E. coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also possess effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. Half life:8. 6 hours Unchanged pefloxacin and its metabolites may be identified in the urine 84 hours after the intake of the product. In elderly, in comparison with younger patients, the plasma clearance and the apparent volume of distribution are decreased approximately by 50%However, the drug is also metabolized and partially cleared through the liver and the intestine. Modification of the dosage is recommended using the table found within the package insert for those with impaired liver or kidney function. (Particularly for patients with severe renal dysfunction. ) However, since the drug is known to be partially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Recommended Doseage:400 mg p. o. BID or QDInjectable; Injection; Pefloxacin Mesylate Dihydrate 400 mg / 5 ml Tablet, Film-Coated; Oral; Pefloxacin Mesylate Dihydrate 400 mgOral Tablets: 400 mg Twice dailyInjection: Administer by slow I. V. at a dosage of 400 mg diluted in 100 or 250 ml of 5% isotonic solution (Over a period of 1 hr) Twice daily.

Susceptible bacteria

*Bordetella pertussis*Campylobacter spp. *Escherichia coli*Haemophilus influenzae*Klebsiella oxytoca*Legionella spp. *Mobiluncus spp. *Moraxella (Branhamella ) catarrhalis *Morganella morganii *Neisseria spp. *Mycoplasma hominis *Pasteurella spp. *Propionibacterium acnes *Proteus vulgaris*Salmonella spp. *Shigella spp. *Methicillin-susceptible staphylococci *Vibrio spp. *Yersinia spp.

Current litigation

There are a significant number of cases currently pending before the United States District Court, District of Minnesota, involving one of the drugs found within the fluoroquinolone class; Levaquin (levofloxacin). 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 well as most recently, a class action lawsuit involving a third fluoroquinolone; Tequin (gatifloxacin). Currently there does not appear to be any class action lawsuits pending that involve pefloxacin, but there are a significant number of law firms aggressively seeking to represent patients who have suffered a spontaneous tendon rupture, or liver injury, following fluoroquinolone therapy.

Regulatory history

Pefloxacin has not been approved for use in the United States, hence there is no FDA regulator history to refer to. However pefloxacin is categorized under the following by the FDA: Anti-Infectives; ATC:J01MA03. In 2008 the FDA manadated a Black Box Warning be added to all fluoroquinolone drugs in reference to the potential for severe adverse reactions resulting in spontaneous tendon ruptures. In 2008 the National Pharmaceutical Control Bureau, Ministry of Health Malaysia required the addition of stronger warnings concerning the tendon issues. The DCA had decided that all drugs found within the fluoroquinolone class must have the following statement in the section “Special Warnings and Precautions for Use” of the package inserts:Musculo-skeletal system:“The risk of developing fluoroquinolone-associated tendonitis and tendon rupture is further increased in people older than 60, in those taking corticosteroid drugs, and in kidney, heart, and lung transplantrecipients. Patients experiencing pain, swelling, inflammation of a tendon or tendon rupture should be advised to stop taking their fluoroquinolone medication (to specify the active ingredient) and to contact their healthcare professional promptly about changing their antimicrobial therapy. Patients should also avoid exercise and using the affected area at the first sign of tendon pain, swelling, or inflammation”

History of the Black Box Warnings

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid. Rheumatic disease after use of a fluoroquinolone was first reported eleven years later. In 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. "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. In 2005, the Illinois Attorney General filed a petition with the FDA 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. The package inserts for Cipro , Avelox , Proquin XR, Factive , Floxin , Noroxin and Levaquin were amended on September 8, 2008 to include these new warnings. Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes. Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November. through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals. Review of the FDA website indicates that the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of April 2009. And there are numerous reports that this information has not been dessiminated to the pharmacist, the 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.

Antibiotic misuse and bacterial resistance

{{See also Antibiotic misuse Antibiotic resistance