Pefloxacin

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Pefloxacin
Pefloxacin.svg
Systematic (IUPAC) name
1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-quinoline-3-carboxylic acid
Clinical data
Legal status ?
Pharmacokinetic data
Bioavailability 100%
Protein binding 20–30%
Metabolism Hepatic
Half-life 8.6 hours
Excretion Mostly renal, also biliary
Identifiers
CAS number 70458-92-3 YesY
ATC code J01MA03
PubChem CID 51081
DrugBank DB00487
ChemSpider 46291 YesY
UNII 2H52Z9F2Q5 YesY
KEGG D02306 YesY
ChEBI CHEBI:50199 YesY
ChEMBL CHEMBL267648 YesY
Chemical data
Formula C17H20FN3O3 
Mol. mass 333.358 g/mol
 YesY (what is this?)  (verify)

Pefloxacin is a synthetic chemotherapeutic agent used to treat bacterial infections. Pefloxacin is commonly referred to as a fluoroquinolone (or quinolone) drug and is a member of the fluoroquinolone class of antibacterials. It is an analog of norfloxacin. It is a synthetic fluoroquinolone, belonging to the 3rd generation of quinolones. Pefloxacin is extensively prescribed in France.[1] Pefloxacin has not been approved for use in the United States.

There are no licensed uses for pefloxacin in the United States, as the FDA has not approved this drug.

History[edit]

Pefloxacin was developed in 1979 (German Patent Roger Bellon/Dainippon). It was approved in France for human use in 1985.[2]

Licensed uses[edit]

  • Uncomplicated gonococcal urethritis in males.[3]
  • Bacterial infections in the gastrointestinal system.[3]
  • Genitourinary tract infections.[3]
  • Lower respiratory tract
  • Bone and joint infections
  • Renal and abdominal infections
  • Infections of skin and soft tissues
  • Gonorrhoeae. however this indication is no longer effective due to bacterial resistance.[4]

Pefloxacin has been increasingly used as a veterinary medicine to treat microbial infections.[5]

Availability[edit]

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.

Mode of action[edit]

Pefloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,[6] 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.[7]

Contraindications[edit]

  • 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).
  • 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.[8][9]

  • Pediatric population

Fluoroquinolones are not licensed for use in children due to the risk of 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.[10] Clinical features included joint swelling or pain in one or more joints. Usually the knees were most often reported. One patient had evidence of significant joint damage to the right hip and both knees.[10][11] One study that calculated the risk of such injury had stated that such injury occurred more often with Pefloxacin.[12] Within another study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event.[13]

Pefloxacin is 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.[14] Musculoskeletal events tended to be more frequent with pefloxacin.[15][16]

Adverse effects[edit]

Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects occurring rarely.[17][18] Some of the serious adverse effects, which occur more commonly with fluoroquinolones than with other antibiotic drug classes, include CNS and tendon toxicity.[17] Rare adverse reactions include psychosis and chorea (involuntary muscle movements).[19][20] [21] The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes.[17] Phototoxicity, neurological symptoms, impaired colour vision, exanthema, abdominal pain, malaise, drug fever, peripheral neuropathy, dysaesthesia and eosinophilia have been observed as adverse effects of Pefloxacin.[22] [23][24] [25] [16][26]

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.[27] Events that may occur in acute overdose are rare and include renal failure and seizure.[27] Children and the elderly are at greater risk.[17][28] Adverse reactions may manifest during, as well as after fluoroquinolone therapy.[29]

  • Irreversible peripheral neuropathy has been associated with Pefloxacin.[24][25]
  • Phototoxic adverse events are also noted for pefloxacin.[30]

[31]

Tendinitis and rupture, usually of the Achilles tendon, are a class-effects of the fluoroquinolones, most frequently reported with pefloxacin.[18][32] 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.[33]

Interactions[edit]

Pefloxacin absorption is influenced by antacid containing aluminium or magnesium hydroxide. Fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, inhibit the metabolic clearance of theophylline and caffeine.[34]

Significant drug interactions[edit]

Given concomitantly, Pefloxacin with theophylline may increase theophylline plasma concentrations. It is recommended to monitor theophylline plasma levels, if necessary, the dose of theophylline should be reduced.[35]

Cimetidine reduces the metabolic clearance of pefloxacin. [34]

Overdose[edit]

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

Pharmacology[edit]

  • Chemical name:

1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Formula: C17H20FN3O3 Pharmacology: 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%[7]

  • Elimination half life is 11–12 hours mainly through metabolites
  • Pefloxacin is metabolized in the liver (85%-90%)
  • Major route of elimination is renal – 9-16% of the drugs is eliminated unchanged. Limited excretion via bile
  • Major metabolites constitute up to 84% of drugs recovered in urine

Pharmacokinetics[edit]

  • Biotransformation:

Cytochrome P450 1A2 (CYP1A2) Hepatic metabolism is considerable. The main metabolites are demethylated pefloxacin, norfloxacin and pefloxacin N-oxide.[7]

  • There are marked changes in pharmacokinetics in patients with hepatic impairment. Careful monitoring of plasma levels together with appropriate dosage adjustment will be necessary.

Dosing[edit]

Pefloxacin should only be administered as described within the Dosage Guidelines table found within the most current package insert. The status of the patient’s renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. Pefloxacin is eliminated partially through renal excretion.[36] 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 Dosage: 400 mg p.o. BID or QD Injectable; Injection; Pefloxacin Mesylate Dihydrate 400 mg / 5 ml Tablet, Film-Coated; Oral; Pefloxacin Mesylate Dihydrate 400 mg Oral Tablets: 400 mg Twice daily Injection: 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.[37]

Susceptible bacteria[edit]

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 transplant recipients. 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[38]


Antibiotic misuse and bacterial resistance[edit]

Resistance to pefloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[39] Widespread veterinary usage of the fluoroquinolones, in particular over in Europe, has been implicated.[40]

For example the use of the fuoroquinolones 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.[41][42]

There are three known mechanisms of resistance.[43] 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.

Package insert links[edit]

References[edit]

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  29. ^ Saint F, Gueguen G, Biserte J, Fontaine C, Mazeman E (September 2000). "[Rupture of the patellar ligament one month after treatment with fluoroquinolone]". Rev Chir Orthop Reparatrice Appar Mot (in French) 86 (5): 495–7. PMID 10970974. 
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  38. ^ http://www.cornerstone-msc.net/bpfk/aeimages//File/ADR_newsletter/200812.pdf See page 6 of this newsletter
  39. ^ M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on Antimicrobial Agents and Resistance 2005.
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External links[edit]