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Pefloxacin is a fluorinated quinolone that is structurally related to nalidixic acid. It can be administered both orally and intravenously, and has a broad spectrum of in vitro activity against Gram-negative organisms and staphylococci. The pharmacokinetic profile of pefloxacin is characterised by high bioavailability after oral administration, a long half-life and good penetration of tissue and body fluids.
Data from mainly non-comparative studies suggest that pefloxacin has the potential for use in a variety of serious or difficult-to-treat and nosocomially acquired infections in hospitalised and immunocompromised patients. Such infections have included respiratory tract, urogenital tract, and bone and joint infections, septicaemia and surgical infections, in addition to severe Gram-negative infections in neutropenic cancer patients. Pefloxacin demonstrates comparable efficacy with ampicillin combined with gentamicin in upper gynaecological tract infections, ceftazidime in nosocomially acquired Gram-negative infections and co-trimoxazole (trimethoprim + sulphamethoxazole) in uncomplicated urinary tract infections and typhoid fever.
Although the place of pefloxacin in this new and expanding class of 4-quinolone antibacterial drugs has yet to be defined and it appears to be a well-tolerated and useful drug for the treatment of serious infections in hospitalised patients, further studies are awaited with interest for confirmation of these preliminary results.
Pefloxacin is a fluorinated quinolone which is structurally related to nalidixic acid. Most species of Enterobacteriaceae are susceptible or moderately susceptible to pefloxacin (MIC90 ≤ 2 mg/L); Providencia rettgeri is only moderately susceptible to the drug. For most species of Enterobacteriaceae the potency of pefloxacin was equivalent to that of enoxacin, ofloxacin, norfloxacin and cefotaxime, less than that of ciprofloxacin, and greater than that of nalidixic acid, ampicillin, amikacin, gentamicin and ceftazidime. Pefloxacin is a potent inhibitor of Neisseria gonorrhoeae and N. meningitidis, while strains of Acinetobacter are susceptible or moderately susceptible to the drug. Branhamella catarrhalis and Campylobacter species are susceptible or moderately susceptible to pefloxacin as well as to the other 4-quinolones tested. Haemophilus ducreyi is highly susceptible (MIC90 ≤ 0.12 mg/L) while H. influenzae is susceptible to pefloxacin. The activity of pefloxacin against Pseudomonas aeruginosa (MIC90 2 to 16 mg/L) is similar to that of enoxacin and norfloxacin, but less than that of ciprofloxacin and ofloxacin. For other species of Pseudomonas the susceptibility to pefloxacin is variable, with MIC90 values ranging from 1 to 64 mg/L. Other Gram-negative species including Aeromonas hydrophila, Legionella, Plesiomonas, Capnocytophaga, Agrobacter and Vibrio species are susceptible to pefloxacin, but Gardnerella vaginalis is resistant.
Staphylococcal strains, including Staphylococcus epidermidis and isolates of Staphylococcus aureus resistant to other antibacterials, are susceptible or moderately susceptible to pefloxacin, but there is an increasing percentage of resistant strains emerging. Streptococcus species including enterococci have only moderate sensitivity to pefloxacin, with MIC90 values ranging from 3.1 to 32 mg/L. Other Gram-positive species such as Listeria monocytogenes and Nocardia asteroides are resistant, whereas Mycobacterium tuberculosis and some other species of mycobacteria are usually only moderately susceptible to pefloxacin. Pefloxacin is inactive against most anaerobic species, including Bacteroides, Clostridium and Fusobacterium.
Pefloxacin is not active against Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum, with MIC90 values of 2 to 8, 16 and 2 to 8 mg/L, respectively; ofloxacin and ciprofloxacin are generally more active than pefloxacin in inhibiting these species.
Bacterial resistance to non-quinolone drugs such as penicillin, oxacillin and methicillin has little influence on the in vitro activity of pefloxacin but there is cross resistance, as shown using nalidixic acid-resistant isolates. Inoculum size has only a minor influence on the in vitro activity of pefloxacin but acidic pH and addition of calcium or magnesium ions has been shown to reduce its activity. Pefloxacin is rapidly bactericidal and has shown no synergistic in vitro effects in combination with other antibacterials, including cephalosporins and aminoglycosides, against Gram-negative and Gram-positive isolates. Amikacin, ceftazidime and piperacillin prevented the emergence of resistance to pefloxacin. Pefloxacin inhibits DNA gyrase activity, preventing the supercoiling of DNA and so interfering with bacterial replication, but alternative mechanisms of action such as the capacity to penetrate the bacterial membrane probably also contribute to its antibacterial effects.
Pefloxacin was shown to have good in vivo activity against S. aureus infections in mice, P. aeruginosa infections in neutropenic guinea-pigs, Escherichia coli-induced endocarditis, mice infected with Mycobacterium leprae and guinea-pig legionellosis.
After administration of single oral doses of pefloxacin 400mg, to healthy volunteers, maximum plasma concentrations of 3.84 to 6.6 mg/L occur within 60 to 90 minutes. In a multiple-dose study both intravenous and oral routes of administration of pefloxacin 400mg produced approximate maximum plasma concentrations of 10 mg/L and AUC values were similar after both routes, indicative of complete bioavailability. Steady-state concentrations were achieved within 48 hours. Plasma trough concentrations 2 to 3 days after the start of multiple-dose 400mg administration were 2.1 to 3.8 mg/L, which are higher than the MIC90s for the majority of susceptible pathogens.
The volume of distribution has been calculated to range from 1.7 to 1.9 L/kg. Tissue pefloxacin concentrations are equivalent or higher than plasma concentrations for blister fluid, bone, brain, cardiac tissue, cerebrospinal fluid, prostate, saliva and sputum. Pefloxacin effectively penetrates extravascular spaces and is only 20 to 30% protein bound.
Pefloxacin is metabolised extensively to form the principal N-demethyl pefloxacin (norfloxacin) and N-oxide metabolites. Following single-dose administration of radiolabelled pefloxacin 70% and 25% of radioactivity was detected in urine and faeces, respectively, within 7 days. Only 8 to 9% of an administered dose appears in the urine as unchanged pefloxacin. Total urinary recovery of parent drug and metabolites was 59% of an administered dose, and renal clearance was 0.6 L/h and was independent of the route of administration. In addition, biliary excretion of pefloxacin and its metabolites also occurs. The elimination half-life following administration of single oral doses of pefloxacin 400mg ranged from 8.6 to 13 hours, increasing to approximately 14 to 15 hours after multiple dosing. In patients with impaired hepatic function plasma clearance of pefloxacin was reduced as further indicated by an increase in elimination half-life. In contrast, studies have shown impaired renal function to have minimal influence on the pharmacokinetics of pefloxacin. However, further studies are needed to verify whether alteration of dosage or dosing interval of pefloxacin is necessary in patients with renal dysfunction.
The majority of clinical trials with oral or intravenous pefloxacin have been conducted in hospitalised patients with a range of infectious conditions including nosocomially acquired infections, serious or difficult-to-treat infections, and infections in immunocompromised patients. In most cases these studies have been carried out under non-blind conditions and with limited comparisons to other antibacterial drugs.
In the treatment of patients with respiratory tract infections pefloxacin 800 to 1200mg daily produced clinical cure rates of 58 to 70% and bacteriological eradication rates ranging from 70 to 94%. Resistant strains of S. pneumoniae and P. aeruginosa were responsible for some of the treatment failures, and 3 studies reported superinfections in 7.5, 22 and 25% of patients. Gynaecological infections, as well as complicated upper or lower urinary tract infections, pelvic infections associated with the genital tract, and acute gonococcal infections were responsive in 72 to 94% of patients treated with pefloxacin 800 to 1200mg daily. In 2 comparative studies pefloxacin 800mg daily was as effective as daily ampicillin 2g combined with gentamicin 180 to 240mg in upper gynaecological tract infections, producing clinical cure rates of 93.3 and 94.4%, respectively, and as effective as co-trimoxazole 160/800mg twice daily in uncomplicated urinary tract infections.
In the treatment of chronic osteitis, chronic osteomyelitis and other bone and joint infections, treatment with pefloxacin 400mg twice a day for up to 18 months produced a clinical cure in 87 to 100% of patients. In a limited number of immunologically compromised patients successful results have been obtained with pefloxacin in non-comparative trials in the prophylaxis and treatment of fever or infections, particularly those caused by Gram-negative bacteria. In patients with septicaemia of varying focal origin caused by Staphylococcus aureus, streptococci, Enterobacteriaceae and Pseudomonas aeruginosa, treatment with pefloxacin 800 to 1200mg daily produced a favourable response in 76 to 100% of patients and eradication of 86 to 96% of bacteriological isolates.
Pefloxacin 800mg was as effective as co-trimoxazole 320/1600mg in the treatment of typhoid fever with both drugs resulting in a clinical cure in 100% of patients, but pefloxacin produced a more rapid onset of apyrexia than co-trimoxazole allowing a shortening of the treatment time. In the treatment of patients with nosocomially acquired Gram-negative infections, which included urinary tract infections, bronchopneumonia, deep soft tissue phlegmon, osteoarticular infections, intra-abdominal infections, chronic otitis media and acute cholangitis, pefloxacin 400mg every 8 or 12 hours was similar in efficacy to ceftazidime 2g every 8 hours and cefotaxime 1g 4 times a day.
Pefloxacin is generally well tolerated, with most adverse effects being of mild to moderate severity and transient in nature. Gastrointestinal disturbances were the most frequent adverse effects experienced, accounting for over 50% of 186 reactions reported in a survey of 1437 patients. Nausea, vomiting, gastralgia, skin reactions and neurological reactions were the most frequently cited adverse effects, and 3% of patients withdrew from therapy as a result of adverse reactions. Photosensitivity developed in 0.83% of patients in this survey, and in a long term study 11 of 36 patients developed pruriginous and erythematous eruptions on the face and forearms after exposure to sunlight.
Minor changes in laboratory values following pefloxacin treatment have been reported, but these were generally not considered to be drug related. Pefloxacin does not adversely affect the gastrointestinal microflora through selection of resistant species.
Dosage and Administration
The recommended dosage of pefloxacin is 400mg administered twice a day orally with meals or intravenously. Parenteral pefloxacin should be administered as a 1-hour intravenous infusion, with the drug mixed with a 5% glucose solution and not saline. Where appropriate a loading dose of 800mg may be used on starting treatment to achieve steady-state concentrations of the drug. In patients with reduced hepatic function dosage adjustments should be made. Patients with impaired renal function may also require dosage adjustment.
As a result of the pharmacokinetic interactions between pefloxacin and theophylline, it is recommended that theophylline concentrations should be monitored in those patients receiving concomitant treatment. In addition, patients receiving pefloxacin and coumarin should have their clotting times monitored. The absorption of pefloxacin may be reduced by the concomitant administration of antacids, especially those containing aluminium or magnesium ions. A reduction in pefloxacin clearance and an increase in its elimination half-life occur with concomitant cimetidine administration.
Pefloxacin is contraindicated in children or adolescents in the growing phase and the drug should not be administered to pregnant women or nursing mothers.
KeywordsQuinolones Ceftazidime Norfloxacin Nalidixic Acid Antimicrobial Chemotherapy
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