Cefoxitin: A Review of its Antibacterial Activity, Pharmacological Properties and Therapeutic Use

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Abstract

Summary

Synopsis: Cefoxitin1is a β-lactam antibiotic derived from cephamycin C, a naturally occurring substance produced by Streptomyces lactamdurans. Its resistance to destruction by β-lactamases results in a broad spectrum of antibacterial activity which includes anaerobic as well as Gram-positive and Gram-negative aerobic bacteria, including many resistant to cephalothin and other cephalosporins. Given by intravenous or intramuscular injection, cefoxitin is effective against a wide variety of infections caused by Gram-positive or Gram-negative aerobes as well as by anaerobic bacteria. It is generally well tolerated, thrombophlebitis, skin rash and some degree of discomfort after intramuscular injection, being the most commonly reported side effects. Cefoxitin has not been shown to cause adverse effects on renal function.

Antibacterial Activity: The presence of the 7α-methoxy group in the nucleus confers upon cefoxitin a high degree of resistance to hydrolysis by β-lactamases produced by Staphylococcus aureus and certain Gram-negative aerobic and anaerobic bacteria. At concentrations readily attained in plasma after administration of usual dosages, cefoxitin is active in vitro against Staphylococcus aureus, Streptococcus pneumoniae and β-haemolytic streptococci, but is inactive against Str. faecalis. However, cefoxitin is less active than the cephalosporins such as cephalothin against many Gram-positive bacteria. Cefoxitin is active in vitro against a broad range of Gram-negative bacteria including Escherichia coli, Klebsiella sp., Proteus mirabilis and the indole-positive species, Haemophilus influenzae, Salmonella, Shigella, Providencia and Serratia species and Neisseria gonorrhoeae. Cefoxitin is usually not active at therapeutic concentrations against Pseudomonas aeruginosa, Enterobacter aerogenes and many strains of Citrobacter freundii and Acinetobacter sp. Although the activity of cefoxitin in vitro against Pr. mirabilis is not greatly different from that of several cephalosporins, against indole-positive Proteus species, cefoxitin is almost invariably more active than the cephalosporins. Unlike the cephalosporins, cefoxitin is active against a large proportion of clinical isolates of Serratia marcescens.

As well as being active in vitro against a wide range of aerobic bacteria, cefoxitin is also active at concentrations attainable in serum against many anaerobic bacteria, notably Bacteroides fragilis.

The efficacy of cefoxitin in vivo has been demonstrated in experimental infection in animals challenged with Gram-negative and Gram-positive aerobic and facultative bacteria or with anaerobic bacteria.

Cefoxitin is generally bactericidal against susceptible Gram-positive and Gram-negative aerobic bacteria at concentrations equal to or only 1 or 2 dilutions higher than the minimum inhibitory concentration. Generally, the bactericidal activity of cefoxitin is not appreciably influenced by the size of the inoculum, but the bactericidal activity against Klebsiella and indole-positive Proteus sometimes decreases as the inoculum size is increased.

The activity of cefoxitin in vitro is not usually influenced to any appreciable extent by different culture media; changes in pH, or the addition of horse serum to the culture medium, but the less protein bound cephalosporins were affected less by the addition of 4% human serum albumin than was cefoxitin.

Pharmacokinetics: After intravenous or intramuscular administration of a 1g dose, high serum concentrations are attained which rapidly decline to about 2μg/ml at 3 hours in persons with normal renal function. Peak serum concentrations are related to dosage and rapidity of administration, but the area under the plasma level-time curve is comparable after bolus injection or intravenous infusion over a period of 120 minutes.

Cefoxitin concentrations in pus, pleural fluid and bronchial secretions would be inhibitory to many susceptible bacteria. Cefoxitin penetrates poorly into the CSF after single doses when the meninges are normal but penetration is improved after multiple dosage, by the concomitant administration of probenecid and when the meninges are inflamed. As with other protein-bound β-lactam antibiotics (e.g. ampicillin, nafcillin, cefamandole) it might be expected that in cases of meningitis the CSF penetration of cefoxitin would be proportional to the CSF protein concentration. Cefoxitin readily crosses the placenta, but only traces of the drug have been reported in human milk. About 70 to 80% of the drug is bound to plasma protein and the volume of distribution is relatively low at about 8 to 12 litres.

Cefoxitin appears in high concentrations in the urine, from which about 80% of a dose is recovered within 2 hours of intravenous injection. Renal elimination is by tubular secretion and glomerular filtration and is retarded by concomitant administration of probenecid. The mean terminal serum half-life is about 50 minutes in persons with normal renal function, but is prolonged in patients with renal impairment, particularly when creatinine clearance is below 30ml/min. Only a small proportion of a dose of cefoxitin (about 2%) is metabolised to descarbamyl cefoxitin, which is biologically inactive.

Therapeutic Trials: Cefoxitin, given largely by the intravenous route, has been successfully used to treat a wide range of infections caused by Gram-positive and Gram-negative aerobes and/or anaerobic bacteria. A dosage of 1 to 2g 6 or 8 hourly has been given in most instances and has generally been adequate except in some severe infections and possibly in bacterial endocarditis.

Comparative studies have shown cefoxitin to be closely comparable with cefazolin and cefamandole against a variety of aerobic infections, and to be more effective than cephalothin against anaerobic and mixed aerobic and anaerobic infections. Cefoxitin also tended to be more effective than cephalothin against aerobic Gram-negative bacterial infections.

Cefoxitin has been used in many parts of the world to treat patients with urinary tract infection, many of whom have had underlying urological abnormalities or have undergone urogenital tract surgery. Infections caused by susceptible organisms have generally been cured in 70 to 90% of instances, but as would be expected, infections caused by Enterobacter, or Str. faecalis have usually resolved less frequently. The rate of bacteriological cure has been similar in patients with normal renal function and in those with renal impairment.

The clinical response to cefoxitin in patients with lower respiratory tract infection has been good or excellent in about 80% of instances including those which have failed to respond to treatment with other antibacterial agents. A good response was obtained in patients with destructive suppurative pneumonia.

Intravenous cefoxitin has been successfully used to treat osteomyelitis and musculoskeletal and skin and soft tissue infections caused by aerobic or anaerobic bacteria or mixtures of aerobes and anaerobes. Surgical drainage and debridement has also been employed as part of treatment in many instances.

As cefoxitin is active against both aerobic and anaerobic bacteria, particularly B. fragilis, it has been used to treat intra-abdominal and female genital tract infections which are often caused predominantly by anaerobes or anaerobic plus aerobic bacteria. Against such infections, cefoxitin has been clinically effective in over 85% of patients including those who had failed to respond to treatment with other antimicrobial agents.

In patients considered to have impaired immune response as a result of primary disease and/or concomitant immunosuppressive therapy for neoplastic disease, cefoxitin was effective and free of troublesome complications. Cefoxitin has been found to be effective in bacteraemia and some cases of bacterial endocarditis, but in bacterial endocarditis it appears that the concomitant administration of probenecid may be beneficial.

In studies in various infections in which results were not given according to diagnosis, cefoxitin has been effective in infection caused by single or multiple organisms, and has been as effective against Gram-positive as Gram-negative bacteria.

Side Effects: Cefoxitin has been administered intravenously to the great majority of patients who have been treated with the drug and has generally been well tolerated when given by this route. Adverse effects most frequently reported in an analysis of data from studies conducted throughout the world have been thrombophlebitis in 5.3% of patients, skin rash in 2.2% and some degree of discomfort after intramuscular injection in 8% of patients. Thrombophlebitis, which necessitated withdrawal of treatment in 0.6% of patients occurs more frequently when an indwelling polyethylene catheter is used than when the infusion is administered via a butterfly needle.

Precautions: As there is some evidence of cross-allergenicity between the cephamycins and the penicillins and cephalosporins, cefoxitin should not be given to patients who have experienced previous serious immediate or delayed reactions with either penicillins or cephalosporins. If an allergic reaction to cefoxitin occurs the drug should be discontinued.

Dosage: Cefoxitin may be administered intravenously or intramuscularly. The usual adult dosage is 1g or 2g every 8 hours, but the dosage should be determined by the severity of infection, susceptibility of the causative organisms and general condition of the patient. In uncomplicated infections the dosage is usually 1g every 8 hours, or occasionally 1g every 6 hours.

In moderately severe or severe infections the usual dosage is 2g every 6 or 8 hours.

For the treatment of infections which generally require higher than usual dosages of antibiotics the dosage is usually 12g daily given either as 2g every 4 hours or 3g every 6 hours.

Children over 2 years with infections caused by susceptible organisms should receive 80 to 160mg/kg daily divided into 3 or 4 equal doses. Total daily dose may be increased to 200mg/kg daily for severe infections.

In adults with reduced renal function the maintenance dosage should be reduced in accordance with the degree of renal impairment.

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