Cefmenoxime

Abstract

Cefmenoxime ¹ is an aminothiazolyl cephalosporin administered intravenously or intramuscularly. Like other ‘third-generation’ cephalosporins it is active in vitro against most common Gram-positive and Gram-negative pathogens, is a potent inhibitor of Enterobacteriaceae (including β-lactamase-producing strains), and is resistant to hydrolysis by β-lactamases. Cefmenoxime has a high rate of clinical efficacy in many types of infection and is at least equal in clinical and bacteriological efficacy to several other cephalosporins in urinary tract infections, respiratory tract infections, postoperative infections and gonorrhoea. Cefmenoxime, like latamoxef, cefoperazone and cefamandole, has an N-methyltetrazole side chain at the 3-position of the cephalosporin nucleus and thus possesses the potential for producing hypoprothrombinaemic bleeding and disulflram-like reactions. However, these reactions have been reported very rarely and the antibacterial is generally well tolerated. It is likely that cefmenoxime will most closely resemble cefotaxime and ceftizoxime in therapeutic profile and usefulness. Cefmenoxime has a spectrum of antibacterial activity and β-lactamase stability which are similar to those of cefotaxime, ceftizoxime and ceftriaxone. Most tested strains of most species of clinically important Gram-positive and Gram-negative bacteria are susceptible to cefmenoxime in vitro, with the exception of Streptococcus faecalis, Listeria monocytogenes, Bacteroides fragilis, Acinetobacter and Pseudomonas species. Methicillin-resistant staphylococci are resistant to cefmenoxime, but penicillin-resistant Streptococcus pneumoniae, chloramphenicol-resistant and/or β-lactamase-producing (ampicillin-resistant) Haemophilus influenzae and β-lactamase-producing Neisseria gonorrhoeae are susceptible. Most species of β-lactamase-producing Enterobacteriaceae which are resistant to cephalothin or cefazolin (and in some instances to cefamandole, cefuroxime and/or cefoxitin) are susceptible to cefmenoxime; exceptions are some strains of Enterobacter cloacae and Proteus vulgaris. In contrast, gentamicin-resistant strains of Enterobacteriaceae are generally also resistant to cefmenoxime. Most species of anaerobic bacteria are resistant to or only moderately susceptible to cefmenoxime, and Chlamydia trachomatis is resistant to the antibacterial. In contrast, Branhamella catarrhalis is susceptible to very low concentrations. Against most susceptible bacteria the cefmenoxime minimum bactericidal concentration (MBC) is equal to or only twice the minimum inhibitory concentration. Generally, the MIC of cefmenoxime for most strains is little affected by increases in inoculum size up to 10⁵ colony-forming units/ml, by different media or pH, or by the addition of 50% human serum. Depending on the study, cefmenoxime has been reported to be synergistic with aminoglycosides against widely variable percentages of tested strains and so testing of individual strains is recommended before using antibacterial combinations clinically. Cefmenoxime shows a high binding affinity for penicillin-binding proteins (PBP)-3 and -1a, and exposure of Gram-negative rods to the antibacterial results in the formation of filamentous cells, which may reflect the high affinity for PBP-3; lysis occurred at higher concentrations. In common with other cephalosporins to which it is structurally related (e.g. ceftizoxime, cefotaxime, ceftriaxone), cefmenoxime is stable or resistant (less than 5% hydrolysis relative to cephaloridine) to hydrolysis by β-lactamases of the Richmond and Sykes Types I, II, IIIa, IIIb and IV (including IVc). Cefmenoxime is hydrolysed by a few R-plasmid-mediated enzymes (OXA-1, OXA-3, PSE-3, PSE-4) and by certain chromosomally-mediated enzymes from Enterobacter cloacae, Bacteroides fragilis, Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris. The in vitro activity of cefmenoxime has been confirmed in vivo against experimental infections in rodents and rabbits. Cefmenoxime is not absorbed from the gastrointestinal tract. Mean peak serum concentrations of 99.4 to 117.4 mg/L were attained immediately after intravenous injection of a 1g bolus dose to healthy volunteers. Peak serum concentrations and areas under the serum concentration-time curve (AUC) increase approximately linearly with dose. Multiple-dose studies reveal no accumulation of the drug. Intramuscularly administered cefmenoxime is completely bioavailable. In healthy volunteers the mean cefmenoxime volume of distribution for the central or plasma compartment is 7 to 12L. Volume of distribution at steady-state was calculated to be 28.IL. Distribution of cefmenoxime in concentrations likely to be inhibitory to susceptible bacteria occurs in most body tissues and fluids, but lower concentrations (< 1 mg/L) were reported in sputum, aqueous humour, bronchial secretions, prostatic fluid and cerebrospinal fluid from patients with non-inflamed meninges. Cefmenoxime crosses the placenta and is excreted slightly into breast milk. The mean cefmenoxime elimination half-life in healthy volunteers is approximately 1 hour. About 75% of a dose is excreted in the urine during the first 24 hours after administration, 80 to 90% as parent drug. Mean renal clearance is approximately 8 L/h and total plasma clearance approximately 12 L/h. While biliary excretion is only a minor route compared with renal excretion, the drug attains high concentrations in bile. Coadministration of cefmenoxime with probenecid 1 to 1.5g decreases mean renal clearance (4 L/h) and increases the mean half-life (1.78h), the mean peak plasma concentration (86.7 mg/L vs 78.1 mg/L without probenecid) and AUC (158.2 mg/L · h vs 112 mg/L · h without probenecid). In patients with impaired renal function the plasma and renal clearance, elimination rate and percentage of drug recovered in the urine are all decreased, while the elimination half-life is increased, reaching approximately 12h when creatinine clearance is less than 10 ml/min. Cefmenoxime is haemodialysable, with a clearance of approximately 2 to 4 L/h. The cefmenoxime elimination half-life is also prolonged in neonates (3.4h) and elderly patients (1.9h), but not in paediatric patients. In multicentre non-comparative clinical trials conducted in Germany (430 patients) and Japan (1499 patients), cumulated clinical cure rates of approximately 80% or greater were obtained in respiratory tract, intra-abdominal, obstetric and gynaecological, skin and soft tissue and ear, nose and throat infections. Clinical cure rates were 70.3% in bone and joint infections (German patients), 76.0% in burn and surgical wound infections (Japanese patients), and 67.6% in septicaemia (Japanese patients). In urinary tract infections the German cure rate was 92%, while that among the Japanese patients was only 73%, which probably reflects differences in evaluation criteria or the types of infections assessed. The causative organisms were eliminated in approximately 80% of the German infections, with eradication rates of 84% or greater for most commonly isolated Gram-positive and Gram-negative species except Pseudomonas aeruginosa (eradication rate 46%). In patients with chronic and/or complicated urinary tract infection, large well-designed double-blind Japanese studies have reported cefmenoxime 1g 12-hourly intravenously for 5 days to be clinically and bacteriologically superior to cefotiam 1g 12-hourly (p < 0.001 for clinical cure rate; p < 0.001 for percentage of patients from whom pathogens were eliminated), and cefazolin 1g 12-hourly (p < 0.01 for clinical cure rate; p < 0.05 for bacteriological eradication rate). Eradication rates for Serratia species were significantly higher for cefmenoxime than for cefotiam (p < 0.05) or cefazolin (p < 0.01). However, susceptibility of the infecting organism to the study drugs was not a criterion for inclusion in these studies and so these results may reflect the antibacterial spectra of the cephalosporins more so than comparative clinical efficacy. In patients with respiratory tract infections, double-blind trials in Japan also found cefmenoxime 1g 12-hourly intravenously for 7 to 14 days to be statistically superior to cefotiam (p < 0.05) in chronic infections (e.g. chronic bronchitis, chronic bronchiolitis, bronchiectasis) but not in bacterial pneumonia or pulmonary suppuration. In a randomised comparative trial, a single dose of cefmenoxime 1g intramuscularly cured a similar percentage of β-lactamase-negative Neisseria gonorrhoeae infections as did procaine penicillin 4.8 × 106 units plus oral probenecid 1g. Cure rates of 96.7% and 100% were obtained in Japanese patients with gonorrhoeal urethritis with single intramuscular doses of cefmenoxime 1g, alone and administered concomitantly with probenecid 1g, respectively; cure rates were 92.5% for single doses of ceftizoxime 0.5g intramuscularly but only 37% for single doses of cefmenoxime 0.5g. Cefmenoxime was assessed in a double-blind study of postoperative infections (mostly intra-abdominal infections following gastrointestinal surgery) in Japan. Cefmenoxime 1g 12-hourly for 7 days was significantly superior in clinical efficacy to cefotiam 1g 12-hourly in the treatment of postoperative superficial purulent infections (p < 0.05). However, there was no statistically significant difference in clinical efficacy between the 2 treatments among patients with peritonitis or dead-space infection. Additionally, there was no statistically significant difference between the 2 treatments in bacteriological efficacy overall. In non-comparative studies cefmenoxime has also demonstrated encouraging clinical cure rates when administered in combination with an antipseudomonal penicillin, an aminoglycoside or cefsulodin to infected immunocompromised patients. Daily cefmenoxime dosages generally ranging from 50 to 150 mg/kg resulted in excellent or good clinical results and in bacterial eradication from approximately 75% to 100% of paediatric patients, most with infections of the respiratory or urinary tract, assessed in non-comparative studies. In common with other cephalosporins, the most frequently reported adverse effects associated with cefmenoxime therapy are mild hypersensitivity, gastrointestinal and local reactions (e.g. pain on injection), and the most frequently reported abnormal laboratory indices are transiently elevated liver function enzymes and haematological abnormalities. In addition, as with latamoxef and cefoperazone, the potential to produce hypoprothrombinaemic bleeding and disulfiram-like alcohol intolerance exists. Cefmenoxime may give false positive urine sugar readings (e.g. with ‘Clinitest’) and direct Coombs test results. The recommended adult dosages of intramuscular or intravenous cefmenoxime vary with the severity of the infection and the manufacturer (Japan vs North America). In North America a maximum dose of 12g daily, administered as 2g every 4 hours, is allowed in life-threatening infections. In contrast, the maximum allowable dosage recommended by the manufacturer in Japan, for intractable or severe infections, is 4g daily administered as 2 to 4 divided doses. Dosage guidelines for children have been established in Japan, but the safety of the drug has not been established in pregnancy. Cefmenoxime is not recommended for use in patients with severe renal function impairment.