Ceftizoxime A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use

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Abstract
Synopsis: Ceftizoxime 1 is a ‘third generation’ cephalosporin administered intravenously or intramuscularly. Like other third generation cephalosporins it has a wide spectrum of in vitro activity against Gram-positive and Gram-negative bacteria, is particularly active against Enterobacteriaceae (including β-lactamase-positive strains), and is resistant to hydrolysis by β-lactamases. However, the third generation cephalosporins are less active than earlier cephalosporins against staphylococci and so could not be considered the drugs of choice. Like many currently available third generation cephalosporins, ceftizoxime has limited activity against Pseudomonas aeruginosa, and thus cannot be recommended as sole treatment of known or suspected non-urinary tract pseudomonal infections. Similarly, although favourable clinical results have been obtained in patients treated with ceftizoxime for infections caused by mixed aerobic/anaerobic organisms (such as intra-abdominal, and obstetric and gynaecological infections), the relatively low in vitro activity of ceftizoxime (in common with most other third generation cephalosporins) against Bacteroides fragilis and enterococci may restrict its usage in situations where these organisms are the suspected or proven pathogens. Ceftizoxime appears to be similar in efficacy to several other cephalosporins in lower respiratory tract infections in elderly and/or debilitated patients, and in chronic and/or complicated urinary tract infections, 2 clinical situations in which third generation cephalosporins may have a major role. Ceftizoxime is also effective clinically and bacteriologically in skin, soft tissue, bone and joint infections, septicaemia/bacteraemia, meningitis and neonatal infections. However, a few large, well designed clinical comparisons of efficacy with aminoglycosides are needed before ceftizoxime can be recommended as an alternative in patients in whom potential aminoglycoside toxicity is a concern. Single intramuscular doses of ceftizoxime appear similar in efficacy to aqueous procaine penicillin G in gonorrhoeae due to nonpenicillinase-producing Neisseria gonorrhoea, and ceftizoxime is also highly effective against penicillinase-producing strains. Although only a few infections have been treated to date, ceftizoxime may be useful in the treatment of gonorrhoea in places where penicillinase-producing strains are common. Thus, ceftizoxime appears to be an ejfective addition to the growing number of third generation cephalosporins. However, further studies are needed to confirm its relative efficacy compared with other new cephalosporins, in particular cefotaxime. Nevertheless, ceftizoxime lacks the acetoxymethyl group of cefotaxime which renders the latter drug susceptible to metabolism: thus, ceftizoxime has a longer half-life. Additionally, ceftizoxime may offer a worthwhile toxicological advantage over moxalactam, cefoperazone, cefamandole, cefmetazole and cefmenoxime in that it lacks the N-methyl-thio-tetrazole side chain which has been associated with coagulopathy and disulfiram-like reactions. Antibacterial Activity: Ceftizoxime is an aminothiazolyl syn-methoxyimino cephalosporin which has a wide spectrum of antibacterial activity in vitro, including Gram-positive and Gram-negative aerobic and some anaerobic bacteria. The minimum concentration of ceftizoxime which inhibits 90% of tested strains (MIC90) is 2 mg/L or less for most species of Enterobacteriaceae. Also, most strains of β-lactamase-positive Enterobacteriaceae, and clinical isolates of Morganella morganii and Proteus vulgaris are at least moderately sensitive to ceftizoxime. Against Enterobacteriaceae in vitro, ceftizoxime generally exhibits both a wider spectrum and greater activity than first generation and second generation cephalosporins and many ureidopenicillins, is more active than cefoperazone, and is similar in activity to other third generation cephalosporins. However, like most third generation cephalosporins, the ceftizoxime MIC90S for Enterobacter Cloacae, Enterobacter aerogenes and Citrobacter freundii vary widely between studies (MIC90 0.1 to > 32 mg/L); the aminoglycosides are generally more potent against these species. Against Pseudomonas aeruginosa, ceftizoxime (MIC90 > 32 mg/L) is similar in potency to cefotaxime, moxalactam and ceftriaxone, and is less active than ceftazidime and cefoperazone. In common with other third generation cephalosporins, ceftizoxime is a highly potent inhibitor of β-lactamase-negative and β-lactamase-positive Haemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidis (MIC90 < 1 mg/L). Most tested strains of Acinetobacter calcoaceticus are at least moderately sensitive to ceftizoxime, but many β-lactamase-positive strains are resistant. While ceftizoxime is active in vitro against Staphylococcus aureus (except methicillin-resistant strains) and streptococci (except enterococci) it is less active than most first generation and second generation cephalosporins against staphylococcal species. Like other third generation cephalosporins, ceftizoxime is less active against Bacteroides fragilis than is moxalactam. Clostridium perfringens and several other species of anaerobic bacteria are sensitive to ceftizoxime, but Clostridium difficile is resistant. Generally the MIC of ceftizoxime for most strains is little affected by increases in inoculum size up to 106 colony-forming units/ml, by different media, or by the addition of up to 50% human serum. Ceftizoxime is stable in vitro against a variety of β-lactamases, including most R plasmid-mediated enzymes. The β-lactamase stability of ceftizoxime, cefotaxime and ceftriaxone are similar. They are inactivated by fewer β-lactamases and/or at a slower rate than most other cephalosporins except cefoxitin, moxalactam or ceftazidime. Pharmacokinetics: Intravenous administration of ceftizoxime 1g to healthy volunteers, as an infusion over 30 to 60 minutes and as a bolus injection, resulted in mean peak plasma concentrations of 46 to 69 and 107 to 136 mg/L, respectively. Approximately 1 hour after intramuscular administration of the same dose, mean peak plasma concentrations of 35 to 41 mg/L are attained. The mean peak plasma concentration and area under the plasma concentration-time curve (AUC) of ceftizoxime appear to increase linearly with dose, and multiple-dose studies reveal no drug accumulation, but the concomitant administration of probenecid 500mg or 1g with ceftizoxime results in higher mean plasma concentrations and a significant increase in the AUC. The apparent volume of distribution of ceftizoxime is usually between 15 and 28L at steady-state. Therapeutic concentrations of ceftizoxime are attained in a variety of tissues and fluids including gynaecological organs and tissues, and kidney, prostatic, testicular, gallbladder, lung, tonsil, gingiva and cardiac atrium tissue, as well as bone marrow, bone marrow blood, extracellular fluid, pus, bile and cerebrospinal fluid (inflamed meninges). However, the drug diffuses poorly into the aqueous humor and cerebrospinal fluid (non-inflamed meninges). The drug readily traverses the placenta, but breast milk concentrations are low. Protein binding is approximately 30%. Ceftizoxime is not metabolised, and the elimination half-life in healthy subjects is 1.1 to 2.3 hours. Total plasma clearance is from 111 to 200 ml/min. From 70 to 100% of a dose is eliminated via renal mechanisms (glomerular filtration and renal tubular secretion). As there is a direct correlation between creatinine clearance and elimination rate, the mean half-life is prolonged in patients with moderate to severe renal impairment (up to 30 hours in uraemic patients). The half-life is also significantly (p < 0.05) prolonged by coadministration of probenecid: mean half-lives of 1.9 to 2.8 hours were reported. Ceftizoxime can be removed from the body by haemodialysis. The pharmacokinetics of ceftizoxime in paediatric patients are similar to those in healthy adult volunteers. However, in elderly patients the mean elimination half-life is increased to 3.2 hours, probably because of the normal decrease in renal function which accompanies the ageing process. Therapeutic Trials: Ceftizoxime (usual dosage 2 to 4g daily administered intravenously or intramuscularly at 8- to 12-hourly intervals) is clinically and bacteriologically effective in a wide variety of infections caused by Gram-negative and Gram-positive bacteria. Cumulated efficacy rates varied with the type of infection and infecting organism. Most species of bacteria, excepting Pseudomonas aeruginosa, Staphylococcus epidermidis, Bacteroides species and Serratia species, were eradicated from at least 80% of patients. Generally 80% or more of infections, including respiratory tract, genitourinary tract, skin, soft tissue, bone and joint, intra-abdominal, obstetric and gynaecological and neonatal infections, as well as bacteraemia/septicaemia and meningitis, were clinically cured. These infections were frequently of moderate or greater severity and were often caused by a bacterial strain that was resistant to alternative antibiotics. Most of the comparative trials assessing ceftizoxime were small, and hence statistical analyses were unlikely to identify small differences between drugs, if any existed. However, as indicated below, ceftizoxime appeared to be similar in efficacy to several ‘standard’ antibiotics with which it was compared. In (generally) elderly and/or severely debilitated patients with pneumonia or bronchitis, ceftizoxime 2 to 4g daily was not statistically different in clinical efficacy from various other cephalosporins [cefamandole 2 to 8g daily, cefazolin 4g daily and cefotaxime ≈ 4g daily (mean dosage)]. However, in the largest study (206 patients), ceftizoxime eradicated 64% of infecting pathogens whereas cefazolin only eradicated 29% (p < 0.05). In several studies, clinical and bacteriological efficacy rates were generally 100% during treatment of patients with chronic and/or complicated urinary tract infections, whether they received ceftizoxime 1 to 4g daily or another cephalosporin (cefamandole 4g daily, cefazolin 2g daily or cefotaxime 1 to 2g daily). Not unexpectedly, when follow-up cultures were obtained 4 to 7 weeks following the cessation of therapy, less than 75% of most patient groups remained free of bacteriuria. There were no statistically significant differences between the ceftizoxime and comparison groups. In contrast, 4 to 6 weeks after treatment of urinary tract infections in spinal cord injury patients bacteriuria had persisted or recurred in only 15% of those who had received ceftizoxime 1g 8-hourly versus 46% of those who had received tobramycin 1 mg/kg 8-hourly (p < 0.05). There were no statistically significant differences between the efficacy of ceftizoxime and comparative cephalosporins (cefoxitin, cefazolin and cefamandole) in either the healing of intra-abdominal, obstetric or gynaecological infections or in the prevention of them postoperatively. However, in 1 small study ceftizoxime appeared less effective than clindamycin 600mg 6-hourly plus gentamicin 3 to 5 mg/kg daily (74 vs 91% cured or improved), whereas in another small study ceftizoxime 3g 8-hourly cured an equal percentage of patients (83%) as did clindamycin 600mg 6-hourly plus tobramycin 1.7 mg/kg 8-hourly. Ceftizoxime 0.5 to 1g 12-hourly appeared similar in efficacy to cefamandole 0.5 to 1g 6-houriy in patients with skin and soft tissue infections due usually to Staphylococcus aureus or non-enterococcal streptococci. Also, single intramuscular doses of ceftizoxime 0.5 to 1g, aqueous procaine penicillin G 4.8 million units plus probenecid 1g orally or cefonicid 1g cured almost all patients having infections due to non-penicillinase-producing Neisseria gonorrhoeae. All 26 and 32 of 33 urethral infections due to penicillinase-producing strains were cured by ceftizoxime 1g and cefonicid 1g, respectively. Side Effects: Ceftizoxime is generally well tolerated. The most commonly reported side effects are similar to those of other β-lactam antibiotics and include hypersensitivity reactions (skin rashes, fever), local intolerance (pain at the injection site, phlebitis), transient eosinophilia, reversible elevation of liver function enzymes, and gastrointestinal reactions (diarrhoea, pseudomembranous colitis). Ceftizoxime lacks the N-methyl-thio-tetrazole side chain which has been associated in some cephalosporins with coagulopathy and disulfiram-like reactions. Dosage: The usual adult dosage is 1g 8- to 12-hourly, but doses of up to 2g 4-hourly may be needed in life threatening infections. A dosage of 0.5g 12-hourly is recommended as sufficient in most urinary tract infections and a single 1g intramuscular dose is the treatment in uncomplicated gonorrhoea. Dose reductions are necessary in patients with renal dysfunction.