Cefotaxime

Summary

Synopsis

Cefotaxime was the first ‘third generation’ cephalosporin to be marketed and is administered intramuscularly or intravenously. Similar to other agents of this class, it has a broad spectrum of in vitro activity, particularly against Enterobacteriaceae, including β-lactamase-producing strains. Cefotaxime forms a metabolite, desacetylcefotaxime, which is antibacterially effective against many bacteria per se and acts additively or synergistically with cefotaxime against many strains. Since the first review of cefotaxime in the Journal, further studies have confirmed its value in the treatment of various infections: complicated urinary tract infections, lower respiratory tract infections, bacteraemia, meningitis, uncomplicated gonorrhoea, infections of skin and soft tissue and of bone and joints, and obstetric and gynaecological infections. Cefotaxime is effective as an empirical treatment of suspected infection due to susceptible organisms in immunocompromised patients and is of proven efficacy in serious, life-threatening infections in general. Cefotaxime reduces the incidence of postsurgical infection but the role of third generation cephalosporins in prophylaxis remains to be determined. The indications for which cefotaxime and other ‘third generation’ cephalosporins would be considered the most appropriate therapy remain largely dependent upon such factors as varied as cost, local medical custom, decisions of regulatory agencies and geographical patterns of bacterial resistance. Cefotaxime nevertheless represents a valuable ‘third generation’ cephalosporin of great clinical value in certain infectious conditions, in particular those which are serious and life-threatening and where resistance to therapies is creating a clinical problem.

Antibacterial Activity

Cefotaxime has a broad spectrum of activity in vitro which includes Gram-positive and Gram-negative aerobic and some anaerobic bacteria. Both penicillin-sensitive and penicillin-resistant strains of Staphylococcus aureus are sensitive to cefotaxime, but methicillin-resistant strains are often resistant. Staphylococcus epidermidis is usually moderately sensitive to cefotaxime although penicillinase-producing strains are usually resistant. Most Streptococcus species (S. pneumoniae, S. pyogenes, S. agalactiae) are sensitive to cefotaxime, but most strains of Streptococcus faecalis are resistant, as are Listeria monocytogenes and Nocardia asteroides. Cefotaxime is highly active against Gram-negative bacteria and in particular the Enterobacteriaceae, including penicillinase-producing strains. Notable exceptions where resistance may often be encountered include Pseudomonas and Enterobacter species. Cefotaxime is active against many anaerobic bacteria (e.g. Peptococcus, Peptostreptococcus and Veillonella species, and Clostridium perfringens) and some Bacteroides species, but Clostridium difficile is frequently resistant. Usually there is little difference between the bactericidal and inhibitory concentrations of cefotaxime for most bacteria.

Cefotaxime is partially metabolised to desacetylcefotaxime, which per se demonstrates significant antibacterial activity. In addition, antibacterial and bactericidal synergy between cefotaxime and desacetylcefotaxime is seen against a high percentage of clinical isolates of S. aureus, B. fragilis and Enterobacteriaeceae.

Cefotaxime and desacetylcefotaxime are stable to inactivation by β-lactamases produced by many bacteria, and while cefotaxime is hydrolysed by β-lactamases produced by Bacteroides fragilis and types IVc and Ic enzymes produced by some species of Klebsiella and Proteus vulgaris, respectively, desacetylcefotaxime is relatively stable. Both compounds are hydrolysed by a Morganella morganii β-lactamase (type Ia), whereas desacetylcefotaxime alone is inhibited by a Proteus penneri type Ic β-lactamase.

Based on inhibitory and bactericidal activity, significant synergy occurs between cefotaxime and many other antibacterial agents, most notably the aminoglycosides. Antagonism has rarely been encountered except with the β-lactamase inhibitor clavulanic acid.

The in vivo antibacterial activity of cefotaxime has been clearly demonstrated in animal models of systemic infection caused by susceptible Enterobacteriaceae and S. aureus, but the drug was ineffective in inhibiting the proliferation of E. faecalis in well established heart lesions in rabbits.

Pharmacokinetic Properties

The disposition of cefotaxime is usually described by an open, 2-compartment model, with dose-dependent linear pharmacokinetics for single intravenous doses up to 2g. Mean peak plasma concentrations of about 100, 40 and 20 mg/L are achieved after a single 1g dose of cefotaxime as a bolus, 30-minute infusion and intramuscular injection, respectively. The bioavailability of the intramuscular dose is about 90 to 95%. Steady-state is achieved after several doses, and trough concentrations of cefotaxime and desacetylcefotaxime exceed 10 and 5 mg/L, respectively, after usual dosages.

The apparent volume of distribution of cefotaxime is 20 to 30 L/1.73m2 and it is 25 to 40% bound to human protein in vitro. Following usual doses cefotaxime concentrations inhibitory for most susceptible organisms are achieved in most body tissues and fluids, although penetration is poor across noninflamed meninges, as with other β-lactam antibiotics. High concentrations of desacetylcefotaxime, the main metabolite, are also achieved in body tissues and fluids, sufficient to be antibacterially effective per se as well as acting additively or synergistically with cefotaxime. This may explain why cefotaxime is therapeutically effective when administered at longer dose intervals than would be theoretically predicted from the elimination pharmacokinetics of cefotaxime alone. Cefotaxime efficiently crosses the placenta, but penetration into breast milk is minimal.

Cefotaxime undergoes hepatic metabolism to form desacetylcefotaxime. The latter undergoes further metabolism to inactive opened β-lactam ring lactones. About 80% of a radiolabelled dose of cefotaxime is excreted in urine; about 50 to 60% as unchanged drug and the remainder as metabolites. About 20% of the dose is recovered in faeces, as a small degree of biliary excretion of cefotaxime and desacetylcefotaxime occurs. Approximate values for plasma clearance, renal clearance and elimination half-life, respectively, are 15 L/h, 9 L/h and 1.2 hours for cefotaxime, and 45 L/h, 13.2 L/h and 1.6 hours for desacetylcefotaxime in subjects with normal renal function.

The effects of age, disease and various other conditions on pharmacokinetics have been well studied. The main findings are that renal insufficiency or inadequate renal development in preterm and low birthweight neonates may decrease the clearance and increase the half-life of cefotaxime, and more particularly its metabolites. Dosage reduction (usually half the normal doses) is therefore required with severe renal insufficiency (creatinine clearance <5 to 10 ml/min) or in low birthweight neonates. Hepatic impairment from cirrhosis or hepatitis did not affect the pharmacokinetics to a clinically significant degree.

Therapeutic Efficacy

Since cefotaxime was first reviewed in the Journal, clinical trials have confirmed its therapeutic efficacy, in particular in comparisons with other standard treatments. Cefotaxime is as effective as other widely used antimicrobial agents in the treatment of mild uncomplicated urinary tract infection or upper respiratory tract infections, but the treatment of these common community-acquired infections is best achieved with more easily administered oral agents. Cefotaxime 2 to 6 g/day is highly effective in the treatment of complicated urinary tract infections, proving superior to usual dosages of cefoxitin, cefazolin, cefuroxime and gentamicin in some studies and equivalent to aztreonam, ampicillin plus netilmicin, ceftizoxime and ceftriaxone. The same dosage of cefotaxime is also highly effective in the treatment of lower respiratory tract infections, in particular pneumonia, proving equivalent to other first, second and third generation cephalosporins. In these areas as well as other conditions where Pseudomonas aeruginosa is proven or suspected, combination with a specific antipseudomonal β-lactam or an aminoglycoside is necessary because of the generally poor activity of cephalosporins against this organism.

Noncomparative studies in patients with bacteraemia indicate a high response rate with cefotaxime, particularly in infections caused by Enterobacteriaceae, but there are few comparative data. Cefotaxime is also effective in combination with an aminoglycoside or a quinolone in the empirical treatment of suspected infection in immunocom-promised patients. However, in one study in such patients a combination of azlocillin plus amikacin was more effective than cefotaxime or ticarcillin each combined with amikacin while in another, the cure rate with ceftazidime alone was higher than with cefotaxime plus gentamicin in granulocytopenic patients. It should be noted that in this study the dosage of gentamicin was not titrated and it is not known whether therapeutic concentrations were achieved. More studies of cefotaxime in these circumstances are needed.

Early clinical information on the use of cefotaxime in skin, soft tissue, bone and joint infections, intra-abdominal infections, and obstetric and gynaecological infections was largely from noncomparative data, but more recently comparative trials have confirmed the efficacy of cefotaxime. Cefotaxime 2g 8-hourly was similar in efficacy to the same dose of cefoxitin in acute salpingitis, to ceftizoxime 6g daily in pelvic inflammatory disease and to clindamycin plus gentamicin in patients with tubo-ovarian complex or abscess but tended to be less effective than ciprofloxacin in skin and soft tissue infections. Clinical and bacteriological response rates seem high, but at present there are insufficient comparative data to clearly define the place of cefotaxime in the treatment of these conditions. Certainly, in those conditions where Bacteroides species might be encountered cefotaxime should be used in combination with another agent such as clindamycin or metronidazole.

Cefotaxime has been particularly well studied in the treatment of meningitis, notably in paediatric patients. Its efficacy is at least equal to that of standard therapy with ampicillin plus chloramphenicol, and it may therefore be considered as suitable first-line agent when resistance to the latter is a clinical problem. Cefotaxime is highly effective against meningitis caused by Enterobacteriaceae and Streptococcus pneumoniae, although there were some failures when Pseudomonas, Enterobacter and Serratia species were pathogens. Cefotaxime should therefore be used in combination with another appropriate antimicrobial agent when the latter infections are suspected or proven and certainly when Listeria monocytogenes, Enterococcus faecalis or Staphylococcus epidermidis, or Staphylococcus aureus are suspected. High dosages of cefotaxime should be used in meningitis: 50 to 100 mg/kg/day in 2 divided doses in low birthweight and premature neonates, up to 200 mg/kg/day in 3 or 4 divided doses in other infants and children, and 6 to 8 g/day in 3 or 4 divided doses in adults. There is some indication that cefotaxime can reduce the incidence of neurological morbidity and the duration of hospitalisation compared with that found following the use of ampicillin plus chloramphenicol. If confirmed, cefotaxime would definitely be proved a first-line agent for this serious condition.

Cefotaxime has been well studied in the empirical treatment of severe life-threatening infections, proving equivalent to ceftazidime, ceftriaxone, imipenem/cilastatin and pefloxacin as monotherapy, and in combination with mezlocillin equivalent to the combination of gentamicin plus cefoxitin plus metronidazole. Cefotaxime monotherapy was clearly superior to a combination of an aminoglycoside and a penicillin, providing higher clinical and microbiological cure rates with a lower frequency of nephrotoxicity and superinfections.

Cefotaxime as a single intramuscular dose of 1 g is virtually 100% effective clinically and microbiologically in the treatment of uncomplicated gonorrhoea, being equally effective against non-penicillinase- and penicillinase-producing strains of Neisseria gonorrhoeae. Single intramuscular injections of cefotaxime 500mg and ceftriaxone 250mg were similarly effective, as were single 1g doses of cefotaxime and ceftimazole. In a large study, cefotaxime 1g produced significantly fewer treatment failures than cefuroxime 1.5g. Cefotaxime may therefore be considered a suitable first-line agent when resistance to penicillin or spectinomycin presents a clinical problem.

Cefotaxime 1 to 2g as a single preoperative dose or as a short course of 3 to 4 doses at 8-hourly intervals peri- and/or postoperatively has proven highly effective in the prevention of infection following a wide range of surgical procedures (urological, obstetrical and gynaecological, gastrointestinal, abdominal, and orthopaedic) with the notable exception of neurosurgery, as β-lactams in general show poor penetration across noninflamed meninges. Cefotaxime was at least as effective as other prophylactic regimens and in some studies superior to cefoxitin, ampicillin, metronidazole, neomycin plus erythromycin and benzylpenicillin plus cloxacillin and cefamandole. No clinical advantage has been clearly demonstrated during single-dose administration for those third-generation cephalosporins with a long elimination half-life, such as-ceftriaxone.

Cefotaxime for a few days in combination with ongoing selective digestive decontamination (SDD) with colistin (polymixin E), tobramycin and amphotericin B has been tested in the prevention of infection in intensive care patients. Cefotaxime reduced primary respiratory infection in selected patients and SDD was found to significantly reduce colonisation by aerobic Gram-negative bacilli and also the incidence of unit-acquired infection compared with no antibiotic prophylaxis.

Adverse Effects

Cefotaxime is generally well tolerated by adults and children following intravenous and intramuscular injection. The overall incidence of adverse events is about 5 to 8%, leading to discontinuation of treatment in about 1 to 2% of patients. The most commonly occurring adverse effects are typical of parenteral cephalosporins: gastrointestinal complaints (mostly diarrhoea, nausea and/or vomiting), dermatological reactions (rash and pruritus) and local reactions at the injection site such as pain and, less frequently, thrombophlebitis. More severe reactions have been reported in rare case reports involving only a few patients: Clostridium difficile pseudomembranous colitis, hypoprothrombinaemia, thrombocytopenia, encephalopathy, status epilepticus, eosinophilia, leucopenia and neutropenia. A causal relationship was not always clearly established in these isolated reports.

Dosage and Administration

The recommended dosage of cefotaxime is 1 to 6 g/day given in divided doses 2 to 3 times daily intravenously or intramuscularly. The usual dosage is 1 to 2 g/day for urinary tract infections, 3 g/day for other moderate to serious infections, with the higher dosages of 6 g/day being reserved for life-threatening infections. The most appropriate regimen was 0.5 to 2g every 8 to 12 hours for highly susceptible organisms. Paediatric dosages are usually 50 mg/kg/day in neonates, and 100 to 150 mg/kg/day in older infants and children. With serious infections such as meningitis 150 to 200 mg/kg/day is recommended for neonates up to 7 days of age and 200 mg/kg/day for older children. Dose frequency is usually 2 to 3 times daily. A single intramuscular dose of 1g is recommended for the treatment of uncomplicated gonorrhoea. For the prevention of surgical infection a single preoperative dose of 1 to 2g is recommended which may be followed by 1 to 3 doses postoperatively at 8-hour intervals. The dosage should be halved but the frequency maintained in patients whose creatinine clearance is less than 10 ml/min.