Cefotaxime

Summary

Synopsis: Cefotaxime ¹ is a new ‘third generation’ semisynthetic cephalosporin administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the ‘first’ and ‘second generation’ cephalosporins. Although cefotaxime has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy for pseudomonal infections. However, cefotaxime has been effective in treating infections due to other ‘difficult’ organisms, such as multidrug-resistant Enterobacteriaceae. Like other cephalosporins, cefotaxime is effective in treating patients with complicated urinary tract and lower respiratory tract infections, particularly pneumonia caused by Gram-negative bacilli. High response rates have also been achieved in patients with Gram-negative bacteraemia. Although favourable clinical results have been obtained in patients with infections caused by mixed aerobic/anaerobic organisms (such as peritonitis or soft tissue infections), the relatively low in vitro activity of cefotaxime against Bacteroides fragilis may restrict its usage in situations where this organism is the suspected or proven pathogen. In preliminary studies, males and females treated with a single intramuscular dose of cefotaxime for uncomplicated gonorrhoea caused by penicillinase-producing strains of Neisseria gonorrhoeae responded very favourably. Encouraging results have also been reported in open studies in children, including neonates, treated with cefotaxime for meningitis and various other serious infections. In some situations, cefotaxime has been given in combination with another antibiotic such as an aminoglycoside, but the merits of such a combination have not been clearly established. Whether cefotaxime alone is appropriate therapy for conditions previously treated with aminoglycosides (other than pseudomonal infections) also needs additional clarification, but if established as equally effective in such conditions cefotaxime offers potentially important clinical and practical advantages in its apparent lack of serious adverse effects and freedom from the need to undertake drug plasma concentration monitoring.

Antibacterial Activity: Cefotaxime has a broad spectrum of activity in vitro which includes Gram-positive and Gram-negative aerobic and anaerobic bacteria. Cefotaxime is as active as benzyl penicillin against Streptococcus pneumoniae and pyogenes, but is also very active against penicillin-resistant and multiple drug-resistant strains of Streptococcus pneumoniae. Like other cephalosporins, cefotaxime has poor activity against enterococci (including Streptococcus faecalis). Penicillin-sensitive and -resistant strains of Staphylococcus aureus are inhibited by low concentrations of cefotaxime, but cephalothin and cefamandole are more active against this species. When compared with other ‘third generation’ cephalosporins, cefotaxime tends to be similar in activity to cefoperazone against S. aureus, but more active than cefoperazone against streptococci in general, and more active than moxalactam against all Gram-positive bacteria.

Cefotaxime exhibits both a wider spectrum and greater activity against Gram-negative aerobic bacteria than ‘first generation’ or ‘second generation’ cephalosporins, is generally more active than cefoperazone except against Pseudomonas aeruginosa, and similar in activity to moxalactam. A multicentre study in the USA found that over 91% of 6000 clinical isolates of Enterobacteriaceae were inhibited by 0.5 μg/ml or less of cefotaxime. This antibiotic is active against many cephalothin-resistant and gentamicin-resistant Enterobacteriaceae and against some strains which show multiple drug resistance. Cefotaxime is also active at very low concentrations (MIC₉₀ ⩽ 0.06 μg/ml) against β-lactamase-producing and non-producing strains of Haemophilus influenzae and Neisseria gonorrhoeae. Although cefotaxime tends to be less active than cefoxitin against Bacteroides fragilis, it inhibits most other anaerobic bacteria at low concentrations.

Like cefuroxime, cefotaxime is highly stable to degradation by β-lactamases produced by S. aureus and various Gram-negative bacteria, but not to that produced by B. fragilis. Although desacetyl-cefotaxime, the principal metabolite of cefotaxime, is less active in vitro than the parent compound, it appears to be more active than cefoxitin and cefuroxime against some Gram-negative bacilli.

A combination of cefotaxime and gentamicin was found to be synergistic for over one-half of the strains of P. aeruginosa tested, including gentamicin-resistant strains but not carbenicillin-resistant strains. Similar results were obtained with cefotaxime plus tobramycin against tobramycin-sensitive strains of P. aeruginosa. However, the synergistic activity of cefotaxime and amikacin varied widely between studies.

In general, there was usually little difference between minimum bactericidal (MBC) and minimum inhibitory concentrations (MIC) of cefotaxime for most Gram-negative organisms studied. Although results tended to vary from study to study, larger differences have been reported for some species such as Enterobacter, indole-positive Proteus and Pseudomonas aeruginosa. Little information is available on the MBC to MIC relationship for Gram-positive organisms.

Renal Tolerance: In studies to date, cefotaxime appeared to be free of adverse effects on renal function. Thus, a renal tolerance study in rabbits found that subcutaneous cefotaxime (750 or 1500 mg/kg/day for 7 days), like moxalactam (same dose), but unlike cephaloridine (100 or 200 mg/kg/day) did not significantly increase plasma creatinine or excretion of the lysosomal enzyme N-acetylglucosaminidase.

A study in healthy volunteers which measured urinary excretion of alanine aminopeptidase (an early sensitive indicator of renal tubular damage) found that cefotaxime 6 g/day alone or given with frusemide 20 mg/day did not affect proximal renal tubule function. Similar results were reported in small groups of patients with serious infections (and normal renal function) treated with cefotaxime 6 g/day alone or combined with azlocillin 15 g/day. Results from this small study also found that cefotaxime given in combination with tobramycin 3 mg/kg/day did not increase the risk of tobramycin nephrotoxicity.

Some patients with impaired renal function have also been treated with cefotaxime, usually without any deterioration in renal function. However, there is relatively little detailed information available on such patients.

Pharmacokinetics: After a 1000mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 μg/ml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200 μg/ml, respectively. There is no accumulation following administration of 1000mg intravenously or 500mg intramuscularly for 10 or 14 days.

The apparent volume of distribution at steady-state of cefotaxime is 21.6 L/1.73m² after 1g intravenous 30-minute infusions. Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 μg/ml in children with meningitis. Concentrations (0.2–5.4/μg/ml) inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gallbladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile.

Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine, about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390 ml/minute and renal clearance 145 to 217 ml/minute.

After intravenous administration of cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours.

In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight babies relative to that in term and average birth weight neonates of the same age.

In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function.

Therapeutic Trials: Published studies on several thousand patients have documented the efficacy of cefotaxime (usual dosage, 2 to 6 g/day at 6-, 8-or 12-hourly intervals) in a wide range of infections caused by Gram-positive and Gram-negative aerobic bacteria and, occasionally, anaerobic bacteria. Cefotaxime has been used successfully in patients who had failed to respond to other antibiotics, and in infections caused by organisms resistant to usual therapy, such as: Enterobacteriaceae resistant to other cephalosporins, gentamicin and/or carbenicillin; Serratia marcescens and Klebsiella pneumoniae resistant to all commercially available antibiotics; ampicillin-resistant Haemophilus influenzae; and penicillin-resistant Neisseria gonorrhoeae. Although cefotaxime alone was effective in some patients with pseudomonal infections, on the basis of present evidence it cannot be recommended as the sole antibiotic for suspected or confirmed pseudomonal infections.

A large number of patients with urinary tract infections, many of which were complicated by underlying urological abnormalities, have been treated successfully with cefotaxime in open or controlled studies. About 70 to 90% of infecting strains of cefotaximesensitive Gram-negative organisms were eradicated from patients with complicated and uncomplicated urinary tract infections immediately following treatment with cefotaxime 2 g/day. In general, E. coli, Klebsiella species, indole-positive and -negative Proteus, Enterobacter and Citrobacter species were eradicated more successfully than Pseudomonas and Serratia species. Although large studies in patients with complicated urinary tract infections have shown intravenous cefotaxime in a dose of 2 g/day to be significantly (p < 0.01) superior to cefazolin 4 g/day, ceftezole 4 g/day and sulbenicillin 10 g/day, caution must be exercised in interpreting these results because of the manner in which response was assessed. Results from smaller comparative studies suggested that better bacteriological responses were obtained with cefotaxime 2 g/day, than with cefazolin 2 g/day, cefuroxime 2.25 g/day, cefoxitin 3 g/day, or gentamicin 160 mg/day in various types of urinary tract infections. However, these results require confirmation in well-controlled studies.

Cefotaxime has been studied in many hospitalised patients with lower respiratory tract infections, frequently caused by Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella species, E. coli and Proteus mirabilis. 75 to 100% of patients with pneumonia showed complete resolution or improvement in clinical signs and symptoms and chest radiographs. In a large comparative study in patients with mild to moderate pneumonia complicated by underlying respiratory disease, or in patients with other lower respiratory tract infections, cefotaxime 4 g/day was as effective clinically, but more effective bacteriologically, than intravenous cefazolin 4 g/day. However, only 35% of 218 patients in this study were bacteriologically assessable.

In the treatment of patients with septicaemia/bacteraemia, cefotaxime-sensitive Gram-negative bacteria such as E. coli, Klebsiella and Proteus species were isolated most frequently and over 90% of these organisms were eradicated from blood. Bacteraemia caused by Serratia marcescens, Pseudomonas species and Gram-positive bacteria was also treated successfully with cefotaxime alone.

Intra-abdominal infections such as peritonitis, and to a lesser extent hepatic and biliary infections, have also been treated with cefotaxime, often as an adjunct to surgery. Cefotaxime 80 mg/kg/day was as effective as a combination of gentamicin 3 mg/kg/day and a rather lower than usual dose of clindamycin (20 mg/kg/day) in treating patients with peritonitis (85% vs 82% cured, respectively) and similar polymicrobial soft-tissue surgical sepsis, despite in vitro susceptibility results suggesting superior activity of the combination therapy.

Satisfactory clinical responses occurred in over 86% of patients treated with cefotaxime (often in conjunction with surgical procedures) for skin and soft tissue infections (average dose 4 g/day) or osteomyelitis (average dose 9 g/day) caused by Gram-positive aerobes (such as S. aureus), Gram-negative aerobes and by anaerobes.

In general, over 90% of women with a variety of obstetric and gynaecological infections have responded to cefotaxime, sometimes in conjunction with surgery. Similar response rates of 96 to 100% have been reported in patients (usually male) treated with a single intramuscular injection of cefotaxime for uncomplicated gonorrhoea caused by penicillinase-producing or non-penicillinase-producing strains of Neisseria gonorrhoeae.

Encouraging results have been obtained with cefotaxime used alone or in combination with another antibiotic in the treatment of patients (mainly neonates and infants) with meningitis caused by the major meningeal pathogens, H. influenzae, S. pneumoniae and N. meningitidis, and also by Gram-negative bacilli (e.g. E. coli and Klebsiella species), including strains resistant to traditional therapy. To date, published clinical experience in other difficult therapeutic areas such as endocarditis, or suspected or proven infections in granulocytopenic and/or cancer patients is rather limited.

Several hundred children with various other types of serious infections have also been treated in open studies with cefotaxime alone or in combination with another antibiotic such as an aminoglycoside or penicillin. In general, clinical response rates varied from about 90% for children with septicaemia, gastrointestinal or multiple infections, to 100% for infections of the respiratory and urinary tracts treated with cefotaxime alone. Several studies in children with bacteriologically confirmed infections found that over 90% of the pathogens (predominantly cefotaxime-sensitive Gram-negative bacteria) were eradicated with cefotaxime alone. Dosages usually ranged between 50 and 100 mg/kg/day, given at 6-, 8-, or 12-hourly intervals.

In some countries cefotaxime is approved for perioperative use to reduce the incidence of postoperative infections in patients undergoing contaminated or potentially contaminated surgery, and in women undergoing caesarean section. Favourable results after prophylactic perioperative treatment with cefotaxime have been reported in several branches of surgery, such as genitourinary, abdominal, gynaecological and obstetric surgery.

Side effects: Cefotaxime has generally been well tolerated by adults and children following intravenous or intramuscular injection. The most commonly reported adverse clinical effects were reactions at the injection site such as pain on intramuscular injection (similar in intensity and incidence to that occurring with procaine penicillin G), and phlebitis (5%). Rash (2%), diarrhoea (1%) and variations in laboratory test results including transient elevations of renal and liver function tests have occurred with cefotaxime, but symptomatic drug-related nephrotoxicity or hepatotoxicity have not been reported. Superinfection (1.2%) and colonisation (1.6%) caused by cefotaxime-resistant Pseudomonas species or other Gram-negative bacilli, group D streptococci or Candida have occurred in patients treated with cefotaxime, particularly those who were seriously ill.

Dosage: Cefotaxime can be administered intravenously or intramuscularly. For adults with uncomplicated infections the usual dosage is 1g 12-hourly, while for those with moderate to severe infections 1 to 2g may be given 6-or 8-hourly, up to a maximum of 12 g/day. The recommended dose in neonates, infants and children usually varies between 50 and 150 mg/kg/day given 6-to 12-hourly, up to a maximum of 200 mg/kg/day in serious infections.