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

Abstract

Synopsis: Cefotetan1 is a new semisynthetic cephamycin antibiotic administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-negative aerobic and most clinically important Gram-positive and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the ‘first and second generation’ agents. Cefotetan is particularly active against Enterobacteriaceae but has little activity against Pseudomonas aeruginosa. An extended plasma elimination half-life of about 3.5 hours, and relatively high achievable serum and tissue levels, enables cefotetan to be administered on a twice daily basis in the treatment of mild to severe infections. Cefotetan has shown good clinical efficacy in intra-abdominal, obstetric and gynaecological infections, postoperative wound infections, and infections in immunocompromised patients — all of which are often complicated due to their polymicrobial nature or by the presence of anaerobic pathogens. A satisfactory clinical response is achieved in over 90% of paediatric patients with acute otorhinolar-yngological infections, whereas in the treatment of chronic disease, as with other agents, the efficacy is dramatically reduced. Like other cephalosporins, cefotetan is effective in treating patients with complicated urinary tract infections and lower respiratory tract infections. Its efficacy in urinary tract infections is at least as good as cefoxitin, although in this and some other clinical areas its activity relative to that of other cephamycins and cephalosporins remains to be assessed. Thus, with its convenient twice daily dosage schedule, cefotetan would appear to be a useful addition to a rapidly expanding group of antibacterial agents. Antibacterial Activity: Cefotetan has a broad spectrum of in vitro antibacterial activity and is resistant to the activity of most β-lactamases. Like the ‘third generation’ cephalosporins and other cephamycins, cefotetan is active against a wide range of Gram-negative bacteria, with 90% of strains of Escherichia coli, Klebsiella species, Proteus mirabilis and Proteus vulgaris being inhibited at concentrations of less than 1 mg/L. Other Gram-negative rods (Proteus, Providencia and Morganella species, and Haemophilus influenzae), Neisseria species, Salmonella and Shigella species and Yersinia enterocolitica are susceptible at concentrations of less than 8 mg/L. The activity of cefotetan against Ser-ratia, Enterobacter and Citrobacter species varied widely between studies (MIC90 s8 to — 64 mg/L), but these species are consistently the least sensitive of the Enterobacteriaceae to cefotetan. Unlike ceftazidime and some ‘third generation’ cephalosporins, cefotetan has little activity against Pseudomonas aeruginosa and other Pseudomonas or Acinetobacter species. Cefotetan displays modest activity (MIC₉₀ = 2 to 16 mg/L) against most Gram-positive bacteria (streptococci and staphylococci) while enterococci, including Streptococcus faecalis and methicillin-resistant Staphylococcus species, show marked resistance. Anaerobes, such as Bacteroides, Clostridium and Fusobacterium species, are usually more sensitive to cefotetan than other cephalosporins, although activity varies markedly between laboratories and species. 90% of isolates of Clostridium perfringens, C. botulinum and B. urealyticus are sensitive to cefotetan (MIC₉₀ < 1 mg/L) whereas B. thetaiotaomicron, B. ovatus, B. diastonis, and C. difficile are markedly less sensitive. Cefotetan usually has modest activity against the clinically important B. fragilis and B. asaccharo-lyticus (MIC₉₀ usually 8 to 32 mg/L). In general, there is usually little difference between the minimum bactericidal concentrations (MBC) and minimum inhibitory concentrations (MIC) of cefotetan for most Gram-negative organisms, although there have been reports of 4-fold (or more) ratios of MBC₉₀: MIC₉₀ for some species of Salmonella, Klebsiella and Proteus. The MIC₉₀ of cefotetan for most strains tested is not greatly affected by increases in inoculum size up to 10⁷ organisms per ml, by changes in pH down to 5.5 or by altering the growth medium (with the exception of the addition of 10% horse serum which caused 2-to 4-fold increases in the MIC of most bacteria). Synergy between cefotetan and other antibacterial agents (including aminoglycosides, piperacillin and other cephalosporins) has been demonstrated in some isolates of Enterobacteriaceae that were poorly sensitive to cefotetan, with additive inhibition or no effects occurring in other strains. Cefotetan has marked in vitro stability to most β-lactamases except those produced by Pseudomonas aeruginosa (type II) and certain uncommon isolates of Bacteroides fragilis, Enterobacter cloacae. Serratia liquifaciens and Citrobacter freundii. Marked direct β-lactamase inhibitory action has also been reported. Pharmacokinetic Properties: Mean peak plasma concentrations of cefotetan (about 140 to 250 mg/L) are attained after a 1g intravenous bolus dose, and over a dosage range of 0.25 to 2g are almost linearly related with dose. Peak cefotetan concentrations of up to 270 and 90 mg/L are seen after 2g intravenous drip infusion (over 60 minutes) and intramuscular administration, respectively. Plasma concentrations were nearly 2-fold higher than those attained after latamoxef (moxalactam) administration at the same doses. The volume of distribution after intravenous and intramuscular administration is usually between 8 and 13L in healthy adult volunteers. Concentrations of cefotetan likely to be active against susceptible organisms are achieved in a variety of tissues and body fluids, including female genital tissues, umbilical cord serum and amniotic fluid, gallbladder tissue and bile, prostatic tissue (but not prostatic fluid), palatine tonsillar tissue and maxillary sinus mucosa. In healthy subjects, protein binding is 78 to 91%. Breast milk concentrations are low and no accumulation has occurred with repeated doses. No metabolites of cefotetan have been detected in either plasma or urine. About three-quarters of a dose is excreted in the urine within 24 hours. Total plasma clearance has been recorded at 1.8 to 2.9 L/h, with renal clearance accounting for about 64 to 84%. The plasma elimination half-life is between 2.8 and 4.2 hours after intravenous doses and between 3.4 and 4.4 hours after intramuscular doses. The plasma half-life is slightly shorter in paediatric patients but is considerably prolonged in patients with renal impairment (to over 10 hours). Increased renal dysfunction also leads to decreased urinary recovery of cefotetan. Therapeutic Trials: The therapeutic efficacy of cefotetan 1 to 4g daily (usually given intravenously or intramuscularly every 12 hours) has been extensively documented in open and comparative trials in patients with intra-abdominal infections, obstetric and gynaecological infections, chronic, complicated urinary tract infection, lower respiratory tract infection, skin and soft tissue infection, or otorhinolaryngological disease. Cefotetan has also been used preoperatively (either alone or in combination with metronidazole) in the prevention of postoperative wound infection. However, there are only limited studies in important disease areas such as bacteraemia and septicaemia, gonorrhoea, meningitis and in immunocompromised patients. Open and controlled studies of patients with intra-abdominal infections such as peritonitis (of various aetiology) report successful treatment in 82 to 100% of patients with cefotetan. Particularly impressive results have been achieved in peritonitis due to appendicitis or other diseases, where cefotetan therapy was an adjunct to surgery and drainage. In such patients cefotetan 1 to 2g twice daily has been at least as effective as cefmetazole 2g twice daily, latamoxef 2g 3 times daily or a combination of ampicillin, gentamicin and metronidazole. Reductions in rates of postoperative infections have been seen with cefotetan in limited numbers of patients who have undergone appendicectomy (more effective than metronidazole), colorectal surgery (at least as effective as gentamicin plus metronidazole or tinidazole), biliary tract surgery (as effective as cefazolin), transurethral surgery (at least as effective as cefotaxime) and upper gastrointestinal tract surgery (more effective than cephazolin). Obstetric and gynaecological infections are often caused by anaerobic bacteria. Therefore, although open studies in large numbers of women have shown a good or excellent clinical response to cefotetan (usually 1 to 4g daily) in over 80% of patients (some of whom were unresponsive to cefmetazole, piperacillin, dibekacin or benzylpenicillin), controlled studies are needed to assess the comparative efficacy of cefotetan with standard antibiotic therapy in anaerobic infections. An overall clinical efficacy rate of 75 to 90% is seen in adults and children with acute otorhinolaryngological infections. Common causative organisms such as Staphylococcus aureus, streptococci, Neisseria species and Haemophilus influenzae are almost invariably eradicated, and treatment failures are usually only seen in acute exacerbations of chronic otitis media or in infections where Pseudomonas aeruginosa, Acinetobacter or Coryne-bacteria species are implicated. In one study of immunocompromised patients with a variety of infections, high dose cefotetan (4 to 6 g/day) therapy produced a satisfactory clinical response in nearly 60% of patients, including patients with suspected sepsis. More studies are needed in these clinical fields. Cefotetan has been used successfully in a few patients requiring oral surgery (79 to 100%), in ophthalmological infections (78%), biliary diseases (80%), and septicaemia (92%). In a large number of Japanese patients with urinary tract infections complicated by underlying urological abnormalities, treatment with cefotetan 1 to 2g daily for 5 days achieved a clinical success rate of about 60% and a bacteriological cure rate of 67 to 88%. Clinical success rates were greater in patients with infection due to a single organism than those with polymicrobial infection (65 vs 49%) and in those patients with no indwelling catheter compared to those with an indwelling catheter. However, in comparative studies conducted mostly in the United States and Europe successful treatment with cefotetan 1 to 2g twice daily occurred in 65 to 97% of patients, with this greater rate of response almost certainly being related to the fact that in Japan there are no strictly adhered to criteria for ensuring the in vitro sensitivity of the organism prior to treatment. Cefotetan was similar in clinical and bacteriological efficacy to cefmetazole 2g daily over a 5-day period; and cefotetan 2 to 4g daily was at least as effective as cefoxitin 3 to 12g daily administered for periods of 3 to 22 days. Eradication rates have exceeded 90% for most species of Enterobacteriaceae and Staphylococcus, whereas Serratia, Pseudomonas and Acinetobacter species, and particularly Pseudomonas aeruginosa and Streptococcus faecalis (eradication rates of 34 and 47%, respectively), were more resistant to cefotetan. Cefotetan has produced a clinical ‘success’ rate of about 72% in open studies of patients with lower respiratory tract infections, and was somewhat more effective in patients with (non-mycoplasmal) pneumonia (79%) than in chronic pulmonary infections, lung abscess and pleural infections (65%). Bacteriological efficacy was assessed in over 300 Japanese patients: cefotetan eradicated over 90% of the common respiratory pathogens (H. influenzae. K. pneumoniae and E. coli), but was poorly active against Pseudomonas infections. Cefotetan was equally effective as cefmetazole in a large number of patients with a variety of respiratory tract infections. In paediatric patients with community-acquired urinary tract and lower respiratory tract infections, cefotetan (usually 50 to 60 mg/kg/day) has shown a greater clinical (90 to 95%) efficacy than that seen in adults. Side Effects: Cefotetan has generally been well tolerated by adults and children following intravenous or intramuscular administration. The most commonly reported clinical adverse effects are local reactions at the site of injection, particularly with intramuscular doses, hypersensitivity reactions, such as rash and fever, and gastrointestinal effects such as nausea, vomiting and diarrhoea. Low incidences of liver function test and haematological abnormalities have been recorded. Unlike many other cephalosporins, no clinical evidence of hypoprothrombinaemic bleeding problems or disulfiram-type reactions has been published. Dosage and Administration: Cefotetan can be administered intravenously (either by bolus dose or drip infusion) or intramuscularly [with lignocaine (lidocaine) 0.5%]. The usual adult dosage is 0.5 to 1g 12-hourly, which may be increased in patients with very severe infections or immunocompromised patients to 4 to 6g daily. The recommended dose in paediatric patients is 40 to 60 mg/kg/day given 12-hourly, which may be increased to 100 mg/kg/day in serious infections.