Aztreonam

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Abstract
Aztreonam 1 zthreonam; SQ 26,776) is the first member of a new class of β-lactam antibiotics, the monobactams. Aztreonam is selectively active against Gram-negative aerobic bacteria and inactive against Gram-positive bacteria. Thus, in vitro, aztreonam is inhibitory at low concentrations (MIC 90 ≤ 1.6 mg/L) against Enterobacteriaceae except Enterobacter species, and is active against Pseudomonas aeruginosa, 90% of pseudomonads being inhibited by 12 to 32 mg/L. Aztreonam is inactive against Gram-positive aerobic bacteria and anaerobes, including Bacteroides fragilis. Therefore, when administered alone, aztreonam has minimal effect on indigenous faecal anaerobes. Aztreonam must be administered intravenously or intramuscularly when used to treat systemic infections, since absolute bioavailability is very low (about 1%) after oral administration. Since elimination half-life is less than 2 hours, 6- or 8-hourly administration is used in the treatment of moderately severe or severe infections, although 12-hourly injection is adequate in less severe systemic and some urinary tract infections. Therapeutic trials have shown aztreonam to be effective in Gram-negative infections including complicated infections of the urinary tract, in lower respiratory tract infections and in gynaecological and obstetric, intra-abdominal, joint and bone, skin and soft tissue infections, uncomplicated gonorrhoea and septicaemia. In comparisons with other antibiotics, aztreonam has been at least as effective or more effective than cefamandole in urinary tract infections and similar in efficacy to tobramycin or gentamicin. Where necessary, aztreonam and the standard drug have both been combined with another antibiotic active against Gram-positive and/or anaerobic bacteria. Aztreonam has been effective in eradicating pseudomonal infections in most patients (except in patients with cystic fibrosis), but the inevitably limited number of pseudomonal infections available for study prevents any conclusions as to the relative efficacy of aztreonam compared with other appropriate regimens against these infections. Thus, with an antibacterial spectrum which differs fromthat of other antibiotics, aztreonam should be a useful alternative to aminoglycosides or ‘third generation’ cephalosporins in patients with proven or suspected serious Gram-negative infections. Aztreonam, a monobactam, is inhibitory in vitro at low concentrations (usually ≤ 1.0 mg/L) against 90% of clinical isolates of the Enterobacteriaceae (except Enterobacter species) as well as Haemophilus influenzae, Neisseria gonorrhoeae, Salmonella and Shigella species. Pseudomonas aeruginosa are generally susceptible to aztreonam, being usually inhibited by 12 to 32 mg/L of the drug. Aztreonam is essentially inactive against Gram-positive bacteria and the important anaerobes. In comparisons with the third generation cephalosporins and other antibiotics, the activity of aztreonam against the enterobacteriaceae is generally similar to that of cefotaxime and ceftazidime and greater than that of cefoperazone, cefoxitin, gentamicin, tobramycin or piperacillin. Against P. aeruginosa, aztreonam is generally similar in activity to cefoperazone, more active than cefotaxime, latamoxef (moxalactam) and ceftizoxime and usually less active than ceftazidime. The inhibitory activity of imipenem against P. aeruginosa is consistently greater than that of aztreonam. In common with third generation cephalosporins and latamoxef, aztreonam is stable to hydrolysis by a wide range of β-lactamases, but not against Class I cephalosporinases. The minimum bactericidal concentration of aztreonam is generally equal to or 2 to 4 times the minimum inhibitory concentration for most strains tested, although for P. aeruginosa the MBC/MIC ratio varied over a wider range. Aztreonam has a high binding affinity for penicillin binding protein 3 and thus produces elongated bacterial forms that are unable to grow. An increase in the inoculum size to 106fu or the addition of up to 75% human serum to the growth media had little effect on the MIC of aztreonam for tested strains of susceptible E. coli and Klebsiella species. A combination of aztreonam and an aminoglycoside has been synergistic against up to 96% of strains of Pseudomonas species, but most often against 50% of tested strains. In vivo, the activity of aztreonam has been demonstrated in a variety of experimental Gram-negative bacterial infections in animals and was similar to that of cefotaxime and ceftazidime against pseudomonal infections and H. influenzae meningitis. In this latter model, aztreonam was more effective in eliminating ampicillin-resistant strains than chloramphenicol. Aztreonam is completely absorbed after intramuscular injection but less than 1% of an orally administered dose is available to the systemic circulation. Mean plasma concentrations generally increase linearly with dosage after intravenous or intramuscular administration and are about 58, 125, 242 and 455 mg/L 10 minutes after bolus intravenous injection of single doses of 0.5, 1.0, 2.0 and 4.0g, respectively. Single-dose intramuscular administration of lg results in a mean peak plasma concentration of about 46 to 66 mg/L. After the first hour, plasma concentrations of aztreonam are comparable whether aztreonam is administered intravenously or intramuscularly. There is no evidence of accumulation in healthy subjects given repeated intravenous or intramuscular doses at 8-hourly intervals. Volume of distribution at steady-state is 0.15 to 0.18 L/kg (total drug) and 0.4 L/kg for the free drug. Following usual parenteral doses aztreonam is present in prostatic tissue, cerebrospinal fluid (inflamed meninges) and skin blister fluid at peak concentrations many times higher than required to inhibit susceptible enterobacteriaceae. Aztreonam reaches the placenta and is present in breast milk, but since the bioavailability of oral aztreonam is very low there is little likelihood of side effects in breast-fed infants of mothers treated with the drug. Binding of aztreonam to plasma proteins has been reported to be between 56 and 60%. Aztreonam is metabolised to a limited extent, there being no evidence of microbiologically active metabolites. Excretion is mainly via the urine, with high urinary concentrations of around 3000 mg/L occurring during the first 2 hours after intravenous administration of a lg dose. The elimination half-life (t1/2β) of aztreonam in healthy subjects is between 1.3 and 2 hours, while that of the main metabolite (SQ26,992) is about 26 hours. Elimination half-life is prolonged proportionally to the extent of renal impairment and in patients with alcoholic cirrhosis, but appears shorter in patients with cystic fibrosis than in healthy subjects. Aztreonam alone, and where necessary combined with an antibiotic effective against Gram-positive and/or anaerobic bacteria, has been used successfully to treat infections of the urinary tract and lower respiratory tract, as well as intraabdominal infections, obstetric and gynaecological infections, septicaemia, bone and joint infections and acute uncomplicated gonorrhoea. In most patients with Gram-negative urinary tract infections there were urological abnormalities or predisposing factors, and infections were usually recurrent. At follow-up 1 to 6 weeks after the end of treatment with aztreonam 1 to 6g daily, 42 to 67% of patients were considered cured. In comparisons with other antibiotics aztreonam was at least as effective as, or more effective than, cefamandole in urinary tract infections and similar in efficacy to the aminoglycosides (gentamicin or tobramycin) in patients with serious urinary tract infections. Four to 6 weeks after the end of treatment, bacteriological cure was achieved in 56 to 93% of patients treated with aztreonam and in 34 to 78% treated with the standard drug. Aztreonam 3 to 6g daily (usually) was clinically effective in about 90% of patients with lower respiratory tract infections caused by Gram-negative bacteria. Bacteriological cure (other than in patients with cystic fibrosis) was achieved in 67 to 79% of patients. As with other antibiotics, aztreonam was less effective in eradicating the infecting pathogen (P. aeruginosa) in patients with cystic fibrosis than in other patients. In comparisons with tobramycin in patients with respiratory tract infections, aztreonam has been of similar efficacy in two studies and more effective in a third. Aztreonam (usually 6g daily) and tobramycin 3 mg/kg daily were also of similar efficacy in eradiciting postoperative or perioperative intra-abdominal infections, as were aztreonam 6g daily and gentamicin 4.5 mg/kg daily in women with endometritis following caesarean section. Septicaemia was cured in 67 to 100% of patients treated with aztreonam 4 to 6g daily or 50 to 100 mg/kg daily administered intravenously. Chronic or acute osteomyelitis was successfully treated in small numbers of patients in whom P. aeruginosa was the most common pathogen and infections of skin and soft tissue were cured in 87% of patients. The frequency of relapse has yet to be adequately determined. Initial studies in men and women with acute uncomplicated gonorrhoea suggest that aztreonam lg intramuscularly may be a suitable alternative to spectinomycin in patients infected with penicillin-resistant gonococci. Preliminary studies in healthy subjects that orally administered aztreonam (300mg daily for 5 days) may be suitable for selective elimination of intestinal Gram-negative bacteria, since these organisms were removed without disturbing the commensal yeasts or anaerobes. Aztreonam has generally been well tolerated, the most frequently reported side effects having been local reactions at the infusion site (1.7%), skin rash (1.8%), nausea and/or vomiting (0.6%) and diarrhoea (0.8%). Superinfection, mostly with Group D streptococci, has been reported in 9.7% of patients, but specific treatment has been required in about half of these infections. Aztreonam appears to have low potential for immunogenicity and also for cross-reactivity with antibodies to other β-lactam antibiotics. Aztreonam has been used safely in patients who are allergic to penicillin. Aztreonam for injection may be administered intravenously or intramuscularly. Dosage should be determined by the severity of infection and the susceptibility in vitro of the pathogen. As a guide, the usual dose is 0.5 to lg 8- or 12-hourly in urinary tract infections, 1 or 2g 8- or 12-hourly in moderately severe systemic infections and 2g 6- or 8-hourly in severe systemic or life-threatening infections or those caused by P. aeruginosa. In patients with moderate to severe renal impairment the dosage of aztreonam should be reduced. As a general rule, aztreonam dosage should be halved in patients whose creatinine clearance is between 0.6 and 1.8 L/h, although an initial loading dose of 1 or 2g should be given in such patients.