Ceftazidime

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Abstract
Ceftazidime is a third generation cephalosporin antibacterial agent which, since its introduction in the early 1980s, has retained a broad spectrum of in vitro antimicrobial activity and clinical utility in serious infections. However, increasing resistance to ceftazidime and other third generation cephalosporins, particularly among Enterobacteriaceae, due to the emergence of plasmid-mediated extended spectrum β-lactamases and the class I chromosomally mediated β-lactamases, is of concern. There is now a wealth of information on the pharmacokinetics of the drug, enabling ceftazidime to be used predictably, and with a low potential for adverse effects, in a diversity of patient populations. Overall, ceftazidime remains an effective agent for the treatment of serious infection, particularly those due to major nosocomial pathogens, and respiratory infections in patients with cystic fibrosis. Ceftazidime-containing regimens also remain an important option for the empirical therapy of febrile episodes in neutropenic patients. The tolerability profile of ceftazidime makes the drug a useful option in seriously ill patients who are at risk of developing adverse events with other antibacterial agents. Although patterns of bacterial resistance have changed in the ensuing years since its introduction, judicious use of this important agent will help maintain its present clinical utility. Like other cephalosporin antibacterial agents, ceftazidime inhibits the biosynthesis of bacterial cell wall peptoglycan, causing inhibition of bacterial growth or cell lysis and death. Ceftazidime remains active in vitro against most major aerobic nosocomial bacterial pathogens. Common nosocomial Gram-negative organisms susceptible to ceftazidime include Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, P. vulgaris and Providencia stuartii. Good activity remains against other Gram-negative species including Salmonella, Shigella and Neisseria spp. Activity is less reliable against Enterobacter, Serratia, Citrobacter and Acinetobacter spp. Historically, ceftazidime is best known for its activity against Pseudomonas aeruginosa. Recent in vitro data for P. aeruginosa show a wide variation in MIC90 values for this organism (0.5 to > 128 mg/L), with 85% of strains showing susceptibility according to National Committee for Clinical Laboratory Standards breakpoints. Of the Gram-positive bacteria, most streptococci remain susceptible to ceftazidime but there is an increasing number of penicillin-resistant strains also resistant to ceftazidime. Methicillin-susceptible staphylococci are moderately susceptible to ceftazidime while methicillin-resistant staphylococci, enterococci and Listeria monocytogenes are resistant to the drug. Ceftazidime has little activity against major anaerobic species with the exception of Clostridium perfringens. Bacterial resistance is an increasing problem associated with the use of β-lactam antibacterial agents, and ceftazidime is no exception. Resistance to ceftazidime is evident in bacterial species possessing extended spectrum β-lactamases (plasmid-mediated TEM and SHV derivatives) which are geographically widespread. Inducible and stably derepressed chromosomally mediated β-lactamases, which are capable of inactivating most β-lactams, are found in the Enterobacteriaceae. Of particular concern is the emergence of enzymes which are plasmid-mediated but possess the characteristics of chromosomally mediated enzymes. Ceftazidime is administered parenterally, is completely absorbed after intramuscular (IM) injection, is widely distributed to body tissues and fluids, and exhibits low protein binding (10 to 17%). Peak drug concentrations generally occur within 3 hours of IM administration. No ceftazidime metabolites have been identified and the drug is excreted almost entirely (> 95%) by renal elimination. Consequently, renal function influences the pharmacokinetics of the drug, and dosage reductions are essential in patients with renal impairment to avoid accumulation of the drug. Ceftazidime is removed by continuous ambulatory peritoneal dialysis and continuous arteriovenous haemodialysis but not by plasmapheresis. In patients with hepatic dysfunction, the pharmacokinetics are essentially unchanged, although in patients with liver cirrhosis and ascites volume of distribution at steady-state and elimination half-life are increased. Increased glomerular filtration rate accounts for increased clearance of ceftazidime in patients with cystic fibrosis. Ceftazidime, either as monotherapy or as a component of an antibacterial regimen, remains effective in the treatment of serious nosocomial infections, especially those associated with Gram-negative bacteria. In comparative studies, ceftazidime monotherapy was at least as effective as other broad spectrum antibacterial agents for the treatment of various infections including hospital-acquired lower respiratory tract infection, complicated urinary tract infection, skin and soft-tissue infection with susceptible organisms, bacteraemia and septicaemia in adults, respiratory infections in patients with cystic fibrosis, and chronic otitis media. As empirical ceftazidime monotherapy may not be appropriate for the treatment of neonatal sepsis, the addition of ampicillin, to cover against enterococci and Listeria monocytogenes, seems prudent in these neonatal patients. Despite numerous studies of the use of ceftazidime-containing regimens for the empirical therapy of febrile episodes in neutropenic patients, the ideal regimen remains elusive and, realistically, is likely to remain so. Overall, the studies show that ceftazidime monotherapy is as effective as other monotherapies or combination regimens for the empirical treatment of febrile episodes in neutropenic patients. The increase in the incidence of Gram-positive infection, and the corresponding decrease in the incidence of Gram-negative infection, in this population, has affected the choice of empirical therapy. Results from clinical studies are equivocal. Some authorities advocate ceftazidime monotherapy; others advocate the addition of vancomycin or an aminoglycoside to ceftazidime. If monotherapy, with ceftazidime or any other agent, is favoured at an institution, the possibility of infection with, or emergence of, resistant pathogens must be considered. If the clinical condition of a febrile neutropenic patient deteriorates during empirical monotherapy, treatment should be modified promptly. In common with other third generation cephalosporins, ceftazidime is generally well tolerated. Adverse events that do occur are usually mild in severity. Ceftazidime-related adverse events have been noted in approximately 9% of patients and resulted in cessation of therapy in 2 to 5% of recipients. The most common (≥ 1%) adverse events are local pain on administration and phlebitis (< 3%), hypersensitivity reactions (1 to 3%), gastrointestinal events (< 2%), transient abnormal liver function tests (3 to 9%) and a positive Coombs’ test (3%). Increases in serum creatinine and blood urea nitrogen occur in < 1% of patients but ceftazidime has not been associated with significant nephrotoxicity and there is no evidence to suggest that the drug can potentiate nephrotoxicity associated with aminoglycosides or loop diuretics. Nervous system events, ranging from headaches and paraesthesias to generalised seizures, have been reported in ≤1 to 4% of patients receiving ceftazidime. Those most at risk, and/or requiring close monitoring, include patients with a history of epilepsy, the elderly, patients with renal failure receiving high doses of ceftazidime, patients receiving intraventricular antibiotic therapy and patients with meningitis. Although ceftazidime is not associated with the haematological adverse events (coagulopathies and bleeding) of the methylthiotetrazole-containing third generation cephalosporin agents, infrequent reports of thrombocytosis, and other blood cell disorders have been noted with the drug. The usual adult dosage of ceftazidime is 3 to 6 g/day by intravenous (IV) or (IM) injection or short IV infusion, depending on the site and severity of infection. Daily doses are divided and usually administered at 8-hourly intervals, although the drug is also approved for 12-hourly administration. Higher dosages of up to 9 g/day have been used in patients with normal renal function, particularly those with cystic fibrosis, and have been well tolerated. Dosage reduction, based on creatinine clearance, is essential for patients with renal impairment. Because of the age-related decline in renal function, reductions are also necessary in the elderly. Dosage reductions for patients with hepatic dysfunction are not necessary. There has been no association of ceftazidime with any teratogenic effects. Ceftazidime is contraindicated in patients who are hypersensitive to cephalosporins. There is a degree of cross-reactivity between β-lactam antibacterial agents, and ceftazidime should be given with caution to patients who have displayed hypersensitivity reactions to penicillin antibiotics.