Ceftazidime

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Abstract
Synopsis: Ceftazidime 1 is a new ‘third generation’ cephalosporin administered intravenously or intramuscularly. Similarly to other third generation cephalosporins it has a broad spectrum of in vitro activity against Gram-positive and Gram-negative aerobic bacteria, is particularly active against Enterobacteriaceae (including β-lactamase-positive strains) and is resistant to hydrolysis by most β-lactamases. Importantly, in vitro ceftazidime is presently the most active cephalosporin available against Pseudomonas aeruginosa, but it is less active against Staphylococcus aureus than first and second generation cephalosporins. Only larger comparative trials are likely to discern any statistically significant differences in clinical efficacy which may exist between ceftazidime and other antibiotics, but ceftazidime appears to be similar in efficacy to ‘standard’ comparative drugs in lower respiratory tract infections and complicated and/or chronic urinary tract infections among debilitated or hospitalised patients. Thus, in patients having Gram-negative infections at these sites and in whom the potential toxicity of the aminoglycosides is a concern, ceftazidime may be a valuable alternative in that it apparently lacks serious side effects and does not require routine drug plasma concentration monitoring. In fibrocystic patients having acute respiratory tract infections, ceftazidime is highly effective at both reducing symptoms of infection and temporarily reducing the sputum counts of Pseudomonas species. However, in these patients resistance to ceftazidime may develop, as seen with other β-lactam antibiotics. In the treatment of fever of unknown origin or documented infections in immunocompromised adults and children, ceftazidime appears to be similar in efficacy to various 2-or 3-drug combinations. Nevertheless, the coadministration of an antibiotic having greater efficacy against Gram-positive bacteria should be considered in immunocompromised patients. Results from a small number of comparative trials suggest that ceftazidime may be as effective as the aminoglycosides in intra-abdominal, obstetric and gynaecological, and skin and soft tissue infections. However, further clinical experience, particularly a few well designed comparative studies, is needed to clarify the comparative efficacy in these conditions as well as in septicaemia/bacteraemia, meningitis, and bone and joint infections. Antibacterial Activity: Ceftazidime is highly resistant to β-lactamases and has a broad spectrum of in vitro antibacterial activity, including Pseudomonas aeruginosa. Like other third generation cephalosporins, ceftazidime is active in vitro at therapeutic concentrations against most Enterobacteriaceae, including β-lactamase-positive strains and those resistant to first generation cephalosporins or other antibiotics. 90% of Serratia marcescens, Providencia species and indole-positive Proteus species are usually inhibited by 8 mg/L or less, and 90% of most other Enterobacteriaceae are usually inhibited by 2 mg/L or less. However, the activity of ceftazidime against Enterobacter and Citrobacter species (except C. diversus) varies widely between studies [minimum concentration inhibitory of 90% of tested strains (MIC90) of 32 mg/L]. 90% of tested strains of P. aeruginosa including β-lactamase-positive, as well as cefsulodin-, piperacillin-, carbenicillin-or aminoglycoside-resistant isolates, are sensitive or moderately sensitive to ceftazidime (MIC90 0.5 to 32 mg/L). Ceftazidime is also active in vitro against P. cepacia, P. alcali genes, P. putida and VA-1 (P. picketti), but some other Pseudomonas species are resistant. In common with most other third generation cephalosporins, ceftazidime is highly active against Haemophilus influenzae, Neisseria gonorrhoeae and Neisseria meningitidis (including β-lactamase-positive strains) [MIC90 < 1 mg/L]. 90% of tested strains of Acinetobacter species are usually at least moderately sensitive to ceftazidime. Ceftazidime is generally active in vitro against Staphylococcus aureus (range of reported MIC90 8 to 64 mg/L) except oxacillin/methicillin-resistant strains, and against streptococci except enterococci. Ceftazidime is less active than first and second generation cephalosporins against S. aureus. Clostridium perfringens is generally sensitive or moderately sensitive to ceftazidime, but most other clinically important anaerobic bacteria tested (including Bacteroides fragilis and Clostridium difficile) are resistant to or at best only moderately sensitive to ceftazidime. Against most susceptible bacteria the ceftazidime minimum bactericidal concentration (MBC) is equal to or twice the MIC. However, the MBC/MIC ratio is greater than 2 for some strains of P. aeruginosa, Enterobacteriaceae, and Acinetobacter species. Generally, the MIC of ceftazidime for most strains is little affected by increases in inoculum size up to 106 colony-forming units/ml, by different media, or by the addition of up to 75% human serum. Synergy between ceftazidime and various aminoglycosides or other antipseudomonal β-lactam antibiotics (cefsulodin or ureidopenicillins) has been demonstrated against P. aeruginosa and Enterobacteriaceae. However, the degree of synergistic activity varies widely with the drug and bacterial strain. As occurs with other cephalosporins, the combination of ceftazidime and cefoxitin is antagonistic in Pseudomonas aeruginosa, probably due to derepression (induction) of type I β-lactamases by cefoxitin. Ceftazidime has marked stability in vitro against a variety of β-lactamases, including most R-piasmid-mediated enzymes. The β-lactamase stability pattern of ceftazidime is similar to those of cefoxitin and moxalactam (latamoxef) which are hydrolysed by fewer β-lactamases than most other cephalosporins. However, in some instances the stability of ceftazidime to hydrolysis by the β-lactamase of a species does not correlate with a low MIC for that species. The in vitro activity of ceftazidime has been confirmed in vivo against experimental infections in rodents, guinea-pigs and rabbits. Pharmacokinetics: Peak ceftazidime serum concentrations of 70 to 72 mg/L are attained immediately after a lg infusion administered over 20 to 60 minutes. Peak values immediately after administration of 1 g by intravenous bolus or approximately 1 hour after intramuscular injection are 120 to 146 and 37 to 43 mg/L, respectively. Ceftazidime mean peak plasma concentrations and the area under the concentration/time curve (AUC) appear to increase linearly with dose. Multiple-dose studies reveal no accumulation of drug. The volume of distribution after intravenous or intramuscular administration is usually between 15 and 20L. Therapeutic concentrations of ceftazidime are achieved in a variety of tissues and body fluids —including female genital tissue, bone, pleural effusions, sputum, bile and cerebrospinal fluid (inflamed meninges), and peritoneal, extravascular, lymphatic and amniotic fluid. Mean ceftazidime concentrations of 5.2 mg/L are attained in human breast milk 1 hour after administration of 2g intravenously. Plasma protein binding of ceftazidime ranges from 5 to 22.8% and is independent of concentration. In healthy subjects the elimination half-life of ceftazidime is 1.5 to 2.8 hours. The drug is not metabolised and is eliminated largely via the urine. As the pharmacokinetics are not significantly affected by probenecid, glomerular filtration and not tubular secretion appears to be the mechanism of renal elimination. Mean renal clearance of ceftazidime from healthy subjects ranges from 72 to 141 ml/min. There is a direct correlation between creatinine clearance and elimination rate. Thus, the half-life is prolonged in patients with moderate to severe renal impairment. In patients having creatinine clearance Therapeutic Trials: Ceftazidime (usual dosage 1 to 6g daily administered at 8-to 12-hourly intervals) has been shown to be effective in a wide range of infections caused by Gram-negative and Gram-positive bacteria. The infections, which were usually of moderate or greater severity, included lower respiratory tract infections (including acute infections in fibrocystic patients), urinary tract infections, septicaemia/bacteraemia, skin, soft tissue, bone and joint infections, intra-abdominal, obstetric and gynaecological infections, meningitis, and infections in febrile neutropenic patients. Frequently the infecting organism was a multidrug-resistant (but ceftazidime-sensitive) species of Enterobacteriaceae or a Pseudomonas species, or the infection had failed to resolve on alternative antibiotics). Bacteriological response rates varied. In complicated urinary tract infections in particular, from 90 to 100% of most Gram-negative and Gram-positive pathogens were eradicated, but percentages were lower for Enterobacter species (85%), Citrobacter species (79%), P. aeruginosa (76%), Staphylococcus epidermidis (73%) and Streptococcus faecalis (67%). Superinfection occurred in 2.5% of ceftazidime-treated patients and the development of resistance during therapy has been reported in a few Pseudomonas and Enterobacter species. Most of the comparative trials (generally open and randomised) were small and hence unlikely to identify small differences between drugs that may have existed, but as indicated below, ceftazidime appeared to be similar in efficacy to the ‘standard’ antibiotics with which it was compared. In patients with bacteriologically confirmed pneumonia or bronchitis, usually complicated by underlying diseases, mean clinical response rates (cured) of 51 to 88% have been reported in various comparative studies following treatment with ceftazidime (3 to 6 g/day as 2 to 4 divided doses). Mean clinical response rates of 53 to 88% were reported for patients in the comparative groups (cefamandole 1.5g 8-hourly or 1g 6-hourly, cefazolin 1.5g plus tobramycin 1.7 mg/kg 8-hourly, or ticarcillin 3g 4-hourly plus tobramycin 1.5 mg/kg 8-hourly). In patients having acute exacerbations of chronic bronchitis, clinical response rates were lower: 40% of patients receiving ceftazidime 2g 12-hourly and 31% of patients receiving cefazolin 2g plus tobramycin 40 to 80mg 12-hourly responded. Fibrocystic patients having acute pseudomonal lower respiratory tract infections were assessed in a randomised double-blind comparison of ceftazidime, cefoperazone, cefsulodin (200 mg/kg daily, each), azlocillin and piperacillin (400 mg/kg daily, each). The patients treated with ceftazidime or cefsulodin had the greatest improvement in their clinical condition and the highest temporary reduction of sputum counts of Pseudomonas species. In these patients the development of resistance was seen regularly with all of the drugs, and with ceftazidime and carbenicillin in a second comparative trial (a reversible resistance), but no significant resistance developed when tobramycin was used as mono-therapy. However, the therapeutic implications of the resistance which developed in these patients are unclear. In complicated and/or chronic urinary tract infections (22 to 100% of which were due to P. aeruginosa) ceftazidime 0.5 to 1g 12-hourly effected a clinical and/or bacteriological response in 81 to 96% of patients (mean values reported in 4 different studies). Response rates for netilmicin lOOmg twice daily (60%), or tobramycin 1 mg/kg 8-hourly (79 to 90%) were not statistically different from the ceftazidime values. Ceftazidime 2g twice daily cured all 27 patients with gallbladder empyema undergoing cholecystectomy whereas 12 of 23 patients receiving cefamandole 2g thrice daily plus tobramycin 80mg twice daily required withdrawal from the study because the pathogens (8 mixed infections of Escherichia coli plus enterococci, and 4 pseudomonal infections) were not sensitive to the drugs. 34 of 38 patients having various types of obstetric and gynaecological infections responded to therapy with ceftazidime 2g 8-hourly versus 34 of 39 patients treated with clindamycin 600mg plus tobramycin 1.5 mg/kg 8-hourly. In paediatric patients, ceftazidime (usual dosage 90 to 150 mg/kg daily) has demonstrated clinical efficacy in chronic or recurrent otitis media complicated by P. aeruginosa (65% cured), complicated pseudomonal urinary tract infections (81% bacterial eradication) and serious infections in neonates less than or greater than 48 hours old (100% and 87.5% cured, respectively). In immunocompromised patients (neutropenic adults and children, and both neutropenic and non-neutropenic adult haematological cancer patients) having fever of unknown origin or documented infection, ceftazidime 3 to 6g daily (as 3 to 6 divided doses) appeared to be similar in efficacy to the various 2-or 3-drug regimens with which it was compared (an aminoglycoside plus a ureidopenicillin and/or a different cephalosporin). However, inadequate efficacy against Gram-positive bacteria (2 studies) or a tendency to superinfection with Gram-positive bacteria (1 study) prompted the investigators to recommend the coadministration of an antibiotic having greater Gram-positive activity. Side Effects: Ceftazidime is generally well tolerated. The most commonly reported side effects are similar to those of other 0-lactam antibiotics and include skin rashes, fever, diarrhoea, transient eosinophilia and reversible elevation of liver function tests. Altered renal function has occurred in 1.2% of patients. Dosage and Administration: The recommended adult dosage is 1 to 6g daily in divided doses by intravenous or intramuscular injection. In urinary tract and less severe infections 500mg or 1g 12-hourly is usually adequate. In children 30 to 100 mg/kg daily and in neonates 25 to 60 mg/kg daily, as 2 to 3 divided doses, is recommended. In patients with renal impairment the dosage must be decreased according to creatinine clearance.

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