Cefixime

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Abstract
Cefixime is an orally active third generation cephalosporin with in vitro antibacterial activity against most important lower respiratory pathogens. The drug is active against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible Streptococcus pneumoniae but not Staphylococcus aureus. Cefixime has a long elimination half-life (3 hours compared with 0.5 hours for cefaclor and 1.5 hours for cefalexin), which allows once daily administration. Several trials have established the clinical efficacy of the drug in patients with lower respiratory tract infection (LRTI). In comparative studies cefixime had similar efficacy to amoxicillin ± clavulanic acid, cefaclor, cefalexin, cefuroxime axetil and clarithromycin. Trials evaluating the efficacy of cefixime as the oral component of intravenous to oral switch therapy have produced promising preliminary results although further carefully designed trials are needed in this area. As with certain other drugs of its class, gastrointestinal disturbances are the most frequently reported adverse events in patients taking cefixime and cases of pseudomembranous colitis have been reported. Thus, cefixime is an effective treatment for mild to moderate LRTI and may have a role as the oral component of intravenous to oral switch therapy although further well designed studies are needed to confirm initial favourable results in this important emerging area of antibacterial therapy. Cefixime has good (MIC ≤0.75 mg/L) in vitro activity against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible (but not penicillin-resistant) Streptococcus pneumoniae, the most common lower respiratory pathogens. Certain acute pneumonia pathogens are susceptible to cefixime including Escherichia coli and Klebsiella pneumoniae, while others, including Bacteroides spp., Peptostreptococcus spp., Enterobacter spp., Pseudomonas aeruginosa, Legionella spp. and Staphylococcus aureus are not. Oral administration of cefixime 200mg produces peak plasma concentrations of approximately 2.0 to 2.6 mg/L after 3 to 4 hours. Time to maximal plasma concentrations is lengthened slightly when the drug is given with food. Accumulation did not occur after administration of cefixime 400 mg/day for 15 days to volunteers. Cefixime does not appear to penetrate well into sputum but reaches useful levels in bronchial mucosa (up to 2.4 mg/L). Total systemic clearance was 4.4 L/hour (73 ml/min) after administration of a single 200mg intravenous dose of cefixime to volunteers; renal clearance accounted for 40% of this. Clearance was 9.7 L/h (162 ml/min) after oral administration of a single 200mg dose and 11.4 L/h (190 ml/min) after oral administration of a single 400mg dose. Up to 20% of a 200mg dose is recovered unchanged from the urine over a 24-hour period. Although maximum plasma concentrations and the area under the plasma concentration versus time curve may be greater in older versus younger patients, the dosage of cefixime does not need to be adjusted according to age. However, elimination half-life and clearance are prolonged in patients with severe renal function impairment and in patients on haemodialysis or continuous ambulatory peritoneal dialysis. Numerous noncomparative and comparative trials have evaluated the efficacy of cefixime as treatment for lower respiratory tract infection (LRTI). In a large noncomparative multicentre trial in patients with acute bronchitis or acute exacerbations of chronic bronchitis, cefixime produced a clinical cure/improvement rate of 96%. The drug has also shown similar efficacy to amoxicillin/clavulanic acid, cefaclor, cefalexin and cefuroxime axetil in patients with various LRTIs. Studies conducted solely in patients with community-acquired LRTI have also shown cefixime to be clinically efficacious. Comparative studies in this indication have shown the drug to be as effective as clarithromycin in adults and amoxicillin/clavulanic acid in children. Comparative studies in hospitalised patients with LRTI reported cefixime was as effective as intravenous ceftriaxone or oral cefalexin or amoxicillin. Three studies have evaluated the use of cefixime as the oral component of cephalosporin-based intravenous to oral switch regimens (a relatively new cost saving strategy) in hospitalised patients with LRTI. Cefixime 400mg once daily administered after a 2- to 3-day course of intravenous ceftizoxime (2 g/day) was clinically effective in 9 patients with severe acute pneumonia. A larger study in this indication also found cefixime to be clinically effective; in this trial cefixime 400mg once daily was given after intravenous ceftizoxime or ceftriaxone. In this study, clear criteria had to be met before the change to oral therapy was made but such criteria were absent in other studies that changed treatment from a parenteral cephalosporin to oral cefixime. 120 patients were enrolled; of these, 45 were withdrawn (many with infections caused by pathogens not susceptible to cefixime). 74 of 75 evaluated patients experienced clinical cure; bacteriological data for these patients were not presented. The sole comparative trial in this indication found cefixime administered after intravenous cefotaxime to be as effective as a full course of intravenous cefotaxime in patients with LRTI of unspecified severity. Analysis of individual comparative studies reveals that the rate of adverse events in cefixime recipients was generally similar to that in patients who received the comparative drug. However, the overall rate of adverse events in these premarketing studies was generally higher than that obtained in postmarketing trials; this variation is probably largely attributable to methodological differences. Gastrointestinal symptoms, especially diarrhoea, are the most frequent adverse events in patients treated with cefixime. Other adverse events associated with cefixime therapy include skin and appendage symptoms, headache and dizziness. Cases of pseudomembranous colitis associated with administration of the drug have also been reported. The recommended adult (including children >12 years of age or weighing >50kg) dosage of cefixime is 400 mg/day which may be given as a single daily dose or 200mg every 12 hours. The recommended dosage for children ≤12 years of age or weighing ≤50kg is 8 mg/kg/day (oral suspension). This may be administered as a single daily dose or 4 mg/kg every 12 hours. The dosage of cefixime should be reduced by 25% (to 300 mg/day) in patients with moderate renal impairment (creatinine clearance 21 to 60 ml/min) or patients undergoing haemodialysis and by 50% (to 200 mg/day) in patients with severe renal impairment (creatinine clearance ≤20 ml/min) or undergoing continuous ambulatory peritoneal dialysis.

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