Cefetamet Pivoxil

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Abstract
Cefetamet pivoxil is an oral third-generation cephalosporin which is hydrolysed to form the active agent, cefetamet. Cefetamet has excellent in vitro activity against the major respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and group A β-haemolytic streptococci; it is active against β-lactamase-producing strains of H. Influenzae and M. catarrhalis, but has poor activity against penicillin-resistant S. pneumoniae. Cefetamet has marked activity against Neisseria Gonorrhoeae and possesses a broad spectrum of activity against Enterobacteriaceae. Both staphylococci and Pseudomonas spp. are resistant to cefetamet. Cefetamet pivoxil has been investigated in the treatment of both upper and lower community-acquired respiratory tract infections and has demonstrated equivalent efficacy to a number of more established agents, namely cefaclor, amoxicillin and cefixime. In patients with group A β-haemolytic streptococcal pharyngotonsillitis, a 7-day course of cefetamet pivoxil was as effective as a 10-day course of the standard agent, Phenoxymethylpenicillin, in this indication. In complicated urinary tract infections, cefetamet pivoxil showed similar efficacy to cefadroxil, cefaclor and cefuroxime axetil. Cefetamet pivoxil was effective in the treatment of otitis media, pneumonia, pharyngotonsillitis and urinary tract infections in children. Preliminary data indicate that single dose cefetamet pivoxil can effectively eradicate N. Gonorrhoeae from both men and women. Cefetamet pivoxil has a tolerability profile similar to that of other oral cephalosporins, with gastrointestinal effects being the most commonly reported adverse events. To date, no symptoms of carnitine deficiency have been reported with cefetamet pivoxil. Cefetamet pivoxil offers effective alternative oral therapy for outpatient treatment of community-acquired respiratory tract infections, with the advantage of improved activity against H. Influenzae and increased β-lactamase stability. However, its use in areas with a high incidence of penicillin-resistant S. Pneumoniae is likely to be limited. Cefetamet pivoxil is also effective in the treatment of urinary tract infections, although further trials are required to define any comparative advantages over other oral agents. Of the Gram-positive bacteria, cefetamet is active against Streptococcus pneumoniae, S. pyogenes and S. agalactiae, has poor activity against penicillin-resistant S. pneumoniae, and is inactive against staphylococci, enterococci and Listeria monocytogenes. Cefetamet has a broad spectrum of activity against Enterobacteriaceae; 79% of isolates were inhibited at concentrations of ⩽ 1 mg/ L. Cefetamet has notable activity against Proteus spp., Klebsiella spp., Providencia spp., and Yersinia enterocolitica. Cefetamet is active against Haemophilus influenzae and Moraxella catarrhalis and, in both cases, its activity is preserved in the presence of β-lactamases. Cefetamet is also very active against Neisseria Gonorrhoeae, including β-lactamase-producing and chromosomally-me-diated resistant strains (MIC90 ⩾ 0.125 mg/L). Cefetamet may have some useful activity against Treponema pallidum, but possesses little useful activity against anaerobic bacteria. The majority of Pseudomonas spp. and other Gram-negative nonfermentative rods, as with other cephalosporins, are resistant to the drug. The activity of cefetamet appears to be preserved in the presence of chromosomal β-lacta-mases, with the exception of some type I cephalosporinases. The activity of cefetamet appears to be little altered by plasmid-mediated β-lactamases. The rate of hydrolysis of cefetamet by the majority of β-lactamases is slow or undetectable. An inoculum effect was observed in some, but not all, isolates expressing inducible β-lactamases. The in vitro activity of cefetamet is unaffected by the composition of the agar medium, agar pH or the addition of serum to the agar. Cefetamet pivoxil is hydrolysed after ingestion by esterases in the gastrointestinal tract during absorption to yield the active free acid, cefetamet. Hydrolysis of cefetamet pivoxil appears to be complete. The primary binding site of cefetamet is penicillin-binding protein (PBP) 3, followed by PBPs la and Ib. Cefetamet has a fast rate of penetration across the outer cell wall of selected Gram-negative bacteria relative to cefixime, cefuroxime and cefaclor. At high concentrations (20 mg/L) in vitro, cefetamet demonstrated the ability to increase the bactericidal activity of human neutrophils and to modulate the release of leukotriene B4 from these cells. For susceptible strains, the minimum bactericidal concentrations of cefetamet were 1- to 4-fold higher than the minimum inhibitory concentrations. Serum complement augmented the bactericidal activity of cefetamet. In vivo, cefetamet demonstrated antibacterial activity consistent with its in vitro activity in animal models of septicaemia, pyelonephritis, respiratory tract infection and syphilis. Peak serum concentrations of approximately 4 mg/L are attained 4 hours after a single oral dose of cefetamet pivoxil 500mg. The oral bioavailability of cefetamet pivoxil is about 50% after food. The rate and extent of absorption are slightly reduced with increasing doses of cefetamet pivoxil, although the observed effects are unlikely to be of clinical consequence. Drug absorption, maximum plasma drug concentrations (Cmax), and time to reach Cmax are unaffected by repeated twice daily administration. Since absorption of cefetamet pivoxil is increased by food, drug administration is recommended within 1 hour of a meal. cefetamet has a small volume of distribution (0.3 L/kg) and 22% of the drug is plasma protein bound. The systemic and renal clearances of cefetamet after intravenous administration of cefetamet 1060mg are 8.2 L/h (137ml/min) and 7.1 L/h (118ml/min), respectively, in normal healthy volunteers, suggesting that cefetamet is eliminated predominantly by the kidney via glomerular filtration. After administration of single oral doses of cefetamet pivoxil 500 to 1000mg, the plasma elimination half-life was 2.2 to 2.8 hours. Since the clearance of cefetamet pivoxil is directly related to renal function, dosage adjustment is needed in patients with renal impairment. The kinetics of cefetamet are minimally affected in children, the elderly or in patients with impaired hepatic function. The therapeutic efficacy of cefetamet pivoxil has been investigated in patients with upper and lower respiratory tract infections, urinary tract infections and gonorrhoea in both Japan and Europe, although many of the data have been presented in preliminary form only. In the treatment of acute otitis media in children, cefetamet pivoxil 10 and 20 mg/kg twice daily administered for 7 days achieved clinical cure rates of 74 to 100 and 80 to 100%, respectively. These results were comparable to those obtained with cefaclor 10 to 20 mg/kg 2- to 3-times daily (55 to 100%). Cefetamet pivoxil demonstrated consistently good efficacy in patients with acute sinusitis. Clinical cure rates of í 90% were obtained after a 7-day course with either cefetamet pivoxil 500 or 1000mg twice daily. In 2 comparative studies, cure/improvement rates of 100% were achieved with cefetamet pivoxil 5.00rrig twice daily vs 94 to 100% with cefaclor 500mg 3-times daily. Cefetamet pivoxil (10 to 20 mg/kg or 1000mg twice daily) administered for 7 or 10 days achieved consistently high (>90%) bacteriological cure rates, similar to those attained after a 10-day course of Phenoxymethylpenicillin, in the treatment of group A β-haemolytic streptococcal pharyngotonsillitis. In the treatment of acute bronchitis or acute exacerbations of chronic bronchitis, 1 to 2 weeks’ treatment with cefetamet pivoxil 500 to 1000mg twice daily achieved clinical cure rates of 83 to 97%. The efficacy of cefetamet was comparable to that of Cefixime 400 mg/day, cefaclor 1500 mg/ day and amoxicillin 2000 to 2250 mg/day. In an overview of 23 noncomparative Japanese studies involving 83 patients with pneumonia, 86% of patients responded to treatment with cefetamet pivoxil 500 to 1500 mg/day; the remaining patients either failed to respond to treatment or relapsed. In comparative studies, cefetamet pivoxil (10 or 20 mg/kg twice daily or 500 to 1000mg twice daily) displayed efficacy comparable to that of cefixime 400 mg/day and amoxicillin 2250 mg/day in adults, and cefaclor 30 mg/kg/ day in children. In uncomplicated urinary tract infections, single dose cefetamet pivoxil 2000mg achieved cure rates of 74 to 93%; cefetamet pivoxil was significantly more effective than single dose cefadroxil 2000mg in one study. In complicated urinary tract infections, cefetamet pivoxil 2000 mg/day, administered in 1 or 2 divided doses for 10 to 15 days, achieved cure rates of 64 to 100% at the end of treatment, while in comparative studies, cefetamet pivoxil 250 to 1000mg twice daily showed similar efficacy to Cefadroxil 2000 mg/day, cefaclor 1500 mg/day and cefuroxime axetil 500 mg/day. The bacteriological efficacy of cefetamet pivoxil was consistent with its in vitro activity, with Enterobacteriaceae and Gram-positive streptococci eradicated in 90% and 88% of cases, respectively, according to an overview of 6 studies. Cefetamet pivoxil was also effective in the treatment of complicated urinary tract infections in children and elderly patients. In male and female patients with gonococcal urethritis, 100% cure rates were achieved after single dose administration of cefetamet pivoxil 1500mg. According to an overview of almost 5000 patients, the overall incidence of adverse events associated with cefetamet pivoxil was 12.3%. Gastrointestinal disorders (diarrhoea, nausea, vomiting and epigastric discomfort) were observed in 8% of adults and 13% of children, necessitating treatment withdrawal in 1% of patients. The incidence of gastrointestinal adverse effects appeared to increase with increasing dose and duration of treatment in adults. To date, diarrhoea with excretion of C. difficile has been reported in 2 patients, with spontaneous resolution of symptoms. Dermatological reactions (< 1% of patients) were the second most commonly reported type of adverse event; reactions included urticaria, exanthema, rash, eczema, aphthosis and purpura. Other clinical adverse events were rare and minor in nature. Laboratory abnormalities (most commonly elevated levels of hepatic transaminases and/or alkaline phosphatase) occurred in 4% of patients; none were clinically significant. Other laboratory abnormalities included eosinophilia and, more rarely, neutropenia, bilirubinaemia, decreased potassium levels and decreased prothrombin activity. Cefetamet pivoxil possesses no N-methyl-thiotetrazole side chain, and accordingly there have been no reports of prolonged prothrombin time in association with this agent. Further, no symptoms of carnitine deficiency, an effect documented with other pivalic acid-containing, prodrugs (pivampicillin, pivmecillinam), have been reported to date with cefetamet pivoxil. The recommended dosage of cefetamet pivoxil in adults and children aged over 12 years with infections caused by susceptible bacteria is 500mg twice daily, and in children í 12 years is 10 mg/kg twice daily. Cefetamet pivoxil 1000mg twice daily is recommended for the treatment of infections caused by less susceptible bacteria. Cefetamet pivoxil 1500 to 2000mg as a single dose is recommended for uncomplicated cystitis in women and for uncomplicated gonococcal infections. For optimum absorption, it is recommended that cefetamet pivoxil be taken within 1 hour of food. Dosage reductions are required in patients with moderate to severe renal impairment and in children. A supplementary 500mg dose is recommended after haemodialysis. No dosage adjustment is required in elderly patients or in patients with hepatic impairment without ascites. Cefetamet pivoxil is contraindicated in patients with cephalosporin hypersensitivity. Data from one study indicate that cefetamet pivoxil can be coadministered with antacids and histamine H2-receptor antagonists.