Cefpirome
Tóm tắt
Cefpirome is an injectable extended-spectrum or ‘fourth generation’ cephalosporin. Its antibacterial activity encompasses many of the pathogens involved in hospital-acquired infections such as Enterobacteriaceae, methicillin-susceptible Staphylococcus aureus, coagulase-negative staphylococci and viridans group streptococci. Cefpirome also has in vitro activity against Streptococcus pneumoniae regardless of penicillin susceptibility. It is stable against most plasmid- and chromosome-mediated β -lactamases, with the exception of the extended-spectrum plasmid-mediated SHV enzymes. Intravenous cefpirome 2g twice daily has shown clinical efficacy comparable to that of ceftazidime 2g 3 times daily in the treatment of hospitalised patients with moderate to severe infections. Clinical response and bacteriological eradication rates were similar in patients with severe pneumonia or septicaemia treated with either cefpirome or ceftazidime. Cefpirome appeared more effective than ceftazidime in the eradication of bacteria in patients with febrile neutropenia in 1 study; however, clinical response rates were similar in the 2 treatment groups. The tolerability of cefpirome appears similar to that of ceftazidime and other third generation cephalosporins, diarrhoea being the most frequently observed event. Thus, cefpirome is likely to be a valuable extended-spectrum agent for the treatment of severe infections. Cefpirome offers improved coverage against some Gram-positive pathogens and Enterobacteriaceae producing class I β-lactamases compared with the third generation cephalosporins, although this has yet to be demonstrated in clinical trials. Cefpirome has shown excellent antibacterial activity against Enterobacteriaceae, although its activity against Enterobacter cloacae is more variable. Its activity was at least 2-fold better than that of ceftazidime and cefotaxime against Citrobacter freundii, E. cloacae, Morganella morganii and Serratia marcescens but was similar to that of the other extended-spectrum agents cefepime and cefoselis. Cefpirome generally remained active against Enterobacteriaceae with reduced susceptibility or resistance to other agents (ceftazidime, cefotaxime, ceftriaxone and aminoglycosides), including Citrobacter spp., Enterobacter spp. and Klebsiella spp. Cefpirome has moderate activity against Pseudomonas aeruginosa, its potency being similar to or 2-fold less than that of ceftazidime, cefepime or cefoselis. Strains of P. aeruginosa resistant to ceftazidime or aminoglycosides were also resistant to cefpirome. β-Lactamase-producing and -nonproducing strains of Moraxella catarrhalis and Haemophilus influenzae are equally susceptible to cefpirome, whereas Acinetobacter spp. are only moderately susceptible or resistant to the drug. Cefpirome demonstrated 2- to 16-fold greater activity than ceftazidime and cefotaxime against methicillin-sensitive Staphylococcus aureus [MSSA; minimum inhibitory concentration required to inhibit 90% of strains (MIC90) values ≤1.56 mg/L] and coagulase-negative staphylococci (MIC90 values ≤4 mg/L). In common with other cephalosporins, it showed little activity against methicillin-resistant staphylococci.
Streptococcus pneumoniae are highly susceptible to cefpirome (MIC90 values ≤0.06 mg/L); strains with intermediate and high resistance to penicillin are susceptible to cefpirome, although with increased MIC90 values (≤2 mg/L). S. agalactiae, S. pyogenes and viridans group streptococci are also susceptible to cefpirome, although penicillin-resistant viridans group streptococci showed varying susceptibility to the drug. Enterococcus faecalis are generally resistant to cefpirome. Among anaerobic organisms, Clostridium perfringens and Peptostreptococcus spp. were susceptible, whereas Bacteroides spp. and C. difficile were resistant to cefpirome. Cefpirome permeates faster through the outer bacterial membrane of E. cloacae than ceftriaxone and cefotaxime. It binds with high affinity to penicillin binding protein (PBP) 3 in E. coli, PBPs 3 and la in P. aeruginosa, PBP1b in S. pneumoniae and PBPs 1 and 2 in S. aureus.
Cefpirome showed stability against broad-spectrum and some extended-spectrum plasmid-mediated β-lactamases including TEM-1 to -10, TEM-12, SHV-1 and -6, OXA-1, -2 and -3, and CAZ-2, but had no activity against bacteria producing SHV-2 to -5. Cefpirome has a low affinity for chromosomal β-lactamases and is stable against hydrolysis by most chromosomally mediated cephalosporinases. Peak plasma concentrations (Cmax) and the area under the plasma concentration-time curve (AUC0-∞) increased in a dose-dependent manner after intravenous or intramuscular administration of cefpirome 0.25 to 2g in healthy male volunteers. Cmax values were between 86.7 and 97.4 mg/L after a single intravenous injection of cefpirome 1g and were between 23.2 and 30.6 mg/L about 2 hours after intramuscular administration of the same dose. Estimates of relative bioavailability of cefpirome after intramuscular administration were 91.6 and 97.6%. No drug accumulation was evident after administration of cefpirome 1 or 2g every 12 hours for up to 5.5 days. The apparent volume of distribution at steady-state was between 15.3 and 21.3L and approximately 8 to 12% of the drug was bound to plasma proteins. About 80% of an administered dose of cefpirome is recovered unchanged in the urine of healthy volunteers over 48 hours. Total and renal clearance rates ranged from 6.6 to 10.6 L/h and 4.9 to 6.7 L/h, respectively. The mean elimination half-life (t½β) of cefpirome ranged from 1.7 to 2.3 hours. Total body and renal clearance were significantly reduced, and AUC0-∞ and t½β significantly increased in patients with moderate to severe renal impairment [creatinine clearance (CLcr) ≤3 L/h] compared with healthy volunteers and patients with mild impairment. Haemodialysis removed about 48% of the drug from the body during a 4-hour session, and the elimination of cefpirome was significantly prolonged during continuous ambulatory peritoneal dialysis (CAPD). In the elderly, t½β correlated with the degree of renal impairment. Intravenous cefpirome 2g twice daily has shown similar efficacy to intravenous ceftazidime 2g 3 times daily in the treatment of moderate to severe infections in hospitalised patients in large randomised multicentre studies. Satisfactory responses occurred in 57% of patients with severe (mostly nosocomial) pneumonia treated with either cefpirome or ceftazidime and the bacteriological eradication rate was 68%. Clinical failure was reported in 34 and 36% of cefpirome and ceftazidime recipients, respectively. A large retrospective analysis of the efficacy of these 2 drugs in patients with severe pneumonia revealed clinical response rates of 82 and 74.5% in cefpirome and ceftazidime treatment groups. In the empirical treatment of suspected bacteraemia and/or sepsis, cefpirome achieved a satisfactory clinical response in 76% of patients compared with 80% of ceftazidime recipients 1 to 5 days after completion of treatment. A satisfactory bacteriological outcome was evident in 90 and 86% of patients, respectively. In the treatment of febrile episodes in patients with neutropenia, cefpirome and ceftazidime each achieved satisfactory clinical responses in 72% of patients. However, the bacteriological success rate was higher in cefpirome recipients (89 vs 74%). Cefpirome in combination with gentamicin also demonstrated similar efficacy to piperacillin and gentamicin in the empirical treatment of febrile patients with neutropenia; a satisfactory response was observed in 58 and 47% of episodes, respectively, after 72 hours according to an intention-to-treat analysis. Cefpirome is well tolerated by the majority of patients. The incidence of adverse events in an analysis of 3103 patients receiving cefpirome in phase II and III clinical trials was 12.5%, similar to that reported for a combined group treated with comparator agents (predominantly ceftazidime; 13.7%). Diarrhoea was the most common adverse event (occurring in 1.6% of patients) followed by rash (1.4%) and nausea (1.3%). Treatment was withdrawn because of adverse events in 5.1 and 5.0% of patients treated with cefpirome or comparator agents. In clinical studies in patients with severe infections, the incidence of adverse events in patients treated with cefpirome ranged between 4 and 30% and was similar to that reported for ceftazidime. The recommended dosage of cefpirome for the treatment of hospitalised patients with severe infections (pneumonia and septicaemia) and febrile episodes in patients with neutropenia is 2g administered by intravenous injection or infusion every 12 hours. As the main route of elimination of cefpirome is renal, dosage reduction is necessary in patients with moderate to severe renal impairment (CLcr ≤3 L/h) and patients undergoing CAPD. A supplementary dose is required at the end of haemodialysis.
Tài liệu tham khảo
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