Cefepime

Abstract

Cefepime is a ‘fourth’ generation Cephalosporin that has a broader spectrum of antibacterial activity than the third generation Cephalosporins and is more active in vitro against Gram-positive aerobic bacteria. The fact that cefepime is stable to hydrolysis by many of the common plasmid and chromosomally-mediated β-lactamases, and that it is a poor inducer of type I β-lactamases, indicates that cefepime may be useful for treatment of infections resistant to earlier Cephalosporins. In comparative trials, cefepime 1 to 2g, usually administered intravenously twice daily, was as effective as ceftazidime 1 to 2g, usually administered 3 times daily, for treatment ofbacteraemia and infections of the lower respiratory tract, urinary tract, pelvis and skin and skin structures. Furthermore, cefepime was as effective as ceftazidime and piperacillin or mezlocillin in combination with gentamicin when administered as empirical treatment for fever in patients with neutropenia. A limited number of trials have found cefepime to be as effective as cefotaxime for the treatment of gynaecological and lower respiratory tract infections. Similarly, cefepime 2g twice daily intravenously (alone or in combination with metronidazole) was as effective as gentamicin in combination with mezlocillin or Clindamycin, respectively, for the treatment of intra-abdominal infection. Cefepime has a linear pharmacokinetic profile, an elimination half-life of approximately 2 hours and is primarily excreted by renal mechanisms as unchanged drug. Cefepime has a tolerability profile similar to that of other parenteral Cephalosporins; adverse events are primarily gastrointestinal in nature. A total of 1.4 and 2.9% of patients receiving cefepime ≤2 g/day and =2 g/day, respectively, required treatment withdrawal as a result of any adverse event. Thus, cefepime has the advantage of an improved spectrum of antibacterial activity, and is less susceptible to hydrolysis by some β-lactamases, compared with third generation Cephalosporins. Despite these advantages, cefepime has not been found to be more effective than ceftazidime and cefotaxime in clinical trials, although most trials selected patients with organisms sensitive in vitro to both comparator agents. Further trials, particularly in areas of widespread bacterial resistance, are required to confirm the positioning of cefepime for treatment of serious infection, and in particular to further explore whether its potential advantages result in clinical benefits. Cefepime is a Cephalosporin with activity against both Gram-positive and Gram-negative aerobic bacteria. In common with other β-lactam agents, cefepime exerts its antibacterial effects by binding to penicillin-binding proteins. Cefepime has greater inhibitory activity than ceftazidime against Streptococcus pneumoniae and most other streptococcal species, and against staphylococcal species. Although cefepime is active against methicillin-sensitive strains, it is not active against methicillin-resistant Staphylococcus aureus or S. epidermidis. Cefepime demonstrates useful inhibitory activity against all common pathogens from the family Enterobacteriaceae, including those that commonly produce chromosomally-mediated β-lactamases. Cefepime also has excellent inhibitory activity against Haemophilus influenzae, regardless of the α-lactamase-producing ability of the organism. In common with most other Cephalosporins, cefepime has limited inhibitory activity against non-fermentative bacteria, although the majority of tested isolates of Pseudomonas aeruginosa were susceptible or moderately susceptible to cefepime, Cefepime has minimal inhibitory activity against enterococci, Bacteroides fragilis and Clostridium difficile. Type I β-lactamases have a low affinity for cefepime, and therefore cefepime retains its inhibitory activity against de-repressed bacteria. In addition, cefepime is not susceptible to hydrolysis by plasmid-mediated β-lactamases expressed by Gram-negative bacteria, particularly Enterobacter species. Furthermore, unlike imipenem and some second generation Cephalosporins, cefepime is a poor inducer of type I β-lactamases. Experimental models of infection have generally found cefepime to have activity superior to that of ceftazidime and cefotaxime against most clinically important Gram-positive and Gram-negative organisms. However, against infections caused by P. aeruginosa, cefepime had activity similar to that of ceftazidime. In healthy volunteers, cefepime reaches maximum serum concentrations (C_max) of approximately 57.5 mg/L after administration of a 2g dose by intramuscular injection. The same dose of cefepime administered intravenously over a period of 30 minutes achieves higher serum concentrations than intramuscular administration, with C_max values ranging from 126 to 193 mg/L. The drug has linear pharmacokinetics and an elimination half-life (t_1/2β) of approximately 2 hours. Plasma protein binding is low, and the drug distributes widely into body tissues and fluids. Cefepime is primarily excreted by renal mechanisms as unchanged drug. The t_1/2β of cefepime increases and clearance decreases progressively as renal function declines, necessitating dosage reduction in patients with renal impairment. Haemodialysis and haemofiltration remove cefepime from the systemic circulation with a t_1/2β approximating that observed in individuals with normal renal function. Cefepime is removed to a lesser extent by continuous peritoneal dialysis....