Cefepime

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Abstract
Cefepime (Maxipime®, Maxcef®, Cepimax®, Cepimex®, Axepim®1), a parenteral fourth-generation cephalosporin, is active against many organisms causative in pneumonia. Cefepime has in vitro activity against Gram-positive organisms including Staphylococcus aureus and penicillin-sensitive, -intermediate and -resistant Streptococcus pneumoniae similar to that of cefotaxime and ceftriaxone. Cefepime also has good activity against Gram-negative organisms, including Pseudomonas aeruginosa, similar to that of ceftazidime. Importantly, cefepime is stable against many of the common plasmid- and chromosome-mediated β-lactamases and is a poor inducer of AmpC β-lactamases. As a result, it retains activity against Enterobacteriaceae that are resistant to third-generation cephalosporins, such as derepressed mutants of Enterobacter spp. Cefepime may be hydrolyzed by the extended-spectrum β-lactamases produced by some members of the Enterobacteriaceae, but to a lesser extent than the third-generation cephalosporins. Monotherapy with cefepime 1 or 2g, usually administered intravenously twice daily, was as effective for clinical and bacteriological response as ceftazidime, ceftriaxone or cefotaxime monotherapy (1 or 2g two or three times daily) in a number of randomized, clinical trials in hospitalized adult, or less commonly, pediatric, patients with generally moderate to severe community-acquired or nosocomial pneumonia. More limited data indicated that monotherapy with cefepime 2g three times daily was also as effective in treating patients with nosocomial pneumonia as imipenem/cilostatin 0.5g four times daily, and when combined with amikacin, cefepime was as effective as ceftazidime plus amikacin. Patients with pneumonia who failed to respond to previous antibacterial therapy with penicillins or other cephalosporins responded to treatment with cefepime. Cefepime is generally well tolerated, with a tolerability profile similar to those of other parenteral cephalosporins. In clinical trials, the majority of adverse events experienced by cefepime recipients were mild to moderate and reversible. The most common adverse events with a causal relationship to cefepime reported in clinical trials included rash and diarrhea. Other, less common, adverse events included pruritus, urticaria, nausea, vomiting oral candidiasis, colitis, headache, fever, erythema and vaginitis. Conclusion: Cefepime is an established and generally well tolerated parenteral drug with a broad spectrum of antibacterial activity which, when administered twice daily, provides coverage of most of the pathogens that may be causative in pneumonia. In randomized clinical trials in hospitalized patients with generally moderate to severe community-acquired or nosocomial pneumonia, cefepime monotherapy exhibited good clinical and bacteriological efficacy. Cefepime may become a preferred antibacterial agent for infections caused by Enterobacter spp. With prudent use in order to prevent the emergence of resistant organisms, cefepime will continue to be a suitable option for the empiric treatment of pneumonia. Antibacterial Activity Cefepime acts by binding to penicillin-binding proteins and inhibiting the synthesis of the bacterial cell wall. Due to its zwitterionic nature, cefepime can penetrate the porins of the outer membrane of Gram-negative bacteria faster than the third-generation cephalosporins. Cefepime has a broad spectrum of antibacterial activity in vitro. Data from large in vitro or surveillance studies collecting isolates since 1997 have shown that cefepime is active against Gram-positive and Gram-negative bacteria commonly implicated in pneumonia. Using the newly revised US National Committee for Clinical Laboratory Standards cefepime breakpoints for Streptococcus pneumoniae, cefepime is highly active against strains of penicillin-susceptible and -intermediate S. pneumoniae and has good activity against penicillin-resistant strains. Ceftazidime, cefotaxime, ceftriaxone and imipenem were also highly active against penicillin-susceptible strains of S. pneumoniae. Against penicillin-intermediate or -resistant strains, cefepime exhibited similar activity to cefotaxime, ceftriaxone and imipenem, but was more active than ceftazidime. Cefepime shows excellent activity against methicillin-susceptible Staphylococcus aureus, similar to that of cefotaxime, ceftriaxone and imipenem, and better than that of ceftazidime. However, like other β-lactam agents, cefepime is inactive against methicillin-resistant S. aureus. Cefepime has excellent in vitro activity against Escherichia coli, Klebsiella spp., Haemophilus influenzae and Moraxella catarrhalis similar to that of ceftazidime, ceftriaxone, cefotaxime and imipenem. Cefepime has good activity against Enterobacter spp. similar to that of imipenem and better than that of the third-generation cephalosporins. Additionally, cefepime has similar activity against Pseudomonas spp. as ceftazidime and imipenem. Cefepime showed little activity against Stenotrophomonas maltophilia and highly variable activity against Acinetobacter spp., similar to that of the third-generation cephalosporins. Additionally, like the third-generation cephalosporins, cefepime had highly variable activity against anaerobes, such as Bacteroides spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Prevotella spp. and Veilonella spp. that are commonly causative pathogens of aspiration pneumonia. Cefepime is stable against the common plasmid-mediated β-lactamases including TEM-1, TEM-2, SHV-1, OXA-2, OXA-3, PSE-1 to PSE-4 and ROB-1 and the chromosomal cephalosporinases K14, P99 and BRO-1. Unlike the third-generation cephalosporins, cefepime does not induce AmpC β-lactamase hyperproduction and has enhanced stability against the AmpC chromosomal β-lactamases produced by Enterobacter spp. and P. aeruginosa. Cefepime has moderate activity against Enterobacteriaceae producing plasmid-mediated AmpC β-lactamases. However, like most β-lactam agents, cefepime may be hydrolyzed by the extended-spectrum β-lactamases, but to a lesser extent than the third-generation cephalosporins. The administration of cefepime (1g twice daily for 5 or 8 days) to a total of 14 healthy men in two studies resulted in few changes to the fecal flora. The total mean counts of bacteria changed only slightly and returned to normal after the cessation of cefepime administration. Clostridium difficile was detected in the feces of one participant in each study; however, neither volunteer experienced diarrhea. Cefepime, like other β-lactam agents, exhibits time-dependent bactericidal activity. A number of studies using pharmacokinetic data from healthy volunteers combined with in vitro data for the inhibition of various bacterial isolates have shown that intermittent doses (1 or 2g twice daily) or continuous infusions (3 or 4g over a 24 hour period) of cefepime were associated with plasma concentrations above the minimum inhibitory concentration required to inhibit the growth of 90% of isolates for a sufficient proportion of the dosage interval for the majority of Enterobacteriaceae, streptococci and staphylococci tested. Pharmacokinetic Properties The absorption kinetics of cefepime are linear over the 0.25–2g dose range. After intravenous administration, maximum cefepime plasma or serum concentrations (Cmax) were 16–133 mg/L over the 0.25–2g dose range, whereas the same doses of cefepime administered via intramuscular injection achieved Cmax values of 8–58 mg/L in healthy volunteers. The absorption of intramuscular cefepime (0.25–2g) was rapid, as the time to Cmax was reached after 1.00–1.58 hours. The bioavailability of intramuscular cefepime was approximately 100% in healthy volunteers. There was no accumulation of cefepime after multiple intravenous or intramuscular administration to individuals with normal renal function. The plasma protein binding of cefepime is relatively low (14–19% in healthy adult volunteers). Cefepime has been shown to penetrate bronchial mucosa and lung tissue. The volume of distribution at steady-state was not dependent on the dose and ranged from 16–19L in healthy adult volunteers. Cefepime undergoes minimal metabolism and is primarily eliminated as unchanged drug by the kidneys. The total clearance (CLT) and renal clearance (CLR) of cefepime are independent of the administered dose, but are directly proportional to the rate of creatinine clearance. After a single intravenous or intramuscular injection of cefepime (0.25–2g), CLT and CLR ranged from 7.32–9.12 L/h (122–152 mL/min) and 5.4–8.28 L/h (90–138 mL/min), respectively. The mean elimination half-life (t1/2) of cefepime is independent of the dose and after intravenous or intramuscular administration of cefepime (0.25–2g) in healthy adults was about 2–2.4 hours. The pharmacokinetics of cefepime were not significantly affected by acute respiratory illness. The elimination kinetics of cefepime in healthy elderly volunteers with normal renal function for their age differed from those of younger volunteers but this was not clinically significant. The pharmacokinetics of cefepime in children and adolescents were similar to those previously determined for healthy adults. As cefepime is eliminated by the kidneys, patients with renal impairment have slower elimination kinetics than healthy volunteers. In a study in patients with varying degrees of renal impairment, the CLT and CLR decreased and the t1/2 increased with decreasing renal function. Studies in patients with renal failure have shown that hemodialysis, hemofiltration and continuous renal replacement therapies effectively eliminate cefepime. The pharmacokinetics of cefepime in individuals with hepatic impairment are not appreciably different from those in healthy volunteers. Therapeutic Efficacy In randomized, generally nonblind trials, cefepime monotherapy was as effective as monotherapy with ceftazidime or ceftriaxone in adult patients with community-acquired (CAP). In clinically evaluable patients with CAP treated with cefepime (1 or 2g twice daily), clinical response rates (resolution or improvement) at the end of therapy ranged from 79–95% of patients and were generally similar to those achieved in the recipients of comparator drugs (1 or 2g two or three times daily; range 73–98% of patients). Bacteriological eradication rates (complete or presumed) in cefepime recipients (91–100% of patients or isolated pathogens) were similar to those achieved with ceftazidime and ceftriaxone (97–100% of patients or isolated pathogens). Similarly, in patients with CAP or nosocomial pneumonia (hospital-acquired pneumonia; HAP) or pneumonia of unspecified origin, cefepime monotherapy (1 or 2g twice daily) provided similar clinical efficacy to monotherapy with ceftazidime (1 or 2g two or three times daily) [58–90% vs 60–94% of patients] or cefotaxime (2g three times daily) [92% and 98% vs 86% and 93% of patients]. Cefepime recipients also achieved similar bacteriological eradication rates to those receiving ceftazidime (85–97% vs 73–97% of pathogens) or cefotaxime (100% vs 93% of patients with bacterial eradication and 95% of pathogens eradicated). Cefepime monotherapy (2g three times daily) produced a similar satisfactory response rate to (59% vs 57% of patients), and a slightly higher bacteriological eradication rate (52% vs 44%) than, imipenem/cilastatin 0.5g four times daily for patients with nosocomial pneumonia admitted to the ICU. In three randomized, comparative clinical trials in pediatric patients with CAP or HAP, monotherapy with cefepime (50 mg/kg/dose two to three times daily) was as effective as ceftazidime (50 mg/kg/dose three times daily) and appeared as effective as cefotaxime (30 mg/kg/dose four times daily) or cefuroxime (100 mg/kg/day in three divided doses), although the latter two comparisons involved ≤10 patients per treatment group. Additionally, in a randomized, double-blind trial in elderly patients with CAP, cefepime 2g twice daily produced a similar clinical (79% vs 75% of patients) and bacteriological response (94% vs 100% of patients) to ceftriaxone (1g twice daily). Cefepime monotherapy also proved clinically effective as a therapy for adult patients with pneumonia who had failed to respond to previous antibacterial therapy with penicillins or other cephalosporins (clinical response rate 70.1%). Cefepime achieved a satisfactory bacteriological response in 87.9% of patients with pneumonia who failed to respond to previous treatment with penicillins and in 78.6% in those previously treated with other cephalosporins. Cefepime was an effective treatment when used as part of a combination regimen with amikacin in ventilated patients with HAP. The cefepime (2g twice daily) plus amikacin (7.5 mg/kg twice daily) regimen was as effective as ceftazidime (2g three times daily) plus amikacin (7.5 mg/kg twice daily), with a clinical cure rate of approximately 68% of patients for the per-protocol analysis in both treatment groups and bacteriological eradication in 86.5% vs 89.3% of microbiologically evaluable patients. Tolerability In clinical trials, intravenous or intramuscular cefepime was generally well tolerated in hospitalized patients with pneumonia. The majority of adverse events were mild to moderate in intensity and reversible upon discontinuation of treatment. In a pooled analysis of patients with pneumonia, urinary tract infections and other serious infections, the most common adverse events that occurred during treatment with cefepime were rash and diarrhea. Other less common adverse events probably related to cefepime included pruritus, urticaria, nausea, vomiting, oral candidiasis, colitis, headache, fever, erythema and vaginitis. Comparative clinical trials in adults with pneumonia have indicated that cefepime 1 or 2g twice daily has a similar tolerability profile to that of ceftazidime, ceftriaxone and cefotaxime (1 or 2g twice or three times daily) with no significant difference in the incidence, type or severity of adverse events. The percentage of patients with HAP admitted to the ICU receiving cefepime 2g three times daily that experienced adverse events was also similar to the percentage of patients receiving imipenem 0.5g four times daily. Pediatric patients with pneumonia treated with cefepime 50 mg/kg/dose three times daily experienced a similar number, type and severity of adverse events as those receiving the same dose of ceftazidime three times daily. According to pooled tolerability data from pediatric patients, the most commonly reported adverse events in cefepime recipients were fever, diarrhea and rash. Cefepime has been associated with rare instances of neurotoxicity, including encephalopathy, myoclonus and seizures in postmarketing experience. Most episodes occurred in patients with renal impairment who received doses of cefepime greater than those recommended by the manufacturer. Pharmacoeconomic Considerations Two cost analyses in patients with HAP or various bacterial infections, using similar acquisition costs for cefepime and ceftazidime, found that the institutional costs associated with cefepime therapy appear less than those of ceftazidime although no statistics were given in one model. When other factors (such as the cost of concomitant antibacterial agents, agents used to treat clinical failures, the preparation costs, and any medications used to treat adverse events) were considered, costs associated with cefepime therapy were significantly lower than those associated with ceftazidime treatment in one model, but not in the other. Dosage and Administration In countries other than the US, cefepime is indicated for the treatment of mild to very severe pneumonia in adults and children (aged ≥1 month). The recommended dosage of cefepime for adult or pediatric patients more than 40kg with mild to moderate pneumonia is 1g twice daily administered by intramuscular injection or intravenous infusion (dependent on the severity of infection) for 7–10 days. For adult or pediatric patients more than 40kg with severe to very severe pneumonia the recommended dosage of cefepime is 2g twice or three times daily via intravenous infusion (again, dependent on the severity of infection) for 7–10 days. For pediatric patients (aged >2 months and up to 40kg in bodyweight), with bacterial pneumonia, the recommended dosage is 50 mg/kg/dose twice daily for 10 days; however, for more severe infections, a dosage interval of 8 hours can be used. Experience of the efficacy and tolerability of cefepime is limited in pediatric patients aged 2 months). The recommended dosage of cefepime for adult patients with moderate to severe pneumonia in the US is 1 or 2g administered intravenously for 10 days. For children (≤40kg in bodyweight), the recommended dosage is 50mg/kg/dose twice daily administered by intravenous infusion for 10 days. No dosage modifications are recommended for the elderly or patients with hepatic dysfunction; however, the dose or frequency of administration of cefepime should be adjusted for patients with renal impairment or those receiving renal dialysis. Cefepime should not be directly mixed with other antibacterial agents. If other antibacterial agents are to be used in a combination regimen they should be administered separately.

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