Ann Carole Scates, Pharm D. Drug Information ResidentCampbell University School of Pharmacy Buies Creek, NC
Cefepime hydrochloride is a parenteral "fourth-" generation cephalosporin antibiotic. It has an expanded spectrum of activity against gram-positive and gram-negative microbes as compared to the third-generation cephalo-sporins. In addition, pathogens resistant to other cephalosporins may be eradicated by cefepime. The chemical structure of cefepime allows it to bind to penicillin-binding proteins and to penetrate through the outer membrane of gram-negative bacteria more rapidly than most cephalosporins. Cefepime is also more stable to b-lactamase hydrolysis, making for an enhanced resistance pattern, especially with gram-negative bacteria. Cefepime (Maxipime) is indicated for use in uncomplicated and complicated urinary tract infections, uncomplicated skin and skin structure infections, and moderate to severe pneumonia.1
Spectrum of Activity
Cefepime has displayed in vitro activity against gram-positive organisms including Streptococcus agalactiae,2,3> Streptococcus pneumoniae, Streptococcus pyogenes, and penicillin-susceptible Staphylococcus aureus.2-4> Cefepime’s demonstrated activity against staphylococci is similar to cefotaxime and cefoperazone, but greater than ceftazidime.3> However, cefepime was not active against methicillin-resistant S. aureus or enterococcus.2-4 S. faecalis has also shown resistance to cefepime.3>
The broad range of gram-negative organisms sensitive to cefepime include the family Enterobacteriaceae, Klebsiella pneumoniae, Haemophilus influenza, Neisseria meningitidis, Neisseria gonorrhoeae and Pseudomonas aeruginosa.3 The in vitro activity of cefepime against Enterobacteriaceae include those resistant to ceftazidime, cefotaxime, cefoperazone and aminoglycosides.5 Those organisms in the family Enterobacteriaceae that have demonstrated less susceptibility to cefepime include Citrobacter freundii, Enterobacter cloacae, and Serratia marcescens.2 H. influenzae has shown excellent susceptibility to cefepime, similar to that shown to ceftazidime and cefotaxime.3 Cefepime has activity against P. aeruginosa comparable to that of ceftazidime.4,5> Those strains of P. aeruginosa that have shown resistance to cefotaxime and/or ceftazidime may be susceptible to cefepime. Amikacin plus cefepime has shown synergistic activity against P. aeruginosa strains resistant to cefepime but susceptible to amikacin.5
Cefepime has shown very limited activity against Enterococcus faecalis, P. cepacia, P. fluorescens, Xanthomonas maltophilia, Listeria monocytogenes, Bacteroides fragilis, and Clostridium difficile; therefore, cefepime would have very little, if any, clinical usefulness against these microbes.6
Pharmacokinetics
Cefepime follows linear kinetics after intramuscular (IM) or intravenous (IV) administration. Complete absorption can be expected following IM administration of cefepime. Peak plasma concentrations (C>max>) of cefepime can be observed 1.0 to 1.6 hours after IM dosing.7 Peak plasma concentrations and minimum plasma concentrations of cefepime following a single IV infusion of 500 mg, 1000 mg, and 2000 mg to healthy subjects are as follows: 31.9, 65.1, and 126 mcg/mL and 1.0, 2.7 and 4.2 mcg/mL, respectively. The area under the plasma drug concentration time curve extrapolated to infinity (AUC>0->·>) for the 500 mg, 1000 mg, and 2000 mg single infusions are 56.6, 135, and 245 mcg> · hr/ml, respectively.8
Cefepime is widely distributed throughout body tissues and fluids. Penetration into bronchial mucosal tissue, appendix tissue, peritoneal fluids, biliary fluids, and cerebrospinal fluids have been reported. However, penetration into breast milk of lactating women is negligible following IV dosing with approximately 0.02% of a daily dose exposed to an infant.9
Cefepime has an average steady state volume of distribution in healthy adult males of approximately 16–20 liters.8,10> Cefepime is similar to other cephalosporins with serum protein binding of approximately 15-19%.11
Cefepime is primarily excreted unchanged by renal elimination with greater than 80% of an administered dose recovered intact in the urine. The mean renal clearance is approximately 100 to 110 mL/min, principally due to glomerular filtration. Mean total body clearance has been estimated at 130–140 mL/min in healthy subjects. The elimination half-life following IV administration is approximately two hours.7,8,10,12 Intravenous dosing of cefepime has not shown the ability to accumulate following multiple daily dosing for a period of up to 10 days.8 Intramuscular cefepime also has an elimination half-life of two hours with no accumulation noted.7> Cefepime undergoes minimal metabolism to the following three compounds: N-methyl pyrrolidine (NMP) N-oxide derivative, the 7-epimer of cefepime, and NMP.10
Pharmacokinetics of Special Populations
Elderly: Twenty-four healthy elderly patients (65–81 years) demonstrated a longer half-life (3.05 vs 2.26 hours) as well as a larger steady state volume of distribution (0.23 vs. 0.21 L/kg) when compared to 24 healthy younger patients (20–40 years) when administered a single one-gram IV dose of cefepime. The elderly subjects also had reductions in renal clearance (1.03 vs. 1.44 mL/min/kg) and total body clearance (1.11 vs. 1.54 mL/min/kg). Although these findings show statistically significant differences, the changes are diminutive and there appear to be no dosage alterations necessary based solely on age. These changes appear to correlate with age-related changes in renal function.13
Renally Impaired: Patients who are renally impaired display altered pharmacokinetics. Barbhaiya et al. conducted a trial to determine if dosage adjustments are necessary in patients with renal impairment. Males between the ages of 27 and 68 years were grouped according to their creatinine clearance (CrCl). One group consisted of hemodialysis patients. All subjects were administered a single one-gram dose of cefepime. As CrCl decreased, the area under the plasma curve (AUC) and elimination half-life increased, while total body clearance and renal clearance (Clr) decreased. Subjects whose CrCl exceeded 90 mL/min had a cefepime half-life of approximately 2.5 hours and a Clr 110 mL/min, while those with a CrCl of 11–30 mL/min had an extended half-life of approximately 10.5 hours and a Clr of 15 mL/min. Those patients with normal renal function (CrCl > 60 mL/min) cleared approximately 80% of unchanged cefepime while those severely compromised excreted approximately 57% of intact cefepime. Based on these results, it is necessary to decrease the dosage or increase the dosing interval of cefepime based on CrCl in renally impaired patients.14 (>See Table 1.)15
Plasma concentrations of cefepime rapidly decrease in patients undergoing hemodialysis. The elimination half-life in this patient population is approximately 13.5 hours which declines during dialysis to almost equal to that in non-renally impaired patients, approximately two hours. Patients remove about 70% of the cefepime present in their body during three hours of dialysis. Therefore, patients on hemodialysis will require an additional dose of cefepime following the procedure.14
Ten patients were enrolled in a trial to evaluate the pharmacokinetic characteristics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Cephalosporin therapy can be vital to these patients due to the increased risk of developing systemic infections as well as peritonitis. All subjects were clear of infection and assigned to receive either a single one-gram or two-gram IV dose of cefepime prior to undergoing CAPD. The cefepime half-life was calculated to be approximately 18 hours in the CAPD population. A total body clearance of 15 ml/min was also reported in these patients. The blood and dialysate was collected over 72 hours and showed that 25% of the dose was recovered in the sample, with an estimated dialytic clearance of 0.24 L/h (4 mL/min). These patients discarded less than 5% of intact drug into their urine. It is suggested that CAPD patients requiring cefepime treatment for a systemic or intraperitoneal infection receive one or two grams once every 48 hours in order to maintain similar blood concentrations as those found in a patient having normal renal function and dosed every eight hours.16
Hepatically Impaired: No dosage adjustments are recommended for hepatically impaired patients on cefepime. This agent is primarily renally eliminated and is not expected to accumulate in patients with liver disease.9
Cystic Fibrosis: The pharmacokinetic measures of cefepime do not significantly differ in patients diagnosed with cystic fibrosis (CF) compared to healthy controls. The calculated mean half-life of cefepime in a trial conducted by Arguedas et al. was 1.6 hours after a single dose and 1.7 hours following multiple dosing. The CF patients demonstrated an increased rate of total body (3.09 mL/min/kg) and renal (1.50 mL/min/kg) clearance when compared with healthy subjects. However, the changes do not require dosage adjustments in CF patients. Doses of cefepime 50 mg/kg every 8 hours appeared to be sufficient to treat this small group (12 patients) of CF patients.17
Therapeutic Clinical Trials
Lower Respiratory Tract Infections: McCabe et al. reported on two trials comparing cefepime with ceftazidime in the treatment of moderate-to-severe bacterial pneumonia in hospitalized patients. Both trials used a treatment regimen of cefepime 1 g every 12 hours or ceftazidime 1 g every 8 hours. All patients enrolled had symptoms of bacterial pneumonia and suspected pathogens sensitive to both agents. In the randomized open-label trial, 68 patients on cefepime and 29 patients receiving ceftazidime were evaluated. A satisfactory clinical response was documented in 85% and 72% of the cefepime and ceftazidime groups, respectively. H. influenzae, S. pneumoniae, P. aeruginosa, and M. catarrhalis were the most frequently isolated pathogens. The bacterial eradication rates were similar for both medications, 93% cefepime and 94% ceftazidime. The second trial was a double blind comparison of 15 cefepime and 8 ceftazidime pneumonia patients. Clinical cure was similar between the groups, 80% cefepime and 88% ceftazidime. Bacteriologic responses were also similar with 85% and 73% eradication from the cefepime and ceftazidime groups, respectively. Cefepime appears to be an effective agent for the treatment of pneumonia caused by susceptible pathogens.18
In an open label randomized trial, cefepime 2 g administered every 12 hours was compared to ceftazidime 2 g given every 8 hours for the treatment of severe bacterial infections, including pneumonia. Fifty-three patients were treated with cefepime with 58% having a satisfactory clinical response. This was comparable to the 49 patients on ceftazidime with a satisfactory clinical response observed in 63%. The most commonly isolated pathogens included S. aureus and P. aeruginosa. The response rates for the agents were similar in terms of bacterial eradication, 87% cefepime and 86% ceftazidime.19
Urinary Tract Infections: A study conducted by Sharifi et al. compared the use of cefepime and ceftazidime in the treatment of hospitalized patients with complicated and uncomplicated urinary tract infections (UTI). One hundred eighty patients were randomized to receive either cefepime or ceftazidime 500 mg IV or IM every 12 hours. Cefepime demonstrated satisfactory clinical efficacy in 89% (83/93) of patients with complicated UTI compared to 86% (43/50) of those on ceftazidime therapy. Eradication of pathogens responsible for complicated UTI was observed in 85% of those on cefepime and 78% of those on ceftazidime. Ninety-two percent (23/25) of those patients with uncomplicated UTI receiving cefepime demonstrated satisfactory clinical efficacy while 100% (12/12) of those receiving ceftazidime had a satisfactory clinical response. Eighty-five percent and 92% of the pathogens were eradicated by cefepime and ceftazidime, respectively. The most common pathogens found susceptible to cefepime include Escherichia coli, Proteus spp, Pseudomonas aeruginosa, and Klebsiella spp.20
Another trial documented clinical and bacteriologic response rates to cefepime 2 g every 12 hours compared to ceftazidime 2 g every 8 hours in 116 patients with UTI, both complicated and uncomplicated. Clinical response rates for those with complicated UTI were satisfactory in 88% of cefepime subjects and 79% of those on ceftazidime. Bacteriologic response rates were similar for the groups, 88% for cefepime and 89% for ceftazidime. Patients with uncomplicated UTI had satisfactory clinical responses, 100% and 87% for cefepime and ceftazidime, respectively. Their microbiology responses were not significantly different at 83% and 88% for cefepime and ceftazidime, respectively.19
Skin and Skin Structure Infections: One hundred thirty patients with serious skin and skin structure infections were randomized to receive treatment with 1 g cefepime every 12 hours or 1 g ceftazidime every 8 hours. Ninety-three patients composed the cefepime treatment arm while 37 patients received therapy with ceftazidime. Eradication of pathogens including S. aureus and P. aeruginosa was similar among the groups: 92% for cefepime and 95% for ceftazidime. Signs and symptoms improved or resolved without the appearance of new signs and symptoms, making for a satisfactory clinical response in 88% of cefepime patients and 89% of ceftazidime patients. Therefore, cefepime is an effective alternative for the treatment of serious skin and skin structure infections such as cellulitis, abscesses, ulcers, and postoperative wound infections.21
In an open-label trial, cefepime (n = 59) was compared with ceftazidime (n = 52) in patients with skin and skin structure infections, including cellulitis, abscesses, postoperative wound infections, human bite wounds, and decubitus ulcers. The cefepime dose of 2 g every 12 hours produced a satisfactory clinical response in 88% of patients and eradicated 89% of the pathogens. Clinical responses were satisfactory in 85% of patients receiving 2 g of ceftazidime every 8 hours. Ninety percent of the pathogens were eradicated.19
Sepsis and Bacteremia: An open-label randomized multicenter trial evaluated the response of patients on 2 g cefepime administered every 12 hours or 2 g ceftazidime given every 8 hours for the treatment of serious bacterial infections including sepsis syndrome. One hundred fourteen patients were evaluated with no statistical differences documented between the treatment groups with regard to clinical responses or pathogen eradication.22
Twenty-eight patients were evaluated for the treatment of gram-negative bacteremia with cefepime or ceftazidime 2 g administered every 8 hours.
E. coli was the most commonly isolated pathogen. Effective clinical and bacteriologic responses were noted in 11 of the 13 cefepime patients and 12 of the 15 ceftazidime patients.23
>Febrile Neutropenia: Ramphal et al. reviewed cefepime therapy in febrile neutropenic cancer patients. Those patients enrolled in two clinical trials had temperatures higher than 38°C with absolute neutrophil counts less than 1,000/mm3. Patients were randomized to receive empiric therapy with IV cefepime 2 g every 8 hours compared to those receiving either ceftazidime 2 g every 8 hours or piperacillin 3 g every 4 hours plus gentamicin 1.5 mg/kg every 8 hours. Vancomycin therapy was initiated in those in which elevated temperatures occurred after 72 to 96 hours of initial therapy, a resistant pathogen was isolated, or a new fever developed following an initial response. The results observed from both of these trials were similar to those observed for all study antibiotics. Fifty-eight percent of cefepime patients and 60% of those on combination antibiotic regimens were afebrile within four days of initiating therapy. Satisfactory clinical responses were observed in 74% and 76% of cefepime and combination antibiotics, respectively. Pathogen eradication was similar between the two groups. In addition, parallel rates of superinfection and mortality were observed between the groups.24
Meningitis: Intravenous cefepime or cefotaxime 50 mg/kg every 8 and 6 hours, respectively, were administered to pediatric patients (2 months–15 years of age) for treatment of bacterial meningitis. Forty-three patients were randomized to receive cefepime therapy and 47 patients received cefotaxime therapy. In addition, dexamethasone 0.15 mg/kg was given to all patients. The most common pathogens isolated included H. influenzae, N. meningitidis, and S. neumoniae. Positive cerebrospinal fluid cultures were documented in 76 patients; however, 24 to 30 hours after antibiotic therapy all cultures were negative. The case-fatality rate was 8.5% for cefotaxime patients and 4.7% for cefepime patients. Both groups of children had similar lengths of stay in the hospital, number of seizures, as well as number of days with fever, meningeal signs, and antibiotic therapy. Neurologic and/or audiologic abnormalities were detected in 25% of children on cefepime and 23% of those on cefotaxime at the time of discontinuance from the hospital. Therefore, cefepime proved to be an effective agent for use against susceptible pathogens in pediatric patients with bacterial meningitis.25
Adverse Effects
Cefepime produces adverse effects characteristic of other extended-spectrum cephalosporins. Neu performed an analysis of the clinical trials conducted in North America and Europe that compared cefepime (2,032 patients) with ceftazidime (1,456 patients) to evaluate the adverse events of cefepime. The patients enrolled in the studies ranged in age from 15 to 100 years. Dosage of both agents was within normal limits, cefepime 1 –4 g/day and ceftazidime 1–6 g/day. Pneumonia, urinary tract infections, and skin and skin structure infections were the most commonly treated disorders with a mean duration of therapy of seven days.26
Analysis of the collected data showed that cefepime was a well-tolerated medication, with most side effects presenting as gastrointestinal and dermatologic events. Patients reported most often headache (2.4%), nausea (1.8%), rash (1.8%), diarrhea (1.7%), and vomiting (1.5%) while taking cefepime. Other, less common, adversities noted include pruritus (1.0%), cardiovascular events (1.0%), respiratory effects (0.8%), and dizziness (0.7%). These effects were not found to be significantly different from those of ceftazidime. The most commonly noted adverse effects of ceftazidime include diarrhea (3.2%), headache (2.5%), nausea (2.1%), rash (1.9%), and constipation (1.5%). In addition, events relating to episodes of anaphylaxis, seizures, neutropenia, and bleeding occurred rarely in patients administered cefepime.26
Laboratory abnormalities were also evaluated by Neu. Elevations in aminotransferases, prothrombin time, and activated partial thromboplastin time were noted in greater than 1% of the cefepime population. More cefepime patients (14.5%) reported a positive Coombs test compared to ceftazidime recipients (8.7%); however, no significant hemolysis was documented in either group of patients. Eosinophilia occurred in fewer cefepime patients than those on ceftazidime (0.8% vs 1.1%).26
Local intolerances to IV or IM administration of cefepime were not statistically different from those of ceftazidime administration. Either route of administration is well tolerated.26 Consequently, Gubbelmans et al. discovered that IM cefepime was significantly better tolerated than IM ceftriaxone, with or without 1% lidocaine.27
Drug discontinuation due to adverse effects from either agent was similar (53 cefepime patients vs. 44 ceftazidime patients).26
Dosage and Administration
Most infections susceptible to cefepime therapy require a dosage regimen of 1 to 2 grams every 12 hours. However, a more definitive dosing schedule depends on the severity of the infection as well as the sensitivity of the microorganism to cefepime. Therefore, those patients with an infection caused by P. aeruginosa may require higher dosing, at least 2 grams every 12 hours. In addition, renal function status, determined by creatinine clearance, dictates the dose of cefepime. Those patients on hemodialysis must receive supplemental dosing. Also, those patients undergoing CAPD therapy must receive appropriate dosing (every 48 hours) in order to prevent underdosing or overdosing the patient. Cefepime can be administered either IV via short infusion (30 minutes) or IM. Lidocaine 1% or sterile water can be used to dilute cefepime for IM use. Therapy should be continued for 48 to 72 hours post-eradication of the pathogen.
Pharmacoeconomic Issues
Paladino conducted a retrospective economic analysis between cefepime and ceftazidime. Cefepime was most commonly administered every 12 hours while patients on ceftazidime received doses every 8 hours. Subjects received a median dose of 14 g of cefepime compared to 24 g of ceftazidime over a median of 8 days. Both the occurrence of adverse events as well as the clinical success rates were similar. The decision and sensitivity analyses revealed that cefepime will be a cost-effective alternative to ceftazidime in the treatment of UTI, skin and skin structure infections, lower respiratory tract infections, and bacteremia.28
Conclusion
Cefepime has demonstrated clinical efficacy in trials involving the lower respiratory tract, urinary tract, skin and skin structures, febrile neutropenia, sepsis and bacteremia, and pediatric meningitis. Pathogens susceptible to cefepime therapy include both gram-negative and gram-positive organisms. The advantages of cefepime over third-generation cephalosporins include its activity against a broad range of in vitro gram-positive and gram-negative microbes, encompassing resistant pathogens. Also, cefepime is administered twice daily and has a well-tolerated safety profile. The clinical data reflects that cefepime is comparable to ceftazidime and cefotaxime; therefore, it is an effective alternative agent for susceptible pathogens.
