Cefepime: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Cefepime is an oxymino b-lactam with an amino thiazolyn side chain classified as a fourth-generation cephalosporin. In general, it has a wider spectrum and greater potency than the third-generation cephalosporins. It shows high stability against some b-lactamases, most notably the AmpC chromosomally mediated b-lactamases produced by Gram-negative pathogens (Hanson, 2003; Ramphal and Ambrose, 2006). Its clinical utility has been questioned by the results of a meta-analysis which showed that patients receiving cefepime had a higher mortality than those receiving comparator agents (Yahav et al., 2007). The findings of this meta-analysis have remained controversial (Nguyen et al., 2009).
The molecular weight of cefepime is 571.49 and its chemical formula is C19H25ClN6O5S2. Its structure is illustrated in Figure 32.1.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Gram-positive aerobic bacteria

Wild-type and clinical isolates of Staphylococcus aureus, coagulasenegative staphylococci, b-hemolytic streptococci, and viridans group streptococci are frequently susceptible to cefepime (Tables 32.1 and 32.2). In contrast, methicillin-resistant staphylococci, Enterococcus spp., and Listeria monocytogenes are consistently resistant to the drug. It should be noted that no criteria of interpretation have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for enterococci and staphylococci, whereas the Clinical and Laboratory Standards Institute (CLSI) suggests criteria only for staphylococci (Table 32.3). Cefepime MICs for clinical isolates of Streptococcus pneumoniae are similar to those of cefotaxime and ceftriaxone. In these strains, the MICs of cefepime are constantly lower than the MICs of penicillin G (Johnson et al., 2006; Jones et al., 2007). In fact, at least 80% of penicillin-intermediate isolates remain susceptible to the drug (Table 32.2).

Gram-negative aerobic bacteria

Wild-type and clinical isolates of Enterobacteriaceae are frequently susceptible to cefepime, although some important resistance mechanisms do exist (Tables 32.4 and 32.5). The majority of published epidemiologic data are interpreted according to the CLSI criteria, in which susceptibility of Enterobacteriaceae to cefepime is defined as an MIC of r8 mg/l. Nevertheless, it should be noted that EUCAST breakpoints are much more conservative, with susceptibility being defined as r2 mg/l (Table 32.3). Therefore, the number of cefepimenon-susceptible Enterobacteriaceae might be higher than generally recorded. For example, MICs90 of Enterobacter spp. and Klebsiella spp. frequently exceed 2 mg/l (Table 32.5).

Anaerobic bacteria

The activity of cefepime appears poor against anaerobes in general. Most isolates of Bacteroides fragilis and other Bacteroides spp., Prevotella spp., and Fusobacterium are resistant (Livermore et al., 2001; Kuriyama et al., 2002; Loza et al., 2003). Clostridium spp. show high MICs for cefepime (Table 32.2) (Chin et al., 1991; Duval et al., 1993; Steyaert et al., 1999; Livermore et al., 2001; Loza et al., 2003). Propionibacterium spp. and Peptostreptococcus spp. showed lower MIC values for cefepime (MIC90 of 4/8 mg/l, respectively) (Livermore et al., 2001; Kuriyama et al., 2002). Data regarding the remaining Gram-positive anaerobes are scarce.

Other bacteria

Cefepime does not have activity against Chlamydia, Mycoplasma, or Rickettsia.

b. Emerging resistance and cross-resistance

Cefepime is hydrolyzed by ESBLs like other expanded-spectrum cephalosporins. The most frequently encountered ESBL types are CTX-M, SHV, and TEM (Paterson and Bonomo, 2005). ESBLs of SHV and TEM-type typically do not hydrolyze cefepime as efficiently as third-generation cephalosporins (Rebuck et al., 2000). Many SHV or TEM-type ESBL-producing strains have cefepime MICs which are r8 mg/l. In contrast, cefepime MICs do tend to be higher in strains that produce the CTX-M-type ESBLs (Yu et al., 2002; Brigante et al., 2005). Cefepime is also hydrolyzed by most carbapenemases, such as the KPC type and metallo-b-lactamases. In general, cefepime is not substantially hydrolyzed by AmpC b-lactamases. However, a number of AmpC variants have been found which can compromise cefepime’s activity (Doi et al., 2009). Finally, outer membrane protein loss and efflux pump systems may contribute to cefepime resistance.

c. In vitro synergy and antagonism

Although synergy may be observed in vitro with aminoglycosides, the clinical significance of this observation is not known.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Cefepime is not absorbed after oral administration and it is usually administered by the intravenous (i.v.) or less commonly the intramuscular (i.m.) route. According to the manufacturer’s instructions, the following scheduled dosages should be used for cefepime treatment: moderately severe infections such as pneumonia due to S. pneumoniae and Gramnegative organisms (1–2 g i.v. every 12 hours for 10 days); empiric therapy for febrile neutropenic patients (2 g i.v. every 8 hours for at least 7 days); mild–moderate uncomplicated or complicated UTIs (0.5–1 g i.v. every 12 hours), severe UTI (2 g i.v. every 12 hours for 10 days); moderate– severe skin and skin soft-tissue infections due to S. aureus or S. pyogenes (2 g i.v. every 12 hours for 10 days); intra-abdominal infections (2 g i.v. every 12 hours for 7–10 days).

b. Newborn infants and children

The dosage in children (over two months) is 50 mg/kg per dose. The dosing interval is every 8 hours in management of febrile neutropenia and every 12 hours for other indications. The total dose should not exceed that which is recommended in adult infections. There are insufficient data to guide dosing in premature neonates.

c. Altered dosages Impaired renal function

In patients with impaired renal function, a dosage reduction is necessary. The Product Information recommends that, if there is renal functional impairment but the creatinine clearance (CLCr) is still W30 ml/min, a dose of 1 g every 12 hours is recommended. If CLCr is 10–30 ml/min, the dosage is 0.5 g every 24 hours, but if CLCr is o10 ml/min, the suggested dosage is 250 mg every 24 hours. We are concerned that these dosage regimens may be inadequate for pathogens with high cefepime MICs – doubling the doses suggested above may be reasonable.

Impaired hepatic function

There are few data available to suggest a need for dosage adjustment in patients with impaired hepatic function.

The elderly

Owing to the progressive decline in glomerular filtration seen during aging, the normal cefepime terminal half-life of 2 hours observed in young volunteers is prolonged to about 3 hours in the elderly. However, the magnitude of age-related changes in the pharmacokinetics of cefepime is not significant enough to recommend dosage adjustment in elderly patients with kidney function normal for their age (Barbhaiya et al., 1992a). Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the CLCr is less than 60 ml/min.

Patients with cystic fibrosis

The elimination half-life of cefepime in these patients is 11% shorter than in other patients, and the clearance is almost 40% higher in patients with CF. However, the difference in pharmacokinetics is minor and, from this point of view, no change in dosage is recommended.

Burns patients

Pharmacokinetic studies of cefepime (2 g every 12 hours) in six burns patients showed that at day 1 half-life was 2.45 hours, and total clearance was 152 ml/min. There was no statistical difference between day 1 and day 3 for any of the pharmacokinetic parameters. Good penetration of cefepime in skin was recorded. These results showed that it is not necessary to change the standard dosage of cefepime in burns patients (Sampol et al., 2000). In another study, a single 2-g dose of cefepime was evaluated in 12 adult patients with thermal burn injury and suspected or documented infection.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Cefepime is not absorbed when given orally. Following i.m. administration, cefepime is completely and rapidly absorbed with a mean peak time of 1.0–1.6 hours. The serum protein binding is approximately 20%, and is independent of its concentration in serum (Barbhaiya et al., 1992c).

b. Drug distribution

Single doses of therapeutic cefepime of 250 mg, 0.5, 1, and 2 g were given to normal adults by a 30 minute infusion (Barbhaiya et al., 1990a). The mean peak serum levels (Cmax) after the i.v. infusion were 16.3, 31.6, 66.9, and 133 mg/l, respectively. Doubling the dose resulted in approximately double the peak serum level. The levels of cefepime in plasma declined with an elimination half-life of about 2 hours, independently of the dose administered. Total body clearance for all doses ranged between 122 and 136 ml/min. The cefepime serum level is approximately 1 and 5 mg/l, 8 hours after administration of 250 mg and 2 g, respectively (Barbhaiya et al., 1990a). If each of the four possible doses were given 8-hourly for 9 days, there was no drug accumulation in the body (Barbhaiya et al., 1992c). When cefepime was administered together with amikacin, the pharmacokinetic parameters of both drugs remained unchanged (Barbhaiya et al., 1992d).

c. Clinically important pharmacokinetic and pharmacodynamic features

Cefepime regimens of 1 g every 12 hours, 1 g every 8 hours and possibly even 2 g every 12 hours may have a suboptimal probability of achieving pharmacodynamic targets associated with good outcome (Burgess and Frei, 2005; Frei and Burgess, 2005).

d. Excretion

Cefepime is primarily eliminated via the kidney as the unchanged active drug by glomerular filtration. Urinary recovery of intact cefepime is about 80–85% of the administered dose. The mean renal clearance of 105 ml/min is nearly the same as that of creatinine in normal humans (Barbhaiya et al., 1990a; Tam et al., 2003a).

e. Drug interactions

There are no specific interactions between cefepime and other drugs. If aminoglycosides are given concomitantly, an assessment for nephrotoxicity should be made.

TOXICITY

Toxic effects appear to be infrequent and similar to those observed with other cephalosporins such as ceftazidime (see Chapter 30, Ceftazidime). However, the meta-analysis of Yahav et al. (2007) found that mortality of patients treated with cefepime was significantly higher than patients treated with comparator agents (relative risk 1.26; 95% confidence intervals 1.08–1.49). Baseline risk factors for mortality were similar between cefepime and comparator agents.

The following adverse events have been related to cefepime during clinical trials: local reactions (3%), including phlebitis (1.3%), pain or inflammation (0.6%), and rash (1.1%). Colitis (including pseudomembranous colitis), diarrhea, fever, headache, nausea, oral candidiasis, pruritus, urticaria, vaginitis, and vomiting were observed in less than 1% of patients. At the higher dosing regimen of 2 g every 6-8 hours the incidence of probably related adverse events was higher: rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). 

CLINICAL USES OF THE DRUG

a. Monotherapy for empiric treatment of febrile neutropenic patients

Cefepime has been assessed in at least 17 trials in febrile neutropenic patients – comparisons have been with ceftazidime in eight trials, imipenem in four, piperacillin–tazobactam in three, and meropenem in two for this indication (Paul et al., 2006). All-cause mortality was significantly higher with cefepime than with other comparator b-lactams (RR = 1.44; p = 0.02). Four studies recruited only children, and mortality was higher with cefepime than with ceftazidime (RR = 2.28), and equal to meropenem. The effect estimate was higher among studies that used less than the registered recommended dose for cefepime in febrile neutropenia (i.e. 2 g every 8 hours or 50 mg/kg every 8 hours for adults and children, respectively), but this did not reach statistical significance. No significant differences were detected between cefepime and comparators with regard to all secondary efficacy outcomes.

b. Serious bacterial infections, including bacteremia and pneumonia

Cefepime, in a dose of 2 g i.v. every 12 hours, has been found to be quite effective for the treatment of such severe infections, which normally occur in the hospital setting (Chang et al., 1998; Ambrose et al., 2002; Huang et al., 2002; Stefanov et al., 2002). However, in the case of infections due to strains expressing high MICs against cefepime (e.g. P. aeruginosa, Acinetobacter spp., ESBL producers and/or hyperproducers of AmpC enzymes), standard therapeutic regimens might be unable to guarantee a good clinical outcome.

c. Osteomyelitis

In an animal study, cefepime administered for 4 weeks to rabbits with chronic experimental osteomyelitis due to S. aureus sterilized the bones of 53% of treated animals. This agent appeared as effective as other b-lactam antibiotics but not as effective as clindamycin (Norden and Gill, 1990). 

d. Meningitis

Current recommendations from the Infectious Diseases Society of America (IDSA) for empiric antimicrobial therapy for postneurosurgical meningitis are for intravenous vancomycin plus either cefepime, ceftazidime, or meropenem (Tunkel et al., 2004). 

e. Urinary tract infection

Results similar to those obtained with ceftazidime were obtained with the use of cefepime in complicated UTIs (Oster et al., 1990; Gentry and Rodriguez-Gomez, 1991).

f. Skin and soft-tissue infections

Cefepime has been successfully used in skin and surgical wound infections (Oster et al., 1990; Gentry and Rodriguez-Gomez, 1991).

g. Gynecologic infections

Patients with acute gynecologic infections were randomized to receive cefepime (2 g every 12 hours) or cefotaxime (2 g every 8 hours), either i.m. or i.v. for 30 minutes for approximately 4–5 days. Clinical response was satisfactory in 85% of cefepime recipients and 83% cefotaxime recipients.

h. Intra-abdominal infections

Cefepime (2 g every 12 hours i.v.) plus metronidazole (500 mg every 6 hours) was compared with imipenem–cilastatin (500 mg every 6 hours) in the treatment of complicated intra-abdominal infections in adults.

Patients treated with cefepime plus metronidazole were deemed clinical cure (88%) more frequently than were imipenem–cilastatintreated patients (76%). Pathogens were eradicated in significantly more patients treated with combined cefepime and metronidazole (89%) than patients treated with imipenem-cilastatin (76%) (p = 0.01) (Barie et al., 1997).

References

Allaouchiche B, Breilh D, Jaumain H et al. (1997). Pharmacokinetics of cefepime during continuous venovenous hemodialfiltration. Antimicrob Agents Chemother 41: 2424.
Ambrose PG, Owens Jr RC, Garvey MJ, Jones RN (2002).
Pharmacodynamic considerations in the treatment of moderate to severe pseudomonal infections with cefepime. J Antimicrob Chemother 49: 445.
Brigante G, Luzzaro F, Perilli M et al. (2005). Evolution of CTX-M-type betalactamases in isolates of Escherichia coli infecting hospital and community patients. Int J Antimicrob Agents 25: 157.
Burgess DS, Frei CR (2005). Comparison of beta-lactam regimens for the treatment of gram-negative pulmonary infections in the intensive care unit based on pharmacokinetics/pharmacodynamics. J Antimicrob Chemother 56: 893.
Canton R, Cobos N, de Gracia J et al., on behalf of the Spanish Consensus Group for Antimicrobial Therapy in the Cystic Fibrosis Patient (2005). Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients. Clin Microbiol Infect 11: 690.
Castanheira M, Gales AC, Pignatari AC et al. (2006). Changing antimicrobial susceptibility patterns among Streptococcus pneumoniae and Haemophilus influenzae from Brazil: report from the SENTRY Antimicrobial Surveillance Program (1998–2004). Microb Drug Resist 12: 91.
Duval J, Soussy CJ, Acar JF et al. (1993). In-vitro antibacterial activity of cefepime: A multicentre study. J Antimicrob Chemother 32: 55.
Edelstein H, Chirurgi V, Oster S et al. (1991). A randomized trial of cefepime (BMY-28142) and ceftazidime for the treatment of pneumonia. J Antimicrob Chemother 28: 569.
Eggimann P, Glauser MP, Aoun M et al. (1993). Cefepime monotherapy for the empirical treatment of fever in granulocytopenic cancer patients. J Antimicrob Chemother 32: 151.
Fritsche TR, Stilwell MG, Jones RN (2005). Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003). Clin Microbiol Infect 11: 974.
Gales AC, Sader HHS, Jones RN (2002). Respiratory tract pathogens isolated from patients hospitalized with suspected pneumonia in Latin America: frequency of occurrence and antimicrobial susceptibility profile: results from the SENTRY Antimicrobial Surveillance Program (1997–2000). Diagn Microbiol Infect Dis 44: 301.
Huls CE, Prince RA, Seilheimer DK, Bosso JA (1993). Pharmacokinetics of cefepime in cystic fibrosis patients. Antimicrob Agents Chemother 37: 1414. Japoni A, Alborzi A, Kalani M et al. (2006). Susceptibility patterns and crossresistance of antibiotics against Pseudomonas aeruginosa isolated from burn patients in the South of Iran. Burns 32: 343.
Jauregui L, Matzke D, Scott M et al. (1993). Cefepime as treatment for osteomyelitis and other severe bacterial infections. J Antimicrob Chemother 32: 141.
Loza E, Morosini MI, Canton R et al. (2003). Comparative in vitro activity of ertapenem against aerobic and anaerobic bacteria. Rev Esp Quimioter 16: 209.
Maglio D, Ong C, Banevicius MA et al. (2004). Determination of the in vivo pharmacodynamic profile of cefepime against extended-spectrum-betalactamase-producing Escherichia coli at various inocula. Antimicrob Agents Chemother 48: 1941.
Malone RS, Fish DN, Abraham E, Teitelbaum I (2001). Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother 45: 3148.

You may like