Cefepime | Survivin Signal

Cefepime A Review of its Use in the Management of Hospitalized Patients with Pneumonia

Therese M. Chapman and Caroline M. Perry

Adis International Inc., Langhorne, Pennsylvania, USA

Various sections of the manuscript reviewed by:

K.A. Bachmann, Center for Applied Pharmacology, University of Toledo, Toledo, Ohio, USA; B.A. Cunha, Infectious Disease Division, Winthrop-University Hospital, Mineola, New York, New York, USA; S. Kohno, Second Department of Internal Medicine, Nagasaki University, Nagasaki, Japan; M.P. Okamoto, Western University of Health Sciences, Pomona, California, USA; J. Segreti, Rush Medical College, Chicago, Illinois, USA; M. Zervos, Infectious Diseases Division, Wayne State University, Detroit, Michigan, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on cefepime, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘cefepime’ and (‘lower respiratory tract infection*’ or ‘pneumonia’). EMBASE search terms were ‘cefepime’ and (‘lower respiratory tract infection*’ or ‘pneumonia’). AdisBase search terms were ‘cefepime’ and (‘PK’ or ‘PD’ or ‘in-vitro’) and ‘cefepime’ and (‘lower respiratory tract infection*’ or ‘pneumonia’). Searches were last updated 17 January 2003.

Selection: Studies in patients with pneumonia who received cefepime. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: cefepime, community-acquired pneumonia, nosocomial pneumonia, pharmacodynamics, pharmacokinetics, therapeutic use.

Contents

Summary ………………………………………………………….. 76
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2. Antibacterial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2.2 In Vitro Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
2.2.1 Gram-Positive Aerobic Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
2.2.2 Gram-Negative Aerobic Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
2.2.3 Anaerobic Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.3 Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.4 Effect on Fecal Flora . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.5 Pharmacodynamic/Pharmacokinetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.1 Plasma Concentrations and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.3 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3.4 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3.4.1 Elderly Patients with or without Respiratory Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3.4.2 Pediatric Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3.4.3 Patients with Impaired Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
3.5 Pharmacokinetic Interaction between Cefepime and Amikacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4.1 Adult Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
4.1.1 Comparisons with Third-Generation Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
4.1.2 Comparison with Imipenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
4.2 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.2.1 Pediatric Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.2.2 Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
4.2.3 Nonresponders to Penicillin and Other Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

76 Chapman & Perry

4.3 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….96
5. Tolerability . . . . . ………………………………………………….. ….97
5.1 Adults . . . . . ………………………………………………….. ….97
5.1.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….97
5.1.2 Local Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….97
5.1.3 Laboratory Test Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….98
5.1.4 Uncommon Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….98
5.2 Pediatric Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….98
6. Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….98
7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ….99
8. Place of Cefepime in the Management of Hospitalized Patients with Pneumonia . . . . . . . . . . . . . . . . . . . . . . …. 101

Summary
Abstract Cefepime (Maxipime®, Maxcef®, Cepimax®, Cepimex®, Axepim®1), a parenteral fourth-generation cephalo-
sporin, 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 cephalo-
sporins. 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 Entero-
bacter 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.
Cefepime acts by binding to penicillin-binding proteins and inhibiting the synthesis of the bacterial cell wall.
Antibacterial Activity
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

1 Use of tradenames is for product identification purposes only and does not imply endorsement.

Cefepime in Hospitalized Patients with Pneumonia: A Review 77

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 imi-penem. 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.
The absorption kinetics of cefepime are linear over the 0.25–2g dose range. After intravenous administration,
Pharmacokinetic
Properties 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 admin-
istration 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 elimina-
tion 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

78 Chapman & Perry

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.
In randomized, generally nonblind trials, cefepime monotherapy was as effective as monotherapy with
Therapeutic Efficacy
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 pneumo-
nia 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. Addi-
tionally, 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 approx-
imately 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.
In clinical trials, intravenous or intramuscular cefepime was generally well tolerated in hospitalized patients
Tolerability
with pneumonia. The majority of adverse events were mild to moderate in intensity and reversible upon discon-
tinuation 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 candi-
diasis, 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

[6-9]
Cefepime in Hospitalized Patients with Pneumonia: A Review 79

and seizures in postmarketing experience. Most episodes occurred in patients with renal impairment who re-
ceived doses of cefepime greater than those recommended by the manufacturer.
Two cost analyses in patients with HAP or various bacterial infections, using similar acquisition costs for
Pharmacoeconomic
Considerations 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.
In countries other than the US, cefepime is indicated for the treatment of mild to very severe pneumonia in adults
Dosage and
Administration 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; however, pharma-
cokinetic modelling suggests that a dose of 30 mg/kg/dose twice daily or three times daily may be considered
in these patients.
In the US, cefepime is approved for the treatment of moderate to severe pneumonia caused by S. pneumoniae,
P. aeruginosa, K. pneumoniae or Enterobacter spp. in adults or children (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.

1. Introduction

Cefepime (Maxipime®, Maxcef®, Cepimax®, Cepimex®, Axepim®1) is a parenteral fourth-generation extended-spectrum cephalosporin. It is indicated for the treatment of a broad range of infections in adult and pediatric patients, including pneumonia, urinary tract, intra-abdominal, and skin and skin structure infec-tions caused by susceptible bacteria in numerous countries world-wide.[1,2] Cefepime is also indicated for the empiric treatment of febrile neutropenic patients.[1,2] In South America, Asia, the Mid-dle East and some European countries, cefepime is also indicated for the treatment of adult patients with lower respiratory tract infec-tions other than pneumonia, septicemia and gynecologic infec-tions and children with bacterial meningitis (aged ≥1 month).[2] In these countries it is also indicated for the surgical prophylaxis of adult patients.[2]

The antibacterial activity, pharmacology and clinical effi-cacy of cefepime in all indications have previously been reviewed in Drugs.[3] This review provides an update on the antibacterial activity and pharmacologic profile of cefepime and focuses on

the clinical use of cefepime in the treatment of hospitalized pa-tients with community-acquired (CAP) or nosocomial (hospital-acquired) pneumonia (HAP).

2. Antibacterial Activity

2.1 Mechanism of Action

Like the third-generation cephalosporins, cefepime has a 2-amino-thiazolylacetamido group at position 7 which increases its stability against bacteria producing β-lactamases (section 2.3). However, cefepime differs structurally from the third-generation cephalosporins in two important ways. It contains an alkoxy-imino substitution in the position 7 side chain which improves its activity against staphylococcal isolates, and a positively charged quaternary N-methyl-pyrrolidine substitution at position 3 of the cephem nucleus and a negative charge at position 4, making it a zwitterion[4,5] which allows for faster penetration into the bacte-
rial cell.

Cefepime acts, as other cephalosporins do, by inhibiting the

80 Chapman & Perry

synthesis of the bacterial cell wall. Cefepime binds to and acy-lates transpeptidase enzymes (penicillin-binding proteins; PBPs) thereby inhibiting peptoglycan synthesis, leading to defects in the cell wall, and the subsequent lysis and death of susceptible or-ganisms.[10,11] Cefepime preferentially binds to PBP3 in isolates of Escherichia coli and Pseudomonas aeruginosa.[12-14] Unlike other cephalosporins, cefepime also has a high affinity for PBP2 of E. coli and limited affinity for PBP2 of P. aeruginosa.[13,14] Cefepime also binds to PBPs 1A and 1B at low concentrations.[14] High affinity for more than one class of PBP is associated with fast bacterial death.[14]

Cefepime enters Gram-negative bacteria by passive diffu-sion through porins in the outer cell membrane. The zwitterionic nature of cefepime allows it to orientate itself toward the negative charge of the interior of bacterial cells and quickly penetrate the outer membrane via the porins.[6-9] Nikaido et al.,[8] using extrap-olations from an experiment with liposomes, calculated that cefepime would penetrate intact cells of Enterobacter cloacae and E. coli 2–10 times more rapidly than ceftazidime or cefotax-ime. Moreover, Bellido et al.,[9] using a direct assay of the per-meation of cephalosporins, found that cefepime penetrated the outer membrane of E. cloacae 5–20 times faster than ceftriaxone or cefotaxime. Faster penetration of the cell wall allows for higher concentrations of cefepime in the periplasmic space of Gram-negative bacteria.[15]

2.2 In Vitro Activity

Cefepime is active against a broad range of Gram-positive and Gram-negative bacteria in vitro; however, it should be noted that in the US cefepime is currently only indicated for the treat-ment of moderate to severe pneumonia caused by susceptible strains of Streptococcus pneumoniae, P. aeruginosa, Klebsiella pneumoniae and Enterobacter spp. (section 7). Nonetheless, this section provides an overview of the in vitro antibacterial activity of cefepime against organisms commonly implicated in pneumo-nia, including S. pneumoniae, Staphylococcus aureus, E. coli, Klebsiella spp., Enterobacter spp., P. aeruginosa, Stenotro-phomonas maltophilia, Acinetobacter spp., Haemophilus in-fluenzae, Moraxella catarrhalis and various anaerobes.

In general, data included in this section have been obtained from in vitro or surveillance studies evaluating more than 1000 clinical isolates. Another study including 350 isolates of S. pneu-moniae classified as penicillin-susceptible, -intermediate or -re-sistant has also been included.[16] Studies were conducted in North and/or South America,[17-27] Europe,[16,28-31] Japan[32,33] or world-wide.[34] Because of the possibility of microbiological suscepti-bilities to cefepime changing over time, only studies that col-

lected isolates since 1997 are included in this section. The major-ity of studies collected consecutive, clinically relevant bacteria from a wide variety of community-acquired or nosocomial infec-tions. Collection centers generally included large medical centers and general wards or intensive care units (ICUs) of hospitals. A summary of the comparative in vitro activity of cefepime versus three other broad-spectrum parenteral cephalosporins (ceftazidime, ceftriaxone, cefotaxime) and imipenem is provided in table I.

The in vitro activity of cefepime and its comparators has been measured by the minimum inhibitory concentration re-quired to inhibit the growth of 50% or 90% of strains (MIC50 and MIC90). Studies used standard agar[16] or broth dilution tech-niques[17-23,26-28,30,34] or Etest methods[24,25,29,31-33] to establish

MICs. Breakpoints determined by the US National Committee for Clinical Laboratory Standards (NCCLS) were used to interpret results. Most studies used the NCCLS breakpoints applicable at the time the study was conducted (1997–2001) to determine the percentage of pathogens susceptible to cefepime and its compa-rators (table I). However, the cefepime susceptibility breakpoints for nonmeningeal infections caused by S. pneumoniae have since been revised from≤0.5 mg/L = susceptible, 1.0 mg/L = intermediate susceptibility and≥2.0 mg/L = resistant prior to 2002,[35] to≤1.0 mg/L = susceptible, 2.0 mg/L = intermediate susceptibility and≥4.0 mg/L = resistant.[36] Consequently, the percentage of S. pneu-moniae isolates susceptible to cefepime and the third-generation cephalosporins is likely to be underestimated by these studies. NCCLS guidelines recommend that susceptibility breakpoints for cefepime (other than for Haemophilus spp. and S. pneumo-niae) are≤8 mg/L = susceptible; 16 mg/L = intermediate suscep-tibility;≥32 mg/L = resistant.[36] Isolates of Haemophilus spp. with an MIC of≤2 mg/L are considered susceptible to cefepime.[36]

2.2.1 Gram-Positive Aerobic Bacteria

Cefepime showed excellent in vitro activity against strains of S. pneumoniae in a number of studies (table I). Studies that did not distinguish between types of S. pneumoniae (penicillin-susceptible, -intermediate or -resistant) demonstrated that the cefepime MIC90 ranged from 0.5–2 mg/L and that 81.1–92.4% of strains were sus-ceptible to cefepime.[17,18,27] Three studies reported the status of S. pneumoniae isolates as penicillin-susceptible, -intermediate or -resistant.[16,20,30] In these studies, cefepime, ceftazidime, cefotaxime and imipenem were all highly active against penicillin-susceptible strains of S. pneumoniae (table I).[16,20,30] The mean MIC90 value of cefepime against S. pneumoniae strains susceptible to penicil-lin was≤0.06 mg/L (99.8–100% susceptibility).[16,20,30]

Table I. In vitro antibacterial activity of cefepime, ceftazidime, ceftriaxone, cefotaxime and imipenem against Gram-positive and Gram-negative organisms; data generally taken from large in vitro or surveillance studies evaluating >1000 clinical isolates collected from 1997 onwards. Studies were performed in North and/or South America,[17-27] Europe,[16,28-31] Japan[32,33] or worldwide.[34] Susceptibility testing was performed using Etest methods[24,25,29,31-33] or broth,[17-23,26-28,30,34] or agar dilution[16] techniques. Data are presented as
medians (mean range)

Organism na Cefepime Ceftazidime Ceftriaxone Cefotaxime Imipenem References

MIC50; MIC90 S (%)b S (%)b MIC50; MIC90 S (%)b S (%)b MIC50; MIC90 S (%)b
MIC50; MIC90 MIC50; MIC90

[mg/L] [mg/L] [mg/L] [mg/L] [mg/L]

Gram-positive
bacteria
Streptococcus 1455 0.06 (≤0.06– 81.1– 0.25d; 4d 76.8d 0.03e; 0.5 86.2– 17,18,27
pneumoniaec 0.06); 1 (0.5–2) 92.4 (0.5–1) 92.5
PS S. pneumoniae 1509 ≤0.06 (0.015– 99.8, 0.185 (0.12– 96.0 s 0.015e; 0.03 99.8, 0.008d; 0.015d NR 16,20,30
0.06);≤0.06e 100 ≤0.25); 0.375 (0.03–0.06) 100
(0.25–0.5)

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Am J Respir Med 2003; 2 (1)

PI S. pneumoniae 436 0.25 (0.12– 76.9, 4e; 12 (8–16) 14.0
0.25); 1 (0.5–1) 88.0
PR S. pneumoniae 289 1 (0.5–1); 7.1, 16e; 32e 2.0
2 (1–2) 22.0
MS Staphylococcus 6270 2 (2–3); 4e 96.5– 14 (8–16); 3.7– 3 (2–4); 4e 95.1,
aureus 100 20 (16–24) 62.3 98.9
S. aureusf 1858 4 (2–8); 50.1– 8 (4–16); 40.6, 2d; 4d NR
8 (4–16) 99.0 16 (8–16) 67.4
Gram-negative
bacteria
Enterobacteriaceae
Escherichia colig 10 815 ≤0.12 (0.047– 95.0– 0.25 (≤0.12– 87.4– ≤0.25 (≤0.06– 89.0–
≤0.12); 100 0.5); 0.5 100 ≤0.25);≤0.25 99.4
≤0.12 (≤0.12–2) (≤0.12–24) (0.12–3)
Klebsiella 3358 ≤0.12 (0.094– 92.1– 0.25 (≤0.12– 74.1– ≤0.25 (0.125– 81.8–
pneumoniaeg ≤0.12); 3 (0.25–4) 99.2 0.5); 16 95.9 ≤0.25); 24 97.2
(1–256) (0.25–32)
Klebsiella spp.g 2435 ≤0.12 (0.047–2); 65.0– 0.25 (≤0.12– 35.0– ≤0.25 (≤0.06– 37.0–
0.5 (≤0.12–32) 100 4); 1 (0.5– 99.1 ≤0.25);≤0.25 98.4
>256) (0.12–>32)
Enterobacter spp.h 5097 ≤0.12 (0.064– 65.0– 0.5 (0.25–2); 33.0– ≤0.25 (≤0.25– 44.0–
0.5); 2.5 (0.25 100 >16 (2–>256) 90.1 0.38); 32 90.1
–16) (8–>256)

0.25 (0.12– 84.6, 0.06d; 0.12d NR 16,20,30
0.25); 0.5 92.0
(0.5–1)
1 (0.5–1); 23.0, 0.25d; 0.5d NR 16,20,30
2 (1–2) 35.7
2d; 4d 98.6d 0.047 (0.047– 97.3– 20,24,30,
0.12); 0.064 100 32,33
(0.064–0.25)
3 (2–4); 8e 99.0e ≤0.06 (≤0.03– 50.1– 17-19
0.25); 0.25 100
(≤0.03–>8)

0.079 (≤0.06– 89.0– 0.25 (0.12– 98.0– 17,19,21,23-
0.25); 3.5 95.0 0.25); 0.5 100 25,28-33
(0.5–64) (0.25–0.5)
0.094d; 32d 87.0, 0.375 (0.25– 99.0– 21,25,28,30
87.8 0.5); 0.69 100
(0.38–1)
≤0.5 (0.125– 43.0, 0.25 (≤0.25– 86.0– 17-19,23,24,
16); 24 (≤0.5– 80.9 0.38); 0.5 100 29,31-33
>64) (≤0.5–1)
0.44 (0.12–4); 42.0– 0.5 (0.12–1); 2 86.0– 17-19,21,23,
160 (0.5– 68.1 (0.25–2) 100 24,30-32
>256)

Review

Am J Respir Med 2003; 2 (1)

Table I. Contd.

Organism na Cefepime Ceftazidime Ceftriaxone Cefotaxime Imipenem References

MIC50; MIC90 S (%)b MIC50; MIC90 S (%)b MIC50; MIC90 S (%)b MIC50; MIC90 S (%)b MIC50; MIC90 S (%)b

[mg/L] [mg/L] [mg/L] [mg/L] [mg/L]

Nonfermentative bacilli
Pseudomonas 15 523 4 (2–8); 45.0– 3 (2–5); >16 51.0– 32 (16–48); 7.6– 24 (4–>32); 13.5– 2 (1–3); 8 (4– 48.0– 17-19,22-
aeruginosa 16 (4–>64) 90.4 (4–>64) 88.0 >32 36.2 160 18.0 >32) 88.8 25,29-34
(>32–>256) (4–>256)
Stenotrophomonas 178 16 (16–48); 8.9– 9 (2–48); >16 27.3– >32 (>32– 0– >256d; >256d 4.2, >8 (>8–>32); 0–5.0 23,25,29,31
maltophilia >16 46.7 (8–>256) 93.3 >256); >32 14.0 18.0 >8 (>8–>256)
(>16–>256) (>32–>256)
Acinetobacter spp. 1348 4 (2–>32); 15.0– 6 (2–>32); >16 9.0– 16 (8–>32); 3.0– 44 (24–>64); 2.0, 0.5 (0.25–1); 2 46.0– 19,23,24,
>16 (6–>64) 96.0 (16–128) 87.0 >32e 57.9 128 (>64–192) 33.8 (0.75–>8) 97.0 29-33
Other Gram-negative
bacteria
Haemophilus 1621 0.12 (≤0.06 100e ≤0.25e; ≤0.25e 100e 0.015d; 0.06d 100d 17,18,26
influenzaei –0.12); 0.25
(0.12–0.25)
Moraxella 593 1e; 4 (2–4) 100e 0.5e; 1 100e 18,26
catarrhalisi (0.5–1)
References 16-34 16-25,28, 19-21,23,25, 16,18-20, 16-19,
30-34 28,30,31 24-28,30,31 23-25,28,30-34

a Total number of isolates used to evaluate the in vitro activity of cefepime.

b Percentage of organisms that were classed as susceptible (S) according to the breakpoints of the US National Committee for Clinical Laboratory Standards (NCCLS) used by the study investigators.

c Includes penicillin-susceptible, -intermediate and -resistant strains. d Data from a single study; mean value.

e All studies (or countries within a study) reported the same value.

f Includes both methicillin-susceptible and -resistant strains.

g Includes isolates with an extended spectrum β-lactamase phenotype.

h Includes both repressed and derepressed AmpC β-lactamase-producing strains.

i Includes both β-lactamase-positive and -negative strains.

MIC50/90 = minimum inhibitory concentrations required to inhibit the growth of 50% or 90% of strains, respectively; MS = methicillin-susceptible (NCCLS methicillin susceptibility breakpoint ≤8.0 mg/L); NR = not reported; PI = penicillin-intermediate (NCCLS penicillin intermediate breakpoint 0.12–1.0 mg/L); PR = penicillin-resistant (NCCLS penicillin resistant breakpoint ≥2.0 mg/L); PS = penicillin-sensitive (NCCLS penicillin susceptibility breakpoint ≤0.06 mg/L).[36]

Chapman & Perry

Cefepime in Hospitalized Patients with Pneumonia: A Review 83

However, against isolates of S. pneumoniae that were classed as penicillin-intermediate, only cefepime, cefotaxime and im-ipenem were active (table I)[16,20,30] while ceftazidime eradicated only 14% of penicillin-intermediate strains of S. pneumoniae (median MIC90 12 mg/L).[20] Using the NCCLS interpretive cri-teria prior to 2002, cefepime was considered only marginally active against penicillin-resistant strains of S. pneumoniae (me-dian MIC90 2 mg/L) with only 7.1% and 22% of strains suscep-tible to cefepime.[16,20,30] Similarly, cefotaxime was also consid-ered marginally active against penicillin-resistant S. pneumoniae (median MIC90 2 mg/L, 23.0% and 35.7% susceptibility), while ceftazidime was considered inactive against these organisms (median MIC90 32 mg/L, 2% susceptibility).[16,20,30]

However, as mentioned earlier, since these studies were con-ducted the NCCLS breakpoints for cefepime against S. pneumo-niae have been revised (section 2.2). The use of the new break-points would mean that more of these isolates would be classed as susceptible to cefepime. For example, a reanalysis of all-years data from a large US surveillance study (SENTRY 1997–2001) indicated that 96.5% of S. pneumoniae strains were susceptible to cefepime using the 2002 NCCLS breakpoints (≤1 mg/L) versus 85.3% of isolates using the NCCLS criteria prior to 2002 (≤0.5 mg/L).[37] In this reanalysis, cefepime, cefotaxime and ceftri-axone were highly active against penicillin-susceptible (>99% susceptibility) and penicillin-intermediate strains of S. pneumo-niae (98.7%, 98.1% and 97.9% susceptibility).[37] Using the new breakpoints for nonmeningeal infections caused by S. pneumo-niae, cefepime was also found to have good activity against pen-icillin-resistant strains of S. pneumoniae (78.5% susceptibil-ity).[37] Cefotaxime and ceftriaxone were similarly active against penicillin-resistant strains of S. pneumoniae (76.7% and 74.2% susceptibility); however, fewer isolates were resistant to cefe-pime than to cefotaxime and ceftriaxone (2.9% vs 8.3% and 8.7% of isolates resistant).[37]

Cefepime, like other β-lactam agents, is not active against methicillin-resistant S. aureus (MRSA). The NCCLS guidelines recommend that isolates of MRSA be reported as resistant to all β-lactam agents, regardless of the results of susceptibility tests obtained with these agents.[36] However, cefepime demonstrated excellent activity against strains of methicillin-sensitive S. au-reus (MSSA) similar to ceftriaxone, cefotaxime and imipenem (table I) in a small number of in vitro studies.[20,24,30,32,33] Ceftazidime is not highly active against MSSA (median MIC90

14 mg/L, 3.7–62.3% susceptibility).[20,24,32,33] In a small number of in vitro studies in which the methicillin status of S. aureus was not reported, the activity of cefepime tended to be greater than that of ceftazidime and similar to that of cefotaxime and im-ipenem (table I).[17-19]

2.2.2 Gram-Negative Aerobic Bacteria

Enterobacteriaceae

Cefepime showed excellent activity against E. coli and Kleb-siella spp., similar to that of ceftazidime, ceftriaxone, cefotaxime and imipenem, in the in vitro and surveillance studies summa-rized in table I.[17-19,21,23-25,28-33] In a large European surveillance study, cefepime was active against a high percentage of isolates of E. coli similar to that of imipenem, ceftriaxone and ceftazidime (99.5% vs 99.9%, 98.8% and 98.5% susceptibility).[30] Addition-ally, cefepime tended to have greater in vitro activity against E. coli and Klebsiella spp. than the third-generation cephalosporins in surveillance studies that included a large percentage of strains of Enterobacteriaceae that expressed an extended-spectrum β-lactamase (ESBL) phenotype (section 2.3).

Cefepime also has similar activity to imipenem and better activity than the third-generation cephalosporins against Entero-bacter spp. (table I).[17-19,21,23,24,30-32] This was largely due to the increased activity of cefepime compared with the third-generation cephalosporins against inducible strains of Enterobacter spp. that are capable of hyperproduction of AmpC β-lactamases (section 2.3). In a large surveillance study conducted in the US, the in vitro activity of cefepime against all strains of Enterobacter spp. (MIC90 2 mg/L, 99.1% susceptibility) was similar to that of im-ipenem (MIC90 1 mg/L, 99.6% susceptibility), and superior to that of ceftazidime (MIC90 >256 mg/L, 66.6% susceptibility), ceftriaxone (MIC90 >256 mg/L, 68.1% susceptibility) and cefo-taxime (MIC90 >256 mg/L, 64.2% susceptibility).[25]

Nonfermentative Bacilli

Cefepime has similar antipseudomonal activity to cefta-zidime and imipenem, but has greater activity against P. aerugin-osa than ceftriaxone or cefotaxime (table I).[17-19,22-25,29-34] In a large study conducted in the US, 80.9%, 80.5% and 84.4% of strains of P. aeruginosa were susceptible to cefepime, cefta-zidime and imipenem, respectively, while cefotaxime and ceftri-axone were active against only 13.5% and 11.4% of P. aerugin-osa isolates.[25] Although cefepime and ceftazidime are active against a similar percentage of organisms, the percentage of or-ganisms resistant to the two antibacterial agents should also be considered. In a worldwide study, a similar percentage of P. aeru-ginosa strains were susceptible to cefepime and ceftazidime (66.5–83.2% vs 65.5–80.1% of isolates susceptible); however, a significantly lower percentage of organisms were resistant to cefepime compared with ceftazidime (6.5–13.9% vs 13.6–27.6% of isolates resistant; p < 0.05).[34]

In in vitro studies S. maltophilia was highly resistant to mul-tiple antibacterial agents.[23,25,29,31] The majority of strains of S. maltophilia tested against cefepime were found to be resistant (8.9–46.7% susceptibility).[23,25,29,31] Ceftriaxone, cefotaxime

84 Chapman & Perry

and imipenem had little or no activity against S. maltophilia whereas ceftazidime exhibited highly variable activity against these isolates (table I).[23,25,29,31]

Cefepime exhibited highly variable activity against Acinetobacter spp., similar to that of ceftazidime and lower than that of imipenem, but was more active than either ceftriaxone or cefotaxime (table I).[19,23,24,29-33]

Other Gram-Negative Bacteria

Cefepime, ceftazidime and cefotaxime were active against 100% of H. influenzae isolates (table I), even though approxi-mately one-third of these isolates were β-lactamase produc-ers.[17,18,26] There was no difference in in vitro activity when the results obtained with cefepime and the third-generation cephalo-sporins against β-lactamase-positive isolates were compared with the results of β-lactamase-negative strains.[26]

In two surveillance studies conducted in North America, ap-proximately 90% of clinical strains of M. catarrhalis were classed as β-lactamase-positive.[18,26] Despite this, cefepime and cefotaxime were both fully active against all isolates of M. catarrhalis (table I).[18,26]

2.2.3 Anaerobic Bacteria

Because of the small amount of data available for the in vitro activity of cefepime against anaerobes, data for this section are from numerous small in vitro studies.[38-49] Cefepime had little activity against Bacteroides fragilis (MIC50 15–64 mg/L; MIC90 >64–≥256 mg/L).[38-43,45-47,49,50] This low in vitro activity against B. fragilis was similar to that of ceftazidime (MIC50 15–128

mg/L; MIC90 64–≥256 mg/L),[38,40,43,45,49] ceftriaxone (MIC50 32–64 mg/L; MIC90 128–≥256 mg/L)[38,40,42] and cefotaxime (MIC50 3–64 mg/L; MIC90 >32–256 mg/L).[38,41-43,46] Con-versely, imipenem had good activity against B. fragilis (MIC50 0.125 and 0.21 mg/L; MIC90 0.8 and 1 mg/L).[40,42]

Cefepime was highly variable in its in vitro activity against various species of other pathogenic anaerobes that have been impli-cated in aspiration pneumonia, including other Bacteroides spp. (MIC50 0.12–>128 mg/L; MIC90 0.25–>256 mg/L),[39,44,45,47,48,50] Fu-sobacterium spp. (MIC50 0.06–>128 mg/L; MIC90 4–>128 mg/L),[39,42,50] Peptococcus spp. (MIC50 0.5 and 16 mg/L; MIC90 >16 mg/L),[44,47] Peptostreptococcus spp. (MIC50 0.25–16 mg/L; MIC90 16–32 mg/L),[39,42,47,50] Prevotella spp. (MIC50 2–4 mg/L; MIC90 >128 mg/L)[39] and Veilonella spp. (MIC50 2 and 3.6 mg/L; MIC90 16 and 20.2 mg/L).[39,42]

2.3 Resistance

Acquired resistance to β-lactam agents among bacteria is a significant problem worldwide. The main mechanisms of resis-tance relevant to β-lactam agents are the production of β-lactamases, alteration of the target PBPs and mutations which reduce cell permeability.[51-53] A summary of the mechanisms of resistance against cephalosporins and the bacteria that use them is provided in table II.

The most common mechanism of resistance is the production of β-lactamases. β-Lactamases are enzymes produced by bacteria in the periplasmic space that inactivate β-lactam antibacterials by

Table II. Mechanisms of resistance that affect the activity of cephalosporins and the organisms that may be causative in pneumonia that use them[11,52-57]

Mechanism Relevant bacteria

β-Lactamases
Plasmid-mediated
Common β-lactamases: TEM-1, TEM-2, SHV-1, OXA-2, OXA-3, Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae,
PSE-1 to -4, ROB-1 Penicillin-resistant Staphylococcus aureus
ESBLs: TEM-3 to -101, SHV-2 to -5, OXA, PER-1 Klebsiella spp., Escherichia coli, P. aeruginosa
AmpC Klebsiella spp., E. coli
Chromosome-mediated
AmpC hyperproduction Enterobacter spp., P. aeruginosa
K1 and K14 hyperproduction Klebsiella spp.
P99 Enterobacter cloacae
BRO-1 to -3 Moraxella catarrhalis
PBP modification
PBPs 1a, 2a, 2x and 2b Penicillin-intermediate or -resistant Streptococcus pneumoniae
PBP2′ Methicillin-resistant S. aureus, H. influenzae
Porin alteration (impermeability) and active efflux
OmpF and OmpC Klebsiella spp., E. coli, Enterobacter spp., P. aeruginosa

ESBL = extended-spectrum β-lactamase; PBP = penicillin-binding proteins.

Cefepime in Hospitalized Patients with Pneumonia: A Review 85

hydrolyzing the amide bonds of the β-lactam ring. β-Lactamases can be plasmid- or chromosome-mediated (table II).

Cefepime, like the third-generation cephalosporins, has an oxyimino-aminothiazolyl 7-acyl side chain attached to the β-lactam ring that hinders access of the plasmid-mediated TEM-1 and SHV-1 β-lactamases and confers stability against these β-lactamases to the drug.[52] In vitro assays have shown that cefepime is not significantly hydrolyzed by the common plasmid-mediated broad-spectrum β-lactamases produced by the Entero-bacteriaceae, P. aeruginosa or H. influenzae, including TEM-1 and TEM-2, SHV-1, OXA-2 and OXA-3, PSE-1 to PSE-4 and ROB-1 or the plasmid-mediated β-lactamases produced by S. au-
reus.[3,12,48,57]

However, cefepime may be hydrolyzed by the production of ESBLs by some members of the Enterobacteriaceae, although to

a lesser extent than the third-generation cephalosporins.[55] Most ESBLs are mutants of TEM- and SHV-type enzymes and are commonly found in E. coli or Klebsiella spp. and other Entero-bacteriaceae (table II).[55] An in vitro study found that cefepime was more active than cefotaxime, ceftriaxone or ceftazidime against 72 clinical strains of ESBL-producing K. pneumoniae from Brazilian hospitals (91.7% vs 52.8%, 38.9% and 36.1% sus-ceptibility).[58] However, imipenem was more active than cefe-pime against these ESBL-producing K. pneumoniae isolates (100%

susceptibility).[58] Among the isolates of E. coli collected in the in vitro or surveillance studies in section 2.2, 0–19.6% were found to have the ESBL phenotype.[19,21,23-25,30,32,33] The ESBL phenotype was more common in Klebsiella spp. isolated in in vitro studies (4.2–62.0%).[17,19,21,23-25,30-33] Imipenem was the most active agent against strains of E. coli and Klebsiella spp. po-tentially harboring ESBLs (96–100% susceptibility).[17,24,25,31,32] However, cefepime exhibited moderate activity against some strains of E. coli and Klebsiella spp. expressing the ESBL phe-notype (61–100% susceptibility).[17,24,25,31,32]

The largest in vitro study reported the activity of cefepime, imipenem, and the third-generation cephalosporins ceftazidime, cefotaxime and ceftriaxone against isolates of E. coli or K. pneu-moniae with the ESBL phenotype.[25] In this study, 15.3% and 28.8% of strains of E. coli and Klebsiella spp. were possible ESBL producers.[25] Cefepime and imipenem were active against most isolates of E. coli potentially harboring an ESBL (99.8% and 100% susceptibility) followed by ceftriaxone, cefotaxime

and ceftazidime (93.4%, 93.2% and 87.4% susceptibility).[25] Iso-lates of Klebsiella spp. with the ESBL phenotype also demon-strated resistance to the third-generation cephalosporins, cefta-zidime, ceftriaxone and cefotaxime (74.1%, 84.8% and 87.8% susceptibility, respectively), while they were generally suscepti-

ble to cefepime and imipenem (97.1% and 100% susceptibil-ity).[25]

Nevertheless, although isolates may appear susceptible to cefepime in vitro, the NCCLS guidelines recommend that all con-firmed ESBL-producing isolates of E. coli and Klebsiella spp. be reported as resistant to all cephalosporins because they may be clinically resistant to treatment with these agents.[36]

Long-term use of the third-generation cephalosporins has resulted in the selection for resistant, derepressed mutants capa-ble of hyperproducing AmpC β-lactamase and inactivating the third-generation cephalosporins.[52] Importantly, unlike the third-generation cephalosporins, cefepime has no AmpC β-lactamase-in-ducing capacity[48] and it is active against the derepressed mutants of Enterobacter spp. and P. aeruginosa capable of hyperproducing the chromosome-mediated AmpC β-lactamase.[ 1 2 ] In a large US surveillance study (section 2.2), 31.3% of strains of Entero-bacter spp. were resistant to ceftazidime, ceftriaxone and cefotax-ime and were classed as derepressed AmpC β-lactamase hyperproducing strains.[25] Both cefepime and imipenem were ac-tive against these strains of Enterobacter spp. (98.4% and 98.9% susceptibility).[25]

Although cefepime is active against these bacteria, it is still affected by the AmpC β-lactamase but to a lesser extent than the third-generation cephalosporins. This is because cefepime can penetrate the outer membrane of the Gram-negative cell faster (section 2.1), it is hydrolyzed more slowly (the rate of hydrolysis of cefepime by AmpC β-lactamases produced by E. cloacae or P. aeruginosa is 30 times slower than that of cefotaxime),[8] and the affinity of the AmpC β-lactamase for cefepime is 1000–10 000 times less than that for cefotaxime and 10–100 times less than that for ceftazidime.[12]

More recently, isolates of the Enterobacteriaceae have ac-quired plasmid-mediated AmpC β-lactamases (table II), although they remain uncommon at this stage. Cefepime has moderate activity against these organisms;[52,59,60] however, one study has reported that two isolates of E. coli each with a plasmid-mediated AmpC β-lactamase were resistant to cefepime.[61]

Cefepime also shows good stability against the chromosom-ally mediated cephalosporinases of E. cloacae (P99), K. pneumo-niae (K14)[57] and M. catarrhalis (BRO-1) [table II].[48]
Alteration to PBPs, commonly in Gram-positive bacteria, reduces the affinity of β-lactam agents for the target site of the bacteria. Cefepime, like other β-lactam agents, is not active against MRSA which produces a supplementary PBP (PBP2′) [table II].[12] S. pneumoniae produces PBPs 1a, 2a, 2b, and 2x.[54,62] Modifications to these PBPs alone, or in combination, result in increases in the MICs of penicillin and cephalosporins and ultimately lead to reduced susceptibility or resistance.[54,62]

86 Chapman & Perry

The MIC90 of cefepime when tested against penicillin-resistant S. pneumoniae was higher than that of cefepime tested against penicillin-sensitive S. pneumoniae; however, using the newly re-vised NCCLS breakpoints for non-meningitis infections, cefepime still has good activity against penicillin-intermediate and -resistant strains of S. pneumoniae (section 2.2.1).

As previously mentioned (section 2.1), cefepime enters Gram-negative bacteria by diffusion through porins in the outer membrane of the cell. Alteration to the shape or a reduction in the number of these porins results in reduced permeability (table II).[53,54] Entry of cefepime, like other antibacterial agents, into the Gram-negative cell is restricted by a change in permeability. This leads to lower concentrations of drug within the periplasmic space and even though cefepime is hydrolyzed slowly, low con-centrations may be inactivated by a β-lactamase present in the periplasmic space.[53]
Cefepime selects for resistance in strains of E. cloacae and

P. aeruginosa more slowly than the third-generation cephalospo-rins ceftazidime, cefotaxime and ceftriaxone.[57,63-65] The per-centage of E. cloacae strains that developed resistance after re-peated incubation with subinhibitory concentrations of cefepime was 7%, compared with 13% for ceftazidime and 15% for ceftriaxone (p values not reported).[63] Cefepime had the added advantage that it rarely selected for cross-resistant bacteria.[63]

The in vitro development of resistance in nine strains of P. aeru-ginosa to cefepime, imipenem, ceftazidime and cefotaxime by stepwise mutations was assessed by bacterial passage of colonies located nearest to the inhibition zone on antibiotic-containing gradient plates.[64] Only after repeated exposure to cefepime did resistance develop in strains of P. aeruginosa (mean 30 pas-sages), while the mean number of serial passages required to confer resistance on P. aeruginosa was much lower for cefta-zidime (18 passages) and cefotaxime (3.3 passages).[64] The mean number of passages required to select for resistance to imipenem was 26 passages.[64]

Spontaneous single-step mutations resulting in resistance to cefepime in P. aeruginosa occur less frequently with cefepime than with ceftazidime or cefotaxime (spontaneous mutations oc-cur at a frequency of 10-11 for cefepime while mutants are isolated at a frequency of 10-5–10-10 with ceftazidime and cefotaxime).[57] This difference may be due to the need for multiple mutations for the development of resistance in P. aeruginosa.[57]

2.4 Effect on Fecal Flora

Intravenous cefepime (1g twice daily for 5 or 8 days) resulted in few changes to the fecal flora in two studies in a total of 14 healthy men.[66,67] In one study, mean total counts of aerobic

organisms such as the Enterobacteriaceae and Lactobacillus spp. were decreased slightly in the feces of healthy volunteers after receiving cefepime for 5 days; however, these counts returned to normal levels after the cessation of cefepime administration.[66] In this study, cefepime did not affect Enterococcus spp. or anaer-obes present in the microflora and there was no increase observed in the counts of Candida spp. in these six volunteers.[66] Pseudo-monas spp. were not detected in the fecal flora of volunteers before they received cefepime but were isolated in small numbers in two cefepime recipients.[66] Clostridium difficile toxin was not detected in any fecal specimens from the six healthy volunteers, but low counts of C. difficile were isolated from the feces of one participant who did not experience diarrhea.[66]

In another study, the bacterial species present in the fecal flora of cefepime recipients did not show any important changes in numbers.[67] Cefepime 1g twice daily for 8 days resulted in a slight increase in the number of clostridia and Bacteroides spp. and a decrease in the number of bifidobacteria and E. coli.[67] C. difficile was detected in the feces of one volunteer; however, C. difficile toxin was not detected and the volunteer did not experi-ence any diarrhea. The number of C. difficile increased from <102 before the study to 107 after 8 days of cefepime treatment and disappeared 20 days after the study.[67] The numbers of other bacteria returned to normal by 48 days after the study.[67]

2.5 Pharmacodynamic/ Pharmacokinetic Considerations

Although MIC90 values are a good predictor of in vitro acti-vity, they do not necessarily correspond with the in vivo antibac-terial activity of an antibacterial agent because they fail to take into account the pharmacokinetic properties of the drug.[68-70] In recent years it has been found that the integration of the pharma-codynamic parameters with the pharmacokinetic profile of the drug may provide a better understanding of the in vivo antibacte-rial activity.

β-Lactam antibacterial agents, including cefepime, exhibit time-dependent bactericidal activity.[69,70] The antibacterial ef-fects of a β-lactam agent are maximized when free serum con-centrations are maintained above the MIC of the pathogen at the site of infection for a significant proportion of the dosing inter-val.[69] The optimal period that antibacterial agents remain above the MIC90 in clinical practice varies with different classes of anti-bacterial agents, pathogens and the immune status of the pa-tient.[68-70] However, data from animal models suggest that the maximum bactericidal effect is achieved when the time above the MIC90 is 60–70% of the recommended dosage interval for En-

Cefepime in Hospitalized Patients with Pneumonia: A Review 87

terobacteriaceae and S. pneumoniae, and 40–50% of the dosage interval for S. aureus.[69,71]
A number of studies using pharmacokinetic data from healthy adult volunteers combined with in vitro data for the inhi-bition of various bacterial isolates have shown that intermittent doses (1 or 2g twice daily)[71-73] or continuous infusions (3 or 4g over a 24 hour period)[73] of cefepime were associated with plasma concentrations above the MIC90 for a sufficient propor-tion of the dosage interval for the majority of Enterobacteriaceae, streptococci and staphylococci tested.

3. Pharmacokinetic Properties

The pharmacokinetics of intravenous and intramuscular cefepime are well established and have been reviewed previously in Drugs,[3] Clinical Pharmacokinetics[74] and elsewhere.[75-77] Therefore, an overview of pharmacokinetic data is presented here. The pharmacokinetics of cefepime have been assessed in numerous randomized, single- or multiple-dose studies in healthy volunteers (n > 150)[73,78-83] and in patients with lower respiratory tract infections (n = 10)[84] or renal insufficiency (n = 75).[85-90] Data on the pharmacokinetics in infants, children and adolescents with various bacterial infections are also available.[91,92] The pharmacokinetics of cefepime (single 1g dose) were unaffected in 11 patients with hepatic impairment, according to the manu-facturer’s prescribing information.[1,2]

A summary of the pharmacokinetic profile for single and multiple administrations of cefepime 1g to different populations is presented in table III.

3.1 Plasma Concentrations and Absorption

The plasma concentration profile of cefepime after intrave-nous or intramuscular administration is linear over the 0.25–2g dose range.[78-80] After single doses of cefepime (0.25–2g) ad-ministered via intravenous infusion to 55 healthy men, the mean maximum concentration in either plasma or serum (Cmax) and the mean area under the cefepime concentration-time curve extrapo-lated to infinity (AUC∞) increased in an approximately dose-pro-portional manner (Cmax 16–133 mg/L, AUC∞ 33–263 mg h/L).[78,79]

The Cmax and the AUC∞ also increased in a dose-proportional manner after single intramuscular doses of cefepime (0.25–2g) in 34 healthy men.[80] AUC∞ values of cefepime after single in-tramuscular doses of the drug (33–262 mg h/L) were similar to those of intravenous infusions of corresponding doses of cefepime; however, Cmax values of cefepime after intramuscular administration were about half to one-third of the values achieved after intravenous infusion of the same doses of cefepime (8–58 mg/L).[80] The absorption of intramuscular cefepime was rapid,

as the mean time to Cmax (tmax) for single doses of cefepime (0.25– 2g) ranged from 1.00–1.58 hours.[80] The bioavailability of intra-muscular cefepime (calculated from the AUC∞ and urinary re-covery data) was approximately 100% in healthy volunteers.[80] The plasma concentrations of cefepime are unaffected by the duration of treatment, as there was no significant difference be-tween the pharmacokinetic parameters after single or multiple doses of cefepime in healthy men (n = a total of 65).[79,80] Multiple doses of cefepime 1g administered intravenously three times daily for 9 days[79] or intramuscular cefepime 1g twice daily for 10 days,[80] resulted in Cmax values similar to that reported after a single dose of the drug (table III). The Cmax and minimum plasma concentration (Cmin) values remained constant through-out the course of these multiple dose studies, which indicates there was no accumulation of cefepime in individuals with nor-

mal renal function.[79,80]
In general, there was no significant difference between the plasma concentration profile of an intermittent infusion over 30 minutes of cefepime 2g twice daily, and that of a continuous infusion of cefepime (3–4g over 24 hours) in 12 healthy volun-teers.[73] The Cmax and Cmin of the intermittent infusion of cefepime 2g twice daily were 112.9 and 1.3 mg/L, respectively, while the steady-state serum concentrations for the 3 and 4g con-tinuous infusion were 13.9 and 20.3 mg/L.[73] Only the AUC over 24 hours for the 3g continuous infusion was significantly lower than for the 4g continuous infusion and the 2g twice-daily inter-mittent infusion (285 vs 411 and 357 mg h/L; p = 0.03).[73]

A single-dose study in 16 healthy men found that the plasma concentration profile of cefepime, administered as a bolus 2g dose over 3–15 minutes, was similar to those previously reported in studies utilizing a longer (30-minute) infusion time.[81] The Cmax increased with the shorter administration time but the dif-ference was not significant.[81]

3.2 Distribution

The plasma protein binding of cefepime is relatively low (14–19%) in healthy adult volunteers,[43,93] which means that cir-culating cefepime exists primarily in the free, microbiologically active form.[78] The volume of distribution at steady state (Vss) of intravenous cefepime (0.25–2g) ranged from 16–19L in healthy adults and was independent of the dose.[79]

Cefepime has shown good penetration into the bronchial mu-cosa.[94] Patients undergoing fiberoptic bronchoscopy for diag-nostic purposes (n = 20) received a single intravenous 2g dose of cefepime and bronchial mucosal samples were biopsied 1–12 hours after the end of the intravenous infusion. After a mean time of 4.8 hours, the mean bronchial mucosal concentration was 24.1

Am J Respir Med 2003; 2 (1)

Table III. Mean pharmacokinetic parameters of cefepime after single or multiple intravenous (IV) or intramuscular (IM) doses in healthy young or elderly volunteers, pediatric or elderly patients with infections and in volunteers with renal impairment[78-80,83,84,86,91]

Dosage regimen (number of Cmax AUC∞ tmax (h) Vd/Vss a t1⁄2 (h) MRT (h) CLT b CL R b
participants) (mg/L) (mg • h/L)
Healthy young volunteers [78-80]
1g IV sd (55)[78,79] 65.1–66.9 135–137 18.3Lc 1.9–2.34 2.2–2.45 7.32–7.56 L/h 6.0–6.18 L/h
(122–126 mL/min) (100–103 mL/min)
1g tid × 9d IV (31)[79] 66.9 137 18.2Lc 2.23 2.45 7.50 L/h 5.94 L/h
(125 mL/min) (99 mL/min)
1g IM sd (34)[80] 29.6 137 1.58 2.37 4.03 7.32 L/h 6.24 L/h
(122 mL/min) (104 mL/min)
1g bid × 10d IM (34)[80] 32.4 124 1.21 2.18 3.41 7.92 L/h 6.72 L/h
(132 mL/min) (112 mL/min)
Elderly patients with
respiratory tract infections[84]
1g bid × 8d IV (10) 71.2 251 0.22 L/kg 3.92 3.57 4.38 L/h/1.73m2 2.958 L/h/1.73m2
(73.0 mL/min/1.73m2) (49.3 mL/min/1.73m2)
Healthy elderly volunteers[83]
Men; 1g IV sd (24) 74.4 199 0.23 L/kg 3.05 3.50 0.0666 L/h/kg 0.0618 L/h/kg
(1.11 mL/min/kg) (1.03 mL/min/kg)
Women; 1g IV sd (24) 83.5 218 0.24 L/kg 2.92 3.30 0.0732 L/h/kg 0.0594 L/h/kg
(1.22 mL/min/kg) (0.99 mL/min/kg)
Volunteers with
renal impairment[86]
CLCR 3.66–5.4 L/h 70.5 225 19.6L 3.33 4.60 4.54 L/h 3.65 L/h
(61–90 mL/min); 1g IV sd (5) (75.7 mL/min) (60.8 mL/min)
CLCR 1.86–3.6 L/h 73.9 292 19.8L 4.89 5.88 3.66 L/h 2.89 L/h
(31–60 mL/min); 1g IV sd (5) (61.0 mL/min) (48.1 mL/min)
CLCR 0.66–1.8 L/h 68.9 683 21.8L 10.5 14.7 1.55 L/h 0.924 L/h
(11–30 mL/min); 1g IV sd (5) (25.9 mL/min) (15.4 mL/min)
CLCR <0.6 L/h 65.5 928 21.7L 13.5 20.0 1.12 L/h 0.253 L/h
(<10 mL/min); 1g IV sd (5) (18.7 mL/min) (4.22 mL/min)
Children with presumed or
documented infections[91]
50 mg/kg/dose IV sd (35) 174 0.35 L/kg 1.7 2.3 0.186 L/h/kg 0.114 L/h/kg
(3.1 mL/min/kg) (1.9 mL/min/kg)
50 mg/kg/dose tid × 2–13d IV (31) 0.33 L/kg 1.8 2.4 0.168 L/h/kg 0.12 L/h/kg
(2.8 mL/min/kg) (2.0 mL/min/kg)
50 mg/kg/dose IM sd (8) 76 0.5 0.55 L/kg 1.9 3.2 0.222 L/h/kg 0.15 L/h/kg
(3.7 mL/min/kg) (2.5 mL/min/kg)
a Results reported as L or L/kg.

b Results reported as L/h, L/h/kg or L/h/1.73m2 (mL/min, mL/min/kg or mL/min/1.73m2).

c Evaluated in 31 patients.

AUC∞ = mean area under the cefepime concentration-time curve extrapolated to infinity; bid = twice daily; CLCR = creatinine clearance; CLR = renal clearance; CLT = total clearance; Cmax = mean maximum concentration in either plasma or serum; MRT = mean residence time; sd = single dose; t1⁄2 = mean elimination half-life; tid = three times daily; tmax = mean time to Cmax; Vd = volume of distribution; Vss = volume of distribution at steady state.

Chapman & Perry

[78-80]
[78-80]
Cefepime in Hospitalized Patients with Pneumonia: A Review 89

mg/kg and the serum concentration was 40.4 mg/L resulting in an average penetration into bronchial mucosal tissue of 59.8% (range 40–90% penetration).[94] Two recent studies, both pre-sented as abstracts, showed that cefepime exhibits excellent pen-etration into lung tissue.[95,96] In one study, cefepime 2g rapidly penetrated the lung tissue of 16 patients undergoing lung surgery for bronchial epithelioma. The mean lung tissue/plasma cefepime concentration ratio was 1.01 over 0.5–12 hours.[95] Also, cefe-pime administered as a continuous intravenous of 4 g/day exhib-ited excellent diffusion into the lung tissue of 28 ICU patients with severe HAP. At steady-state, the mean serum concentration of cefepime was 17.9 mg/L and the mean concentration of cefepime in epithelial lining fluid was 15.7 mg/L resulting in an average diffusion into lung tissue of 87.7%.[96]

Cefepime has also been shown to achieve clinically useful concentrations in sputum.[1,2,97] An intravenous infusion of cefe-pime (2g) achieved an average concentration of 7.4 mg/L 4 hours after administration to five healthy men (no further details re-ported).[1,2] Similarly, the peak levels of cefepime (1g) in the sputum of three patients, 1–2 hours after an intravenous infusion were 0.56, 2.0 and 2.7 mg/L.[97]

Cefepime distributes in low concentrations into human breast milk. However, because a nursing infant would consume approximately 0.5mg of cefepime per day in 1L of human breast milk, caution is recommended when cefepime is administered to nursing women (section 7).[1]

3.3 Metabolism and Elimination

Cefepime undergoes minimal metabolism; single- and mul-tiple-dose studies have shown that the majority of the adminis-tered dose (66–91%) of cefepime (0.25–2g) is eliminated as un-changed drug in the urine of healthy volunteers,[78-80,86] primarily by glomerular filtration.[78,79,85] These findings were confirmed in a study in healthy volunteers with normal renal function in whom the relative proportions of metabolites excreted in urine from a 1g dose of radiolabeled cefepime were determined using

a radiometric assay.[85] Following a single intravenous adminis-tration of radiolabeled cefepime, 88% of the administered dose was recovered as intact cefepime, the main metabolite was N-methyl pyrolidine N-oxide constituting 6.8% of the recovered radioactivity and the other two metabolites identified were the 7-epimer of cefepime (2.5%) and N-methyl pyrolidine (<1%).[85]

The total clearance (CLT) and renal clearance (CLR) of cefepime in healthy volunteers are independent of the dose re-gardless of the method of administration,[78,80] but are directly proportional to the rate of creatinine clearance.[78,85,86] CLT ranged from 7.32–9.12 L/h (122–152 mL/min) after a single in-

travenous or intramuscular administration of cefepime (0.25–2g)

to healthy volunteers. CLR was about 80% of total clearance

ranging from 5.4–8.28 L/h (90–138 mL/min) after a single intra-venous or intramuscular administration of cefepime (0.25–2g) in healthy volunteers.

The mean elimination half-life (t1⁄2) or the mean residence time (MRT) of cefepime are not dose-dependent, regardless of the method of administration.[78-80] The t1⁄2 of cefepime after a single intravenous dose (0.25–2g) in individuals with normal kid-ney function ranged from 1.8–2.34 hours[78,79] and 2.05–2.37 hours after an intramuscular dose (0.25–2g).[80] The MRT of a single intravenous infusion of cefepime (0.25–2g) was 1.9–2.5 hours,[78,79] while the MRT for a single intramuscular adminis-tration of the same dose range of cefepime was 3.8–4.0 hours.[80]

3.4 Special Populations

3.4.1 Elderly Patients with or without Respiratory Tract Infections

The steady-state pharmacokinetic parameters of cefepime were not significantly altered by acute illness in ten hospitalized adult patients (aged 50–98 years) diagnosed with moderate to severe lower respiratory tract infections (table III).[84] After mul-tiple intravenous infusions of cefepime (1g twice daily) the mean steady state Cmax and mean Vss for patients with moderate to severe lower respiratory tract infections were similar to corre-sponding parameters observed after a single dose of intravenous cefepime (1g) in healthy elderly volunteers (table III).[83,84] How-ever, the mean steady state CLT and CLR were about 50% lower than those reported in healthy young volunteers, and the mean steady state t1⁄2 was nearly twice as long (table III).[84]

The pharmacokinetic profile of cefepime in healthy elderly volunteers (aged 65–81 years) differed from that of younger healthy volunteers (aged 20–40 years) after administration of a single 1g dose of cefepime (table III), but the changes were not clinically significant.[83]

3.4.2 Pediatric Patients

A review of three studies examining the pharmacokinetics of single- or multiple-dose (twice to three times daily for at least 48 hours), intravenous or intramuscular cefepime (50 mg/kg/dose) in pediatric patients aged 2 months to 16 years (n = 88), with mild to serious bacterial infections, reported that the pharmacokinetic profile of cefepime in children was similar to that of adults.[92] The mean t1⁄2 across the three studies was 1.7 hours, the mean Vss was 0.37 L/kg and the CLT 0.186 L/h/kg (3.1 mL/min/kg).[92] The pharmacokinetic profile of cefepime after a single dose or multi-ple doses was similar, which suggests there is little accumulation of cefepime in pediatric patients after twice-daily doses of cefepime.[92]

[85-87]
90 Chapman & Perry

In one of these studies, including children and adolescents (aged 2 months to 16 years) with a presumed or documented bacterial infection, the Cmax of cefepime after a single intrave-nous administration of cefepime 50 mg/kg (n = 35) was 2- to 3-fold higher than the same dose of intramuscular cefepime in a subgroup of children (n = 8), and was nearly 3-fold higher than after a 1g intravenous dose in adults (table III).[91] The difference in the MRT and CLT in children after single-dose and steady-state intravenous administration of cefepime compared with intramus-cular injection was statistically significant (MRT 2.3 and 2.4 vs 3.2 hours, p < 0.05; CLT 0.168 and 0.186 vs 0.222 L/h/kg [2.8 and 3.1 vs 3.7 mL/min/kg], p < 0.02).[91] The bioavailability of cefepime in a subgroup of eight children after intramuscular ad-ministration averaged 82%.[91] Approximately 57 to 68% of the administered dose of cefepime was recovered from the urine of pediatric patients as unchanged drug.[91]

CVVHDF was significantly higher (1.56 vs 0.78 L/h [26 vs 13 mL/min]; p = 0.002) and the corresponding t1⁄2 significantly lower (8.6 vs 12.9h; p = 0.005) than those obtained with CVVH.[88] Special dosage regimens may be required for patients undergoing CRRT.[88]

Continuous ambulatory peritoneal dialysis (CAPD) was also effective in removing intravenous cefepime from the body, but to a lesser extent than hemodialysis.[90] After the administration of a single 1 or 2g dose of cefepime to ten patients receiving CAPD therapy, approximately 25% of the administered dose was re-moved over a 72-hour dialysis period.[90] The mean t1⁄2 of cefepime after a single dose of intravenous cefepime (1 or 2g) in patients undergoing CAPD was 18 hours and was not dose-dependent.[90] It is recommended that normal doses of cefepime (1 or 2g) be administered to patients undergoing CAPD; however, the dosage interval should be increased (section 7).

3.4.3 Patients with Impaired Renal Function

The renal clearance of cefepime is significantly reduced in

patients with renal impairment (table III). Intravenous

cefepime was eliminated more slowly from patients with renal impairment than from healthy volunteers in three single-dose studies.[85-87] As renal function decreased, the t1⁄2, MRT and AUC increased, while the CLT and CLR decreased.[85-87] The CLR was similar to CLCR [85,86] or the glomerular filtration rate[87] for all levels of renal impairment. Therefore, a reduction in the dosage of cefepime is necessary in patients with renal impairment (sec-tion 7).

Hemodialysis and hemofiltration rapidly and effectively re-moved cefepime from 16 otherwise healthy volunteers.[86,87,89] In patients on hemodialysis receiving single or multiple intravenous doses of cefepime (1 or 2g) the t1⁄2 of cefepime prior to dialysis (13.5–22.0 hours) was significantly shortened to 1.6–2.3 hours during hemodialysis (p values not reported) to a t1⁄2 similar to that seen in individuals with normal renal function.[86,87,89] A 3- to 5-hour hemodialysis procedure using low- or high-flux mem-branes removes 40–72% of the original dose of cefepime from the body; therefore, an additional dose is required to maintain therapeutic concentrations after hemodialysis (section 7).[86,87,89]

Continuous renal replacement therapies (CRRT) such as continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) are used as alterna-tives to intermittent hemodialysis in patients with severe renal failure.[88] A study in 12 patients undergoing CRRT found that CRRT was effective in eliminating multiple doses (2–5 doses) of intravenously administered cefepime from patients with renal failure.[88] However, CVVHDF more effectively eliminated cefe-pime than CVVH, as clearance of cefepime in recipients of

3.5 Pharmacokinetic Interaction between Cefepime and Amikacin

There is limited data on the interaction of cefepime with other drugs; however, see section 7 for recommendations on the combination of cefepime with other antibacterial drugs.

In the clinical setting, cefepime is often combined with aminoglycosides in order to provide good coverage against a very broad range of pathogens. There was no evidence of a pharmaco-kinetic interaction between cefepime 2g and amikacin 300mg following the combined intravenous administration of multiple doses of both drugs to 16 healthy men.[82] It appears that these two drugs can be coadministered to patients with normal renal function over the recommended dosage range.[82]

4. Therapeutic Efficacy

A large number of comparative clinical trials have assessed the therapeutic efficacy of intravenous cefepime as a treatment for bacterial pneumonia in hospitalized patients with generally moderate to severe infection.[98-112] Studies have included adults, children and the elderly, with either CAP or HAP. The efficacy of cefepime in adult and pediatric patients has also been studied in several noncomparative trials.[111,113-117] However, because of the availability of a large amount of comparative data in adult patients, the results of noncomparative trials in adults are not discussed in this review.

Only comparative trials with more than 50 adult patients in the intention-to-treat population are included in this review. Most comparative trials were randomized and fully published; how-ever, one is a retrospective study[109] and another is only available as an abstract.[110] Comparative trials have been conducted in

Cefepime in Hospitalized Patients with Pneumonia: A Review 91

several countries, including the US,[99,102,103,105,108,109,111] Can-ada,[101] Japan,[106,118] Taiwan[104] and a number of European countries.[98,100,107,110,112]

Patients included in the trials had clinical signs and symp-toms consistent with bacterial pneumonia, such as cough, fever, leukocytosis, purulent sputum production, or an infiltrate present on a chest radiograph. Before starting therapy, specimens such as sputum,[98-105,107-109,111] bronchial aspirate or brush sam-ples[100,107] were obtained. Any bacteria isolated from these spec-imens were identified and their susceptibility to the study drugs determined. For patients to be eligible for inclusion in compara-tive trials, the causative pathogen was required to be susceptible (either proven or suspected) to the study drugs. Further speci-mens were taken during treatment and at the end of antibacterial therapy, if possible.

Exclusion criteria generally included allergy to β-lactam agents, concomitant antibacterial therapies or any previous anti-bacterial treatment for the current infection, pregnancy or lacta-tion, hepatic impairment or granulocytopenia.[98-105,107-109] Pa-tients with renal impairment received an adjusted dose of the study drugs,[103,104] or were excluded from the patient popula-tion.[98-102,105,107,108] Some studies excluded patients with severe underlying diseases (such as pneumonia distal to an obstructive bronchogenic carcinoma, cystic fibrosis, cardiac disease or cen-tral nervous system infections) that could mask any response to
the study drug.[100-103,105,108]

Assessments of the therapeutic efficacy of cefepime and comparators were based on clinical and bacteriological criteria. Generally, the primary endpoints were the clinical and bacteriolog-ical response. In most comparative trials, evaluations of clinical and bacteriological responses to therapy were made at the end of treat-ment (usually 2–14 days after the end of treatment).[98-105,108,109] Some trials included a post-therapy evaluation (7–14 days after the completion of treatment).[99,101,109] The clinical response in most trials was usually defined as satisfactory when there was a resolution or an improvement in clinical signs and symptoms associated with the original infection, with no new signs or symp-toms presenting at the post-treatment evaluation.[98-105,107-109,111] Bacteriological response in these trials was generally defined as the complete or presumed eradication of the causative pathogens where they had been identified, or an inability to collect a suitable specimen for culture (presumed eradication). The persistence of an infection, reinfection after the eradication of the initial patho-gen, or superinfection with a different organism were deemed to be bacteriological failures.[99,100,102-105,107-109,111] The Japanese study[106] described the clinical and bacteriological responses as excellent, good, fair or poor. In this review, patients with an ‘ex-cellent’ or ‘good’ clinical or bacteriological response are in-

cluded as a satisfactory response. The primary endpoint in an empiric trial was efficacy after 3–5 days of treatment.[107] Success was defined as the continuation of the study drug, while failure was resistance of the infecting organism to the empiric drug or worsening of signs and symptoms despite treatment with the drug.[107] Secondary endpoints in this trial were the clinical and bacteriological responses. Another trial[101] reported secondary endpoints; these included the time to the discontinuation of intra-venous therapy and the proportion of patients changed to oral therapy.

Results were usually reported for evaluable patients (per-protocol analysis). In general, patients who received any other antibacterial therapy, received an insufficient duration of treat-ment, were lost to follow-up, or had other lower respiratory tract diseases were not evaluable.[98-103,105,107,108,111] Microbiologi-cally evaluable patients included those clinically evaluable pa-tients with a confirmed causative pathogen that was susceptible to the study drugs.[99,101,107,111] The requirement that the caus-ative organism be susceptible to the study drugs for patients to be included in the evaluation of clinical or bacteriological effi-cacy led to an inherently lower likelihood that any difference would be seen between cefepime and its comparators. A number of trials did not report any statistical analysis.[99,100,106,111]

4.1 Adult Patients

Fourteen clinical trials have evaluated the efficacy of cefepime monotherapy in hospitalized adult patients (aged 18–98 years) with generally moderate to severe bacterial pneumonia. Studies were either exclusively in patients with CAP (table IV) or HAP[104,109,110] or included patients in whom the origin of pneumonia was undefined or results for the different types of pneumonia were not reported separately (section 4.1.2). These trials were mostly nonblind;[100,102,103,107,108] however, one was double-blind[101] another was single-blind[110] and four others did not report the blinding protocol used.[98,99,104,106] McCabe et al.[105] reported two separate trials in one paper. The first trial was nonblind and the second was a small double-blind trial.[105] One trial included elderly patients with CAP (section 4.2.2).[101]
Patient characteristics, including age, sex and race, were generally similar between treatment groups. In addition, patient populations were generally similar for the type and severity of pneumonia and for the presence of any underlying diseases.

4.1.1 Comparisons with Third-Generation Cephalosporins

The majority of these trials compared cefepime with ceftazidime;[98-100,103-106,109] in addition, cefepime has been com-pared with ceftriaxone[101,102] and cefotaxime.[107,108]

[98-102]
92 Chapman & Perry

In these trials, cefepime 1 or 2g was usually administered intravenously (or in some cases intramuscularly)[100,102,103] twice daily until resolution of the infection or for a maximum of 14 days.[100-102,104,106,108] Therapeutically equivalent dosages of cefta-zidime, ceftriaxone or cefotaxime for patients with moderate to severe infections were administered in these trials.[98-105,107,108] Ceftazidime and cefotaxime were generally administered more frequently (1–2g three times daily) than cefepime (1–2g twice daily).[98-100,103-105,107,108] In the trial conducted by Saito et al. ceftazidime 1g was administered twice daily.[106] In the two trials in which ceftriaxone was the comparator, ceftriaxone was adminis-tered at a similar dosage interval to cefepime (twice daily).[101,102]

Community-Acquired Pneumonia

Results of trials comparing cefepime monotherapy with cefta- zidime or ceftriaxone in hospitalized patients with CAP are summarized in table IV. The total number of bacterial isolates recovered from patients at baseline in these studies was relatively small; thus, there were no obvious or significant differences between treatment groups in the species eradicated. The most common orga-nisms recovered from patients with CAP were S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis and K. pneumoniae.[98-102]

Monotherapy with cefepime, like ceftazidime and ceftriaxone, demonstrated good clinical efficacy in the treatment

of hospitalized adult patients with CAP. Cefepime 1 or 2g

twice daily for 7.5–9.8 days was as effective as the more frequent administration of ceftazidime (1 or 2g three times daily) for 6.5– 10.4 days in producing a satisfactory clinical response (84–89% vs 73–87% of patients) [see table IV].[98-100] In addition, cefepime 1g twice daily was as effective as ceftazidime 1g three times daily in achieving a bacteriological response (table IV).[99,100] Furthermore, cefepime 2g twice daily and twice-daily ceftriaxone 1g produced similar clinical and bacteriological responses (table IV).[101,102]

Cefepime, ceftazidime and ceftriaxone were generally effec-tive in eradicating the causative organisms of CAP.[98-102] Cefe-pime eradicated the common pathogens of CAP including all isolates of Haemophilus spp./H. influenzae (including those re-sponsible for concurrent septicemia),[99] M. catarrhalis and Entero-bacter spp.[98-100] All S. pneumoniae isolates were eradicated in two studies,[99,100] including one isolate responsible for septice-mia,[99] but persisted in 2 of 5 patients in another series.[98] In this latter trial, cefepime eradicated all P. aeruginosa isolates;[98] bacte-riological failure in another trial was due to one isolate each of P. aeruginosa and Pseudomonas spp.[99] Other bacteriological

Table IV. Comparative efficacy of cefepime (CEF) in hospitalized adult patients with community-acquired pneumonia (CAP). Assessments were made at the end of treatment

Reference Dosage regimen (mean No. of patients Clinical response rate:
(trial design) duration of IV treatment; randomized to patients with satisfactory
days) treatment response (%) [no. evaluable]

Bacteriological response rate: pathogens eradicated (%) [no. of pathogens isolated from evaluable patients]

Versus ceftazidime (CAZ)
Bonfitto et al.[98] (NR) CEF 2g bid (9.8) 77 84 [74] NR
CAZ 2g tid (10.4) 71 73 [66] NR
Edelstein et al.[99] (NR) CEF 1g bid (7.5) 43 89 [38] 91 [34]a
CAZ 1g tid (6.5) 22 84 [19] 100 [17]a
Leophonte et al.[100]b (nb) CEF 1g bidc (8.6) 87d 87 [67] 94 [68]
CAZ 1g tidc (8.6) 44d 87 [32] 97 [34]
Versus ceftriaxone (CTR)
Grossman et al.[101]e (db) CEF 2g bidc (5.8) 76 79 [67] 94 [18]a
CTR 1g bidc (6.7) 75 75 [61] 100 [17]a
Zervos & Nelson[102] (nb) CEF 2g bidc (6.5)f 59 95 [40] 100 [32]
CTR 1g bidc 56 98 [46] 97 [39]

a Percentage of patients with bacterial eradication and number of microbiologically evaluable patients.

b Trial included patients with moderate to severe community-acquired lower respiratory tract infections; however, clinical and bacteriological response rates were reported separately for patients with pneumonia.
c Administered via intravenous infusion or intramuscular injection[100,102] or method of administration not stated.[101]

d Total number of treated patients with lower respiratory tract infections. e This trial included elderly patients (>65y) with CAP.

f Mean duration of treatment for all patients.

bid = twice daily; db = double-blind; IV = intravenous; nb = nonblind; NR = not reported; tid = three times daily.

Cefepime in Hospitalized Patients with Pneumonia: A Review 93

failures included single isolates of S. marcesens (clinical success),[99] S. aureus,[100] Acinetobacter baumanii and S. maltophilia.[98] Cefepime and ceftazidime had generally similar eradication rates,[99,100] al-though the rates for S. pneumoniae in one trial were 100% and 94%, respectively, for the two drugs.[99]

Community-Acquired or Nosocomial Pneumonia and Pneumonia of Unspecified Origin

Table V summarises the results of randomized trials compar-ing the efficacy of monotherapy cefepime with that of cefta-zidime or cefotaxime in patients in whom the origin of infection was not specified, or trials including patients with CAP or HAP. As for the previous subsection the total numbers of organisms isolated in these studies were relatively small, so there were no significant differences between treatment groups in the types of isolates eradicated. The most common pathogens identified in patients with CAP or HAP were S. pneumoniae, H. influenzae, P. aeruginosa, S. aureus, M. catarrhalis and K. pneumoniae.

Cefepime monotherapy had similar efficacy to ceftazidime and cefotaxime in the treatment of CAP or HAP.[103-108] Cefe-pime 1 or 2g twice daily was as effective in achieving a satisfac-tory clinical response in patients with CAP or HAP as the more frequent administration of ceftazidime (1 or 2g three times daily) [58–90% vs 60–94% of patients][103-105] or the same dose of ceftazidime (1g twice daily) [90% vs 94% of patients].[106] Ad-ditionally, cefepime eradicated a similar percentage of pathogens as ceftazidime (85–97% vs 73–97%).[103,105,106] Cefepime 2g twice daily for 6.6 and 7.0 days was also as effective as the more frequent administration of cefotaxime 2g three times daily for 6.9 and 7.7 days for clinical response (92% and 98% vs 86% and 93% of patients).[107,108] Further, both cefepime 2g twice daily and cefotaxime 2g three times daily achieved similar bacteriological responses (table V).[107,108]

In trials in patients with CAP or HAP that reported bacteri-ological data on a per pathogen basis, cefepime therapy eradi-cated 100% of H. influenzae, 100% of M. catarrhalis, 100% of E. coli, 100% of Klebsiella spp., 95 to 100% of S. pneumoniae, 50–100% of S. aureus, 50–100% of Enterobacter spp. and 20– 57% of P. aeruginosa.[103,105,107,108] Eradication rates achieved with comparators (ceftazidime and cefotaxime) were similar to those observed with cefepime therapy in all trials.[103,105,107,108]

The primary endpoint of a clinical trial that evaluated the efficacy of empiric treatment with cefepime in immuno-compromised (HIV-infected) patients was efficacy after 3–5 days of treatment; success was defined as the continuation of the study drug, and failure defined as the isolation of resistant pathogens, the need for concomitant antibiotics or the discontinuation of treatment with the study drug.[107] There was no significant dif-ference between the cefepime and cefotaxime treatment groups

for the primary endpoint in the intent-to-treat analysis (85.7% vs 77.6% of patients). However, significantly more patients in the per protocol analysis receiving cefepime remained on the study drug after 3–5 days of treatment than those in the cefotaxime treatment group (93.5% vs 81% of evaluable patients; p < 0.05).[107] Pneumonia progressed in four patients receiving cefepime and in six patients in the cefotaxime group according to chest radiographs after 3–5 days of treatment.[107] The clinical and bacteriological response rates at the end of treatment were similar for cefepime and cefotaxime (table V).

This trial allowed for a change to oral therapy if the clinical signs and symptoms of pneumonia improved.[107] The duration of cefepime or cefotaxime therapy and the total duration of anti-bacterial therapy were similar in both treatment groups (intrave-nous therapy 7.0 vs 7.7 days and intravenous plus oral 12.1 vs 12.7 days), as was the mean length of stay in hospital (11.1 vs

14.4 days).[107]
As well, superinfections occurred in a similar number of these immunocompromised patients receiving cefepime or cefo-taxime (four patients in each treatment group). The organisms causing superinfections in the cefepime treatment group were Mycobacterium kansasii, Pneumocystis carinii, Leishmania spp. and P. aeruginosa, while in the cefotaxime group superinfections were caused by A. baumannii, S. epidermidis, Candida albicans and C. difficile.[107]
A nonrandomized, retrospective cost analysis model evalu-ated the clinical efficacy of cefepime (1 or 2g once or twice daily) compared with that of ceftazidime (1 or 2g once, twice or three times daily) in 100 consecutive patients with HAP admitted to the ICU.[109] The severity of illness and the distribution of the common pathogens were similar between the two treatment groups.[109] The clinical response at the end of therapy with cefepime, either alone or in combination with another antibacte-rial agent, was similar to that of ceftazidime either alone or in combination with another antibacterial agent (80% vs 68% of patients; no significant difference).[109] However, there was a dif-ference in the clinical response rate between the two treatment groups at the 14-day post-therapy evaluation (78% vs 60% of patients; p = 0.05).[109] The overall bacteriological response rate was significantly better after treatment with cefepime compared with ceftazidime (77% vs 55% of isolates eradicated; p < 0.05).[109]

4.1.2 Comparison with Imipenem

The therapeutic efficacy of cefepime 2g three times daily as monotherapy for patients with nosocomial pneumonia admitted to the ICU was similar to that of imipenem/cilastatin 0.5g four times daily (method of administration not reported) [table V].[110]

94 Chapman & Perry

Two-thirds of the patients randomized to treatment were mechan-ically ventilated. The satisfactory clinical response rate of cefepime in the intent-to-treat analysis (n = 270) was similar to

that of imipenem/cilastatin (table V).[110] Clinical failures attrib-uted to resistance of the causative organism to the randomized treatment were also similar for both treatment groups (5.3% vs

Table V. Comparative efficacy of cefepime (CEF) in hospitalized patients with pneumonia (CAP and/or HAP or origin not specified). All trials were randomized and nonblind unless stated otherwise. Assessments were made at the end of treatment

Reference (cause of Dosage regimen (mean No. of patients Clinical response rate:
pneumonia or severity) duration of IV treatment randomized to patients with satisfactory
[days]) treatment response (%) [no. evaluable]

Bacteriological response rate: pathogens eradicated (%) [no. of pathogens isolated from evaluable patients]

Versus ceftazidime (CAZ)
Holloway & Palmer[103]a CEF 2g bidb,c NR 58 [53] 87 [61]
(severe)
CAZ 2g tidb,c NR 63 [49] 86 [65]
Lin et al. [104]d (HAP) CEF 1 or 2g bidc,e (10.2) 21 76 [21] NR
CAZ 1 or 2g tidc,e (10.2) 20 60 [20] NR
McCabe et al.[105]a,f CEF 1g bid NR 85 [68] 93 [81]
(mod to severe)
CAZ 1g tid NR 72 [29] 94 [32]
McCabe et al.[105]a,f,g CEF 1g bid NR 80 [15] 85 [20]
(mod to severe)
CAZ 1g tid NR 88 [8] 73 [11]
Saito et al.[106]g CEF 1g bid 183h 90 [72] 97 [32]
CAZ 1g bid 94 [67] 97 [30]
Versus cefotaxime (CTX)
Cordero et al.[107]i CEF 2g bidj (7.0) 84 92 [76] 100 [29]k
(CAP and HAP)
CTX 2g tid (7.7) 76 86 [73] 93 [30]k
Willis et al.[108] CEF 2g bidb (6.6) 56 98 [40] 100 [16]
(CAP and HAP)
CTX 2g tidb (6.9) 55 93 [40] 95 [20]
Versus imipenem/
cilastatin (IMP)
Zanetti et al.[110]l (HAP) CEF 2g tidb 281h 59 [132] 52 [NR]
IMP 0.5 qidb 57 [138] 44 [NR]

a These trials included patients with other serious infections[103] or patients with lower respiratory tract infections[105] beyond the scope of this review. The clinical and bacteriological response presented is reported for patients with pneumonia only.

b Administered via intravenous infusion or intramuscular injection[103] or method of administration not stated.[108,110] c Dosage reduced for patients with renal impairment.

d This trial included a comparative and a noncomparative arm, only the comparative arm is included in this review. The number of patients randomised to receive cefepime 1 or 2g was not reported.

e When atypical pathogens were suspected combination therapy with a macrolide was used or Pseudomonas aeruginosa or methicillin-resistant Staphy-lococcus aureus was suspected combined therapy with an aminoglycoside or glycopeptide was used.

f This article reported two trials which are reported separately in this review. g Double-blind trial[105] or blinding not stated.[106]

h Total number of patients enrolled.

i This trial allowed for a change to oral therapy if clinical signs and symptoms improved. j When P. aeruginosa was suspected the cefepime dosage was increased to 2g tid.
k Percentage of patients with bacterial eradication and number of microbiologically evaluable patients. l Reported as an abstract.

bid = twice daily; CAP = community-acquired pneumonia; HAP = hospital-acquired pneumonia; mod = moderate; NR = not reported; qid = four times daily; tid = three times daily.

Cefepime in Hospitalized Patients with Pneumonia: A Review 95

Table VI. Comparative and noncomparative trials of intravenous (IV) cefepime (CEF) in hospitalized infants, children and adolescents with pneumonia. Assessments were made at the end of treatment. All studies reported by Bradley and Arrieta[111]

Comparator (trial design) Dosage regimen Median age No. of patients Clinical response rate: Bacteriological
[type of pneumonia or (median duration of IV (range) randomized to patients with response rate:
severity] treatment; [days]) treatment satisfactory response pathogens eradicated
(%) [no. evaluable] (%) [no. of pathogens
isolated from evaluable
patients]

Versus ceftazidime (CAZ) (r, nb, mc) [CAP and HAP]

CEF 50 mg/kg/dose tida (3) 21mo 81 93 [71] 95 [21]
(2mo to 12y)
CAZ 50 mg/kg/dose tida (3) 22mo 85 95 [64] 100 [14]
(4mo to 12y)

Versus cefotaxime CEF 50 mg/kg/dose bid (4) 4y 10 100 [8] 75 [4]b
(CTX) (mc) [NR] (21mo to 12y)
CTX 30 mg/kg/dose qid (4) 4y 6 100 [5] 100 [2]b
(3 to 13y)
Versus cefuroxime CEF 50 mg/kg/dose bid (5) 3y 7 100 [6] 100 [1]
(CFX) (r, nb, mc) [NR] (2 to 5y)
CFX 100 mg/kg/dayc (6) 2y 5 100 [4] 100 [1]
(2 to 3y)
Noncomparative trial CEF 50 mg/kg/dose bid 2y 65 91 [58] 93 [42]
(NR) [mild to severe] or tid (5) (2mo to 18y)

a Administered via IV infusion or intramuscular injection.

b Percentage of patients with bacteriological eradication and number of microbiologically evaluable patients. c Administered in three divided doses.

bid = twice daily; CAP = community-acquired pneumonia; HAP = hospital-acquired pneumonia; mc = multicenter; nb = nonblind; NR = not reported; qid = four times daily; r = randomized; tid = three times daily.

5.8% of patients).[110] The causative pathogen was identified in 180 patients, the most common causative organism was P. aeru-ginosa (70 patients) and an ESBL-producing organism was found in 28 patients.[110] The bacteriological eradication rate for the cefepime treatment group tended to be higher than that of the imipenem/cilastatin recipients (table V).[110] Resistance to the allocated treatment emerged in 4.1% of pathogens in the cefepime treatment group and 6.9% in the imipenem/cilastatin treatment group (no significant difference).[110]

4.2 Special Populations

4.2.1 Pediatric Patients

Bradley and Arrieta[111] reported the efficacy of cefepime monotherapy in hospitalized infants, children and adolescents (aged 2 months to 18 years) with CAP or HAP in a noncompara-tive trial and in three randomized, multicenter, comparative trials with ceftazidime, cefotaxime and cefuroxime as the comparators (table VI). Treatments were administered intravenously or intra-muscularly and dosages were adjusted according to bodyweight (for dosage details see table VI). Treatment was continued until resolution of the infection or for up to 21 days. Evaluations of

clinical or bacteriological responses were made after the cessa-tion of therapy and again at a post-treatment follow-up at 10–14 days.

The results of these trials comparing the efficacy of cefepime with that of ceftazidime, cefotaxime or cefuroxime in pediatric patients are summarised in table VI. Because of the small number of patients enrolled in these trials, the number of identified patho-gens was very low. The most commonly isolated organisms were

S. pneumoniae, H. influenzae, S. aureus, M. catarrhalis and E. coli.

Cefepime monotherapy was as effective as ceftazidime, and appeared as effective as cefotaxime or cefuroxime in studies in

children with bacterial pneumonia.[111] However, two of the stud-ies (versus cefotaxime and cefuroxime) were very small (n≤10 per treatment group).[111] In a noncomparative trial, cefepime 50 mg/kg/dose two or three times daily produced a satisfactory clin-

ical response in 91% of pediatric patients with pneumonia.[111] In addition, these regimens of cefepime also achieved a satisfactory

bacteriological response (93% of pathogens eradicated).[111]
In the largest comparative trial, cefepime 50 mg/kg/dose three times daily was as effective as the same dose of ceftazidime,

96 Chapman & Perry

also given three times daily, in producing a satisfactory clinical and bacteriological response (table VI).[111] Of the most common pathogens causing pneumonia in children, only some isolates of

S. pneumoniae, M. catarrhalis, E. coli and P. aeruginosa persist-ed at the end of therapy.[111] At the follow-up assessment (10–14 days after the completion of therapy), 73% of pediatric patients receiving cefepime and 70% of ceftazidime recipients were con-sidered clinically cured (the signs and symptoms of the original infection were resolved and no new signs and symptoms were present).[111]

4.2.2 Elderly Patients

Monotherapy with cefepime has also shown efficacy in the treatment of elderly patients with pneumonia.[101,105] Cefepime 2g twice daily was as effective as ceftriaxone 1g twice daily in a double-blind trial in elderly patients with CAP (n = 151) [table IV].[101] The average age of patients in each treatment group was >77 years and the majority of patients presented with significant underlying disease, including pulmonary and cardiovascular disease. There was no difference in clinical response rates between cefepime and ceftriaxone at the end of therapy (table IV) and satisfactory clinical responses persisted until the end of follow-up (10–14 days after the completion of therapy) in 92% and 87% of cefepime and ceftriaxone patients.[101]

The bacteriological response rate achieved in cefepime re-cipients at the end of treatment was similar to that in the ceftriaxone group (table IV).[101] The one bacteriological failure in the cefepime treatment group occurred in a patient with S. pneumoniae and M. catarrhalis isolated at study entry, in whom the M. catarrhalis persisted after the end of treatment.[101] The most common bacterial pathogens identified in evaluable pa-tients were S. pneumoniae, H. influenzae, M. catarrhalis and S. aureus. At the follow-up evaluation (10–14 days after completion of therapy), new infections were present in six patients in the cefepime treatment group (including one C. difficile, one oral herpes simplex virus infection, one lower respiratory tract infec-tion, one skin lesion, one rhinorrhea and one pneumonia) and five ceftriaxone recipients (including two urinary tract infections, one breast infection, one skin lesion and one pneumonia).[101]

McCabe et al.[105] in the nonblind study (table V) reported differences in clinical response in a subgroup of elderly patients (≥65 years of age) who had moderate to severe pneumonia. Cefepime produced a higher clinical response rate than cefta-zidime (80% vs 58%; p value not reported).[105]

4.2.3 Nonresponders to Penicillin and Other Cephalosporins

A noncomparative trial has assessed the efficacy of cefepime in Japanese patients with lower respiratory disease (aged <15– >85 years) who were classed as nonresponders to treatment with penicillins and other cephalosporins (n = 423).[118] Ninety per

cent of patients in the efficacy analysis had disease classified as pneumonia; only these results are covered in this review. The antibacterial agents previously received by nonresponders in-cluded piperacillin (121 cases), ampicillin, cefotiam (70 cases), cefazolin, cefmetazole, cefoperazone, ceftriaxone, ceftazidime and cefotaxime.[118] Most patients had underlying disease and were being treated with concomitant drugs, including other anti-bacterials. Clinical efficacy was defined as ‘excellent’, ‘good’, ‘fair’, ‘poor’ or ‘deterioration’ and bacteriological efficacy was defined as ‘eradication’, ‘reduction and partial eradication’, ‘change of bacterium’ or ‘no change’ by the attending physi-cian.[118] Patients with an ‘excellent’ or ‘good’ clinical response were included in the clinical efficacy analysis.

The overall clinical efficacy of cefepime 1 or 2g twice daily intravenously for ≤14 days was 70.1% in patients with pneumo-nia who had previously not responded to treatment with penicil-lins or other cephalosporins, and was 70.8% in a subgroup of patients with pneumonia treated with cefepime without concom-itant antibacterials (n = 325).[118] After cefepime monotherapy the clinical response rate was significantly higher in women than in men (77.4% vs 66.1%; p = 0.026), and in patients with mod-erate pneumonia than with severe infection also receiving cefe-pime (48.3% vs 75.8% efficacy; p < 0.001).[118]

The most commonly isolated organisms in this group of non-responders to penicillin and other cephalosporins were P. aeru-ginosa, K. pneumoniae, H. influenzae, S. aureus, S. pneumoniae, Acinetobacter spp., Enterobacter spp. and E. coli (assessed in

186 isolates).[118] The bacterial eradication rate in patients receiv-ing cefepime previously treated with penicillin was 87.9% com-pared with 78.6% for those receiving cefepime previously treated with other cephalosporins.[118] The overall rate of eradication of β-lactamase-producing strains was 92.6% while the bacteriolog-ical response for organisms that were nonproducers of β-lactamases was 82.6% (no significant difference).[118]

4.3 Combination Therapy

The combination of cefepime and amikacin resulted in clin-ical and bacteriological efficacy similar to that of ceftazidime plus amikacin in the treatment of ventilated patients with HAP.[112] A randomized, nonblind, multicenter trial compared cefepime 2g twice daily plus amikacin 7.5 mg/kg twice daily (n =

141) with ceftazidime 2g three times daily plus amikacin 7.5 mg/kg twice daily (n = 134) as therapy for patients with HAP requiring mechanical ventilation.[112] Treatment with cefepime or ceftazidime was administered for up to 14 days and amikacin was administered for up to 10 days.

Cefepime in Hospitalized Patients with Pneumonia: A Review 97
The clinical cure rate, defined as the complete resolution of 3.5 Cefepime
all signs and symptoms of pneumonia, for the cefepime plus ami- Ceftazidime
kacin treatment group was similar to those receiving ceftazidime 3.0

plus amikacin (42.8% vs 44.8% of patients in the intent-to-treat patients 2.5
population and 67.7% vs 68.2% of patients in the per-protocol

population).[112] For patients with pneumonia with an identified of 2.0
cause, the clinical response rate was significantly higher with Percentage 1.0
(53.3% vs 39.3% of patients in the intent-to-treat analysis; p =
cefepime plus amikacin than with ceftazidime plus amikacin 1.5

0.05).[112] A satisfactory bacteriological response was reported in
86.5% of microbiologically evaluable patients treated with cefe- 0.5

pime plus amikacin and 89.3% of microbiologically evaluable 0.0
patients receiving ceftazidime plus amikacin.[112] The mean du-
Headache Nausea Rash Diarrhea Vomiting Constipation
ration of treatment was similar for the two treatment groups (11.8 Adverse events
days for cefepime and 7.8 days for amikacin vs 11.4 days for Fig. 1. Incidence of the most common (occurring in >1% of cefepime or
ceftazidime and 7.5 days for amikacin).[112]
ceftazidime recipients) adverse events in adult patients receiving cefepime

0.5g twice daily to 2g three times daily (n = 2032) versus ceftazidime 0.5g
5. Tolerability twice daily to 2g three times daily (n = 1456) recipients after intravenous
administration in a pooled tolerability analysis (no significant difference).[119]

Overall, cefepime appears to be generally well tolerated. Re-
sults are available from several comparative trials;[99-103,105- erated the drug as well as younger patients and there were no
108,110] in addition, pooled tolerability data are available from
clinical trials conducted in North America and Europe comparing deaths in either treatment group.[119]
This is supported by data from individual comparative trials
cefepime (0.5g twice daily to 2g three times daily; n = 2032) with
reviewed in section 4 showing that cefepime was as well tolerated
ceftazidime (0.5g twice daily to 2g three times daily; n = 1456)
as ceftazidime,[99,100,103,105,106] ceftriaxone,[101,102] and cefotax-
in patients with pneumonia, urinary tract infections and other
ime[107,108] in adult patients with bacterial pneumonia. There were no
serious infections.[119] More recent data are pooled from 5598
patients with various bacterial infections (type of infections not statistically significant differences in the incidence, type or severity
of adverse events between cefepime and the third-generation
reported) who received multiple doses of intravenous cefepime
cephalosporins.[99-103,105-108] In addition, the overall incidence of
(0.5–2g twice daily).[2]
adverse events for patients with HAP admitted to the ICU was
5.1 Adults similar for those receiving cefepime 2g three times daily and
recipients of imipenem/cilastatin 0.5g four times daily (57% vs
5.1.1 General Profile 48%).[110] Most of the adverse events considered related to
cefepime were mild to moderate in intensity and reversible upon
Among patients with various infections included in the large the discontinuation of treatment.[99-101]
pooled analysis, the most common adverse events considered to be
As for the above pooled analysis the most common adverse
causally related to cefepime were rash (1.8% of patients) and
events that occurred during treatment with cefepime for bacterial
diarrhea (1.2%). Events occurring at an incidence of 0.1–1% includ-
pneumonia in clinical trials reviewed in section 4 were mild gas-
ing pruritus, urticaria, nausea, vomiting, oral candidiasis, colitis (in-
trointestinal events (diarrhea, nausea, vomiting, abdominal pain,
cluding pseudomembranous colitis), headache, fever, erythema
constipation), headache, fever and rash.[99-103,105,107,108] Diarrhea
and vaginitis.[2]
secondary to the overgrowth of C. difficile was rarely reported

Comparisons with Other Antibacterials with cefepime treatment in only two trials in patients with pneu-
Pooled tolerability data from trials comparing cefepime with monia.[99,105]
ceftazidime suggest the two agents have broadly similar tolerabil-
ity profiles, with recipients reporting similar types and incidence 5.1.2 Local Adverse Events
of adverse events, and rates of discontinuation due to adverse Local reactions at the site of the intravenous infusion oc-
events. Headache, rash and gastrointestinal complaints were the curred in 5.2% of patients in the pooled analysis;[2] these included
most common events experienced (figure 1). Elderly patients tol- phlebitis and inflammation (2.9% and 0.1% of patients).[2] Intra-

[98-103,105,107,108]
98 Chapman & Perry

muscular administration of cefepime was very well tolerated with 2.6% of patients experiencing inflammation or pain at the injec-tion site.[2] Both intravenous and intramuscular administration of cefepime or ceftazidime were well tolerated locally by >90% of patients treated in another pooled analysis.[119] Similar percent-ages of patients receiving cefepime or ceftazidime in individual trials experienced mild, local intolerance at the injection site (8– 23% vs 5–18%; not statistically significant).[103,105] Local intol-erance did not require discontinuation of treatment.[105]

Intramuscular cefepime (0.5g) with and without 1% lido-caine was subjectively assessed by 20 healthy volunteers as less painful than intramuscular ceftriaxone (0.5g) with and without 1% lidocaine in a single-blind, randomised study.[120]

5.1.3 Laboratory Test Abnormalities

Mild variations in laboratory values occurred infrequently in clinical trials in patients with bacterial pneumonia and generally resolved after the end of therapy.[98,103] Abnormal test results included elevation of white blood cell counts,[99] hepatic en-zymes[99,100,103] and neutropenia.[103] Laboratory test abnormali-ties were also generally uncommon in the pooled analysis of trials comparing cefepime and ceftazidime.[119] A significantly higher percentage of patients receiving cefepime >2g per day (usually 4g per day) had a positive Coombs’ test compared with those receiving ceftazidime >3g per day (14.5% vs 8.7%; p < 0.05); however, no episodes of significant hemolysis were reported for either treatment group.[119] Eosinophilia, neutropenia, elevations in hepatic enzymes (ALT and AST), hypophosphatemia and ele-vated thromboplastin times occurred rarely in patients receiving cefepime or ceftazidime therapy.[119]

5.1.4 Uncommon Events

Pooled data from 6649 patients from comparative and non-comparative clinical trials conducted in North America, Europe and Japan found that 0.1% of cefepime recipients experienced an episode of anaphylaxis.[119] This is slightly higher than the inci-dence reported in another pooled analysis (<0.05%).[2] Anaphy-laxis was not reported in clinical trials in patients with pneumonia (section 4), probably because patients with hypersensitivity to cephalosporins were excluded from studies.

As with some other drugs in this class, cefepime has been associated with neurotoxicity (including encephalopathy, myoc-lonus, seizures [including nonconvulsive status epilepticus]) and renal failure during postmarketing surveillance.[2,121-124] Most of these episodes occurred in patients with renal impairment who received doses of cefepime that exceeded recommendations for these patients (section 7).[121-124] In most cases, symptoms of neu-rotoxicity resolved after treatment with cefepime was discon-

tinued or after hemodialysis;[121-124] however, some cases in-cluded a fatal outcome (specific data not available).[2]

In addition to the adverse events reported specifically for cefepime, the following adverse events and abnormal laboratory test results have rarely been reported for the cephalosporins: Ste-vens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic ane-mia, hemolytic anemia, hemorrhage, hepatic dysfunction includ-ing cholestasis and pancytopenia.[1]

5.2 Pediatric Patients

The tolerability of cefepime in infants, children and adoles-cents (aged 2 months to 18 years) with bacterial pneumonia was reported in four clinical trials reviewed in section 4.2.1.[111] Tol-erability data were pooled for the noncomparative trial and two small comparative trials (n = 75 total) and reported separately for the large trial comparing cefepime (n = 80) and ceftazidime (n = 84).

Pooled data showed that 41% of children receiving cefepime experienced at least one adverse event;[111] the most common adverse events were fever (9%), diarrhea (7%) and rash (5%).[111] However, only one adverse event, a case of oral candidiasis, was considered to be probably related to cefepime.[111] One patient discontinued treatment with cefepime because of abnormal lab-oratory parameters.[111]

In the large study comparing cefepime with ceftazidime, 75% of all patients experienced at least one adverse event, with no significant difference between the treatment groups for the number of adverse events.[111] The most common adverse events experienced by cefepime or ceftazidime recipients were respira-tory disorders (31% vs 29%), rash (28% vs 12%), abnormal breath sounds (19% vs 11%), diarrhea (13% vs 8%) and fever (10% for both treatment groups).[111] All adverse events experi-enced by these cefepime recipients were considered mild, except for a case of rash and another of vaginitis which were rated as moderately severe.[111]

6. Pharmacoeconomic Considerations

Cost considerations are important in the choice of an appro-priate antibacterial agent for the treatment of patients with pneu-monia. Two cost analysis models have investigated relative costs associated with cefepime versus ceftazidime therapy (table
VII).[109,125]

Both studies used retrospective clinical data and were con-ducted from an institutional perspective. Efficacy was similar for both drugs in one study using clinical response and adverse event rates in patients with various infections, including infections of

Cefepime in Hospitalized Patients with Pneumonia: A Review 99

table 7 (landscape table) to go here the lower respiratory tract, urinary tract or skin and skin structure
infections,[125] but was higher with cefepime in the study using
bacteriological eradication rates in ICU patients with pneumo-
nia[109] (table VII). Mean duration of therapy was similar in these
latter patients,[109] but was shorter with cefepime, and a lower
total cefepime dosage was used, in the other model[125] (table
VII). Direct costs and total hospitalization costs were lower with
cefepime than with ceftazidime in one study which did not give
statistical information[125] (table VII). In the other trial, drug ac-
quisition costs were similar for both drugs but direct costs (costs
of the study antibiotics and concomitant antibacterial agents,
drugs used to treat clinical failures or adverse events, and drug
preparation and administration) were significantly lower with
cefepime (table VII).[109] This was probably due in part to signif-
icantly fewer patients in the cefepime treatment group receiving
concomitant antimicrobial therapy (particularly vancomycin)
[44% vs 74% for ceftazidime, p < 0.005]. Sensitivity analysis
showed the results to be robust until ceftazidime became 51%[109]
or 31%[125] more effective than cefepime.
7. Dosage and Administration
As previously stated in section 1, cefepime is approved for
the treatment of numerous bacterial infections in numerous coun-
tries worldwide (including Asian, Middle Eastern, South Amer-
ican, some European countries and the US). However, prescrib-
ing recommendations differ between the US[1] and the rest of the
world.[2] A summary of the different dosage and administration
recommendations for cefepime between the US and other coun-
tries is provided in table VIII.
According to international (non-US) labeling,[2] the dose,
dosage interval and route of administration vary according to the
susceptibility of the causative organisms, the severity of the in-
fection and the renal function and overall condition of the patient
(for dosage recommendations see table VIII). Cefepime 1g via
intramuscular injection or intravenous infusion for 7–10 days is
indicated for the treatment of adult or pediatric patients more than
40kg with mild to moderate pneumonia and 2g twice to three
times daily administered via intravenous infusion for 7–10 days
is indicated for the treatment of adult pediatric patients more than
40kg with severe to very severe pneumonia.[2] For pediatric pa-
tients (aged >2 months and up to 40kg in bodyweight) with bac-
terial 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.[2] Experience of the effi-
cacy and tolerability of cefepime is limited in pediatric patients
aged <2 months; however, pharmacokinetic modelling suggests
that a dose of 30 mg/kg/dose twice or three times daily may be

Table VII. Cost analyses of cefepime (CEF) versus ceftazidime (CAZ) in patients (pts) with various infections. Models used an institutional perspective and retrospective efficacy data; costs are in US dollars. Efficacy assessments were made at the end of treatment. Not stated whether costs in this study were per patient or per patient group with or without concomitant antibacterial agents

Reference Type of clinical data Regimen and mean Efficacy Costs
(currency year) duration

clinical bacteriological acquisition treatmenta hospitalizationb

(% of pts) (% of isolates
eradicated)

rights reserved.

Ambrose et al.[109] (1997)

Paladino[125] (1993)

sb, nr; 100 ICU pts with HAP

r; 1637 pts with various infections

CEF 1–2g od-bid IV × 7.29d

CAZ 1–2g od-tid IV × 7.29d

CEF total 17.6g** × 8.7d* IV

CAZ total 29.1g × 9.2d IV

80 77* 150.89 266.59* 19 996.21
68 55 161.00 395.93 24 528.10
88 (AE: 16.5) 10/g (total NR) 281 6839
88 (AE: 19.0) 9/g (total NR) 398 7309

Am J Respir Med 2003; 2 (1)

a Costs were those of the study antibiotics, drugs used to treat clinical failures or adverse events, and drug preparation and administration[109,125] and concomitant antibacterial agents.[109]

b Includes treatment costs plus the cost of a hospital bed while receiving antibiotics.

AE = adverse events; bid = twice daily; HAP = hospital-acquired pneumonia; ICU = intensive care unit; IV = intravenous; nr = nonrandomized; NR = not reported; od = once daily; r = randomized; sb = single-blind; tid = three times daily; * p < 0.05, ** p < 0.01 vs CAZ.

Chapman & Perry

100 Chapman & Perry

Table VIII. Dosage and administration recommendations for cefepime in hospitalized patients with pneumonia, based on US product information[1] and international (non-US) labeling (ROW)[2]

Recommendations US ROW

Indication Treatment of moderate to severe pneumonia due to Treatment of pneumonia in adults or children
Streptococcus pneumoniae, Pseudomonas aged >1mo
aeruginosa, Klebsiella pneumoniae or Enterobacter
spp. in adults or children aged >2mo
Recommended dosage regimen
Adults and pediatric patients 1 or 2g IV bid × 10d Mild to moderate pneumonia: 1g IV or IM
(bodyweight >40kg) bid × 7–10d
Severe pneumonia: 2g IV bid × 7–10d
Very severe or life-threatening pneumonia:
2g IV tid × 7–10d
Pediatric patients 50 mg/kg/dose IV bid × 10d 50 mg/kg/dose bid 10d; for more severe
(aged >2 mo, bodyweight ≤ 40kg) infections a dosage interval of 8h can be used
Pediatric patients Not indicated in this age group Experience of the efficacy and tolerability of
(aged ≥1–2mo) cefepime is limited in pediatric patients aged
<2mo; however, pharmacokinetic modelling
suggests that a dose of 30 mg/kg/dose bid or
tid may be considered

bid = twice daily; IM = intramuscular; IV = intravenous; tid = three times daily.

considered in pediatric patients aged 1 month or older.[2] Accord-ing to international (non-US) labeling, the usual recommended duration of treatment with cefepime is 7–10 days; however, more severe infections may require longer treatment.[2]

In the US, intravenous infusion of cefepime over 30 minutes is indicated for the treatment of moderate to severe pneumonia caused by susceptible strains of S. pneumoniae, P. aeruginosa, K. pneumoniae or Enterobacter spp. in adults and pediatric pa-tients (aged >2 months).[1] The usual recommended duration of treatment with cefepime in the US is 10 days.[1]
There is no need to adjust the dose of cefepime for patients with hepatic impairment[1,2] or for healthy elderly patients with normal renal function (section 3.4.1).[83] However, adjustments to the dose of cefepime or the frequency of administration should be made for patients with varying degrees of renal impairment to compensate for the slower rate of renal elimination of the drug (section 3.4.3).[1,2] In the US, it is recommended that the dosage of cefepime should be adjusted in patients with creatinine clear-ance ≤3.6 L/h (≤60 mL/min).[1] International (non-US) labeling recommends that adjustments be made to the cefepime dosage in patients with creatinine clearance ≤3.0L/h (≤50 mL/min).[2] The recommended maintenance doses in adult patients with renal im-pairment in the US and other countries are presented in table IX.

In patients undergoing hemodialysis, approximately 40– 72% of the total amount of cefepime present in the body at the start of dialysis is removed during a 3- to 5-hour dialysis period (section 3.4.3).[86,87,89] Pharmacokinetic modeling indicates that a

reduced dose is necessary for these patients.[1,2] However, recom-mendations for patients undergoing hemodialysis vary. In the US it is recommended that a repeat dose equivalent to the initial dose should be given at the completion of each dialysis session,[1] while international (non-US) labeling recommends a 1g load dose on the first day and a maintenance dose of 0.5g per day at the com-pletion of each dialysis session.[2] For patients with pneumonia undergoing CAPD, cefepime may be administered at normally recommended doses (1 or 2g) at a dosage interval of 48 hours.[1,2] Data for pediatric patients with impaired renal function are not available; however, because cefepime has a pharmacokinetic profile in children similar to that of adults (section 3.4.2), changes in the dose of cefepime or intervals between doses similar to those for adults in table IX should be considered for children.[1,2]

Cefepime is contraindicated in patients who have had pre-vious hypersensitivity reactions to cefepime, other cephalospo-rins, penicillins or other β-lactam antibacterial agents.[1,2] If a patient does experience a hypersensitivity reaction to cefepime, treatment should be discontinued.[1,2] If the reaction is severe, the patient should be treated with epinephrine and other supportive therapy.[1,2]

As with other antibacterial agents, pseudomembranous coli-tis has been reported to occur with cefepime treatment (section 5.1.1).[1,2] It is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.[1,2] As with other antibacterial agents, pro-

Cefepime in Hospitalized Patients with Pneumonia: A Review 101

longed use of cefepime may lead to the overgrowth of resistant organisms, which should be treated appropriately.[1,2]
International (non-US) labeling[2] states that antibacterial drugs such as metronidazole, vancomycin, gentamicin sulfate, tobramycin sulfate or netilmicin sulfate should not be mixed with cefepime because of physical or chemical incompatibility. In the US, it is recommended that cefepime not be combined with these drugs listed above or with aminophylline or ampicillin at a con-centration greater than 40 g/L because of potential physical in-teraction.[1] However, if concurrent therapy with cefepime and any of these drugs is required, they may be administered sepa-rately.[1,2] The renal function of patients receiving cefepime should be monitored if drugs with a nephrotoxic potential (e.g. aminoglycosides, furosemide) are administered with cefepime.[1,2]

There have been no clinical studies on cefepime in pregnant women. As a result, cefepime should be used during pregnancy only if clearly needed.[1,2] Though cefepime is distributed into human breast milk at very low concentrations, the drug should be administered with caution to nursing women.[1,2]

8. Place of Cefepime in the Management of Hospitalized Patients with Pneumonia

Bacterial and viral pneumonia affects millions of people glo-bally each year. In the US alone, there were an estimated 4.8 million cases of pneumonia in 1996 and in 2000, 1.3 million indi-viduals were hospitalized and 63 500 died of pneumonia.[126] Pneumonia also remains an important cause of death in Europe. Current mortality from pneumonia in European countries ranges from fewer than 15 per 100 000 inhabitants (e.g. Switzerland, Italy, Spain) to more than 45 per 100 000 inhabitants (e.g. UK, Ireland), while its incidence ranges from fewer than 250 per 100 000 inhab-itants (e.g. France, Spain) to more than 45 per 1000 inhabitants (e.g. Germany, Poland).[127]

The most common causative pathogen in bacterial CAP is S. pneumoniae (causing up to two-thirds of cases among hospital-ized patients).[128] It is generally accepted that Gram-negative

bacteria cause 55–85% of cases of HAP, Gram-positive cocci including S. aureus cause 20–30% of cases, and 40–60% of cases are polymicrobial.[129] The prognosis of patients with pneumonia caused by Gram-negative bacilli is much worse than those with pneumonia of Gram-positive origin.[130]

Hospitalized patients with bacterial CAP or HAP generally require prompt treatment with appropriate generally empiric, an-tibacterial therapy.[131-134] Guidelines for the antibacterial treat-ment of adult patients with CAP[128,131,132,135,136] and HAP[129,133,134,137] have been developed to aid clinicians in se-lecting an appropriate antibacterial agent from the many avail-able. The agents commonly recommended for the empiric treat-ment of hospitalized patients with CAP or HAP are summarized in table X.

The parenteral fourth-generation cephalosporin, cefepime has good activity against a broad spectrum of organisms com-monly causative of CAP and HAP. It has similar or better activity than cefotaxime, ceftriaxone or ceftazidime against strains of S. pneumoniae with reduced susceptibility to penicillin- and meth-icillin-sensitive S. aureus (section 2.2.1) and similar activity to ceftazidime against Gram-negative isolates, including P. aeru-ginosa (section 2.2.2).

Extensive use of the third-generation cephalosporins has led to the emergence and spread of resistant strains of Gram-negative bacteria capable of producing AmpC β-lactamases and ESBLs. Importantly, cefepime is active against AmpC β-lactamase hyperproducing bacteria and has greater stability against ESBLs than the third-generation cephalosporins (section 2.3). Reasons for this include cefepime’s reduced affinity for common β-lactamases, enhanced penetration into the bacterial cell, and high affinity for multiple PBPs, including PBP2 (section 2.1). Clinical experience with cefepime against resistant Gram-negative organ-isms is limited. Cefepime is also less prone than the third-generation cephalosporins to select for resistant strains of bacteria (section 2.3). However, it is uncertain whether resistance to cefepime by

Table IX. Recommended dosage adjustments to the maintenance schedule for adults with impaired renal function requiring therapy with cefepime for the treatment of pneumonia. According to US product information and international (non-US) labeling (ROW) there is no need to adjust the dose of cefepime for patients with creatinine clearance >3.6 L/h (>60 mL/min)[1] and >3.0 L/h (>50 mL/min),[2] respectively.

US ROW

Creatinine clearance Recommended adjustment for standard Creatinine clearance Recommended adjustment for standard
(L/h) [mL/min] maintenance dosages of: (L/h) [mL/min] maintenance dosages of:

1g bid 2g bid 1g bid 2g bid 2g tid

1.8–3.6 [30–60] 1g od 2g od 1.8–3.0 [30–50] 1g od 2g od 2g bid
0.66–1.74 [11–29] 0.5 od 1g od 0.66–1.74 [11–29] 0.5g od 1g od 2g od
<0.66 [<11] 0.25 od 0.5 od ≤0.6 [≤10] 0.25g od 0.5g od 1g od

bid = twice daily; od = once daily; tid = three times daily.

102 Chapman & Perry

Table X. Preferred and alternative antibacterial agents for the empiric treatment of hospitalized adult patients with CAP or HAP[128,129,131,133-137]

Type and severity of pneumonia Treatment regimen
(location of patient)

preferred alternative

Moderate CAP (general ward) β-Lactam (e.g. cefotaxime, ceftriaxone) plus macrolide β-Lactam/β-lactamase inhibitor (e.g.
(e.g. azithromycin, clarithromycin, erythromycin) or ampicillin/sulbactam, piperacillin/tazobactam) plus
doxycycline macrolide or doxycycline or monotherapy with an
anti-pneumococcal fluoroquinolone (e.g. levofloxacin,
gatifloxacin, moxifloxacin)
Severe CAP, Pseudomonas β-Lactam (e.g. cefotaxime or ceftriaxone) plus β-Lactam/β-lactamase inhibitor (e.g.
aeruginosa not suspected (ICU) antipneumococcal fluoroquinolone (e.g. levofloxacin, ampicillin/sulbactam, piperacillin/tazobactam) plus
gatifloxacin, moxifloxacin) or macrolide (e.g. antipneumococcal fluoroquinolone (e.g. levofloxacin,
azithromycin, erythromycin) gatifloxacin, moxifloxacin) or macrolide
(e.g. azithromycin, erythromycin)
Severe CAP, P. aeruginosa Broad-spectrum β-lactam (e.g. cefepime, ceftazidime, Broad-spectrum β-lactam agents (e.g. cefepime,
suspected (ICU) piperacillin, imipenem or meropenem) plus ceftazidime, piperacillin, imipenem or meropenem)
antipseudomonal fluoroquinolone plus aminoglycoside and macrolide or
(e.g. ciprofloxacin) nonpseudomonal fluoroquinolone
Mild to moderate HAP Monotherapy with a second- (e.g. cefuroxime) Monotherapy with a β-lactam/β-lactamase inhibitor
(general ward) or third-generation cephalosporin (e.g. ampicillin/sulbactam, piperacillin/tazobactam,
(e.g. cefotaxime or ceftriaxone) ticarcillin/clavulanic acid) or monotherapy with a
fluoroquinolone (e.g. levofloxacin, gatifloxacin)
Mild to moderate HAP with Antipseudomonal β-lactam (e.g. cefepime Antipseudomonal β-lactam (e.g. piperacillin,
multiple risk factors (general ward) or imipenem) plus aminoglycoside ceftazidime, aztreonam or imipenem) plus
or severe HAP (ICU) or antipseudomonal fluoroquinolone aminoglycoside or antipseudomonal fluoroquinolone
(e.g. ciprofloxacin) (e.g. ciprofloxacin)

CAP = community-acquired pneumonia; HAP = hospital-acquired pneumonia; ICU = intensive care unit.

Gram-positive bacteria or P. aeruginosa will emerge once it has been used more widely.

Cefepime achieves good penetration into the bronchial mu-cosa and lung tissue and has also been found in the sputum of healthy volunteers (section 3.2). The pharmacokinetic profile of cefepime allows for a usual dosage interval of 12 hours for mod-erate pneumonia and 8 hours for severe pneumonia, which is an advan-tage over the usual 8-hour dosage interval of the third-generation cephalosporins.

In clinical trials, cefepime was as effective as the third-gen-eration cephalosporins (ceftazidime, cefotaxime and ceftriaxone) and, on limited evidence, imipenem in achieving satisfactory clin-ical and bacteriological response rates in the treatment of adult patients with generally moderate to severe CAP or HAP (section 4). In single trials, cefepime was also effective in the treatment of pediatric and elderly patients with moderate to severe bacterial pneumonia, two populations commonly affected by pneumonia (section 4.2.1 and section 4.2.2).

However, antibacterial clinical trials rarely prove that one drug is superior to another, because small numbers of patients are included and patient inclusion and evaluability criteria require that the cultured pathogen must be susceptible to both study drugs. Thus, any potential bacteriological advantage that

cefepime may have over the third-generation cephalosporins would not be detected. Nonetheless, cefepime has shown efficacy in patients with pneumonia who have failed treatment with pen-icillins or other cephalosporins (section 4.2.3).

Although cefepime is generally active against organisms that commonly cause mild to moderate CAP, it is not recommended as a first-line therapy in treatment guidelines because it would provide broader activity than is necessary.[128] As well, cefepime is not recommended for the empiric treatment of critically ill patients with severe CAP admitted to the ICU without specific risk factors for P. aeruginosa, as it should be reserved for difficult-to-treat infections.[128]

The American Thoracic Society (ATS) guidelines for the treatment of HAP were published in 1996, and have not been updated since.[129] When these guidelines were released, cefe-pime was a relatively new drug and so was not included in the ATS recommendations for the treatment of HAP. The ATS guide-lines recommend that the empiric treatment of early onset, mild to moderate HAP in patients without underlying disease or prior exposure to antibacterial agents be directed against a core group of causative organisms including Gram-negative bacilli, MSSA and S. pneumoniae.[129] However, monotherapy with a β-lactam is not recommended for the empiric treatment of infections sus-

Cefepime in Hospitalized Patients with Pneumonia: A Review 103

pected to be caused by Enterobacter spp. because of the possi-bility of inducing the production of β-lactamases.[129,134] Newer recommendations have suggested that patients with HAP without specific risk factors be treated with cefepime monotherapy, while patients allergic to penicillin could be treated with an extended-spectrum fluoroquinolone (e.g. levofloxacin, gatifloxacin).[134]

Broad-spectrum antibacterial agents such as cefepime are also recommended for patients with mild to moderate HAP with multiple risk factors or critically ill patients with severe HAP admitted to the ICU to provide activity against P. aeruginosa, Acinetobacter spp. and other resistant organisms.[129,134]

Alternative antibacterial agents to cefepime may have higher acquisition costs and have associated tolerability concerns. The carbapenems (e.g. imipenem, meropenem) have a very broad spectrum of activity. They are resistant to hydrolysis by AmpC β-lactamases and ESBLs and are active against organisms resis-tant to other antibacterials.[138,139] However, due to the high ac-quisition cost of the carbapenems, and to limit the emergence of resistance to these agents, it has been suggested that they should be reserved for the treatment of serious infections caused by mul-tiresistant or mixed organisms.[138,139]

The fluoroquinolones (e.g. levofloxacin, gatifloxacin, moxi-floxacin) are also active against organisms commonly associated with pneumonia, such as Gram-positive (including penicillin-resistant

S. pneumoniae) and Gram-negative bacteria, atypical organisms and anaerobes.[140-143] They have proven effective in the treat-ment of community-acquired infections, including CAP.[140-143] The fluoroquinolones have a convenient once-daily administra-tion regimen, and may be used orally in place of intravenous antibacterial agents, with associated cost benefits.[140,141,143] However, the fluoroquinolones have been associated with serious adverse events such as phototoxicity, prolongation of the QTc interval, hypoglycemia and hepatotoxicity.[140-143]

Cefepime is generally well tolerated. The most common ad-verse events with a causal relationship to cefepime experienced by patients with pneumonia included rash and diarrhea (section 5.1.1). Other adverse events (experienced in less than 1% of pa-tients) that were probably related to cefepime included pruritus, urticaria, nausea, vomiting, oral candidiasis, colitis (including pseudomembranous colitis), headache, fever, erythema and vag-initis (section 5.1.1). Most adverse events were mild to moderate in intensity and reversible upon discontinuation of treatment. Cefepime has also been associated rarely with neurotoxicity in patients with renal impairment who received excessive dosage (section 5.1.4). However, this can be avoided by strict adherence to the recommended dosage regimens for these patients (section 7). There is no requirement for dosage adjustment in patients with hepatic dysfunction (section 7). In comparative clinical trials,

adult patients receiving cefepime experienced a broadly similar number and type of adverse events as those receiving the third-generation cephalosporins (section 5) and, although data are lim-ited, pediatric and elderly patients also tolerated treatment with cefepime (section 5.2 and section 5.1.1).

Cost analyses (section 6) suggest that the institutional costs associated with drug therapy with cefepime may be lower than those of ceftazidime; however, more rigorous cost-effectiveness studies are required to confirm this.

In conclusion, cefepime is an established and generally well tolerated parenteral drug with a broad spectrum of antibacterial activity which, when administered twice daily, provides cover-age of most of the pathogens that may be causative in pneumonia. In randomized clinical trials in hospitalized patients with gener-ally moderate to severe community-acquired or nosocomial pneumonia, cefepime monotherapy exhibited good clinical and bacteriological efficacy. Cefepime may become a preferred anti-bacterial agent for infections caused by Enterobacter spp. With prudent use in order to prevent the emergence of resistant organ-isms, cefepime will continue to be a suitable option for the em-piric treatment of pneumonia.

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Correspondence: Therese M. Chapman, Adis International Inc., 860 Town Center Drive, Langhorne, PA 19047, USA. E-mail: [email protected]