The Role of Cefepime in the Treatment of Extended-Spectrum Beta-Lactamase Infections

Hansita B. Patel, PharmD1, Kathleen A. Lusk, PharmD, BCPS1, and Jason M. Cota, PharmD, MSc1
Journal of Pharmacy Practice 1-6
ª The Author(s) 2017 Reprints and permission:
sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190017743134
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Abstract
≤
Objective: To review the efficacy of cefepime for use in infections caused by extended-spectrum beta-lactamase (ESBL)-pro- ducing organisms. Data Sources: A PubMed literature search (May 2000 to June 2017) was performed using the keyword cefepime and the MeSH terms beta-lactamases, cephalosporinases, and Enterobacteriaceae infections. Study Selection and Data Extraction: All human, English language studies evaluating cefepime use for the treatment of ESBL-producing Escherichia coli and Klebsiella pneumoniae infections were included. Data Synthesis: Studies assessing the use of cefepime for ESBL infections are few, and clinical studies are limited by design and sample size. The largest pharmacokinetic/pharmacodynamic study, a Monte Carlo simulation using data from the U.S. SENTRY antimicrobial surveillance program, evaluating cefepime use for infections due to ESBL-producing organisms found a 95% to 100% probability of target attainment with traditional cefepime dosing regimens. Most clinical studies found that patients treated with cefepime empirically and definitively had higher rates of mortality than those treated with carbapenems. However, in concordance with other studies reporting minimum inhibitory concentration (MIC) data, lower MICs were associated with lower mortality. Conclusions: Cefepime should be avoided for empiric treatment of suspected ESBL infections and should only be considered for definitive treatment if the MIC 1 mg/mL. However, the site and severity of infection, local resistance patterns, and patient-specific risk factors should also help guide antimicrobial selection.

Keywords
cefepime, beta lactamases, cephalosporinases, Enterobacteriaceae infections

Background
Extended-spectrum beta-lactamase (ESBL) enzymes are pro- duced by multidrug-resistant Enterobacteriaceae such as Escherichia coli or Klebsiella pneumoniae. They are just one type of several beta-lactamases that mediate resistance to beta- lactam antibiotics, specifically penicillins, monobactams, and most third-generation cephalosporins with the exception of cephamycins.1-4 Although the exact prevalence of ESBLs is not known, it is increasing in many parts of the world, with at least 10% to 40% of strains of E coli and K pneumonia- producing ESBL enzymes globally.5
Delineation between community and hospital-acquired ESBL infections can be challenging; however, it is necessary to distinguish them for treatment purposes as hospital-acquired

awareness regarding how to select effective antibiotic treat- ment is crucial for clinicians.
ESBLs acquire resistance to beta-lactams and many other antimicrobial agents via plasma-mediated resistance.1,14-16 As a result, these organisms are resistant to most broad-spectrum antimicrobial classes including fluoroquinolones, aminoglyco- sides, trimethoprim, sulfonamides, and tetracyclines.1,14-16 Carbapenems are considered as the treatment of choice for severe infections caused by ESBL-producing organisms.14,16,17 However, carbapenem overuse possesses significant concern for antimicrobial resistance, including the development of carbapenem-resistant Enterobacteriaceae. Cefepime is a fourth-generation cephalosporin frequently used as first-line empirical treatment of health-care-associated infections.

infections tend to be more severe (Table 1).2,4,6,7 The lack of

appropriate antibiotic therapy for these infections may result in increased mortality, prolonged length of stay, and increased hospital costs.2,8-11 Unfortunately, treatment decisions can be difficult due to resistance of these organisms to multiple broad- spectrum antibiotics. Treatment failure may still occur despite use of antibiotics chosen based on culture and susceptibility data, as seen in the case of cephalosporins.1,12,13 Therefore,
1 Department of Pharmacy Practice, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX, USA

Corresponding Author:
Hansita B. Patel, Department of Pharmacy Practice, Feik School of Pharmacy, University of the Incarnate Word, 4301 Broadway, CPO 99, San Antonio, TX 78229, USA.
Email: [email protected]

Table 1. Key Characteristic Differences and Risk Factors for Community-Acquired and Hospital-Acquired ESBL Infections.2,4,6,7,9,36
Characteristic Community Acquired Hospital Acquired

Organism Escherichia coli Klebsiella spp.
these lower break points. They found that up to 20% of ESBL- producing E coli and 30% of ESBL-producing K pneumoniae isolates could be reported as susceptible to cefepime.3 There- fore, even with lower break points, cefepime may be consid- ered more often for the treatment of ESBL infections than it was in the past.

Type of
infectionsa
Urinary tract infection
bacteremia
Respiratory infection
bacteremia

Intra-abdominal infection Intra-abdominal infection;
urinary tract infection (UTI)
Data Sources/Study Selection
In conducting this narrative review of cefepime effectiveness

Risk factors Previous beta-lactam use,
including cefepime and beta-lactam/beta- lactamase inhibitor combinations
Previous beta-lactam use, including cefepime and beta-lactam/beta- lactamase inhibitor combinations
against infections due to the most common ESBL-producing
organisms, a PubMed literature search (May 2000 to June 2017) was performed using the keyword cefepime and the MeSH terms beta-lactamases, cephalosporinases, and Entero- bacteriaceae infections. This time period was chosen because

Recurrent UTI Central venous catheter
Prior instrumentation to Urinary catheter urinary tract
Diabetes mellitus Burns; renal failure

Abbreviation: ESBL, extended-spectrum beta-lactamase.
aListed most common to least common from top to bottom.

Table 2. Clinical Laboratory Standards Institute (CLSI) Cefepime MIC Break Points (mg/mL) Against Enterobacteriaceae.19,20

2010 2014 Cefepime Dosing Regimena
the first trial evaluating the outcomes of cephalosporin therapy for ESBL bloodstream infections was published after 2000. However, we also sought to include relevant cited references that may have fallen out of this time frame. All relevant studies and review articles, including cited references, evaluating cefe- pime monotherapy for empiric or definitive treatment for infec- tions caused by the most common ESBL-producing E coli and K pneumoniae were reviewed. Studies evaluating cefepime effectiveness against organisms harboring AmpC cephalospor- inases, such as Serratia, Enterobacter, or Citrobacter, were

excluded because cefepime is known to maintain activity

S: MIC ≤ 8 S: MIC ≤ 2 1 g every 12
I: MIC ¼ 16 SDD: MIC ¼ 4 2 g every 12 or 1 g every 8
SDD: MIC ¼ 8 2 g every 8 R: MIC ≤ 32 R: MIC ≤ 16 NA

Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; NA, not applicable; R, resistance; S, susceptible; SDD, susceptible dose-dependent. aAssumes normal renal and hepatic function and is based on achievable serum concentration.

Compared to most other cephalosporins, cefepime has potent activity against gram-negative bacteria and may withstand degradation by certain ESBLs.1,13 However, its use has been limited due to these organisms historically being reported as resistant to all cephalosporins regardless of their minimum inhibitory concentration (MIC).18
≤ ≤
As of 2010, the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing no longer recommends testing for ESBL production or reporting all cephalosporin susceptibilities as “resistant” for treatment purposes.19 As a result of these recommendations, cephalosporins may now be reported as susceptible to ESBL- producing organisms, and cefepime will likely be considered for the treatment of ESBL infections.13 To reduce the risk of treatment failures, CLSI also lowered cefepime susceptibility break points in 2014 (Table 2) from MIC 8 to MIC 2 mg/mL with a susceptible dose-dependent (SDD) category from MIC 4 to 8 mg/mL.20 This change will decrease the likelihood of an ESBL-positive isolate being reported as susceptible to cefe- pime. In 2014, McWilliams and colleagues evaluated the inci- dence of cefepime susceptibility to ESBL-producing isolates at
against these inducible mechanisms of resistance. Twelve clin- ical studies were identified, 4 of which were excluded. Three of the 4 studies did not include ESBL-producing E coli or K pneumoniae, and all 4 studies included AmpC-producing organisms or organisms that more commonly produce AmpC beta-lactamases.17,21-23

Pharmacokinetic and Pharmacodynamics Data
As mentioned previously, CLSI recently recommended low- ering cefepime MIC break points. These break points are set with consideration of pharmacokinetic/pharmacodynamic (PK/ PD) data based on the probability of target attainment, clinical outcomes, and minimization of false susceptibility.20 Most clinical outcome studies of antimicrobial treatments are limited in design and sample size, especially for rare infections caused by ESBLs. Thus, optimal antimicrobial regimens are largely determined by PK/PD studies that analyze the relationship between drug exposure, antibiotic potency, and treatment effi- cacy. The efficacy of beta-lactam antibiotics is dependent on the percentage of the dosing interval time that the concentration remains above MIC, time above the MIC (T > MIC). Optimal efficacy of cephalosporins such as cefepime is associated with T > MIC of 50%. There are few published studies assessing specific cefepime dosing for ESBL infections, all of which are Monte Carlo simulation.18,24 Monte Carlo simulations account for interpatient variability and for differing susceptibilities among species of bacteria to help estimate percentage target attainment (PTA) for specific time over MIC goals.13 Ambrose and colleagues used data from the US SENTRY surveillance

≤
≤
≤
study in 2000 which monitored the occurrence of E coli and K pneumonia and antimicrobial-resistance patterns for pipera- cillin–tazobactam and cefepime throughout a broad network of hospitals within the United States and Canada to conduct a PK/PD target attainment analyses using Monte Carlo simula- tions. Based on their simulations, they found dosing regimen models of cefepime 1 or 2 g every 12 hours administered over 30 minutes demonstrated a 95% to 100% probability of reach- ing the PD target of 50% time over the MIC (T > MIC) at an MIC90 4 mg/mL.18 In contrast, Reese and colleagues found that cefepime 2 g every 12 hours could only achieve a 64% PTA and could not achieve the 90% PTA needed to be con- sidered adequate with continuous infusion. Reese and col- leagues conducted their study at an academic center with a more resistant population of pathogens with MIC50 of 8 mg/mL and MIC90 of 16 mg/mL.24 Taking the data from both these studies into consideration, traditional dosing of cefepime may achieve a PTA of >90% for ESBL isolates with MIC 4 mg/mL, but not in more resistant populations with MIC
>8 mg/mL. Therefore, it would be best to avoid cefepime use
for ESBL infections when MICs fall within or above the SDD category of 4 to 8 mg/mL.

Outcome Data
≤
Based on PK/PD data alone, it is evident that cefepime may be a reasonable alternative to carbapenem therapy if MIC 4 mg/mL. Unfortunately, outcome studies show conflicting
data.
A 2005, single-center, retrospective, case–control study of 30 patients compared clinical and microbiological responses of patients infected with ESBL-producing Klebsiella species and E coli to those infected with non-ESBL pathogens.25 Each group received at least 3 days of cefepime monotherapy, dosed at the physicians’ discretion. Controls were matched based on age, site of infection, intensive care unit (ICU) stay, and patho- gen. Patients with ESBL infections were nearly 10 times more likely to have an unsuccessful clinical response and 30 times more likely to have an unsuccessful microbiological response. All-cause and infection-related mortality did not differ between groups. This lack of difference is likely a result of treatments being broadened from cefepime to carbapenem therapy if there was no clinical improvement after 3 days. A major study lim- itation was that cefepime doses were not optimized for all patients. All treatment failures occurred in severe pulmonary infections for which lower cefepime doses of 1 g every 12 to 24 hours may not have been adequate.25
A 2006, single-center, retrospective study evaluated the clinical and microbiological outcomes for 13 medical and sub-ICU patients with a total of 17 sites of infection caused by either ESBL-producing E coli or K pneumoniae treated with cefepime.26 The infections included 10 episodes of pneumonia requiring mechanical ventilation. Treatment failures were defined as either a lack of improvement or worsening of symp- toms. Clinical cure with resolution of symptoms or improve- ment without resolution of symptoms was achieved in all but
2 patients. These treatment failures occurred in critically ill patients with pneumonia, one of which had a resistant K pneu- moniae isolate with an MIC >64 mg/mL. Limitations to this study are small sample size and the inclusion of a patient who received concurrent amikacin therapy. The use of cefepime with MIC 1 mg/mL is supported based on the study’s find- ings, but should be avoided in critically ill patients with more severe infections such as pneumonia.26
≤
¼
¼
¼
¼
¼ ¼
In 2013, a multicenter, retrospective, propensity-matched, case-control study compared clinical failures, microbiological failures, and 30-day mortality for patients with ESBL- producing Enterobacteriaceae monomicrobial bacteremia treated either empirically or definitively with cefepime or a carbapenem.27 Choice of antibiotic treatment was at the phy- sicians’ discretion at doses preapproved by infectious disease specialists or pharmacists. The majority of patients were treated with carbapenems, with 91 patients receiving empirical treatment and 161 patients receiving definitive treatment with ertapenem 1 g every 24 hours, imipenem 500 mg every 6 hours, or meropenem 1 g every 8 hours. Thirty-three patients received cefepime 1 to 2 g every 8 hours. Seventeen of these patients received definitive treatment and were included in the propensity-matched analysis against patients on carbapenem treatment. Patients treated empirically or definitively with cefepime had a greater risk of clinical failure, microbiological failure, and mortality within 30 days than those treated with a carbapenem. Of the thirty-three patients given cefepime, 25 (75.8%) had a clinical failure and 13 (39.4%) died of sepsis. In patients found to have a cefepime-susceptible isolate, a greater likelihood of clinical failure (P .02), microbiological failure (P .04), and 30-day mortality (P < .001) occurred in patients receiving cefepime as compared to carbapenem. Patients treated empirically with cefepime found to have a cefepime-susceptible isolate had a higher, 30-day mortality rate (P .001). Study limitations included a lack of adequate dos- ing given to patients who fell within the SDD range and the inclusion and predominance of Enterobacter cloacae species.27 In 2012, a multicenter, retrospective study of 151 patients comparing clinical outcomes of bloodstream infections due to ESBL-producing Klebsiella species and E coli found differing results. No difference in mortality between patients treated with cefepime empirically (n 43) or definitively (n 9) versus a carbapenem was found (40% vs 35%; P .07). In addition, no correlation between MIC and mortality was seen.28 However, trends were noted between empirical cefepime ther- apy and increased risk of mortality. Although the authors attempted to control for bias of severity of illness in a multi- variate analysis, patients on empirical carbapenem therapy may have had a greater severity of illness. The authors concluded that it is reasonable to use cefepime for empirical therapy of infections due to gram-negative pathogens in hospitalized patients. However, they recommend carbapenems as the treat- ment of choice for patients at increased risk of infections due to ESBL-producing organisms or patients at increased risk of mortality (including those with an ICU stay), those with pres- ence of central line catheter, and those with rapidly fatal

Table 3. Rate of Clinical Failure or Mortality With Cefepime Use for ESBL Infections.

MIC (mg/mL)
Kotapati et al25 (N ¼ 10)
LaBombardi et al26
(N ¼ 13)

Chopra et al28 (N ¼ 43)

Lee et al27 (N ¼ 17)
Paterson et al12 (N ¼ 3)

Bhat et al30 (N ¼ 11)

Wang et al29 (N ¼ 17)

Seo et al31 (N ¼ 6)

Total (N ¼ 113)

≤8 3/4 (75%) 1/1 (100%) 11/26 (42%) 3/5 (60%) – 1/4 (25%) 0/4 (0%) – 19/44 (43.2%)
4 2/4 (50%) – 1/4 (25%) 1/3 (33.3%) – 2/3 (66.7%) 5/9 (55.5%) – 11/23 (47.8%)
2 – 0/2 (0%) 5/13 (39%) 1/3 (33.3%) 1/2 (50%) 2/3 (66.7%) – 3/4 (75%) 9/24 (37.5%)
≤1 1/2 (50%) 1/10 (10%) – 1/6 (16.7%) 1/1 (100%) – 2/4 (50%) 1/2 (50%) 7/25 (28.0%)
Abbreviation: MIC, minimum inhibitory concentration.

underlying conditions. Unfortunately, the cefepime dosing regimens were not described in the study, making it more dif- ficult to apply these results to practice.28
A 2016, single-center, propensity-matched, retrospective study compared 14-day mortality of patients with ESBL bac- teremia receiving empiric cefepime 1 to 2 g every 8 hours or carbapenem therapy. Fifty-one patients received carbapenem treatment for the entire duration of therapy and 17 patients received empiric cefepime treatment. The majority of patients receiving cefepime (71%) were treated with high doses (cefe- pime 2 g every 8 hours). A trend toward increased mortality in the cefepime group was found, with risk of death being almost 3 times more likely to occur if patients received cefepime therapy instead of a carbapenem (hazard ratio: 2.87, 95% con- fidence interval: 0.88-9.41).29
≤
≤
Two additional studies showed an increase in the number of treatment failures as the cefepime MIC increased above MIC 1 mg/mL. These studies did not primarily assess cefepime use for ESBL infections, but both studies are worth mentioning as they included a subgroup analysis with a small number of patients on cefepime that found unfavorable outcomes despite MIC 2 mg/mL.12,30 In addition, a recent randomized control trial evaluating piperacillin–tazobactam, ertapenem, and cefe- pime for ESBL-producing E coli urinary tract infections was conducted. Unfortunately, robust data could not be gathered from this trial because the cefepime arm of the study was dis- continued early after 4 of 6 cefepime recipients had treatment
failure and 2 of the 4 died despite having MIC ≤2 mg/mL.31

Discussion
Efficacy of cefepime therapy for the treatment of infections caused by ESBL-producing organisms relies on evidence from in vitro PK/PD studies and observational studies. Recently, the CLSI recommended lowering cefepime break points and to report only MICs versus performing confirmatory testing for ESBL production with the assumption that presence of beta- lactamase genes is irrelevant as long as PD targets are attain- able by commonly used doses of antibiotics.32 Based on PK/PD data alone, cefepime dosed at 2 g every 12 hours or 1 g every 8 hours achieve adequate target attainment to effectively treat ESBL isolates if MIC <4 mg/mL.18,24 However, the majority of outcome data from clinical observational studies do not support the use of cefepime as an alternative to empiric
carbapenem treatment for treatment of infections that may be a result of ESBL-producing bacteria.12,25-27,30 With the exception of the study conducted by Wang and colleagues, one major limitation of the outcome studies is the lack of standardized doses.29 It is likely doses were not always opti- mized, and this concern affects our ability to apply this out- come data to patient care.
≤
≤
≤
The available outcome data are more in concordance with current recommended cefepime susceptibility break point of MIC 1 mg/mL from the European Committee on Antimicro- bial Susceptibility Testing (EUCAST) than the current break point of MIC 2 mg/mL recommended by CLSI. EUCAST is a European organization similar to CLSI in the United States.33 Given the current data, it would be best to only consider use of cefepime as definitive treatment of ESBL infections if MIC 1 mg/mL. Consideration of the site and severity of infection should also be given as cefepime’s benefit was lacking in more severe infections such as bacteremia, sepsis, and pulmonary infections. Although their characteristic differences are becom- ing increasingly blurred, it is necessary to distinguish between community-acquired and hospital-acquired ESBL infections for treatment purposes as hospital-acquired infections tend to be more severe.2,4,6,7 In addition, some studies have shown an inoculum effect or an increase of in vitro MICs for cephalos- porins, including cefepime, at increased inoculums of ESBL- producing bacteria.34,35 Therefore, it may be best to switch more critically ill patients with risk factors for mortality or ESBL pneumonia or bacteremia to carbapenem therapy given severity. This recommendation also holds especially true if a patient does not show clinical improvement after 2 to 3 days on cefepime treatment regardless of MIC or site and severity of
infection.25-28,31
≤
≤ ¼
It remains controversial whether cefepime could be uti- lized more frequently within the CLSI recommended suscep- tible (MIC 2 mg/mL) and SDD ranges (MIC 4-8 mg/mL). There is only 1 small, single-center study in which 71% of patients received recommended dosing more in accordance with CLSI’s SDD, and it showed a trend toward higher mor- tality with empiric cefepime treatment.29 Even in less severe cases of ESBL, such as urinary tract infections, high treatment failure rates were observed despite patients receiving cefe- pime 2 g every 12 hours and having MIC 2 mg/mL.31 Future, well-designed studies are needed to determine the optimal cefepime dose using extended or continuous infusions.

Unfortunately, potential limitations of such future studies include the ethical issues of conducting a prospective, rando- mized control trial with cefepime versus carbapenem therapy for ESBL infections given the current mortality data and the difficulty obtaining a large sample size given the rarity of ESBL infections. Conducting a meta-analysis may also be challenging as dosing data are not available for many of the clinical studies, and clinical failures and mortality data were not evaluated uniformly among all studies.
≤
As illustrated from the conflicting outcome data, it is diffi- cult to formulate a decisive approach on how to best use cefe- pime for treatment of ESBL infections. If we collectively consider all results from all studies that provided MIC data, rather than focusing on just outcomes from the individual stud- ies, it is more evident that there may be a trend toward lower mortality with use of cefepime in ESBL-producing E coli or K pneumoniae in the presence of lower MICs especially if MIC 1 mg/mL (Table 3). Despite its utility for broad-spectrum empiric coverage for non-ESBL infections, cefepime should be avoided for empiric treatment of suspected ESBL infections. In addition to site and severity of infections, clinicians should be cognizant of local resistance patterns and of patient-specific risk factors for ESBL infections to help guide treatment deci-
sions regarding antimicrobial selection.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, author- ship, and/or publication of this article.

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