Research ArticleClinical Outcomes of Extended-SpectrumBeta-Lactamase-ProducingEnterobacteriaceae Infections with Susceptibilities amongLevofloxacin, Cefepime, and Carbapenems

Kristy J. Walker,1 Young R. Lee ,2 and Amanda R. Klar2

1Hendrick Medical Center, 1900 Pine St., Abilene, TX 79601, USA2Department of Pharmacy Practice, Texas Tech University Health Sciences Center, School of Pharmacy, 1718 Pine St., Abilene,TX 79601, USA

Correspondence should be addressed to Young R. Lee; young.lee@ttuhsc.edu

Received 31 August 2017; Accepted 28 December 2017; Published 8 February 2018

Academic Editor: Kapil Chousalkar

Copyright © 2018Kristy J.Walker et al.*is is an open access article distributed under the Creative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. Highly resistant Gram-negative bacterial infections are associated with high mortality. Increasing resistance to standardtherapy illustrates the need for alternatives when treating resistant organisms, especially extended-spectrum beta-lactamase-(ESBL-) producing Enterobacteriaceae. Methods. A retrospective chart review at a community hospital was performed. Patientswho developed ESBL-producing infections were included. Patients less than eighteen years old, who were pregnant, or who wereincarcerated were excluded. *e primary outcome was hospital mortality. *e secondary outcomes included intensive care unit(ICU) mortality, ICU length of stay, and hospital length of stay. Results. 113 patients with ESBL-producing infections met thecriteria for review. Hospital mortality: carbapenem (16.6%), cefepime (0%), and levofloxacin (15.3%) (p � 0.253). ICU mortality:carbapenem (4.5%), cefepime, (0%), and levofloxacin (3.7%) (p � 0.616). Mean ICU and hospital length of stay: carbapenem(9.8± 16, 12.1± 1 days), cefepime (7.8± 6, 11.1± 10.5 days), and levofloxacin (5.4± 4.1, 11.1± 10.4 days) (p � 0.805, 0.685). Nopredictors were clearly found between the source of infection and mortality. Conclusion. Cefepime or levofloxacin can bea potential alternative agent for infections with ESBL-producing Enterobacteriaceae, and larger clinical trials investigating theseoutcomes are warranted.

1. Introduction

Extended-spectrum beta-lactamase- (ESBL-) producingEnterobacteriaceae infections are increasingly identifiedwith subsequent hospitalization [1, 2]. ESBL is a resistancemechanism inwhich the beta-lactam ring of antibiotics such aspenicillins, cephalosporins, and aztreonam is hydrolyzed,inactivating the antibiotic. Increasing resistance was demon-strated in a 2013 Centers for Disease Control and Prevention(CDC) report, which included 26,000 ESBL-producingEnterobacteriaceae infections and 1700 deaths in the UnitedStates [3]. Traditionally, the treatment of choice for ESBL-producing Enterobacteriaceae infections has been the car-bapenem class. However, trends in resistance demonstratethe need of conservative use of carbapenems and illustratethe need for alternative therapies against ESBL-producing

organisms. Additionally, chromosomally mediated in-ducible resistance has manifested as porin loss, whichdecreases drug entry in strains already retaining high levelsof AmpC [4]. Emerging incidence of community-acquiredESBL-identified infections has demonstrated a positiveassociation with the increasing trend of carbapenem re-sistance in Enterobacteriaceae. *ough prospective re-search demonstrating effectiveness of other therapies hasbeen limited, there is emerging retrospective evidence insupport of the use of cefepime, fluoroquinolones, andpiperacillin/tazobactam in certain clinical situations [5–10].

It is of interest to the patient for organisms (E. coli beingthe most common to exhibit ESBLs) to be detected and re-ported to healthcare providers in a timely fashion for bothappropriate treatment to be initiated and resulting morbidityand mortality to be significantly reduced. However, reporting

HindawiCanadian Journal of Infectious Diseases and Medical MicrobiologyVolume 2018, Article ID 3747521, 6 pageshttps://doi.org/10.1155/2018/3747521

of ESBL can be delayed by a few days due to the screening andidentification process. Many microbiology laboratories arechallenged by increasingly changing and complicated recom-mendations [11]. Minimum inhibitory concentrations (MICs)of β-lactamase-producing Enterobacteriaceae might be re-ported as high but are still in the susceptible range (i.e., “hiddenresistance”) [7, 8]. If diagnostic microbiology laboratories areunable to adequately test for ESBL production, it could beargued that suspect cases of hidden resistance will go un-recognized by the microbiologists and clinicians, increasing thelikelihood for adverse consequences [8–10]. Other data showedthat carbapenem use whenMIC is ≥4mg/liter had outcomes ofincreased mortality compared to patients whose microbio-logical isolate MICs were lower, demonstrating carbapenemtherapy limitations [12].

Because Enterobacteriaceae organisms are becomingincreasingly resistant to standard therapy, treatment selectedby interpretation of MICs of ESBL producers and by clinicaloutcome may offer therapeutic alternatives in more chal-lenging situations [7, 12–14]. Appealing to the cause ofantimicrobial stewardship, the fourth-generation cephalo-sporin cefepime could be a considerable alternative againstESBL-producing organisms and could shift trends for car-bapenem use. Cefepime has shown to have greater, stableactivity against ESBL (i.e., AmpC enzymes) compared to theother extended-spectrum cephalosporins [9, 10, 14]. Cefe-pime does not rely on porins for entry into the bacterial cell,making it useful in the down-regulated porin resistancemechanism [15, 16]. Appealingly, cefepime could be used intherapy for ESBL-EC and ESBL-K strains highly resistant tothird-generation cephalosporins (including ceftazidime)and to aztreonam [14, 17–21]. Fluoroquinolones may alsooffer a place as alternative therapy in treating ESBL-producingEnterobacteriaceae. *ough many bacteria are becoming in-creasingly resistant to fluoroquinolones, treatments with thisclass when susceptibilities allow have demonstrated improvedinpatientmortality when compared to carbapenems [22–25]. Asmall retrospective review with in vitro samples indicated nodifference in inpatient mortality with levofloxacin whencomparing low, intermediate, and high MICs. However, theydid demonstrate trends for a shorter improved mortality andshorter length of stay in the lower MIC group [22].

*e objective of this study is to evaluate clinical out-comes among levofloxacin, cefepime, and carbapenem usedfor ESBL-producing Enterobacteriaceae infections. Addi-tional objectives include identifying risk factors that can helptailor antibiotic therapy.

2. Methods

*is is a retrospective chart review conducted at one 522(including 22 ICU) bed tertiary community medical center.Patient charts were included from January 1, 2012, toSeptember 30, 2015. Records and profiles of discharged pa-tients who received cefepime, levofloxacin, or carbapenemfor ESBL pathogens within the specified time span wereidentified by the microbiology lab department. *is studyreceived approval by the Texas Tech University HealthSciences Center Institutional Review Board. Individuals with

ESBL-producing Enterobacteriaceae infections were identi-fied, who also waived the need for informed consent. Eligiblepatients fulfilled each of the following criteria: (1) aged 18 yearsor older, (2) clinically diagnosed with the ESBL-producingEnterobacteriaceae isolate demonstrated on culture, (3) re-ceived empirical treatment with cefepime, levofloxacin, orcarbapenem for at least 48 hours after initial cultures had beendrawn, and (4) admitted for inpatient treatment. Ninety daysprior to culture, risk factors were identified. *e researcherstook no part in the conduct of the study, nor did they playa role in the analysis of the data.

An infection occurring in the ICU was defined as thepatient being present in the ICU when the culture wasidentified for the Gram-negative organism. Infectious andother diagnoses were identified by ICD-9 codes in the pa-tient chart. Acute renal failure is identified when the serumcreatinine is increased by 50% or more from the patient’sbaseline serum creatinine on the onset of infection. In-cluded in this were patients with a past medical history ofchronic kidney disease (CKD) noted in the chart. Anti-microbial therapy administered after diagnosis wasregarded as empirical treatment, and therapy adminis-tered afterward was defined as definitive therapy.

*is single medical center has a centralized clinicalmicrobiology laboratory which processes 96,000 samplesannually. At this laboratory, bacteria can be identified downto a genus species, and the susceptibilities are further out-lined by predefined antimicrobials. An automated brothmicrodilution system (MicroScan; Siemens AG, Germany)allows for susceptibility reporting, and an analysis isconducted in accordance with the Clinical and Labora-tory Standards Institute (CLSI) criteria [26]. To identifyESBL-producing bacteria, isolates are processed usingthe MicroScan WalkAway system. *is system initiallyscreens for ceftazidime and cefpodoxime resistance,which is subsequently confirmed on demonstration ofsynergy between these two antibiotics and additionally byclavulanic acid on disc synergy testing. *e interpretationfollowed the current breakpoints recommended by theCLSI. *e severity of underlying medical illness wascalculated by the Elixhauser scoring system [27].

*e primary study outcome was hospital mortality. *esecondary outcomes were ICUmortality, ICU length of stay,and hospital length of stay.

*e following baseline characteristics were also collected:age, gender, type of infection, source of infection, culturespecies, and sensitivities.

All analyses were performed using Strata Version 13.1(StataCorp, College Station, TX). Descriptive statistics wereused to quantify patient characteristics, as well as for analysisof the primary and secondary outcomes. Categorical vari-ables were expressed as percentages of total numbers ofpatients analyzed. Continuous variables were expressed asmean values± SDs. *e Kruskal–Wallis test was used tocompare differences between groups. Multivariate re-gression analyses were used to identify risk factors that mayhave association with clinical outcomes. Data are sum-marized as n (%). Adjusted odds ratios (ORs) are presentedwith 95% confidence intervals and were calculated using

2 Canadian Journal of Infectious Diseases and Medical Microbiology

multivariate logistic regression. OR p values correspond toadjusted ORs.

3. Results

3.1. Baseline Characteristics. In this review, 113 patients withESBL-producing Enterobacteriaceae infections were suc-cessfully identified at the community hospital during the3-year study period (Table 1). 66 patients were in the car-bapenem group, 21 in the cefepime group, and 26 inthe levofloxacin group. Table 1 shows the characteristics ofthe patients at baseline. *e mean age of the patients was69.8 years, and 60% were female. *ere were 77.3% patientsin the carbapenem group, 85.7% in the cefepime group, and88.9% in the levofloxacin where the pathogen was identifiedas E. coli. *e predominant infection treated was urinarytract infection (UTI) with 66.7% in the carbapenem group,57.1% in the cefepime group, and 70.4% in the levofloxacingroup. Additionally, 7.6% in the carbapenem group, 0% inthe cefepime group, and 7.4% in the levofloxacin group weretreated for intra-abdominal infection. *erefore, no patientswere treated with cefepime for intra-abdominal infection.

Furthermore, 15.2% in the carbapenem group, 28.6% inthe cefepime group, and 7.4% in the levofloxacin group weretreated for skin and soft tissue infection (SSTI). Of note,carbapenem and levofloxacin groups were treated for over60% hospital-acquired or healthcare-associated infections,while the cefepime group was treated for 61.9% community-acquired infections.

3.2. Primary and Secondary Outcomes. Hospital mortalityand ICU mortality were not different in all three groups. Noone died in the cefepime group even though there was nostatistical difference (Table 2). ICU length of stay was shorterin the cefepime and levofloxacin groups, by 2.0 and 4.4 days,respectively. Hospital length of stay was shorter by 1 day inthe cefepime and levofloxacin groups compared to the car-bapenem group, although this was not statistically different.

3.3. Multivariate Analysis. *ere were no predictors foundbetween the source of infection and mortality (Table 3).

4. Discussion

*ere is controversy in recent literature regarding alternativetherapies against infections due to ESBL-producing Enter-obacteriaceae. *is study has outlined outcomes for a ruralhealthcare system where cefepime and levofloxacin wereused as alternatives for treatment of infections.

Studies demonstrate improved inpatient mortality whensusceptibilities have allowed treatment with fluoroquinolonessuch as ciprofloxacin and levofloxacin [22–24]. However, mostof these studies only studied bacteremia as the primary type ofinfection, whereas our study allowed for all types of infection.Furthermore, these studies were following the earlier breakpoints of MIC susceptibility established by the CLSI. Anti-microbial sensitivity to cefepime and levofloxacin amongEnterobacteriaceae is defined by the 2014 CLSI update as an

Table 1: Baseline characteristics.

Characteristics Carbapenem (n� 66) Cefepime (n� 21) Levofloxacin (n� 26) p valueDemographicsAge (years), mean (SD) 69.5 (15.9) 67.5(10.5) 72.5 (12.8) 0.357Gender 0.065Female, n (%) 41 (62.1) 8 (38.1) 19 (70.4)Male, n (%) 25 (37.9) 13 (61.9) 8 (29.6)Comorbidity score, mean (SD) 14.7 (10.4) 10 (8.4) 14.4 (13.1) 0.213Type of infectionHospital acquired, n (%) 21 (31.8) 1 (4.8) 8 (29.6) 0.046Healthcare associated∗, n (%) 21 (31.8) 6 (28.6) 10 (37) 0.814Community acquired, n (%) 24 (36.4) 13 (61.9) 9 (33.3) 0.082Source of infectionCatheter LSI, n (%) 0 (0) 1 (4.8) 0 (0) 0.109Bacteremia, n (%) 4 (6.1) 2 (9.5) 3 (11.1) 0.684Septic shock, n (%) 8 (12.1) 2 (9.5) 5 (18.5) 0.614Intra-abdominal, n (%) 5 (7.6) 0 (0) 2 (7.4) 0.434Pneumonia, n (%) 7 (10.6) 1 (4.8) 1 (3.7) 0.452SSTI, n (%) 10 (15.2) 6 (28.6) 2 (7.4) 0.136UTI, n (%) 44 (66.7) 12 (57.1) 19 (70.4) 0.618Culture speciesE. coli, n (%) 51 (77.3) 18 (85.7) 24 (88.9) 0.369K. pneumoniae, n (%) 11 (16.7) 1 (4.8) 1 (3.7) 0.118P. mirabilis, n (%) 15 (22.7) 5 (23.8) 0 (0) 0.024∗Healthcare-associated infections� acquired in nursing resident or recent hospitalization.

Canadian Journal of Infectious Diseases and Medical Microbiology 3

MIC of less than or equal to 2 μg/mL [26]. A randomizedcontrol trial by Seo et al. demonstrated a high treatmentfailure comparing cefepime, piperacillin/tazobactam, andertapenem in treatment of ESBL-producing E. coli infection[28]. However, the baseline characteristics of patients in thestudy were not well aligned. *e sex differences betweencefepime and the other 2 groups varied, as well as the averageage of patients in the cefepime group was approximately10 years greater than the piperacillin/tazobactam and erta-penem groups. Our study, however, showed similar reportingbetween ages and sexes.

Previous literature showed an association betweenclinical outcomes and MICs. *ese studies have suggestedthat a low MIC value is positively associated with betterclinical outcomes versus a higher MIC [9, 10, 17, 19–22].Recent literature has trended favorably from a sensitivity-based approach to an MIC-based approach in settings whereESBL producers are endemic [29–31]. Studies have shownthat cefepime and levofloxacin can both favorably achievepharmacodynamic targets against isolates of fully suscep-tible Enterobacteriaceae at lowered MIC susceptibilities[11, 12, 15, 18, 22]. *ere have been underlying issues withstudies regarding the lack of clinical experience using thesemedications, as well as the conflicting reports of clinical out-comes in the literature when studying treatments for ESBL-producing E. coli infection. Additional research would helpdemonstrate that drug target attainment in ESBL-producingEnterobacteriaceae with cefepime and levofloxacin will achieveadequate drug target levels when using the recent updates forsusceptible breakpoints for cefepime and levofloxacin.

Additionally, the doses of cefepime used in the studymay have been subtherapeutic, whereas our doses were

reviewed for therapeutic efficacy and we also took intoaccount if renal dose adjustments had been made [28].Lower doses of cefepime have been associated with treat-ment failure and higher mortality [28, 32]. Literature sug-gests that higher maximal doses of cefepime, even whenrenally adjusted, may be more beneficial than standardcefepime dosing [32]. Because time above MIC is critical forclinical success of cefepime dosing, our study evaluated if thedose was appropriate based on the infection type and renalfunction [32, 33].

Previous retrospective chart review had observed a trendof lower 30-day mortality in the fluoroquinolone groupcompared to the carbapenem group, although not statisti-cally significant (OR 4.53; 95% CI 0.98–21) [23]. Similarly,a higher 30-day mortality in the cefepime group wasdemonstrated when CLSI breakpoints were 8 or greater(OR 7.1; 95% CI 2.5–20.3) [21]. However, unlike our study,these two trials only looked at bacteremia infection andhad used previously defined CLSI breakpoints for cefepime.Although this study did not find a statistically significantdifference either, when using a lower MIC breakpoint, therewas a trend for lower mortality for both alternative therapygroups. *ereby, it was suggested that cefepime therapy waslimited for bacteremia caused by ESBL-producing Enter-obacteriaceae organisms when cefepime MIC was less than orequal to 1 μg/mL [21, 23]. Additional comparisons of length ofhospital stay had shown that higherMIC resulted in increasedlength of stay of 5.67 days (95% CI 0.77–10.62 days; p � 0.02)with levofloxacin [22]. Similar to other studies, our study waslimited by allowing other antimicrobial agents that could havealtered the outcomes, although matched group analysis wasapplied to our study to offset this limitation.

Table 2: Primary and secondary outcomes.

Outcome Carbapenem (n� 66) Cefepime (n� 21) Levofloxacin (n� 26) p valuePrimaryExpired patients in hospital, n (%) 11 (16.6) 0 (0) 4 (15.4) 0.253SecondaryExpired patients in ICU, n (%) 3 (4.5) 0 (0) 1 (3.7) 0.616ICU length of stay, mean (SD) 9.8 (16.0) 7.8 (6) 5.4 (4.1) 0.805Hospital length of stay, mean (SD) 12.1 (11) 11.1 (10.5) 11.1 (10.4) 0.685

Table 3: Multivariate analysis.

MortalityUnadjusted OR Adjusted OR p

No (n� 99) Yes (n� 15)Vascular catheter LSI 1 (1.0) 0 (0.0) — — —CLSI 0 (0.0) 0 (0.0) — — —Ventilator-related infection 0 (0.0) 0 (0.0) — — —Bacteremia 8 (8.1) 1 (6.7) 0.81 (0.02–6.92) 0.63 (0.07–6.08) 0.692Sepsis shock 14 (14.1) 1 (6.7) 0.43 (0.01–3.34) 0.31 (0.03–3.00) 0.314Intra-abdominal infection 7 (7.1) 0 (0.0) 0.00 (0.00–3.57) — —Pneumonia 6 (6.1) 3 (20.0) 3.87 (0.54–20.9) 2.28 (0.26–20.15) 0.458Skin and soft tissue infection 17 (17.2) 1 (6.7) 0.34 (0.01–2.59) 0.26 (0.02–2.97) 0.278Urinary tract infection 66 (66.7) 9 (60.0) 0.75 (0.21–2.79) 0.53 (0.10–2.84) 0.461

4 Canadian Journal of Infectious Diseases and Medical Microbiology

Our study did not identify a statistically significant dif-ference in hospital mortality between patients who were re-ceiving treatment with carbapenem and those who received analternative treatment. However, this study did find a trendbetween carbapenem therapy and an increased risk ofmortalityand alternative therapy and a decreased risk of mortality. Itfollows that there might be greater in vitro activity in favor forcefepime, specifically for not being induced by the AmpC gene.Interestingly, no one died in the cefepime group even thoughthere was no statistical difference. *is could be explained bymany community-acquired infections in the cefepime group,but this suggests that cefepime can be a good treatment optionin ESBL community-acquired infections. Carbapenem therapywas associated with a trend for longer hospital stay than withcefepime therapy. *is association is not entirely clear but ispossibly related to increased level of severity of illness amongpatients receiving carbapenem therapy. More patients withseptic shock and pneumonia were included in the carbapenemgroup, and more community-acquired infections were in thecefepime group. Although unable to demonstrate an associa-tion between mortality and source of infection for patientsreceiving cefepime or levofloxacin, it is possible that this studywas underpowered to identify an association. Although unableto demonstrate an association between increased MIC ofcefepime and mortality among patients receiving cefepimemonotherapy, it is possible that the results might have beendiluted due to the inability to detect definitive MIC values.

Our study had a few strengths. First, this research wasspecifically looking at clinical outcomes for the hospital andICU. Additionally, this study allowed for identification ofmultiple Enterobacteriaceae organisms. *is study alsoallowed for several types of infection. Up until this point,previous literature had been limited to specific types ofEnterobacteriaceae (e.g., only E. coli) and had only studiedoutcomes in cases of bacteremia or UTI.

*is study did have several limitations. First, there wasa low sample size for the cefepime and levofloxacin groupscompared to the carbapenem group. *is is likely due to thephysician’s preference for the carbapenem group. Carbapenemtherapy is used in this healthcare setting predominantly forESBL-producing Enterobacteriaceae. Additionally, it waschallenging to determine the exact MIC, as the MIC reportedused automated log2 dilution. In previous literature, an MIC of1 or less proved to have a positive association betweencefepime therapy and mortality. If this study had been ableto detect an exact MIC of 1, there might have been a betterdetection for outcomes. Finally, there potentially wasa physician selection bias for cefepime therapy in pa-tients receiving treatment for community-acquired ESBL-producing infections.

5. Conclusion

Results from this study suggest that either cefepime orlevofloxacin can be a potential alternative agent for in-fections with ESBL-producing Enterobacteriaceae for hos-pitalized patients when isolates are susceptible. Furtherstudies with larger sample size and well-balanced type ofinfections between groups are warranted.

Conflicts of Interest

*e authors declare that there are no conflicts of interestregarding the publication of this article.

Acknowledgments

*is study was supported in part by the TTUHSC ClinicalResearch Institute. Raw data were provided by the InfectionPrevention at Hendrick Medical Center.

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