Abstract
Background: As the prevalence of obesity climbs, dosing of antimicrobials, particularly cephalosporins, is becoming a greater challenge for clinicians. Data are lacking for appropriate dosing of cefepime, an anti-pseudomonal cephalosporin that is widely used as an empiric anti-pseudomonal agent. Objective: The purpose of this study was to determine the rate of clinical treatment failure in obese patients compared with nonobese patients receiving cefepime as definitive monotherapy. Methods: Adult inpatients treated with cefepime monotherapy for ≥72 hours were included. Patients were excluded if they (1) were not able to achieve culture clearance within 72 hours and (2) had polymicrobial infections requiring more than one antibiotic for definitive therapy. Results: Fifty-eight obese patients and 56 nonobese patients were included. Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp were the most prevalent organisms isolated. Most organisms had a minimum inhibitory concentration of ≤1 µg/mL to cefepime with no differences in minimum inhibitory concentration distributions between groups. Definitively, 60% of patients received cefepime 1 g, while almost 40% received cefepime 2 g. Clinical failure occurred in 52% of patients (67% obese vs 36% nonobese; P = .001), with study group (odds ratio = 1.057, 95% confidence interval = 1.008-1.109) and respiratory source (odds ratio = 3.251, 95% confidence interval = 1.378-7.667) being independent predictors of failure. There were no differences in hospital length of stay, all-cause mortality, or 30-day readmissions. Conclusions: Obese patients treated with cefepime are more likely to experience treatment failure than nonobese patients. Larger trials examining the reasons for clinical failure in obese patients treated with cefepime are needed to confirm the findings from this preliminary work.
Keywords: obesity, cephalosporins, bacterial infections, antibiotics, outcomes
Introduction
Obesity rates continue to climb in the United States, with a significant increase in prevalence over the past 10 years.1,2 Obese patients are at an increased risk of infection and poor therapeutic outcomes when compared with nonobese patients.3 Clinicians are faced with the challenge of optimizing medication dosing in obese patients. Due to obese patients’ unique pharmacokinetic (PK) characteristics, such as increased volume of distribution (Vd) and altered renal clearance,3-6 package insert dosing may not be sufficient to ensure clinical treatment success.
Cefepime, one of the most frequently utilized empiric antibiotics, lacks data in the obese population. The pharmacodynamic parameter associated with cefepime is the percentage of the dosing interval that the free drug concentration remains above the minimum inhibitory concentration (MIC) of the infecting organism (fT > MIC).7 The recommended fT >MIC target for cefepime is 50% to 70%.8 The altered drug Vd and increased renal clearance in obese patients may lead to pharmacodynamic target attainment failure, consequently resulting in increased morbidity and mortality.7 Due to altered PKs in obese patients, and findings from PK assessments, 2 g every 8 hours is recommended in morbidly obese patients.9 However, minimal data exist on clinical outcomes in obese patients treated with cefepime. Therefore, the purpose of this study was to evaluate the impact of cefepime dosing strategies on clinical outcomes of obese patients compared with nonobese patients.
Methods
We conducted a retrospective cohort of hospitalized adult patients admitted from July 1, 2015, through July 31, 2017, who were treated with cefepime monotherapy for ≥72 hours for definitive therapy. All courses of cefepime were infused over 30 minutes, and dose adjustments for renal function were determined by the primary medical team. Exclusion criteria were the following: (1) adult patients who were not able to achieve culture clearance within 72 hours and (2) polymicrobial infections requiring more than one antibiotic for definitive therapy. Culture clearance was not achieved if subsequent cultures from the same site remained positive or if there was an undrainable infection (eg, repeated positive blood cultures of the same organism separated by at least 24 hours, undrained abscess/deep-seated intraabdominal infection; undrained moderate-to-severe hydronephrosis). The need for subsequent cultures were chosen by the treating physicians. If a patient had multiple occurrences of cefepime monotherapy during the study period, only the first episode was included. Patients were classified into 2 comparison groups based on body mass index (BMI): nonobese (BMI ≤29.9 kg/m2) and obese (BMI ≥30.0 kg/m2).10 Data extracted from the medical record included demographics, comorbidities, microbiological and antimicrobial treatment data, and clinical outcomes. The primary outcome was clinical treatment failure, defined as a composite of (1) change in definitive therapy >72 hours due to clinical worsening; (2) residual leukocytosis (white blood cell >10 × 109/L) >72 hours after treatment initiation; (3) presence of a fever (single temperature >100.9 °F) >72 hours after treatment initiation; or (4) readmission within 30 days due to reinfection with the same organism.11,12 Secondary outcomes were identification of risk factors for clinical failure, hospital length of stay (LOS), inpatient all-cause mortality, and 30-day all-cause readmission. Univariate data were analyzed using Pearson’s χ2 or Fisher’s exact test for categorical data and Mann-Whitney U test for continuous data. Power and sample size were not calculated, as a convenience sample of all patients within the study period were evaluated for inclusion. A 2-sided P value of <.05 was considered statistically significant. Multivariable logistic regression was performed to assess for independent variables associated with treatment failure. Variables with P < .2 in bivariate analysis and clinical rationale were considered for model inclusion, restricted to a subject-to-variable (n:k) ratio of 10:1, and reported as odds ratios (ORs) and 95% confidence intervals (CIs). Statistical analyses were performed using SPSS (version 24.0, IBM). This study was approved by the University of Mississippi Medical Center Institutional Review Board. All methods were carried out in accordance with relevant guidelines and regulations. The institutional review board granted a Waiver of Consent as this was a retrospective study.
Results
A total of 114 patients met eligibility criteria: 56 (49%) to the nonobese group and 58 (51%) to the obese group. The median [interquartile range] BMI was 24.4 kg/m2 [22.2-27.2] and 35.3 kg/m2 [32.2-41.2] in the nonobese and obese groups, respectively. A comparison of baseline characteristics of the nonobese and obese groups is summarized in Table 1. Empirically, over half the patients (64%) received cefepime, with most receiving 1 g (70%), adjusted for renal function, for a median duration of 3 [2-4] days prior to culture results (Table 2). The most common indications for empiric use of cefepime included bloodstream infection (73%), urinary tract infection (61%), and respiratory tract infection (59%), with no differences between obese and nonobese patients. Several patients had multiple sites of infection. Sixty-nine (61%) patients were classified as having a healthcare–associated infection, defined as culture positive after 48 hours of inpatient status. A total of 136 Gram-negative organisms were cultured from 114 patients (Table 3). The majority (79%) had a MIC of ≤1 µg/mL to cefepime, and only 8 (8%) organisms had a MIC of ≥8 µg/mL (7 organisms with a MIC of 8 µg/mL; 1 organism with a MIC of 16 µg/mL). There were no differences in MIC distributions between groups. Definitively, 2 (2%) patients received cefepime 500 mg, 69 (60%) patients received cefepime 1 g, and 43 (38%) patients received cefepime 2 g all infused over 30 minutes with frequencies adjusted for renal function. Obese patients were more likely to receive 2 g every 12 hours (18% vs 5%; P = .033). The duration of definitive therapy was a median of 5 [4-8] days, leading to a median total treatment duration of 8 days. There was no difference in duration of therapy between groups (obese: 5 days, nonobese: 5 days; P = .857).
Table 1.
Baseline Characteristics of Patients Treated With Cefepime Monotherapy for Infection.
| Variable, n (%) or median [IQR] | Total (N = 114) | Nonobese (N = 56) | Obese (N = 58) | P |
|---|---|---|---|---|
| Age, years | 58 [46-66] | 58 [44-66] | 59 [47-65] | .912 |
| Sex, male | 66 (58) | 38 (67.9) | 28 (48.3) | .034 |
| Weight, kg | 90.7 [74.8-108.6] | 74.8 [62.675-83.8] | 107 [95.25-123.9] | <.001 |
| BMI, mg/kg2 | 29.8 [24.5-35.8] | 24.5 [22.2-27.2] | 35.3 [32.3-41.3] | <.001 |
| Serum creatinine, mg/dL | 1.07 [0.75-2.11] | 0.91 [0.67-2.21] | 1.13 [0.78-2.14] | .979 |
| Comorbidities | ||||
| Hypertension | 98 (86) | 46 (82.1) | 52 (89.7) | .248 |
| History of myocardial infarction | 10 (8.8) | 5 (8.9) | 5 (8.6) | .954 |
| Congestive heart failure | 29 (25.4) | 8 (14.3) | 21 (36.2) | .007 |
| Peripheral vascular disease | 23 (20.2) | 11 (19.6) | 12 (20.7) | .889 |
| Cerebrovascular disease | 26 (22.8) | 14 (25) | 12 (20.7) | .583 |
| Dementia | 4 (3.5) | 3 (5.4) | 1 (1.7) | .36 |
| Chronic pulmonary disease | 28 (24.6) | 12 (21.4) | 16 (27.6) | .445 |
| Connective tissue disease | 13 (11.4) | 4 (7.1) | 9 (15.5) | .16 |
| Peptic ulcer disease | 2 (1.8) | 1 (1.8) | 1 (1.7) | 1.000 |
| Diabetes mellitus, uncomplicated | 7 (6.1) | 2 (3.6) | 5 (8.6) | .439 |
| Diabetes mellitus, complicated | 31 (27.2) | 11 (19.6) | 20 (34.5) | .075 |
| Moderate-severe chronic kidney disease | 32 (28.1) | 15 (26.8) | 17 (29.3) | .764 |
| Hemiplegia/paraplegia | 7 (6.1) | 4 (7.1) | 3 (5.2) | .714 |
| Leukemia | 6 (5.3) | 3 (5.4) | 3 (5.2) | 1.000 |
| Malignant lymphoma | 5 (4.4) | 2 (3.6) | 3 (5.2) | 1.000 |
| Solid tumor, not metastatic | 15 (13.2) | 6 (10.7) | 9 (15.5) | .448 |
| Solid tumor, metastatic | 9 (7.9) | 7 (12.5) | 2 (3.4) | .091 |
| Liver disease, mild | 4 (3.5) | 2 (3.6) | 2 (3.4) | 1.000 |
| Liver disease, moderate to severe | 5 (4.4) | 4 (7.1) | 1 (1.7) | .202 |
| Charlson Score | 3 [2-5] | 3 [1-5] | 3 [2-5] | .478 |
Abbreviations: IQR, interquartile range; BMI, body mass index.
Table 2.
Empiric and Definitive Treatment Characteristics.
| Variable, n (%) | Total (N = 114) | Nonobese (N = 56) | Obese (N = 58) | P |
|---|---|---|---|---|
| Empiric Gram-negative regimens | ||||
| β-lactam, β-lactamase inhibitor combinations | 22 (19.3) | 10 (17.9) | 12 (20.7) | .702 |
| Third-generation cephalosporins | 22 (19.3) | 15 (26.8) | 7 (12.1) | .047 |
| Fourth-generation cephalosporins | 73 (64) | 33 (58.9) | 40 (69) | .264 |
| Aztreonam | 4 (3.5) | 3 (5.4) | 1 (1.7) | .360 |
| Antipseudomonal carbapenems | 5 (4.4) | 2 (3.6) | 3 (5.2) | 1.000 |
| Trimethoprim-sulfamethoxazole | 1 (0.9) | 1 (1.8) | — | .491 |
| Cefepime definitive regimens | ||||
| 500 mg every 24 hours | 2 (1.8) | 2 (3.6) | — | .239 |
| 1 g every 8 hours | 43 (37.7) | 23 (39.7) | 20 (35.7) | .664 |
| 1 g every 12 hours | 10 (8.8) | 5 (8.6) | 5 (8.9) | 1.000 |
| 1 g every 24 hours | 16 (14) | 8 (13.8) | 8 (14.3) | .940 |
| 2 g every 8 hours | 22 (19.3) | 14 (24.1) | 8 (14.3) | .183 |
| 2 g every 12 hours | 13 (11.4) | 3 (5.2) | 10 (17.9) | .033 |
| 2 g every 24 hours | 8 (7) | 5 (8.6) | 3 (5.4) | .717 |
| Cefepime regimens by renal function | ||||
| CrCl >50 mL/min + 2 g every 8 hours | 16 (14) | 6 (10.7) | 10 (17.2) | .316 |
| CrCl >50 mL/min + 2 g every 12 hours | 7 (6.1) | 7 (12.5) | — | .006 |
| CrCl >50 mL/min + 1 g every 8 hours | 27 (23.7) | 15 (26.8) | 12 (20.7) | .444 |
| CrCl >50 mL/min + 1 g every 12 hours | 5 (4.4) | 4 (7.1) | 1 (1.7) | .202 |
Abbreviation: CrCl, creatinine clearance.
Table 3.
Diagnostic and Microbiology of Patients Treated With Cefepime Monotherapy for Infection.
| Variable, n (%) | Total (N = 114) | Nonobese (N = 56) | Obese (N = 58) | P |
|---|---|---|---|---|
| Diagnosisa | ||||
| Bloodstream | 18 (15.8) | 11 (19.6) | 7 (12.1) | .268 |
| Bone/joint | 3 (2.6) | 2 (3.6) | 1 (1.7) | .615 |
| Infective endocarditis | 1 (0.9) | — | 1 (1.7) | 1.000 |
| Skin/wound | 2 (1.8) | — | 2 (3.4) | .496 |
| Respiratory | 62 (54.4) | 26 (46.4) | 36 (62.1) | .094 |
| Intra-abdominal | 2 (1.8) | 1 (1.8) | 1 (1.7) | 1.000 |
| Urinary tract/gynecological | 38 (33.3) | 22 (39.3) | 16 (27.6) | .185 |
| Pseudomonas aeruginosa | 25 (22) | 12 (21) | 13 (22) | .899 |
| Klebsiella spp | 19 (17) | 12 (21) | 7 (12) | .18 |
| Escherichia coli | 24 (21) | 11 (20) | 13 (22) | .717 |
| Enterobacter spp | 22 (19) | 10 (18) | 12 (21) | .702 |
| Citrobacter spp | 5 (4) | — | 5 (9) | .057 |
| Proteus spp | 9 (8) | 5 (9) | 4 (7) | .74 |
| Acinetobacter baumannii | 3 (3) | 1 (2) | 2 (3) | 1.000 |
| Other Gram-negative species | 29 (25) | 15 (27) | 14 (24) | .746 |
| MIC, µg/mL | ||||
| ≤1 | 75/95 (78.9) | 40/48 (83.3) | 35/47 (74.5) | .289 |
| 2 | 14/95 (14.7) | 5/48 (10.4) | 9/47 (19.1) | .23 |
| 4 | 5/95 (5.3) | 3/48 (6.3) | 2/47 (4.3) | 1.000 |
| 8 | 7/95 (7.4) | 3/48 (6.3) | 4/47 (8.5) | .714 |
| 16 | 1/95 (1.1) | 0/47 (0) | 1/47 (2.1) | .495 |
Abbreviations: spp, species; MIC, minimum inhibitory concentration.
Patients could have more than 1 site of infection and more than 1 Gram-negative organism isolated.
Clinical failure occurred in 39 (67%) obese patients and 20 (36%) nonobese patients (P = .001). The obese group had significantly more changes in definitive therapy due to clinical worsening (31% vs 14%; P = .033) and persistent leukocytosis (50% vs 30%; P = .033). No statistical differences were observed between nonobese and obese groups regarding fever (obese: 26% vs nonobese: 14%; P = .124) and 30-day infection-related readmission (obese: 24% vs nonobese: 18%; P = .472). Patients who experienced clinical failure were more likely to have a respiratory source (68% vs 40%; P = .003) and less likely to have a urinary source (24% vs 44%; P = .024). In a multivariable regression model containing sex, group, definitive cefepime therapy of 2 g every 12 hours, respiratory source, and urinary source as the covariates, only group (OR = 0.305, 95% CI = 0.132-0.708) and respiratory source (OR = 2.893, 95% CI = 1.005-8.329) were found to be independent predictors of treatment failure (Table 4). There were no differences in hospital LOS (obese: 19 days vs nonobese: 17 days; P = .770), inpatient, all-cause mortality (obese: 22% vs nonobese: 13%; P = .164), and 30-day all-cause readmissions (obese: 27% vs nonobese: 29%; P = 1.000).
Table 4.
Multivariable Regression Identifying Risk Factors for Clinical Failure.
| Variable | Adjusted | |||
|---|---|---|---|---|
| Exp(B) | Lower 95% CI | Upper 95% CI | P | |
| Obesity (BMI ≥30.0 kg/m2) | 0.305 | 0.132 | 0.708 | .006 |
| Sex, male | 1.482 | 0.588 | 3.734 | .404 |
| Definitive cefepime 2 g every 12 hours | 1.593 | 0.426 | 5.952 | .489 |
| Respiratory source | 2.893 | 1.005 | 8.329 | .049 |
| Urinary source | 0.744 | 0.248 | 2.235 | .598 |
Abbreviations: CI, confidence interval; BMI, body mass index.
Discussion
In this study, we identified that obese patients had high rates of treatment failure at 67% compared with 36% in nonobese patients. In multivariable regression, BMI group and respiratory source were identified as independent risk factors for failure despite comparable comorbid conditions and severity of illness between the obese and nonobese patients. While organism and MIC often dictate success or failure with antimicrobial therapy, nearly 80% of the isolates had low MICs at ≤1 µg/mL, eliminating this as a potential cause for failure. Additionally, there were no differences in MIC distribution or organisms identified between the 2 groups of patients. The most common source of infection and definitive dose was respiratory tract infections and 1 g every 8 hours.
While obese patients had more treatment failures than nonobese patients, this was primarily driven by antibiotic therapy changes due to clinical worsening and persistent leukocytosis. Altering antibiotic therapy at 72 hours due to clinical worsening is not uncommon in clinical practice; however, we found there to be an association with obese patients having a higher likelihood of worsening by 72 hours than nonobese patients. This could be explained from cefepime single-dose PK data in morbidly obese patients before bariatric surgery, which found low probability of target attainment with 2 g every 12 hours.9 Additionally, in obese non–critically ill patients, high renal clearance was identified as a risk factor for insufficient drug concentrations to treat infections, which could also explain the clinical worsening observed in our patients.13 In critically ill patients, the effect is further worsened with an inability to attain a fT > MIC >50%, which is associated with a 32% decreased likelihood of a positive clinical outcome.14 While leukocytosis is often indicative of infection, a study by Herishanu et al noted that obese patients were more likely to have a low-grade reactive leukocytosis,15 which could explain findings of persistent leukocytosis in our cohort.
We did have several limitations to our study. As the first 48 to 72 hours of antibiotic therapy has been linked to clinical success,16 empiric therapy selection could have confounded our primary outcome. However, there were no differences in empiric therapy between groups. Additionally, our sample size was small, therefore limiting our ability to detect differences between groups, especially regarding specific infection types or organisms. While we did not collect the specific type of antibiotic resistance present in the organisms isolated on culture, use of cefepime for definitive therapy was chosen based on the attending physician’s discretion, which is representative of real-world clinical practice. Other limitations to this study included severity of illness and location of the patient in the hospital at the time of positive culture. However, there were no differences in the number of patients who died during hospitalization or in the incidence of health care–associated infection between the groups.
Conclusion
Data are emerging regarding the impact of obesity on infection-related clinical failure. While we did not find a statistical difference in hospital LOS or morality, there was a clinical difference between the obese and nonobese patients. Our data would suggest that obese patients, particularly those with respiratory sources of infection, warrant more aggressive cefepime dosing strategies. However, future studies should aim to elucidate differences between obese and nonobese patients treated with cefepime, focusing on organism and additional comorbidities leading to clinical failure.
Footnotes
Author Contributions: KEB, KRS, and JLW developed the project idea. ARM, JTL, KEB, KRS, and JLW wrote the protocol, collected and analyzed data, wrote the main manuscript text, and reviewed the manuscript.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ARM, JTL, and KRS declare that they have no conflict of interest. JLW has received research grants from MAD-ID unrelated to this work. KEB serves as a speaker for Paratek Pharmaceuticals.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Kayla R. Stover 
https://orcid.org/0000-0002-8635-0137
Jamie L. Wagner
https://orcid.org/0000-0002-6006-7894
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