Acute Kidney Injury Risk in Patients Treated with Vancomycin Combined with Meropenem or Cefepime

Abstract

Background:

No previous studies have determined the incidence of acute kidney injury (AKI) in trauma patients treated with vancomycin + meropenem (VM) versus vancomycin + cefepime (VC). The purpose of this study was to fill this gap.

Methods:

A series of 99 patients admitted to an American College of Surgeons-verified level 1 trauma center over a two-year period who received VC or VM for >48 hours were reviewed retrospectively. Exclusion criteria were existing renal dysfunction or on renal replacement therapy. The primary outcome was AKI as defined by a rise in serum creatinine (SCr) to 1.5 times baseline. Multi-variable analysis was performed to control for factors associated with AKI (age, obesity, gender, length of stay [LOS], nephrotoxic agent(s), and baseline SCr), with significance defined as p < 0.05.

Results:

The study population was 50 ± 19 years old, 76% male, with a median LOS of 21 [range 15–39] days, and baseline SCr of 0.9 ± 0.2 mg/dL. Antibiotics, diabetes mellitus, and Injury Severity Score were independent predictors of AKI (odds ratio [OR] 4.4; 95% confidence interval [CI] 1.4–12; OR 9.3; 95% CI 1–27; OR 1.2; 95% CI 1.023–1.985, respectively). The incidence of AKI was higher with VM than VC (10/26 [38%] versus 14/73 [19.1%]; p = 0.049).

Conclusions:

The renal toxicity of vancomycin is potentiated by meropenem relative to cefepime in trauma patients. We recommend caution when initiating vancomycin combination therapy, particularly with meropenem.

Vancomycin is a tricyclic glycopeptide antibiotic originally derived from Streptococcus orientalis that inhibits cell wall synthesis in gram-positive organisms. It was introduced in 1954 and now is sold as a generic drug that is listed as an essential medicine by the World Health Organization [1]. Vancomycin's use has increased since the 1980s because of its efficacy in treating methicillin-resistant Staphylococcus aureus (MRSA) and other infections unresponsive to many antibiotics. Its approved indications include Clostridiodes difficile-associated diarrhea; Staphylococcus enterocolitis; diptheroid, streptococcal, and staphylococcal endocarditis; septicemia; and skin, soft tissue, and bone infections [2].

Acute kidney injury (AKI) is a relatively common consequence of antimicrobial drug therapy that increases hospital length of stay (LOS), costs, morbidity, and the mortality rate [3]. Greater trough concentrations of vancomycin typically correlate with higher rates of AKI [4]. There are several combination therapies that are employed routinely to broaden coverage, including vancomycin plus piperacillin-tazobactam (VPT) [5], vancomycin plus meropenem (VM) [6,7], and vancomycin plus cefepime (VC) [8,9]. The rate of AKI in patients treated with vancomycin in combination with other antibiotics exceeds 40% in some series [8 –11].

The risk of AKI differs with the patient population, co-morbidities, and the pharmacokinetics of the various combinations. Previous studies have compared AKI risk after VPT with VC [12,13] and with VM [10], but to our knowledge, no previous studies have compared VC with VM in the population with trauma. Also, VC and VM often are used interchangeably and have substantial overlap in coverage; however, it is unclear from previous studies which regimen poses the greater risk of AKI in patients with trauma. Compared with general medicine patients, trauma patients are at higher risk of hemodynamic instability and often require blood transfusions, vasopressors, or nephrotoxic agents such as intravenous (IV) contrast medium [14] In this study, we evaluated the rate of AKI in trauma patients in the intensive care unit (ICU) receiving combination therapy with either VC or VM.

Patients and Methods

Study setting

Jackson Memorial Hospital (JMH) is a non-profit, tertiary-care teaching and safety net county hospital affiliated with the University of Miami Leonard M. Miller School of Medicine in Miami, Florida. It has 1,550 licensed beds. Attached to JMH is Ryder Trauma Center, an American College of Surgeons-verified, Level One trauma facility with patient wards and a trauma intensive care unit (ICU). This study was approved by the JMH Institutional Review Board.

Study design and patient population

Using our institutional trauma registry, adult patients admitted to Ryder Trauma Center ICU from January 1, 2016, to December 30, 2017 after trauma who received empiric broad-spectrum antibiotic therapy with either VC or VM for >48 hours were reviewed retrospectively. In cases where patients were eventually changed to a different therapy, the patient was included only if he or she received VM or VM for >48 hours and if AKI occurred while on that regimen. Patients who were admitted for or died before 72 hours after admission, pregnant women, pediatric patients, and those with established renal dysfunction (defined as structural kidney disease, previous kidney transplantation, or serum creatinine (SCr) > 1.5 mg/dL on admission) or on renal replacement therapy were excluded.

Endpoints

The primary outcome was the incidence of AKI, defined as a rise in SCr to 1.5 times baseline according to the Risk, Injury, Failure, Loss, and End stage (RIFLE) criteria and Acute Kidney Injury Network (AKIN) classification [15]. Secondary outcomes were in-hospital death and hospital LOS.

Variables and statistical analysis

Patient demographics (age, gender, race, ethnicity, and Body Mass Index), co-morbidities, nephrotoxic drug exposures IV contrast medium, vasopressors, aminoglycosides, amphotericin, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARB], loop diuretics, non-steroidal anti-inflammatory drugs [NSAIDs], and acyclovir) and clinical factors (baseline SCr, Injury Severity Score [ISS], and Charlson Comorbidity Index [CCI]) were recorded. In addition, information related to antibiotic treatment (indication, loading dose, maintenance dose, trough concentration, and treatment duration) was collected. The patients were divided into VC and VM cohorts, which were then compared using the χ² test for categorical variables and the Student t-test for continuous variables. Binomial logistic regression was performed to identify independent predictors of AKI. The variables included in the regression analysis were those that differed significantly (p < 0.05) between the two cohorts in univariable analysis as well as variables considered to be significant risk factors for the development of AKI. All statistical calculations were performed using SPSS version 26.0.0 (IBM, Armonk, NY). Data are reported as mean ± standard deviation (SD) if parametric or median (interquartile range); if not, with significance at p < 0.05.

Results

Ninety-nine patients met inclusion criteria; 73 (74%) in the VC cohort and 26 (26%) in the VM group. The mean age was 50 ± 19 years old, 76% were male, the median LOS was 21 [interquartile range 15–39] days, a mean baseline SCr of 0.90 ± 0.24 mg/dl, and a mean ISS of 19 ± 13.

Table 1 demonstrates the demographic factors, co-morbidities, and treatment characteristics of the VC compared with the VM cohort. There were no statistically significant differences between the groups in age, gender, race, ethnicity, weight, ISS, baseline SCr, or duration of antibiotic therapy. Although there was no difference in the vancomycin loading and maintenance doses, the maximum vancomycin trough concentration was different (VC 12.5 ± 6.3 versus VM 15.8 ± 7.9 mcg/mL; p = 0.050). However, after dichotomizing trough concentrations into ≥20 mcg/mL and <20 mcg/mL, there was no significant difference between the groups.

Table 1.

Demographics and Co-Morbidities in Patients Who Underwent Combination Therapy with Vancomycin-Cefepime (VC) versus Vancomycin-Meropenem (VM)

	Cefepime-vancomycin (n = 73)	Meropenem-vancomycin (n = 26)	P
Age (y) (mean ± SD)	51.1 ± 19.1	47.2 ± 18.2	0.426
Male gender (%)	53 (72.6)	22 (84.6)	0.22
Race
White	48 (65.8)	15 (57.7)	0.791
Black	22 (30.1)	10 (38.5)
Asian	1 (1.4)	0
Hispanic	33 (45.2)	8 (30.8)	0.199
Obese (%)	16 (21.9)	9 (34.6)	0.201
Diabetes mellitus (%)	9 (12.3)	3 (11.5)	0.916
Heart failure (%)	2 (2.7)	0	0.394
Hypertension (%)	17 (23.3)	5 (19.2)	0.669
Peripheral vascular disease (%)	4 (5.5)	0	0.223
COPD (%)	1 (1.4)	1 (3.8)	0.441
Alcohol use (%)	4 (5.5)	2 (7.7)	0.685
Smoking (%)	13 (17.8)	4 (15.4)	0.778
Malignant disease (%)	0	1 (3.8)	0.092
Charlson Comorbidity Index^a	1 (0–2.5)	1 (0–4)	0.33
Injury Severity Score (ISS) ± SD	19.9 ± 12.7	16.1 ± 12.3	0.205
Level of care
ICU	20 (27.4)	6 (23.1)	0.667
Floor	53 (72.6)	20 (76.9)
Baseline serum creatinine, mg/dL ± SD	0.90 ± 0.23	0.88 ± 0.25	0.69
Vancomycin loading dose, g/d ±SD	1.6 ± 0.6	1.7 ± 0.8	0.382
Vancomycin maintenance dose, g/d ±SD	2.6 ± 1.0	2.6 ± 1.0	0.719
Vancomycin trough >20 mcg/m (%)	7 (9.6)	6 (23.1)	0.08
Maximum vancomycin trough, mcg/mL ± SD	12.5 ± 6.3	15.8 ± 7.9	0.05
Days of antibiotic treatment ± SD	5.4 ± 2.9	6.3 ± 4.9	0.4

Median (interquartile range).

Significant values are in boldface type.

Table 2 shows that both cohorts were similarly exposed to potentially nephrotoxic agents including IV contrast medium, vasopressors, aminoglycosides, loop diuretics, NSAIDs, acyclovir, and angiotensin II receptor blockers (ARBs). However, the VC cohort had greater exposure to ACE inhibitors (VC 18% versus VM 0; p = 0.01).

Table 2.

Concomitant Nephrotoxin Exposure in Patients Who Underwent Combination Therapy with Vancomycin-Cefepime (VC) versus Vancomycin-Meropenem (VM)

Nephrotoxin	Cefepime-vancomycin (n = 73) N (%)	Meropenem-vancomycin (n = 26) N (%)	P
Intravenous contrast	51 (70)	22 (85)	0.143
Vasopressors	28 (38)	12 (46)	0.487
Aminoglycosides	2 (2.7)	2 (7.7)	0.271
Amphotericin B	1 (1.4)	1 (3.8)	0.441
Angiotensin converting enzyme inhibitor	13 (18)	0	0.021
Loop diuretics	43 (59)	15 (58)	0.914
Non-steroidal anti-inflammatory drug	18 (25)	11 (42)	0.089
Acyclovir	3 (4.1)	3 (12)	0.173
Angiotensin receptor blocker	3 (4.1)	1 (2.8)	0.953
Median number of nephrotoxins^a	2	3	0.1

Median (interquartile range).

Significant values are in boldface type.

The indication for antibiotic therapy is summarized in Table 3. The VC and VM cohorts did not differ significantly by site of infection, incidence of polymicrobial infections, gram-positive/negative features of the organisms cultured, or infection with Pseudomonas spp (Table 4).

Table 3.

Site of Infection in Patients Who Underwent Combination Therapy with Vancomycin-Cefepime (VC) versus Vancomycin-Meropenem (VM)^a

Site of infection	Cefepime-vancomycin (n = 73) (%)	Meropenem-vancomycin (n = 26) (%)	P
Respiratory tract	43 (56)	14 (54)	0.715
Urinary tract	9 (12)	4 (15)	0.490
Bacteremia	23 (30)	5 (19)	0.225
Skin and soft tissue	4 (5)	2 (7)	0.746
Empiric therapy	18 (24)	4 (15)	0.274
Bone and joint	1 (1)	0	0.512

No intra-abdominal infections were seen.

Table 4.

Causative Organism of Culture-Positive Infection in Patients who Underwent Combination Therapy with Vancomycin-Cefepime (VC) versus Vancomycin-Meropenem (VM)

Causative organism	Cefepime-vancomycin (n = 73) (%)	Meropenem-vancomycin (n = 26) (%)	P
Polymicrobial	26 (34)	10 (43)	0.418
Gram-positive bacteria	34 (45)	10 (38)	0.715
Staphylococcus aureus	18 (23)	3 (12)	0.159
Gram-negative bacteria	37 (47)	15 (58)	0.158
Pseudomonas	8 (10)	5 (19)	0.163
Enterobacteriaceae	9 (12)	2 (8)	0.372

The primary and secondary outcomes of the two cohorts are shown in Table 5. A significantly greater incidence of AKI was observed in the VM cohort than in the VC cohort (38 versus 19%; p < 0.050). There was no difference in hospital LOS (29 versus 19 days; p = 0.330) or in-hospital mortality rate (19% versus 18%; p = 0.872).

Table 5.

Primary and Secondary Outcomes

Outcome	Cefepime-vancomycin (n = 73) (%)	Meropenem-vancomycin (n = 26) (%)	P
Acute kidney injury	14 (19.1)	10 (38.4)	0.049
In-hospital death	13 (17.8)	5 (19.2)	0.872
Length of stay	19 (13–34)	29 (16–54)	0.330

Median (interquartile range).

On multi-variable analysis (Table 6), after factoring in variables found to be significantly different in the two treatment cohorts, as well as known risk factors for AKI, receipt of VM was independently associated with increased AKI risk (OR 4.439 [95% CI 1.4–12.3]; p = 0.012). Other independent risk factors were diabetes mellitus (OR 9.3 [95% CI 1.3–29.2]; p = 0.023) and ISS (OR 1.2 [95% CI 1.0–2.0]; p = 0.007). Notably, the maximum vancomycin trough concentrations and receipt of ACE inhibitors, two variables inadequately matched between the two cohorts, were not associated with AKI.

Table 6.

Risk Factors for Development of Acute Kidney Injury (Multivariable Analysis)

	Odds ratio	95% Confidence interval		P
Age	1.01	0.97	1.06	0.581
Female gender	2.18	0.34	10.93	0.343
VM vs. VC given	5.24	1.25	22.05	0.024
Vancomycin trough >20 mcg/mL	1.80	0.34	9.62	0.494
Baseline creatinine concentration	2.35	0.17	31.03	0.518
Charleson Comorbidity Index	1.16	0.78	1.74	0.455
Obesity	2.58	0.71	9.44	0.151
Hypertension	1.52	0.39	5.89	0.542
Vasopressors given	3.04	0.92	10.06	0.069
Intravenous contrast medium given	0.57	0.14	2.32	0.432
ACE inhibitor given	2.15	0.30	15.54	0.447
Injury Severity Score	1.08	1.02	1.14	0.010

Significant values are in boldface type.

ACE = angiotensin converting enzyme; VC = vancomycin + cefepime; VM = vancomycin + meropenem.

Discussion

Several studies [10,16 –19] have evaluated the incidence of AKI in patients receiving combination therapy with either VPT or alternative anti-pseudomonal beta-lactam drugs (e.g., cefepime and meropenem). However, to our knowledge, this is the first study directly comparing AKI incidence in trauma patients receiving VC versus VM. The major new findings are a two-fold increase in the rate of AKI with VM versus VC therapy. With multi-variable logistic regression modeling, receipt of VM was independently associated with a greater incidence of AKI compared with receipt of VC. The matched design of this study strengthens the conclusions by evenly distributing between the VC and VM cohorts several known confounding variables such as concomitant nephrotoxic exposure, baseline SCr, vancomycin dosage, baseline demographics, and co-morbidities.

The rate of VM-related and VC-related AKI in the present study (38% and 19%) is markedly higher than the rates identified by Rutter et al. (15% and 13%) in a similarly designed study of general medicine patients [20]. This difference could be attributable to the fact that trauma patients, even a comparison between blunt and penetrating injuries, confer unique risks for infection from early blood transfusion [21], the risk of venous thromboembolism [22], the risk of AKI after fluid resuscitation [23], and outcomes in hyperglycemic patients [24].Trauma patients often are exposed to multiple risk factors for AKI, including hypovolemic shock, invasive surgery, blood transfusions, and systemic inflammation. Indeed, greater injury severity is an independent risk factor for the development of AKI [25]. Furthermore, patients in the trauma ICU may have more exposure to nephrotoxic agents such as vasopressors, IV contrast, and loop diuretics than the cohort in the study by Rutter et al. Although trauma patients tend to be younger with fewer co-morbidities than general medicine patients, trauma ICU patients are at particularly higher risk for AKI because of both trauma-related and pharmacologic insults.

In addition, trauma patients may be at high risk for AKI because of the type of infections they develop, and the antibiotic regimens used to treat them. Trauma ICU patients have significantly higher rates of nosocomial infections than surgical ICU patients (11.6% versus 6.4%; p < 0.001) [26]. Nosocomial pathogens tend to have greater antimicrobial resistance, greater virulence, and higher associated mortality rates than community-acquired pathogens [26,27]. Trauma patients often are treated with broad-spectrum antibiotics for longer durations and thus experience greater nephrotoxicity. Many previous studies have been conducted, predominately in the non-critically ill population, but one large retrospective cohort study compared AKI in 2,492 ICU patients treated with vancomycin and VPT compared with patients who received vancomycin alone, VC, or VM [28]. However, their study population was focused on medical and surgical ICU patients, not trauma ICU patients.

The practical significance of these present findings is that trauma ICU patients with changing clinical parameters should have early cultures so that targeted antibiotic therapy is achieved quickly. If organisms are susceptible to both cefepime and meropenem, we suggest that dual therapy with VC confers less risk of AKI development than VM.

One potential confounding factor is the fact that the average maximum vancomycin trough concentration was slightly higher in the VM group (16 versus 13 mcg/mL; p = 0.05). Supra-therapeutic vancomycin trough concentrations are generally, but not universally, considered a risk factor for AKI [29]. However, on multi-variable analysis, a higher maximum vancomycin trough concentration and supra-therapeutic trough concentrations were not correlated with the risk of AKI. Thus, although the groups were inadequately matched on the basis of vancomycin trough concentrations, this was not associated with AKI. Furthermore, given that vancomycin is secreted renally, it is difficult to distinguish whether elevated vancomycin trough concentrations contribute to the development AKI or if AKI from other causes leads to reduced renal clearance and accumulation of vancomycin [29,30].

The limitations of this study include those inherent in its retrospective design; only correlation, not causation, can be demonstrated. Furthermore, any retrospective study is subject to potential selection bias. Patients received VM or VC on the basis of a complex risk:benefit analysis by the treatment team, the hospital's particular antibiogram, as well as clinician preference. To minimize the contribution of this bias, multi-variable analysis was performed to account for risk factors considered to impact the incidence of AKI, including age, gender, race, co-morbidities, baseline SCr, vancomycin dosage, duration of antibiotic exposure, and nephrotoxic exposure. Additionally, we were unable to obtain the accuracy of initial antibiotic coverage with culture results to determine if one group was infected with more resistant organisms, which could confound the results. However, we did compare the exposure to multiple organisms in both groups and found that they had similar incidences of pathogens and types of infection. Lastly, all potentially confounding nephrotoxic agents were weighted equally, and exposure to other nephrotoxins was defined as a binary variable. This dichotomy does not account for the dose of the agent received or the length of exposure, both of which may influence the degree of AKI risk. We demonstrated previously that augmented renal clearance occurs in more than half of all high-risk trauma ICU patients and is underestimated by standard clinical equations [31]. Unfortunately, we were unable to collect 24-hour creatinine clearance in all patients to determine how augmented renal clearance affects the risk of AKI in patients receiving VC or VM combination therapy.

Despite its limitations, this is the first study to demonstrate that, in a population of vulnerable trauma ICU patients, receipt of VM is associated with a four times higher risk of AKI compared with receipt of VC. We therefore recommend caution when using VM combination therapy, especially in populations at high risk for AKI. Furthermore, we recommend early de-escalation of antibiotics according to culture results and tailored therapy according to hospital antibiograms.

Footnotes

Acknowledgments

This study was supported with funds from the Daughtry Family Department of Surgery, Divisions of Trauma, Burns, and Surgical Critical Care, University of Miami Miller School of Medicine

KGP had full access to all the data and takes responsibility for the accuracy of the analysis. Other contributions: Study concept and design: MBM and NN. Acquisition, analysis, or interpretation of data: MSS, MBM, and KGP. Drafting of the manuscript: MSS and KGP. Critical revision of the manuscript for important intellectual content: ELR, HML, CIS, SAE, AB, GAL, and EMU. Statistical analysis: MSS. Administrative, technical, or material support: NN. Study supervision: NN and KGP.

SriGita Madiraju, BS, Gina Riggi, PharmD, BCPS, BCCCP, and Douglas E. Houghton, ARNP were instrumental in patient identification and data acquisition for this study.

*Portions of these data were presented in abstract form at the 48^th Critical Care Congress, San Diego, CA February 2019 and published in Crit Care Med 2019;47(Supp 1):297.

Author Disclosure Statement

None of the authors reports a material or intellectual conflict of interest.

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