Comparison of the Nephrotoxicity of Vancomycin In

AOPXXX10.1177/1060028018757497Annals of PharmacotherapyMullins et al research-article7574972018

Research Report

Annals of Pharmacotherapy 2018, Vol. 52(7) 639–644 Comparison of the Nephrotoxicity © The Author(s) 2018 Reprints and permissions: sagepub.com/journalsPermissions.nav of Vancomycin in Combination DOI:https://doi.org/10.1177/1060028018757497 10.1177/1060028018757497 With Cefepime, Meropenem, or journals.sagepub.com/home/aop Piperacillin/Tazobactam: A Prospective, Multicenter Study

Brandon P. Mullins, PharmD1, C. Joseph Kramer, PharmD2, Billie J. Bartel, PharmD3, Jennifer S. Catlin, PharmD4, and Richard E. Gilder, RN-BC, MS2

Abstract Background: Patients often receive broad-spectrum antibiotics for nosocomial infections commonly with activity against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Previous retrospective and/or single-center studies have suggested that the combination of vancomycin and piperacillin/tazobactam might be associated with an increased risk of acute kidney injury. Objectives: To compare the incidence of nephrotoxicity in patients receiving intravenous vancomycin in combination with cefepime, meropenem, or piperacillin/tazobactam. Methods: This was a prospective, multicenter observational study of patients receiving vancomycin in combination with piperacillin/tazobactam versus cefepime or meropenem. Adult patients 18 years of age or older who were hospitalized and received 72 or more hours of intravenous vancomycin and 72 hours or more of cefepime, meropenem, or piperacillin/tazobactam were eligible. Patient and medication characteristics were examined for the 242 patients included. Results: The incidence of acute kidney injury for patients treated with vancomycin and piperacillin/tazobactam was significantly higher than for those treated with vancomycin and cefepime or meropenem, 29.8% versus 8.8%, respectively, P < 0.001. Binary logistic regression demonstrated that patients receiving vancomycin and piperacillin/tazobactam were 6.7 times more likely to develop acute kidney injury compared with the other cohort. Conclusions: The combination of vancomycin with piperacillin/tazobactam significantly increases the risk of acute kidney injury compared with other broad-spectrum antibiotic combinations. Clinicians should be vigilant when employing this regimen.

Keywords vancomycin, nephrotoxicity, antibiotics, beta-lactams, cephalosporins

Background trend is likely to continue and it is important to ensure that all safety concerns with these agents are fully understood. Empiric antimicrobial coverage for health care–related Until recently, acute kidney injury (AKI) was not a infections typically includes multiple broad-spectrum anti- major concern when selecting between anti-pseudomonal biotics, specifically those with activity against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus 1St Luke’s Hospital, Chesterfield, MO, USA 1,2 2Baylor Scott and White Research Institute, Dallas, TX, USA aureus, as well as other likely pathogens. Choice of which 3 agents to use depends on several factors including local sus- Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA ceptibility patterns as well as patient-specific characteristics 4CoxHealth Medical Centers, Springfield, Missouri, MO, USA (ie, recent history of antibiotic use and drug allergies). In the previous decade, antibiotic use has increased 36%, with Corresponding Author: Brandon P. Mullins, St Luke’s Hospital, 232 S Woods Mill Road, the largest increases seen with broad-spectrum penicillins, Chesterfield, MO 63017, USA. 3 cephalosporins, flouroquinolones, and carbapenems. This Email: [email protected] 640 Annals of Pharmacotherapy 52(7)

beta-lactams; however, recent literature has raised con- vancomycin in combination with cefepime, meropenem, or cerns about the potential AKI occurrence with piperacil- PT. This study was conducted at 4 medical centers around lin/tazobactam (PT) in combination with vancomycin. the United States (see the appendix for full list of participat- Vancomycin nephrotoxicity is a well-documented concern ing institutions). The study was approved by all institutional that has persisted since the drug’s introduction, but cases review boards of the participating institutions before collec- are generally mild and reversible.4 Many risk factors for tion of data. The primary objective of this study was to vancomycin-induced nephrotoxicity exist: prolonged determine if there is a difference in the incidence of AKI in treatment duration, vancomycin concentrations >15 mg/L, patients receiving a combination of IV vancomycin with PT use of concurrent nephrotoxic agents, and certain host fac- versus meropenem or cefepime. For the purposes of this tors (history of AKI, chronic kidney disease [CKD], and investigation, the definition of AKI is a minimum 1.5-fold admission to the intensive care unit).4 increase in serum creatinine (SCr; baseline vs maximum Previously, 3 retrospective studies were published exam- within first 7 days of antimicrobial therapy) similar to pre- ining the correlation of AKI in conjunction with PT or vious studies.5-7 Secondary objectives were to determine if cefepime. In one study of patients treated for osteomyelitis, the presence of the following risk factors increased the inci- Moenster and colleagues5 reported the incidence of AKI for dence of AKI for patients receiving the above-mentioned vancomycin + PT (VPT) and vancomycin + cefepime (VC) antibiotic combinations: intensive care unit admission, con- to be 31.2% and 19.5%, respectively, but this difference comitant use of nephrotoxic agents (see the appendix), age was not statistically significant. In another retrospective ≥65, certain comorbid disease states (see the appendix), or study, it was found that VPT patients had a 34.8% incidence vancomycin trough concentrations ≥15 mg/L. All partici- of AKI compared with only 12.5% of VC patient (95% con- pating institutions used a 4-hour extended-infusion of PT fidence interval [CI] 1.89-7.39, P < 0.0001).6 Last, a third rather than standard intermittent infusion of 30 minutes. study published looked at patients receiving vancomycin with and without PT and reported that patients in their study Participants who were receiving VPT were almost 2.5 times more likely to develop AKI than those patient receiving vancomycin Adult patients 18 years of age or older who were hospital- alone (95% CI >1.11, P = 0.032).7 ized and received 72 or more hours of IV vancomycin and While this study was being conducted, 3 additional pub- 72 hours or more of cefepime, meropenem, or PT were eli- lications were found examining this subject. A single-center, gible for inclusion into this study (antibiotics must overlap retrospective study examining VPT versus VC in critically for at least 48 hours). Patients were excluded from the study ill patients conducted by Hammond and colleagues8 did not if they had a documented history of CKD (K/DOQI stage 3 find a difference in the rates of AKI (VPT 32.7% vs 28.8%, or higher), baseline SCr ≥ 1.5 mg/dL, or AKI at any time P = 0.761). Likewise, a meta-analysis of 10 studies of van- during their hospital stay prior to receipt of study antibiotics comycin versus VPT and 5 studies of VPT versus vancomy- (defined as creatinine clearance [CrCl] < 30 mL/min via cin combined with another beta-lactam found similar Cockroft-Gault or a 1.5-fold increase in SCr or greater). If results.9 Vancomycin alone had lower rates of AKI com- at any time a random or trough vancomycin concentration pared with VPT (odds ratio [OR] 3.980, P < 0.001) but the was measured <10 mg/L before discontinuation of therapy comparison of VPT versus vancomycin + beta-lactam had the patient was excluded as this does not represent an ade- similar rates of AKI (OR 3.029, P = 0.063). Last, a small, quate steady-state vancomycin regimen. Additionally, if a single-center study compared VPT with VC or vancomycin patient switched from one stratification of antibiotics to + meropenem (VM), similar to our study, and found the another or if they received any dose of the study antibiotics rates of AKI for VPT to be 37.3% versus 7.7% for the VC/ between hospital admission and enrollment into the study VM group, P = 0.005.10 they were excluded. Furthermore, if a patient suffered car- Based on the conflicting results of the aforementioned diac arrest before initiation of antimicrobials they were studies and the uncertainties that remain with certain broad- excluded. spectrum antibiotic combinations, this prospective study was designed to compare the incidence of AKI in patients Data Collection receiving intravenous (IV) vancomycin in combination with cefepime, meropenem, or PT. The following patient information and laboratory values were recorded from the electronic medical records of the participating institutions: age, gender, weight, height, con- Methods comitant nephrotoxic agents, comorbid disease states, Study Design and Outcomes Charlson Comorbidity Index, dosing regimen and duration of specified antibiotics, SCr concentrations (initial and max- This was a prospective, multicenter observational study imum), vancomycin concentrations (trough and random), examining the incidence of AKI in patients receiving IV hospital unit, length of hospital stay, incidence of renal Mullins et al 641 replacement therapies (RRT), time to resolution of AKI, pri- Table 1. Justification for Exclusiona. mary infection site, if sepsis type of sepsis (not indicative of n primary site of infection), and SCr at day of hospital discharge or last measured SCr. Vancomycin concentrations CKD 3 or higher 139 obtained before steady state (before fourth scheduled dose) Baseline SCr 1.5 mg/dL or higher 32 or trough concentrations drawn >2 hours before the next Baseline CrCl <30 ml/min 33 scheduled dose were regarded as random concentrations. If AKI before antibiotics 103 a steady-state trough concentration was obtained between 2 [Vancomycin] <10 mg/L 91 and 1 hours prior to the next scheduled dose the value was Antibiotic switch 59 extrapolated using population-based pharmacokinetic equa- Prior receipt of study drug 31 tions (see the appendix). Patients were followed from time Cardiac arrest prior to antibiotics 2 of inclusion until hospital discharge. No vancomycin concentration 8 Total 498 Statistical Analysis Abbreviations: CKD, chronic kidney disease; SCr, serum creatinine; CrCl, creatinine clearance; AKI, acute kidney injury. a To detect a 10% difference in the incidence of AKI between Data are from total number of patients. VPT and VC or (VM) groups, a sample size of 540 patients (270 in each arm) was estimated to achieve a statistical Table 2. Baseline Patient Characteristics. power of 80% based on the estimates of a 25% risk of AKI VC/VM in the VPT group and 15% AKI in both the VC and VM Characteristica VPT (n = 94) (n = 148) P Value groups. Chi-squared or Fisher exact test were used for differences in nominal data. Comparisons between continuous Age (years) 67.1 ± 1425 65.1 ± 15.18 0.883 data were performed using Student’s t test, median test, or Male gender (%) 60.6 (57/94) 71.4 (80/148) 0.314 Mann-Whitney U test, as appropriate. A multivariate analy- Height (cm) 170 ± 18.74 171.4 ± 10.73 0.692 sis was performed to determine if certain characteristics or Weight (kg) 91.3 ± 38.66 87.4 ± 27.10 0.736 medications were independent risk factors for development Baseline SCr (mg/dL) 0.86 ± 0.20 0.84 ± 0.23 0.305 of AKI. The Type I error (α) probability is 0.05. A P value Baseline CrCl (mL/min) 77.3 ± 29.44 80 ± 34.08 0.769 ICU (%) 34 (32/94) 41 (61/148) 0.263 of 0.05 or less was considered statistically significant for PMH diabetes (%) 37.2 (35/94) 33.1 (49/148) 0.511 the purposes of this study. A prespecified subgroup analysis PMH COPD (%) 30.9 (29/94) 35.1 (53/148) 0.491 was performed of patients in the VPT arm to identify any PMH CHF (%) 23.4 (22/94) 18.2 (27/148) 0.33 additional risk factors for developing AKI. A preplanned PMH CAD (%) 35.1 (33/94) 31.8 (47/148) 0.589 interim analysis at 200 patients was conducted to surveil for PMH PVD (%) 12.8 (12/94) 12.2 (18/148) 0.89 an overwhelming difference or no difference between CCI 2.9 ± 1.92 2.6 ± 1.80 0.182 cohorts based on previous reports. This was done to ensure no further delay of potentially significant results would Abbreviations: VPT, vancomycin + piperacillin/tazobactam; VC, ensue. vancomycin + cefepime; VM, vancomycin + meropenem; SCr, serum creatinine; CrCl, creatinine clearance; ICU, intensive care unit; PMH, past medical history; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; CAD, coronary artery disease; PVD, Results peripheral vascular disease. aData are mean ± SD values unless otherwise indicated. Between December 2014 and August 2016, 740 patients were screened for inclusion into the study, of which 242 patients were included. Ninety-four patients received VPT Table 3. Primary Site of Infection. and 148 received either VM (47) or VC (101). A total of 498 patients were excluded mostly due to having baseline CKD Site of Infection VPT (n = 94) VC/VM (n = 148) P Value stage 3 or higher or development of AKI before initiation of Blood (%) 3.2 (3/94) 6.8 (10/148) 0.231 antimicrobials (Table 1). There were no differences in Intraabdominal (%) 8.5 (8/94) 4.1 (6/148) 0.148 Charlson Comorbidity Index or any other baseline charac- Osteomyelitis (%) 1.1 (1/94) 2 (3/148) 1.000 teristics between patient groups (Table 2). During a pre- Other (%) 4.3 (4/94) 9.5 (14/148) 0.133 specified interim analysis, there was a significant difference Respiratory (%) 60.1 (57/94) 60.8 (90/148) 0.979 between the 2 groups for the primary outcome, and thus, Skin (%) 20.2 (19/94) 15.5 (23/148) 0.350 patient enrollment was stopped before the target sample UTI (%) 2.1 (2/94) 1.4 (2/148) 0.643 size was reached. Abbreviations: VPT, vancomycin + piperacillin/tazobactam; VC, Most patients in the study were being treated for respira- vancomycin + cefepime; VM, vancomycin + meropenem; UTI, urinary tory infections or skin and skin structure infections (Table 3). tract infection. 642 Annals of Pharmacotherapy 52(7)

Table 4. Sepsis Type If Present. Table 6. Concomitant Nephrotoxic Agents.

Sepsis Category VPT (n = 94) VC/VM (n = 148) P Value Medication (%) VPT (n = 94) VC/VM (n = 148) P Value None (%) 60.6 (57/94) 64.1 (94/148) 0.577 ACEI/ARB 29.8 31.8 0.777 Sepsis (%) 25.5 (24/94) 20.3 (31/148) 0.338 Acyclovir 1.1 2 1.000 Severe sepsis (%) 8.5 (8/94) 8.8 (13/148) 0.941 Aminoglycosides 1.1 1.4 1.000 Septic shock (%) 5.3 (5/94) 6.8 (10/148) 0.651 Amphotericin B 0 0.7 1.000 Calcineurin inhibitor 0 3.4 0.160 Abbreviations: VPT, vancomycin + piperacillin/tazobactam; VC, IV contrast 44.8 37.2 0.282 vancomycin + cefepime; VM, vancomycin + meropenem. IV immunoglobulin 0 0.7 1.000 Loop diuretic 50 50.7 1.000 Table 5. Vancomycin Characteristicsa. NSAID 8.5 11.5 0.404 Sulfonamide 2.1 3.4 0.709 VPT VC/VM Vasopressors 7.5 11.5 0.380 Characteristic (n = 94) (n = 148) P Value Abbreviations: VPT, vancomycin + piperacillin/tazobactam; VC, Median individual dose (mg) 1250 1250 0.598 vancomycin + cefepime; VM, vancomycin + meropenem; ACEI, Duration of Tx (hours) 131.7 153.7 0.681 angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor Minimum trough (mg/L)b 16.3 15.2 0.180 blocker; NSAID, nonsteroidal antiinflammatory drug. Maximum trough (mg/L) 19.6 18.9 0.619 mg/kg/dose 14.9 15.0 0.895 those who received VC or VM (OR 6.65, 95% CI 2.79- mg/kg/day 29.1 29.7 0.692 15.84, P < 0.001). Additionally, patients receiving loop Abbreviations: VPT, vancomycin + piperacillin/tazobactam; VC, diuretics (OR 3.27, 95% CI 1.42-7.53, P = 0.005) or vaso- vancomycin + cefepime; VM, vancomycin + meropenem. pressors (OR 5.04, 95% CI 1.66-15.35, P = 0.004) were aData are mean values unless otherwise indicated. b also at increased risk of developing AKI. Last, any patient Trough concentrations at steady state. with a maximum vancomycin trough >30 mg/L was also at increased risk of AKI (OR 13.33, 95% CI 3.13-56.77, P < Just over a third of patients (37.2%) had a diagnosis of sepsis 0.001). Other variables analyzed were not found to be asso- (90/242). Of those that did, 22.3% (54/242) had sepsis and ciated with the development of AKI. 14.9% (36/242) had a diagnosis of either severe sepsis or sep- A prespecified subgroup analysis of the 94 patients tic shock (Table 4). Vancomycin dose and duration were receiving VPT showed 3 significant risk factors for the comparable between groups. Both the minimum and maxi- development of AKI. Patients receiving VPT plus either a mum trough concentrations were similar between groups loop diuretic (42.5%, P = 0.012) or vasopressors (85.7%, (Table 5). There was no difference in the incidence of con- P = 0.003) had a further increased risk of AKI occurrence. comitant nephrotoxic agents between groups (Table 6). Additionally, VPT patients that had a maximum trough The incidence of AKI for patients in the VPT group was value ≥30 mg/L also had the same increased risk (100%, 29.8% (28/94) versus 8.8% (13/148) in the VC/VM group, P = 0.024); however, this only encompassed 3 patients. P < 0.001. When analyzing the combined treatment arm VC/VM separately compared with VPT the same difference Discussion was seen for VPT versus VC (29.8% vs 5.9%; P < 0.001). There was no statistical difference in the incidence of AKI This was the first prospective, multicenter study exploring between VPT and VM (29.8% vs 14.9%, P = 0.054). differences in the development of AKI between patients The maximum mean recorded SCr was higher in the receiving VPT and VC/VM. Like other studies, VPT was VPT group compared with the VC/VM group (1.4 mg/dL vs associated with an independent, increased risk of AKI, 1.0 mg/dL; P < 0.001). Of the 41 patients that developed which was further compounded by the concomitant use of AKI during treatment, 23 (56%) never returned to their loop diuretics, vasopressors, and, potentially, vancomycin baseline SCr. Of the 18 patients (44%) that did return to concentrations greater than 30 µg/mL. These risk factors baseline, the average time to baseline was 164 hours. Three seem to make logical sense and can be interpreted in a vari- patients in the VPT group required RRT while no patients in ety of ways given the difficulty in assessing the onset of the VC/VM group required RRT (P = 0.057). There was no injury and the delayed manifestation of kidney failure. It is difference in the length of stay between the 2 groups (12.2 unclear in our study whether the loop diuretics and vaso- days vs 13 days, P = 0.791). pressors were the cause of kidney injury, a signal of a more A binary logistic regression of the entire cohort was con- complex patient population, or more likely, a combination ducted to determine independent predictors of AKI. Patients of the two. While focusing on the associated toxicity of van- receiving VPT were at a higher risk of developing AKI than comycin concentrations, it is not clear whether elevated Mullins et al 643 vancomycin concentrations were causative of AKI or rather should consider using these methods to help delineate renal kidney injury that led to accumulation. damage risk and occurrence rates. The mechanism of observed nephrotoxicity with the The findings of our research, in addition to other previ- combination of VPT is still unclear, as is whether the com- ously published studies, should allow clinicians to clearly bination is truly nephrotoxic. While vancomycin has recognize the risks of using VPT as initial empiric antimi- clearly reported risk factors associated with the develop- crobial therapy. The decision of which anti-pseudomonal ment of AKI, PT is not as simple. In point of fact, one pub- agent to use is largely based on local susceptibility patterns, lished report evaluated rates of AKI with amikacin with or site of infection, and individual patient factors. Clinicians without piperacillin, and suggested a lower rate of AKI should incorporate these into the decision-making process with the combination than with amikacin alone.11 It is to adequately weigh risks and benefits for each patient. In unclear and needs further evaluation as to whether the this study, we did not include any patients with a history of combination of VPT itself is nephrotoxic or if piperacillin CKD stage 3 or higher or with ongoing AKI prior to enroll- and/or tazobactam enhances the already nephrotoxic poten- ment, but it might be prudent to avoid VPT combination tial of vancomycin. The previously reported data on this altogether for this group of patients. More important, it is topic unfortunately did not routinely evaluate the require- the opinion of these authors that early, broad-spectrum anti- ment of renal replacement therapy in this context. biotic use may be helpful in the management of severe Interestingly, 2 studies did report this and found lower rates infections, but commonly, indefinite combination therapy is of renal replacement therapy in the VPT group than in the rarely warranted. Thus, we recommend that clinicians control group.6,8 In the present study, all patients that employ appropriate culture-based and non–culture-based required renal replacement therapy (n = 3) were in the VPT organism identification techniques as soon as possible to cohort. Questions have also been raised regarding the accu- encourage antimicrobial deescalation and, thus, minimize racy of SCr in diagnosing AKI in this setting. As a competi- the risk of this particularly significant adverse event. tive inhibitor of tubular secretion, piperacillin can increase the accumulation of nephrotoxic drugs into the renal Conclusion tubules, as well as reduce the excretion of creatinine. This may raise questions about using SCr as a marker of AKI in Our data further substantiates that of earlier data to suggest this context; however, 56% of patients with AKI never an independent association between the combination of returned to baseline during the observation period, and VPT and AKI. We suggest that our data, along with other those that did return to baseline took, on average, 164 hours published data, should be used to guide clinicians in the to return to baseline, which may argue against tubular management of antibiotic selection. Keeping in line with secretion as a sole contributor. core measures and best practice statements from national Using a prospective, multicenter, observational design, organizations, empiric antibiotic selection should continue we attempted to enhance the strength and quality of this to be based on local susceptibility patterns and suspected study over previous retrospective and/or single-center sites of infection. Additionally, the focus should be primar- cohorts. A previously reported meta-analysis attempts to ily on reducing overall antibiotic exposure, and secondarily, remedy the limitations of the observational studies, but nat- a consideration should be made to select other combina- urally remains inadequate by inherent limitations of these tions of broad-spectrum antibiotics to avoid the toxic com- analyses within the larger model.9 There are also limitations bination of vancomycin and piperacillin/tazobactam. Last, within our analysis. A possible type II error exists in the the authors recommend daily monitoring of SCr, appropri- separate comparison of vancomycin and meropenem. Due ate antibiotic deescalation, and avoidance of identified con- to the study stopping early and the smaller amount of comitant nephrotoxins if possible. patients in the VM arm, it is possible that VM indeed does have a higher rate of nephrotoxicity, and we feel this should Appendix be explored further before coming to a conclusion. Controlling for the impact of AKI risk and patient complex- Concomitant nephrotoxic agents surveilled for the following: ity is imperfect, although we did evaluate Charlson Comorbidity Index and concomitant nephrotoxins, as in •• ACEIs/ARBs previous publications. Additionally, our study was not able •• Acyclovir to examine the mechanism behind the cause of nephrotoxic- •• Aminoglycosides ity and is an area for future research to pursue. Last, this •• Amphotericin B study does not answer the question of whether novel bio- •• Calcineurin inhibitors (cyclosporine, tacrolimus) markers, such as tissue inhibitor of metalloproteinase-2 and •• Colistin insulin-like growth factor binding protein-7, can assist in •• IV contrast antibiotic management decisions through measuring renal •• Intravenous immune globulin stress and damage before AKI develops. Future studies •• Loop diuretics 644 Annals of Pharmacotherapy 52(7)

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