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Comparison of the incidence of acute kidney injury during treatment with vancomycin in combination with piperacillin–tazobactam or with meropenem Majed S. Al Yami a,b,∗ a b
King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia The University of Arizona, College of Pharmacy, Tucson, USA
a r t i c l e
i n f o
Article history: Received 19 July 2016 Received in revised form 17 October 2016 Accepted 18 November 2016 Keywords: Acute kidney injury Nephrotoxicity Vancomycin Piperacillin–tazobactam Meropenem
a b s t r a c t The purpose of this study was to evaluate the observed incidence of acute kidney injury (AKI) in adult patients receiving either piperacillin–tazobactam (PT) and vancomycin or meropenem and vancomycin for at least 48 h. In this retrospective cohort study, we included adult patients with no known renal dysfunction who received either the combination of PT-vancomycin or meropenem–vancomycin for at least 48 h. The study’s primary outcome was the incidence of acute kidney injury (AKI), defined by the Kidney Disease: Improving Global Outcomes (KDIGO) in patients with baseline normal renal function as an increase in serum creatinine (Scr) by ≥0.3 mg/dl within 48 h. A total of 183 patients were evaluated for AKI. The incidence of AKI was higher but not statistically different in the PT-vancomycin group (7.41%) compared with the meropenem–vancomycin group (5.33%). This study was not able to detect a statistically significant difference in AKI between the two treatment groups. A larger prospective study is warranted. © 2017 The Author. Published by Elsevier Limited. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction The development of acute kidney injury (AKI) is associated with poor outcomes in hospitalized patients, with increased morbidity and mortality in these patients [1,2]. Drugs are among the most common causes of AKI in both hospital and community settings. Risk factors for drug-induced AKI include underlying renal disease, diabetes, hypotension, sepsis, volume depletion, human immunodeficiency virus and advanced age [3]. Vancomycin is a glycopeptide antibiotic that has been used in clinical practice for more than fifty years. It is commonly prescribed to treat Gram-positive infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA). The use of vancomycin alone has been associated with a 5%–43% incidence of AKI [3,4]. Piperacillin–tazobactam (PT), an antipseudomonal -lactam/ lactamase inhibitor antibiotic is frequently used in combination with vancomycin for empiric therapy in hospitalized patients. According to PT’s manufacturer, the product has a less than 1% incidence of AKI [5]. However, published data have shown a higher rate of AKI when PT is used alone (11%) or in combination with vancomycin (16%–49%) [6–10].
∗ Tel.: 857 4882525. E-mail address:
[email protected]
Meropenem is a carbapenem antibiotic that is also used concomitantly with vancomycin as part of an empiric broad spectrum antibiotic regimen. According to its manufacturer, the incidence of AKI in patients receiving meropenem is less than 1% [11]. However, there are limited data regarding the incidence of AKI when meropenem is used in combination with vancomycin. Purpose, hypotheses, and rational We compared the observed incidence of AKI between PTvancomycin and meropenem–vancomycin in adult patients without documented impaired renal function. To our knowledge, no retrospective studies have evaluated the effect of meropenem on kidney function when used in combination with vancomycin. We hypothesize that the incidence of AKI in patients receiving meropenem-vancomycin is less than that in patients receiving PTvancomycin. Methods Study setting This study was conducted at two hospitals: Banner-University Medical Center Tucson, a 479-bed tertiary academic hospital and Banner-University Medical Center South, a 245-bed academic med-
http://dx.doi.org/10.1016/j.jiph.2016.11.007 1876-0341/© 2017 The Author. Published by Elsevier Limited. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
Please cite this article in press as: Al Yami MS. Comparison of the incidence of acute kidney injury during treatment with vancomycin in combination with piperacillin–tazobactam or with meropenem. J Infect Public Health (2017), http://dx.doi.org/10.1016/j.jiph.2016.11.007
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Table 1 Comparison of clinical characteristics and outcomes.a Characteristics
PT-vancomycin (n = 108)
Vancomycin–meropenem (n = 75)
p
Mean ± S.D. age, yr Male, no. (%) Mean ± S.D. weight, kg Mean ± S.D. vancomycin trough concentration Mean ± S.D. Scr at start of antibiotics Mean ± S.D. Scr at 48 h Mean ± S.D. estimated Clcr at baseline, ml/min Critically ill patients, no (%) Systemic infection
52.4 ± 17.29 71 (65.74) 84 ± 21.2 15.7 ± 9.2 0.8 ± 0.2 0.8 ± 0.4 100.6 ± 37.6 19 (17.6) 35 (32.4)
54 ± 18.46 50 (66.67) 77.9 ± 23.9 16.9 ± 8.6 0.8 ± 0.2 0.7 ± 0.3 98.8 ± 41.6 13 (17.3) 27 (36)
0.7 0.5 0.03 0.8 0.3 0.1 0.3 0.56 0.36
Comorbidities Diabetes mellitus, no. (%) Heart failure, no. (%) Hypertension, no. (%) Malignancy, no. (%) Other comorbidities, no. (%) Diagnosis of sepsis, no. (%) Use of pressors, no. (%) Mean ± S.D. length of antibiotic treatment
19 (17.59) 7 (6.48) 44 (40.74) 19 (17.59) 93 (86.11) 21 (19.44) 13 (12) 4.36 ± 1.9
27 (36) 4 (5.33) 33 (44) 22 (29.33) 72 (96) 18 (24) 15 (20) 5.42 ± 3.0
0.004 0.5 0.38 0.04 0.02 0.2 0.1 0.9
Concomitant nephrotoxic drugs Contrast, no. (%) NSAID, no. (%) ACE inhibitor, no. (%) Aminoglycosides, no. (%)
45 (41.67) 14 (12.96) 9 (8.33) 0
24 (32) 4 (5.33) 7 (9.33) 0
0.12 0.07 0.5 –
Antibiotic indication, no. (%) Bacteremia, no. (%) Skin and soft tissue infection, no. (%) Respiratory tract infection, no. (%) Intra-abdominal infection, no. (%) Urinary tract infection, no. (%) Empiric therapy, no. (%) Endocarditis, no. (%) CNS infection, no. (%) Bone and joint infection, no. (%) Neutropenic fever, no. (%)
3 (2.77) 20 (18.52) 37 (34.26) 5 (4.63) 3 (2.78) 32 (29.63) 0 0 8 (7.41) 0
1 (1.33) 7 (9.33) 24 (32) 3 (4) 3 (4) 14 (18.67) 1 (1.33) 2 (2.67) 8 (10.67) 12 (16)
. . .b ... ... ... ... ... ... ... ... ...
a b
Scr = serum creatinine, Clcr = creatinine clearance, NSAID = nonsteroidal anti-inflammatory drug, ACE = angiotensin-converting enzyme, CNS = central nervous system. Data unavailable.
ical center in Tucson, Arizona. This study was approved by the Human Subjects Protection Program Institutional Review Board (IRB) of the University of Arizona. Study design and population A retrospective cohort study was conducted, including eligible adult patients admitted to medical/surgical units and the medical/surgical intensive care units at the two hospitals between November 1, 2013 and November 30, 2014. Data obtained from the electronic health record system Epic were reviewed and analyzed for each patient. Patients were included in the study if they were at least 18 years of age, had a baseline Scr within 24 h of admission, and had received either PT-vancomycin or meropenem–vancomycin for at least 48 h. Patients were excluded if they were currently receiving renal replacement therapy or if they had a history of underlying renal dysfunction (defined as a serum creatinine > 1.5 mg/dl, structural kidney disease, or post-kidney transplant). Study endpoint The primary outcome measured in this study was the incidence of AKI, defined by the Kidney Disease: Improving Global Outcomes (KDIGO) in patients with baseline normal renal function as an increase in Scr by ≥0.3 mg/dl within 48 h. Statistical analysis A sample size of 180 (90 patients in each arm) was required to achieve a statistical power of 80% based on the estimates
of a 25% rate of AKI in the PT-vancomycin group and 10% in the meropenem–vancomycin group. Descriptive and demographic categorical variables were compared using Fisher’s exact test. Continuous outcome variables were compared using an unpaired Student’s t-test. A p value of less than 0.05 was considered statistically significant. STATA 14.0 (StataCorp, College Station, TX) was used for statistical analyses. Results 183 patients met the inclusion criteria and were included in the study (108 in the PT-vancomycin group and 75 in the meropenem–vancomycin group). Overall, patients who received PT-vancomycin had a higher mean body weight compared to those who received meropenem–vancomycin. Table 1 summarizes the baseline demographic characteristics of the two groups. There was a comparable proportion of critically ill patients in both groups. There was no significant difference in the rate of systemic infection vs organ related infection in both groups. There was no significant difference between the two groups in terms of comorbidities, such as heart failure and hypertension. However, the meropenem–vancomycin group included more patients with diabetes mellitus and malignancy compared with PT-vancomycin group. No significant differences were found between the two groups in terms of the use of concomitant nephrotoxic agents (e.g., ACE inhibitors, intravenous radiocontrast, NSAIDS or aminoglycosides). Between the two groups, no significant differences were observed in the mean estimated creatinine clearance Clcr at baseline, mean vancomycin trough concentration, mean Scr, Scr at 48 h, and number of treatment days. In the PT-vancomcin group, 8 of
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108 (7.41%) patients developed AKI, compared to 4 of 75 (5.33%) patients in the meropenem–vancomycin group (p = 0.4). In the PTvancomcin group 1 of 19 critically ill patients (5.3%) developed AKI compared with 2 of 13 critically ill patients (15.4%) in the meropenem–vancomycin group (p = 0.36). Furthermore, the rate of AKI in patients who had systemic infection vs organ related infection was 8.5% in the PT-vancomcin group compared with 3.7% in the meropenem–vancomycin group (p = 0.41).
Discussion Several observational studies have evaluated the incidence of AKI in patients receiving vancomycin alone or in combination with PT [6–10,12,13]. However, the incidence of AKI when using vancomycin in combination with meropenem is not well studied. We found that the incidence of AKI was higher but not statistically different in patients receiving PT-vancomycin compared to patients receiving meropenem–vancomycin. The rate of AKI in patients receiving meropenem–vancomycin observed in this study (5.33%) is higher than the rate of AKI reported in the literature for patients receiving meropenem alone (1%) [11]. To our knowledge, this study provides the first retrospective report of the increased risk of AKI when using vancomycin in combination with meropenem. A previous retrospective study evaluated 139 diabetic patients with osteomyelitis but found no significant difference in the rates of AKI in patients who received PT-vancomycin or vancomycin–cefepime (29.3% vs 13.3%, p = 0.099) [6]. A recent retrospective study of critically ill patients conducted by Hammond et al. failed to show a significant difference in the rates of AKI in patients who received PTvancomycin or vancomycin–cefepime (32.7% vs 28.8%, p = 0.647) [12]. Recently, Vincent et al. enrolled 87 adult patients in a prospective study in a community academic medical center [13]. The observed rate of AKI was higher in patients who received the combination of PT-vancomycin (37.3%) versus those who received the combination of cefepime or meropenem and vancomycin (7.7%). Furthermore, Gomes et al. conducted a retrospective study to compare the incidence of AKI during treatment with vancomycin in combination with either PT or cefepime [7]. The difference in incidence of AKI was significantly higher in patients who received PT-vancomycin than in those who received cefepime–vancomycin (36.4% vs. 10.9%, p = 0.003). Burgess and Drew conducted a retrospective cohort study to compare the incidence of drug-induced nephrotoxicity in hospitalized patients treated with vancomycin alone and in combination with PT [8]. Nephrotoxicity was observed in 8.01% and 16.30% of patients in the vancomycin alone and combination groups, respectively (p = 0.041). Min et al. compared the incidence of AKI in surgical ICU patients during treatment with vancomycin alone or in combination with PT [9]. A higher rate of AKI was observed in the combination group than in the vancomycin alone group (40.5% vs. 9.0%, p ≤ 0.001). Meany et al. conducted a retrospective cohort study to predict the prevalence of vancomycin associated nephrotoxicity in adult internal medicine patients [10]. AKI occurred in 17 (13.6%) patients, and concomitant use of vancomycin with PT was associated with increased nephrotoxicity (adjusted odds ratio of 5.36, 95% CI 1.41–20.5). Compared to previous studies, our study did not find any statistically significant differences in the rates of AKI in patients receiving vancomycin in combination with PT or with meropenem. However, the rates of AKI in our study fall within the reported range of vancomycin-induced nephrotoxicity (5%–43%) [3,4]. Our results are consistent with the results reported by Hammond et al. for critically ill patients. However, we had a heterogeneous population including both internal medicine patients and critically ill patients, which may explain the lower rates of AKI in our study. It is well known that critically ill patients are at higher risk for developing AKI since they have
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impaired renal blood flow, which may alter vancomycin pharmacokinetics. Moreover, the definitions of AKI were not consistent among all the studies, which may contribute to the variations in the reported rates of AKI. It is not clear whether or not vancomycin alone can cause AKI. As delineated by Gupta et al., the incidence of nephrotoxicity with the use of vancomycin may vary based on the study, patient population, risk factors, and the definitions of nephrotoxicity [14]. In the literature, it has been proposed that vancomycin can cause AKI via direct oxidative stress and allergic interstitial nephritis [15]. On the other hand, little is known about the mechanism of AKI when vancomycin is used in combination with other antibiotics. It has been noted that PT delays renal recovery in critically ill patients with renal failure [16]. Few case reports have described the AKI induced by PT as an acute interstitial nephritis [17,18]. However, when vancomycin is used in combination with meropenem, the mechanism of AKI is not clear. The limitations of this study include the relatively small sample size. We assumed a sample size of 180 patients would be required to achieve a power of 80%. Thus, the study was underpowered, which may result in a type II error. Furthermore, the data were retrospectively extracted in a non-blinded fashion. The baseline characteristics were well matched, with few statistical differences in the baseline characteristics of weight, DM, and malignancy found between the two groups. Lastly, a heterogeneous patient population was evaluated, which may have contributed to our findings. In conclusion, our study was not able to detect a statistically significant difference in AKI between the two treatment groups. A large prospective study is warranted. Funding No funding sources. Competing interests None declared. Ethical approval Not required. References [1] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int 2012;2(Suppl):1–138. [2] Elyasi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol 2012;68:1243–55. [3] Van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter antimicrob. Agents Chemother 2013;57(2):734. [4] Carreno J, Kenney R, Lomaestro B. Vancomycin-associated renal dysfunction: where are we now? Pharmacotherapy 2014;34(12):1259–68. [5] Pfizer. Zosyn (piperacillin-tazobactam) package insert. Philadelphia, PA: Pfizer; 2012. [6] Moenster RP, Linneman TW, Finnegan PM, Hand S, Thomas Z, McDonald JR. Acute renal failure associated with vancomycin and beta-lactams for the treatment of osteomyelitis in diabetics: piperacillin/tazobactam compared to cefepime. Clin Microbiol Infect 2014;20(6):O384–9. [7] Gomes DM, Smotherman C, Birch A, Dupree L, Della Vecchia BJ, Kraemer DF, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin–tazobactam or cefepime. Pharmacotherapy 2014;34:662–9. [8] Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin–tazobactam. Pharmacotherapy 2014;34:670–6. [9] Min E, Box K, Lane J, Sanchez J, Coimbra R, Doucet J, et al. Acute kidney injury in patients receiving concomitant vancomycin and piperacillin/tazobactam. Crit Care Med 2011;39:200 [abstract 714].
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[10] Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy 2014;34:653–61. [11] AstraZeneca. Merrem (meropenem) package insert. Wilmington, DE: AstraZeneca; 2014. Revised 2015 April. [12] Hammond DA, Smith MN, Painter JT, Meena NK, Lusardi K. Comparative incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin tazobactam or cefepime: a retrospective cohort study. Pharmacotherapy 2016;36:463–71. [13] Vincent P, Samantha S, Henry C. Prospective comparison of acute kidney injury during treatment with the combination of piperacillin–tazobactam and vancomycin versus the combination of cefepime or meropenem and vancomycin. Journal of Pharmacy Practice 2016, http://dx.doi.org/10.1177/0897190016628960, first published on February 23. [14] Gupta A, Biyani M, Khaira A. Vancomycin nephrotoxicity: myths and facts. Neth J Med 2011;69:379–83.
[15] Rybak M, Lomaestro B, Rotschafer J, Moellering R, Craig W, Billeter M, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66(1):82–98. [16] Jensen J, Hein L, Lundgren B, Bestle MH, Mohr T, Andersen MH, et al. Kidney failure related to broad-spectrum antibiotics in critically-ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open 2012;2(2):e000635. [17] Liu T, Lam J. Piperacillin–tazobactam-induced acute interstitial nephritis with possible meropenem cross-sensitivity in a patient with osteomyelitis. Am J Health Syst Pharm 2012;69(13):1109. [18] Pratt J, Stricherz M, Verghese P, Burke MJ. Suspected piperacillin tazobactam induced nephrotoxicity in the pediatric oncology population. Pediatr Blood Cancer 2014;61(12):366–8.
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