Given the high frequency of infections in hospitalized patients caused by drug resistant pathogens, empiric broad spectrum antibiotic use will be common for the foreseeable future. In this retrospective study of non-critically ill inpatients, we found that compared to vanc monotherapy, the odds of AKI were over five times higher during combV/P therapy. We also found that odds of AKI were significantly lower for males during therapy with these antibiotics. These associations remained statistically significant in the multivariable analyses that included propensity scoring.

At the time of this study, there was a paucity of published data examining the incidence of AKI with combV/P therapy versus monotherapy with either agent, particularly in hospitalized patients who are not critically ill [18, 19]. Since we completed our analysis, however, two studies were published in 2014 that focused on this question in non-critically ill hospitalized patients [20, 21]. Each study incorporated definitions of AKI similar to ours and both also showed that combV/P was independently associated with AKI compared with vanc monotherapy. In the study by Burgess et al., 191 patients who had received treatment with vancomycin were analyzed. In a multivariable analysis, comb V/P was associated with an AKI odds ratio of 2.48 (p = 0.032) compared to vanc monotherapy. In the study by Meaney et al., 125 patients treated with vancomycin were analyzed. Again, comb V/P was associated with an AKI odds ratio of 5.36 (95 % CI 1.41–20.5) compared to vanc monotherapy in multivariate analyses. Our study provides further proof of this association and extends the finding to a setting in which patients are predominantly African-american. Our study provides additional evidence through a propensity score analysis that shows the same statistically significant AKI odds ratio associated with combV/P. While a randomized controlled trial would be ideal to evaluate such risks, propensity score analysis can provide an estimate of the likelihood of exposure based on demographics and other co-morbidities.

The mechanisms that could underpin AKI during combV/P are not clear at this time. Beta lactam agents, in particular penicillin derivatives, are purported to cause AKI through interstitial nephritis [22]. Interestingly, the study by Meaney et al. found that almost one-third of patients with AKI also had either eosinophilia or eosinophiluria. This may be additional evidence that AKI on combV/P may be in part immune mediated. It should be noted that there are conflicting reports on whether combV/P is more associated with AKI than the combination of vancomycin and cefepime and other cephalosporins [23, 24]. Therefore, AKI during combination therapy with vancomycin and beta-lactams may or may not be a class effect. Larger prospective studies are needed to more definitively address this question.

Our multivariable analysis showed that female patients were more likely to develop AKI during treatment with at least one of the two antimicrobials in the study. To our knowledge this finding has not been previously reported, but female gender has been identified as a risk factor for AKI in the most recent Kidney Disease Improving Global Outcomes (KDIGO) statement [25]. The mechanism for this is unclear, but based on our study clinicians should be aware that female inpatients may be at higher risk for AKI during treatment with vanc or piptazo. Unexpectedly, we found a trend for increased AKI odds with increasing creatinine clearance (by 10 ml/min increase). This association is counterintuitive but has also been found in at least two other studies of vancomycin nephrotoxicity which also used the Cockroft-Gault (CG) equation for estimate of renal function [21, 26]. Both antibiotics are dosed renally meaning that patients with higher CrCl are often given a higher dose of drug. This may have played a role in this finding. However, this association became statistically non-significant in the propensity score analysis. We also acknowledge that the CG equation is not considered the gold standard for measurement of renal function and has variability based on body surface area [27]. It would be ideal to measure glomerular filtration rate directly in order to gauge renal function, but the feasibility of accomplishing this in a large study is significantly lower.

We acknowledge the other limitations of our study. Propensity scoring is one way to compare the risks of exposure to drug (and thus can in some ways account for demographic and disease differences), but is not a perfect substitute for a randomized trial. For example, the lower odds of AKI associated with skin/soft tissue infection could be a reflection of less severe illness and may have influenced the finding of lower AKI odds in the vanc monotherapy group. While we attempted to account for illness severity in the multivariable analysis and propensity score analysis by including comorbidities and indication for antibiotics, we were not able to perform analyses of illness severity as measured by scores such as APACHE (Acute Physiologic Assessment and Chronic Health Evaluation) and other equations [28]. Ideally, prospective studies are necessary to address causality and a randomized clinical trial would be the most rigorous means to determine a causal treatment effect.

We also acknowledge the lack of collection of some data points, including duration of hospitalization. We also were not able to evaluate the potential role of vancomycin concentrations in this study of AKI. While very few patients in the group as a whole were given vancomycin dosing greater than the 4 g daily threshold that has been shown to be associated with AKI, we were not able to specifically analyze whether this was a risk factor for AKI at an individual level. We also did not analyze the data with respect to the companies that provided the drugs over the course of the study.

We did not assess the reversibility of AKI over time, but did find that there were no patients who required renal replacement therapy during the hospitalization. As with other recently published studies, we excluded patients who received antibiotics for less than 48 h [20, 21]. However, other study designs may have been appropriate, such as including all patients who had at least one dose of antibiotic. For the definition of AKI in our study, we chose to include the lowest level of injury defined by the RIFLE criteria as well as an additional criterion that has been advocated by some experts to define AKI. It is possible that the use of these two criteria was overly inclusive and that the results may have been different if a more stringent definition of AKI had been used. However, we believe that an inclusive definition was appropriate for this study given that even low levels of renal injury have been associated with poor clinical outcomes in hospitalized patients [14]. It is also possible that our definition of AKI was not inclusive enough. However, an exploratory analysis using a particularly inclusive measure of AKI also showed increased AKI in those on combV/P compared to vanc monotherapy.