VN + PT was associated with increased creatinine concentrations at day two and an increased rate of creatinine-defined AKI at day 14. In contrast, VN + PT was not associated with changes in Cys-C or BUN at day two. We further observed that VN + PT-associated AKI did not translate into higher dialysis or mortality rates. Taken together, these findings suggest that the association with AKI represents pseudotoxicity, and that avoidance of this essential antibiotic combination may be unwarranted.
To our knowledge, this is the first study of VN + PT to employ Cys-C as an alternative to creatinine, which allowed us to conduct the most direct mechanistic assessment of the VN + PT interaction in humans to date. Cys-C is a validated biomarker of kidney function that has a shorter half-life than creatinine . Thus, the absence of any discernable effect of VN + PT on Cys-C concentrations at day two suggests that the significant increases in creatinine over that time period were not associated with underlying changes in kidney function. VN + PT also showed no association with changes in BUN, an additional kidney biomarker that does not undergo tubular secretion. These consonant findings, as well as the consistency of BUN and creatinine analyses between the Cys-C subcohort and the full antibiotic cohort, suggest that the Cys-C results are not due to selection bias.
Both piperacillin and tazobactam are substrates for organic anion transporters that have been implicated in the tubular handling of creatinine (OAT1, OAT3) [11, 13, 14, 17, 18]. In addition, VN suppresses OAT1 and OAT3 expression [11, 15, 16]. Thus, competitive inhibition of creatinine secretion and VN-mediated transporter suppression seems a plausible mechanism of increased creatinine concentration . Our findings of isolated increases in creatinine that were not matched by changes in either Cys-C or BUN are consistent with this hypothesized mechanism. Our findings are also consistent with animal studies suggesting that PT does not enhance VN toxicity [6, 8,9,10], with some suggesting that PT may actually reduce VN nephrotoxicity. A caveat to the animal models is that, beyond demonstrating no adverse effect on kidney function, some have also shown that VN + PT does not increase creatinine concentrations [8, 9]. Nevertheless, regardless of mechanism, the data raise doubt that PT enhances VN-mediated nephrotoxicity.
Our analysis of Cys-C was limited to change over the first two days of treatment, which could miss potential delayed toxicity. However, Kaplan–Meier analysis suggests that VN + PT was associated with an excess of creatinine defined AKI events primarily during the first 2–3 days of treatment, in line with the significantly elevated average creatinine concentrations observed at day two. This pattern is consistent with inhibition of creatinine secretion, which would likely manifest shortly after drug initiation, as creatinine transporter inhibition happens rapidly. Given that cystatin C has a shorter half-life compared to creatinine, it seems unlikely that the early rise in creatinine reflects underlying parenchymal injury that would only manifest delayed Cys-C elevations. In addition, VN + PT was not associated with BUN changes through day-14. Taken together, these data suggest that the day two analysis of Cys-C captures the key time period during which VN + PT mediated its effects.
Based on the magnitude of creatinine change observed with other drugs affecting creatinine secretion (0.2–0.5 mg/dL) , creatinine-defined AKI via this mechanism should generally be associated with stage 1 episodes, reflecting relatively small increases in creatinine. We observed a substantially attenuated association between VN + PT and creatinine-defined AKI when analysis was restricted to stage 2 or higher AKI, and no association between VN + PT and patient centered outcomes such as dialysis or mortality, consistent with previous studies [45,46,47]. Schreier found no association between short courses of VN + PT and stage 2 or higher AKI, dialysis, or mortality at 60 days . Similarly, Buckley showed a significant association between VN + PT and stage 1 AKI, but not stage 2 or stage 3, dialysis, or mortality . Lastly, although Blevins et al. observed significant associations between VN + PT and all AKI stages, this did not translate into higher dialysis or mortality rates . In contrast, Cote observed a significant association between VN + PT and higher risk of dialysis . However, they examined dialysis events that occurred within 30 days of antibiotic initiation, regardless of antibiotic duration or the timing of AKI onset. Thus, it’s unclear whether dialysis initiation was attributable to drug exposure. Our study examined dialysis initiated within seven days of AKI events that occurred during antibiotic exposure, targeting events that could plausibly be attributable to drug exposure. In sum, the preponderance of evidence suggests that any potential interaction between VN + PT has limited impact on patient centered outcomes.
Only one other study has examined the VN + PT association with a biomarker other than creatinine. Kane-Gill et al. examined cell cycle arrest markers (tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 [TIMP-2]∙[IGFBP7]) in patients who received VN alone, PT alone, or VN + PT . They showed that urinary [TIMP-2]∙[IGFBP7] concentrations on the day after antibiotic initiation were higher for VN + PT vs. PT alone, but not different compared to VN alone. However, the analysis was not adjusted for baseline [TIMP-2]∙[IGFBP7] concentration . Moreover, it’s difficult to know whether the result represents an interaction between VN + PT, the effect of VN alone, or differences in underlying severity of illness between patients treated with monotherapy versus combination therapy.
Strengths of our study include the prospective study design, extensive confounding adjustment, and multiple imputation of missing data. Our study also has limitations. First, Cys-C concentrations can be affected by body mass index, corticosteroids, thyroid activity, cancer, diabetes mellitus, and solid organ transplant [25, 40]. We mitigated confounding from these factors through IPTW analysis. IPTW balances the distribution of these factors such that their effect would influence Cys-C to a similar extent in both groups. Second, we only had Cys-C concentrations for a subset of patients. However, we showed that the Cys-C subcohort had similar characteristics to the full antibiotic cohort, and supplemented Cys-C with analysis of changes in BUN concentration. Nevertheless, it is important to note that BUN changes can reflect factors other than kidney function; thus, the lack of association with BUN may reflect in part BUN’s low specificity for kidney function . Third, the cohort design is susceptible to confounding. We minimized confounding by comparing VN + PT to VN + CP, which is given for the same indication. We controlled for an extensive set of covariates and showed that our results were minimally changed by propensity score trimming, suggesting that confounding from propensity score misspecification is minimal. Further, because risk factors for mortality and AKI overlap substantially, and differences in effectiveness between PT and CP are unlikely  mortality can be viewed as a negative control outcome . Thus, our finding of a significant crude association between VN + PT and mortality that was nearly completely nullified in weighted analysis suggests that confounding was minimized. Fourth, there were missing data. We minimized missing data bias with multiple imputation, which allowed us to control for additional covariates such as albumin, lactate, and bilirubin that have generally been unaccounted for in studies of VN + PT and AKI. Fifth, we were unable to account for potential dilutional effects of fluid resuscitation. However, such dilution would be expected to impact creatinine, Cys-C, and BUN similarly. Sixth, we did not have urine output data (UOP). However, UOP data are often incomplete, and are susceptible to ascertainment bias, wherein UOP data are more often complete in patients with urinary catheters, which are typically placed in patients with high severity of illness. Seventh, given the low dialysis rate, our study was underpowered for this endpoint. Lastly, we included critically ill patients enrolled at a single center, which may limit generalizability. However, our replication of associations between VN + PT and creatinine suggest that our findings are not unique to our population.