Introduction
Vancomycin (VAN) is a glycopeptide antibiotic and is primarily utilized in the treatment of infections including bacteremia, infective endocarditis, osteomyelitis, pneumonia and intra-abdominal infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria.1 Piperacillin-tazobactam (TZP) exhibits broad-spectrum bactericidal activity against gram-negative bacteria and is indicated for moderate to severe infections such as community-acquired pneumonia, hospital-acquired pneumonia, urinary tract infections, skin and soft tissue infections, but it is ineffective against MRSA. Hence, the combination of both antibiotics covers a wide range of pathogens and empirical concomitant antimicrobial therapy of VAN and TZP (VPT) is recommended for most hospital-acquired infections, in order to cover Pseudomonas aeruginosa and MRSA. Clinically, this combination is also used in patients with febrile neutropenia2 as febrile neutropenic patients are at a high risk of life-threating bacterial infections.3 After decades of clinical use, it is well-recognized that VAN is related with an increasing risk of acute kidney injury (AKI). AKI stands as a significant healthcare challenge in contemporary medicine, with reported incidences ranging from 1% to 32% among hospitalized patients and 10% to 90% in intensive care unit (ICU) patients. The occurrence of AKI in hospitalized patients is associated with increased costs, prolonged hospital stays, and elevated rates of mortality and morbidity. TGF-β14 and interleukin-10 (IL-10) are key regulators of immune homeostasis.5 IL-10 plays a role in AKI caused by different aetiologies.6 Macrophage provide a role in TGF-β signalling in fibrosis after AKI.7 In addition, numerous factors influence the development and occurrence of AKI.
A summary of clinical studies included in the review were listed in Table 1. Since Hellwig T et al and Min E et al8,9 reported in 2011 that the co-administration of VPT leads to an increased risk of AKI, which was based on increases in serum creatinine, a plethora of studies on the subject of AKI due to concomitant of VPT therapy has emerged in recent years. While the initial reports faced scrutiny owing to potential biases in the study design, a consensus has emerged indicating a plausible elevation in the risk of AKI associated with the combined administration of VPT therapy. This consensus is grounded in a substantial body of evidence, although many of them were not high-quality, underscoring instances wherein patients undergoing VPT treatment exhibited heightened serum creatinine levels. As a result of these findings, certain clinicians may have opted to refrain from employing the combined therapeutic approach. Multiple clinical studies10–12 have reported that the risk of AKI can escalate to 31.7%~35% when VPT were administered in combination.13,14 This heightened risk persists with the prolonged co-administration of VPT over an extended duration (median duration approximately 1 month).15 As demonstrated in Figure 1, a forest plot was generated. The forest plot demonstrates the ascending order of odds ratios (OR) or hazard ratios (HR) for AKI associated with VPT regimens, revealing considerable variability in the risk conferred by VPT regimens across different studies.
|
Table 1 A Summary of Clinical Studies Investigating the Risk of AKI Induced by VTP Included in the Review
|
 |
Figure 1 Forest plot of ORs and HRs of AKI induced by VPT concomitant therapy. The forest plot demonstrates the ascending order of ORs or HRs with 95% CI for AKI associated with VPT regimens, revealing considerable variability in the risk conferred by VPT regimens across different studies. The study by Qian et al,30 presented in bold text, is the only large – scale RCT to date.
|
Currently, the mechanisms underlying co-administration of VPT induced AKI remain unclear. Some studies suggest a potential pseudo-nephrotoxicity mediated by impaired renal tubular creatinine secretion,31 casting doubt on whether the observed relationship between co-administration of VPT and AKI truly reflects genuine renal toxicity. Referring to all above, the objective of this review is to consolidate the latest research findings from recent years, delineate the influencing factors contributing to AKI arising from the concurrent administration of VPT, and succinctly summarize the currently proposed potential nephrotoxic mechanisms.
We performed a comprehensive PubMed, Ovid-EMBASE, Biosis, Web of Science and Cochrane search up until December 2023, utilizing the terms “vancomycin” and “piperacillin-tazobactam” in conjunction with the terms “combination”, “concomitant”, “acute kidney injury”, “nephrotoxicity”. Our investigation focused on studies that explored the clinical outcomes and mechanisms of nephrotoxicity. This article relies on data from previously conducted studies and does not involve any new research with human participants or animals by the authors.
Risk Factors of AKI in Concomitant Therapy of Vancomycin and Piperacillin-Tazobactam
Severity of Illness
It is known to all that the severity of illness is a significant risk factor of AKI. In critically ill patients, the current research findings regarding the incidence of AKI in the VPT group, compared to the control group receiving VAN plus other β-lactams or VAN alone, are inconsistent. Some studies suggest an elevated risk of AKI with VPT compared to VAN combined with other β-lactams or VAN alone.18,20–22,24,29,32 However, other studies indicate no significant difference in AKI incidence when comparing VPT with VAN combined with other β-lactams or VAN alone.23,33 Discrepancies in the proportions of critically ill patients included in the studies contribute to varying outcomes. In an analysis including less than 50% ICU patients, a higher AKI risk was observed in the VPT group (adjusted Odds Ratio, aOR=3.04; 95% Confidence Interval, 95% CI: 1.49 to 6.22). Conversely, when over 50% ICU patients were included in the analysis, no increased AKI risk was observed in the VPT group (aOR=2.83; 95% CI: 0.74 to 10.85).34 If the combination of two drugs significantly increase the risk of AKI in non-critical patients, it is plausible that this risk may be magnified rather than diminished in critically ill patients. Consequently, this contradictory observation has sparked debates: does the VPT concomitant therapy truly elevate the risk of AKI?
Dosing Strategy of Vancomycin
The nephrotoxicity of VAN has long been a focal point of scholarly inquiry, with a wealth of research endeavors dedicated to optimizing its dosing regimens through the analysis of its pharmacokinetics and variations in blood drug concentrations. The elevated trough concentrations may be associated with the nephrotoxicity of VAN. A consensus guideline focusing on VAN therapy (name as “consensus guideline”) published by American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP) advocate for VAN dosing based on a daily area under the curve (AUC) target exposure of 400 to 600 mg × h/L, superseding the previous target trough concentration of 15–20 mg/L.1 Analysis of VAN trough concentrations in patients guided by trough levels revealed a significantly higher trough level in the acute kidney injury (AKI) group compared to the non-AKI group (25.79±7.8 vs 15.7±6.9 μg/mL).35 Other studies also indicate a significant association between drug exposure exceeding 15 mg/L and nephrotoxicity.19,36–39 Given that most patients can achieve AUC24 > 400 mg × h/L with trough levels < 15 mg/L, considering VAN’s nephrotoxicity as dose-dependent, perhaps AUC-guided dosing could be a modifiable risk factor for AKI.40–42 The IDSA guidelines in 2020 shifted from recommending trough-guided dosing to AUC-guided dosing for VAN. A systematic review and meta-analysis have summarized the safety differences between AUC-guided and trough concentration-guided vancomycin dosing strategies.43 Although most current studies are observational and lack randomized controlled trials, AUC-guided dosing strategies are associated with a lower incidence of vancomycin-induced AKI compared to trough-based strategies. Despite several limitations, the AUC-guided vancomycin dosing strategy remains a key approach for reducing vancomycin-induced nephrotoxicity.
Presently, several studies have focused on the issues surrounding drug dosing regimens and the nephrotoxicity associated with VPT therapy. However, a retrospective cohort study subset analysis44 (n=636) suggested that, compared to trough-guided dosing, AUC-guided dosing did not lower the risk of AKI with VPT (17.8% vs 13.6%), although the initially estimated sample size might have been insufficient to detect a decrease in AKI risk, and the AUC-guided dosing group had a higher proportion of obese patients. A meta-analysis45 also yielded similar results, indicating that AUC-guided dosing did not reduce the incidence of AKI compared to trough-guided dosing (OR=0.715, 95% CI: 0.439 to 1.163) in patients receiving concomitant therapy of VAN and antipseudomonal beta-lactam antibiotics. Furthermore, the AKI incidence in the VPT group with AUC-guided dosing was higher than that in the control group (OR=3.861, 95% CI: 2.165 to 6.887, P < 0.05). Additionally, AUC-guided dosing did not appear to reduce blood drug concentrations; the median initial daily total dose per weight (mg/kg) was higher in the trough-guided group (26.6±8.2 vs 24.1±7.3).44 The meta-analysis45 also indicated that the total daily dose of VAN with AUC-guided dosing did not decrease (standard mean difference, SMD=−0.139, 95% CI −0.458 to 0.179) compared to trough-guided dosing.
Current research questions the recommended AUC guided dosing strategy in the guidelines, since the AKI risk was not decreased when following the AUC guided dosing strategy. Whether following trough concentration-guided dosing or AUC guided dosing strategies, the risk of AKI induced by the concomitant of VPT has not been reduced.40 A prospective observational study found significant nephrotoxicity when treating MRSA bacteremia with an AUC level ≥ 515 mg × h/L.46 The optimal level related to reducing nephrotoxicity with AUC-guided dosing remains to be determined. A single-institution study compared the AUC level of 103 patients demonstrated that a higher prevalence of AKI in the VPT group (29.5%) when comparing with the VAN group (7.1%), under the circumstance of an AUC level <600 mg × h/L, which means prevention of AKI may be difficult with AUC-guided VAN dosing in patients receiving VPT.25 As depicted in Figure 2, insights gleaned from the aforementioned literature suggest that co-administration of VPT may potentially narrow the therapeutic window of vancomycin, thereby reducing the threshold of VAN exposure leading to nephrotoxicity.
 |
Figure 2 The average incidence of AKI under the concomitant VPT therapy defined by different criteria. The highest average AKI incidence rate is indicated by red, representing studies defined according to the AKIN standard (37.0%), followed by studies defined according to the KDIGO standard, indicated by blue (27.7%). The lowest average AKI incidence rate is found in studies defined according to the RIFLE standard, indicated by green (22.8%). The average AKI incidence rate of all definitions is above 20%.
|
Individual Susceptibility of Vancomycin-Induced AKI
One study explored the role of Osteopontin (OPN) and Apolipoprotein E (APOE) gene polymorphisms in influencing susceptibility to vancomycin-induced AKI in critically ill patients.47 The research identified significant differences in OPN and APOE genotype distributions between patients who developed AKI and those who did not. Notably, individuals carrying the APOE e2e3 genotype exhibited a significantly increased risk of AKI. Moreover, pharmacokinetic parameters of vancomycin were correlated with AKI incidence. Parallel to these investigations of genetic risk factors and the study of OPN and APOE, research has sought therapeutic interventions. One such study examined the potential of dapagliflozin (DAPA), an oral antidiabetic agent, to mitigate vancomycin-induced AKI in a rat model.48 VCM administration induced renal tubular damage, impaired renal function, and increased oxidative stress and apoptosis in the kidneys. DAPA pretreatment, particularly at a higher dose, attenuated these effects, reducing NADPH oxidase-4 (NOX4)-induced renal reactive oxygen species (ROS), inhibiting activin A activation, and modulating miRNA-21/PTEN/pAKT signaling. DAPA also improved antioxidant enzyme expression and alleviated kidney injury markers, leading to improved renal function and reduced apoptosis. Recent research has turned to the role of Klotho, a protein associated with kidney health, in mitigating vancomycin-AKI.49 In vivo and in vitro studies demonstrated that vancomycin challenge reduced Klotho expression in renal tissue. Introduction of Klotho, either through recombinant Klotho administration or siRNA knockdown, modulated reactive oxygen species production, cell apoptosis, and expression of the JAK2/STAT3/GPx3 axis. Klotho enhances antioxidant capacity through the JAK2/STAT3/GPx3 axis, which in turn improves vancomycin-induced AKI. Taken together, these studies highlight the multi-faceted nature of vancomycin-induced AKI, involving patient-specific genetic factors, modifiable pathways amenable to therapeutic intervention, and the protective role of Klotho. The identification of OPN and APOE polymorphisms as potential risk factors may inform personalized risk assessment strategies. The demonstration of DAPA’s protective effects and the identification of Klotho’s protective mechanisms in preclinical models suggest potential therapeutic avenues for mitigating vancomycin-induced nephrotoxicity. Further research is needed to translate these findings into clinical practice and to explore the potential synergistic benefits of combining genetic risk stratification with targeted therapeutic interventions and Klotho augmentation strategies.
Different Definitions of AKI
Current Guidelines
As shown in Table 2, the definition of AKI varies among four established criteria, namely, Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury Network (AKIN), Kidney Disease: Improving Global Outcomes (KDIGO), and a consensus guideline focusing on VAN therapy published by ASHP, IDSA, PIDS, and SIDP.1 These standards exhibit slight differences in the classification of AKI (Figure 2). AKIN and KDIGO criteria encompass a broader spectrum of AKI cases, incorporating smaller increases in serum creatinine (0.3 mg/dL) compared to the RIFLE criteria (at least a ≥50% increase). This distinction may impact the reported incidence of AKI. Indeed, research supports this conjecture, revealing alterations in AKI occurrence rates based on different AKI definition criteria. For instance, when compared to VAN combined with cefepime, the combined use of VPT is significantly associated with an increased risk of AKI.12 Another analysis showed that the VPT primarily affects Stage I AKI incidence rates, with no significant impact on Stages II or III AKI rates.16 In summary, the current determination of AKI predominantly relies upon the levels of serum creatinine.
 |
Table 2 Different Definitions of AKI
|
Other Biomarkers of AKI
During the acute phase of AKI, before a detectable increase in serum creatinine (SCr), the glomerular filtration rate (GFR) can decrease by up to 50%. Defining AKI based solely on SCr changes lacks clinical sensitivity, necessitating the incorporation of more sensitive and specific biomarkers. Biomarkers such as Kidney Injury Molecule 1 (KIM-1) and clusterin, which are sensitive to histopathological changes in renal parenchyma and show detectable increases within hours of mild tubular injury, along with Cystatin C (CysC), a biomarker enabling subclinical AKI detection, and tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7), which have FDA approval for assessing moderate to severe AKI risk in laboratory settings. Notably, only two clinical studies investigating the nephrotoxicity of concomitant VPT have utilized renal biomarkers other than creatinine. In a prospective cohort study, a secondary analysis employing TIMP-2 and IGFBP7 demonstrated their efficacy in assessing renal stress in critically ill patients in different groups, with levels exceeding 0.3 on the first day correctly identifying progression to Stage 2/3 AKI. Moreover, in patients with high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, TIMP-2 and IGFBP7 levels in the concomitant administration of VPT group did not significantly differ from those in the VAN group.50 In another prospective cohort study that aimed to validate the correlations of creatinine and Cystatin C changes in patients receiving combined VPT therapy,28 the findings revealed a significant association between the co-administration of VPT and an 8.04% increase in creatinine (95% CI: 1.21% to 15.34%). This elevated creatinine level was further associated with a higher incidence of AKI defined by serum creatinine levels. However, there was no discernible correlation between this concomitant therapy and changes in Cystatin C (Cystatin C: −5.63%) or Blood Urea Nitrogen (BUN: −4.51%). In summary, while there is evidence suggesting an increased incidence of AKI defined by serum creatinine levels with the concomitant use of VPT, the conclusions drawn from comparisons with other kidney-related biomarker levels are contradictory. Therefore, the definition of AKI in the context of combined administration of VPT may warrant further exploration, necessitating comparisons with alternative AKI criteria beyond creatinine for a more comprehensive understanding.
Major Adverse Kidney Events
Although numerous studies have investigated AKI resulting from VPT regimens, most focus on AKI defined primarily by elevated serum creatinine levels. In terms of more clinically relevant kidney events, such as anuria, need for renal replacement therapy (RRT), AKI-related mortality, and progression to chronic kidney disease (CKD), it appears that VPT does not significantly affect their incidence. A meta-analysis summarizing observational studies found that the VPT regimen is most likely to cause severe AKI (stage 3 or failure) and the need for RRT. However, this tendency is not statistically significant.51 Additionally, there were no significant differences in AKI recovery, length of hospital stay, or mortality rates. In a study analyzing renal recovery in septic patients with AKI, the recovery rates were 42.3% for those treated with VPT compared to 40.3% for those receiving vancomycin plus cefepime (p = 0.78).27 This suggests that initial empiric therapy with VPT in sepsis does not increase the risk of AKI when appropriately de-escalated. In the only current randomized controlled trial (RCT), the incidence of Stage 3 AKI (85/997, 8.5%) and mortality (73/997, 7.3%) caused by the VPT regimen was not higher than that of the vancomycin combined with cefepime regimen (Stage 3 AKI: 70/942, 7.4%; mortality: 84/942, 8.9%). The length of hospital stay was similar between the two groups.30 The aforementioned studies suggest that, although VPT may be associated with a higher incidence of AKI, this increased risk does not necessarily lead to more severe clinical events or extend hospitalization duration.
Potential Mechanisms of AKI in VPT
Synergistic Increase in the Risk of AKI
At the outset of the recognition of VPT-induced AKI, the prevailing hypothesis centered on the synergistically heightened risk of AKI. According to this hypothesis, TZP does not affect the metabolism of vancomycin but rather contributes to synergistic nephrotoxicity. As illustrated in Figure 3, the VPT concomitant regimen may potentially narrow the therapeutic window of vancomycin.
 |
Figure 3 A hypothesis suggests that concomitant TZP therapy narrows the VAN therapeutic window and increases AKI risk. The blue area indicates suboptimal antimicrobial effect, the green shows the therapeutic window, and the red signifies higher nephrotoxicity risk. The dashed line represents vancomycin exposure in monotherapy; the solid line shows exposure with VPT co-administration. VPT may cause synergistic nephrotoxicity, lowering the VAN exposure threshold for AKI.
|
Nowadays, regarding the mechanism of nephrotoxicity associated with the concomitant of VPT, major perspectives have been proposed: interstitial nephritis caused by TZP, increased exposure of VAN, VAN-induced oxidative stress induced by VPT and elevated serum creatinine level caused by tubular secretion inhibition. Some studies suggest that the nephrotoxicity of VPT results from the additive effects of VAN-induced cell necrosis and acute interstitial nephritis caused by TZP.52 Another study proposes that the nephrotoxicity of VPT is due to piperacillin-induced subclinical interstitial nephritis, which is exacerbated by VAN-induced oxidative stress.53 Some case reports support this hypothesis.54 It is known that TZP can induce interstitial nephritis, whereas VAN, when used with other antibiotics, may lead to acute tubular necrosis and tubulointerstitial nephritis. A reported case indicates that AKI reached stage 2 three days after VPT exposure, with renal biopsy revealing acute tubular necrosis and interstitial nephritis, suggesting that interstitial nephritis may be a potential cause of the rapid decline in renal function. It is noteworthy that, although there are rare case reports of interstitial nephritis in patients receiving VPT treatment, it is extremely uncommon in routine practice.However, a retrospective cohort study26 presents a contrasting view, indicating a synergistic increase in the risk of AKI with VPT. The adjusted Hazard Ratio (aHR) for AKI after VPT exposure is 2.56 (95% CI: 2.49–2.63). The adjusted model shows a significant interaction between VAN and TZP, with an estimated aHR of 2.28 in the independent additive model. This cumulative toxicity was also not replicated in preclinical rat models.55 Other mechanisms included increased exposure of VAN, pseudo-renal-toxicity, and increased VPT-induced tubular toxicity due to OAT-3 and piperacillin interaction.
Increased Exposure of Vancomycin
As shown in Figure 4, one of the major hypotheses is the increased risk of VPT induced nephrotoxicity may be attributed to piperacillin reducing the clearance of VAN, leading to its accumulation in the renal unit.17 This accumulation may cause oxidative stress and mitochondrial damage to the proximal renal tubules.56 As discussed earlier, numerous studies have found a substantial increase in VAN exposure in patients experiencing VPT-induced AKI, whether based on trough concentrations or AUC guided dosing strategy.25,38–46 However, there is currently a lack of high-quality pharmacokinetic investigations analyzing this phenomenon. Most studies predominantly compare VAN exposure metrics (AUC or trough concentrations) and other clinical indicators between AKI and non-AKI patients, without delving into pharmacokinetic alterations, particularly in terms of changes in VAN clearance rates.
 |
Figure 4 A hypothesis suggests that increased nephrotoxicity risk during VPT combination therapy is due to TZP reducing VAN clearance, leading to accumulation in the kidneys. The blue area indicates suboptimal antimicrobial effectiveness, the green area shows the therapeutic window, and the red zone represents the risk of nephrotoxicity. The dashed line shows vancomycin exposure over time in monotherapy, while the solid line depicts exposure with VPT co-administration.
|
OAT-3, Piperacillin and Vancomycin: Nephrotoxicity or Pseudo-Nephrotoxicity?
TZP is a substrate for organic anion transporter-1 (OAT-1) and organic anion transporter-3 (OAT-3) on the basolateral side of proximal renal tubule cell membranes,57 with competitive inhibition effects on creatinine. VAN may also partially inhibit messenger RNA and protein expression of OAT-1 and OAT-3.58 The combined use of VAN and TZP leads to impaired creatinine secretion and increased serum creatinine (SCr). Therefore, the joint use of VPT sodium often exhibits a phenomenon of increased SCr with evident AKI, possibly mediated by pseudo-renal toxicity involving impaired tubular secretion, without actual tubular or renal function damage, as seen in trimethoprim-sulfamethoxazole and cimetidine.31 This theory is supported by studies that show an increased risk of AKI with VPT but no significant increase in severe clinical outcomes such as the need for RRT or mortality, compared to the control group.51,59 A clinical study by Jensen et al60 found that patients taking TZP sodium had faster recovery of GFR calculated by SCr after discontinuation compared to patients receiving meropenem or cefepime. However, a secondary analysis of a prospective multicenter randomized clinical trial50 studying urinary renal biomarkers TIMP-2 and IGFBP7 suggests renal stress with VPT; the levels of urinary TIMP-2 and IGFBP7 increased on the first day after VPT exposure. Moreover, if the nephrotoxicity of VPT is mediated by pseudo-renal toxicity due to impaired creatinine secretion, there should not be a concurrent increase in BUN and cystatin C, and the BUN/Cr ratio should be at normal level or lower than normal level. A prospective cohort study exploring the correlation between VPT-induced AKI and creatinine and cystatin C28 showed that VPT was associated with a higher percentage increase in creatinine on the second day, 8.04% (95% CI 1.21 to 15.34), and a higher rate of AKI defined by creatinine (RR=1.34, 95% CI 1.01 to 1.78). In contrast, VPT showed no association with changes in alternative biomarkers (cystatin C: −5.63%, 95% CI −18.19 to 8.86; urea nitrogen: −4.51%, 95% CI −12.83 to 4.59). This provides support for the creatinine secretion hypothesis of VPT, but considering the single-center nature of the study, the limited data on cystatin C, and the susceptibility of BUN to extrarenal factors, further research is needed to confirm the pseudo-renal toxicity of VPT.
On the other hand, some studies focusing on the relationship between β-lactam antibiotics and the AKI suggest that the increased nephrotoxicity observed when β-lactam antibiotics are co-administered with VAN might occur through the augmentation of VAN-induced proximal tubular oxidative stress, coupled with intracellular accumulation of β-lactam antibiotics.61 This phenomenon displays variations among different types of β-lactam antibiotics.62,63 The toxicity of β-lactam antibiotics to proximal tubular cells is contingent upon their accumulation within these cells, a process dictated by the variations in drug uptake and excretion abilities. The accumulation of β-lactam antibiotics in proximal tubular cells depends on their affinity to the basolateral membrane transporters, constituting the first step of excretion, wherein OAT-3 plays a pivotal role. Some β-lactam antibiotics exhibit a higher affinity to OAT-3. For the majority of β-lactam antibiotics, the apical membrane passage through proximal tubular cells for urinary excretion mitigates their nephrotoxic potential. Notably observed differences in the inherent nephrotoxicity among cephalosporins and anti-staphylococcal β-lactam antibiotics during treatment of methicillin-sensitive Staphylococcus aureus bacteremia highlight this phenomenon.64,65
Upon entry into proximal tubular cells, β-lactam antibiotics induce oxidative damage by impeding mitochondrial function.66 Co-administration of VAN with different β-lactam antibiotics accentuates the tendency for variations in proximal tubular injury induced by these antibiotics, surpassing the risk of AKI resulting from each antibiotic’s individual use. This observation emerged unexpectedly from the CAMERA2 trial, a multicenter prospective randomized clinical trial aiming to investigate whether the addition of flucloxacillin to VAN in the treatment of methicillin-resistant Staphylococcus aureus bacteremia might confer benefits.67 The CAMERA2 study showed a reduction in the duration of MRSA bacteremia by adding β-lactam antibiotics to VAN. However, due to a significant increase in AKI risk observed with the concomitant of VAN and β-lactam antibiotics compared to VAN alone, the study was prematurely terminated. Among 90 individuals treated with VAN and flucloxacillin, 25 cases (28%) experienced AKI risk, while among 21 individuals treated with VAN and cloxacillin, 5 cases (24%) were observed, and only 1 case (4%) occurred among 27 individuals treated with VAN and cefazolin. The discrepancy between the VAN and anti-Staphylococcus β-lactam antibiotic group versus the cefazolin group signifies the first direct comparison of different β-lactam antibiotics combined with VAN in terms of nephrotoxic risk, laying the foundation to understand why certain combinations lead to AKI risk while others do not.Studies analyzing the substrate affinity of various β-lactam antibiotics towards OAT-3 have revealed a strong correlation between the hydrophilicity of β-lactam antibiotics and their affinity for OAT-3 and subsequent cellular uptake. Most β-lactam antibiotics that bind to OAT-3 also act as competitive inhibitors. Examination of the inhibitory activity of β-lactam antibiotics on OAT-3 indicates a close relationship between their binding propensity and the potential nephrotoxicity observed when co-administered with VAN. The high expression of OAT-3 on the basolateral membrane of the blood-brain barrier and the apical membrane of the choroid plexus suggests its role in aiding antibiotic penetration into the cerebrospinal fluid. This finding enhances our understanding of how hydrophobicity influences antibiotic entry into the central nervous system.
Based on the above discussion, the key mechanism underlying the risk of AKI induced by VPT is believed to be associated with the binding of piperacillin to OAT-3 (Figure 5). On one hand, this binding might competitively inhibit the secretion of creatinine after binding of piperacillin and OAT-3, potentially leading to elevated creatinine level and pseudo-nephrotoxicity. On the other hand, the binding of piperacillin to OAT-3 might exacerbate the intracellular accumulation of drugs in the proximal tubule cells, thereby intensifying the oxidative stress-induced injury induced by VAN.
 |
Figure 5 VPT may increase serum creatinine levels by affecting organic anion transporters (OAT-3). This effect can involve oxidative stress and the accumulation of proximal tubular cells. Additionally, interaction with VPT might inhibit creatinine secretion into the tubular lumen, causing pseudo-toxicity and elevated serum creatinine. Abbreviations: MATE, multidrug and toxin extrusion; OAT, organic anion transporter; OCT, organic cation transporter.
|
How Can We Address the Risk of VTP-Related AKI?
Appropriate Dosing Strategy and Therapeutic Drug Monitoring
As the exposure levels of VAN are recognized as a risk factor contributing to AKI, it is imperative to employ strategies to mitigate the risk of AKI by controlling its exposure within the recommended ranges outlined in current guidelines. As previously discussed, VAN trough concentrations exceeding 20 mg/L significantly escalate the risk of AKI. Various studies have also indicated a significant increase in VAN-induced AKI risk with AUC24 values surpassing 515 mg × h/L,46 600 mg × h/L,68 or 650 mg × h/L;69 however, consensus on the optimal AUC cutoff values remains elusive. Considering the need to maintain a certain level of drug exposure for optimal therapeutic outcomes in antimicrobial treatment, defining an optimal AUC threshold becomes a nuanced task. There is no consistent conclusion regarding the AKI risk with different dosing regimens, and the recommendation persists to design VAN dosing based on the consensus guidelines’ therapeutic drug monitoring scheme, ie, targeting AUC 400 to 600 mg × h/L or trough concentrations of 15–20 mg/L.1 Although current research indicates that AUC-guided vancomycin dosing may not reduce nephrotoxicity in VPT regimens,45 it still offers advantages over trough concentration-guided vancomycin in managing nephrotoxicity.43 Therefore, we recommend using the AUC-guided vancomycin approach to minimize potential kidney toxicity. We recommend aligning AUC24 targets with guideline recommendations and, for patients with compromised renal function, contemplating a more strict AUC24 range to between 400 to 515 mg × h/L46 to mitigate further renal impairment when AUC24 is utilized as a target parameter.
Continuous infusion protocols of VAN may also prove beneficial in reducing the risk of AKI when comparing with intermittent infusion protocols. Instances where continuous infusion might be warranted include critically ill patients, particularly those undergoing RRT, and individuals intolerant to intermittent infusion.1 Pot disadvantages encompass the necessity for establishing a dedicated venous access route or compatibility considerations with other drugs administered through the same venous route. Data comparing intermittent and continuous administration of VAN are limited. Due to differences in study design, controls, and/or adjustments for confounding factors, as well as insufficient statistical power, it has not been definitively established whether continuous infusion is superior or inferior to intermittent infusion in terms of efficacy or safety to date. However, considering its potential to mitigate the risk of AKI, adopting a continuous infusion strategy during VPT concomitant therapy may contribute to reducing potential nephrotoxicity.70
In recent years, β-lactam antibiotics, particularly carbapenems, have been increasingly recommended for extended infusion protocols to reduce the incidence of adverse reactions and enhance therapeutic efficacy. Recent research has indicated that extending the infusion time of TZP may also contribute to more favorable clinical outcomes, especially in patients with sepsis and febrile neutropenia.71,72 Although a meta-analysis conducted by Bellos et al observed a statistically non-significant trend in reducing the risk of nephrotoxicity with the co-administration of VAN and extended-infusion TZP, the renal protective effects of this strategy were not definitively confirmed.51 Similarly, several retrospective cohort studies found no significant difference in the incidence of AKI between patients receiving extended-infusion TZP combined with VAN and those treated with standard-infusion TZP combined with VAN.73,74 Nevertheless, considering the superior clinical efficacy associated with the extended-infusion regimen of TZP and until randomized controlled trials prove otherwise, it is suggested that adopting the extended-infusion protocol of TZP may be beneficial in reducing the occurrence of AKI.
Evaluaterenal Function Through Multiple Methodologies
Currently, among the predominant hypotheses regarding the mechanisms underlying AKI induced by VPT, there exists a theoretical concept of pseudo-nephrotoxicity supported by some clinical and basic research, primarily manifested through an elevation in creatinine levels. However, robust clinical evidence substantiating this notion is presently lacking. While it remains a plausible mechanism, studies have also indicated that the elevation of cystatin C levels, a potential biomarker, is not significantly pronounced in patients with VPT-induced AKI.28 Consequently, we lean towards employing a comprehensive approach for the discrimination and diagnosis of AKI by incorporating various clinical indicators, such as cystatin C and BUN, as mentioned in the aforementioned studies. Numerous studies have suggested a substantial diagnostic and predictive value of neutrophil gelatinase-associated lipocalin (NGAL) in the context of AKI. However, despite its recognized potential, the clinical application of NGAL remains somewhat limited. Furthermore, there is currently a lack of research analyzing the effectiveness of AKI assessment utilizing NGAL specifically in patients receiving VPT therapy. Additional evidence is required to substantiate the predictive utility of NGAL in this particular clinical scenario. A study conducted in mice examined the alterations in NGAL levels and expression during TZP treatment.56 The findings revealed an elevation of NGAL expression in the kidneys; however, serum NGAL levels did not exhibit a significant elevation comparable to that observed in creatinine or BUN. In summary, a judicious diagnostic approach for AKI is advocated, involving a holistic assessment of factors including urine output and other pertinent clinical signs. Diagnosing AKI in patients utilizing the VPT regimen should not solely rely on an elevation in creatinine but rather integrate a multifaceted evaluation.
Reducing the Duration of VPT Concomitant Therapy
According to a previous study, the highest risk of AKI occurs on the fifth day of VPT treatment.75 In the latest RCT analyzing the nephrotoxicity risk of cefepime and TZP in acute infections, the AKI risk in patients co-administered VAN was found to be comparable.30 However, it is noteworthy that the median treatment duration for included patients in this study was 3 days, shorter than the median treatment duration reported in prior studies on VPT-induced nephrotoxicity. Also, the TZP was administered 3.375g every 8 hours, lower than the standard dose of 3.375 to 4.5g every 6 hours. Consequently, we hypothesize that timely assessment of infection status and microbiological evaluation, coupled with prompt adjustment of antimicrobial therapy, facilitates rapid de-escalation of antibiotic treatment and reduces the duration of concomitant therapy involving VPT, potentially mitigating the risk of AKI.76 Nonetheless, there is limited evidence supporting the renal protective effects of early antibiotic regimen adjustments, as patients receiving treatment for <48 hours are typically excluded from the analysis in the majority of studies. In Figure 6, we provide a summary of the current research on the timeline of AKI onset and recovery. Despite this, Lorentz et al conducted a study restricting the course of VPT concomitant therapy to within 72 hours, significantly reducing the exposure time to the regimen and lowering the incidence of VPT-related AKI.77 In line with this research, Schreier et al conducted a single-center retrospective cohort study involving 3,299 ICU patients to compare the risk of AKI associated with a short course of VPT (24–72 hours) against other antipseudomonal β-lactam plus VAN combinations.22 The results indicated that short-term VPT therapy did not increase the risk of stage II or III AKI after adjusting for relevant confounders. The adjusted odds ratios were 1.11 (95% CI [0.85–1.45]) for VPT versus FEP-VAN, and 1.04 (95% CI [0.71–1.42]) for VPT versus MER-VAN. Additionally, a retrospective single-center cohort study found that a short-course VPT regimen (24–60 hours) was significantly associated with a lower risk of AKI compared to extended-course VPT therapy (>72 hours).78 Therefore, based on the aforementioned studies and theoretical considerations, we posit that minimizing the duration of concomitant therapy involving VPT through timely infection assessment and microbiological examination may be a strategy to reduce the risk of AKI.
 |
Figure 6 A summary of the current research on the timeline of AKI onset and recovery.
|
Based on current evidence, VPT regimens are unlikely to cause AKI within the short term (around three days). However, to improve stewardship decisions, we recommend implementing more frequent renal function monitoring and utilizing a panel of renal biomarkers. If signs of AKI or indications of renal impairment emerge during VPT therapy, clinicians should consider switching to alternative antibiotics such as cefepime or meropenem. Despite these recommendations, the optimal adjustment strategies remain unclear, highlighting the need for further research to establish evidence-based guidelines for timely and effective therapy modification.
Other Strategies
To navigate this complex clinical scenario, a meticulous risk assessment should be conducted, considering the intricate interplay between therapeutic benefits and potential nephrotoxicity inherent in VTP regimens. Renal function monitoring, utilizing established indicators such as serum creatinine levels and estimated glomerular filtration rate (eGFR), is imperative. Incorporating emerging biomarkers indicative of early renal damage may further refine the sensitivity of detection for incipient nephrotoxic effects.
Firstly, the engagement of a multidisciplinary team, comprising infectious disease physicians, nephrologists,and pharmacists, is pivotal for a comprehensive evaluation and decision-making process. Clear and precise communication, coupled with meticulous documentation of decisions, is essential for ensuring patient safety and adhering to evidence-based medical practice. This approach aligns with the tenets of precision medicine, recognizing the inherent variability in individual responses to drug therapy and aiming to optimize therapeutic outcomes while minimizing the risk of adverse effects, particularly within the context of AKI associated with VTP regimens. To address the risk of prolonged VPT exposure and promote standardized AUC-based vancomycin monitoring, our institution has implemented protocols guided by our antimicrobial stewardship team. These include regular therapeutic drug monitoring and automated alerts set up by the stewardship team to prompt timely dose adjustments and prevent unnecessarily extended therapy durations. This approach helps ensure that vancomycin use is optimized for each patient and reduces the risk of nephrotoxicity associated with prolonged exposure.
Secondly, in patients with a history of renal insufficiency or established AKI, the use of VPT should be avoided. While the specific mechanisms of VPT and its potential nephrotoxic effects remain subjects of ongoing investigation, it is prudent to minimize the administration of drug combinations that could exacerbate renal toxicity in individuals with confirmed pre-existing renal dysfunction or AKI. In instances where renal impairment is either detected or suspected, timely intervention involves the judicious discontinuation or modification of the implicated agents, with a preference for discontinuing the therapy exhibiting a higher potential for nephrotoxicity. Subsequent management strategies may encompass supportive measures, such as hydration, diuretics, or, in severe cases, renal replacement therapy.
Thirdly, utilizing prognostic indicators or predictive tools can help assess the risk of AKI in patients. Currently, there are no tools specifically designed to predict the AKI risk associated with VPT regimens. However, the development of AI tools or nomogram models could facilitate future management of VPT-related AKI risks. Due to the absence of dedicated predictive models, clinicians and pharmacists can turn to existing AKI prediction tools, such as risk prediction models and prognostic indicators. Hematological parameters are widely used for their simplicity and cost-effectiveness. Blood tests provide hematological indices that are inexpensive and reliable markers for AKI, allowing comparison with other risk factors. The neutrophil-to-lymphocyte ratio (NLR) is a reliable prognostic marker for predicting AKI development, especially in patients with severe sepsis.79,80 Red cell distribution width is another easily accessible inflammatory biomarker, which also holds predictive value for mortality in patients with sepsis-induced AKI.81 Mean platelet volume (MPV), measured in femtoliters (fL), indicates the average platelet size, with MPV ≥ 10.2 fL identified as a significant prognostic risk factor for AKI patients requiring RRT.82–84 Utilizing these simple indicators may aid in managing patients with AKI. In addition, machine learning-based predictive models are emerging. A notable model published by Tomašev et al in Nature in 2019, involving data from 172 hospitals and 1,062 clinics, demonstrated excellent predictive capabilities, forecasting AKI up to 48 hours earlier than traditional clinical approaches.85 Although this method has not been independently validated for the VPT cohort, it represents a potential strategy for managing AKI risks.
Summary
This review summaries the current evidence of AKI induced by the combination of VPT. VPT-induced AKI is a relatively common and high-risk adverse event in clinical practice, with occurrence rates varying across studies but often reaching 30% in critically ill patients. Its development significantly impacts patient morbidity, prolongs hospital stays, increases healthcare costs, and complicates treatment outcomes. Distinguishing true AKI from pseudo-AKI is particularly urgent, as misclassification may lead to unnecessary treatment modifications or delays, potentially compromising patient recovery. The precise mechanism underlying VPT-induced AKI, whether attributed to heightened exposure to VAN, exacerbated vancomycin-induced oxidative stress injury by piperacillin, pseudo-nephrotoxicity mediated by VPT-induced impaired creatinine secretion, or a combination of the aforementioned mechanisms, remains elusive and warrants further investigation. Potential mechanisms and possible strategies to reduce the risk of VPT-associated AKI were summarized in Figure 7.
 |
Figure 7 A summary of potential mechanisms and possible strategies to reduce the risk of VPT-associated AKI.
|
To address these challenges, further research is essential. Critical gaps include the need for validation of novel renal biomarkers such as NGAL, TIMP-2, and IGFBP7, which could enable earlier and more accurate detection of AKI. Additionally, more pharmacokinetic studies are required to understand vancomycin clearance when combined with TZP to optimize dosing and minimize toxicity. Finally, well-designed prospective trials comparing different β-lactam and vancomycin regimens are needed to determine the safest and most effective strategies, ultimately improving patient outcomes and reducing the incidence of VPT-induced AKI.
Based on current research, several strategies can help reduce the risk of VPT-associated AKI. First, while guidelines recommend an AUC range of 400 to 600 mg×h/L for vancomycin, it is advisable to pursue a more cautious target range of 400 to 515 mg×h/L when feasible. To support this, increasing the frequency of vancomycin TDM and incorporating additional renal function indicators can facilitate early detection of kidney injury. Additionally, minimizing the duration of combined VPT therapy may help decrease nephrotoxicity. Avoiding the concomitant use of other nephrotoxic medications whenever possible can further reduce AKI risk. Incorporating these measures into clinical practice can enhance the safety and efficacy of VPT therapy.
Acknowledgments
Funding was provided by Jiangsu Pharmaceutical Association Research Foundation of Pharmacy (202495070), Nanjing Municipal Health Commission’s key development project in medicine (ZKX23020), Project of Modern Hospital Management and Development Institute, Nanjing University & Aid Project of Nanjing Drum Tower Hospital Health, Education & Research Foundation (NDYG2021044), Jiangsu Pharmaceutical Association—Hengrui Research Foundation of Hospital Pharmacy (H202305) and Nanjing Medical Center for Clinical Pharmacy (NWKJ 2020-1). The authors thank Jinglin Wang, Xiaoyuan Chen, Simin Yan, Huanyu Ni, Huiyan Jiang and Yanran Zhao for their valuable suggestions in manuscript drafting.
Author Contributions
These authors contributed equally to this work and share first authorship (Dayu Chen, Jingjing Kan & Qiaoling Gu). All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The funders had no role in the design of the study; in the collection, analyses, or interpretation of references; in the writing of the manuscript; or in the decision to publish the manuscript.
References
1. Rybak MJ, Le J, Lodise TP. et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2020;77(11):835–864. doi:10.1093/ajhp/zxaa036
2. Ouyang W, Xue H, Chen Y, et al. Clinical characteristics and antimicrobial patterns in complicated intra-abdominal infections: a 6-year epidemiological study in southern China. Int J Antimicrob Agents. 2016;47(3):210–216. doi:10.1016/j.ijantimicag.2015.12.019
3. Elgendy SG, Abdel Hameed MR, El-Mokhtar MA. Tigecycline resistance among Klebsiella pneumoniae isolated from febrile neutropenic patients. J Med Microbiol. 2018;67(7):972–975. doi:10.1099/jmm.0.000770
4. Abdel Hammed MR, Ahmed YA, Adam EN, Bakry R, Elnaggar MG. sVCAM-1, and TGFβ1 in chronic phase, chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Egyptian Journal of Immunology. 2022;29(4):163–173. doi:10.55133/eji.290416
5. Mohammed D, Khallaf S, El-Naggar M, Abdel-Hameed M, Bakry R. Interleukin-10: a Potential Prognostic Marker in Patients with Newly Diagnosed Multiple Myeloma. Res Oncol. 2021;17(1):38–41. doi:10.21608/resoncol.2021.51503.1127
6. Kellum JA, Romagnani P, Ashuntantang G, Ronco C, Zarbock A, Anders H-J. Acute kidney injury. Nat Rev Dis Primers. 2021;7(1):52. doi:10.1038/s41572-021-00284-z
7. Chung S, Overstreet JM, Li Y, et al. TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration. JCI Insight. 2018;3(21):e123563. doi:10.1172/jci.insight.123563
8. Hellwig T, Hammerquist R, Loecker B, Shields J. Retrospective evaluation of the incidence of vancomycin and/or piperacillin-tazobactam induced acute renal failure. Crit Care Med. 2011;39(12):79. doi:10.1097/01.ccm.0000408627.24229.88
9. Shirey TL. Identification of acute kidney injury. Crit Care Med. 2011;39(1):200. doi:10.1097/CCM.0b013e3181ffe3b7
10. Carreno J, Smiraglia T, Hunter C, Tobin E, Lomaestro B. Comparative incidence and excess risk of acute kidney injury in hospitalised patients receiving vancomycin and piperacillin/tazobactam in combination or as monotherapy. Intl. J Antimicrob Agents. 2018;52(5):643–650. doi:10.1016/j.ijantimicag.2018.08.001
11. Choudhury D, Ahmed Z. Drug-associated renal dysfunction and injury. Nature Clinical Practice Nephrology. 2006;2(2):80–91. doi:10.1038/ncpneph0076
12. Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin–tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis. 2017;64(2):116–123. doi:10.1093/cid/ciw709
13. Blair K, Covington EW. Incidence and risk factors of acute kidney injury in patients receiving concomitant vancomycin and continuous-infusion piperacillin/tazobactam: a retrospective cohort study. Ann Pharmacother. 2020;54(11):1096–1101. doi:10.1177/1060028020921170
14. Yamashita Y, Kawaguchi H, Yano T, Sakurai N, Shibata W. Oshima K, Imai T, Yamada K, Nakamura Y, Nagayama K, Kakeya H. Risk factors for acute kidney injury in vancomycin and piperacillin/tazobactam combination therapy: a retrospective study. J Infect Chemother. 2021;27(11):1614–1620. doi:10.1016/j.jiac.2021.07.017
15. Dolly LM, Rivera CG, Jensen KL, et al. Comparative renal risk of long-term use of beta-lactams in combination with vancomycin across the continuum of care. Ther Adv Infect Dis. 2023;10:20499361231189589. doi:10.1177/20499361231189589
16. Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy. 2014;34(7):662–669. doi:10.1002/phar.1428
17. Burgess LD, Drew RH. Comparison of the Incidence of Vancomycin-Induced Nephrotoxicity in Hospitalized Patients with and without Concomitant Piperacillin-Tazobactam. Pharmacotherapy. 2014;34(7):670–676. doi:10.1002/phar.1442
18. 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(5):463–471. doi:10.1002/phar.1738
19. McQueen KE, Clark DW. Does Combination Therapy With Vancomycin and Piperacillin-Tazobactam Increase the Risk of Nephrotoxicity Versus Vancomycin Alone in Pediatric Patients? J Pediatr Pharmacol Ther. 2016;21(4):332–338. doi:10.5863/1551-6776-21.4.332
20. Buckley MS, Hartsock NC, Berry AJ, et al. Comparison of acute kidney injury risk associated with vancomycin and concomitant piperacillin/tazobactam or cefepime in the intensive care unit. J Crit Care. 2018;48:32–38. doi:10.1016/j.jcrc.2018.08.007
21. Molina KC, Barletta JF, Hall ST, Yazdani C, Huang V. The risk of acute kidney injury in critically ill patients receiving concomitant vancomycin with piperacillin-tazobactam or cefepime [published online ahead of print February 10, 2019. J Intensive Care Med. 2019;35(12):1434–1438. doi:10.1177/0885066619828290
22. Schreier DJ, Kashani KB, Sakhuja A, et al. Incidence of acute kidney injury among critically ill patients with brief empiric use of antipseudomonal β-lactams with vancomycin. Clin Infect Dis. 2019;68(9):1456–1462. doi:10.1093/cid/ciy724
23. Blevins AM, Lashinsky JN, McCammon C, Kollef M, Micek S, Juang P. Incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin-tazobactam, cefepime, or meropenem. Antimicrob Agents Chemother. 2019;63(5). doi:10.1128/aac.02658-18
24. Inage S, Nakamura S, Isoe Y, et al. Acute kidney injury in non-intensive care and intensive care patients treated with vancomycin and piperacillin-tazobactam. J Nippon Med Sch. 2020;87(2):66–72. doi:10.1272/jnms.JNMS.2020_87-203
25. Okada N, Izumi Y, Nakamoto A, et al. Impact of Area Under the Concentration–Time Curve on the Prevalence of Vancomycin-Induced Nephrotoxicity in Combination With Tazobactam/Piperacillin or Cefepime: a Single-Institution Retrospective Study. Clin Ther. 2021;43(11):1910–1920.e3. doi:10.1016/j.clinthera.2021.09.007
26. Lee JD, Heintz BH, Mosher HJ, Livorsi DJ, Egge JA, Lund BC. Risk of Acute Kidney Injury and Clostridioides difficile Infection With Piperacillin/Tazobactam, Cefepime, and Meropenem With or Without Vancomycin. Clin Infect Dis. 2021;73(7):e1579–e1586. doi:10.1093/cid/ciaa1902
27. Elliott BP, Tang MM, Madden JA, et al. A retrospective cohort study assessing acute kidney injury and renal recovery among septic patients empirically treated with vancomycin piperacillin–tazobactam versus vancomycin cefepime. Intern Emerg Med. 2022;17(1):91–99. doi:10.1007/s11739-021-02772-2
28. Miano TA, Hennessy S, Yang W, et al. Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study. Intensive Care Medicine. 2022;48(9):1144–1155. doi:10.1007/s00134-022-06811-0
29. Chen AY, Deng C-Y, Calvachi-Prieto P, et al. A large-scale multicenter retrospective study on nephrotoxicity associated with empiric broad-spectrum antibiotics in critically ill patients. Chest. 2023;164(2):355–368. doi:10.1016/j.chest.2023.03.046
30. Qian ET, Casey JD, Wright A, et al. Vanderbilt Center for Learning Healthcare and the Pragmatic Critical Care Research Group. Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: the ACORN Randomized Clinical Trial. JAMA. 2023;330(16):1557–1567. doi:10.1001/jama.2023.20583
31. Avedissian SN, Pais GM, Liu J, Rhodes NJ, Scheetz MH. Piperacillin-tazobactam added to vancomycin increases risk for acute kidney injury: fact or fiction. Clin Infect Dis. 2020;71(2):426–432. doi:10.1093/cid/ciz1189
32. Blears EE, Morris J, Popp D, Lee JO, Norbury WB. Kidney Injury in Critically Ill Patients Treated with Vancomycin and Zosyn or an Alternative: a Systematic Review and Meta-Analysis. Surg Infect. 2022;23(6):516–524. doi:10.1089/sur.2022.128
33. Saad MO, Mohamed AM, Mitwally HA, Shible AA, Hssain AA, Abdelaty MA. Evaluation of the risk of acute kidney injury with the use of piperacillin/tazobactam among adult critically ill patients. Infect. 2020;48(5):741–747. doi:10.1007/s15010-020-01480-x
34. Hammond DA, Smith MN, Li C, Hayes SM, Lusardi K, Bookstaver PB. Systematic Review and Metaanalysis of Acute Kidney Injury Associated With Concomitant Vancomycin and Piperacillin/Tazobactam. Clin Infect Dis. 2017;64(5):666–674. doi:10.1093/cid/ciw811
35. Saito S, Sugimoto T, Takenaka K. Goto H, Kumahara A, Watanabe R, Sugiyama D, Yasutomo Y, Takatsuki K. The association of high Vancomycin trough concentration with acute kidney injury during combination therapy of Piperacillin/Tazobactam and Vancomycin. Practical Laboratory Medicine. 2022;29:e00266. doi:10.1016/j.plabm.2022.e00266
36. Liang X, Fan Y, Yang M, et al. A prospective multicenter clinical observational study on vancomycin efficiency and safety with therapeutic drug monitoring. Clinical Infectious Diseases. 2018;67(suppl_2):S249–S255. doi:10.1093/cid/ciy680
37. Cao L, Li Z, Zhang P, Yong S. Relationship between vancomycin trough serum concentrations and clinical outcomes in children: a systematic review and meta-analysis. Antimicrob Agents Chemother. 2022;66(8):e00138–22. doi:10.1128/aac.00138-22
38. Meng L, Fang Y, Chen Y, Zhu H, Long R. High versus low vancomycin serum trough regimen for Gram-positive infections: a meta-analysis. J Chemother. 2015;27(4):213–220. doi:10.1179/1973947814Y.0000000182
39. Fiorito TM, Luther MK, Dennehy PH, LaPlante KL, Matson KL. Nephrotoxicity with vancomycin in the pediatric population: a systematic review and meta-analysis. Pediatr Infect Dis J. 2018;37(7):654–661. doi:10.1097/INF.0000000000001882
40. Clark L, Skrupky LP, Servais R, Brummitt CF, Dilworth TJ. Examining the relationship between vancomycin area under the concentration time curve and serum trough levels in adults with presumed or documented staphylococcal infections. Ther Drug Monit. 2019;41(4):483–488. doi:10.1097/FTD.0000000000000622
41. Finch NA, Zasowski EJ, Murray KP, et al. A quasi-experiment to study the impact of vancomycin area under the concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity. Antimicrob Agents Chemother. 2017;61(12). doi:10.1128/aac.01293-17
42. Ghasemiyeh P, Vazin A, Zand F, et al. Pharmacokinetic assessment of vancomycin in critically ill patients and nephrotoxicity prediction using individualized pharmacokinetic parameters. Front Pharmacol. 2022;13:912202. doi:10.3389/fphar.2022.912202
43. Abdelmessih E, Patel N, Vekaria J, et al. Vancomycin area under the curve versus trough only guided dosing and the risk of acute kidney injury: systematic review and meta-analysis. Pharmacotherapy. 2022;42(9):741–753. doi:10.1002/phar.2722
44. Muklewicz JD, Steuber TD, Edwards JD. Evaluation of area under the concentration–time curve-guided vancomycin dosing with or without piperacillin-tazobactam on the incidence of acute kidney injury. International Journal of Antimicrobial Agents. 2021;57(1):106234. doi:10.1016/j.ijantimicag.2020.106234
45. Chiu C-Y, Sarwal A. Evaluating the Nephrotoxicity of Area-under-the-Curve-Based Dosing of Vancomycin with Concomitant Antipseudomonal Beta-Lactam Antibiotics: a Systematic Review and Meta-Analysis. Medicina. 2023;59(4):691. doi:10.3390/medicina59040691
46. Lodise TP Jr, Rosenkranz SL, Finnemeyer M, et al. The emperor’s new clothes: prospective observational evaluation of the association between initial vancomycin exposure and failure rates among adult hospitalized patients with methicillin-resistant Staphylococcus aureus bloodstream infections (PROVIDE). Clin Infect Dis. 2020;70(8):1536–1545. doi:10.1093/cid/ciz460
47. Firouzabadi N, Karbasi D, Ghasemiyeh P, et al. Investigation on the association between Osteopontin and Apolipoprotein E gene polymorphisms and vancomycin-induced acute kidney injury: a pharmacokinetic/pharmacogenetic study in critically ill patients. Gene. 2025;952:149386. doi:10.1016/j.gene.2025.149386
48. Darwish SF, Mahmoud AMA, Abdel Mageed SS, Sallam AM, Oraby MA. Dapagliflozin improves early acute kidney injury induced by vancomycin in rats: insights on activin A/miRNA-21 signaling and FOXO3a expression. Eur J Pharmacol. 2023;955:175908. doi:10.1016/j.ejphar.2023.175908
49. Wang M, Zhou Y, Hao G, et al. Recombinant Klotho alleviates vancomycin-induced acute kidney injury by upregulating anti-oxidative capacity via JAK2/STAT3/GPx3 axis. Toxicology. 2023;499:153657. doi:10.1016/j.tox.2023.153657
50. Kane-Gill SL, Ostermann M, Shi J, Joyce EL, Kellum JA. Evaluating renal stress using pharmacokinetic urinary biomarker data in critically ill patients receiving vancomycin and/or piperacillin–tazobactam: a secondary analysis of the multicenter sapphire study. Drug Saf. 2019;42(10):1149–1155. doi:10.1007/s40264-019-00846-x
51. Bellos I, Karageorgiou V, Pergialiotis V, Perrea DN. Acute kidney injury following the concurrent administration of antipseudomonal β-lactams and vancomycin: a network meta-analysis. Clin Microbiol Infect. 2020;26(6):696–705. doi:10.1016/j.cmi.2020.03.019
52. Ciarambino T, Giannico OV, Campanile A, et al. Acute kidney injury and vancomycin/piperacillin/tazobactam in adult patients: a systematic review. Intern Emerg Med. 2020;15(2):327–331. doi:10.1007/s11739-020-02287-2
53. Watkins RR, Deresinski S. Increasing evidence of the nephrotoxicity of piperacillin/tazobactam and vancomycin combination therapy—what is the clinician to do. Clin Infect Dis. 2017;65(12):2137–2143. doi:10.1093/cid/cix675
54. Adisa O, Ananthaneni A, Rushing B, Rinehouse N, Morisetti P. Vancomycin-and piperacillin-induced acute interstitial nephritis in a patient with lupus: a case report showcasing rapid decline in renal function. Clin Nephrol Case Stud. 2023;11(1):99. doi:10.5414/CNCS111180
55. Chang J, Pais G, Marianski S, et al. Iohexol-measured glomerular filtration rate and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model. bioRxiv. 2023;3:532007. doi:10.1101/2023.03.09.532007
56. Yang J, Ko YS, Lee HY, et al. Mechanisms of Piperacillin/Tazobactam Nephrotoxicity: piperacillin/Tazobactam-Induced Direct Tubular Damage in Mice. Antibiotics. 2023;12(7):1121. doi:10.3390/antibiotics12071121
57. Wen S, Wang C, Duan Y, et al. OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam. Int J Pharm. 2018;537(1–2):172–182. doi:10.1016/j.ijpharm.2017.12.037
58. Wen S, Wang C, Huo X, et al. JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats. Toxicol Lett. 2018;295:195–204. doi:10.1016/j.toxlet.2018.06.1220
59. He M, Souza E, Matvekas A, Crass RL, Pai MP. Alteration in acute kidney injury potential with the combination of vancomycin and imipenem-cilastatin/relebactam or piperacillin/tazobactam in a preclinical model. Antimicrob Agents Chemother. 2021;65(4). doi:10.1128/aac.02141-20
60. Jensen J-US, Hein L, Lundgren B, 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. doi:10.1136/bmjopen-2011-000635
61. Alosaimy S, Rybak MJ, Sakoulas G. Understanding vancomycin nephrotoxicity augmented by β-lactams: a synthesis of endosymbiosis, proximal renal tubule mitochondrial metabolism, and β-lactam chemistry. Lancet Infect Dis. 2023;S1473-3099(23):00432. doi:10.1016/S1473-3099(23)00432-2
62. Tune BM. Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention. Pediatr Nephrol. 1997;11(6):768–772. doi:10.1007/s004670050386
63. Wolman AT, Gionfriddo MR, Heindel GA, et al. Organic anion transporter 3 interacts selectively with lipophilic β-lactam antibiotics. Drug Metab Dispos. 2013;41(4):791–800. doi:10.1124/dmd.112.049569
64. Monogue ML, Ortwine JK, Wei W, Eljaaly K, Bhavan KP. Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia. J Infect Public Health. 2018;11(5):727–731. doi:10.1016/j.jiph.2018.02.004
65. McDanel JS, Roghmann M-C, Perencevich EN, et al. Comparative Effectiveness of Cefazolin Versus Nafcillin or Oxacillin for Treatment of Methicillin-Susceptible Staphylococcus aureus Infections Complicated by Bacteremia: a Nationwide Cohort Study. Clin Infect Dis. 2017;65(1):100–106. doi:10.1093/cid/cix287
66. Jiang S, Li T, Zhou X, Qin W, Wang Z, Liao Y. Antibiotic drug piperacillin induces neuron cell death through mitochondrial dysfunction and oxidative damage. Can J Physiol Pharmacol. 2018;96(6):562–568. doi:10.1139/cjpp-2016-0679
67. Davis JS, Sud A, O’Sullivan MVN, et al. Combination Antibiotics for MEthicillin Resistant Staphylococcus aureus (CAMERA) study group; Combination Antibiotics for MEthicillin Resistant Staphylococcus aureus (CAMERA) study group Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: a Pilot Multicenter Randomized Controlled Trial. Clin Infect Dis. 2016;62(2):173–180. doi:10.1093/cid/civ808
68. Suzuki Y, Kawasaki K, Sato Y, et al. Is Peak Concentration Needed in Therapeutic Drug Monitoring of Vancomycin? A Pharmacokinetic-Pharmacodynamic Analysis in Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia. Chemotherapy. 2012;58(4):308–312. doi:10.1159/000343162
69. Aljefri DM, Avedissian SN, Rhodes NJ, Postelnick MJ, Nguyen K, Scheetz MH. Vancomycin Area Under the Curve and Acute Kidney Injury: a Meta-analysis. Clin Infect Dis. 2019;69(11):1881–1887. doi:10.1093/cid/ciz051
70. Hanrahan TP, Harlow G, Hutchinson J, et al. Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis. Crit Care Med. 2014;42(12):2527–2536. doi:10.1097/CCM.0000000000000514
71. Rhodes NJ, Liu J, O’Donnell JN, et al. Prolonged Infusion Piperacillin-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: results of a Systematic Review and Meta-Analysis. Crit Care Med. 2018;46(2):236–243. doi:10.1097/CCM.0000000000002836
72. Ram R, Halavy Y, Amit O, et al. Extended vs Bolus Infusion of Broad-Spectrum β-Lactams for Febrile Neutropenia: an Unblinded, Randomized Trial. Clin Infect Dis. 2018;67(8):1153–1160. doi:10.1093/cid/ciy258
73. Cotner SE, Rutter WC, Burgess DR, Wallace KL, Martin CA, Burgess DS. Influence of β-Lactam Infusion Strategy on Acute Kidney Injury. Antimicrob Agents Chemother. 2017;61(10):e00871–17. doi:10.1128/AAC.00871-17
74. Mousavi M, Zapolskaya T, Scipione MR, Louie E, Papadopoulos J, Dubrovskaya Y. Comparison of Rates of Nephrotoxicity Associated with Vancomycin in Combination with Piperacillin-Tazobactam Administered as an Extended versus Standard Infusion. Pharmacotherapy. 2017;37(3):379–385. doi:10.1002/phar.1901
75. Karino S, Kaye KS, Navalkele B, et al. Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: opportunities for Antimicrobial Stewardship. Antimicrob Agents Chemother. 2016;60(6):3743–3750. doi:10.1128/AAC.03011-15
76. Chen D, Ren H, Zhao Y. Cefepime vs Piperacillin-Tazobactam for Acute Infection in Hospitalized Adults. JAMA. 2024;331(8):708–709. doi:10.1001/jama.2023.27894
77. Lorenz MA, Moenster RP, Linneman TW. Effect of piperacillin/tazobactam restriction on usage and rates of acute renal failure. J Med Microbiol. 2016;65(2):195–199. doi:10.1099/jmm.0.000211
78. Traversa A, Hammond DA, Peksa GD, DeMott JM. Short Versus Extended Duration Vancomycin and Piperacillin/Tazobactam and the Incidence of Acute Kidney Injury in Noncritically Ill Patients. J Pharm Pract. 2021;34(6):882–887. doi:10.1177/0897190020933488
79. Abdel Hammed MR, El-Amien HA, Asham MN, Elgendy SG. Can platelets indices and blood neutrophil to lymphocyte ratio be used as predictors for diagnosis of spontaneous bacterial peritonitis in decompensated post hepatitis liver cirrhosis? Egyptian Journal of Immunology. 2022;29(4):12–24. doi:10.55133/eji.290402
80. Yilmaz H, Cakmak M, Inan O, Darcin T, Akcay A. Can neutrophil–lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis? Ren Fail. 2015;37(2):225–229. doi:10.3109/0886022X.2014.982477
81. Abdel Hammed MR, Tohamy MA, Boshra SZ, Taha SM, Saleh MFM. Red cell distribution width is an inflammatory predictor marker of contrast induced nephropathy in patients undergoing percutaneous coronary intervention. Egyptian Journal of Immunology. 2023;30(3):1–12. doi:10.55133/eji.300301
82. Lai H, Wu G, Zhong Y, et al. Red blood cell distribution width improves the prediction of 28-day mortality for patients with sepsis-induced acute kidney injury: a retrospective analysis from MIMIC-IV database using propensity score matching. Journal of Intensive Medicine. 2023;3(3):275–282. doi:10.1016/j.jointm.2023.02.005
83. Muhamad R, El-Hameed A, Abozied AM. Mean platelet volume in impaired fasting glucose subjects and diabetic patients as a risk factor for thrombotic complications. J Am Sci. 2013;9(9):12–17. doi:10.7537/marsjas090913.02
84. Han JS, Park KS, Lee MJ, et al. Mean platelet volume is a prognostic factor in patients with acute kidney injury requiring continuous renal replacement therapy. J Crit Care. 2014;29(6):1016–1021. doi:10.1016/j.jcrc.2014.07.022
85. Tomašev N, Glorot X, Rae JW, et al. A clinically applicable approach to continuous prediction of future acute kidney injury. Nature. 2019;572(7767):116–119. doi:10.1038/s41586-019-1390-1