Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem.

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

Risk and Time-to-Onset of Acute Kidney Injury With Vancomycin Plus Piperacillin-tazobactam Combination: Analysis Using JADER.

BACKGROUND/AIM: Pharmacovigilance data and clinical studies have indicated a risk of acute kidney injury (AKI) associated with concomitant administration of vancomycin and piperacillin-tazobactam. However, no pharmacovigilance studies have evaluated time-to-onset and outcomes of AKI related to this combination. Therefore, this study used a pharmacovigilance database to investigate the incidence, time-to-onset, and outcomes of AKI in patients treated with intravenous vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics. PATIENTS AND METHODS: From data in the Japanese Adverse Drug Event Report (JADER) database, we calculated the reporting odds ratios (RORs) and 95% confidence intervals (CIs), time-to-onset, and outcomes of AKI following intravenous administration of vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics and with other vancomycin regimens, including monotherapy. RESULTS: The JADER database contained 4,471 reports of intravenous vancomycin treatment, including 517 reports of AKI. The adjusted RORs (95%CIs) of AKI in cases with co-administration of intravenous vancomycin and piperacillin-tazobactam was 2.58 (2.06-3.24). The median time-to-onset for AKI in vancomycin plus piperacillin-tazobactam was 6.0 (interquartile range=3.0-10.3). Weibull shape parameter analysis showed that the pattern of onset of AKI in vancomycin plus piperacillin-tazobactam represented a wear out failure, predicting an increasing hazard with time. For the outcome of AKI, there was no significant difference between all vancomycin regimen and the piperacillin-tazobactam combination groups. CONCLUSION: Concomitant use of intravenous vancomycin and piperacillin-tazobactam may increase the incidence of AKI but may not affect the outcome. This combination does not necessarily have to be avoided, but long-term use is not advisable.

Association between piperacillin/tazobactam use and acute kidney injury in critically ill patients: a retrospective multicentre cohort study.

BACKGROUND: Piperacillin/tazobactam is one of the most common antibiotics prescribed in the ICU and the combination of piperacillin/tazobactam with vancomycin has been associated with acute kidney injury (AKI) in critically ill patients. However, data on the risk of AKI with piperacillin/tazobactam, despite vancomycin co-exposure, are lacking. OBJECTIVES: To investigate the association of piperacillin/tazobactam with AKI and renal replacement therapy (RRT) among adult ICU patients. METHODS: We analysed data from patients included in two open access databases (MIMIC-IV and eICU). Critically ill patients who received piperacillin/tazobactam or cefepime (a cephalosporin with similar broad-spectrum activity to piperacillin/tazobactam) during their first ICU stay were eligible for the study. Marginal structural Cox models, accounting for time-fixed covariates and time-dependent covariates were performed. The primary outcomes were AKI and need of RRT. RESULTS: A total of 20 107 patients were included, with 11 213 in the piperacillin/tazobactam group and 8894 in the cefepime group. Exposure to piperacillin/tazobactam was associated with AKI (HR 1.77; 95% CI 1.51-2.07; P < 0.001) and with need of RRT (HR 1.31; 95% CI 1.08-1.57; P = 0.005). Tests for interaction were not statistically significant for occurrence of AKI and RRT in the subgroup of patients exposed to vancomycin or not (P = 0.26 and P = 0.6, respectively). CONCLUSIONS: In critically ill patients, exposure to piperacillin/tazobactam was associated with increased risk of AKI and with increased risk of RRT, regardless of combination therapy with vancomycin.

Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial.

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]). Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study.

INTRODUCTION: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5-43%. VCM-induced AKI was reported to be more likely to occur 4-17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI2days) and seven (AKI7days) days of VCM administration. METHODS: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. RESULTS: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 µg/mL within the 48 h threshold (AKI2days) and 19.03 µg/mL within the 7-day threshold (AKI7days). CONCLUSION: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.

Piperacillin-tazobactam induced immune hemolytic anemia led to increased renal impairment and eventual death from multiple organ failure in a patient with hypertensive nephropathy: case report and literature review.

BACKGROUND: Piperacillin is one of the most common drugs that cause drug-induced immune hemolytic anemia, but a complete description of the serological features and course of the disease is rare. This study completely describes the serological characteristics and course of a patient with hypertensive nephropathy who developed drug-induced immune hemolytic anemia and worsened renal function during repeated administration of piperacillin-tazobactam. CASE PRESENTATION: A 79-year-old male patient with hypertensive nephropathy who developed severe hemolytic anemia and worsened renal function during intravenous piperacillin-tazobactam anti-infective treatment due to lung infection. Serological tests showed that the result of the direct antiglobulin test for anti-IgG was positive (4 +) and anti-C3d was negative, and the irregular red blood cell antibody screening test was negative. Plasma samples collected at different times from 2 days before to 12 days after the discontinuation of piperacillin-tazobactam administration were incubated with piperacillin solution and red blood cells of O-type healthy blood donors at 37 °C, IgG piperacillin-dependent antibodies were detected, and the highest titer was 128. However, no tazobactam-dependent antibody was detected in any plasma samples. Therefore, the patient was diagnosed with piperacillin-induced immune hemolytic anemia. Although blood transfusion and continuous renal replacement therapy were given, the patient died of multiple organ failure 15 days after the administration of piperacillin-tazobactam was stopped. CONCLUSION: This is the first complete description of the disease course and serological changes of piperacillin-induced immune hemolytic anemia, which is bound to help deepen the understanding of drug-induced immune hemolytic anemia and draw profound lessons from it.

Prevalence and risk factors for severe linezolid-associated thrombocytopenia in pediatric patients: An analysis of a public database.

Linezolid is widely used in various clinical settings. Studies have revealed that it may cause thrombocytopenia in adults. However, the correlation between the use of linezolid and thrombocytopenia in pediatric patients is still unclear. This study aimed to identify the impact of Linezolid on the occurrence of thrombocytopenia in children. A retrospective observational study was conducted using data on patients treated with linezolid from the Pediatric Intensive Care clinical database. Univariate and multiple logistic regression analyses were performed to identify the risk factors of linezolid-related severe thrombocytopenia. A total of 134 patients were included. The prevalence of severe thrombocytopenia was 8.96% (12/134). Univariate analysis indicated that the severe thrombocytopenia group showed significantly higher proportion of concomitant carbapenem (75% vs 44.3%; P < .05) and piperacillin/tazobactam (25% vs 6.6%; P < .05) than that of the non-severe thrombocytopenia group. Multivariate analysis also revealed that the occurrence of severe thrombocytopenia was significantly associated with concurrent use of carbapenem (odd ratio = 4.058; 95% confidence interval: 1.012-16.274; P = .048) and piperacillin/tazobactam (odd ratio = 5.335; 95% confidence interval: 1.117-25.478; P = .036). 75% of patients (9/12) developed severe thrombocytopenia within the first 7 days of linezolid use. The concomitant use of carbapenem and piperacillin/tazobactam was associated with an increased probability of severe thrombocytopenia in pediatric patients undergoing linezolid treatment. Further prospective clinical studies are required, and more detailed mechanisms of blood toxicity in pediatric patients must be investigated.

Piperacillin-Tazobactam Versus Anti-Pseudomonal Cephalosporins and Renal and Neurologic Outcomes in Critically Ill Adults: A Secondary Analysis of the SMART Trial.

Background: Prior studies suggest associations between receipt of piperacillin-tazobactam and development of acute kidney injury and receipt of anti-pseudomonal cephalosporins and neurotoxicity. We compared clinically-relevant renal and neurologic outcomes in critically ill patients who received piperacillin-tazobactam versus anti-pseudomonal cephalosporins. Methods: We conducted a secondary analysis of data from the Isotonic Solutions and Major Adverse Renal Events Trial examining patients who received piperacillin-tazobactam or an anti-pseudomonal cephalosporin within 24 h of intensive care unit admission. We performed multivariable analysis using a proportional odds model to examine the association between the first antibiotic received and the outcomes of Major Adverse Kidney Events within 30 days (MAKE30) and days alive and free of delirium and coma to day 28. Results: 3199 were included in the study; 2375 (74%) receiving piperacillin-tazobactam and 824 (26%) receiving anti-pseudomonal cephalosporin. After adjustment for prespecified confounders, initial receipt of piperacillin-tazobactam, compared to anti-pseudomonal cephalosporins, was not associated with higher incidence of MAKE30 (adjusted odds ratio, 1.03; 95% CI, 0.83-1.27; P = .80) but was associated with a greater number of days alive and free of delirium and coma (adjusted odds ratio, 1.18; 95% CI, 1.00-1.38; P = .04). In a sensitivity analysis adjusting for baseline receipt of medications which may impact neuro function, this finding was not significant. Conclusion: Among critically ill adults, receipt of piperacillin-tazobactam was not associated with an increased incidence of death, renal replacement therapy, or persistent renal dysfunction or a greater number of days alive and free of delirium and coma. Randomized trials are needed to inform the choice of antibiotics for empiric treatment infection in critically ill adults.

Evaluating the Nephrotoxicity of Area-under-the-Curve-Based Dosing of Vancomycin with Concomitant Antipseudomonal Beta-Lactam Antibiotics: A Systematic Review and Meta-Analysis.

Background and Objectives: Vancomycin combined with piperacillin/tazobactam (vancomycin + piperacillin/tazobactam) has a higher risk of acute kidney injury (AKI) than vancomycin combined with cefepime or meropenem. However, it is uncertain if applying area under the curve (AUC)-based vancomycin dosing has less nephrotoxicity than trough-based dosing in these combinations. Materials and Methods: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to December 2022. We examined the odds ratio (OR) of AKI between vancomycin + piperacillin/tazobactam and the control group. The control group was defined as vancomycin combined with antipseudomonal beta-lactam antibiotics, except for piperacillin-tazobactam. Results: The OR for AKI is significantly higher in vancomycin + piperacillin/tazobactam compared with the control group (3 studies, 866 patients, OR of 3.861, 95% confidence interval of 2.165 to 6.887, p < 0.05). In the sample population of patients who received vancomycin + piperacillin/tazobactam (2 studies, 536 patients), the risk of AKI (OR of 0.715, 95% CI of 0.439 to 1.163, p = 0.177) and daily vancomycin dose (standard mean difference-0.139, 95% CI-0.458 to 0.179; p = 0.392) are lower by AUC-based dosing than trough-based dosing, although it is not statistically significant. Conclusions: Nephrotoxicity is higher when combined with piperacillin/tazobactam than other antipseudomonal beta-lactam antibiotics (cefepime or meropenem) using the AUC-based dosing. However, applying the AUC-based dosing did not eliminate the risk of AKI or significantly reduce thedaily vancomycin dose compared with the trough-based dosing in the available literature.

A Large-Scale Multicenter Retrospective Study on Nephrotoxicity Associated With Empiric Broad-Spectrum Antibiotics in Critically Ill Patients.

BACKGROUND: Evidence regarding acute kidney injury associated with concomitant administration of vancomycin and piperacillin-tazobactam is conflicting, particularly in patients in the ICU. RESEARCH QUESTION: Does a difference exist in the association between commonly prescribed empiric antibiotics on ICU admission (vancomycin and piperacillin-tazobactam, vancomycin and cefepime, and vancomycin and meropenem) and acute kidney injury? STUDY DESIGN AND METHODS: This was a retrospective cohort study using data from the eICU Research Institute, which contains records for ICU stays between 2010 and 2015 across 335 hospitals. Patients were enrolled if they received vancomycin and piperacillin-tazobactam, vancomycin and cefepime, or vancomycin and meropenem exclusively. Patients initially admitted to the ED were included. Patients with hospital stay duration of < 1 h, receiving dialysis, or with missing data were excluded. Acute kidney injury was defined as Kidney Disease: Improving Global Outcomes stage 2 or 3 based on serum creatinine component. Propensity score matching was used to match patients in the control (vancomycin and meropenem or vancomycin and cefepime) and treatment (vancomycin and piperacillin-tazobactam) groups, and ORs were calculated. Sensitivity analyses were performed to study the effect of longer courses of combination therapy and patients with renal insufficiency on admission. RESULTS: Thirty-five thousand six hundred fifty-four patients met inclusion criteria (vancomycin and piperacillin-tazobactam, n = 27,459; vancomycin and cefepime, n = 6,371; vancomycin and meropenem, n = 1,824). Vancomycin and piperacillin-tazobactam was associated with a higher risk of acute kidney injury and initiation of dialysis when compared with that of both vancomycin and cefepime (Acute kidney injury: OR, 1.37 [95% CI, 1.25-1.49]; dialysis: OR, 1.28 [95% CI, 1.14-1.45]) and vancomycin and meropenem (Acute kidney injury: OR, 1.27 [95%, 1.06-1.52]; dialysis: OR, 1.56 [95% CI, 1.23-2.00]). The odds of acute kidney injury developing was especially pronounced in patients without renal insufficiency receiving a longer duration of vancomycin and piperacillin-tazobactam therapy compared with vancomycin and meropenem therapy. INTERPRETATION: VPT is associated with a higher risk of acute kidney injury than both vancomycin and cefepime and vancomycin and meropenem in patients in the ICU, especially for patients with normal initial kidney function requiring longer durations of therapy. Clinicians should consider vancomycin and meropenem or vancomycin and cefepime to reduce the risk of nephrotoxicity for patients in the ICU.

[A Case of Thrombocytopenia Following Minocycline Administration].

Drug-induced thrombocytopenia is associated with bleeding tendency and suggests the need for the immediate suspected drug withdrawal. Patients with drug-induced thrombocytopenia usually experience an acute drop in platelet (PLT) levels a week or two after starting a new medication. Thrombocytopenia has both immune and non-immune mechanisms. Minocycline (MINO)-induced thrombocytopenia is rare; thus, there are few studies of this condition. In the present study, intravenous administration of MINO led to thrombocytopenia. The female patient was 80 years old. She was receiving radiation therapy for tongue cancer and medication for pain control. She had fever and aspiration pneumonia and was being treated with an antibacterial drug. Empiric therapy consisting of intravenous administration of tazobactam/piperacillin was performed; however, inflammation and fever did not improve. The bacterial drug was changed to vancomycin and cefmetazole. Sputum culture was positive for Enterobacter cloacae thus, we changed her treatment to MINO. Seven days after starting MINO, PLT levels were low; however, they recovered when treatment was stopped. Our findings suggest that MINO may rarely cause severe thrombocytopenia; thus, it is necessary to observe the patient's blood collection.

Nephrotoxin Exposure and Acute Kidney Injury in Adults.

BACKGROUND: Rates of nephrotoxic AKI are not well described in adults due to lack of a clear definition, debate over which drugs should be considered nephrotoxins, and illness-related confounding. Nephrotoxic Injury Negated by Just-in Time Action (NINJA), a program that reduces rates of nephrotoxic AKI in pediatric populations, may be able to address these concerns, but whether NINJA can be effectively applied to adults remains unclear. METHODS: In this retrospective cohort study conducted at the University of Iowa Hospital, we included adult patients admitted to a general hospital floor for ≥48 hours during 2019. The NINJA algorithm screened charts for high nephrotoxin exposure and AKI. After propensity score matching, Cox proportional hazard modeling was used to evaluate the relationship between nephrotoxic exposure and all-stage AKI, stage 2-3 AKI, or death. Additional analyses evaluated the most frequent nephrotoxins used in this population. RESULTS: Of 11,311 patients, 1527 (16%) had ≥1 day of high nephrotoxin exposure. Patients with nephrotoxic exposures subsequently developed AKI in 29% of cases, and 22% of all inpatient AKI events met nephrotoxic AKI criteria. Common nephrotoxins were vancomycin, iodinated contrast dye, piperacillin-tazobactam, acyclovir, and lisinopril. After propensity score matching, Cox proportional hazard models for high nephrotoxin exposure were significantly associated with all AKI (hazard ratio [HR] 1.43, 1.19-1.72, P<0.001), stage 2-3 AKI (HR 1.78, 1.18-2.67, P=0.006), and mortality (HR 2.12, 1.09-4.11, P=0.03). CONCLUSIONS: Nephrotoxin exposure in adults is common and is significantly associated with AKI development, including stage 2-3 AKI.

Piperacillin/tazobactam and risk of acute kidney injury in adults hospitalized with infection without vancomycin: a multi-centre real-world data analysis.

BACKGROUND: There is uncertainty about whether piperacillin/tazobactam (PT) increases the risk of acute kidney injury (AKI) in patients without concomitant use of vancomycin. This study compared the risk of hospital-acquired AKI (HA-AKI) among adults treated with PT or antipseudomonal ß-lactams (meropenem, ceftazidime) without concomitant use of vancomycin. METHODS: This real-world study analysed the data from China Renal Data System and assessed the risk of HA-AKI in adults hospitalized with infection after exposure to PT, meropenem or ceftazidime in the absence of concomitant vancomycin. The primary outcome was any stage of HA-AKI according to the Kidney Disease Improving Global Outcomes guidelines. A multi-variable Cox regression model and different propensity score (PS) matching models were used. RESULTS: Among the 29,441 adults [mean (standard deviation) age 62.44 (16.84) years; 17,980 females (61.1%)] included in this study, 14,721 (50%) used PT, 9081 (31%) used meropenem and 5639 (19%) used ceftazidime. During a median follow-up period of 8 days, 2601 (8.8%) develped HA-AKI. The use of PT was not associated with significantly higher risk of HA-AKI compared with meropenem [adjusted hazard ratio (aHR) 1.07, 95% confidence interval (CI) 0.97-1.19], ceftazidime (aHR 1.09, 95% CI 0.92-1.30) or both agents (aHR 1.07, 95% CI 0.97-1.17) after adjusting for confounders. Results were consistent in stratified analyses, PS matching using logistic regression or random forest methods to generate a PS, and in an analysis restricting outcomes to AKI stage 2-3. CONCLUSIONS: Without concomitant use of vancomycin, the risk of AKI following PT therapy is comparable with that of meropenem or ceftazidime among adults hospitalized with infection.

Relationship between piperacillin concentrations, clinical factors and piperacillin/tazobactam-associated acute kidney injury.

BACKGROUND: Piperacillin/tazobactam, a commonly used antibiotic, is associated with acute kidney injury (AKI). The relationship between piperacillin concentrations and AKI remains unknown. OBJECTIVE: Estimate piperacillin exposures in critically ill children and young adults administered piperacillin/tazobactam to identify concentrations and clinical factors associated with piperacillin-associated AKI. PATIENTS AND METHODS: We assessed piperacillin pharmacokinetics in 107 patients admitted to the paediatric ICU who received at least one dose of piperacillin/tazobactam. Piperacillin AUC, highest peak (Cmax) and highest trough (Cmin) in the first 24 hours of therapy were estimated. Piperacillin-associated AKI was defined as Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2/3 AKI present >24 hours after initial piperacillin/tazobactam dose. Likelihood of piperacillin-associated AKI was rated using the Naranjo Adverse Drug Reaction Probability Scale. Multivariable logistic regression was performed to identify patient and clinical predictors of piperacillin-associated AKI. RESULTS: Out of 107 patients, 16 (15%) were rated as possibly or probably having piperacillin-associated AKI. Estimated AUC and highest Cmin in the first 24 hours were higher in patients with piperacillin-associated AKI (2042 versus 1445 mg*h/L, P = 0.03; 50.1 versus 10.7 mg/L, P < 0.001). Logistic regression showed predictors of piperacillin-associated AKI included higher Cmin (OR: 5.4, 95% CI: 1.7-23) and age (OR: 1.13, 95% CI: 1.05-1.25). CONCLUSIONS: We show a relationship between estimated piperacillin AUC and highest Cmin in the first 24 hours of piperacillin/tazobactam therapy and piperacillin-associated AKI, suggesting total piperacillin exposure early in the course is associated with AKI development. These data could serve as the foundation for implementation of model-informed precision dosing to reduce AKI incidence in patients given piperacillin/tazobactam.

Piperacillin-Tazobactam-Induced Immune Thrombocytopenia: A Case Report.

Drug-induced immune thrombocytopenia is an isolated thrombocytopenia caused by accelerated platelet destruction from drug-dependent, platelet-reactive antibodies. Heparin-induced thrombocytopenia is the most common drug-induced immune thrombocytopenia. Common implicated antibiotics for drug-induced immune thrombocytopenia include ceftriaxone, trimethoprim-sulfamethoxazole, vancomycin, and penicillin. The platelet nadir can be less than 20 × 10 (9)/L and typically occurs within 1 to 2 weeks of exposure to the inciting drug. Although rare, drug-induced immune thrombocytopenia can be fatal. Diagnosis is made by excluding other causes of thrombocytopenia. Laboratory testing for drug-dependent antiplatelet antibodies is often helpful but not required. Thrombocytopenia typically improves within 1 to 2 days of drug discontinuation and platelet count returns to normal within a week. Identifying and discontinuing the implicated medication is key to prevention of serious complications. A patient case of drug-induced immune thrombocytopenia is described after initiation of empiric piperacillin-tazobactam for refractory right foot cellulitis in the setting of right fourth toe diabetic ulcer.

Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.