Piperacillin-tazobactam Group Research Articles

Effect of Targeted Single-Dose Antibiotics to Reduce the Occurrence of Pediatric Central Line–Associated Bloodstream Infections Post Alteplase Administration

OBJECTIVE Previous studies have shown an association between alteplase for line clearance and central line–associated bloodstream infections (CLABSIs). The objective of this study was to evaluate the use of post-alteplase antibiotics as a CLABSI reduction strategy in pediatric intensive care unit (PICU) patients. METHODS This was a single center, retrospective, observational study evaluating PICU patients from ­January 1, 2014, through August 1, 2021, conducted at a tertiary academic PICU. Included in this study were critically ill patients who had 1 or more central venous lines (CVLs) requiring alteplase for line clearance. The primary objective was incidence of CLABSI occurrence post alteplase administration for CVL clearance, with or without targeted single-dose antibiotics (piperacillin-tazobactam or vancomycin) post alteplase. Secondary outcomes included evaluation of total alteplase administrations and risk factors associated with CLABSI occurrence. RESULTS Two hundred fifty patients were included, with 156 receiving alteplase only, 82 piperacillin-­tazobactam, and 12 vancomycin, and with median ages of 2.8, 3.8, and 3.8 years, respectively. Seven ­CLABSIs occurred in the alteplase-only group, with 0 incidences in both the piperacillin-tazobactam (exact OR, 0.12; exact 95% CI, <0.01–0.59; p < 0.01) and vancomycin (exact OR, 1.20; exact 95% CI, 0.03–9.80; p = 1.00) groups. Patients in the piperacillin-tazobactam group achieved statistical significance for CLABSI risk factors that may benefit by decreasing CLABSI incidence (p values <0.01–0.02). CONCLUSIONS Alteplase use has been associated with CLABSIs. Providing a single dose of post-alteplase antibiotics targeting the most likely site-specific pathogens may reduce the incidence of CLABSIs.

Population Pharmacokinetic Modeling of Cefepime, Meropenem, and Piperacillin-Tazobactam in Patients with Cystic Fibrosis.

Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to beta-lactam antibiotics. The pharmacokinetics of these agents are inadequately characterized in patients with CF. One hundred fifty-five pediatric and adult participants with CF receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK analysis was conducted using nonlinear mixed-effects modeling. Clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations were performed to evaluate probability of target attainment (PTA) for different dosing regimens. Estimated creatinine clearance, and total or lean body weight, affected the pharmacokinetics of cefepime and meropenem. No covariates were identified for piperacillin and tazobactam. In the cefepime group, a 3-h infusion achieved higher PTA than a 0.5-h infusion for all participants. Estimated breakpoints (the respective minimum inhibitory concentration (MIC) up to which ≥90% of patients are predicted to reach a PK/PD target) were two- to four-fold higher in pediatric participants receiving a 3-h vs. 0.5-h infusion. In the meropenem group, increased creatinine clearance led to reduced PTA. In the piperacillin-tazobactam group, total daily dose and mode of administration were principal drivers of PTA. Standard dosing regimens fail to achieve specific MIC targets in patients with CF. Therefore, clinicians should incorporate local antibiograms and PK models to determine optimal dosing. Further PK optimization to account for interindividual differences could be achieved by real-time beta-lactam therapeutic drug monitoring.

Chloramphenicol treatment revisited - demographics, clinical characteristics, and outcomes of hospitalized patients.

Limited literature exists on chloramphenicol's clinical use. In this retrospective, single-center case-series, we examined 183 chloramphenicol-treated and 81 piperacillin-tazobactam-treated medical patients. Chloramphenicol recipients were older, more debilitated, cognitively impaired, and penicillin allergic, while increased need for inotropics, higher leukocyte count, and higher creatinine levels were notable in the piperacillin-tazobactam group. Pneumonia was the most common indication, with no mortality difference between groups. While acknowledging its antimicrobial activity and potential benefit in specific conditions such as pneumonia, further clinical studies are needed to assess the role of chloramphenicol in the setting where other alternatives are available.

Antibiotic prophylaxis with piperacillin–tazobactam reduces organ/space surgical site infection after pancreaticoduodenectomy: a retrospective and propensity score-matched analysis

BackgroundThe occurrence of surgical site infection (SSI) after pancreaticoduodenectomy (PD) is still relatively high. The aim of this retrospective study is to evaluate the efficacy of piperacillin-tazobactam as perioperative prophylactic antibiotic on organ/space SSI for patients underwent PD.MethodsFour hundred seven consecutive patients who underwent PD between January 2018 and December 2022 were enrolled and analyzed retrospectively. The univariate and multivariate analysis were used to identify independent risk factors of organ/space SSI. Postoperative complications were compared between the two groups according to the use of prophylactic antibiotics by a ratio of 1:1 propensity score-matched (PSM) analysis.ResultsBased on perioperative prophylactic antibiotic use, all 407 patients were divided into the ceftriaxone group (n = 192, 47.2%) and piperacillin–tazobactam group (n = 215, 52.8%). The rate of organ/space SSI was 31.2% with the choice of perioperative antibiotics (OR = 2.837, 95%CI = 1.802–4.465, P < 0.01) as one of independent risk factors. After PSM, there were similar baseline characteristics among the groups. Meanwhile, the piperacillin–tazobactam group had a significant lower rate of organ/space SSI compared to the ceftriaxone group both before and after PSM(P < 0.05).ConclusionsThe adoption of piperacillin–tazobactam as perioperative prophylaxis for patients underwent PD reduced organ/space SSI significantly.

Antibiotic definitive treatment in ventilator associated pneumonia caused by AmpC-producing Enterobacterales in critically ill patients: a prospective multicenter observational study

BackgroundVentilator associated pneumonia (VAP) due to wild-type AmpC-producing Enterobacterales (wtAE) is frequent in intensive care unit (ICU) patients. Despite a low level of evidence, definitive antimicrobial therapy (AMT) with third generation cephalosporins (3GCs) or piperacillin is discouraged.MethodsObservational prospective study including consecutive wtAE VAP patients in 20 French ICUs. The primary objective was to assess the association of the choice of definitive AMT, i.e. piperacillin ± tazobactam (PTZ), 3GCs or other molecule (4GCs, carbapenems, quinolones, cotrimoxazole; control group), with treatment success at day-7. Recurrence of infection was collected as a secondary outcome, and analyzed accounting for the competing risk of death.ResultsFrom February 2021 to June 2022, 274 patients were included. Enterobacter cloacae was the most prevalent specie (31%). Seventy-eight patients (28%) had PTZ as definitive AMT while 44 (16%) had 3GCs and 152 (56%) were classified in the control group. Day-7 success rate was similar between the 3 groups (74% vs. 73% vs. 68% respectively, p = 0.814). Recurrence probability at day-28 was 31% (95% CI 21–42), 40% (95% CI 26–55) and 21% (95% CI 15–28) for PTZ, 3GCs and control groups (p = 0.020). In multivariable analysis, choice of definitive AMT was not associated with clinical success, but definitive AMT with 3GCs was associated with recurrence at day-28 [csHR(95%CI) 10.9 (1.92–61.91)].ConclusionChoice of definitive antimicrobial therapy was not associated with treatment success at day 7. However, recurrence of pneumonia at day-28 was higher in patients treated with third generation cephalosporins with no differences in mortality or mechanical ventilation duration.

Piperacillin/Tazobactam Use vs Cefepime May Be Associated With Acute Decompensated Heart Failure.

Piperacillin/tazobactam (PTZ) has been cautiously used or avoided in patients with a history of heart disease due to concern for heart failure (HF) exacerbation given its relatively high sodium content. However, no prior studies have established this association. The Antimicrobial Stewardship Team at the James H. Quillen Veterans Affairs Medical Center reviewed the use of PTZ vs the comparator antibiotic, cefepime, in 2 consecutive years to determine whether the use of PTZ was more likely to be associated with acute decompensation of HF. Records of 389 veterans hospitalized in 2018 and 2019 were reviewed and included in this study. Acute decompensation of HF was significantly associated with the use of PTZ (n = 25; 12.3%) compared with cefepime (n = 4; 2.2%) (P < .001). Additionally, hospital readmissions due to HF were higher in the PTZ group compared with the cefepime group (11 vs 1, P = .02). There were no significant differences identified in the length of stay or overall mortality between 204 patients who received PTZ compared with 185 patients who received cefepime (P = .54 and P = .63, respectively). PTZ use was significantly associated with a higher incidence of acute decompensation of HF and hospital readmission with HF exacerbation compared with cefepime. PTZ use among hospitalized patients with a history of HF should be carefully monitored or avoided.

Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis

Abstract Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. The management of these infections becomes increasingly complex due to decreased antimicrobial susceptibility and inadequate pharmacokinetic/pharmacodynamic (PK/PD) characterization of the most commonly used antimicrobial agents in this population. Methods One hundred fifty-five pediatric and adult participants receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK (PopPK) analysis was conducted using nonlinear mixed effects modeling in NONMEM, and clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) for different dosing regimens. Multiple targets, defined as percentage of a 24-h time period that the free drug concentration exceeds the MIC (fT&amp;gt; MIC), were selected based on prior studies of beta-lactam antibiotics. Results Preliminary PopPK modeling results show that lean body weight, creatinine clearance, daily dose, mode of administration (standard vs. extended infusion), and age affect PK parameters, with varying effects by drug. As anticipated, extended or continuous infusions resulted in higher PTA (Table 1). In the cefepime group, the 3-h infusion regimen achieved higher PTAs than the 0.5-h regimen across all age groups. Estimated breakpoints (in which ≥ 90% of patients are expected to achieve a PK/PD target) were 2-4 fold higher in pediatric participants receiving a 3-h infusion vs. 0.5-h infusion, based on age and target fT&amp;gt; MIC. In the meropenem group, increased creatinine clearance led to reduced PTA, and in the piperacillin-tazobactam group, total daily dose and interval were the principal drivers of PTA. Conclusions To our knowledge, this is the largest PopPK study to date of these antimicrobials in individuals with CF. Clinicians should incorporate local antibiograms with these PopPK models to determine optimal dosing in patients with CF, since standard dosing regimens may fail to achieve specific PK/PD targets. This population may also benefit from beta-lactam therapeutic drug monitoring.

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

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. To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. 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. Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. 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. 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]). 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. ClinicalTrials.gov Identifier: NCT05094154.

The clinical efficacy of cefoperazone-sulbactam versus piperacillin-tazobactam in the treatment of severe community-acquired pneumonia.

The objective was to compare the clinical efficacy of cefoperazone-sulbactam with piperacillin-tazobactam in the treatment of severe community-acquired pneumonia (SCAP). The retrospective study was conducted from March 1, 2018 to May 30, 2019. Clinical outcomes were compared for patients who received either cefoperazone-sulbactam or piperacillin-tazobactam in the treatment of SCAP. A total of 815 SCAP patients were enrolled. Among them, 343 received cefoperazone-sulbactam, and 472 received piperacillin-tazobactam. Patients who received cefoperazone-sulbactam presented with higher Charlson Comorbidity Index scores. (6.20 ± 2.77 vs 5.72 ± 2.61; P = .009). The clinical cure rates and effectiveness for patients receiving cefoperazone-sulbactam and piperacillin-tazobactam were 84.2% versus 80.3% (P = .367) and 85.4% versus 83.3% (P = .258), respectively. In addition, the overall mortality rate of the cefoperazone-sulbactam group was 16% (n = 55), which was also comparable to the piperacillin-tazobactam group (17.8%, n = 84, P = .572). The primary clinical outcomes for patients receiving cefoperazone-sulbactam were superior compared to those receiving piperacillin-tazobactam after adjusting disease severity status. The clinical efficacy of cefoperazone-sulbactam in the treatment of adult patients with SCAP is comparable to that of piperacillin-tazobactam. After adjusting for disease severity, cefoperazone-sulbactam tended to be superior to piperacillin-tazobactam.

The effect of meropenem versus piperacillin-tazobactam in critically ill patients with sepsis and septic shock

BackgroundAntibiotics are a popular and efficient treatment for sepsis and septic shock. However, there is presently little proof of Meropenem with piperacillin-therapeutic tazobactam's benefits. MethodsFrom January 1, 2010 to January 1, 2021, we treated a total of 1244 patients with sepsis and septic shock using either Meropenem (n = 622, 1 g every 8 h) or piperacillin-tazobactam (n = 622, 3.375 g or 4.5 g every 8 h). The intervention was administered for 7 days following randomization and continued for up to 14 days thereafter, or until the patient was discharged from the critical care unit or passed away, whichever occurred first. ResultsFirst, we discovered that there were no significant changes in the duration of stay in ICU, Cardiovascular in SOFA, Coagulation in SOFA, Hepatic in SOFA, or Central Nervous System in SOFA between the meropenem alone group and the piperacillin-tazobactam group. In addition, WBC beyond the standard limit was 68.00% in the meropenem alone group against 61.89% in the piperacillin-tazobactam group (P = 0.03). However, Meropenem had a lower mortality rate on ventilator-free days, vasopressor-free days, and hospital-free days. ConclusionThis procedure may offer clinical evidence for the safety and efficacy of meropenem with piperacillin-tazobactam in critically sick patients with sepsis and septic shock.

Cefepime Versus Piperacillin-Tazobactam for the Treatment of Intra-Abdominal Infections Secondary to Potential AmpC Beta-Lactamase-Producing Organisms.

Background: Recent studies have established cefepime as an effective treatment option for AmpC beta-lactamase (AmpC) Enterobacterales; however, the efficacy of beta-lactam/beta-lactamase inhibitors is unclear. Objective: The objective of this study was to determine if piperacillintazobactamis an appropriate alternative to cefepime for the treatment of intra-abdominal infections (IAIs) secondary to AmpC-producing organisms. Methods: This multicenter, retrospective cohort study was conducted in hospitalized adults with an IAI caused by an AmpC-producing organism and received either cefepime or piperacillin-tazobactam for definitive treatment after a source control procedure. The primary outcome was a composite of surgical site infections, recurrent IAIs, or in-hospital mortality. Secondary outcomes included the individual components of the composite outcome, hospital length of stay (LOS), microbiologic failure, study antibiotic duration, time to clinical resolution, and incidence of Clostridioides difficile infection (CDI). Results: This study included 119 patients. There was no difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (35% vs 27%, P = 0.14). Microbiological failure was the only secondary outcome with an observed difference between groups (17% vs 0%, P = 0.01): hospital LOS (15 vs 13 days, P = 0.09), days of therapy (7 vs 7 days, P = 0.87), time to clinical resolution (7 vs 4 days, P = 0.30), and CDI (1% vs 2%, P = 0.58) were all similar.

Efficacy and safety of piperacillin-tazobactam compared with meropenem in treating complicated urinary tract infections including acute pyelonephritis due to extended-spectrum β-lactamase-producing Enterobacteriaceae.

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae pose a huge threat to human health, especially in the context of complicated urinary tract infections (cUTIs). Carbapenems and piperacillin-tazobactam (PTZ) are two antimicrobial agents commonly used to treat cUTIs. A monocentric retrospective cohort study focused on the treatment of cUTIs in adults was conducted from January 2019 to November 2021. Patients with a positive urine culture strain yielding ≥ 103 colony-forming units per milliliter (CFU/mL), and sensitive to PTZ and carbapenems, were included. The primary endpoint was clinical success after antibiotic therapy. The secondary endpoint included rehospitalization and 90-day recurrence of cUTIs caused by ESBL-producing Enterobacteriaceae. Of the 195 patients included in this study, 110 were treated with PTZ while 85 were administered meropenem. The rate of clinical cure was similar between the PTZ and meropenem groups (80% vs. 78.8%, p = 0.84). However, the PTZ group had a lower duration of total antibiotic use (6 vs. 9; p < 0.01), lower duration of effective antibiotic therapy (6 vs. 8; p < 0.01), and lower duration of hospitalization (16 vs. 22; p < 0.01). In terms of adverse events, the safety of PTZ was higher than that of meropenem in the treatment of cUTIs.

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy

Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. ClinicalTrials.gov Identifier: NCT03269994.

1988. Piperacillin-tazobactam plus Ceftriaxone for Enterococcus faecalis endocarditis: A Single Center Experience

Abstract Background Enterococcus faecalis is a leading cause of Infective Endocarditis (IE). IE guidelines recommend combination of penicillin (PCN) or ampicillin (AMP) with ceftriaxone (CTX) in susceptible strains. OPAT allows for antibiotic continuation at home; however outpatient AMP is limited due to frequent dosing and instability. Piperacillin-tazobactam (PTZ) has similar but not identical activity against penicillin binding proteins (PBP) compared to AMP and PCN, suggesting that PTZ may be a substitute in OPAT. This study compares outcomes in those with E. faecalis IE discharged with either PTZ or PCN with CTX. Results of primary outcomes including death at 90 days and readmission at 90 days for those discharged on either PTZ or PCN in combination with CTX for E. faecalis endocarditis Results of non infectious complications and changes in antibiotic therapy in both groups post discharge Methods This single center retrospective study took place from 2016 - 2020. Adults &amp;gt; 18 years with AMP susceptible E. faecalis IE diagnosed using Duke’s criteria and blood or tissue cultures were included, with cultures confirming PCN susceptibility. Primary endpoint was failure of therapy at 90 days, defined as death due to any cause or infection relapse. Secondary outcomes were duration of antibiotics, change in regimen and non-infectious complications. Results Overall, 34 patients were identified, 17 in each group. Average age was 60–80 years, majority having a high Charleston comorbidity index. One did not have available AMP susceptibility but was PCN susceptible. 19 were managed surgically (65% PTZ group, 47% PCN group). Average total antibiotic course was 8.2 and 7.3 weeks in PTZ and PCN groups, with average OPAT course being 4.5 and 4.4 weeks. Primary endpoint was met in 18% patients in the PTZ group and 24% in the PCN group. Of the PCN group, 1 was admitted 4 months later due to an E. faecalis device infection, outside of primary endpoint. Nearly 80% completed antibiotic therapy with 29% in the PTZ group and 35% in the PCN group readmitted for non-infectious complications, including metabolic imbalances, stroke, volume overload and gastro-intestinal bleed. Hyperkalemia was seen in the PCN group with 3 patients requiring readmission. Seizures were not reported with combined PCN and ceftriaxone. Conclusion Similar outcomes were seen using either PTZ or PCN with CTX for treatment of enterococcal IE. Discharging patients on PCN is not always a feasible option. In these instances, PTZ could be considered as an alternative OPAT agent despite dissimilar mechanism of action compared to AMP and PCN. Disclosures All Authors: No reported disclosures.

597. Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis

Abstract Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. The management of these infections becomes increasingly complex due to decreased antimicrobial susceptibility and inadequate pharmacokinetic/pharmacodynamic (PK/PD) characterization of the most commonly used antimicrobial agents in this population. Methods One hundred fifty-five pediatric and adult participants receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK (PopPK) analysis was conducted using nonlinear mixed effects modeling in NONMEM, and clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) for different dosing regimens. Multiple targets, defined as percentage of a 24-h time period that the free drug concentration exceeds the MIC (fT &amp;gt; MIC), were selected based on prior studies of beta-lactam antibiotics. Results Preliminary PopPK modeling results show that lean body weight, creatinine clearance, daily dose, mode of administration (standard vs. extended infusion), and age affect PK parameters, with varying effects by drug. As anticipated, extended or continuous infusions resulted in higher PTA (Table 1). In the cefepime group, the 3-h infusion regimen achieved higher PTAs than the 0.5-h regimen across all age groups (Figure 1, Figure 2). Estimated breakpoints (in which ≥ 90% of patients are expected to achieve a PK/PD target) were 2-4 fold higher in pediatric participants receiving a 3-h infusion vs. 0.5-h infusion, based on age and target fT &amp;gt; MIC (Table 1). In the meropenem group, increased creatinine clearance led to reduced PTA, and in the piperacillin-tazobactam group, total daily dose and interval were the principal drivers of PTA. Table 1:Breakpoints (mg/L, highest minimum inhibitory concentration (MIC) with ≥ 90% PK target attainment) for different infusion durations, based on Monte Carlo simulations.Figure 1:Comparison of PTA between the two durations of infusion for 50 mg/kg (3 to 11 years) or 2 g (12 years and above) cefepime q8h at the target of 65% fT&amp;gt; MIC.Figure 2:Comparison of PTA between two durations of infusion for 50 mg/kg (3 to 11 years) or 2 g (12 years and above) cefepime q8h at the target of 100% fT&amp;gt; MIC. Conclusion To our knowledge, this is the largest PopPK study to date of these antimicrobials in individuals with CF. Clinicians should incorporate local antibiograms with these PopPK models to determine optimal dosing in patients with CF, since standard dosing regimens may fail to achieve specific PK/PD targets. This population may also benefit from beta-lactam therapeutic drug monitoring. Disclosures C. Buddy Creech, MD, MPH, Altimmune: Advisor/Consultant|Astellas: Advisor/Consultant|Merck: Grant/Research Support|Premier: Advisor/Consultant.

Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase-Producing Enterobacter spp, Citrobacter freundii, Morganella morganii, Providencia spp, or Serratia marcescens: A Pilot Multicenter Randomized Controlled Trial (MERINO-2).

BackgroundCarbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative.MethodsWe enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days.ResultsSeventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, –12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC β-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified.ConclusionsAmong patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen.Clinical Trials RegistrationNCT02437045.

Clinical Efficacy of Cefoperazone-Sulbactam versus Piperacillin-Tazobactam in the Treatment of Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia.

ObjectiveThe aim of this study was to compare the usefulness of cefoperazone-sulbactam and that of piperacillin-tazobactam in the treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).MethodsThis retrospective study included the adult patients receiving cefoperazone-sulbactam or piperacillin-tazobactam against HAP/VAP in nine hospitals in Taiwan from March 1, 2018 to May 30, 2019. Primary outcome was clinical cure rate.ResultsA total of 410 patients were enrolled. Among them, 209 patients received cefoperazone-sulbactam and 201 patients received piperacillin-tazobactam. Overall, cefoperazone-sulbactam group had similar distribution of age, sex, or SOFA scores as piperacillin-tazobactam group. However, cefoperazone-sulbactam had higher comorbidity score and disease severity than piperacillin-tazobactam group (Charlson score: 6.5 ± 2.9 vs 5.7 ± 2.7, p < 0.001; APACHE II score: 21.4 ± 6.2 vs 19.3 ± 6.0, p = 0.002). Regarding clinical outcomes, no significant difference in clinical cure and failure rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical cure rate: 80.9% vs 80.1% and clinical failure rate: 17.2% vs 18.4%, p = 0.943). Moreover, no significant difference in clinical effectiveness and ineffectiveness rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical effective rate: 80.9% vs 80.6% and clinical ineffective rate: 17.7% vs 18.9%, p = 0.711). The all-cause mortality rates of the cefoperazone-sulbactam and piperacillin-tazobactam groups were similar (23.9% vs 20.9%, p = 0.48). After adjustment of Charlson score and APACHE II score, the similarities in these clinical outcomes did not change in overall patients and patients with HAP or VAP.ConclusionFor treating adult patients with nosocomial pneumonia, cefoperazone-sulbactam was as effective as piperacillin-tazobactam.

Assessing the incidence of acute kidney injury with combination vancomycin and piperacillin-tazobactam therapy compared to that of vancomycin and cefepime

Previous studies have shown a correlation between acute kidney injury (AKI) and combination antimicrobial therapy comprising piperacillin-tazobactam and vancomycin. In this study, AKIs were compared in patients who received vancomycin plus piperacillin-tazobactam with those who received vancomycin plus cefepime. We found a statistically significant increase in AKI risk in the vancomycin plus piperacillin-tazobactam group when compared to the vancomycin plus cefepime group using both AKI criteria [KDIGO 18.9% vs. 4.5% (p = 0.0012); RIFLE 11.2% vs. 1.8% (p = 0.0029)]. Vancomycin in combination with piperacillin-tazobactam led to an increased risk of AKI in comparison to vancomycin and cefepime.

Impact of intensifying primary antibiotic prophylaxis in at-home autologous stem cell transplantation program for lymphoma patients

Despite the use of fluoroquinolone (FQ) prophylaxis, neutropenic fever (NF) is the most frequent cause of hospital readmission in ambulatory care programs for patients treated with autologous stem cell transplantation (ASCT). We analyzed the impact of intensifying primary prophylaxis with the addition of piperacillin/tazobactam (PT) to FQ. Between January 2002 and August 2018, 154 lymphoma patients conditioned with BEAM were included (40% received ceftriaxone (Ct) plus FQ and 60% PT plus FQ). NF and hospital readmission were required in 84 vs. 41% (p < .0001) and 12 vs. 1% (p = .007) of patients within the Ct and PT groups, respectively. The multivariate analysis showed that PT plus FQ retained its independent protective factor for NF (odds ratio (OR): 0.13; p < .001) and for hospital readmission (OR: 0.07; p = .01). The use of PT and FQ prophylaxis may effectively prevent episodes of NF and hospitalizations in lymphoma patients managed in our at-home ASCT care model.

Acute kidney injury and vancomycin/piperacillin/tazobactam in adult patients: a systematic review.

The aim of this systematic review was to assess AKI (acute kidney injury) in adult patients, treated with vancomycin (V) + piperacillin/tazobactam (PT) compared to V monotherapy. Studies were found in Pubmed, Web of Science and Scopus databases. Articles not in English, pediatric studies and case reports were excluded. A study is eligible for inclusion if the adjusted Odds ratio (aOR) for AKI in V + PT compared to V monotherapy groups, could be extracted or determined from available data. Six retrospective cohort studies were eligible for inclusion criteria and so they were included in the analysis. All studies separately showed a significant higher risk of developing AKI (OR > 1, p < 0.05) in V + PT group compared to V monotherapy group. Considering the methodological difference of included studies, a random effect model was preferred. The model showed a pooled significant higher risk of developing AKI [OR 2.77 (95% CI 1.94, 3.96), p < 0.0001] in V + PT group compared to V group. Association of V and PT appears to be associated with a greater risk of AKI compared to V in monotherapy. These results may serve as the impetus for further evaluation into true mechanisms behind this additive nephrotoxic effect and its potential implications on mortality.