The OPAT opportunity for beta-lactam individualization.

Beta-lactam therapeutic drug monitoring has been growing in prevalence in the acute care hospital setting. Expansion of its use to outpatient parenteral antimicrobial therapy requires careful consideration of potential logistical and therapeutic barriers.

Trends in the appropriateness of oral antibiotic prescriptions dispensed in the United States from 2010 to 2018.

BACKGROUND: One of the goals established by the United States National Action Plan to Combat Antibiotic-Resistant Bacteria is to reduce inappropriate outpatient antibiotic prescriptions by 50% by 2020. Recent data on the achievement of this goal is lacking. The objective of our study was to examine recent trends in the appropriateness of oral antibiotic prescriptions dispensed to a commercially insured population in outpatient settings in the United States to quantify the relative trend in inappropriate antibiotic prescribing from 2010 to 2018. METHODS: Our cross-sectional analysis examined oral antibiotic prescriptions dispensed in outpatient settings using the IBM MarketScan Commercial Data from January 2010 to December 2018. Trends in the annual proportion of antibiotic prescriptions classified as appropriate, potentially appropriate, inappropriate, or without any medical visit during a 7 days look-back period were estimated using multivariable generalized linear models with Poisson distribution adjusting for beneficiaries' demographic and infectious conditions. RESULTS: Approximately 170 million oral antibiotic prescriptions were dispensed to 86 million beneficiaries during 2010 to 2018. The mean age of the study population was 34.5 (±19.1) years, with 58.4% females and 24.6% children. We observed a 12.9% (95% Confidence Interval [CI] = 12.6%-13.2%; p < 0.01) decline in rates of antibiotic use, from 832 to 727 prescriptions per 1000 beneficiaries, from 2010 to 2018. The proportion of prescriptions classified as appropriate increased by 36.7% (95% CI = 36.4%-36.9%; p < 0.01); potentially appropriate prescriptions increased by 9.3% (95% CI = 9.1%-9.4%; p < 0.01); whereas inappropriate prescriptions and those without a medical visit declined by 11.3% (95% CI = 11.2%-11.4%; p < 0.01) and 14.0% (95% CI = 13.9%-14.2%; p < 0.01), respectively. Similar declining trends were observed in use and proportion of inappropriate prescriptions for broad-spectrum antibiotics. In 2018, amoxicillin and azithromycin were the most common appropriate and inappropriate prescription fills, respectively. CONCLUSION: Although antibiotic use and inappropriate prescribing declined steadily from 2010 to 2018 in the United States, this study demonstrates that we have not achieved the national goal of reducing inappropriate antibiotic prescribing by 50%.

Delayed interval delivery and survivability of the second twin with and without emergency cerclage in dichorionic diamniotic pregnancy. A systematic review.

BACKGROUND: There are no systematic reviews analyzing cervical cerclage's role in improving the perinatal outcome of the second twin in dichorionic diamniotic (DCDA) pregnancies following a second trimester or very early preterm birth of the first twin. OBJECTIVE: The primary objective of this systematic review was to evaluate the effect of rescue cervical cerclage on delaying the delivery of the second twin after the delivery of the first twin in DCDA twin pregnancies. The secondary objective was to analyze the effect of rescue cervical cerclage on the perinatal outcome of the second twin in DCDA pregnancies compared to the non-cerclage group. METHODS: A literature search was performed using PubMed, Medline databases, and the Cochrane Library. The studies selected were limited to human subjects and published online by December 2023. Two sets of results in this systematic review are described; the first set includes the outcomes of pregnancies with a DCDA twin pregnancy from the cohort of case series. The meta-analysis was performed for the cohort, and a combined narrative report was provided for the second set of results for the case reports. RESULTS: A literature search resulted in 27 case series and 36 case reports. The case series analysis demonstrated that the mean gestation age of twin 2 at delivery with cervical cerclage (27.5 weeks) compared to those without cervical cerclage (24.4 weeks) was statistically significant (p < 0.001). Furthermore, analysis of the case series showed that twin 2 with cerclage had a statistically significant increase in latency period (days 44.7 vs 23.67) and birth weight (grams 3320 vs 2460) compared to the group without cerclage (p = -value was 0.001 and 0.01, respectively). It is difficult to draw any significant conclusion with complications of cervical cerclage; however, there were slightly more chorioamnionitis and respiratory distress syndrome in the cerclage group. The case report analysis showed no significant difference with or without cervical cerclage. CONCLUSIONS: From this review, it can be concluded that in DCDA twin pregnancies, cervical cerclage insertion after the extremely premature delivery or miscarriage of twin 1 may increase the gestational age at delivery, prolong the delivery interval, and increase the birth weight of twin 2. However, a large prospective multicenter randomized control trial should be performed to assess the benefit of cervical cerclage in DCDA twins to improve the delivery interval latency period and perinatal outcome of twin 2 after the delivery of twin 1.

Ampicillin-Sulbactam for Carbapenem-Susceptible Acinetobacter baumannii Pneumonia: A Case for High-Dose, Continuous Infusion Dosing Strategy in the Trauma ICU.

Background: The optimal ampicillin-sulbactam dosing regimen for carbapenem-susceptible Acinetobacter baumannii isolates in critically ill trauma patients has not been clearly defined. One strategy to provide the adequate sulbactam dose includes high-dose continuous infusion. Case(s) Description: We present three cases of critically ill trauma patients with augmented renal clearance treated with high-dose ampicillin-sulbactam through an intravenous continuous infusion for ventilator-associated pneumonia. All A. baumannii isolates were susceptible to sulbactam with low minimum inhibitory concentrations. All achieved clinical cure at the end of therapy and no recurrent pneumonia was noted. No clinically substantial adverse effect attributable to ampicillin-sulbactam therapy occurred. Discussion: There is limited evidence to endorse high-dose, continuous infusion ampicillin-sulbactam for treatment of infections caused by carbapenem-susceptible A. baumannii. This report presents three critically ill trauma patients with augmented renal clearance that achieved positive clinical outcomes with higher doses of ampicillin-sulbactam administered through a continuous infusion.

Implementation of standard setting for high-stakes objective structured clinical examinations.

BACKGROUND AND PURPOSE: To describe one institution's approach to transformation of high-stakes objective structure clinical examinations (OSCEs) from norm-referenced to criterion-referenced standards setting and to evaluate the impact of these changes on OSCE performance and pass rates. EDUCATIONAL ACTIVITY AND SETTING: The OSCE writing team at the college selected a modified Angoff method appropriate for high-stakes assessments to replace the two standard deviation method previously used. Each member of the OSCE writing team independently reviewed the analytical checklist and calculated a passing score for active stations on OSCEs. Then the group met to determine a final pass score for each station. The team also determined critical cut points for each station, when indicated. After administration of the OSCEs, scores, pass rates, and need for remediation were compared to the previous norm-referenced method. Descriptive statistics were used to summarize the data. FINDINGS: OSCE scores remained relatively unchanged when switched to a criterion-referenced method, but the number of remediators increased up to 2.6 fold. In the first year, the average score increased from 86.8% to 91.7% while the remediation rate increased from 2.8% to 7.4%. In the third year, the average increased from 90.9% to 92% while the remediation rate increased from 6% to 15.6%. Likewise, the fourth-year average increased from 84.9% to 87.5% while the remediation rate increased from 4.4% to 9%. SUMMARY: Transition to a modified Angoff method did not impact average OSCE score but did increase the number of remediations.

Brincidofovir for disease progression due to suspected tecovirimat resistance in association with advanced HIV.

A man with advanced HIV presented with verrucous plaques 2-3 months after initial mpox infection. He received two courses of tecovirimat without resolution of initial mpox lesions and development of new lesions raising concern for resistance. He was treated with two doses of brincidofovir and demonstrated improvement 6 months later.

Association of piperacillin and vancomycin exposure on acute kidney injury during combination therapy.

Objectives: Acute kidney injury (AKI) is a well-documented adverse effect observed with piperacillin/tazobactam in combination with vancomycin. The pharmacokinetics of these antibiotics when given in combination have not been previously evaluated. The purpose of this study was to compare the exposure of vancomycin + piperacillin/tazobactam in patients with and without AKI. Methods: Ninety adult patients, who received at least 72 h of vancomycin + piperacillin/tazobactam combination therapy and had available serum concentrations of vancomycin and piperacillin were included in the study. Nephrotoxicity was defined as a 1.5-fold increase in serum creatinine within 7 days from baseline. Median daily AUCs were calculated in those with nephrotoxicity (vancomycin + piperacillin/tazobactam 'N') versus those without nephrotoxicity (vancomycin + piperacillin/tazobactam 'WN') during the first 7 days of combination therapy. Results: The overall incidence of AKI in those receiving vancomycin + piperacillin/tazobactam was 20% (18/90). The median daily vancomycin AUCs did not differ between the vancomycin + piperacillin/tazobactam 'WN' and vancomycin + piperacillin/tazobactam 'N' groups. Although not statistically significant, the median daily vancomycin AUCs in the vancomycin + piperacillin/tazobactam 'N' group were numerically greater on Day 5 and trended downwards thereafter. For the piperacillin group, the median daily AUCs did not vary between groups, except on Day 7 where the vancomycin + piperacillin/tazobactam 'WN' group had statistically greater median piperacillin AUC than the vancomycin + piperacillin/tazobactam 'N' group (P = 0.046). Conclusions: Utilizing serum creatinine-defined AKI, our study did not find any significant differences in vancomycin and piperacillin/tazobactam exposure between the groups with and without nephrotoxicity. These data indicate that vancomycin + piperacillin/tazobactam should not be avoided due to the risk of overexposure; instead, clinicians should continue to use these therapies cautiously.

A Randomized Clinical Trial of Bayesian-Guided Beta-Lactam Infusion Strategy and Associated Bacterial Resistance and Clinical Outcomes in Patients With Severe Pneumonia.

BACKGROUND: Antimicrobial resistance is a growing health concern worldwide. The objective of this study was to evaluate the effect of beta-lactam infusion on the emergence of bacterial resistance in patients with severe pneumonia in the intensive care unit. METHODS: Adult intensive care patients receiving cefepime, meropenem, or piperacillin-tazobactam for severe pneumonia caused by Gram-negative bacteria were randomized to receive beta-lactams as an intermittent (30 minutes) or continuous (24 hours) infusion. Respiratory samples for culture and susceptibility testing, with minimum inhibitory concentrations (MIC), were collected once a week for up to 4 weeks. Beta-lactam plasma concentrations were measured and therapeutic drug monitoring was performed using Bayesian software as the standard of care. RESULTS: The study was terminated early owing to slow enrollment. Thirty-five patients were enrolled in this study. Cefepime (n = 22) was the most commonly prescribed drug at randomization, followed by piperacillin (n = 8) and meropenem (n = 5). Nineteen patients were randomized into the continuous infusion arm and 16 into the intermittent infusion arm. Pseudomonas aeruginosa was the most common respiratory isolate (n = 19). Eighteen patients were included in the final analyses. No differences in bacterial resistance were observed between arms ( P = 0.67). No significant differences in superinfection ( P = 1), microbiological cure ( P = 0.85), clinical cure at day 7 ( P = 0.1), clinical cure at end of therapy ( P = 0.56), mortality ( P = 1), intensive care unit length of stay ( P = 0.37), or hospital length of stay ( P = 0.83) were observed. Achieving 100% ƒT > MIC ( P = 0.04) and ƒT > 4 × MIC ( P = 0.02) increased likelihood of clinical cure at day 7 of therapy. CONCLUSIONS: No differences in the emergence of bacterial resistance or clinical outcomes were observed between intermittent and continuous infusions. Pharmacokinetic/pharmacodynamic target attainment may be associated with a clinical cure on day 7.

Cefepime pharmacokinetics in adult extracorporeal membrane oxygenation patients.

BACKGROUND: The impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics/dynamics (PK/PD) of beta-lactam antibiotics have not been well studied in general, but cefepime specifically has the least amount of data. We aimed to investigate whether ECMO alters the PK of cefepime in adult intensive care unit (ICU) patients. METHODS: This single-center, retrospective case-control study evaluated cefepime therapeutic drug monitoring (TDM) results from ECMO patients that were matched 1:1 with TDM results in non-ECMO patients for drug regimen and renal function. The primary outcome was the difference in PK/PD of cefepime in ECMO compared with non-ECMO ICU patients. Secondary outcomes included hospital length of stay, treatment failure, superinfection, bacterial resistance, and survival to discharge. RESULTS: Eighty-two patients were included with 44 matched cefepime concentrations in each group. ECMO patients had higher free maximum concentrations (fCmax) (p = 0.003), lower free minimum concentration (fCmin)/1x minimum inhibitory concentration (MIC) ratios (p = 0.040), and lower attainment of free Cmin/4x MIC (p = 0.010). There were no differences between the groups for free Cmin, time above 1xMIC or 4x MIC, and pharmacokinetic parameters (ke, half-life, and Vd). Of those who survived to discharge, hospital length of stay was longer in the ECMO group (p < 0.001). Patients on ECMO were more likely to experience treatment failure (p = 0.036). The incidence of bacterial resistance, superinfection, or survival were similar among the groups. CONCLUSION: These data suggest that more aggressive empiric dosing may be warranted in patients on ECMO. Therapeutic drug monitoring and future prospective studies would provide more evidence to guide decision making regarding dose adjustments.

Utilization of cefepime therapeutic drug monitoring in febrile neutropenia patients with hematologic malignancies.

INTRODUCTION: Cefepime is a fourth-generation cephalosporin and is a workhorse for the empiric treatment of febrile neutropenia (FN). Beta-lactam therapeutic drug monitoring (TDM) has emerged as a dose optimization strategy in patient populations with altered kinetics. Prior literature has demonstrated that patients with FN exhibit augmented renal clearance which may lead to subtherapeutic drug concentrations with standard dosing regimens. The aim of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) target attainment and clinical outcomes in patients with hematologic malignancies and FN who were treated empirically with cefepime. METHODS: This was a prospective, single-center study of adults with hematologic malignancies and FN admitted to the inpatient unit. The primary outcome was PK/PD target attainment (defined as 100% free time greater than minimum inhibitory concentration (100% fT > MIC)). Secondary clinical outcomes were time to defervescence, time to ANC recovery, in-hospital mortality, and cefepime failure. RESULTS: There were 55 patients in our study. Forty-three (78%) patients achieved the primary outcome of PK/PD target attainment. The mean time to defervescence was similar between those that achieved PK/PD target attainment and those that did not (95% CI -0.75 to 1.25, p = 0.62). CONCLUSIONS: This study showed that standard cefepime dosing in patients with hematologic malignancies and FN does not result in achievement of 100% fT > MIC in all patients. Patients in the group that did not achieve PK/PD target attainment were younger with increased creatinine clearance, indicating that cefepime TDM may be especially beneficial in these patients.

Making the case for precision dosing: visualizing the variability of cefepime exposures in critically ill adults.

OBJECTIVE: To investigate and describe the variability in cefepime exposures among 'real-world', critically ill patients by using population pharmacokinetic modelling and simulations, and with translation of these findings to visualizations. METHODS: A cohort of adult medical ICU patients who received cefepime with therapeutic drug monitoring was studied. Two compartment models were developed to estimate cefepime clearance (Model 1) and simulate cefepime exposures among 1000 patients, each with identical creatinine clearance of 60 mL/min and receiving a regimen of cefepime 1 gram IV over 30 minutes, every 8 hours (Model 2). Variability in the relationship between cefepime clearance and creatinine clearance (CrCL) was visualized, and a random, representative sample of 10 simulated patients was utilized to illustrate variability in cefepime exposures. RESULTS: A total of 75 adult medical ICU patients (52% female) and 98 serum cefepime samples were included in the study. Population parameter estimates for cefepime displayed a wide range of variation in Model 1 (CV: 45% to 95%), with low bias at the individual level at 0.226 mg/L but high bias in the population model 10.6 mg/L. Model 2 displayed similar fits, demonstrating that correcting for individual patient creatinine clearance slightly improves the bias of the population model (bias = 4.31 mg/L). Among 10 simulated patients that a clinician would deem similar from a dosing perspective (i.e. equivalent creatinine clearance), maximum concentrations after three simulated doses varied more than 8-fold from 41.2 to 339 mg/L at the 5th and 95th percentiles, and clearance profiles were highly different. CONCLUSION: Creatinine clearance estimates alone are inadequate for predicting cefepime exposures. Wide variations in cefepime exposure exist among ICU patients, even for those with similar kidney function estimates. Current population adjustment schemes based solely on creatinine clearance will result in unintended high and low exposures leading to safety and efficacy concerns, respectively.

Oral fluoroquinolones and risk of aortic aneurysm or dissection: A nationwide population-based propensity score-matched cohort study.

STUDY OBJECTIVE: To investigate risk of aortic aneurysm or dissection in patients using oral fluoroquinolones compared to those using macrolides in real-world clinical practice among a large US general population. DESIGN: Retrospective cohort study design. DATA SOURCE: MarketScan commercial and Medicare supplemental databases. PATIENTS: Adults patients with at least one prescription fill for fluoroquinolone or macrolide antibiotics. INTERVENTION: Fluoroquinolone or macrolide antibiotics. MEASUREMENTS AND MAIN RESULTS: The primary outcome was estimated incidence of aortic aneurysm or dissection associated with the use of fluoroquinolones compared with macrolides during a 60-day follow-up period in a 1:1 propensity score-matched cohort. We identified 3,174,620 patients (1,587,310 in each group) after 1:1 propensity score matching. Crude incidence of aortic aneurysm or dissection was 1.9 cases per 1000 person-years among fluoroquinolone users and 1.2 cases per 1000 person-years among macrolide users. In multivariable Cox regression, compared with macrolides, the use of fluoroquinolones was associated with an increased risk of aortic aneurysm or dissection (aHR: 1.34; 95% CI: 1.17-1.54). The association was primarily driven by a high incidence of aortic aneurysm cases (95.8%). Results of sensitivity (e.g., fluoroquinolone exposure ranging from 7 to 14 days (aHR: 1.47; 95% CI: 1.26-1.71)) and subgroup analyses (e.g., ciprofloxacin (aHR: 1.26; 95% CI: 1.07-1.49) and levofloxacin (aHR: 1.44; 95% CI: 1.19-1.52)) remained consistent with main findings. CONCLUSIONS: Fluoroquinolone use was associated with a 34% increased risk of aortic aneurysm or dissection compared with macrolide use among a general US population.

Exploring Trends in Social Vulnerability for Pharmacy Students at a Large Public University.

OBJECTIVE: This study aimed to describe trends in social vulnerability (SV) among pharmacy students at a large public college of pharmacy, and to describe differences in SV by race and ethnicity using the Centers for Disease Control and Prevention Social Vulnerability Index (SVI). METHODS: The SVI was determined for each student admitted between Fall 2017 and Fall 2022 using the submitted permanent address for each student in a deidentified fashion. International students and students not from the 50 US states were excluded from the analysis. RESULTS: During the study period, 1427 pharmacy students met the study inclusion criteria and were included in the final analysis. Students from historically minoritized populations accounted for 53.4% (n = 763/1427) of students. The median SVI score for all students was 0.4091 (interquartile range [IQR]: 0.2091-0.6395), which is consistent with low/moderate SV risk. When considering SVI by race, students from historically minoritized populations had a higher median SVI (0.4807 [IQR: 0.2791-0.7071] vs 0.3562 [IQR: 0.1561-0.5523]), and were more likely to come from moderate/high SV regions compared with White students (odds ratio 2.00 [95% confidence interval: 1.609-2.486]). CONCLUSION: Among pharmacy students at a large public university, a substantial proportion of students had moderate/high SV risk, particularly those from historically minoritized backgrounds. Colleges and schools of pharmacy need to consider the unique needs of students from high SV backgrounds and provide intentional equity-based mitigation strategies to maximize the potential for student success for all.

Re-evaluation of cefepime or piperacillin/tazobactam to decrease use of carbapenems in ESBL-producing Enterobacterales urinary tract infections (REDUCE-UTI).

Objectives: To re-examine the use of non-carbapenems (NCBPs), specifically piperacillin/tazobactam and cefepime, for ESBL-producing Enterobacterales (ESBL-E) urinary tract infections (UTIs). Patients: Retrospective cohort study of adults hospitalized between January 2016 and June 2020 with pyuria on urinalysis, a urine culture positive for ESBL-E treated with a study antibiotic (meropenem, ertapenem, cefepime or piperacillin/tazobactam) and did not meet criteria for study exclusion. Methods: To compare carbapenems (CBPs) with cefepime or piperacillin/tazobactam for the treatment of ESBL-E UTI. The primary outcome was clinical cure, defined as complete resolution of signs and symptoms of infection. Secondary outcomes included in-hospital mortality, recurrence within 30 days and resistance emergence within 30 days. Results: One-hundred and thirty-three patients were included, based on definitive therapy received; 69 (51.9%) received CBP and 64 (48.1%) received NCBP therapy. Of the total patient population, 17 (12.8%) were admitted to the ICU, 84 (63.1%) had a complicated UTI and 64 (48.1%) had pyelonephritis. There was no difference in clinical cure between the CBP and NCBP groups (95.7% versus 96.9%, P = 0.999). Additionally, no differences in secondary outcomes were observed. Conclusions: When compared with CBPs, cefepime and piperacillin/tazobactam resulted in similar clinical cure, in-hospital mortality, recurrence and resistance emergence in the treatment of ESBL-E UTI.

Use of therapeutic drug monitoring to characterize cefepime-related neurotoxicity.

STUDY OBJECTIVES: Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime-related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN. DESIGN: This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration-time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity. MAIN RESULTS: Four hundred eighty-one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non-NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non-NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p = 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3-fold increased risk of CRN. CONCLUSION: Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.

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.

Re-evaluation of cefepime or piperacillin-tazobactam to decrease use of carbapenems in extended-spectrum beta-lactamase-producing Enterobacterales bloodstream infections (REDUCE-BSI).

Objective: To re-examine the use of noncarbapenems (NCBPs), specifically piperacillin-tazobactam (PTZ) and cefepime (FEP), for extended-spectrum beta-lactamase-producing Enterobacterales bloodstream infections (ESBL-E BSIs). Design: Retrospective cohort study. Setting: Tertiary-care, academic medical center. Patients: The study included patients hospitalized between May 2016 and May 2019 with a positive blood culture for ESBL-E. Patients were excluded if they received treatment with antibiotics other than meropenem, ertapenem, PTZ, or FEP. Patients were also excluded if they were aged <18 years, received antibiotics for <24 hours, were treated for polymicrobial BSI, or received concomitant antibiotic therapy for a separate gram-negative infection. Methods: We compared CBPs with FEP or PTZ for the treatment of ESBL-E BSI. The primary outcome was in-hospital mortality. Secondary outcomes included clinical cure, microbiologic cure, infection recurrence, and resistance development. Results: Data from 114 patients were collected and analyzed; 74 (65%) patients received carbapenem (CBP) therapy and 40 (35%) patients received a NCBP (30 received FEP and 10 received PTZ). The overall in-hospital mortality was 6% (N = 7), with a higher death rate in the CBP arm than in the N-CBP arm, (8% vs 3%; P = .42). No difference in mortality was detected between subgroups with Pitt bacteremia score ≥4, those requiring ICU admission, those whose infections were cause by a nongenitourinary source or causative organism (ie, 76 had Escherichia coli and 38 had Klebsiella spp). We detected no differences in secondary outcomes between the groups. Conclusion: Compared to CBPs, FEP and PTZ did not result in greater mortality or decreased clinical efficacy for the treatment of ESBL-E BSI caused by susceptible organisms.

Effectiveness and Safety of Beta-Lactam Antibiotics with and without Therapeutic Drug Monitoring in Patients with Pseudomonas aeruginosa Pneumonia or Bloodstream Infection.

This objective of this study was to compare clinical outcomes in hospitalized patients with Pseudomonas aeruginosa pneumonia (PNA) or bloodstream infection (BSI) receiving beta-lactam antibiotic (BLA) infusions with and without the guidance of therapeutic drug monitoring (TDM). A retrospective, parallel cohort study was conducted at two academic medical centers between December 2015 and January 2020, UF Shands Gainesville, which uses BLA TDM for select patients (BLA TDM), and UF Health Jacksonville, which does not use BLA TDM (No-BLA TDM). All hospitalized adult patients with respiratory or blood culture positive for P. aeruginosa who met diagnosis criteria for lower respiratory tract infection with a positive P. aeruginosa respiratory culture and who received ≥48 h of intravenous BLA with in vitro susceptibility within 72 h of positive culture collection were included. The primary outcome was a composite of presumed treatment failure defined as the presence of any of the following from index-positive P. aeruginosa culture collection to the end of BLA therapy: all-cause mortality, escalation of and/or additional antimicrobial therapy for P. aeruginosa infection after 48 h of treatment with susceptible BLA due to worsening clinical status, or transfer to a higher level of care (i.e., the intensive care unit [ICU]). Analyses were adjusted for possible confounding with inverse probability of treatment weighting (IPTW). Two-hundred patients were included (BLA TDM, n = 95; No-BLA TDM, n = 105). In IPTW-adjusted analysis of the primary composite endpoint, BLA TDM demonstrated a significant decrease in presumed treatment failure compared to No-BLA TDM (adjusted odds ratio [aOR] 0.037, 95% confidence interval [CI] [0.013 to 0.107]; P < 0.001). BLA TDM had more 30-, 60- and 90-day infection-related readmissions ([aOR], 11.301, 95% CI (3.595 to 35.516); aOR 10.389, 95% CI [2.496 to 43.239], and aOR 24.970, 95% CI [6.703 to 93.028]) in IPTW analyses. For both unadjusted and IPTW-adjusted cohorts, there was no significant difference in hospital and ICU length of stay, adverse effects while on BLA, or microbiological eradication between BLA TDM and No-BLA TDM. In hospitalized adult patients with P. aeruginosa PNA or BSI, the use of TDM-guided BLA infusions decreased the odds of presumed treatment failure compared to patients receiving BLA infusions without TDM guidance. Future studies should evaluate BLA TDM impact on readmission.

Implementation of a ß-lactam therapeutic drug monitoring program: Experience from a large academic medical center.

PURPOSE: To describe the implementation and operationalization of a ß-lactam (BL) therapeutic drug monitoring (TDM) program at a large academic center. SUMMARY: BLs are the most used class of antibiotics. Suboptimal antibiotic exposure is a significant concern in hospitalized patients, particularly in those with altered pharmacokinetics. BL-TDM provides clinicians the opportunity to optimize drug concentrations to ensure maximal therapeutic efficacy while minimizing toxicity. However, BL-TDM has not been widely adopted due to the lack of access to assays. The University of Florida Shands Hospital developed a BL-TDM program in 2015. This is a consultative service primarily run by pharmacists and is conducted in all patient care areas. An analysis was performed on the first BL-TDM encounter for 1,438 patients. BL-TDM was most frequently performed for cefepime (61%, n = 882), piperacillin (15%, n = 218), and meropenem (11%, n = 151). BL-TDM was performed a median of 3 days (interquartile range, 1-5 days) from BL initiation. Among patients with available minimum inhibitory concentration (MIC) values and trough concentrations, the pharmacokinetic/pharmacodynamic (PK/PD) target of 100% fT>MIC was attained in 308 patients (88%). BL-TDM resulted in a dosage adjustment in 25% (n = 361) of patients. CONCLUSION: Implementation of a BL-TDM program requires the concerted efforts of physicians, pharmacists, nursing staff, phlebotomists, and personnel in the analytical laboratory. Standard antibiotic dosing failed to achieve optimal PK/PD targets in all patients; utilizing BL-TDM, dose adjustments were made in 1 of every 4 patients.

Cefepime Precision Dosing Tool: from Standard to Precise Dose Using Nonparametric Population Pharmacokinetics.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation. Two data sets (680 patients) were used to build the cefepime PK model in Pmetrics, and three data sets (34 patients) were used for the validation. A separate application data set (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 h-1 (adults) and 0.96 h-1 (children), the central volume of distribution was 13.85 L, and the rate of transfer from the central to the peripheral compartments was 1.22 h-1 and from the peripheral to the central compartments was 1.38 h-1. After integration in BestDose, the observed versus predicted cefepime concentration fit using the application data set was excellent (R2 > 0.98), and the median difference between what was observed and what BestDose predicted on a second occasion was 4%. For the OID, cefepime at a 0.5- to 1-g 4-h infusion every 8 to 24 h (q8 to 24 h) with a CrCl of <70 mL/min was needed to achieve a target range of free trough:MIC 1 to 4 at a MIC of 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation, and the median concentration prediction bias was 4%. The OID algorithm was provided.