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.

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.

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.

Impact of Empiric Linezolid for Necrotizing Soft Tissue Infections on Duration of Methicillin-Resistant Staphylococcus aureus-Active Therapy.

Background: Necrotizing soft tissue infections (NSTIs) require prompt surgical debridement and antimicrobial therapy. Indicated antimicrobial therapy involves broad-spectrum coverage against common pathogens and toxin inhibition. Linezolid provides both methicillin-resistant Staphylococcus aureus (MRSA) coverage and toxin inhibition, however, there is limited evidence evaluating its role in empiric treatment. The purpose of this study was to evaluate the impact of empiric linezolid use for NSTIs on the total duration of MRSA-active therapy. Patients and Methods: This retrospective, single-center study included adult surgical intensive care unit (ICU) patients treated with empiric vancomycin and clindamycin or linezolid along with gram-negative and anaerobe coverage for NSTIs. The primary end point of this study was the duration of MRSA-active therapy. Secondary end points included ICU and hospital length of stay (LOS; days), new-onset acute kidney injury (AKI), and Clostridioides difficile infection (CDI). Results: There were 21 patients in the vancomycin/clindamycin cohort and 28 patients in the linezolid cohort. The average duration of vancomycin was 3.9 days versus 2.9 days of linezolid (p = 0.04). The average hospital LOS for the vancomycin/clindamycin cohort was somewhat longer than the linezolid cohort, although the difference was not statistically significant (p = 0.07), and the incidence of new-onset AKI during hospitalization was higher in the vancomycin/clindamycin cohort (38.1% vs. 0%; p < 0.001). No differences were observed for ICU LOS or CDI. Conclusions: Empiric linezolid use for NSTI was associated with one less day of MRSA-active therapy and lower incidence of new-onset AKI during hospitalization. Linezolid was a safe and effective alternative to vancomycin/clindamycin for empiric treatment of NSTIs.

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.

Impact of supplemental individual verbal defense on confidence, engagement, and performance in a team-based learning therapeutics course.

BACKGROUND AND PURPOSE: Team-based learning (TBL) has been successfully applied to multiple healthcare education disciplines. A primary tenet of TBL is the development of solutions leveraging the collective knowledge of a team rather than the individual competency of any one student. In an effort to enhance individual student accountability, an individual verbal defense (IVD) format was implemented in a multi-campus TBL-based pharmacotherapeutics course. The study sought to investigate the use of TBL-IVD embedded within a traditional TBL format on student engagement, teaching style preferences, and exam performance compared to a TBL-only format. EDUCATIONAL ACTIVITY AND SETTING: In this cross-sectional study, second-year pharmacy students enrolled in a pharmacotherapeutics course during fall 2019 completed an 11-item survey. The survey was designed to assess TBL-IVD on student engagement and teaching style preference. Free-response qualitative feedback was solicited to assess positive-negative themes related to the activity. Aggregate exam performance for community-acquired pneumonia (CAP) related content was compared to historical exam data to assess the impact on student performance. FINDINGS: The majority of students (72%, n = 54) preferred the TBL-IVD compared to a TBL-only format. Students reported higher engagement with TBL-IVD (84%, n = 63). Correct exam responses for CAP related content were higher in the TBL-IVD group (67% vs. 55%, P < .001). Positive themes included an increased opportunity to defend recommendations verbally and increased interaction with an on-campus faculty member. SUMMARY: The study demonstrates the addition of IVD can enhance student perceptions, confidence, and performance within a large, multi-campus, TBL-based pharmacotherapeutics course.

Doing More With Less: Review of Dolutegravir-Lamivudine, a Novel Single-Tablet Regimen for Antiretroviral-Naïve Adults With HIV-1 Infection.

OBJECTIVE: To review data on efficacy and safety of dolutegravir (DTG) and lamivudine (3TC) in treatment-naïve adults with HIV-1 infection. DATA SOURCES: Phase III clinical trials and review articles were identified through PubMed (1996 to March 2020) and ClinicalTrials.gov (2000 to May 2020) using the keywords dolutegravir, lamivudine, and HIV. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials and review articles available in English evaluating efficacy and safety of DTG and 3TC were included. DATA SYNTHESIS: The once-daily, single-tablet regimen of DTG/3TC is the first dual antiretroviral therapy (ART) recommended for initial therapy in treatment-naïve adults with HIV-1 infection. DTG and 3TC were compared with a regimen of DTG and tenofovir disoproxil fumarate/emtricitabine in the GEMINI studies and demonstrated noninferiority for the primary end point of virological suppression at up to 96 weeks. No treatment-emergent resistance mutations were identified in a small group of participants who did not reach virological suppression. The regimen is well tolerated, and the most common adverse events reported in trials include headache, diarrhea, nausea, insomnia, and fatigue. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This dual-ART regimen is a favorable treatment option for ART-naïve patients with HIV-1 RNA <500 000 copies/mL, absence of hepatitis B virus, and no resistance to DTG or 3TC. Benefits of dual ART include reduction in treatment-related adverse events and toxicities, drug interactions, and cost. In addition, the once-daily, single-tablet formulation promotes adherence. CONCLUSIONS: DTG/3TC has demonstrated efficacy in maintaining virological suppression in ART-naïve patients at up to 96 weeks while minimizing treatment-related adverse events and toxicities.

In Vitro Activity of Ceftolozane/Tazobactam vs Nonfermenting, Gram-Negative Cystic Fibrosis Isolates.

Ceftolozane/tazobactam (C/T) was tested and compared against 93 nonfermenting, Gram-negative clinical isolates from cystic fibrosis specimens. Based on current breakpoints for intra-abdominal and urinary tract infections (which may not be appropriate for pulmonary infections), C/T was found to be the most active agent against P. aeruginosa (95.7% susceptible), followed by piperacillin/tazobactam (89.4% susceptible). For other Gram-negative pathogens included, C/T had varying activity.

Clinical experience with ceftazidime/avibactam for treatment of antibiotic-resistant organisms other than Klebsiella pneumoniae.

BACKGROUND: Ceftazidime/avibactam is a newly approved ß-lactam/ß-lactamase inhibitor combination with activity against antibiotic-resistant Gram-negative organisms, including many carbapenem-resistant strains. Although this agent may offer a promising treatment option for serious infections with limited alternatives available, clinical experience with ceftazidime/avibactam in treatment of infections caused by multidrug-resistant Gram-negative organisms other than Klebsiella pneumoniae is limited. METHODS: A retrospective case series was performed to evaluate patients treated with ceftazidime/avibactam for infections caused by organisms other than K. pneumoniae at our institution over a 1-year period. Patients aged at least 18 years who received at least one dose of ceftazidime/avibactam were eligible for inclusion. Clinical and microbiological data were collected, and investigators assessed adverse effects, microbiological cure, clinical success, and 30-day in-hospital mortality following completion of ceftazidime/avibactam therapy. RESULTS: Ten patients were included. The most common index infection was pneumonia (n = 6/13, 46%) and the most frequently isolated organism was Pseudomonas aeruginosa (n = 8/21, 38%). Fifty percent of patients received ceftazidime/avibactam as monotherapy. Microbiological cure was achieved in 67% (n = 6/9) of patients and 70% (n = 7/10) of patients met criteria for clinical success. The 30-day in-hospital mortality rate was 30%. No patients experienced adverse events because of ceftazidime/avibactam therapy. CONCLUSIONS: For infections caused by antibiotic-resistant Gram-negative organisms other than K. pneumoniae, clinical and microbiological success rates for patients treated with ceftazidime/avibactam were similar to those that have been reported for K. pneumoniae. Ceftazidime/avibactam appears to be a promising treatment option for infections caused by a variety of resistant Gram-negative organisms when limited alternatives exist.