Kyle C. Molina

Background: Ensitrelvir is an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with associated drug–drug interactions (DDIs) through CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporter-3 (OAT-3) inhibition. We present the development and implementation of an online DDI screener to assess interactions during the STRIVE ensitrelvir trial. Methods: The STRIVE Network is conducting a randomized, double-blind, placebo-controlled trial evaluating ensitrelvir's efficacy and safety in hospitalized adults with coronavirus disease 2019 (COVID-19) and lower respiratory tract involvement. DDI guidance was compiled into a database accessed via a web portal where a multidisciplinary team categorized medications as permitted, prohibited, or conditionally permitted. For prohibited medications, washout periods and start/restart criteria were provided with alternative medication suggestions. Sites could request new medications for addition. After 18 months, a survey was conducted to assess the tool's usefulness. Results: Version 1 of the DDI screener launched in December 2022 with 615 medications, expanding to 1182 through 6 updates by version 7. In 11 cases, prohibited medications were revised to conditionally permit enrollment after dosage adjustments (antihypertensives, anti-infectives, and psychiatric medications). Anticoagulants, immunosuppressants, and emergency use medications posed the greatest challenges due to trial blinding. With 334 participants enrolled across 150 sites in 13 countries, 117192 screener searches were completed by May 2024. The most searched medication classes were antihypertensive, antibiotics, corticosteroids, and anticoagulants. Sites found the DDI screener most helpful during screening/enrollment and valued the washout guidance. Conclusions: DDI resources for investigational medications like ensitrelvir, with high DDI potential, are crucial for safe conduct of clinical trials. Effective implementation requires a multidisciplinary, iterative approach that incorporates real-time feedback from trial sites.

Eravacycline is a synthetic fluorocycline approved by the U.S. Food and Drug Administration in 2018. This study aimed to describe clinical and microbiological outcomes in addition to associated adverse effects of eravacycline used in U.S. hospitals. Real-world, observational study involving patients receiving ≥72 h of eravacycline at 19 medical centers located in all 5 regions of the United States between October 2018 and August 2022. The primary outcome was clinical success, defined as survival and absence of microbiological recurrence at 30 days from the end of eravacycline therapy and clinical improvement within 96 h of eravacycline initiation. In total, 416 patients met study criteria and were evaluated. Index culture specimens were most often isolated from the respiratory tract (24.8%, n = 103/416), wound(s) (20.9%, n = 87/416), or blood (19.5%, n = 81/416). As definitive therapy, eravacycline was most often used to treat infections caused by Enterobacterales spp. (42.3%, n = 176/416; 24.4%, n = 43/176 carbapenem-resistant), Enterococci spp. (24.0%, n = 100/416; 49.0%, 49/100 vancomycin-resistant), and Acinetobacter spp. (23.3%, n = 97/416; 47.4%, n = 46/97 carbapenem-resistant). Clinical success occurred in 75.7% of patients ( n = 315/416). Thirty-nine (9.4%, n = 39/416) patients experienced a treatment emergent adverse event (TEAE) potentially related to eravacycline with the majority (51.3%, n = 20/39) being gastrointestinal intolerance. Only 27 isolates (6.5%, n = 27/416) underwent eravacycline susceptibility testing. Eravacycline is being used to treat a broad range of Gram-negative and Gram-positive bacteria in the United States including those demonstrating multidrug-resistance with consistently low reported drug-related TEAE; however, antimicrobial susceptibility testing and subsequent in vitro susceptibility data of clinical isolates was sparingly performed. IMPORTANCE: The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline’s efficacy in addressing the pressing global challenge of MDR bacterial infections.

IDSA guidelines for invasive candidiasis recommend echinocandins (ECH) as first-line agents for initial therapy, with fluconazole (FLU) as an acceptable alternative. Transitioning from an ECH to FLU is also recommended in clinically stable patients with FLU susceptible isolates. All-cause mortality is high for candidemia, typically due to medical comorbidities in patients who develop candidiasis. The objective of this study is to report outcomes of invasive candidiasis stratified by antifungal therapy received, comparing micafungin (MIC), fluconazole, and micafungin to fluconazole step down therapy. This multicenter, retrospective study was conducted at Scripps Health from 6/1/2019 – 6/30/2022. Adult patients with culture confirmed invasive candidiasis were included. Patients were excluded if they were pregnant, care was withdrawn within 7 days of treatment initiation, or had prolonged course of therapy due to uncontrolled source. The primary endpoint was 28-day mortality based on antifungal therapy. Secondary outcomes included time-to-death among and duration of therapy trends. A total of 95 patients were included. Candida glabrata was most frequently isolated (43.2%) followed by Candida albicans (36.8%). There was no difference in 28-day mortality among patients receiving fluconazole only (15.4%, n = 13), micafungin only (20.5%, n = 44), micafungin only due to fluconazole resistance (12.5%, n = 8), and micafungin to fluconazole step down therapy (13.3%, n = 30), p = 0.849. Among patients who died, there was no difference in time-to-death between groups (p = 0.678) or mortality by organism (C. albicans 37.5%, p = 0.952 and C. glabrata 43.8%, p = 0.958). Six patients with non-C. albicans isolates that were susceptible dose-dependent (SDD) to FLU were successfully treated with FLU step-down therapy with a dose/MIC ratio of > 100. There was no difference in 28-day mortality or time-to-death between patients who received fluconazole versus micafungin for invasive candidiasis. Fluconazole step down therapy (including oral) is a viable option for patients who are candidates, including non-C. albicans SDD organisms. All Authors: No reported disclosures

Augmented renal clearance (ARC) is defined by supraphysiologic renal function and is associated with drug failure due to subtherapeutic drug exposure. Burn patients are cited as being at high risk for ARC, yet rates of ARC have not been well described. This retrospective study described the prevalence and incidence of ARC, and compared 12-hour urine collection values (CrCl-12) vs. common estimates of renal function in assessed patients at an American Burn Association-verified burn center. All thermally injured burn patients with a CrCl-12 result were included. ARC was defined as a CrCl-12 >130 ml/min. Cockcroft-Gault, modification of diet in renal disease (MDRD), and CKD-EPI-2021 estimates were calculated. Over 13 months, 163 CrCl-12 results were collected in 68 patients at a median of 9 days from admission with an average value of 160 ml/min. The median total body surface area (total body surface area [TBSA]%) was 17.25%. ARC prevalence was 70.6% with an incidence of 66.3% in all CrCl-12 assessments. Those with ARC were less likely to have heart failure, P = .007. Age, TBSA%, and trauma were not different between those with or without ARC. ARC incidences in those with TBSAs of ≥20%, <20%, or <10%, were 70.5%, 58.6%, and 76.7%, respectively. Agreement of Cockcroft-Gault, MDRD, and CKD-EPI-2021 to CrCl-12 was moderate to weak and frequently failed to identify ARC. ARC is common in burn patients, regardless of TBSA%. Widely accepted estimations of renal function may be incorrect resulting in under-dosing of medications. Additional research is required to identify burn patients at greatest risk for ARC and subsequent dosing strategies to maintain pharmacologic efficacy without unduetoxicity.

To the Editor—We thank Mahatanan and Kang [ 1] for their commentary on our study. which evaluated the role of dalbavancin (DAL) in the treatment of Staphylococcus aureus bloodstream infections [ 2]. The authors highlight that the majority of our cohort treated with DAL were retrospectively categorized as having uncomplicated bloodstream infection, as defined by Infectious Diseases Society of America (IDSA) guidelines, and that these patients possibly received longer therapy than recommended by current guidelines. Among patients with uncomplicated bacteremia (n = 25), the mean (standard deviation) time of inpatient intravenous therapy was 12.9 (5.1) days, compared with 23.7 (15.6) days in patients with complicated infection (n = 20). Unadjusted rates of 90-day clinical failure at 90 were similar among DAL-treated patients when stratified by disease complication (uncomplicated vs complicated, 12% [3 of 25] vs 15% [3 of 20], respectively). Similar rates of failure were seen in the standard-of-care treatment group for uncomplicated (15.6% [12 of 77]) and complicated disease (20.4% [21 of 103]).

Background: Neutralizing monoclonal antibodies (mAbs) are highly effective in reducing hospitalization and mortality among early symptomatic COVID-19 patients in clinical trials and real-world data. While resistance to some mAbs has since emerged among new variants, characteristics associated with treatment failure of mAbs remain unknown.Methods: This multicenter, observational cohort study included patients with COVID-19 who received mAb treatment between November 20, 2020, and December 9, 2021. We utilized electronic health records from a statewide health system plus state-level vaccine and mortality data. The primary outcome was mAb treatment failure, defined as hospitalization or death within 28 days of a positive SARS-CoV-2 test.Results: COVID-19 mAb was administered to 7406 patients. Hospitalization within 28 days of positive SARS-CoV-2 test occurred in 258 (3.5%) of all patients who received mAb treatment. Ten patients (0.1%) died within 28 days, and all but one were hospitalized prior to death. Characteristics associated with treatment failure included having two or more comorbidities excluding obesity and immunocompromised status (adjusted odds ratio [OR] 3.71, 95% confidence interval [CI] 2.52–5.56), lack of SARS-CoV-2 vaccination (OR 2.73, 95% CI 2.01–3.77), non-Hispanic black race/ethnicity (OR 2.21, 95% CI 1.20–3.82), obesity (OR 1.79, 95% CI 1.36–2.34), one comorbidity (OR 1.68, 95% CI 1.11–2.57), age ≥ 65 years (OR 1.62, 95% CI 1.13–2.35), and male sex (OR 1.56, 95% CI 1.21–2.02). Immunocompromised status (none, mild, or moderate/severe), pandemic phase, and type of mAb received were not associated with treatment failure (all p > 0.05).Conclusions: Comorbidities, lack of prior SARS-CoV-2 vaccination, non-Hispanic black race/ethnicity, obesity, age ≥ 65 years, and male sex are associated with treatment failure of mAbs.

Dalbavancin (DAL) is a long-acting lipoglycopeptide with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). This study investigates DAL as sequential therapy in S. aureus bloodstream infections (BSIs). We conducted a retrospective cohort study from 2014 to 2021 comparing sequential DAL with standard-of-care therapy (SoC) for S. aureus BSI. The primary outcome was 90-day clinical failure (90-day all-cause mortality or 90-day recurrence). Secondary outcomes were incidence of acute kidney injury, creatinine phosphokinase elevations, catheter-related thrombosis, and hospital-acquired infections. Analyses were adjusted using inverse probability of treatment weighting (IPTW). Overall, 225 patients (45 DAL, 180 SoC) were included. DAL patients had a higher incidence of community-acquired infection and persons who use drugs; SoC patients had more comorbidities and a longer duration of bacteremia. MRSA incidence was similar between the DAL and SoC groups. The median length of stay was 16 days among DAL recipients compared with 24 days among SoC recipients. Central catheter placement was 17.8% compared with 57.2% in the SoC group. Ninety-day clinical failure occurred in 13.3% and 18.3% of participants in the DAL and SOC groups, respectively. In IPTW-adjusted analysis, sequential DAL was not associated with 90-day clinical failure (adjusted odds ratio, 0.94; 95% CI, 0.333–2.32). This study provides preliminary evidence that select patients with S. aureus BSI treated with sequential DAL have similar clinical failure rates, with significant reductions in catheter placement and hospital length of stay compared with SoC. Further prospective evaluation is needed.

A liver transplant recipient developed a urinary tract infection with Citrobacter freundii complex and Klebsiella aerogenes, both producing dual carbapenemases (KPC‐3/NDM‐1). Whole‐genome sequencing suggested plasmid transfer between organisms. Silent plasmid transmission highlights emergent threats to infection prevention, with implications for screening and antimicrobial stewardship.

The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults. Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule–based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis. A median (range) of 3 (2–4) blood and 3 (2–5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF C_max and C_min values (interquartile range [IQR]) were 2.97 (1.76–8.56) mg/L and 1.59 (0.77–2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%–10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively. Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic–pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.