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Kyle C Molina, Kathleen A Fairman, David A Sclar Department of Pharmacy Practice, Midwestern University College of Pharmacy–Glendale, Glendale, AZ, USA Background: Opioids are not recommended for routine treatment of migraine because their benefits are outweighed by risks of medication overuse headache and abuse/dependence. A March 2016 US Food and Drug Administration (FDA) safety communication warned of the risk of serotonin syndrome from using opioids concomitantly with 5-hydroxytryptamine receptor agonists (triptans) or serotonergic antidepressants: selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs). Epidemiological information about co-prescribing of these medications is limited. The objective of this study was to estimate the nationwide prevalence of co-prescribing of an opioid with a serotonergic antidepressant and/or triptan in US office-based physician visits made by 1) all patients and 2) patients diagnosed with migraine.Methods: National Ambulatory Medical Care Survey (NAMCS) data were obtained for 2013 and 2014. Physician office visits that included the new or continued prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI were identified. Co-prescribed opioids were stratified by agent to determine the proportion of co-prescriptions with opioids posing a higher risk of serotonergic agonism (meperidine, tapentadol, and tramadol).Results: Of an annualized mean 903.6 million office-based physician visits in 2013–2014, 17.7 million (2.0% of all US visits) resulted in the prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI. Opioid–SSRI/SNRI was co-prescribed in 16,044,721 visits, while opioid–triptan was co-prescribed in 1,622,827 visits. One-fifth of opioid co-prescribing was attributable to higher-risk opioids, predominantly tramadol (18.6% of opioid–SSRI/SNRI, 21.8% of opioid–triptan). Of 7,672,193 visits for patients diagnosed with migraine, 16.3% included opioid prescribing and 2.0% included co-prescribed opioid–triptan.Conclusion: During a period approximately 2 years prior to an FDA warning about the risk of serotonin syndrome from opioid–SSRI/SNRI or opioid–triptan co-prescribing, use of these combinations was common in the USA. Studies on prescribing patterns following the March 2016 warning, and on the risk of serotonin syndrome associated with these co-prescriptions, are needed. Keywords: serotonin syndrome, medication safety, FDA adverse event reporting system, SNRI, SSRI

Importance: During the COVID-19 pandemic, the effective distribution of limited treatments became a crucial policy goal. Yet, limited research exists using electronic health record data and machine learning techniques, such as policy learning trees (PLTs), to optimize the distribution of scarce therapeutics., Objective: To evaluate whether a machine learning PLT-based method of scarce resource allocation optimizes the treatment benefit of COVID-19 neutralizing monoclonal antibodies (mAbs) during periods of resource constraint., Design, Setting, and Participants: This retrospective cohort study used electronic health record data from October 1, 2021, to December 11, 2021, for the training cohort and data from June 1, 2021, to October 1, 2021, for the testing cohort. The cohorts included patients who had positive test results for SARS-CoV-2 and qualified for COVID-19 mAb therapy based on the US Food and Drug Administration's emergency use authorization criteria, ascertained from the patient electronic health record. Only some of the qualifying candidates received treatment with mAbs. Data were analyzed between from January 2023 to May 2024., Main Outcomes and Measures: The primary outcome was overall expected hospitalization, assessed as the potential reduction in overall expected hospitalization if the PLT-based allocation system was used. This was compared to observed allocation using risk differences., Results: Among 9542 eligible patients in the training cohort (5418 female [56.8%]; age distribution: 18-44 years, 4151 [43.5%]; 45-64 years, 3146 [33.0%]; and ≥65 years, 2245 [23.5%]), a total of 3862 (40.5%) received mAbs. Among 6248 eligible patients in the testing cohort (3416 female [54.7%]; age distribution: 18-44 years, 2827 [45.2%]; 45-64 years, 1927 [30.8%]; and ≥65 years, 1494 [23.9%]), a total of 1329 (21.3%) received mAbs. Treatment allocation using the trained PLT model led to an estimated 1.6% reduction (95% CI, -2.0% to -1.2%) in overall expected hospitalization compared to observed treatment allocation in the testing cohort. The visual assessment showed that the PLT-based point system had a larger reduction in 28-day hospitalization compared with the Monoclonal Antibody Screening Score (maximum overall hospitalization difference, -1.0% [95% CI, -1.3% to -0.7%]) in the testing cohort., Conclusions and Relevance: This retrospective cohort study proposes and tests a PLT method, which can be linked to a electronic health record data platform to improve real-time allocation of scarce treatments. Use of this PLT-based allocation method would have likely resulted in fewer hospitalizations across a population than were observed in usual care, with greater expected reductions than a commonly used point system.

Background: Cytomegalovirus retinitis (CMVR) is a well-described complication of CMV disease in immunocompromised hosts. While robust data exists for CMVR in patients with acquired immunodeficiency syndrome (AIDS), the incidence and risk factors for CMVR in solid organ transplant recipients (SOTR) with CMV viremia are less defined., Methods: We performed a retrospective cohort study of SOTR who had CMV viremia and underwent routine ophthalmologic examination between 1/1/2018 and 3/16/2022. Univariate statistics were performed to evaluate risk factors for development of CMVR., Results: Overall, 38 patients were included, primarily kidney (78.9%), heart (7.9%), and liver (7.9%) transplant recipients. Five patients (13.2%) developed CMVR during the study period. CMVR was diagnosed an average 281 days after index transplantation, 84 days from the most recent rejection episode, and 69 days from onset of viremia. Only 1 patient (20%) had symptoms at the time of CMVR diagnosis. CMVR was associated with preceding allograft rejection as well as transplanted organ type., Conclusion: While CMV tissue disease more commonly manifests in other organs, CMVR occurred relatively frequently in this group of high-risk SOTR with CMV viremia. As most of the patients in our study did not have ocular symptoms at the time of diagnosis, routine ophthalmologic screening should be considered in SOTR with CMV viremia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5., Methods: We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality., Results: Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23-0.67], p < 0.001) than no treatment. All-cause mortality at 28 days was numerically lower among remdesivir-treated patients (0.1% vs. 0.4%; aOR 0.32 [95% CI 0.03-1.40]). Similar benefit of RDV treatment on 28-day all-cause hospitalization was observed across Omicron periods, aOR (95% CI): BA.2/BA2.12.1 (0.77[0.19-2.41]), BA.4/5 (0.50[95% CI 0.50-1.01]), BQ.1/BQ.1.1/XBB.1.5 (0.21[95% CI 0.08-0.57]., Conclusion: Among outpatients with SARS-CoV-2 during recent Omicron surges, remdesivir was associated with lower hospitalization than no treatment, supporting current National Institutes of Health Guidelines., (© 2024. The Author(s).)

Background: Antimicrobial resistance among Enterobacterales continues to be a growing problem, particularly in those with urinary infections. Previous studies have demonstrated safety and efficacy with the use of single-dose aminoglycosides in uncomplicated cystitis. However, data in complicated infections are limited. Single-dose aminoglycosides may provide a convenient alternative for those with or at risk for resistant pathogens causing complicated urinary infections, especially when oral options are unavailable due to resistance, allergy, intolerance, or interactions with other medications. This study evaluated the safety and effectiveness of single-dose aminoglycosides in treatment of complicated cystitis in the emergency department (ED)., Methods: This was a multicenter, prospective study performed between July 2022 and March 2023 of patients who met criteria for complicated cystitis and were otherwise stable for discharge at an academic ED. Primary outcomes were clinical or microbiologic failure within 14 days of treatment. Safety was assessed by review of adverse events. Descriptive statistics were used., Results: Thirteen patients were included. Complicating factors were male sex (n = 4), kidney stone (n = 2), urinary catheter (n = 6), recent urologic procedure (n = 1), urinary hardware (n = 1), antibiotic allergy precluding use of alternate oral options (n = 4), immunocompromised status (n = 2), and <1-year history of multidrug-resistant organisms on urine culture (n = 8). Eleven patients (85%) had positive urine cultures in the preceding 12 months with no oral antimicrobial option. Eight patients (62%) received amikacin (median dose 15 mg/kg), four patients (31%) received gentamicin (median dose 5 mg/kg), and one patient (8%) received tobramycin (5 mg/kg) for treatment. Ten patients (77%) reported resolved urinary symptoms after treatment and 11 patients (85%) reported no new urinary symptoms since discharge. No patient required hospital admission for treatment failure, and no adverse events were noted., Conclusions: Single-dose aminoglycosides appear to be a reasonably effective and safe treatment for complicated cystitis, which avoided hospital admission in this cohort., (© 2024 Society for Academic Emergency Medicine.)

Pyoderma gangrenosum is a rare dermatologic disorder that disrupts the skin barrier, requiring immunosuppressive therapy. We successfully used cefiderocol for the treatment of an extensively drug-resistant Pseudomonas aeruginosa bacteremia, and presumed osteomyelitis in a patient with severe pyoderma gangrenosum and associated immunosuppressive therapy while being medically optimized for skin grafting. We obtained bone and skin/subcutaneous tissue while the patient was on cefiderocol under an institutional review board-approved biologic waste recovery protocol. Cefiderocol concentrations in bone and skin/subcutaneous tissue were 13.9 and 35.9 mcg/g, respectively. The patient recovered from bacteremia and underwent autografting without further complications. Cefiderocol at approved dosing of 2 g IV (3-hour infusion) every 8 hours resulted in bone and skin/subcutaneous tissue concentrations adequate to treat extensively drug-resistant Gram-negative bacteria that remain susceptible to cefiderocol., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association.)

Urinary tract infections (UTIs) are one of the most common infections and are frequently caused by Gram-negative organisms. The rise of resistant isolates has prompted evaluation of alternative therapies, including amoxicillin-clavulanate which has potent activity against Ambler class A enzymes. This study sought to evaluate clinical outcomes of patients with ceftriaxone non-susceptible UTIs receiving amoxicillin-clavulanate or standard of care (SOC). This was a single-center, retrospective, cohort study of adult patients with urinary tract infections caused by a ceftriaxone non-susceptible pathogen who received amoxicillin-clavulanate or SOC. The primary outcome was clinical failure at 90 days. Secondary outcomes included time to failure, isolation of a resistant organism, and hospital length of stay. Fifty-nine patients met study inclusion: 26 received amoxicillin/clavulanate and 33 received SOC. Amoxicillin-clavulanate recipients did not have higher failure rates compared to SOC recipients. For patients requiring hospital admission, hospital length of stay was numerically shorter with amoxicillin-clavulanate. The frequency of amoxicillin-clavulanate and carbapenem-resistant organisms did not differ significantly between groups. Amoxicillin-clavulanate may be a useful alternative therapy for the treatment of ceftriaxone non-susceptible Enterobacterales UTIs.

Objectives: To evaluate whether subcutaneous neutralizing monoclonal antibody (mAb) treatment given in the emergency department (ED) setting was associated with reduced hospitalizations, mortality, and severity of disease when compared to nontreatment among mAb-eligible patients with coronavirus disease 2019 (COVID-19)., Methods: This retrospective observational cohort study of ED patients utilized a propensity score-matched analysis to compare patients who received subcutaneous casirivimab and imdevimab mAb to nontreated COVID-19 control patients in November-December 2021. The primary outcome was all-cause hospitalization within 28 days, and secondary outcomes were 90-day hospitalization, 28- and 90-day mortality, and ED length of stay (LOS)., Results: Of 1340 patients included in the analysis, 490 received subcutaneous casirivimab and imdevimab, and 850 did not received them. There was no difference observed for 28-day hospitalization (8.4% vs. 10.6%; adjusted odds ratio [aOR] 0.79, 95% confidence intervals [CI] 0.53-1.17) or 90-day hospitalization (11.6% vs. 12.5%; aOR 0.93, 95% CI 0.65-1.31). However, mortality at both the 28-day and 90-day timepoints was substantially lower in the treated group (28-day 0.6% vs. 3.1%; aOR 0.18, 95% CI 0.08-0.41; 90-day 0.6% vs. 3.9%; aOR 0.14, 95% CI 0.06-0.36). Among hospitalized patients, treated patients had shorter hospital LOS (5.7 vs. 11.4 days; adjusted rate ratio [aRR] 0.47, 95% CI 0.33-0.69), shorter intensive care unit LOS (3.8 vs. 10.2 days; aRR 0.22, 95% CI 0.14-0.35), and the severity of hospitalization was lower (aOR 0.45, 95% CI 0.21-0.97) compared to untreated., Conclusions: Among ED patients who presented for symptomatic COVID-19 during the Delta variant phase, ED subcutaneous casirivimab/imdevimab treatment was not associated with a decrease in hospitalizations. However, treatment was associated with lower mortality at 28 and 90 days, hospital LOS, and overall severity of illness., Competing Interests: All authors attest to meeting the four ICMJE.org authorship criteria., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: Ritonavir-boosted Nirmatrelvir (NMV-r), a protease inhibitor with in vitro activity against SARS-CoV-2, can reduce risk of progression to severe COVID-19 among high-risk individuals infected with earlier variants, but less is known about its effectiveness against omicron variants BQ.1/BQ.1.1/XBB.1.5. We sought to evaluate effectiveness of NMV-r in BQ.1/BQ.1.1/XBB.1.5 omicron variants by comparing hospitalisation rates to NMV-r treated patients during a previous omicron phase and to contemporaneous untreated patients., Methods: We conducted a retrospective observational cohort study of non-hospitalised adult patients with SARS-CoV-2 infection using real-world data from three health systems in Colorado and Utah, and compared hospitalisation rates in NMV-r-treated patients in a BA.2/BA.2.12.1/BA.4/BA.5 variant-predominant (first) phase (April 3, 2022-November 12, 2022), with a BQ.1/BQ.1.1/XBB.1.5 variant-predominant (second) phase (November 13, 2022-March 7, 2023). In the primary analysis, we used Firth logistic regression with a two-segment (phase) linear time model, and pre-specified non-inferiority bounds for the mean change between segments. In a pre-specified secondary analysis, we inferred NMV-r effectiveness in a cohort of treated and untreated patients infected during the second phase. For both analyses, the primary outcome was 28-day all-cause hospitalisation. Subgroup analyses assessed treatment effect heterogeneity., Findings: In the primary analysis, 28-day all-cause hospitalisation rates in NMV-r treated patients in the second phase (n = 12,061) were non-inferior compared to the first phase (n = 25,075) (198 [1.6%] vs. 345 [1.4%], adjusted odds ratio (aOR): 0.76 [95% CI 0.54-1.06]), with consistent results among secondary endpoints and key subgroups. Secondary cohort analyses revealed additional evidence for NMV-r effectiveness, with reduced 28-day hospitalisation rates among treated patients compared to untreated patients during a BQ.1/BQ.1.1/XBB.1.5 predominant phase (198/12,061 [1.6%] vs. 376/10,031 [3.7%], aOR 0.34 [95% CI 0.30-0.38), findings robust to additional sensitivity analyses., Interpretation: Real-world evidence from major US healthcare systems suggests ongoing NMV-r effectiveness in preventing hospitalisation during a BQ.1/BQ.1.1/XBB.1.5-predominant phase in the U.S, supporting its continued use in similar patient populations., Funding: U.S. National Institutes of Health., Competing Interests: NRA reports grants from the US National Institutes of Health (NIH), during the conduct of the study. KCM reports grants from the National Center for Advancing Translational Sciences (NCATS), during the conduct of the study, and grants from the National Institute of Child Health and Human Development (NICHD) and the National Heart, Lung, and Blood Institute (NHLBI), outside of the submitted work. TDB reports grants from the NCATS, during the conduct of the study, and grants from the NICHD and NHLBI, outside of the submitted work. NEC reports grants from the US NIH, during the conduct of the study. AAG reports grants from the US NIH during the conduct of the study, grants from the US Centers for Disease Control, the US Department of Defense, AbbVie, and Faron Pharmaceuticals, and participation on an NIH data safety monitoring board, outside of the submitted work. BJW reports institutional grant support for serving as a investigator for COVID clinical trials sponsored by US Administration for Strategic Preparedness and Response (ASPR) Biomedical Advanced Research and Development Authority (BARDA), NHLBI, Gilead, Regeneron, Abbvie, Roche/Genetech for which he received no direct remuneration, All other authors declare no competing interests., (© 2024 The Author(s).)

Background: Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE)., Methods: We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance., Results: Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5-17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient)., Conclusions: The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance., (© 2024. The Author(s).)

Background: Severe gram-positive infections are frequent in people who inject drugs, and successful completion of treatment presents unique challenges in this population., Objectives: We aimed to evaluate the feasibility of a long-acting antibiotic, dalbavancin, as an alternative to standard-of-care antibiotics for severe infections due to vancomycin-susceptible pathogens requiring ⩾2 weeks of therapy., Design: We designed an investigator-initiated single-arm unblinded prospective cohort study to evaluate the safety and efficacy of an early switch to dalbavancin in two doses administered 1 week apart., Methods: We screened patients admitted with bloodstream infection, osteomyelitis, septic arthritis, infective endocarditis or deep abscesses, and comorbid substance use disorder (SUD) for eligibility. Consenting patients were switched to dalbavancin within 7 days from their index culture. They were monitored in the hospital for efficacy and safety of the treatment until the second dose of dalbavancin 7 days later and then discharged if stable. Study participants were evaluated with a decision support engine for a hypothetical appropriate level of care regarding their SUD after discharge. Their follow-up was planned for 12 months from the index culture, either in-person or via telehealth/telephone., Results: The enrollment was terminated early due to significant loss-to-follow-up. In all, 11 patients were enrolled, 4 completed 12 months of follow-up, 2 completed 8 months of follow-up, and 1 was seen once after discharge. The remaining five patients were lost to follow-up immediately after discharge. All 11 patients continued to improve after switching to dalbavancin between the first and second doses. There were two per-protocol failures of treatment. Dalbavancin was well tolerated, though some adverse events were reported., Conclusion: Dalbavancin may be a safe and effective alternative for an early switch in treating severe gram-positive infections., Trial Registration: The trial was registered as NCT04847921 with clinicaltrials.gov., Competing Interests: The authors declare that there is no conflict of interest. The Editor in Chief of Therapeutic Advances in Infectious Disease is an author on this paper. Therefore, the review process was managed by alternative members of the Editorial Board and the submitting Editor had no involvement in the decision-making process., (© The Author(s), 2024.)

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., Competing Interests: S.A. is a current employee of Nestle Health Sciences. T.M. is currently funded through Stellus Rx and has participated in scientific advisory boards for AbbVie Inc. and Basilea Pharmaceutica. J.A. is a speaker for Shionogi Inc. M.A.K. is a speaker for Tetraphase. M.P.V. received research funding from Paratek Pharmaceuticals, Cumberland Pharmaceuticals, NIAID, and advisory Boards for Ferring Pharmaceuticals, Melinta Therapeutics, and Merck & Co. K.C.M. has consulted for Shionogi. B.M.J. has participated in speaking bureaus for Abbvie, La Jolla, and Paratek. A.L.V.H. has participated in speaking bureaus and has received research funding from Tetraphase. M.J.R. has received research and consulting from or participated in speaking bureaus for Abbvie, Melinta, Merck, Paratek, Shionogi, T2 Biosystems, and Tetraphase (La Jolla). All other authors declare no conflict of interest.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75)., Competing Interests: A.E., T.M., K.L., M.G.T-O., R.V., C.W., Y.H., R.W.S., J.D.Z, A.J.W., A.S., C.L.C, M.M., V.E.U, S.B., K.C.M., M.T., E.A.K., J.B., T.W.G., C.H., M.G.C., D.J.H., J.J.F., M.B., A.O., J.S. have no conflicts of interest to disclose. S.A. is currently an employee of Aimmune Therapeutics, a Nestle Company. J.V.P. has been on advisory boards for Insmed, A2N, Paratek Pharmaceuticals, and Cipla Technologies, and has spoken for Insmed. M.P.V. received research funding from Paratek Pharmaceuticals, Cumberland Pharmaceuticals, Insmed, AN2, Spero, Hillrom, and Electromed. C.M-C. has consulted for HIVE Medical Inc, and has received grant funding from the CDC (CDC# 1U54CK000617-01-00). C.T.F. has spoken for Insmed. R.H. has consulted for and received research funding from Biofire Diagnostics. K.A.C. is currently employed by Janssen pharmaceutical companies of Johnson & Johnson and has received consulting fees from Insmed, Hillrom, Merck, and Microbion, and AN2, unrelated to the current investigation, and was supported by National Heart, Lung, and Blood Institute K08 HL1139994 and the Burroughs Welcome Fund Career Award for Medical Scientists. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Abbvie, Baselia, Ferring, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Tetraphase, and T2 Biosystems and is partially supported by National Institute of Allergy and Infectious Diseases R21 AI163726. Conflicts that the editors considered relevant to the content of the manuscript have been disclosed.

Introduction: Cytomegalovirus (CMV) can cause significant morbidity and mortality in cord blood transplant (CBT) recipients. Development of CMV-specific cell-mediated immunity (CMV-CMI) has been associated with protection against CMV clinically significant reactivation (CsCMV). In this study, we evaluated CMV-CMI reconstitution during letermovir prophylactic therapy, which prevents CsCMV without complete suppression of CMV reactivation., Methods: We measured CMV-CMI in CMV-seropositive CBT recipients pre-transplant after Day+90 of letermovir prophylaxis and at Days +180, and +360- post-transplant using a dual color CMV-specific IFNγ/IL2 FLUOROSpot. CsCMV and nonCsCMV reactivations were abstracted from medical records. CsCMV was defined as CMV viral load ≥5,000 IU/ml using a whole blood assay., Results: Among 70 CBT recipients, 31 developed CMV-CMI by Day+90 and an additional eight and five participants by Days +180 and +360, respectively. Thirty-eight participants developed CMV reactivation, including nine with CsCMV. Most reactivations (33 of 38) occurred before Day+180. Early CMV-CMI was present in six out of nine participants with CsCMV, indicating a lack of protection against CsCMV. Moreover, the magnitude of CMV-CMI at Day+90 did not differ between participants with CsCMV and nonCsCMV., Conclusion: Approximately 50% of CBT recipients reconstituted CMV-CMI during letermovir prophylactic therapy. However, CMV-CMI did not reach levels protective against CsCMV. Extension of CMV prophylaxis beyond Day+90 may be considered in CMV-seropositive CBT recipients., (© 2023 Wiley Periodicals LLC.)

Competing Interests: KCM reports grants from the US National Center for Advancing Translational Sciences, the National Institute of Child Health and Human Development, and National Heart, Lung, and Blood Institute. AAG reports investigator-initiated grants from the US National Institutes of Health, Centers for Disease Control and Prevention, and Department of Defense, AbbVie, and Faron Pharmaceuticals. He served on a US National Institutes of Health data and safety monitoring board.

Objectives: Bebtelovimab is an anti-SARS-CoV-2 monoclonal antibody active against Omicron lineage variants authorized to treat high-risk outpatients with COVID-19. We sought to determine the real-world effectiveness of bebtelovimab during the Omicron phases BA.2/BA2.12.1/BA4/BA5., Methods: We conducted a retrospective cohort study of adults with SARS-CoV-2 infection between April 6 and October 11, 2022, using health records linked to vaccine and mortality data. We used propensity scores to match of bebtelovimab-treated with untreated outpatients. The primary outcome was 28-day all-cause hospitalization. The secondary outcomes were 28-day COVID-19-related hospitalization, 28-day all-cause mortality, 28-day emergency department visits, maximum respiratory support level, intensive care unit admission, and in-hospital mortality among hospitalized patients. We used logistic regression to determine bebtelovimab treatment effectiveness., Results: Among 22,720 patients with SARS-COV-2 infection, 3739 bebtelovimab-treated patients were matched to 5423 untreated patients. Compared with no treatment, bebtelovimab was associated with lower odds of 28-day all-cause hospitalization (1.3% vs 2.1%, adjusted odds ratio: 0.53; 95% confidence interval: 0.37-0.74, P <0.001), as well as COVID-19-related hospitalization (1.0% vs 2.0%, adjusted odds ratio: 0.44 [95% confidence interval: 0.30-0.64], P <0.001). Bebtelovimab appeared to be more beneficial in lowering the odds of hospitalization among patients with two or more comorbidities (interaction P = 0.03)., Conclusion: During the Omicron BA.2/BA.2.12.1/BA.4/BA.5 variant phase, bebtelovimab was associated with lower hospitalization., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Nirmatrelvir is a protease inhibitor with in-vitro activity against SARS-CoV-2, and ritonavir-boosted nirmatrelvir can reduce the risk of progression to severe COVID-19 among individuals at high risk infected with delta and early omicron variants. However, less is known about the effectiveness of nirmatrelvir-ritonavir during more recent BA.2, BA2.12.1, BA.4, and BA.5 omicron variant surges. We used our real-world data platform to evaluate the effect of nirmatrelvir-ritonavir treatment on 28-day hospitalisation, mortality, and emergency department visits among outpatients with early symptomatic COVID-19 during a SARS-CoV-2 omicron (BA.2, BA2.12.1, BA.4, and BA.5) predominant period in Colorado, USA., Methods: We did a propensity-matched, retrospective, observational cohort study of non-hospitalised adult patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, using records from a statewide health system in Colorado. We obtained data from the electronic health records of University of Colorado Health, the largest health system in Colorado, with 13 hospitals and 141 000 annual hospital admissions, and with numerous ambulatory sites and affiliated pharmacies around the state. Included patients had a positive SARS-CoV-2 test or nirmatrelvir-ritonavir medication order. Exclusion criteria were an order for or administration of other SARS-CoV-2 treatments within 10 days of a positive SARS-CoV-2 test, hospitalisation at the time of positive SARS-CoV-2 test, and positive SARS-CoV-2 test more than 10 days before a nirmatrelvir-ritonavir order. We propensity score matched patients treated with nirmatrelvir-ritonavir with untreated patients. The primary outcome was 28-day all-cause hospitalisation., Findings: Among 28 167 patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, 21 493 met the study inclusion criteria. 9881 patients received treatment with nirmatrelvir-ritonavir and 11 612 were untreated. Nirmatrelvir-ritonavir treatment was associated with reduced 28-day all-cause hospitalisation compared with no antiviral treatment (61 [0·9%] of 7168 patients vs 135 [1·4%] of 9361 patients, adjusted odds ratio (OR) 0·45 [95% CI 0·33-0·62]; p<0·0001). Nirmatrelvir-ritonavir treatment was also associated with reduced 28-day all-cause mortality (two [<0·1%] of 7168 patients vs 15 [0·2%] of 9361 patients; adjusted OR 0·15 [95% CI 0·03-0·50]; p=0·0010). Using subsequent emergency department visits as a surrogate for clinically significant relapse, we observed a decrease after nirmatrelvir-ritonavir treatment (283 [3·9%] of 7168 patients vs 437 [4·7%] of 9361 patients; adjusted OR 0·74 [95% CI 0·63-0·87]; p=0·0002)., Interpretation: Real-world evidence reported during a BA.2, BA2.12.1, BA.4, and BA.5 omicron surge showed an association between nirmatrelvir-ritonavir treatment and reduced 28-day all-cause hospitalisation, all-cause mortality, and visits to the emergency department. With results that are among the first to suggest effectiveness of nirmatrelvir-ritonavir for non-hospitalised patients during an omicron period inclusive of BA.4 and BA.5 subvariants, these data support nirmatrelvir-ritonavir as an ongoing first-line treatment for adults acutely infected with SARS-CoV-2., Funding: US National Institutes of Health., Competing Interests: Declaration of interests NRA reports grants from the US National Institutes of Health (NIH), during the conduct of the study. KCM reports grants from the National Center for Advancing Translational Sciences (NCATS), during the conduct of the study, and grants from the National Institute of Child Health and Human Development (NICHD) and the National Heart, Lung, and Blood Institute (NHLBI), outside of the submitted work. TDB reports grants from the NCATS, during the conduct of the study, and grants from the NICHD and NHLBI, outside of the submitted work. NEC reports grants from the US NIH, during the conduct of the study. AAG reports grants from the US NIH during the conduct of the study, grants from the US Centers for Disease Control, the US Department of Defense, AbbVie, and Faron Pharmaceuticals, and participation on an NIH data safety monitoring board, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Potential conflicts of interest. M. A. M. has been on the speakers’ bureau for AbbVie. M. K. has received dalbavancin from AbbVie for an unfunded investigator-initiated clinical trial. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Managing infection in patients with neutropenia is a difficult challenge, as fever is often the only clinical symptom. At JADPRO Live 2022, Kyle C. Molina, PharmD, BCIDP, AAVHIP, of the University of Colorado Hospital, discussed the epidemiology and pathophysiology associated with febrile neutropenia in patients with cancer. He reviewed appropriate treatment settings and empiric antimicrobial regimens for a patient and how to formulate a plan to safely de-escalate and target therapy for patients with febrile neutropenia., Competing Interests: The presenter has no relevant financial relationships to disclose., (© 2023 Harborside™.)

Background: HIV-negative patients have substantial mortality from Pneumocystis jirovecii pneumonia (PJP). We lack predictors of HIV-negative PJP-associated mortality., Objective: We aim to characterize the role of prior corticosteroid exposure in PJP-related mortality., Methods: We queried a global research network to identify adult HIV-negative patients with PJP with or without corticosteroid exposure in the preceding year before diagnosis ( n  = 8,021). We performed a propensity score-matched analysis to adjust baseline patient characteristics and analyzed outcomes. We follow-up the results with a multicenter ten years retrospective case-control cohort of HIV-negative patients tested for PJP by PCP Direct Fluorescent Antigen. We used a Cox proportional hazards model for survival analysis., Results: 1822 HIV-negative propensity-scored matched patients with prior corticosteroid exposure had significantly increased 10 weeks (16% versus 9%, p < 0.0001) and one-year mortality after PJP diagnosis (23% versus 14%, p  < 0.0001). (1→3)-β-D-glucan (197.6 ± 155.8 versus 63 ± 0 pg/ml, p  = 0.014), ferritin levels (1227 ± 2486 versus 768 ± 1060 mcg/l, p  = 0.047), lymphopenia (1.5 ± 1.5 versus 2.0 ± 1.6 10 3 cells/µl, p  < 0.0001) and hypoxia (SatO 2 : 86.7% versus 91.6%, p  < 0.0001) were higher or worse in those with prior steroid use. Patients who died were more likely to have previously received dexamethasone (35% versus 16%, p  < 0.001) or prednisone (49% versus 29%, p  < 0.001). Adjusted Cox proportional-hazard model validation showed an independently increased mortality at 10 weeks (HR: 3.7, CI: 1.5-9.2, p  = 0.004) and 1 year (HR: 4.5, CI: 2.0-10.4, p  < 0.0001) among HIV-negative patients with previous corticosteroid exposure., Conclusion: Preceding corticosteroids in HIV-negative patients with PJP are associated with higher mortality. A higher fungal burden may influence corticosteroid-mediated mortality. Assessment of PJP prophylaxis must become a standard clinical best practice when instituting corticosteroid therapy courses., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Shapiro reports receiving grants from the Emily Foundation during the study. Dr Henao-Martínez reported receiving a K12-clinical trial award as a co-principal investigator for the Expanded Access IND Program (EAP) to provide the Yellow Fever vaccine (Stamaril) to persons in the United States outside the submitted work. The Editor-in-Chief of Therapeutic Advances in Infectious Disease is an author of this paper, therefore, the peer review process was managed by alternative members of the Editorial Board and the submitting Editor had no involvement in the decision-making process. No other disclosures were reported., (© The Author(s), 2023.)

Objectives: Sotrovimab effectively prevented progression to severe disease and mortality following infection with pre-Omicron SARS-CoV-2 variants. We sought to determine whether sotrovimab is similarly effective against SARS-CoV-2 Omicron variant infection., Methods: Observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from December 26, 2021, to March 10, 2022, using electronic health records from a statewide health system. We propensity-matched patients not receiving authorized treatment for each patient treated with sotrovimab. The primary outcome was 28-day hospitalization; secondary outcomes included mortality. We also propensity-matched sotrovimab-treated patients from the Omicron and Delta phases. Logistic regression was used to determine sotrovimab effectiveness during Omicron and between variant phases., Results: Of 30,247 SARS-CoV-2 Omicron variant infected outpatients, we matched 1542 receiving sotrovimab to 3663 not receiving treatment. Sotrovimab treatment was not associated with reduced odds of 28-day hospitalization (2.5% vs 3.2%; adjusted odds ratio [OR] 0.82, 95% CI 0.55, 1.19) or mortality (0.1% vs 0.2%; adjusted OR 0.62, 95% CI 0.07, 2.78). Between phases, the observed treatment OR was higher during Omicron than during Delta (OR 0.85 vs 0.39, respectively; interaction P-value = 0.053)., Conclusion: Real-world evidence demonstrated that sotrovimab was not associated with reduced 28-day hospitalization or mortality among COVID-19 outpatients during the Omicron BA.1 phase., Competing Interests: Declaration of competing interest The authors do not have a commercial or other association that might pose a conflict of interest (e.g., pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Potential conflicts of interest. M. J. R. has received grant support, consulted, or spoken on behalf of AbbVie, Melinta, Merck, Paratek, Shionogi, and Tetraphase and is partially supported by the National Institutes of Health (R21 Al163726). W. D. K. has received grant support from Merck. S. A. is an employee of Seres Therapeutics. C. Y., D. H., D. L., E. C., G. S., I. S., W. J. M., J. T., J. W., K. M., L. A., M. B., M. J. R., M. M., M. P., M. R., M. V., N. F., N. R., N. T., P. W., R. P., S. D., S. J., S. S., T. M., and V. V. have nothing to disclose. G. S. has received speaking honoraria from AbbVie, Paratek, and Sunovion, consulting fees from Octapharma, Ferring, AbbVie and Paratek, and Research funding from Octapharma. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022. The Author(s).)

Forty-six patients were treated with eravacycline (ERV) for Acinetobacter baumannii infections, where 69.5% of isolates were carbapenem resistant (CRAB). Infections were primarily pulmonary (58.3%), and most patients received combination therapy (84.4%). The median (IQR) ERV duration was 6.9 days (5.1 to 11.1). Thirty-day mortality was 23.9% in the cohort and 21.9% in CRAB patients. One patient experienced an ERV-possible adverse event. IMPORTANCE Acinetobacter baumannii, particularly when carbapenem resistant (CRAB), is one of the most challenging pathogens in the health care setting. This is complicated by the fact that there is no consensus guideline regarding management of A. baumannii infections. However, the recent Infectious Diseases Society of America guidelines for treatment of resistant Gram-negative infections provided expert recommendations for CRAB management. The panel suggest using minocycline among tetracycline derivatives rather than eravacycline (ERV) until sufficient clinical data are available. Therefore, we present the largest multicenter real-world cohort in patients treated with ERV for A. baumannii, where the majority of isolates were CRAB (69.5%). Our analysis demonstrate that patients treated with ERV-based regimens achieved a 30-day mortality of 23.9% and had a low incidence of ERV-possible adverse events (2.1%). This study is important as it fills the gap in the literature regarding the use of a novel tetracycline (i.e., ERV) in the treatment of this challenging health care infection.

Background: 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)., Methods: 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)., Results: 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)., Conclusions: 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Tedizolid has activity against Gram-positive pathogens as well as Mycobacterium spp and Nocardia spp. Real-world evidence supporting long-term tolerability and clinical success of tedizolid is lacking. Prolonged tedizolid therapy (median, 188 days; interquartile range, 62-493 days) appeared to be well tolerated in 37 patients (8.1% experienced adverse effect leading to discontinuation). Clinical success was 81.3% in those evaluated., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bezlotoxumab (BEZ) is a monoclonal antibody used to prevent recurrent Clostridioides difficile infection (rCDI). This study investigates BEZ effectiveness in relation to rCDI and patient-specific risk factors in a real-world setting., Methods: A matched, retrospective cohort study was conducted from 2015 to 2019 to compare BEZ to historical standard of care (SoC) therapy with vancomycin or fidaxomicin. The primary outcome was incidence of 90-day rCDI. Secondary outcomes were incidence of all-cause hospital readmission and all-cause mortality at 90 days, infusion-related reactions, and incidence of heart failure exacerbation. Baseline confounding was addressed using inverse probability of treatment weighting (IPTW)., Results: Overall, 107 participants were included (54 BEZ and 53 SoC). Mean number of prior CDI episodes was 2, median number of risk factors for rCDI was 4, and 28% of participants had severe CDI. Incidence of 90-day rCDI was 11% BEZ vs 43% SoC (P = < .001) and 90-day all-cause readmission was 40% BEZ vs 64% SoC (P = .011). In IPTW-adjusted analyses, BEZ was associated with significantly reduced odds of rCDI (odds ratio [OR], 0.14 [95% confidence interval {CI}: .05-.41]) and all-cause readmission (OR, 0.36 [95% CI: .16-.81]). No safety signals were detected with BEZ use., Conclusions: BEZ is effective for the prevention of rCDI and reduction in all-cause hospital readmission for patients at high risk for recurrence, supporting current guideline recommendations., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: There is a need for improved antibiotic formulations for the treatment of acute bacterial skin and soft structure infection (ABSSSI), especially with the rise of antimicrobial resistance among Gram-positive bacteria. A new formulation of oritavancin was developed to reduce intravenous infusion volume (from 1000 mL to 250 mL), shorten infusion time (from 3 hours to 1 hour), and provide pharmacies with flexibility in oritavancin preparation (from 5% dextrose in sterile water to either normal saline or 5% dextrose in sterile water) compared with the current formulation., Methods: A total of 102 adult patients with a diagnosis of ABSSSI suspected or confirmed to be caused by a Gram-positive pathogen were randomized 1:1 to receive either the new formulation of oritavancin or the current formulation. After a single 1200-mg intravenous infusion of oritavancin, the relative area-under-the-curve exposure of the new formulation and current formulation groups were compared. Safety and tolerability of the new formulation were assessed for treatment-emergent adverse events, serious adverse events, and changes to laboratory parameters., Results: The area under the curve for 0 hour to 72 hours postdose was very similar in the new formulation group compared with the current formulation group. No differences in treatment-emergent adverse events were observed between the current and new formulation groups, and all treatment-emergent adverse events were consistent with the known safety profile of the current formulation., Conclusions: The new formulation of oritavancin with reduced volume and duration of intravenous infusion demonstrates a safety profile and pharmacokinetics similar to that of the original formulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Dalbavancin is a synthetic lipoglycopeptide that exerts its antimicrobial activity through two distinct modes of action, inhibition of cell wall synthesis and an anchoring mechanism. Compared with previous glycopeptide antibiotics, dalbavancin demonstrates improved antibacterial potency against Gram-positive organisms and a long half-life of approximately 1 week, which is longer in tissues (e.g., skin, bone) than plasma. These factors facilitated the development of single-dose or once-weekly dosing regimens to treat acute bacterial skin and skin structure infections (ABSSSI). Dalbavancin exhibits dose-proportional pharmacokinetics and is highly protein bound (93%). Despite being highly protein bound, it has a steady-state volume of distribution >10 L and distributes widely into the skin, bone, peritoneal space, and epithelial lining fluid, but not cerebrospinal fluid. Dalbavancin elimination occurs via a combination of renal (approximately 45%) and non-renal clearance, with dose adjustments recommended only in patients with a creatinine clearance <30 mL/min not receiving any form of dialysis. The established pharmacokinetic/pharmacodynamic index associated with bacterial kill is free area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC), with a goal 24-h fAUC/MIC of at least 27.1 for Staphylococcus aureus infections. Recent data suggest usefulness in the treatment of infections beyond ABSSSI, with convenient dosing and redosing strategies for complicated infections requiring extended treatment durations. Additional studies are needed to confirm these preliminary findings., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Survival models with a frailty term are presented as an extension of Cox's proportional hazard model, in which a random effect is introduced in the hazard function in a multiplicative form with the aim of modeling the unobserved heterogeneity in the population. Candidates for the frailty distribution are assumed to be continuous and non-negative. However, this assumption may not be true in some situations. In this paper, we consider a discretely distributed frailty model that allows units with zero frailty, that is, it can be interpreted as having long-term survivors. We propose a new discrete frailty-induced survival model with a zero-modified power series family, which can be zero-inflated or zero-deflated depending on the parameter value. Parameter estimation was obtained using the maximum likelihood method, and the performance of the proposed models was performed by Monte Carlo simulation studies. Finally, the applicability of the proposed models was illustrated with a real melanoma cancer data set.

Background: We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE)., Methods: This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR)., Results: Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours ( P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081-0.941)., Conclusions: Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction : Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality despite significant advancements in currently available therapy. With a flush pipeline of investigational antifungals, the clinician must identify appropriate roles of currently available therapies, potential advantages of emerging antifungals, and shortcomings in the evolving clinical evidence. Areas covered : Standard and developing treatment approaches for IFIs with currently available antifungals are summarized with a focus on invasive candidiasis and invasive aspergillosis. Emerging investigational antifungals are discussed in depth, including mechanisms of action, fungal activity, clinical evidence, and ongoing research. An opinion on the impact and potential role of therapy for emerging antifungals of interest is also provided. Expert opinion : Despite advances and clinical studies optimizing antifungal use, current therapies fall short in preventing IFI morbidity and mortality. Further optimization of currently available antifungals may improve outcomes; however, novel agents are required for historically difficult-to-treat infections, transitions to oral treatment, minimizing adverse drug effects, decreasing drug interactions, and ultimately improving patient quality of life. Emerging antifungals may positively revolutionize the treatment of IFIs.

Background: Bezlotoxumab significantly reduces the incidence of recurrent Clostridioides difficile infection (CDI); however, limited data are available in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients., Methods: We conducted a single-center retrospective analysis comparing recurrent CDI in SOT and HCT recipients receiving standard of care alone (oral vancomycin, fidaxomicin, or metronidazole) or bezlotoxumab plus standard of care. The primary outcome was 90-day incidence of recurrent CDI, and secondary outcomes included 90-day hospital readmission, mortality, and incidence of heart failure exacerbation., Results: Overall, 94 patients received bezlotoxumab plus standard of care (n = 38) or standard of care alone (n = 56). The mean age was 53 years; patients had a median of 3 prior Clostridioides difficile episodes and 4 risk factors for recurrent infection. Most patients were SOT recipients (76%), with median time to index CDI occurring 2.7 years after transplantation. Ninety-day recurrent CDI occurred in 16% (6/38) in the bezlotoxumab cohort compared to 29% (16/56) in the standard of care cohort ( P  = .13). Multivariable regression revealed that bezlotoxumab was associated with significantly lower odds of 90-day recurrent CDI (odds ratio, 0.28 [95% confidence interval, .08-.91]). There were no differences in secondary outcomes, and no heart failure exacerbations were observed., Conclusions: In a cohort of primarily SOT recipients, bezlotoxumab was well tolerated and associated with lower odds of recurrent CDI at 90 days. Larger, prospective trials are needed to confirm these findings among SOT and HCT populations., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Complicated methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSIs), particularly those with delayed culture clearance, are associated with high mortality. Combination therapy with daptomycin and ceftaroline (DAP+CPT) represents a novel therapeutic approach to MRSA-BSI owing to synergistic bactericidal activity. This study aimed to compare DAP+CPT with historical standard of care (SoC) for treatment of complicated MRSA-BSI. This single-centre retrospective cohort study included patients with complicated MRSA-BSI at University of Colorado Hospital. Patients receiving DAP+CPT for ≥48 h between November 2013 and March 2020 or SoC with vancomycin or DAP ± gentamicin and/or rifampicin from November 2011 to December 2013 were compared. The primary outcome was clinical failure defined as a composite of MRSA-related mortality and recurrent infection at 60 days. A total of 60 patients received DAP+CPT (n = 30) or SoC (n = 30). Median age was 56 years and median Pitt bacteremia score was 3. Common infectious sites were endovascular (63%) and musculoskeletal (40%). DAP+CPT was associated with a numerically lower incidence of clinical failure compared with SoC (20% vs. 43%; P = 0.052). Multivariable analysis controlling for immunocompromised status (OR, 6.90, 95% CI 1.08-44.15), Charlson comorbidity index (OR, 1.12, 95% CI 0.90-1.39) and source control (OR, 0.35, 95% CI 0.08-1.46) associated DAP+CPT with 77% lower odds of clinical failure (OR, 0.23, 95% CI 0.06-0.89). In patients with complicated MRSA-BSI with delayed clearance, DAP+CPT trended towards lower rates of clinical failure than SoC and was significantly associated with decreased clinical failure after adjustment for baseline differences., (Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined., Methods: This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America., Results: Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P  = .136)., Conclusions: Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: The objective of this study was to compare the incidence of acute kidney injury (AKI) among critically ill patients receiving combination therapy with vancomycin plus piperacillin-tazobactam (VPT) against patients receiving vancomycin plus cefepime (VC)., Methods: A retrospective cohort study of adult patients admitted to an intensive care unit between September 2012 and December 2016 was conducted. Patients were included if they received combination therapy with VPT or VC for ≥48 hours. Patients were excluded if creatinine clearance was <60 mL/min or received renal replacement therapy prior to the initiation of therapy. The primary end point was AKI, as defined by the Acute Kidney Injury Network classification, during or within 48 hours of completion of therapy. The incidence of AKI was compared between groups and multivariate analysis was performed to control for relevant confounders., Results: A total of 394 patients received either VPT (n = 258) or VC (n = 136). There were no differences in baseline serum creatinine (0.8 [0.3]mg/dL vs 0.7 [0.3] mg/dL, P = 0.207), use of vasopressors (44% vs 38%, P = 0.255), mechanical ventilation (45% vs 40%, P = 0.350), or initial vancomycin trough (11.2 [5] mg/L vs 11 [4.8] mg/L, P = 0.668) between VPT and VC groups, respectively. The incidence of AKI was 28.7% for VPT patients versus 21.3% for VC patients ( P = 0.114). Multivariate analysis revealed vancomycin trough >20 mg/L (odds ratio, OR [95% confidence interval, CI] = 2.69 [1.62-4.47]), baseline SCr (OR [95% CI] = 3.34 [1.43-7.80]), vasopressors (OR [95% CI] = 1.77 [1.04-3.04]), and duration of combination therapy (OR [95% CI] = 1.009 [1.003-1.015]) as independent risk factors for AKI., Conclusion: The risk of AKI was similar between VPT and VC groups in critically ill patients. Risk factors for AKI were related to baseline renal function, duration of combination therapy, supratherapeutic vancomycin troughs, and severity of illness.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN and DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "seesaw effect," where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy., (Copyright © 2020 American Society for Microbiology.)

Eravacycline (ERV) was used in 35 patients for various infections. The most common pathogen was Klebsiella pneumoniae, and 30-day survival was 74%. Absence of 30-day recurrence and resolution of signs and symptoms of infection were 91% and 57%, respectively. ERV was well-tolerated, with adverse events leading to drug discontinuation in one patient., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2020.)

Background: The Augmented Renal Clearance in Trauma Intensive Care (ARCTIC) scoring system is a validated system to predict augmented renal clearance in trauma patients. This study examined the ability of the ARCTIC score to identify patients at risk for subtherapeutic vancomycin trough concentrations relative to estimated creatinine clearance (eCrCl) alone. Methods: Trauma patients admitted to the intensive care unit from September 2012 to December 2017 who received vancomycin and had a vancomycin trough concentration recorded were included. Patients were excluded if their serum creatinine concentration was >1.3 mg/dL, if they had received vancomycin doses <30 mg/kg per day, an improperly timed trough concentration measurement, or renal replacement therapy. The primary endpoint was an initial subtherapeutic vancomycin trough concentration (<10 mg/L). Classification and regression tree (CART) analysis was used to identify thresholds for the ARCTIC score and other continuous data where subtherapeutic troughs were more common. A step-wise logistic regression analysis was performed to control for confounders for subtherapeutic troughs whereby inclusion of ARCTIC was modeled sequentially after eCrCl. Results: A total of 119 patients with a mean age of 42 ± 17 years and eCrCl 142 ± 39 mL/min met the inclusion criteria. The mean daily vancomycin dose was 44 ± 9 mg/kg, and the incidence of subtherapeutic trough concentration was 46%. The CART analysis identified two variables creating three groups where subtherapeutic trough concentrations differed: eCrCl >105 mL/min and ARCTIC score ≥7, eCrCl >105 mL/min and ARCTIC score <7, and eCrCl ≤105 mL/min. The base logistic regression model identified eCrCl >105 mL/min and pelvic fracture as risk factors for subtherapeutic trough values. The final model included the addition of ARCTIC score ≥7, which improved the model significantly (p = 0.009). Predictors of subtherapeutic trough concentrations were (odds ratio [95% confidence interval]): eCrCl >105 mL/min (6.5 [1.66-25.07]), ARCTIC score ≥7 (3.26 [1.31-8.09]), and pelvic fracture (4.36 [1.27-14.93]). Conclusion: The ARCTIC score is useful when applied in conjunction with eCrCl. Patients with a eCrCl >105 mL/min and an ARCTIC score ≥7 may require a more aggressive dosing strategy.

4-Factor Prothrombin Complex Concentrate (4F-PCC) is the standard-of-care intervention in patients with major bleeding taking oral vitamin K antagonists. Despite growing clinical experience with 4-FPCC, the optimal dosing strategy remains unclear. In balancing efficacy, safety, and cost of this treatment, many institutions have adopted a low, fixed-dose regimen, with average doses lower than that in the package insert. The fixed-dose 4F-PCC strategy is supported by the available observational studies and case reports; however, the current body of literature is highly heterogenous. The purpose of this narrative review is to address the advantages and shortcomings with clinical use of fixed-dose 4F-PCC, as well as limitations of the available literature. The heterogeneity of the current literature should guide future studies to support or refute this potentially life-saving intervention.

The role of vancomycin in the treatment of serious Staphylococcus aureus infections, both methicillin-susceptible and methicillin-resistant, is becoming increasingly ineffective due to increasing MIC and failure. The development of reduced vancomycin susceptibility by S. aureus to glycopeptides highlights the need for clinicians to reexamine the roles of non-glycopeptide therapy. As the use of these alternative non-glycopeptides antimicrobials increases, it will become pertinent to monitor the rates of resistance. Large surveillance programs have provided data for resistance against S. aureus for the non-glycopeptides (daptomycin, ceftaroline, tigecycline, linezolid, and tedizolid). The current published literatures suggest that worldwide resistance rates to these non-glycopeptides for serious MRSA infections are still low. Implementation of antimicrobial stewardship programs will be crucial in prevention of resistance of these antimicrobials against S. aureus.

This study assessed the role of melatonin in modulating running wheel(RW)-induced hippocampal neurogenesis in adult C3H/HeN mice. Chronic melatonin (0.02 mg/mL, oral for 12 days) treatment did not affect cell proliferation or cell survival determined by the number of BrdU-positive cells in dentate gyrus of mice with access to fixed wheel (FW). RW activity significantly increased cell proliferation [RW (n = 8) versus FW (n = 6): dorsal, 199 ± 18 versus 125 ± 12, P < 0.01; ventral, 211 ± 15 versus 123 ± 13, P < 0.01] and newborn cell survival [RW (n = 7) versus FW (n = 8): dorsal, 45 ± 8.5 versus 15 ± 1.8, P < 0.01; ventral, 48 ± 8.1 versus 15 ± 1.4)] in the dorsal and ventral dentate gyrus. Oral melatonin treatment further potentiated RW activity-induced cell survival in both areas of the dentate gyrus [melatonin (n = 10) versus vehicle (n = 7): dorsal, 63 ± 5.4 versus 45 ± 8.5 P < 0.05; ventral, 75 ± 7.9 versus 48 ± 8.1, P < 0.01] and neurogenesis [melatonin (n = 8) versus vehicle (n = 8): dorsal, 46 ± 3.4, versus 34 ± 4.5, P < 0.05; ventral, 41 ± 3.4 versus 25 ± 2.4, P < 0.01]. We conclude that melatonin potentiates RW-induced hippocampal neurogenesis by enhancing neuronal survival suggesting that the combination of physical exercise and melatonin may be an effective treatment for diseases affecting the hippocampus neurogenesis., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Early-life seizures result in increased susceptibility to seizures and greater neurologic injury with a second insult in adulthood. The mechanisms which link seizures in early-life to increased susceptibility to neurologic injury following a 'second hit' are not known. We examined the contribution of microglial activation and increased proinflammatory cytokine production to the subsequent increase in susceptibility to neurologic injury using a kainic acid (KA)-induced, established 'two-hit' seizure model in rats. Postnatal day (P)15 rats were administered intraperitoneal KA (early-life seizures) or saline, followed on P45 with either a 'second hit' of KA, a first exposure to KA (adult seizures), or saline. We measured the levels of proinflammatory cytokines (IL-1 beta, TNF-alpha, and S100B), the chemokine CCL2, microglial activation, seizure susceptibility and neuronal outcomes in adult rats 12 h and 10 days after the second hit on P45. The 'two-hit' group exposed to KA on both P15 and P45 had higher levels of cytokines, greater microglial activation, and increased susceptibility to seizures and neurologic injury compared to the adult seizures group. Treatment after early-life seizures with Minozac, a small molecule experimental therapeutic that targets upregulated proinflammatory cytokine production, attenuated the enhanced microglial and cytokine responses, the increased susceptibility to seizures, and the greater neuronal injury in the 'two-hit' group. These results implicate microglial activation as one mechanism by which early-life seizures contribute to increased vulnerability to neurologic insults in adulthood, and indicate the potential longer term benefits of early-life intervention with therapies that target up-regulation of proinflammatory cytokines.

Purpose: Early-life seizures increase vulnerability to subsequent neurologic insult. We tested the hypothesis that early-life seizures increase susceptibility to later neurologic injury by causing chronic glial activation. To determine the mechanisms by which glial activation may modulate neurologic injury, we examined both acute changes in proinflammatory cytokines and long-term changes in astrocyte and microglial activation and astrocyte glutamate transporters in a "two-hit" model of kainic acid (KA)-induced seizures., Methods: Postnatal day (P) 15 male rats were administered KA or phosphate buffered saline (PBS). On P45 animals either received a second treatment of KA or PBS. On P55, control (PBS-PBS), early-life seizure (KA-PBS), adult seizure (PBS-KA), and "two-hit" (KA-KA) groups were examined for astrocyte and microglial activation, alteration in glutamate transporters, and expression of the glial protein, clusterin., Results: P15 seizures resulted in an acute increase in hippocampal levels of IL-1beta and S100B, followed by behavioral impairment and long-term increases in GFAP and S100B. Animals in the "two-hit" group showed greater microglial activation, neurologic injury, and susceptibility to seizures compared to the adult seizure group. Glutamate transporters increased following seizures but did not differ between these two groups. Treatment with Minozac, a small molecule inhibitor of proinflammatory cytokine upregulation, following early-life seizures prevented both the long-term increase in activated glia and the associated behavioral impairment., Conclusions: These data suggest that glial activation following early-life seizures results in increased susceptibility to seizures in adulthood, in part through priming microglia and enhanced microglial activation. Glial activation may be a novel therapeutic target in pediatric epilepsy.