Infectious Diseases

Open-label noninferiority RCT of 391 patients with ceftriaxone-resistant (largely ESBL-producing) *E. coli* or *Klebsiella* bloodstream infection randomized to piperacillin-tazobactam versus meropenem. 30-day mortality was 12.3% with piperacillin-tazobactam versus 3.7% with meropenem — piperacillin-tazobactam failed to meet noninferiority (risk difference 8.6%). The result overturned the practice of using piperacillin-tazobactam for ESBL bacteremia. Board takeaway: for serious ESBL Enterobacterales bloodstream infection, use a carbapenem, not piperacillin-tazobactam, even when in vitro susceptibility appears favorable.

Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018;320(10):984-994. PMID 30208454 →

Phase 3 open-label RCT in patients with confirmed/suspected carbapenem-resistant Enterobacteriaceae (CRE) infections comparing meropenem-vaborbactam monotherapy with best available therapy (often combination regimens including polymyxins). Meropenem-vaborbactam yielded higher clinical cure, lower 28-day mortality, and fewer nephrotoxic adverse events. Trial was small and stopped early. Board takeaway: meropenem-vaborbactam is a preferred, less nephrotoxic option for KPC-type CRE infections versus older polymyxin/aminoglycoside-based "best available therapy."

Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther. 2018;7(4):439-455. PMID 30270406 →

Small double-blind RCT (~47 patients) in imipenem-nonsusceptible gram-negative infections (HABP/VABP, cIAI, cUTI) comparing imipenem-cilastatin/relebactam with colistin plus imipenem. Favorable clinical response was similar between arms, but the relebactam combination had markedly lower nephrotoxicity (10% vs 56%) and numerically lower 28-day mortality. Board takeaway: imipenem/relebactam is an effective, less nephrotoxic alternative to colistin-based regimens for imipenem-nonsusceptible gram-negative infections.

Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections. Clin Infect Dis. 2020;70(9):1799-1808. PMID 31400759 →

Double-blind phase 3 noninferiority RCT of 726 mechanically ventilated patients with ventilated HABP or VABP randomized to high-dose (3 g) ceftolozane-tazobactam versus meropenem. 28-day mortality (24.0% vs 25.3%) and clinical cure met noninferiority criteria. Board takeaway: high-dose ceftolozane-tazobactam is a noninferior option to meropenem for gram-negative nosocomial/ventilated pneumonia, useful when resistant *Pseudomonas* is a concern.

Kollef MH, Nováček M, Kivistik Ü, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2019;19(12):1299-1311. PMID 31563344 →

Double-blind phase 3 noninferiority RCT of 300 patients with gram-negative nosocomial pneumonia comparing the siderophore cephalosporin cefiderocol with high-dose, extended-infusion meropenem. 14-day all-cause mortality was similar (12.4% vs 11.6%), meeting noninferiority. Board takeaway: cefiderocol is noninferior to meropenem for gram-negative nosocomial pneumonia and is a key option for carbapenem-resistant/difficult-to-treat gram-negatives (e.g., *Acinetobacter*, metallo-β-lactamase producers).

Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021;21(2):213-225. PMID 33058798 →

Landmark placebo-controlled RCT (Pediatric AIDS Clinical Trials Group Protocol 076) of 363 HIV-positive pregnant women randomized to a three-part zidovudine (ZDV) regimen (antepartum, intrapartum, neonatal) versus placebo. ZDV reduced perinatal HIV transmission from 25.5% to 8.3% — roughly a two-thirds relative reduction. Board takeaway: this trial established antiretroviral prophylaxis in pregnancy as standard of care and launched the entire prevention-of-mother-to-child-transmission field.

Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med. 1994;331(18):1173-80. PMID 7935654 →

Multinational RCT of 1,763 HIV-serodiscordant couples (mostly heterosexual) randomizing the infected partner to immediate versus delayed ART. Early ART reduced linked HIV transmission by 96% and also reduced clinical events in the treated partner. Board takeaway: this is the foundational "Treatment as Prevention" trial — viral suppression prevents sexual transmission, supporting immediate ART for all regardless of CD4 count.

Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. PMID 21767103 →

Placebo-controlled RCT of 2,499 HIV-negative men (and transgender women) who have sex with men, randomized to daily oral tenofovir-emtricitabine (TDF/FTC) versus placebo. PrEP reduced HIV acquisition by 44% overall, with efficacy strongly tied to adherence (>90% reduction with detectable drug). Board takeaway: iPrEx established daily oral TDF/FTC pre-exposure prophylaxis as an effective HIV prevention tool; adherence drives efficacy.

Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-99. PMID 21091279 →

RCT of 4,685 ART-naïve HIV-positive adults with CD4 >500 randomized to immediate ART versus deferral until CD4 ≤350. Immediate ART reduced the composite of serious AIDS-related and non-AIDS events by 57%. Board takeaway: START provided definitive evidence to start ART immediately at diagnosis regardless of CD4 count, cementing universal "treat everyone" guidelines.

INSIGHT START Study Group; Lundgren JD, Babiker AG, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807. PMID 26192873 →

Two prospective observational cohorts of serodifferent couples having condomless sex where the HIV-positive partner had suppressed viral load (<200 copies/mL). Across thousands of couple-years and ~77,000 condomless sex acts, there were zero phylogenetically linked HIV transmissions. PARTNER2 extended this to gay male couples. Board takeaway: these studies are the evidence base for U=U (Undetectable = Untransmittable) — durable viral suppression eliminates sexual transmission risk.

Rodger AJ, Cambiano V, Bruun T, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. JAMA. 2016;316(2):171-81. **AND** Rodger AJ, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393(10189):2428-2438. PMID 27404185 →

Randomized noninferiority trial of 400 stable patients with left-sided endocarditis (streptococci, *E. faecalis*, *S. aureus*, coagulase-negative staph) who, after initial IV therapy, were randomized to continue IV or switch to oral antibiotics. The oral step-down arm was noninferior for the composite of death, embolic events, unplanned surgery, and relapse. Board takeaway: in carefully selected, stabilized left-sided endocarditis patients, oral step-down antibiotics are noninferior to full-course IV therapy.

Iversen K, Ihlemann N, Gill SU, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. N Engl J Med. 2019;380(5):415-424. PMID 30152252 →

Randomized noninferiority trial of 1,054 patients with bone or joint infection who, within 7 days of surgery or antibiotic start, were assigned to oral versus IV antibiotics for the first 6 weeks. Treatment failure at 1 year was 13.2% (oral) versus 14.6% (IV) — oral was noninferior. Board takeaway: early oral antibiotics are noninferior to prolonged IV for bone and joint infection, reducing line complications and hospital stay.

Li HK, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019;380(5):425-436. PMID 30699315 →

Open-label RCT of 352 patients with MRSA bacteremia randomized to standard therapy (vancomycin or daptomycin) with or without an added antistaphylococcal β-lactam. The combination did not improve the 90-day composite outcome and was stopped early for increased acute kidney injury (23% vs 6%). Board takeaway: do NOT routinely add a β-lactam to standard therapy for MRSA bacteremia — no benefit and more nephrotoxicity.

Tong SYC, Lye DC, Yahav D, et al. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial. JAMA. 2020;323(6):527-537. PMID 32044943 →

Open-label noninferiority RCT of low-risk *S. aureus* (MSSA/MRSA) bacteremia patients randomized after 5–7 days of IV therapy to early oral switch versus continued IV. In low-risk patients (no endocarditis, no deep foci, no prosthetic material), early oral switch was noninferior for the 90-day composite of complications. Board takeaway: in carefully selected low-risk *S. aureus* bacteremia, early oral step-down is a reasonable, noninferior strategy — a shift from the traditional all-IV dogma.

Kaasch AJ, López-Cortés LE, Rodríguez-Baño J, et al. Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): an international, open-label, parallel-group, randomised, controlled, non-inferiority trial. Lancet Infect Dis. 2024;24(5):523-534. PMID 38244557 →

SNAP is a large international Bayesian adaptive platform trial in *S. aureus* bacteremia, testing multiple domains (antibiotic backbone, adjunctive therapy, early oral switch). Its 2026 backbone results are practice-shaping. In methicillin-susceptible *S. aureus* bacteremia, cefazolin was noninferior to antistaphylococcal penicillins (flucloxacillin/cloxacillin) for 90-day mortality (15.0% vs 17.0%; adjusted OR 0.81, 99.2% probability of noninferiority) and caused significantly less acute kidney injury (13.9% vs 19.6%; adjusted OR 0.67) — N Engl J Med 2026. In penicillin-susceptible *S. aureus* bacteremia, benzylpenicillin had a high probability of mortality noninferiority with markedly less AKI, and the antistaphylococcal-penicillin arm was stopped early for excess AKI, favoring benzylpenicillin (Lancet 2026, PMID 42309115). Board takeaway: for MSSA bacteremia, cefazolin is a noninferior, less-nephrotoxic backbone; for true PSSA, narrow-spectrum penicillin is preferred. (Early-oral-switch domain protocol: PMID 37921609; SNAP results review: Goodman AL, et al. J Antimicrob Chemother 2026, PMID 42396858.)

Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group. Cefazolin for Methicillin-Susceptible Staphylococcus aureus Bacteremia. N Engl J Med. 2026 Jun 18;394(23):2329-2339. PMID 42308484 →

Large pragmatic open-label platform RCT of 6,425 hospitalized COVID-19 patients randomized to dexamethasone 6 mg daily versus usual care. Dexamethasone reduced 28-day mortality in patients requiring oxygen (23% vs 26%) or mechanical ventilation (29% vs 41%), but showed no benefit — and a trend toward harm — in patients not needing oxygen. Board takeaway: dexamethasone reduces mortality only in hypoxemic/ventilated COVID-19; avoid steroids in non-hypoxemic patients.

RECOVERY Collaborative Group; Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. PMID 32678530 →

Double-blind placebo-controlled RCT of 1,062 hospitalized COVID-19 patients randomized to remdesivir versus placebo. Remdesivir shortened median time to recovery from 15 to 10 days; the mortality benefit was not statistically significant. Board takeaway: remdesivir shortens recovery time in hospitalized COVID-19 (greatest benefit in those needing supplemental oxygen but not mechanical ventilation), supporting its use in selected hospitalized patients.

Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020;383(19):1813-1826. PMID 32445440 →

Double-blind RCT of 2,246 unvaccinated, nonhospitalized adults at high risk for severe COVID-19 randomized to nirmatrelvir-ritonavir (Paxlovid) versus placebo within 5 days of symptom onset. Treatment reduced COVID-19-related hospitalization or death by ~89% (0.8% vs 7.0% in those treated within 3 days). Board takeaway: early nirmatrelvir-ritonavir markedly reduces progression in high-risk outpatients — early treatment timing is essential.

Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408. PMID 35172054 →

Double-blind phase 3 RCT of 2,184 high-risk outpatients with influenza randomized to single-dose baloxavir marboxil, oseltamivir, or placebo. Baloxavir shortened time to improvement of symptoms versus placebo (median 73 vs 102 hours) and reduced complications, with efficacy comparable to oseltamivir. Board takeaway: single-dose oral baloxavir shortens influenza illness in high-risk outpatients.

Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-1214. PMID 32526195 →

TOGETHER was an adaptive platform RCT in high-risk COVID-19 outpatients (Brazil) that tested numerous repurposed therapies. This representative publication showed fluvoxamine modestly reduced a composite of emergency observation/hospitalization. Across the platform, most repurposed agents (e.g., ivermectin [PMID 35353979], hydroxychloroquine, metformin, lopinavir) failed to show meaningful benefit. Board takeaway: the TOGETHER platform rigorously tested repurposed COVID-19 therapies and most did not work — reinforcing evidence over enthusiasm.

Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022;10(1):e42-e51. PMID 34717820 →

Open-label RCT (stopped early for efficacy) comparing donor fecal microbiota transplantation via duodenal infusion (after brief vancomycin) versus a standard vancomycin course for recurrent *C. difficile* infection. FMT cured 81% after one infusion (94% overall) versus ~31% with vancomycin alone. Board takeaway: this landmark trial established fecal microbiota transplantation as highly effective for recurrent *C. difficile* — the proof-of-concept that reshaped recurrence management.

van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-15. PMID 23323867 →

Double-blind noninferiority RCT of 629 patients with *C. difficile* infection comparing fidaxomicin with oral vancomycin. Initial clinical cure was similar (~88% vs 86%), but fidaxomicin significantly reduced recurrence (15% vs 25%) and improved sustained cure. Board takeaway: fidaxomicin achieves similar initial cure with fewer recurrences than vancomycin — now guideline-preferred for CDI, especially when recurrence risk is high.

Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-31. PMID 21288078 →

Two double-blind RCTs (MODIFY I and II) of patients receiving standard-of-care CDI antibiotics randomized to a single infusion of the anti-toxin B monoclonal antibody bezlotoxumab versus placebo. Bezlotoxumab reduced recurrent CDI (~17% vs ~28%) over 12 weeks; actoxumab added no benefit. Board takeaway: bezlotoxumab is an adjunct to standard CDI antibiotics that reduces recurrence, particularly in high-risk patients (caution with heart failure).

Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017;376(4):305-317. PMID 28121498 →

Double-blind placebo-controlled RCT of 182 patients with recurrent *C. difficile* infection who, after standard antibiotics, received oral SER-109 (a purified live-bacterial spore microbiome therapeutic) versus placebo. SER-109 reduced recurrence at 8 weeks (12% vs 40%). Board takeaway: SER-109 (now FDA-approved as an oral microbiome therapy) prevents recurrent CDI after standard antibiotic treatment — part of the modern shift toward microbiome-based recurrence prevention.

Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022;386(3):220-229. PMID 35045228 →

Randomized unblinded trial of 277 patients (mostly hematologic) with invasive aspergillosis comparing initial voriconazole with conventional amphotericin B deoxycholate. Voriconazole produced better successful outcomes at 12 weeks (53% vs 32%), improved survival (71% vs 58%), and fewer severe drug toxicities. Board takeaway: voriconazole is first-line therapy for invasive aspergillosis — a practice-defining trial.

Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-15. PMID 12167683 →

Double-blind phase 3 noninferiority RCT of 527 patients with invasive mould disease (predominantly aspergillosis) comparing isavuconazole with voriconazole. All-cause 42-day mortality was noninferior (19% vs 20%), and isavuconazole had fewer drug-related adverse events (notably hepatobiliary, ocular, and skin). Board takeaway: isavuconazole is noninferior to voriconazole for invasive mould disease with a better tolerability profile and more predictable pharmacokinetics (no routine level monitoring).

Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760-9. PMID 26684607 →

Double-blind RCT of 245 patients with invasive candidiasis/candidemia comparing the echinocandin anidulafungin with fluconazole. Anidulafungin achieved higher treatment success at end of IV therapy (76% vs 60%) and met noninferiority (with a trend to superiority). Board takeaway: echinocandins are first-line for candidemia/invasive candidiasis, outperforming fluconazole — this trial helped establish that standard.

Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356(24):2472-82. PMID 17568028 →

Phase 3 noninferiority RCT (sub-Saharan Africa) of ~844 patients with HIV-associated cryptococcal meningitis comparing a single high-dose (10 mg/kg) liposomal amphotericin B (plus flucytosine and fluconazole) with the WHO-standard 7-day amphotericin course. 10-week mortality was noninferior (24.8% vs 28.7%) with fewer adverse events. Board takeaway: a single high-dose liposomal amphotericin B regimen simplifies and de-toxifies induction therapy for HIV-associated cryptococcal meningitis (now WHO-recommended).

Jarvis JN, Lawrence DS, Meya DB, et al. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. N Engl J Med. 2022;386(12):1109-1120. PMID 35320642 →