This week in Infectious Disease

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Welcome to This Week in Infectious Disease. This week we're covering 10 notable papers spanning resistant Gram-negative infections and the new agents built to treat them, HIV treatment and prevention, and the long tail of respiratory viruses alongside a returning old foe. Let's dive in.

We start with a question many stewardship teams face daily: how much in vitro susceptibility really tells us about how a patient will do with resistant Enterobacterales. In Clinical Infectious Diseases, Peters and colleagues ran a multicenter prospective cohort of 374 hospitalized patients with invasive ceftriaxone-resistant Enterobacterales infections, all with isolates confirmed susceptible to imipenem or meropenem by broth microdilution, all lacking carbapenemase genes, and all treated definitively with one of those higher-order carbapenems [1]. Current IDSA guidance suggests that a susceptible carbapenem is reasonable here. Yet after weighting to balance baseline differences, patients whose isolates were ertapenem-resistant had roughly double the odds of dying within 30 days compared with those whose isolates were ertapenem-susceptible, and 14-day and in-hospital mortality told the same story. Mortality was highest when isolates were resistant to two carbapenems. Genomic work pointed to porin alterations combined with extra non-carbapenemase beta-lactamases, which the authors suggest may allow partial hydrolysis of meropenem or imipenem despite a susceptible result. It is observational, so residual confounding remains possible, but it directly challenges the guidance and raises the question of whether ertapenem resistance should be read as a warning sign even without a carbapenemase. A complementary and somewhat more reassuring picture comes from the International Journal of Antimicrobial Agents, where Shah and colleagues retrospectively studied 639 patients with bacteremia due to Enterobacter cloacae complex, Klebsiella aerogenes, or Citrobacter freundii complex [2]. About a third of these patients had ceftriaxone-resistant isolates, and those patients were sicker, more often had recent exposure to third-generation cephalosporins or piperacillin-tazobactam, and were far more likely to receive inactive empiric therapy, roughly a quarter versus about one in a hundred. Crude 30-day mortality was higher with resistance, but the authors attribute this to illness severity and delayed active therapy. Among patients with resistant isolates, definitive cefepime was not associated with worse survival than meropenem after propensity weighting. Taken together, the two papers suggest the resistance phenotype matters in different ways: for AmpC producers, the gap seems to reflect delay rather than drug choice, while for ertapenem-resistant organisms, the carbapenem itself may underperform. Both are observational and neither settles the question on its own.

Two non-inferiority trials this week test new agents against established standards. In The Lancet Infectious Diseases, Chang and colleagues randomized 450 patients with hospital-acquired or ventilator-associated bacterial pneumonia, mostly in China with a few sites in the United States and Spain, to imipenem-cilastatin-funobactam or imipenem-cilastatin-relebactam [3]. Fourteen-day all-cause mortality was about 3 percent in both arms, meeting the non-inferiority margin, and serious treatment-related adverse events were somewhat less frequent with funobactam. The very low mortality for this population and the handling of missing data as survival are worth noting when judging generalisability, and the trial does not tell us how funobactam performs against carbapenemase producers specifically. Also in The Lancet Infectious Diseases, Fofana and colleagues reported the KALUMI phase 2 trial of ganaplacide plus a solid dispersion formulation of lumefantrine in children with uncomplicated falciparum malaria across five African countries [4]. Food roughly doubled lumefantrine exposure in run-in cohorts, which led to a once-daily, three-day regimen given with a light meal. In the main trial of 220 children, cure rates at day 29 were about 99 percent in both the new combination and artemether-lumefantrine arms, meeting non-inferiority. The trade-off was tolerability: vomiting occurred in nearly three in ten children on ganaplacide compared with about one in ten on the comparator, and hypokalaemia was also more common. As a non-artemisinin partner with a novel mechanism, this matters for the artemisinin resistance threat, though this remains phase 2 evidence.

Turning to HIV, this week brings reassurance, a reality check, and a lesson in prevention biology. In The Lancet Global Health, Zash and colleagues report the complete Tsepamo surveillance data from Botswana, covering more than 235,000 deliveries through 2022, including over 11,000 with dolutegravir exposure at conception [5]. The neural tube defect prevalence was about 0.1 percent with dolutegravir, essentially identical to other antiretroviral regimens, and major external structural abnormalities were also similar. The original 2018 signal appears concentrated in conceptions during the first year after rollout, and the authors also observed seasonal variation, with more defects in early dry season conceptions. The authors describe these as definitive data supporting dolutegravir safety in pregnancy. In Clinical Infectious Diseases, Wood and colleagues offer a narrative review of persistent myths about modern antiretroviral therapy, arguing that second-generation integrase inhibitors, two-drug regimens, and long-acting injectables have overturned many longstanding assumptions about dosing, side effects, and laboratory monitoring [6]. It is expert opinion rather than new data, but a useful update. On the prevention side, deCamp and colleagues in Science Translational Medicine analysed the antibody-mediated prevention trials of the broadly neutralizing antibody VRC01 through the final week 104 visit [7]. Against highly sensitive viruses, cumulative prevention efficacy held at about two thirds. But after dosing stopped at week 72, more diagnoses with moderately sensitive or resistant virus occurred in the VRC01 groups than with placebo, eleven versus one. The authors propose that waning antibody concentrations allowed suppressed infections, often with evolving resistance, to emerge, strengthening the case that single antibodies are insufficient and combinations will likely be needed.

Our final theme covers viral infections that continue to fill hospital wards and clinic schedules. In Open Forum Infectious Diseases, Hurwitz and colleagues used target trial emulation across roughly 400 United States hospitals to study nearly 98,000 immunocompromised patients hospitalized with COVID-19 [8]. Starting remdesivir within two days of admission was associated with about a fifth lower 14-day in-hospital mortality than never starting it, and a smaller benefit compared with later initiation, with consistent findings across age, variant era, and severity of immunosuppression. This is a population largely excluded from trials, so the data are useful, though still observational. In Annals of Internal Medicine, Reeder and colleagues followed just over 1,000 RECOVER-Adult participants who still had likely long COVID a year after infection [9]. About half of these participants experienced meaningful symptom reduction by 36 months, but only about a quarter of them reached complete remission, and timing of improvement looked similar whether people still had symptoms at 18 or 24 months. The authors frame this as evidence of natural recovery for some and an argument for placebo-controlled treatment trials. Finally, also in Annals of Internal Medicine, Lo provides a clinical review of measles aimed at internists and hospitalists, noting that most physicians in the United States have never managed a case, that adults are increasingly affected, and that prompt suspicion, infection control, and public health notification remain central to diagnosis and control [10].

If you only have time for one paper this week, make it the Peters study in Clinical Infectious Diseases [1]. It reopens a question that current guidance treats as settled, suggesting that ertapenem resistance may signal meaningful carbapenem underperformance even when meropenem or imipenem test susceptible.

That's your roundup for This Week in Infectious Disease. The full transcript and references are available on the episode page. See you next week.

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