Issue: Newsletter 28 | September 1, 2026
| Citation of Articles | PICO | Main Results | Risk of Bias |
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P: 508 patients with infective endocarditis on the left side of the heart caused by Staphylococcus aureus, Enterococcus faecalis, or streptococcus species, who had already received 2–4 weeks of standard therapy and met criteria for clinical stabilization (255 randomised to tailored therapy, 253 to standard-duration therapy) I: Response-tailored antibiotic therapy (antibiotics discontinued once stabilization criteria were met) C: Standard-duration antibiotic therapy (total duration 4–6 weeks) O: Days alive without antibiotic treatment for infective endocarditis or bacteremia within 6 months (efficacy, tested for superiority); composite of death, unplanned cardiac surgery, or symptomatic embolic events within 6 months (safety, tested for noninferiority, margin 7.5 percentage points); relapse of bacteremia/infective endocarditis (key secondary) |
Response-tailored therapy resulted in a longer median time alive without antibiotics than standard-duration therapy (183 days vs 169 days; Hodges–Lehmann difference 13 days, 95% CI 12–13; p<0.001 for superiority). The primary safety composite occurred in 8.2% of the tailored group versus 10.7% of the standard group (absolute difference −2.4 percentage points, 95% CI −7.7 to 2.7), meeting the criterion for noninferiority. However, relapse of bacteremia or infective endocarditis was more frequent with tailored therapy (5.1% vs 1.6%; p=0.04); overall, tailored therapy reduced antibiotic exposure without compromising the composite safety endpoint but was associated with a higher relapse rate. |
Moderate risk: The open-label design could introduce performance or detection bias in an outcome that includes clinician-driven decisions (e.g., unplanned cardiac surgery), though the primary efficacy endpoint (days alive without antibiotics) is relatively objective. The noninferiority margin (7.5 percentage points) is fairly wide, and the higher relapse rate in the tailored-therapy arm, despite meeting the composite safety noninferiority criterion, suggests the composite endpoint may not fully capture clinically important harm. Large sample size (508) and clear stabilization criteria before randomization strengthen internal validity. |
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P: 1831 participants (modified intention-to-treat population) aged 2–65 years with blood culture-confirmed or clinically suspected uncomplicated typhoid fever across 13 hospitals in Nepal, Bangladesh, and Pakistan (915 azithromycin–cefixime, 916 azithromycin–placebo; 350 with blood culture-confirmed typhoid) I: Oral azithromycin (20 mg/kg, max 1 g, once daily) plus oral cefixime (10 mg/kg, max 400 mg, twice daily) for 7 days C: Oral azithromycin plus matched placebo for 7 days O: Composite treatment failure (fever clearance time ≥7 days, microbiological failure at day 7, need for rescue treatment, or complication/relapse within 28 days); fever clearance time (secondary) |
Treatment failure occurred in 5.10% of both groups (44/915 vs 44/916; absolute risk difference 0.00 percentage points, 95% CI −2.08 to 2.08; p=1.00). Among blood culture-confirmed participants, treatment failure occurred in 11.16% (19/179) of the azithromycin–cefixime group versus 16.00% (26/171) of the azithromycin–placebo group (difference 4.84 percentage points, 95% CI −2.52 to 12.21; p=0.20). Fever clearance time was similar between groups (median 1.83 vs 1.80 days overall; acceleration factor 0.99, 95% CI 0.90–1.09; p=0.86). Adverse events occurred in 16% of each group; overall, adding cefixime to azithromycin gave no additional benefit over azithromycin alone, supporting the WHO recommendation of azithromycin monotherapy. |
Low risk: Double-blind, placebo-controlled design with concealed, computer-generated block randomisation stratified by site and age minimises performance and detection bias. Large sample size (1831) recruited across three countries and a prespecified statistical analysis plan strengthen internal validity and generalisability. Loss to follow-up (147 vs 114 participants) was moderate but broadly similar between groups, limiting attrition bias. |
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Editorial commentary: |
P: 840 patients aged 18–59 months presenting to the emergency department with moderate-to-severe acute wheezing (521 tested positive for pathogenic bacteria [Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae] — the positive cohort; the remainder formed the negative cohort) I: Azithromycin 12 mg/kg once daily for 5 days C: Matching placebo for 5 days O: Sum of Asthma Flare-up Diary for Young Children (ADYC) scores over 5 days (range 5–35, higher = more severe symptoms), assessed separately in positive and negative cohorts; secondary outcomes were emergency department length of stay, hospital length of stay, and return visits/hospitalizations within 72 hours |
ADYC scores did not differ significantly between azithromycin and placebo in either the positive cohort (median 9.59 vs 9.72; p=0.70) or the negative cohort (median 9.30 vs 9.10; p=0.69). In the positive cohort, bacterial clearance was substantially higher with azithromycin than placebo (58.7% vs 11.4%). Secondary outcomes, development of antimicrobial resistance, and adverse events were similar between groups; the trial was stopped early for futility after a planned interim analysis; overall, azithromycin did not reduce wheezing-related symptom severity compared with placebo despite achieving greater bacterial clearance. |
Low risk: Randomised, placebo-controlled design with prespecified interim analysis and independent data and safety monitoring board oversight support internal validity. Early stopping for futility, while appropriate given a lack of efficacy signal, reduces the trial's power to detect smaller effects or differences in secondary and safety outcomes. Separate analysis by bacterial-positive and bacterial-negative cohorts strengthens interpretability of the dissociation between microbiological and clinical response. |
P: 418 patients with positive blood cultures, both arms receiving antimicrobial stewardship (208 standard of care [SOC], 210 multiplex PCR) I: SOC plus BioFire BCID2 multiplex PCR testing C: SOC (culture and phenotypic susceptibility testing) alone O: Time to first effective antimicrobial modification within 120h (primary); persistent bloodstream infection, mortality, length of stay (secondary) |
Time to first effective antimicrobial modification was significantly shorter with multiplex PCR (23.2 vs 64.5h; p<0.001), consistent across gram-negative, gram-positive, and yeast infections and regardless of lab hours or ICU status. Persistent bloodstream infection was lower with multiplex PCR (5.7% vs 11.5%, p=0.038). No significant differences in 30-day mortality or length of stay; overall, rapid multiplex PCR shortened time to effective therapy without affecting mortality or length of stay. |
Low-to-moderate risk: Randomised 1:1 design with a clear, objective primary endpoint supports internal validity, though the open-label nature of antimicrobial decision-making may introduce performance bias. Adequate sample size (418) for the primary endpoint but likely underpowered for mortality and length-of-stay secondary outcomes. |
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P: 146 analyzed immunocompetent adults with suspected ventilator-associated (84.9%) or hospital-acquired pneumonia requiring mechanical ventilation (74 intervention, 72 control); median age 58 years I: FilmArray Pneumonia Panel (FAPP) plus conventional microbiology C: Conventional microbiology alone O: Proportion of patients receiving targeted antimicrobial therapy (AMT) at 24h |
Targeted AMT at 24h occurred in 35.1% of the FAPP group vs 23.6% of controls (absolute difference 11.5%, 95% CI −0.03 to 26.2; p=0.13) — not statistically significant overall. Among patients with culture-documented pneumonia (45.9%), targeted AMT at 24h was significantly higher with FAPP (55.3% vs 31.0%; p=0.048). Secondary outcomes did not differ significantly; overall, FAPP increased targeted AMT only in patients with confirmed pneumonia. |
Moderate risk: Open-label design could introduce performance and detection bias in antimicrobial decision-making. Small sample size (146) limits power, reflected in the wide CI crossing zero for the primary outcome. Ten of 156 randomised patients withdrew consent, introducing minor attrition bias. |
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P: 1373 patients with suspected sepsis followed for 90 days across 14 centres, randomised 3:1 I: Droplet digital PCR (ddPCR)-guided pathogen monitoring and antibiotic adjustment C: Standard of care O: Diagnostic efficacy (primary); mortality and SOFA score (secondary) |
ddPCR showed higher detection positivity than standard care (54.1% vs 21.6%, p<2×10⁻¹⁶), faster turnaround, and 80.6% sensitivity. It increased appropriate antimicrobial coverage (12.91% vs 6.1%, p=0.0039), and coverage achieved within 0–3 days was associated with improved outcomes (p=0.026); overall, ddPCR-guided precision antimicrobial adjustment increased appropriate coverage and translated into improved survival. |
Moderate risk: Unequal 3:1 randomisation and lack of blinding for the standard-care comparator could introduce performance bias. Large sample size (1373) across 14 centres strengthens generalisability. Mortality-predicting pathogen-load thresholds were derived from the same dataset without external validation, risking overfitting. |
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P: 410 ICU patients receiving continuous renal replacement therapy via nontunneled femoral catheters (205 per group) I: Antimicrobial glucose chlorhexidine dressing, changed every 7 days C: Sterile gauze dressing, changed every 48 hours O: Local infection at catheter insertion site; suspected/confirmed catheter-related bloodstream infection (CRBSI); hospital/ICU stay; mortality |
Local infection at the insertion site was significantly lower with chlorhexidine dressings (15.6% vs 40.0%, p<0.001). Total CRBSI rate was also lower (6.3% vs 13.7%, p=0.014); confirmed CRBSI, hospital/ICU stay, and mortality did not differ significantly; overall, chlorhexidine dressings reduced local infection and overall CRBSI without affecting harder clinical endpoints. |
Moderate risk: Single-blind design (patients masked, staff possibly not) could introduce detection bias for infection assessment. Adequate a priori sample size and balanced baseline characteristics strengthen validity, though exclusive femoral access (rather than the guideline-preferred internal jugular site) limits generalisability. |
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P: 216 healthy Kenyan infants aged 9±1 months randomised across six dose/adjuvant/placebo arms (20–46 per group), plus 16 adults and 16 children in earlier dose-escalation cohorts I: SF2a-TT15 conjugate vaccine (2μg or 10μg oligosaccharide dose, adjuvanted or non-adjuvanted), days 0, 90, 270 C: Matching adjuvanted or non-adjuvanted placebo O: Incidence/severity of adverse events (primary safety); serum IgG GMT/GMR and proportion of responders to SF2a lipopolysaccharide (primary immunogenicity) |
SF2a-TT15 was well tolerated with no vaccine-related serious adverse events; 94% of infants had at least one unsolicited adverse event, mostly mild-to-moderate and unrelated to study product. The vaccine induced significantly higher serum IgG GMTs than placebo at 28 days after each injection (p<0.001 for nearly all comparisons), with the adjuvanted 10μg dose eliciting the highest titres and up to 100% responders after the second injection; overall, SF2a-TT15 was safe and strongly immunogenic in infants. |
Low-to-moderate risk: Double-blind, placebo-controlled design with masked outcome assessment supports internal validity. Small, uneven group sizes (20–46 per arm) across six infant dose/adjuvant combinations limit power for between-group comparisons. Retention varied by group (as low as 46% per-protocol in the first-enrolled arm due to procedural difficulties), introducing some attrition bias. |
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Editorial commentary: |
P: 300 pregnant women in Uganda (150 living with HIV, 150 without), aged 18–40, 27–35 weeks' gestation, randomised 1:1 within HIV strata I: Single intramuscular dose of GBS6 hexavalent capsular polysaccharide conjugate vaccine (20μg) C: Saline placebo O: Maternal/infant safety through 12 months postpartum (primary); anti-serotype IgG concentrations and placental antibody transfer (secondary) |
Serious adverse events were similar across groups and none were vaccine-related. GBS6 induced serotype-specific IgG increases 30–100-fold from baseline, with no difference by maternal HIV status (p>0.05 for all serotypes). Infants born to vaccinated mothers had substantially higher antibody concentrations at birth than placebo recipients' infants, sustained above placebo through 18 weeks; overall, GBS6 was safe and immunogenic regardless of maternal HIV status, with effective placental transfer. |
Low risk: Double-blind design with pharmacist-masked syringe preparation and HIV-stratified randomisation minimises performance/detection bias. High retention to delivery (298/300). Study population had high CD4+ counts and was stable on antiretroviral therapy, limiting generalisability to women with advanced or untreated HIV. |
P: 525 patients (intention-to-treat) aged ≥16 years with newly diagnosed drug-susceptible tuberculosis across four Buenos Aires hospitals (255 intervention, 270 control) I: Standard of care plus TB-TST digital adherence app (daily reporting, messaging, education, weekly urine isoniazid test) C: Standard of care alone O: Treatment success — cure or completion (primary); loss to follow-up (secondary) |
Treatment success was higher with TB-TST (82% vs 74%; risk ratio 1.10, p=0.04). Loss to follow-up was lower (17% vs 24%; risk ratio 0.70, p=0.04). Per-protocol analysis showed larger effects (84% vs 74%, p<0.01). Benefit was greater among women and participants under 35; overall, the digital tool improved TB treatment outcomes, particularly in younger and female patients. |
Moderate risk: Lack of participant/provider blinding (inherent to a digital intervention) could introduce performance bias, though masked outcome assessors reduce detection bias. Per-protocol analysis excluding non-engaged participants may overstate the effect. COVID-19-related disruptions and uneven enrolment across sites (one site contributing 51% of participants, with better outcomes in both arms) introduce site-level heterogeneity. |
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Editorial commentary: |
P: 6940 healthy newborns (0–14 days, birthweight ≥2.3kg) across ten sub-Saharan African sites, including 720 born to mothers living with HIV (3471 VPM1002, 3469 BCG analyzed) I: Single 0.05mL intradermal VPM1002 (recombinant BCG) C: Single 0.05mL intradermal standard BCG O: Non-inferiority for prevention of M. tuberculosis infection, defined by incident QuantiFERON-TB Gold Plus (QFT) conversion (non-inferiority margin: upper 95% CI of HR <1.25) |
QFT conversion occurred in 5.3% (VPM1002) vs 4.3% (BCG), HR 1.23 (95% CI 0.99–1.53), exceeding the pre-specified non-inferiority margin — VPM1002 did not demonstrate non-inferiority. Adverse event profiles were similar between groups with no vaccine-related serious adverse events; overall, VPM1002 failed to show non-inferiority to BCG, and secondary disease endpoints numerically favoured BCG. |
Moderate risk: Large sample size (6940) and central, HIV-stratified randomisation strengthen validity, though unmasked vaccine-preparation staff could introduce minor performance bias. Early termination due to lower-than-expected event rate (334 of 632 planned events) reduced power and certainty. A ~33% imbalance in household TB exposure between arms is an unaddressed confounder. |
P: 1,172 hospitalised adults living with HIV in 11 hospitals in Tanzania and Mozambique, without an existing TB diagnosis or recent TB treatment (61% female; median age 44 years; 75.4% on ART; median CD4 count 232 cells/μL) I: Expanded universal TB screening with Xpert MTB/RIF Ultra testing of sputum, stool and urine plus urine LF-LAM testing, irrespective of symptoms (n=582) C: Standard-of-care WHO-recommended symptom-based screening with sputum Xpert Ultra and urine LF-LAM according to eligibility criteria (n=590) O: Microbiologically confirmed TB with treatment initiation within 72 h (primary); 8-week all-cause mortality; TB diagnosis and treatment initiation; time to TB diagnosis/treatment |
Moderate risk: Computer-generated, site-stratified randomisation with concealed allocation, balanced baseline characteristics, intention-to-treat analysis and similar per-protocol findings strengthen internal validity. However, the pragmatic trial was unblinded, allowing potential performance bias, and there were protocol deviations and some over-testing in the control group. Follow-up at 8 weeks was incomplete (~69–73%), and the study was underpowered to detect smaller-than-anticipated differences because the incremental diagnostic yield of expanded testing was lower than expected. |
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P: 82 adults with tuberculous meningitis (TBM) enrolled in a single-centre trial (42 streptomycin; 40 ethambutol) I: Streptomycin 15 mg/kg intramuscularly daily plus isoniazid, rifampicin and pyrazinamide during the intensive phase, followed by rifampicin and isoniazid C: Ethambutol 15 mg/kg orally daily plus isoniazid, rifampicin and pyrazinamide during the intensive phase, followed by rifampicin and isoniazid O: 6-month mortality (primary); in-hospital mortality; neurological disability at 3 and 6 months; adverse events |
Six-month mortality did not differ significantly between streptomycin and ethambutol (28.6% [12/42] vs 35.0% [14/40]; HR 0.78, 95% CI 0.36–1.70, p=0.54), with no significant differences in in-hospital mortality or neurological disability at 3 or 6 months. Two patients in the streptomycin group developed ototoxicity and two in the ethambutol group developed vision loss. Overall, ethambutol and streptomycin showed similar effectiveness and safety, although the trial lacked sufficient power to reliably exclude a clinically meaningful difference. |
High risk: The open-label design could introduce performance and detection bias, particularly for assessment of neurological disability. The very small sample size (82 patients) and early termination due to slow recruitment substantially reduced statistical power, as reflected by the wide confidence interval around the mortality estimate. The single-centre design also limits generalizability, although baseline characteristics were balanced and intention-to-treat analysis was used. |
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P: 12 geographic areas (~80 residential houses per area) in a 50-km² Buruli ulcer-endemic urban region of Melbourne, Australia; 6 areas were randomized to intervention and 6 to control I: ~100 In2Care autodissemination mosquito stations per intervention area for 8 weeks, containing pyriproxyfen larvicide and Beauveria bassiana entomopathogenic fungus C: Control areas with no autodissemination stations O: Aedes notoscriptus mosquito population measured by egg counts (primary); exploratory/post-hoc human Buruli ulcer incidence |
Autodissemination stations reduced average mosquito egg counts by 70.3% across intervention areas compared with controls during the 3 weeks after intervention, with significantly fewer positive ovitraps after intervention (33.4% vs 52.7%, p<0.001). In a post-hoc analysis of Buruli ulcer notifications, there was no significant difference in inferred infection risk across the overall 8-week intervention period (RR 1.023, 95% CI 0.874–1.231); however, at the predicted peak intervention effect, Buruli ulcer incidence was 83% lower in intervention than control zones (1 vs 6 cases; IRR 0.167, 95% CI 0.026–1.054, p=0.047), with mosquito suppression strongly correlated with reduced disease risk (R²=0.85). Overall, the intervention effectively suppressed Ae. notoscriptus, while the apparent reduction in Buruli ulcer risk is exploratory and requires confirmation. |
Moderate risk: Random assignment of matched geographic areas and contemporaneous controls strengthen the assessment of the primary mosquito outcome. However, only 12 areas were randomized, the intervention lasted just 8 weeks, and mosquito egg counts were not measured during the intervention itself. More importantly, Buruli ulcer incidence was not a prespecified primary outcome and was assessed post hoc using very few cases, inferred exposure dates and multiple sliding-window comparisons without adjustment for multiple testing; therefore, the reported disease reduction should be interpreted cautiously. |
Trial Protocols / Trial Ideas
Summary: This is a protocol for a single-center, double-blind RCT in China that will randomize around 98 mechanically ventilated patients with severe multidrug-resistant bacterial pneumonia to standard treatment plus high-dose inhaled nitric oxide or sham inhalation, with change in Clinical Pulmonary Infection Score by day 7 as the primary outcome.
Guidelines and Recommendations
Summary: A 24-member multisociety expert panel issued consensus, evidence-informed hospital-level recommendations to improve sepsis outcomes across six domains, with top priorities including rapid multiplex blood culture testing paired with stewardship, antibiotic delivery within one hour of septic shock recognition, prolonged-infusion antipseudomonal beta-lactams, and giving beta-lactams before vancomycin.
Summary: This focused update to the 2023 international consensus recommendations re-evaluates prolonged- versus short-infusion beta-lactam dosing in severely ill adults in light of new randomized trials, splitting the original mortality-and-cure question into two separate PICO questions given diverging evidence on each outcome.
Phage Therapy
Summary: This review examines key aspects of phage biology relevant to therapy and outlines current approaches and challenges in translating phages into clinical use against bacterial infections.
Summary: A reanalysis of the PhagoBurn burn-wound phage therapy trial found evidence of non-canonical phage-bacterium interactions such as chronic infection and pseudolysogeny rather than straightforward lytic clearance, suggesting these dynamics have been overlooked in phage therapy trial design and may explain variable treatment outcomes.
Antibiotic Therapy Reviews
Summary: This viewpoint argues against routine empirical vancomycin or other anti-Gram-positive coverage for febrile neutropaenia, noting that randomized evidence shows no mortality benefit and contemporary studies link early shock and death primarily to Gram-negative bacilli, inadequate Gram-negative coverage, pneumonia, septic shock and candidaemia; instead, patients should receive rapid, locally informed anti-pseudomonal beta-lactam therapy, with vancomycin reserved for documented infection or specific syndromes with a high likelihood of resistant Gram-positive disease, while negative MRSA nasal screening may further support withholding empirical anti-MRSA therapy.
Summary: Beta-lactam antibiotics (amoxicillin, cefuroxime, meropenem, piperacillin-tazobactam) exhibited dose-dependent immunomodulatory effects on monocytes and CD4+ lymphocytes in vitro, including reduced monocyte HLA-DR expression and altered lymphocyte viability consistent with sepsis-induced immunosuppression, supporting the case for therapeutic drug monitoring to avoid unintended immune consequences of high-dose therapy.
Summary: This review examines the pharmacology, phase 3 evidence, and stewardship implications of the newly FDA-approved oral carbapenems/penems tebipenem and sulopenem for multidrug-resistant Gram-negative urinary tract infections, concluding that while they close a critical oral treatment gap, their expanding community use could shift carbapenem resistance pressure into the community and requires strict formulary restriction and surveillance.
Summary: In this nationwide Qatari cohort of 90 patients with Stenotrophomonas maltophilia bacteraemia, all-cause 90-day mortality was 44.4%, isolates were genomically diverse but remained largely susceptible to trimethoprim-sulfamethoxazole.
Summary: In this observational subgroup analysis of 161 severely ill patients treated with intravenous fosfomycin (mostly combined with ceftazidime-avibactam or colistin) for carbapenem-resistant Gram-negative infections, clinical success was achieved in 79.4% of patients with acceptable tolerability.
Summary: In this multinational retrospective cohort of 119 ICU patients with difficult-to-treat Stenotrophomonas maltophilia pneumonia, tigecycline was associated with significantly higher 30-day mortality, while aztreonam/ceftazidime-avibactam and colistin trended toward lower mortality without reaching statistical significance, and neither combination therapy nor longer treatment duration improved outcomes. This is observational data only and should be viewed only as hypothesis generating.
Summary: This is a retrospective single-center cohort of 56 patients with ceftazidime-avibactam-resistant Enterobacterales or Pseudomonas aeruginosa infections. Its results should be regarded for hypothesis generation only.
PK/PD and Drug Dosing
Summary: In this case series of three critically ill patients with carbapenem-resistant Klebsiella pneumoniae infections and varying renal trajectories, therapeutic drug monitoring showed that continuous venovenous hemodiafiltration significantly cleared aztreonam-avibactam (with filter type affecting drug levels) and that all patients achieved full pharmacokinetic target attainment and clinical cure with monitoring-guided dose adjustments during acute kidney injury recovery.
Antibiotics - In vitro susceptibility
Summary: In this decade-long surveillance study of over 14,000 Pseudomonas aeruginosa isolates from 56 US medical centers, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam remained highly active (97.0-97.9% susceptible) with only minimal decline over ten years, while piperacillin-tazobactam and ceftazidime susceptibility decreased slightly and meropenem, levofloxacin, and tobramycin activity improved since 2017.
Beta-Lactamases and Other Resistance Mechanisms
Summary: This review traces how multidrug-resistant Escherichia coli evolved through two major waves of convergent resistance—first merging fluoroquinolone-resistance mutations with CTX-M beta-lactamases in the 2000s (exemplified by clone ST131), then combining penicillin-binding protein-3 insertions with NDM carbapenemases in the 2010s (exemplified by ST410/ST167)—with the latter conferring reduced susceptibility to newer beta-lactam/beta-lactamase inhibitors and cefiderocol.
Molecular and proteomic epidemiology
Summary: This proof-of-concept study introduces MALDI-ST, a convolutional neural network trained on MALDI-TOF mass spectra to rapidly predict bacterial strain type across four key pathogens (E. coli, P. aeruginosa, S. aureus, E. faecium), achieving balanced accuracies of 91-97% on internal testing but showing that centre- and instrument-specific spectral variation substantially affects performance on external validation, indicating multi-centre data collection will be needed before clinical adoption as a faster alternative to whole genome sequencing for outbreak detection.
Antibiotic Stewardship and Hospital in the Home
Summary: In a blinded, expert-scored evaluation of seven large language models across 30 adversarial antimicrobial stewardship scenarios, four commercial models (Claude Sonnet 4.5, Gemini 2.5 Pro, Grok 4, GPT-5) scored above 3.9/5.0 for content quality while open-weight models scored significantly lower, but no model exceeded 63% of responses free of fabrication or dangerous recommendations, leading evaluators to endorse LLMs as useful for supervised, non-clinical stewardship tasks like documentation and education rather than unsupervised clinical decision-making.
Summary: In this 10-year Swedish population-based cohort study linking antibiotic prescribing to infection outcomes across 2.4 million residents, sustained reductions in outpatient antibiotic prescribing for upper respiratory tract infections were accompanied by declining rates of most infectious complications (with only mastoiditis showing a modest increase).
Summary: This mixed-methods study combining qualitative interviews at 6 Midwestern VA medical centers with a national survey of 106 facilities found substantial variability in how outpatient parenteral antimicrobial therapy (OPAT) is delivered, with challenges including uncertainty about roles and responsibilities at sites lacking a designated OPAT team and communication breakdowns between VA and non-VA clinicians after discharge, suggesting that establishing dedicated processes and standardized guidelines could improve safe OPAT delivery.
Infection Prevention / Antibiotic Prophylaxis
Summary: The AHRQ Safety Program for MRSA Prevention, implemented across 106 ICUs and 87 non-ICUs in 94 US hospitals over 18 months, was associated with a 65% reduction in laboratory-identified hospital-onset MRSA bacteremia events along with significant decreases in all-cause bacteremia, MRSA-positive cultures, and central line-associated bloodstream infections, supported by increased uptake of nasal decolonization and environmental cleaning monitoring.
Summary: In this prospective cohort study of 13,646 surgical patients across 26 UK hospitals, increasing doses of antimicrobial prophylaxis were not associated with reduced surgical site infection (8.0% overall) but were associated with a dose-dependent increase in antimicrobial side effects (occurring in 6.4% of patients, roughly three times the previously expected rate) and postoperative complications.
Summary: This systematic review and meta-analysis of 85 randomized trials (16,980 patients) found that incisional negative pressure wound therapy significantly reduced overall, deep, and superficial surgical site infection along with wound dehiscence, seroma, and reoperation, but increased the risk of skin blistering and device-related adverse events, supporting selective rather than routine use in patients at elevated risk of wound complications.
Summary: Marking the 50th anniversary of the landmark SENIC study that established the value of organized infection prevention programs, this Ideas and Opinions piece argues that despite the resulting dramatic decline in healthcare-associated infection rates, current NHSN surveillance definitions and CMS public reporting metrics are confounded by numerous factors and may not accurately capture true quality of infection prevention care.
Summary: Among 110 invasive KPC-producing Klebsiella pneumoniae bloodstream isolates from a Brazilian hospital, a local ST258 sub-lineage showed markedly reduced chlorhexidine susceptibility (MIC50 64 vs 16 µg/mL) and survived low-concentration chlorhexidine exposure, traced through whole-genome sequencing and genetic complementation to a frameshift mutation inactivating the smvR repressor that independently drives efflux-mediated chlorhexidine tolerance without conferring cross-resistance to colistin.
Summary: This report describes the first known clonal hospital outbreak of aztreonam-avibactam- and cefiderocol-resistant NDM-5-producing Escherichia coli, in which whole-genome sequencing linked six of seven infected or colonized patients to a shared ST405 clone traced to duodenoscope exposure during endoscopic retrograde cholangiopancreatography, with resistance driven by a PBP3 insertion combined with DHA-1 or CMY-42 β-lactamase production.
Bloodstream Infections and Endocarditis
Summary: This study found that valve leaflet thickening, recently incorporated into the 2023 Duke-ESC criteria as an imaging marker of infective endocarditis, is a frequent but non-specific finding that substantially reduces diagnostic specificity when included, suggesting caution in relying on this criterion alone.
Summary: In this large multicentre propensity-score-matched cohort study across 27 French hospitals, infective endocarditis in solid organ and haematopoietic stem cell transplant recipients showed a distinct microbiological profile (more coagulase-negative staphylococci, enterococci, HACEK organisms, and fungi) and significantly higher 1-year mortality compared with non-transplant controls.
Summary: This state-of-the-art multidisciplinary review comprehensively examines infections in mechanical circulatory support devices (both durable LVADs and temporary devices like ECMO and Impella), covering pathophysiology, the updated 2024 ISHLT infection classification, diagnostic imaging strategies (with FDG-PET/CT emerging as the most accurate modality for LVAD infection), and management ranging from antibiotics and driveline debridement to pump exchange and heart transplantation, noting infection affects roughly 37% of durable device patients and remains a leading cause of morbidity, mortality, and reduced transplant eligibility.
Summary: In this 20-year retrospective study of 142 neutropenic patients with Pseudomonas aeruginosa bloodstream infection, skin involvement occurred in 21% of cases and was independently associated with underlying acute myeloid leukemia and recurrent infection, while prolonged neutropenia and hospitalization suggested a more complicated clinical course, highlighting the value of increased vigilance for skin lesions in high-risk patients.
Summary: This narrative review examines the emerging use of data-driven phenotyping and unsupervised machine learning to identify clinically meaningful subphenotypes within bloodstream infections, most extensively studied in Staphylococcus aureus bacteraemia where distinct subgroups with significantly different mortality rates have been reproducibly identified across international cohorts, and argues this approach holds promise for personalizing antimicrobial therapy and enriching future clinical trial design.
Gastrointestinal Tract Infections
Summary: Using a THP-1 macrophage infection model, this study found that azithromycin accumulates to 20-72 fold higher concentrations intracellularly than extracellularly and shows dose-dependent bactericidal activity against intracellular azithromycin-susceptible Salmonella Typhi, but azithromycin-resistant isolates require intracellular concentrations exceeding 460 mg/L to inhibit growth (far above levels achievable with standard oral dosing), a finding consistent with clinical treatment failures observed in azithromycin-resistant typhoid patients and warranting reconsideration of azithromycin as monotherapy for these infections.
Summary: In this prospective cohort study of 1400 Zambian children under five, Shigella-associated moderate-to-severe diarrhoea had an incidence of 24.0 per 1000 child-months (highest among 2-3 year-olds), with genomic analysis revealing multidrug-resistant Shigella flexneri, S sonnei, and S boydii strains including plasmid-mediated quinolone resistance (qnrS1) in 40% of S flexneri isolates, though no resistance to azithromycin (the first-line treatment) was detected, underscoring both a substantial disease burden and the need for continued antimicrobial resistance surveillance and vaccine development.
Summary: In this study of hospitalized adults with Clostridioides difficile infection, atypical presentations involving gastrointestinal dysmotility (affecting 32% of episodes and often the small bowel, persisting radiologically for up to 6 weeks) were common, frequently unrecognized, and associated with significantly higher mortality, challenging the conventional view of CDI as a primarily diarrheal illness.
Bone and Joint Infections
Summary: In this study of 475 patients evaluated for septic arthritis, adjunctive synovial fluid PCR testing identified additional pathogens missed by culture alone (particularly with antibiotic pretreatment or N. gonorrhoeae) and is projected to increase the timeliness of emergency department diagnosis and pathogen-specific treatment, though a few PCR-positive gonococcal cases went untreated due to clinical uncertainty.
Summary: Using a murine implantation model to compare in vivo and in vitro gentamicin release from two commercial antibiotic-loaded ceramic bone grafts, this study found that both grafts released over 98% of their gentamicin within 6 hours and over 99% within 24 hours, with model calculations suggesting that previous in vitro assays only appeared to show prolonged sustained release due to the assay's washout design rather than true extended drug delivery, challenging the clinical assumption that these grafts protect against infection for 28 to 42 days.
Skin and Soft Tissue Infections
Summary: This narrative review found that skin and soft tissue infections occupy a diagnostic continuum where uncomplicated cellulitis is frequently overdiagnosed (misdiagnosis rates of 19-83%, pooled average 41%) while life-threatening necrotizing soft tissue infections are often under-recognized in early stages (misdiagnosed as cellulitis in up to 96% of cases), concluding that improved outcomes depend on structured clinical pathways, early reassessment, and selective imaging rather than any single diagnostic test or score.
Summary: In this five-year analysis of over 61,000 severely injured patients from the German TraumaRegister DGU, sepsis developed in 5.7% of patients and was associated with markedly prolonged ICU stay, a 68.7% rate of multiple organ failure, and 31.5% in-hospital mortality (versus 15.8% overall), with pulmonary infections being most common (63.6% of cases) while abdominal sepsis carried the highest case-fatality (38.0%), and early mechanical ventilation at ICU admission showing the strongest association with sepsis development.
Summary: This diagnostic and prognostic study developed a deep learning model to detect surgical wounds suspicious for surgical site infection from postoperative photographs, achieving strong discrimination in internal testing (AUC 0.91) and independent external validation (AUC 0.82), with good calibration and clinical utility, suggesting that automated wound image analysis could be integrated into telemedicine to support scalable at-home postoperative monitoring and earlier triage of patients at risk of surgical site infection.
CNS Infections
Summary: In a prospective cohort of 1,226 patients undergoing lumbar puncture for suspected CNS infection, CSF Gram stain showed excellent specificity (100%, no false positives) but limited sensitivity (53% for microbiologically confirmed bacterial meningitis, dropping to 38% when clinically diagnosed cases were included), with sensitivity varying markedly by pathogen (67% for S. pneumoniae versus 0% for Listeria monocytogenes and Haemophilus influenzae), and while a positive result reliably confirmed disease and prompted antibiotic narrowing in a meaningful subset of patients, its overall impact on clinical management across all suspected CNS infections was modest.
Respiratory Tract Infections
Summary: In this single-center retrospective cohort of 204 patients with Pseudomonas aeruginosa pneumonia, piperacillin-tazobactam and cefepime outcomes were compared. The results from this observational study are controversial, and should be regarded as hypothesis generating only.
Summary: This clinical practice review outlines a risk-stratified approach to managing pulmonary nodules, distinguishing solid from subsolid (part-solid or pure ground-glass) nodules, describing prediction models to guide surveillance, PET-CT, biopsy, or surgical resection decisions, and emphasizing the goal of balancing timely cancer diagnosis against avoidance of unnecessary invasive procedures for benign disease.
Summary: Using Enhanced Pertussis Surveillance data, this study found that the 2020 CSTE pertussis case definition change (classifying PCR-positive cases as confirmed regardless of cough duration) accounted for an estimated 38.0% of the 2024 increase in reported US pertussis cases, meaning that without the definition change the observed 133% increase in cases from 2019 to 2024 would have instead been a more modest 44% increase.
Urinary Tract Infections
Summary: This perspective argues that, unlike in most patient populations where asymptomatic bacteriuria (ASB) should be left untreated, ASB in pregnant women behaves as the same condition as symptomatic UTI at a different point on the symptom spectrum given shared risk, causative organisms, and treatment recommendations, and uses a case of recurrent UTI culminating in preterm delivery with chorioamnionitis to question whether current diagnostic thresholds (100,000 CFU/mL for ASB versus as low as 100 CFU/mL for symptomatic UTI) are appropriate during pregnancy.
Summary: Across ten registrational RCTs totaling 5,971 patients, acute pyelonephritis achieved significantly higher composite cure rates at test-of-cure than other complicated urinary tract infections (pooled risk ratio 1.12), with this gap driven mainly by differences in microbiologic eradication rather than clinical cure, leading the authors to call for future trials to harmonize AP/cUTI definitions and separately report clinical versus microbiologic outcomes given the heterogeneity and limited stratified reporting that currently reduce comparability across studies.
Infections in Children
Summary: This national cohort study of 252 children ages 3 months to 17 years diagnosed with community-acquired pneumonia found that physicians frequently disagreed on common lung sounds used to diagnose pneumonia (including crackles, decreased breath sounds, and rhonchi), showing that physical examination alone may not reliably diagnose pneumonia in children.
Summary: This perspective piece from the SNAP-PY trial investigators explains the rationale for continuing the whole-of-life Staphylococcus aureus Network Adaptive Platform trial into children and youth, building on recent adult results showing cefazolin was non-inferior to flucloxacillin/cloxacillin for methicillin-susceptible S. aureus bacteremia.
Summary: In this retrospective cohort study of 1,413 preterm infants across two Dutch NICUs, implementation of a multistrain probiotic (Bifidobacterium infantis Bb-02, Bifidobacterium lactis BB-12, and Streptococcus thermophilus TH-4) was associated with a reduction in necrotizing enterocolitis incidence from 11.9% to 5.3% (adjusted risk ratio 0.49), though non-NEC-associated mortality unexpectedly increased from 7.2% to 9.6%. These results should be regarded as hypothesis generating for an RCT.
Mycobacterial Infections
Summary: In a genetic characterization of Mycobacterium tuberculosis isolates from participants who developed pulmonary tuberculosis during the M72/AS01E phase 2b vaccine trial, researchers found no apparent preferential distribution of M. tuberculosis strains between vaccine and placebo recipients, suggesting the vaccine's protective effect is not strain-specific.
Summary: In a longitudinal cohort study of household contacts of adults with confirmed pulmonary tuberculosis in Lima, Peru, researchers examined the impact of isoniazid preventive therapy on both progression to active TB disease and the separate question of preventing new TB infection altogether, finding that while IPT's protective effect against disease progression is well established, its effect on preventing new infection had previously remained uncertain.
Summary: In this study of 12 children under 18 years old (median age 2.8 years) with multidrug/rifampicin-resistant tuberculosis, a revised once-daily dosing strategy using a novel 50-mg clofazimine tablet achieved a median predicted weekly steady-state exposure of 106 mg·h/L, within 25% of the adult target of 111.79 mg·h/L, though two grade 3 adverse events (drug-induced liver injury and skin hyperpigmentation) and five instances of QTcF interval prolongation occurred, supporting cautious use with ECG and laboratory monitoring before broader adoption.
Summary: In a murine model of latent tuberculosis, adjunctive immunotherapy with recombinant APRIL significantly reduced tuberculosis relapse following BCG vaccination (while BCG alone had only modest effects), with protection associated with selective remodeling and activation of marginal-zone B cell compartments rather than changes in T cell populations, supporting further investigation of B cell-targeted immunomodulation to improve durable TB immune control.
Ambrosio AR, Pego H. Scrofuloderma. N Engl J Med. 2026 Aug 29; doi:10.1056/NEJMicm2517515
Summary: This images-in-clinical-medicine case describes a 72-year-old man with a 2-month history of a painful neck lump that was cytologically consistent with suppurative lymphadenopathy and subsequently ulcerated with purulent discharge, illustrating scrofuloderma as a cutaneous manifestation resulting from direct extension of tuberculous infection from an underlying lymph node to the overlying skin.
Summary: This post-hoc analysis of a stepped-wedge cluster randomized trial in Zambia found that a person-centered care intervention improved both the likelihood of returning to HIV care and the durability of sustained reengagement after treatment interruptions, suggesting person-centered approaches can help address the persistent challenge of care disengagement among people living with HIV.
Summary: This systematic review and meta-analysis found that artificial intelligence and machine learning models show promising predictive performance for identifying tuberculosis treatment failure, highlighting their potential to support early clinical decision-making and targeted intervention for patients at high risk of poor treatment outcomes.
Summary: In this multi-center retrospective cohort study, targeted next-generation sequencing demonstrated strong clinical utility for rapidly detecting Mycobacterium tuberculosis, differentiating species, profiling drug resistance, and informing prognosis, supporting its integration into routine clinical microbiology workflows as a faster alternative to conventional culture-based methods.
Summary: This systematic review and meta-analysis comparatively evaluated molecular technologies for identifying the most prevalent non-tuberculous mycobacteria species causing pulmonary infections, providing guidance on which diagnostic platforms offer the best accuracy for distinguishing NTM species relevant to clinical management decisions.
Fungal Infections and antifungal agents
Summary: This narrative review examines chimeric antigen receptor (CAR)-based immunotherapy as a promising strategy to restore pathogen-specific immunity in immunocompromised patients, with CAR-T cells targeting conserved fungal cell wall components like β-glucans and mannans showing encouraging preclinical activity against Aspergillus and Candida, while alternative platforms like CAR-natural killer cells and CAR macrophages offer potential advantages in toxicity and off-the-shelf availability, though complex manufacturing, antigen heterogeneity, and limited clinical evidence remain significant barriers to translation into routine practice.
Summary: This report describes the successful containment of a 6-month Candidozyma auris outbreak in an acute care hospital using massive rapid PCR screening combined with rigorous infection control measures, addressing the pathogen's tendency toward prolonged asymptomatic colonization and silent healthcare transmission that typically hampers outbreak control.
Summary: This major review synthesizes growing evidence that Aspergillus is an important and probably under-recognized problem in people with COPD, spanning a spectrum of interactions from airway colonization and sensitization through to chronic pulmonary aspergillosis and invasive pulmonary aspergillosis, arguing for greater clinical awareness of fungal disease in this population.
Summary: In this retrospective diagnostic accuracy study of 774 bronchoalveolar lavage qPCR episodes for Pneumocystis jirovecii pneumonia (PCP), a Ct value cutoff of 30 showed good diagnostic performance (AUC 0.85) with qPCR negativity providing high sensitivity to rule out PCP, while serum β-D-glucan showed excellent discrimination (AUC 0.96, cutoff 9 pg/mL) and proved especially valuable for resolving intermediate Ct values (26-36) where PCR alone could not reliably distinguish true infection from colonization, supporting an integrated diagnostic strategy combining both tests.
Summary: This reanalysis applies a desirability of outcome ranking (DOOR) approach—combining efficacy and safety into a single ordinal endpoint—to the original 2002 voriconazole versus amphotericin B deoxycholate trial for invasive aspergillosis, offering a more holistic examination of patient experience beyond the original binary success/failure outcome.
Host Response in Infection
Summary: This Review examines the immune-mediated pathogenesis of rheumatic heart disease following Streptococcus pyogenes infection, highlighting how molecular mimicry, antigen-driven T-cell responses, chemokine-mediated recruitment to heart valves, dysregulated Th1–Th17 cytokine networks, endothelial activation, and stromal remodelling contribute to progressive valvular inflammation, fibrosis and injury, while identifying gaps in current evidence and potential biomarkers, experimental models and immunomodulatory targets for earlier diagnosis, improved secondary prevention and targeted treatment.
Summary: This retrospective cohort study of 142 patients with culture-confirmed melioidosis and 76 healthy blood donors in northeast Thailand found that IgG and IgA antibody responses to Burkholderia pseudomallei Hcp1 and OPS antigens showed high diagnostic accuracy but could remain above diagnostic thresholds for more than a year after infection, particularly in people with diabetes who had higher peak responses and slower antibody decay, suggesting that persistent seropositivity may complicate differentiation of recent from past infection while combined antigen–isotype cutoffs and modelling of antibody dynamics could improve diagnosis and population-level serosurveillance.
Diagnostics
Summary: This Commentary questions the routine reliance on minimum inhibitory concentration (MIC) values to guide antimicrobial therapy, arguing that although MICs are increasingly used for antibiotic selection, dose optimisation and pharmacokinetic/pharmacodynamic approaches, their clinical interpretation can be limited by measurement variability and uncertain associations with patient outcomes, supporting a more cautious and clinically contextualised approach to antimicrobial susceptibility reporting and treatment decisions.
Summary: This narrative review evaluates rapid organism identification, resistance-marker detection and rapid phenotypic antimicrobial susceptibility testing for bloodstream infections, finding that these technologies most consistently shorten time to active or optimal therapy and enable earlier antimicrobial escalation or de-escalation, while effects on mortality, length of stay and cost are less consistent, and proposes a five-domain clinical actionability framework emphasising result certainty, patient risk, pretest resistance probability, result-to-action capacity and antimicrobial stewardship quality to guide effective local implementation
Improving Clinical Research
Summary: This methodological study highlights how substantial heterogeneity in cluster sizes and structures can distort inference in cluster-randomized trials, particularly pragmatic trials, and proposes the CARE (Clarify, Apply, Refine, Evaluate) protocol, which uses cluster diagnostics and a design-based, cluster-robust analysis as a benchmark before incorporating more assumption-dependent methods, aiming to make trial analyses more robust, transparent and comparable across studies.
Summary: This methodology paper proposes a systematic process for distinguishing clinical interventions from implementation strategies in trials, using logic models and causal pathway diagrams to identify mechanisms of action, treatment effect modifiers and proximal and distal outcomes, with classification primarily determined by whether the innovation acts through clinical or implementation mechanisms, thereby helping trialists appropriately select outcomes, comparators, study populations, trial designs and reporting frameworks.
Summary: This article defines randomized quality improvement trials, which use randomization to evaluate health-care quality improvement interventions, and proposes a streamlined, fit-for-purpose framework for ethical oversight, arguing that such trials require careful ethical justification and monitoring even when they do not formally qualify as research, while recommending systems for internal registration, point-of-care randomization and standardized statistical analyses to support their routine use in learning health systems.
Summary: This Review provides clinicians with a practical overview of the principles underlying randomised trials, covering trial purposes and designs, randomisation and allocation concealment, ethical and governance considerations, internal and external validity, common sources of bias, missing data, intention-to-treat and per-protocol analyses, and reporting standards, emphasising that reliable interpretation and application of trial findings depend on rigorous design and conduct as well as careful assessment of whether results are valid and generalisable to real-world clinical practice.
Summary: This Clinical Trials Workshop article reviews key principles for designing, conducting, analysing and interpreting cluster-randomized trials, using cardiovascular prevention as an illustrative example to explain when cluster randomization is appropriate, how to select the unit of randomization, protect internal validity and account for statistical efficiency, and why outcomes and analyses should align with the level and mechanism at which interventions are delivered to strengthen the validity, interpretation and policy relevance of trial findings.
Summary: This Comment highlights growing concerns about the reliability of observational epidemiology amid rapidly expanding access to large datasets, increasing publication pressures and the use of artificial intelligence, and proposes seven practices to strengthen evidence and public trust: use appropriate causal methods for causal claims, establish plausible causal mechanisms, avoid redundant analyses when strong evidence already exists, publish all analyses and improve research transparency, involve and appropriately credit biostatisticians, avoid overinterpreting ecological studies, and prioritise rigorous research and effective science communication in an environment of misinformation and declining trust in science.
General Interest
Summary: This Personal View examines the overlap between sepsis and endemic and emerging infectious diseases such as malaria, leptospirosis, tuberculosis and gastroenteric illnesses, highlighting implications for estimates of disease burden, pathophysiology, treatment and precision medicine, and proposes disease-specific stratification to distinguish milder disease from life-threatening infection with organ dysfunction—termed sepsis from an endemic and emerging infectious disease (SEEID)—while emphasising the need for early recognition, disease-specific guidance and more randomised clinical trials, particularly in resource-limited settings.
Summary: Using ancient DNA analysis of seven 19th-20th century German osteomyelitis bone specimens, researchers identified authentic Acinetobacter baumannii, Staphylococcus aureus, and Streptococcus pyogenes genomes and found that while these historical pathogens already carried extensive virulence factors and intrinsic resistance mechanisms (including beta-lactamases predating antibiotics), they lacked the extensive acquired resistance seen in modern strains, indicating that the genetic foundations for pathogenicity existed over a century before antibiotic-driven selection expanded resistance in contemporary hospital lineages.
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