Issue: Newsletter 24 | July 1, 2026
Randomised Controlled Trials
| Citation of Articles | PICO | Main Results | Risk of Bias |
|---|---|---|---|
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P: 299 adults hospitalized with complicated UTIs due to ESBL-producing Enterobacterales who improved after 3–7 days of intravenous antibiotics, across four tertiary hospitals in South Korea I: Oral fosfomycin trometamol (3 g once daily) as step-down therapy C: Continued intravenous carbapenem or β-lactam/β-lactamase inhibitor therapy O: Primary: Clinical cure (resolution of UTI-related symptoms and signs within 4 days after treatment completion). Secondary: Microbiological cure, readmission, adverse events, 30-day recurrence |
Oral fosfomycin was noninferior to continued intravenous therapy for clinical cure (92.8% vs 95.2%, risk difference −2.47%, 95% CI −7.84 to 2.89). Microbiological cure rates were similarly high in both groups for urine (98.0% vs 96.6%) and blood cultures (97.3% vs 97.5%). Safety profiles and 30-day outcomes, including readmission and recurrence, were comparable between groups, supporting oral fosfomycin as a viable carbapenem-sparing transition strategy. | Moderate risk: The open-label design introduces potential performance and detection bias, as clinicians and patients were aware of treatment allocation. Conduct across only four tertiary hospitals in South Korea may limit generalizability to other settings and populations. However, the randomized design, clear noninferiority margin, and high completion rates strengthen internal validity. |
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P: 1,287 adults with penicillin-resistant, methicillin-susceptible S. aureus bacteremia enrolled in an international Bayesian adaptive platform trial I: Intravenous cefazolin C: Antistaphylococcal penicillin (flucloxacillin or cloxacillin) O: Primary: All-cause mortality within 90 days. Secondary: Acute kidney injury within 14 days |
Cefazolin was noninferior to antistaphylococcal penicillins for 90-day mortality (15.0% vs 17.0%, adjusted OR 0.81, 95% credible interval 0.59–1.12; probability of noninferiority 99.2%, probability of superiority 89.8%). Cefazolin was also associated with a significantly lower incidence of acute kidney injury within 14 days (13.9% vs 19.6%, adjusted OR 0.67, 95% credible interval 0.50–0.89; probability of superiority 99.7%). These findings support cefazolin as a preferred option for MSSA bacteremia given comparable efficacy and a superior renal safety profile. | Moderate risk: The open-label design introduces potential performance and detection bias. However, the use of a Bayesian adaptive platform design with pre-specified noninferiority criteria, hierarchical modelling, and a hard primary endpoint (90-day mortality) mitigates subjective outcome assessment concerns. The international multicentre design strengthens generalizability. The trial was stopped at a pre-specified statistical threshold, which is methodologically sound but may limit detection of smaller differences in secondary outcomes. |
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P: 281 adults (median age 67 years; 69% male) with penicillin-susceptible S. aureus (PSSA) bacteremia enrolled across 67 hospitals in eight countries (Australia, New Zealand, Canada, Israel, the Netherlands, the UK, Singapore, and South Africa) I: Benzylpenicillin (1.8 g IV every 4h or 2.4 g every 6h) C: Anti-staphylococcal penicillin (flucloxacillin 2.0 g IV every 6h or cloxacillin 2.0 g IV every 4h) O: Primary: All-cause mortality at 90 days. Secondary: Acute kidney injury, serious adverse reactions |
The prespecified noninferiority criterion for benzylpenicillin was not formally met, though the probability of noninferiority was high. Ninety-day mortality was 14% in the benzylpenicillin group versus 22% in the flucloxacillin/cloxacillin group (adjusted OR 0.67, 95% CrI 0.35–1.28; posterior probability of noninferiority 96.1%, superiority 88.9%). Benzylpenicillin was associated with a significantly lower incidence of acute kidney injury (11% vs 22%, adjusted OR 0.50, 95% CrI 0.26–0.94; posterior probability of noninferiority 99.8%, superiority 98.4%). Serious adverse reactions were numerically lower in the benzylpenicillin group (4% vs 7%). The trial was stopped early by the DSMB due to excess AKI in the comparator arm before prespecified stopping thresholds were reached. | Moderate-to-high risk: The open-label design introduces performance and detection bias. Early termination by the DSMB before prespecified stopping thresholds were reached resulted in a smaller-than-planned sample size (281 of 493 screened), limiting statistical power and preventing formal demonstration of noninferiority. Imbalanced randomization (156 vs 125) may reflect adaptive platform dynamics. However, the international multicentre design, Bayesian hierarchical modelling, and use of a hard primary endpoint (90-day mortality) strengthen internal validity. |
| Donovan J, Hung TT, Hiep NTT, Nghia HDT, Ngoc LHB, Bang ND, et al. A randomised comparison of management strategies for drug-induced liver injury associated with tuberculous meningitis treatment. J Infect. 2026 Jun 17;93(2):106796. doi:10.1016/j.jinf.2026.106796 | P: 67 adults with tuberculous meningitis (TBM) who developed drug-induced liver injury (DILI) during anti-TB treatment, nested within two corticosteroid RCTs (ACT HIV, N=520; LAST ACT, N=720) I: Strategy 1: Continue all drugs unless ALT ≥10× ULN, bilirubin ≥43 µmol/L, or symptoms worsen (n=21); Strategy 2: Stop pyrazinamide alone unless ALT ≥5× ULN by day 6, bilirubin ≥43 µmol/L, or symptoms worsen (n=21) C: Strategy 3: Stop rifampicin, isoniazid, and pyrazinamide; continue ethambutol; add levofloxacin and aminoglycoside (n=25) O: Primary: Proportion of time over 60 days post-DILI randomization without rifampicin or isoniazid (or death). Secondary: Acute liver failure, death or new neurological events up to 12 months |
Participants had fewer days without rifampicin and isoniazid in strategy 1 (median 7 days, IQR 0–31) and strategy 2 (median 9 days, IQR 0–21) compared with strategy 3 (median 18 days, IQR 11–35; p=0.022 and p=0.041, respectively). No participants in any group developed acute liver failure. Strategy failure requiring switch to strategy 3 occurred in 38.1% (8/21) of strategy 1 and 61.9% (13/21) of strategy 2 participants. Death or new neurological events were numerically lower in strategy 1 (7/21) and strategy 2 (9/21) compared with strategy 3 (14/25), though differences were not statistically significant (p=0.20 and p=0.42, respectively). Overall, strategies prioritizing drug continuation appeared safe and reduced rifampicin/isoniazid interruptions. | High risk: The very small sample size (67 participants across three arms) severely limits statistical power and the ability to detect clinically meaningful differences in safety and efficacy outcomes. The nested design within two parent corticosteroid trials introduces potential confounding from the parent trial interventions. The open-label design introduces performance and detection bias. Unequal group sizes (21, 21, 25) and high strategy-failure crossover rates (up to 61.9% in strategy 2) complicate interpretation of the intention-to-treat analysis. The study population is highly selected (only those developing DILI), limiting generalizability. |
| Mohan G, Hanrahan CF, Martinez-Amezcua P, Hoffmann CJ, Biché P, Martinson NA, et al. Multidimensional poverty and implementation reach of household contact tracing for tuberculosis in South Africa: analysis of a randomized trial. Clin Infect Dis. 2026 Jun 17; doi:10.1093/cid/ciag321 | P: 3,392 households of tuberculosis index cases in South Africa (urban and rural settings) within a cluster-randomized trial I: Household contact tracing (HHCT) implementation examined in relation to household multidimensional poverty (composite deprivation score encompassing health, education, and living standards) C: Households with lower multidimensional poverty scores (within-trial comparison across the poverty spectrum) O: Primary: HHCT reach measured as (1) initiation (≥1 household contact screened), (2) continuous proportion of eligible contacts screened, and (3) completion (all eligible contacts screened once initiated) |
Despite near-universal stated comfort with HHCT (97%), only 43% of households initiated screening and 19% completed it. Greater multidimensional poverty was significantly associated with lower HHCT initiation in urban households (aPR 0.903 per 10% higher deprivation, 95% CI 0.831–0.984, p=0.021) but not in rural households (aPR 1.06, 95% CI 0.99–1.13, p=0.083). Across all households, greater poverty was modestly but significantly associated with a lower proportion of contacts screened (aAME −1.22% per 10% higher deprivation, 95% CI −2.20% to −0.236%, p=0.015). Among households that initiated HHCT, multidimensional poverty was not significantly associated with screening completion (aPR 0.945, 95% CI 0.865–1.03, p=0.207), suggesting that barriers to completion may be operational or health-system related rather than poverty-driven. | Moderate risk: The cluster-randomized design is appropriate for this community-level intervention, but the observational nature of the poverty-outcome analysis within the trial limits causal inference. The open-label design and reliance on household self-reported comfort with HHCT may introduce social desirability and detection bias. Low HHCT initiation (43%) and completion (19%) rates suggest significant implementation challenges that may differentially affect results across poverty strata. The single-country setting (South Africa) limits generalizability to other high-burden TB contexts. |
| Ingelbeen B, Valia D, Mbangi B, van Kleef E, Campbell L, Kouanda JS, et al. Effect of a community-based behavioural intervention bundle to improve antibiotic use and patient management in Burkina Faso and DR Congo (CABU-EICO): a cluster-randomised controlled trial. Lancet Infect Dis. 2026 Jun 16; doi:10.1016/S1473-3099(26)00169-6 | P: 44 villages or neighbourhoods (≥500 inhabitants each) with community-level or primary-care providers in Nanoro, Burkina Faso, and Kimpese, DR Congo; 10,430 patients surveyed across baseline and post-intervention periods, and 1,092 simulated patient visits completed I: Community-based, co-created intervention bundle over 9 months consisting of three rounds of community health education campaigns and educational/feedback sessions with providers, introducing WHO AWaRe Antibiotic Book guidance for infections with highest antibiotic use C: Standard care (no intervention) O: Primary: Baseline-to-post-intervention change in Watch-group antibiotic use (measured via repeated patient surveys, cluster-adjusted and offset for healthcare utilisation). Secondary: Patient management scores for five common infections (assessed via simulated patient visits) |
Watch-group antibiotic use decreased from 26.8% (95% CI 8.8–44.8) to 17.1% (7.7–26.5) in the intervention group, while it increased from 13.4% (4.8–22.0) to 21.2% (8.9–33.5) in the control group, yielding an adjusted prevalence ratio of 0.33 (95% CI 0.14–0.78), indicating a substantial intervention effect. Changes in patient management scores across five common infections were minimal, suggesting the reduction in broad-spectrum antibiotic use did not negatively affect quality of care. These findings support the potential of community-based behavioural interventions to improve antibiotic stewardship across diverse provider types in sub-Saharan Africa. | Moderate risk: Field workers conducting patient surveys and simulated patient visits were masked to group allocation, reducing detection bias. However, providers and communities were unmasked, introducing performance bias as awareness of the intervention may have influenced prescribing behaviour beyond the educational content itself. Baseline imbalances in Watch-group antibiotic prevalence between groups (26.8% vs 13.4%) are notable, though the analysis adjusted for this. Exclusion of providers with fewer than 20 completed surveys may introduce selection bias. The two-country setting enhances generalizability within sub-Saharan Africa but may not extend to other regions. |
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P: 611 internal medicine residents, attending physicians, and advanced practice providers across multiple centres I: Diagnostic test characteristics presented as interval likelihood ratios (ILRs) C: (1) Single-threshold test characteristic presentation; (2) Binary test characteristic presentation O: Primary: Correct management decision rate across two fictional clinical vignettes (pulmonary embolism diagnosis and heart failure treatment). Secondary: Comparison between threshold and binary groups; subgroup analyses by case vignette |
The correct decision rate was significantly higher in the ILR group (93.4%) compared with the threshold group (82.2%, difference 11.2 percentage points, 95% CI 6.9–15.6, p<0.001) and the binary group (75.1%, difference 18.3 percentage points, 95% CI 13.5–23.1, p<0.001). The magnitude of improvement varied by vignette: in the pulmonary embolism case, correct response rates were 91.9% (ILR), 70.9% (threshold), and 64.7% (binary); in the heart failure case, rates were 94.9% (ILR), 93.4% (threshold), and 85.6% (binary), indicating that the ILR advantage was most pronounced when the clinical scenario required more nuanced interpretation of test results. | Moderate risk: The use of fictional vignettes rather than real clinical encounters limits external validity, as decision-making in simulated settings may not reflect actual practice behaviour. Participants were randomized to presentation format, reducing selection bias, but could not be blinded to the format they received. The clearly correct response design may overestimate the benefit of ILRs in ambiguous real-world scenarios. The multicentre design and inclusion of diverse provider types strengthen generalizability within the study population. The vignette-dependent magnitude of effect suggests results may not be uniformly applicable across all clinical contexts. |
| Conradie F, Badat T, Poswa A, Rajaram S, Kooverjee S, Maartens G, et al. A pragmatic trial of a 6-month strategy for rifampicin-resistant tuberculosis. N Engl J Med. 2026 Jun 24;394(24):2429-2439. doi:10.1056/NEJMoa2503687 | P: 403 participants aged ≥6 years with pulmonary rifampicin-resistant tuberculosis in South Africa, including persons who were pregnant or breastfeeding and those with fluoroquinolone-resistant tuberculosis I: 6-month regimen of bedaquiline, linezolid, delamanid, and levofloxacin or clofazimine or both, adjusted based on second-line drug susceptibility testing C: 9-month standard-of-care treatment regimen current in South Africa, adjusted based on second-line drug susceptibility testing O: Primary efficacy: Successful outcome (cure or treatment completion) at end of treatment and at 76 weeks after randomization. Primary safety: Adverse events of grade 3 or higher |
The 6-month trial strategy was noninferior to the 9-month standard-of-care regimen. A successful outcome was observed in 86.1% (174/202) of the trial-strategy group and 86.0% (172/200) of the control group (adjusted risk difference −0.2 percentage points, 95% CI −6.9 to 6.5, p=0.001 for noninferiority). Grade 3 or higher adverse events occurred in 31.2% (63/202) of the trial-strategy group versus 37.0% (74/200) of the control group, with 10 deaths in each group, indicating similar safety profiles. The shorter regimen offers a meaningful reduction in treatment duration without compromising efficacy or safety. | Moderate risk: The open-label, pragmatic design introduces potential performance and detection bias, though the use of objective primary endpoints (cure or treatment completion) mitigates subjective outcome assessment concerns. The single-country setting (South Africa) may limit generalizability to other high-burden settings with different resistance patterns or healthcare infrastructure. The pragmatic design allowing treatment adjustments based on drug susceptibility testing reflects real-world practice but introduces heterogeneity in actual regimens received. Inclusion of pregnant/breastfeeding persons and fluoroquinolone-resistant cases strengthens external validity for these underrepresented populations. |
| Crook G, Lamberth E, Lockhart SP, Lowry F, Zhang H, Peng Y, et al. Randomized phase 3 comparison of a 2-dose and 3-dose regimen of a detoxified toxin A/B Clostridioides difficile vaccine in adults 50 years and older. Open Forum Infect Dis. 2026 May 20;13(5):ofag219. doi:10.1093/ofid/ofag219 | P: 1,994 adults aged ≥50 years at increased risk of Clostridioides difficile infection I: 2-dose PF-06425090 C. difficile vaccine regimen C: 3-dose PF-06425090 C. difficile vaccine regimen O: Primary: Immunogenicity noninferiority (anti–toxin A and anti–toxin B responses). Secondary: Safety profile comparison |
The overall primary noninferiority objective of the 2-dose regimen compared with the 3-dose regimen was not met. Noninferiority criteria were satisfied for C. difficile toxin-A immunogenicity but not for toxin-B immunogenicity. Both regimens demonstrated similar safety profiles with no notable differences in adverse events. These findings suggest that the 3-dose regimen remains necessary to achieve adequate immune responses against both toxins. | Low-to-moderate risk: The phase 3 trial design with pre-specified noninferiority criteria provides methodological rigor. Limited information is available from this abstract regarding blinding, allocation concealment, and attrition rates, which prevents a comprehensive bias assessment. The population restricted to adults ≥50 years at increased C. difficile infection risk is clinically appropriate but limits generalizability to younger or lower-risk populations. The clear failure to meet the primary composite noninferiority endpoint lends transparency to the reporting of results. |
| Nachum Z, Soltsman S, Narane A, Lauz N, Petrusyevich T, Wattad M, et al. Oral metronidazole versus clindamycin to treat bacterial vaginosis in pregnancies at risk for preterm labor. Clin Microbiol Infect. 2026 Jun 29; doi:10.1016/j.cmi.2026.06.023 | P: 166 pregnant women at high risk for preterm labor diagnosed with bacterial vaginosis (BV) or abnormal vaginal flora (AVF) (Nugent score ≥4) from 914 screened, across multiple centres I: Oral metronidazole 500 mg twice daily for one week (n=82) C: Oral clindamycin 300 mg twice daily for one week (n=84) O: Primary: Rate of BV/AVF eradication after first-line treatment. Secondary: Total eradication rate after second-line crossover treatment, rate of preterm delivery/late miscarriage, adverse effects |
There were no significant differences between metronidazole and clindamycin in BV/AVF eradication after first-line treatment (60% vs 56%), total eradication after second-line crossover treatment (77% vs 79%), or preterm delivery/late miscarriage rates (30% vs 24%; p>0.05 for all comparisons). Adverse effects were reported in 31% (36/115) of those receiving metronidazole and 26% (31/117) of those receiving clindamycin at any line, with treatment discontinuation due to adverse effects occurring in only 3% and 5%, respectively (p>0.05). Overall, the two antibiotics demonstrated comparable efficacy, safety, and obstetric outcomes in this high-risk pregnant population. | Moderate-to-high risk: The abstract does not specify whether blinding was employed, raising concern for performance and detection bias. The relatively small sample size (166 analysed) limits statistical power to detect clinically meaningful differences between groups. The crossover design for treatment failures, while pragmatic, complicates interpretation of second-line eradication rates as participants received the alternative drug. The eradication rates in both groups were modest (56–60%), and the study may have been underpowered for the preterm delivery outcome. Nugent scoring for diagnosis is objective and well-validated, which strengthens outcome ascertainment. |
| Boussina A, Allison C, Quintero K, Jain S, VanDenBerg C, Hogarth M, et al. Medical record abstraction for quality improvement in sepsis care using artificial intelligence: a cluster randomized trial. JAMA Netw Open. 2026 Jun 25;9(6):e2611885. doi:10.1001/jamanetworkopen.2026.11885 | P: 66 attending emergency department physicians treating 301 patients meeting CMS inclusion criteria for SEP-1 (median age 64.3 years, 56.8% male) at two academic emergency departments within the University of California, San Diego health system I: Near-real-time targeted feedback from large language model (LLM)-determined compliance with the CMS SEP-1 sepsis quality metric delivered at the time of patient discharge C: Standard quality reporting process O: Primary: Overall compliance with SEP-1 (Severe Sepsis and Septic Shock Management Bundle). Secondary: Expert agreement with LLM SEP-1 determination, 30-day mortality, ICU admissions |
Physicians in the intervention group had a significantly higher SEP-1 compliance rate than controls (82.9% vs 70.1%, absolute improvement 13.0%, 95% CI 2.5–23.4%, OR 2.10, 95% CI 1.15–3.81, p=0.02). The largest difference was in the 30 mL/kg fluid bolus component, a documentation-sensitive element (1.7% non-completion vs 13.2% in controls). Agreement between LLM determination and expert review was 92%. No significant differences were observed in ICU admissions or 30-day mortality between groups, suggesting the intervention primarily improved metric compliance and documentation rather than clinical outcomes. | Moderate risk: The single-blind design (physicians were aware of feedback but patients were not) introduces performance bias, as physicians receiving feedback may have altered behaviour specifically to meet metric requirements rather than improve underlying care quality. The improvement being largest in a documentation-sensitive component (fluid bolus) raises concern that the effect may partly reflect documentation improvement rather than clinical practice change. The single health system, two-site design limits generalizability. Imbalanced group sizes (180 vs 121 patients) and a relatively small physician sample (66) may affect precision. The cluster randomization at the physician level is appropriate, and the use of mixed-effects modelling accounting for physician-level clustering strengthens the analysis. The absence of mortality benefit despite improved compliance warrants cautious interpretation of clinical significance. |
| Benítez-Cano A, Sancho-Araiz A, Carazo J, et al. Intrapulmonary penetration of ceftolozane/tazobactam and ceftazidime/avibactam administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial. Crit Care. 2026 May 13;30:305. doi:10.1186/s13054-026-06075-w | P: 30 critically ill patients with nosocomial pneumonia at a single centre I: Ceftolozane/tazobactam (TOL/TAZ) 6 g/3 g administered by continuous infusion (n=15) C: Ceftazidime/avibactam (CAZ/AVI) 6 g/1.5 g administered by continuous infusion (n=15) O: Primary: Epithelial lining fluid (ELF) penetration (AUC₀₋₈ ELF/AUC₀₋₈ plasma ratio) and pharmacokinetic/pharmacodynamic (PK/PD) target attainment (100% fT>MIC for β-lactam and 100% fT>CT for β-lactamase inhibitor) across simulated dosing regimens and MIC scenarios |
Median intrapulmonary penetration ratios were 0.66 for ceftolozane, 0.41 for ceftazidime, 0.44 for tazobactam, and 0.44 for avibactam. Under prespecified ELF PK/PD targets, standard dosing achieved adequate target attainment for both combinations. Simulations showed all CAZ/AVI regimens achieved high ELF target attainment under conservative assumptions (ceftazidime MIC = 8 mg/L, avibactam CT = 1 mg/L), whereas TOL/TAZ required at least standard dosing (ceftolozane MIC = 4 mg/L, tazobactam CT = 2 mg/L). More aggressive target scenarios, particularly inhibitor thresholds of 4 mg/L and Enterobacterales-oriented joint targets, reduced the probability of target attainment for both combinations. Interindividual variability and risk of plasma overexposure supported individualized dosing and therapeutic drug monitoring. | Moderate risk: Randomised allocation strengthens study validity, and objective PK/PD measurements reduce detection bias. However, the open-label design and single-center setting may introduce performance bias and limit generalisability. The small sample size (n=30) reduces precision and limits ability to assess clinical outcomes. As a pharmacokinetic study, it was not powered to determine differences in mortality, microbiological cure, or safety outcomes. Variability in critically ill patients’ physiology may affect external validity. |
| Wu Y, Liu S, Shi C, et al. Continuous versus intermittent vancomycin infusions in critically ill children with gram-positive bacterial infections: a randomized controlled trial. BMC Infect Dis. 2026 Feb 19;26:410. doi:10.1186/s12879-026-12560-y | P: 80 critically ill children (1 month to 14 years) with suspected or confirmed Gram-positive infections requiring vancomycin in the PICU of a tertiary pediatric critical care centre in Beijing, China I: Continuous intravenous infusion (CIV) of vancomycin 40 mg/kg/day as a 24-hour continuous infusion (n=40) C: Intermittent intravenous infusion (IIV) of vancomycin 40 mg/kg/day administered every 6 hours as 1-hour infusions (n=40) O: Primary: PK/PD target attainment (AUC₀₋₂₄/MIC ≥400). Secondary: Clinical outcomes (fever resolution, inflammatory markers), renal adverse events |
CIV achieved significantly higher steady-state vancomycin concentrations than IIV (15.22 mg/L vs 6.25 mg/L, p<0.05). AUC₀₋₂₄/MIC values were numerically higher in the CIV group (median 456.5, IQR 291.9–590.9) compared with IIV (median 358.0, IQR 276.1–714.4), though the difference was not statistically significant (p>0.05). No between-group differences were observed in clinical efficacy outcomes including fever resolution and inflammatory markers (p>0.05). Renal safety profiles were comparable between the two groups. CIV appeared to rapidly achieve target vancomycin exposure without requiring dose escalation. | Moderate risk: Randomised allocation strengthens internal validity, but the single-center open-label design may introduce performance bias and limit generalisability. Lack of blinding may influence clinical outcome assessment, although PK/PD measurements are objective. The small sample size reduces power to detect differences in clinical outcomes and renal adverse events. Short study duration and specialised PICU population may limit applicability to broader paediatric populations. |
| Miao X, Shen J, Zhao J, Wang R, Wang H, Dai Q. Adjuvant intravenous immunoglobulin in elderly sepsis: a randomized controlled study of mortality, organ function, and inflammation. Front Med (Lausanne). 2026 Jun 24;13:1857404. doi:10.3389/fmed.2026.1857404 | P: 120 elderly patients (≥65 years) meeting Sepsis-3 criteria at a single centre I: Intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 3 days plus conventional sepsis therapy (n=60) C: Conventional sepsis therapy alone (n=60) O: Primary: 28-day all-cause mortality and change in SOFA score. Secondary: Inflammatory markers (CRP, PCT), ICU length of stay, duration of mechanical ventilation, adverse events |
IVIG was associated with significantly reduced 28-day mortality (18.3% vs 31.7%, RR 0.58, 95% CI 0.31–0.97, p=0.043). SOFA scores declined more rapidly in the IVIG group (mean reduction at day 7: 3.7 ± 1.2 vs 2.1 ± 1.0 points, p<0.001). CRP and PCT levels decreased more substantially with IVIG (CRP: 55.6 ± 10.4 vs 38.3 ± 9.7 mg/L, p<0.001; PCT: 5.3 ± 1.6 vs 3.1 ± 1.4 ng/mL, p<0.001). ICU length of stay was shorter in the IVIG group (9.8 ± 2.7 vs 12.4 ± 3.1 days, p=0.024), as was duration of mechanical ventilation (4.2 ± 1.1 vs 5.7 ± 1.4 days, p=0.011). Adverse events were infrequent and comparable between groups. | Moderate risk: Randomised design and blinded outcome assessment reduce selection and detection bias. However, the open-label design may introduce performance bias, as clinicians and participants were aware of treatment allocation. Single-center recruitment and relatively small sample size limit generalisability and statistical power. Lack of placebo control may influence subjective clinical management decisions, although objective outcomes such as mortality and SOFA score strengthen validity. |
| Sun WW, Ren F, Yang FP, Zhang SJ, Wang H, Su FF, et al. Efficacy and safety of a radiographic severity-stratified all-oral short treatment regimen for multidrug/rifampicin-resistant tuberculosis in China: an open-label, multi-center, randomized controlled, non-inferiority trial. Clin Microbiol Infect. 2026 Jun 29; doi:10.1016/j.cmi.2026.06.026 | P: 259 participants with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) in China I: All-oral short-course treatment regimen (STR) stratified into three subgroups by radiographic severity scores (n=173) C: 18-month regimen based on 2019 WHO guidelines (n=86) O: Primary efficacy: Favourable treatment outcome up to 6 months after treatment discontinuation. Primary safety: Grade ≥3 adverse events during the study period |
In the mITT population, the STR group achieved a favourable outcome rate of 87.1% (148/170) versus 81.5% (66/81) in the control group (between-group difference 5.6 percentage points, 95% CI −5.7 to 13.8, p=0.03 for noninferiority). In the per-protocol population, favourable outcome rates were 89.0% (146/164) versus 83.1% (64/77), with a difference of 5.9 percentage points (95% CI −7.9 to 11.7, p=0.02 for noninferiority). Grade ≥3 adverse events occurred significantly less frequently in the STR group (27.7% vs 43.0%, p<0.01), indicating a superior safety profile for the shorter regimen. The radiographic severity-stratified approach demonstrated noninferiority to the traditional longer regimen with meaningfully reduced treatment burden and toxicity. | Moderate risk: The randomised controlled design and predefined non-inferiority framework strengthen internal validity. However, the open-label nature may introduce performance and detection bias, particularly for safety outcomes. Lack of blinding may influence reporting of adverse events. Attrition appears limited based on similar mITT and per-protocol populations, reducing attrition bias. Generalisability may be limited as the study was conducted in China and used radiographic severity-based treatment stratification. |
Phage Therapy
Summary: This review explores the emerging role of bacteriophage-based therapies as promising alternatives or adjuncts to conventional antibiotics for treating skin and soft tissue infections, highlighting their ability to target antibiotic-resistant bacteria and biofilms, advances in delivery systems such as hydrogels and nanocarriers, current clinical evidence, and the challenges that must be addressed for wider adoption in precision antimicrobial treatments.
PK/PD and Drug Dosing
Summary: This study evaluates piperacillin/tazobactam pharmacokinetics and treatment target attainment in critically ill patients with sepsis or septic shock in Malaysian intensive care units, showing that therapeutic drug exposure was achieved in only a proportion of patients and suggesting that continuous infusion with optimized dosing may improve the likelihood of effective and safe antibiotic exposure.
Summary: This study developed a population pharmacokinetic model to examine vancomycin exposure in serum and cerebrospinal fluid among neurosurgical patients with meningitis, revealing significant variability in CSF penetration that cannot be reliably predicted by serum concentrations and highlighting the need for CNS-specific dosing strategies and PK/PD targets.
Summary: This study investigates the intrapulmonary pharmacokinetics of the novel β-lactamase inhibitor funobactam combined with imipenem/cilastatin, demonstrating effective penetration into lung tissues and higher pulmonary exposure compared with imipenem and cilastatin, supporting further clinical evaluation of this combination for treating serious infections caused by carbapenem-resistant gram-negative bacteria such as CRE, CRAB, and CRPA.
Summary: This study evaluates cefiderocol pharmacokinetic/pharmacodynamic target attainment in critically ill patients with Klebsiella pneumoniae infections, showing that renal function and body weight influence drug exposure, with standard PK/PD targets generally achieved but higher exposure targets remaining difficult to reach, highlighting the complexity of optimizing cefiderocol therapy beyond drug pharmacokinetics alone.
Summary: This study develops a quantitative modelling framework using resistome information to predict treatment responses of multidrug-resistant Pseudomonas aeruginosa, demonstrating that ceftolozane–tazobactam and meropenem monotherapies can drive resistance emergence while combination therapy provides synergistic bacterial killing and suppresses resistance, supporting a more personalized approach to antibiotic selection based on pathogen resistance mechanisms.
Summary: This editorial explains how combining dynamic hollow-fibre in vitro infection models with mathematical modeling optimizes pharmacokinetic/pharmacodynamic (PK/PD) targets for teicoplanin, aiding in dosage optimization. By simulating clinical dosing regimens, this integrated approach enhances the translation from laboratory findings to patient treatment ("bench to bedside") while reducing reliance on animal studies.
Antibiotics - In vitro susceptibility
Summary: This study evaluates the accuracy of routine antimicrobial susceptibility testing methods for detecting piperacillin-tazobactam and cefepime resistance in blaOXA-1-producing Escherichia coli, showing significant discrepancies compared with reference broth microdilution that may lead to resistance underestimation or overestimation and highlighting the need for cautious interpretation of susceptibility results to prevent treatment failure.
Beta-Lactamases and Other Resistance Mechanisms
Summary: This study investigates how the PBP2V516M mutation in Pseudomonas aeruginosa affects the activity and target binding of zidebactam and related β-lactams, demonstrating that the mutation drives resistance to zidebactam while revealing distinct susceptibility patterns among other agents, providing insights to guide the development of next-generation diazabicyclooctane antibiotics.
Antibiotic Stewardship
Summary: This study introduces a novel antimicrobial stewardship framework that separately evaluates antibiotic initiation, duration, and spectrum using Days of Antimicrobial Spectrum Coverage and Length of Therapy, providing a risk-adjusted composite S3 metric to benchmark hospital prescribing practices and identify targeted opportunities for stewardship improvement.
Summary: This article highlights that successful antimicrobial stewardship in low- and middle-income countries depends not only on policies but on investing in and mentoring empowered local multidisciplinary teams that can implement sustainable, context-specific interventions to combat antimicrobial resistance.
Infection Prevention / Antibiotic Prophylaxis
Summary: This study demonstrates that CT-derived subcutaneous fat area and kidney function predict cefazolin concentrations at the surgical site more accurately than body weight in patients with obesity undergoing colorectal surgery, suggesting that physiologic dosing based on body composition and renal function could better optimize surgical antibiotic prophylaxis and reduce the risk of underdosing.
Summary: This report describes a 2025 Legionnaires’ disease outbreak in Central Harlem, New York City linked to cooling tower systems, where rapid public health surveillance, environmental sampling, and whole-genome sequencing identified highly related Legionella pneumophila isolates from patients and two nearby cooling towers, resulting in 118 confirmed cases and seven deaths.
Summary: This review examines the role of chlorhexidine gluconate bathing as an infection prevention strategy across healthcare settings, highlighting evidence of reduced device-associated infections and microbial colonization while emphasizing that effectiveness varies by setting, protocol, and implementation quality, with further research needed to define its optimal use and impact on patient-centered outcomes.
Bloodstream Infections and Endocarditis
Summary: This study evaluates the significance of valve strands (Lambl’s excrescences) in patients investigated for suspected infective endocarditis, showing that most detected valve strands are not infectious lesions and that expert multidisciplinary assessment can help distinguish them from vegetations, preventing unnecessary treatment while maintaining safe patient outcomes.
Catheter-Related Infections
Summary: This multicentre study evaluates local signs of infection at intravascular catheter insertion sites, finding that redness is common but frequently under-recognised during routine assessment compared with expert review, varies by catheter type, and is associated with positive blood cultures, highlighting the need for standardized assessment methods and potential AI-assisted monitoring.
Gastrointestinal Tract Infections
Jay R, Hughes M, Angelo KM. Vibriosis. JAMA. 2026 Jun 17; doi:10.1001/jama.2026.9892
Summary: This article reviews noncholera Vibrio infections (vibriosis), describing their environmental characteristics, preferred coastal habitats, and increasing geographic spread driven by climate-related factors such as rising sea temperatures, changing salinity, precipitation, and extreme weather events, with outbreaks occurring mainly during warmer months.
Summary: This review describes the evolution of Clostridioides difficile infection in the United States as a phased epidemic, highlighting its rise driven by antibiotic-resistant, toxin-producing strains and healthcare outbreaks, followed by declining incidence and a shift toward community-acquired infections, suggesting future CDI challenges may involve persistent community reservoirs and less overt but ongoing transmission.
Summary: This article examines trends in antibiotic prescribing for uncomplicated diverticulitis following updated guidelines recommending selective rather than routine antibiotic use, highlighting antimicrobial stewardship efforts to reduce unnecessary antibiotic exposure given limited clinical benefit and potential harms associated with routine treatment.
CNS Infections
Summary: This review highlights the rare but serious neurological complications of flea-borne typhus caused by Rickettsia typhi, describing cases ranging from meningitis and seizures to encephalitis and stroke, and emphasizing the importance of early recognition and doxycycline treatment to improve outcomes in endemic regions.
Bone and Joint Infections
Summary: This multicentre retrospective study evaluates doxycycline-based regimens as an alternative treatment option for staphylococcal prosthetic joint infections of the hip and knee, finding comparable two-year outcomes and acceptable tolerability compared with standard therapies, suggesting tetracyclines may be a practical option when rifampicin or fluoroquinolone-based treatments are unsuitable.
Respiratory Tract Infections
Summary: This study evaluates diagnostic strategies for pneumonia in immunocompromised patients, showing that early bronchoscopy improves pathogen detection rates and that plasma microbial cell-free DNA sequencing can further increase diagnostic yield regardless of testing timing, supporting prompt and enhanced diagnostic approaches in this high-risk population.
Summary: This article discusses the evolving landscape of community-acquired pneumonia research, highlighting a shift from a pathogen-focused approach toward understanding host inflammatory responses and treatable traits, while emphasizing the growing impact of immunocompromised populations due to ageing, increasing comorbidities, and advances in medical therapies.
Urinary Tract Infections
Summary: This review examines intravesical therapy as a targeted approach for treating and preventing catheter-associated urinary tract infections, highlighting its potential to overcome limitations of systemic antibiotics by delivering antimicrobials directly to the bladder, addressing biofilm-related infections and antimicrobial resistance, while discussing current evidence, alternative therapies, and challenges requiring further research.
Infections in Children
Summary: This study analyzes a 2024 pertussis outbreak in South Korea using Bayesian modelling to estimate the incubation period, finding a median of 11 days and a 95th percentile of 26 days, suggesting that contact monitoring may need to extend beyond the traditional 21-day period during ongoing outbreaks.
Summary: This review explores the development and clinical impact of the preterm infant gut microbiome, highlighting how dysbiosis contributes to conditions such as necrotizing enterocolitis and affects multiple organ systems through gut-organ interactions, while examining current and emerging microbiome-targeted interventions including nutrition strategies, probiotics, phage therapy, and precision approaches to improve neonatal outcomes.
Mycobacterial Infections
Summary: This study investigates whether the strength of immune responses measured by tuberculosis infection tests can predict short-term progression to active tuberculosis among exposed household contacts, finding that higher TST and IGRA response levels were associated with increased risk and suggesting that magnitude-based interpretation of existing tests may improve tuberculosis risk stratification and prevention strategies in high-incidence settings.
Summary: This study evaluates azithromycin exposure in patients with non-tuberculous mycobacterial disease and demonstrates that concurrent rifampicin use reduces azithromycin concentrations by more than half, highlighting the importance of therapeutic drug monitoring, dose adjustment, or alternative treatment strategies to optimize therapy.
Summary: This systematic review and meta-analysis evaluates the efficacy, immune response, and safety of adult BCG revaccination against tuberculosis, finding that while revaccination enhances certain T-cell immune responses, it provides limited measurable protection against Mycobacterium tuberculosis infection and may cause more adverse events, highlighting the need for vaccines with stronger evidence of protective effectiveness.
Summary: This systematic review evaluates host blood biomarkers for diagnosing childhood tuberculosis, identifying several biomarker signatures that meet WHO diagnostic targets but noting limited validation, high risk of bias, and insufficient evidence for commonly studied markers such as interferon-γ-inducible protein 10, emphasizing the need for larger studies and accessible point-of-care tests.
Summary: This meta-analysis examines the global prevalence and genetic patterns of ethambutol-resistant tuberculosis, finding substantial regional variation in resistance rates and identifying embB gene mutations as key drivers of resistance, while emphasizing the need for improved molecular diagnostics, genomic surveillance, and standardized reporting to better manage and monitor EMB-resistant TB.
Summary: This study investigates a tuberculosis transmission cluster in a non-clinical hospital setting in Australia during the COVID-19 pandemic, showing that prolonged workplace exposure to an employee with cavitary pulmonary TB led to secondary cases and highlighting the importance of rapid contact tracing, genomic surveillance, and pre-employment screening to prevent transmission in healthcare environments.
Summary: This study uses event-driven simulations to design a feasible phase 3 trial for the M72/AS01E-4 tuberculosis vaccine, showing that an IGRA-positive–enriched population can efficiently confirm vaccine efficacy against pulmonary TB while reducing feasibility challenges compared with broader enrolment strategies and allowing safety and immunogenicity assessment across different risk groups.
Summary: This multicentre UK cohort study evaluates paradoxical reactions in central nervous system tuberculosis, finding that PR occurs frequently and is associated with disability, longer hospital stays, and need for neurosurgical intervention, while highlighting the importance of repeat imaging and cerebrospinal fluid analysis for diagnosis and the need for evidence-based approaches to host-directed therapy.
Fungal Infections and Antifungal Agents
Summary: This multicentre Australian study examines infection patterns after CD19 CAR-T therapy, showing that nearly half of patients developed infections and that late infections beyond one year remain common, particularly respiratory viral infections, while prolonged corticosteroid exposure and prior bacterial infections were associated with invasive fungal disease risk, highlighting the need for long-term infection surveillance and prevention strategies.
Summary: This study develops and validates the first probe-based qPCR assay targeting Trichosporon asahii for rapid detection from positive blood cultures, demonstrating 100% sensitivity and specificity with results available within three hours, offering a potential tool for earlier diagnosis and improved antifungal management of life-threatening invasive trichosporonosis.
Summary: This review challenges traditional approaches to invasive fungal infection management by exploring the potential for shorter treatment durations and earlier oral therapy, highlighting emerging evidence and ongoing trials in candidemia, invasive mould infections, and novel antifungal strategies while emphasizing the need for robust clinical studies to move antifungal care toward more evidence-based, patient-focused treatment models.
Summary: This multicentre retrospective study evaluates antifungal treatment duration for uncomplicated candidaemia, finding that shorter courses of 7–13 days were not associated with higher mortality or recurrence compared with the conventional 14–20 day treatment duration in patients with adequate source control and blood culture clearance, supporting further investigation of shorter antifungal regimens.
Summary: This review highlights the emerging recognition of pulmonary fungal infections in immunocompetent individuals, driven by factors such as climate change, postviral conditions, and evolving ICU practices, while emphasizing the diagnostic challenges and need for increased clinical suspicion, improved testing strategies, and integrated risk assessment for timely management.
Summary: This review explores the role of the skin fungal microbiome in maintaining epidermal homeostasis and contributing to inflammatory skin diseases, highlighting interactions between commensal fungi such as Malassezia and Candida with host immune pathways, microbial communities, and disease processes, while discussing emerging therapies and future research directions.
Summary: This study evaluates the role of 18F-FDG PET/CT in staging paracoccidioidomycosis, showing that it detects substantially more disease sites than conventional methods, frequently reclassifies patients into higher severity categories, and provides quantitative measures that correlate with disease activity, supporting its use as an important tool for treatment planning and follow-up.
Summary: This study evaluates mortality outcomes among hematological malignancy patients with culture-confirmed invasive aspergillosis, finding that while deaths directly attributable to IA have decreased, overall and contributable mortality remain high, suggesting that improving survival requires not only better antifungal therapies but also strategies to enhance host immune response.
Diagnostics
Summary: This article discusses the evolving role of rapid diagnostics and diagnostic stewardship in antimicrobial stewardship, highlighting that while advanced tools such as molecular assays, rapid susceptibility testing, and AI can improve antibiotic decision-making and reduce unnecessary exposure, their impact on major clinical outcomes remains variable and depends heavily on appropriate test selection, expert interpretation, and integration within effective stewardship programs.
Improving Clinical Research
Summary: This article highlights the importance of replication studies in healthcare research to validate findings, improve clinical decision-making, and inform policy, while emphasizing the current challenges in replicating complex healthcare interventions and the need to consider factors such as foundational evidence, implementation fidelity, and clinical context to guide successful replication efforts.
Summary: Using an illustrated graphic medicine format, this visual narrative insightfully depicts the emotional journey researchers often experience after a grant rejection—from disappointment, fleeting acceptance, anger, and despair to renewed hope, determination, and the challenges of resubmission—highlighting the importance of resilience, mentorship, and perseverance in academic research.
Summary: This survey of US intensivists found that although Bayesian adaptive clinical trials were perceived as more difficult to understand and elicited greater concerns about methodological validity than traditional frequentist trials, physicians showed similar acceptance of the trial results, suggesting that improving familiarity with Bayesian methods may enhance confidence without affecting their overall clinical acceptance.
Summary: This systematic review of 591 randomized controlled trials found that baseline comorbidity data were reported in only one-third of sepsis ICU trials, with multimorbidity rarely assessed despite its high prevalence, highlighting the need for standardized reporting frameworks to improve trial representativeness, enable subgroup analyses, and strengthen the external validity of sepsis research.
Company News
Summary: The US FDA has approved Utebzi (tebipenem pivoxil), the first and only oral carbapenem antibiotic for adults with complicated urinary tract infections who have limited or no alternative oral treatment options, based on phase III evidence demonstrating non-inferiority to intravenous imipenem-cilastatin, offering a potential outpatient alternative for managing resistant infections and reducing reliance on hospital-based intravenous therapy.
Summary: Positive topline results from the global Phase 3 OASIS trial showed that the investigational oral antifungal olorofim was non-inferior to AmBisome® followed by standard of care for treating invasive aspergillosis in patients unsuitable for or refractory to azole therapy, with a comparable mortality rate and fewer treatment-related adverse events, supporting its potential as the first antifungal with a novel mechanism of action approved for this indication in more than 20 years.
General Interest
Summary: This profile highlights Professor Sabiha Essack’s journey from growing up in Durban to becoming a globally recognised leader in antimicrobial resistance and One Health, showcasing her pioneering research, advocacy, and leadership in advancing strategies to combat antibiotic resistance in Africa and beyond.
Summary: This article presents a standardized consensus framework developed by ESCMID for clinical guideline panels, introducing mandatory anonymous voting with an ≥80% agreement threshold, defined procedures for resolving disagreements, and transparent documentation requirements to improve the quality, consistency, transparency, and trustworthiness of evidence-based clinical guidelines.
Summary: This article reviews the 2026 Bundibugyo virus disease outbreak in the Democratic Republic of Congo, highlighting ongoing challenges in outbreak detection, diagnosis, clinical management, and public health response, while emphasizing the importance of rapid surveillance, supportive care, coordinated control measures, and the potential for Ebola virus vaccines and therapeutics to provide cross-protection as pathogen-specific countermeasures continue to be developed.
Summary: This article provides a practical guide for emergency department clinicians on evaluating fever in returning travelers, outlining the epidemiology, clinical features, diagnosis, and initial management of common travel-related infections such as malaria, dengue, and typhoid fever to support timely treatment, appropriate referral, and consideration of both travel- and non-travel-related causes of illness.
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