Infectious Diseases (all articles) | Links Medicus Content Curation & Alerts in Medicine

Systematic Review: Shorter Antibiotic Courses Often Prove Non-Inferior for Common Bacterial Infections

3 Feb, 2025 | 10:00h | UTC

Background: The overuse of antibiotics contributes significantly to the global rise in antimicrobial resistance (AMR). Shorter antibiotic treatment courses have gained traction as an important antimicrobial stewardship intervention. They can potentially reduce drug-related side effects, healthcare costs, and selection pressure favoring resistant pathogens. This review synthesizes findings from randomized controlled trials (RCTs) on antibiotic duration across various common bacterial infections—including respiratory tract, genitourinary, skin and soft tissue, bone/joint, and intra-abdominal infections—to inform practical, day-to-day clinical decision-making.

Objective:

To assess the comparative efficacy of short- versus long-course antibiotic therapy for frequent bacterial infections.
To highlight key evidence gaps, particularly for severe infections, critically ill populations, and low- to middle-income settings.
To propose practical treatment durations in light of current guidelines and study outcomes.

Methods:

Comprehensive search of MEDLINE and Embase through July 2024 (PROSPERO 2021, CRD42021276209).
Inclusion: RCTs that compared differing antibiotic durations for bacterial infections or perioperative prophylaxis, reporting clinical cure, relapse, or mortality.
Exclusion: Non-bacterial infections (viral/fungal), pilot studies, non-randomized designs.
Data extraction: Patient demographics, infection type, interventions, outcomes, adherence, and risk-of-bias assessment per the RoB 2 tool.
Guideline review: Major international guidelines (e.g., IDSA, NICE, WHO) were examined to contextualize trial findings.

Results:

A total of 315 RCTs were included; 85% concluded no difference, non-inferiority, or equivalence of shorter compared with longer antibiotic courses.
Shorter therapy (often 5–7 days) is well-supported for uncomplicated bacterial sinusitis, community-acquired pneumonia (CAP), simple urinary tract infections (UTIs), cellulitis, and intra-abdominal infections with adequate surgical source control.
Evidence for reducing duration in severe infections (e.g., bloodstream infections, ventilator-associated pneumonia caused by non-fermenting Gram-negative bacilli) or in critically ill populations remains limited.
Only 7% of RCTs involved intensive care unit (ICU) patients, and 14% were conducted in low- or middle-income countries.
Methodologically, 15% of trials posed a low risk of bias; however, non-adherence to assigned durations was common (median 11% per study). Very few trials tracked emergence of resistant organisms through follow-up cultures.

Key findings:

Acute GAS Pharyngotonsillitis:
10 days of penicillin V or amoxicillin remains the conventional standard to ensure microbiological eradication and minimize rheumatic fever risk. While 5 days of azithromycin may be used in macrolide-responsive settings, it is not preferred as first-line therapy due to broader-spectrum activity and limited evidence for preventing complications, particularly in high-risk populations.
Community-Acquired Pneumonia (CAP):
- Outpatient adults with mild to moderate CAP typically improve with 5 days of appropriate therapy (e.g., amoxicillin, doxycycline, or a macrolide), provided patients show clinical stability.
- Severe CAP or complicated presentations (e.g., MRSA, Pseudomonas, multi-lobar involvement) may need 7–10 days or until clinical stability is achieved.
Acute Bacterial Sinusitis (Adults):
- 5–7 days of amoxicillin/clavulanate or other first-line agents usually suffice if the diagnosis is certain.
Genitourinary Infections:
- Uncomplicated Cystitis (Non-Pregnant Women):
  - 3–5 days of nitrofurantoin or trimethoprim/sulfamethoxazole is often adequate, reflecting strong RCT support.
- Pyelonephritis or Complicated UTIs (e.g., in men, catheter-associated):
  - While some RCTs show 7 days can be as effective as 14 days in afebrile males with mild UTI, a trial in febrile males demonstrated inferior outcomes with shorter courses. Clinicians should exercise caution in febrile or higher-risk cases.
Skin and Soft Tissue Infections (e.g., Cellulitis):
- 5–6 days of effective oral therapy is sufficient for uncomplicated cellulitis if there is marked clinical improvement by Day 5.
- For recurrent abscesses or complicated scenarios, duration may need to be extended or individualized.
Bone and Joint Infections:
- 6 weeks is often sufficient for vertebral osteomyelitis in stable patients.
- For prosthetic joint infections with retained hardware, 6 weeks of therapy was inferior to 12 weeks in a key trial, necessitating individualized duration based on surgical management.
Intra-Abdominal Infections:
- With adequate source control, 4–5 days of antibiotics commonly yields outcomes on par with extended courses.
- Longer therapy (≥7 days) may be needed when abscesses are not fully drained or in immunocompromised patients.
Perioperative Prophylaxis:
- A single preoperative dose (possibly repeated if surgery is prolonged or blood loss is excessive) is sufficient in most procedures.
- Continuing prophylaxis beyond 24 hours rarely provides additional benefit and may increase adverse events.

Conclusions: Numerous well-conducted RCTs support shorter antibiotic courses for many common bacterial infections. Nonetheless, high-quality data are sparse for severe or complex infections, pediatric populations with significant comorbidities, and low-resource settings. Clinicians should tailor antibiotic duration to the infection type, disease severity, patient factors, and local resistance patterns—while remaining cognizant that shorter courses can safely balance efficacy, safety, and stewardship aims in many cases.

Study Strengths and Limitations:

Strengths: Large volume of RCTs, broad infection scope, and inclusion of diverse study designs. Substantial evidence supports shortening antibiotic regimens for multiple common infections.
Limitations: Underrepresentation of severe, ICU-level infections, children with serious comorbidities, and low-resource settings. High variation in diagnostic criteria, antibiotic choices, and adherence monitoring. Many trials reported low event rates, posing potential non-inferiority bias.

Future Research:

Well-powered RCTs focusing on severe infections (e.g., MDR Gram-negative bloodstream infections, staphylococcal bacteremia, ventilator-associated pneumonia with resistant pathogens).
Trials in low- and middle-income countries with robust microbiological and economic assessments.
Studies using adaptive designs and validated biomarkers to refine duration–response relationships and detect shifts in AMR at the population level.

Reference: Mo Y, Tan WC, Cooper BS. Antibiotic duration for common bacterial infections—a systematic review. JAC-Antimicrobial Resistance. 2025;7(1):dlae215. DOI: https://doi.org/10.1093/jacamr/dlae215

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28 Jan, 2025 | 00:54h | UTC

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Multidrug-resistant Gram-negative bacterial infections: Key Updates and Practical Strategies

25 Jan, 2025 | 22:53h | UTC

Introduction: This summary highlights essential points from a recent review in The Lancet addressing multidrug-resistant Gram-negative bacterial (MDR-GNB) infections. It discusses the global epidemiology, diagnostic advances, and therapeutic approaches, aiming to guide clinicians in managing these difficult-to-treat pathogens, which include resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Key Recommendations:

Use Rapid Diagnostics to Guide Therapy
- Employ molecular tests (e.g., multiplex PCR) to detect resistance genes quickly and facilitate targeted treatment.
- Consider phenotypic assays (e.g., CarbaNP, carbapenemase inactivation method) and MALDI-TOF for rapid organism identification and mechanism-specific information.
Optimize Antibiotic Selection Based on Resistance Mechanisms
- AmpC-Producing Enterobacterales (e.g., Enterobacter spp.): Use cefepime if in vitro susceptibility is confirmed.
- ESBL-Producing Enterobacterales: Carbapenems (e.g., meropenem) remain the mainstay for serious infections.
- Carbapenem-Resistant Enterobacterales (CRE): Use novel β-lactam/β-lactamase inhibitor agents (e.g., ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam) based on specific carbapenemase mechanisms. For metallo-β-lactamase producers, consider aztreonam plus ceftazidime–avibactam or future co-formulations (e.g., aztreonam–avibactam).
- DTR-Pseudomonas aeruginosa: Ceftolozane–tazobactam is preferred if active in vitro. Ceftazidime–avibactam or imipenem–relebactam may also be options depending on local susceptibility data.
- Carbapenem-Resistant Acinetobacter baumannii (CRAB): High-dose sulbactam combinations (e.g., sulbactam–durlobactam) were studied in combination with imipenem–cilastatin during trials; further data are needed to clarify optimal clinical use.
Consider Non-Antibiotic Modalities for Refractory Cases
- Investigational therapies—such as bacteriophages and antivirulence agents—are under clinical evaluation.
- Fecal microbiota transplantation has shown variable decolonization efficacy in small studies, and randomized trials have yielded limited or inconclusive results.
Emphasize Antimicrobial Stewardship and Infection Control
- Restrict newer agents to cases where standard treatments have failed or resistance patterns require them.
- Maintain rigorous infection control practices (e.g., contact precautions, hand hygiene, isolation measures) to reduce nosocomial spread of MDR-GNB.
- Observational data suggest shorter antibiotic courses (7–10 days) might be adequate in select cases, but robust clinical trial evidence is still pending.

Conclusion:
By combining rapid diagnostics, judicious use of existing and novel antibiotics, and robust infection prevention measures, clinicians can significantly improve outcomes for patients with MDR-GNB infections. However, access to advanced diagnostics and new therapies remains limited in many regions, and further clinical trials are needed to determine optimal treatment and duration strategies. Early mechanism-focused detection and targeted therapy enhance clinical success, reduce toxicity, and help preserve the efficacy of newly approved agents.

Reference:
Macesic N, Uhlemann A-C, Peleg AY. Multidrug-resistant Gram-negative bacterial infections. The Lancet. 2025;405(10474):257-272. DOI: https://doi.org/10.1016/S0140-6736(24)02081-6

RCT: Albendazole–Ivermectin Co-Formulation Achieves Higher Cure Rates for T. trichiura and Hookworms

22 Jan, 2025 | 12:41h | UTC

Background: Soil-transmitted helminthiases (STH) affect an estimated 1.5 billion people worldwide, with Trichuris trichiura and hookworms remaining particularly challenging to treat. Although single-dose albendazole or mebendazole is standard in mass deworming programs, these agents show limited efficacy against T. trichiura and often leave Strongyloides stercoralis under-treated. Ivermectin has demonstrated broad activity against multiple parasites, suggesting that a combined albendazole–ivermectin regimen might enhance treatment outcomes, simplify protocols, and potentially curb emerging drug resistance.

Objective: This trial aimed to evaluate the safety, efficacy, and acceptability of a novel fixed-dose co-formulation (FDC) tablet containing albendazole (400 mg) plus a higher-than-standard, fixed dose of ivermectin (9 mg or 18 mg), administered once daily (FDC×1) or for three consecutive days (FDC×3). Investigators compared these regimens against single-dose albendazole alone for the treatment of T. trichiura, hookworms, and S. stercoralis in children and adolescents.

Methods: In this adaptive, randomized, parallel-group, phase 2/3 trial, 1001 participants aged 5–18 years were recruited from schools in Ethiopia, Kenya, and Mozambique. All were infected with at least one of T. trichiura, hookworms, or S. stercoralis. Eligible participants were allocated (by computer-generated block randomization) to either a single dose of albendazole 400 mg (control), a single-dose FDC of albendazole–ivermectin (FDC×1), or a three-day FDC regimen (FDC×3). Primary endpoints included safety (phase 2) and efficacy (phase 3), determined by cure rates at day 21 using the Kato–Katz and Baermann methods. Laboratory staff were blinded to treatment assignment.

Results: No serious adverse events were reported; mild-to-moderate gastrointestinal symptoms were the most frequent treatment-related events, resolving spontaneously within 48 hours. Cure rates for T. trichiura were 35.9% (95% CI 27.7–44.1) in the albendazole group, 82.9% (78.2–87.5) in FDC×1, and 97.2% (95.2–99.3) in FDC×3. For hookworms, cure rates were 65.1% (56.0–74.2) with albendazole, 79.8% (72.8–86.9) with FDC×1, and 95.0% (91.1–98.9) with FDC×3. Egg reduction rates in FDC arms consistently surpassed those of albendazole alone, especially for multi-day dosing. The sample size for S. stercoralis was insufficient to power a definitive efficacy conclusion, though ivermectin-containing arms trended toward favorable results. Palatability questionnaires indicated the orodispersible FDC was well accepted in taste, texture, and overall ease of administration.

Conclusions: A new co-formulation of albendazole plus ivermectin delivered at higher, fixed doses demonstrated an excellent safety profile and superior efficacy against T. trichiura and hookworms compared with albendazole monotherapy. This approach may streamline programmatic control of multiple STH species, including S. stercoralis, while contributing to reduced transmission in endemic communities.

Implications for Practice: For mass deworming initiatives, a single-dose FDC offers improved cure rates over albendazole alone while preserving simplicity. Where higher efficacy is critical—such as programs targeting near-elimination goals or in clinical settings—the three-day regimen may be preferable. Nonetheless, implementation feasibility, cost considerations, and further confirmation of efficacy against S. stercoralis and other co-endemic parasites remain important next steps.

Study Strengths and Limitations: Strengths include a multicenter design across three countries and a rigorous adaptive protocol that assessed both safety and efficacy. Limitations include the lack of blinding for participants and care providers (though outcome assessors were blinded), the underpowered sample size for S. stercoralis, and reliance on single-stool diagnostics, which may underestimate residual infections.

Future Research: Additional large-scale studies should confirm these findings in varied geographic regions and evaluate the cost-effectiveness of both single-dose and multi-day FDC strategies. Integrating albendazole–ivermectin with treatment programs for other neglected tropical diseases (e.g., onchocerciasis) could further amplify public health benefits. Genomic and pharmacokinetic analyses will clarify resistance patterns and optimize dosing regimens for broader implementation.

Reference: Krolewiecki A, Kepha S, Fleitas PE, van Lieshout L, Gelaye W, Messa A Jr, et al. “Albendazole–ivermectin co-formulation for the treatment of Trichuris trichiura and other soil-transmitted helminths: a randomised phase 2/3 trial.” The Lancet Infectious Diseases. Published January 10, 2025. DOI: https://doi.org/10.1016/S1473-3099(24)00669-8

Network Meta-analysis: Oseltamivir Fails to Improve Key Outcomes in Nonsevere Influenza

20 Jan, 2025 | 11:17h | UTC

Background: Influenza causes significant respiratory morbidity and can lead to severe complications, especially in high-risk individuals. Current guidelines endorse antiviral therapy, yet the evidence for reducing mortality, hospital admission, and symptom duration in nonsevere cases remains controversial. Recent recommendations have often focused on neuraminidase inhibitors (e.g., oseltamivir), despite uncertainties regarding clinical impact and adverse effects. An editorial accompanying this study underscores the need to reexamine routine antiviral use, especially oseltamivir, given minimal benefit observed in outpatient populations.

Objective: To assess and compare the efficacy and safety of direct-acting antiviral medications (baloxavir, oseltamivir, laninamivir, zanamivir, peramivir, umifenovir, favipiravir, and amantadine) in treating patients with nonsevere influenza.

Methods: This systematic review and network meta-analysis included 73 randomized clinical trials (N=34,332) that evaluated antivirals vs placebo, standard care, or another antiviral. Eligible studies enrolled nonhospitalized patients with confirmed or suspected influenza. Outcomes included mortality, hospital admission, time to symptom alleviation, adverse events, and emergence of antiviral resistance. Risk of bias was assessed with a modified Cochrane tool, and the certainty of evidence was rated using the GRADE approach. Pooled estimates were generated with a frequentist random-effects model, focusing on both absolute risk differences and relative measures.

Results:

Mortality: Across all antiviral agents, there was high-certainty evidence of little or no effect on mortality in both low-risk and high-risk patients compared with standard care or placebo.
Hospital Admission: In low-risk patients, none of the antivirals significantly altered admission rates (high certainty). In high-risk patients, oseltamivir had little or no effect on hospitalization (high certainty), whereas baloxavir may reduce admissions (low certainty).
Time to Alleviation of Symptoms: Baloxavir shortened symptom duration by approximately one day (moderate certainty) without increasing adverse events. Oseltamivir and zanamivir likely produced smaller decreases (<1 day; moderate certainty). Umifenovir may also shorten symptoms (low certainty).
Adverse Events: Baloxavir did not increase treatment-related adverse events (high certainty) but may lead to viral resistance in around 10% of cases (low certainty). Oseltamivir probably increases adverse events such as nausea and vomiting (moderate certainty).
Serious Outcomes (ICU Admission, Duration of Hospitalization): Data were limited, with uncertainty regarding meaningful reductions in these measures.

Conclusions: Baloxavir may reduce hospital admissions for high-risk patients and significantly shorten symptom duration without notable treatment-related adverse events. Oseltamivir shows little effect on mortality or hospitalization for nonsevere influenza, with only modest (likely not clinically important) reductions in symptom duration and a higher rate of adverse events. Other antivirals either demonstrate uncertain clinical benefits or likely provide no major advantages in this patient population.

Implications for Practice: These findings suggest that routine use of oseltamivir for outpatients with nonsevere influenza should be reconsidered, especially in low-risk groups. Baloxavir appears favorable for high-risk patients, though clinicians should monitor potential drug resistance. Given the minimal impact on major outcomes and the cost considerations, prescribers should weigh the benefits and harms of these antivirals, aligning treatment decisions with patient risk profiles and clinical judgment.

Study Strengths and Limitations: Strengths include a comprehensive search, large pooled population, and rigorous GRADE-based analysis of certainty. Limitations involve low event rates for hospital admissions and mortality, limiting power for certain outcomes, and sparse data on some antivirals (e.g., amantadine). Additionally, few trials reported ICU admissions or mechanical ventilation needs, restricting conclusions about severe complications.

Future Research: Further high-quality studies should evaluate patient-important outcomes such as mechanical ventilation and severe complications in diverse populations. Investigations into combination strategies, alternative dosing, and resistance patterns would help clarify the long-term viability of baloxavir and other antivirals, particularly in high-risk cohorts.

Reference:

Gao Y, Zhao Y, Liu M, et al. Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7193
Baghdadi JD, Grady D, Morgan DJ. The Limited Role for Antiviral Therapy in Influenza. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7258

Network Meta-Analysis: TMP-SMX May Need Reassessment as First-Line Therapy for PCP in People With HIV

13 Jan, 2025 | 10:25h | UTC

Background: Pneumocystis jirovecii pneumonia (PCP) remains a severe opportunistic infection in people living with HIV (PWH), especially those with low CD4 counts. Trimethoprim–sulfamethoxazole (TMP-SMX) is widely recommended as first-line therapy; however, its toxicity profile can limit use. Alternative regimens such as dapsone–trimethoprim, clindamycin–primaquine, atovaquone, and pentamidine have been explored, but comprehensive comparative data are scarce.

Objective: This systematic review and network meta-analysis aimed to compare the efficacy (treatment failure, mortality) and tolerability (treatment change due to toxicity) of PCP treatment regimens in PWH. The goal was to determine whether TMP-SMX maintains superiority across these outcomes or if alternative regimens offer similar efficacy with improved safety profiles.

Methods: Researchers systematically searched Embase, Medline, and CENTRAL (inception through 3 February 2024) for randomized controlled trials (RCTs) comparing at least two PCP treatment regimens in PWH. Independent reviewers screened titles/abstracts and performed full-text reviews. Data extraction included population demographics, treatment arms, outcomes (treatment failure, all-cause mortality, treatment change), and risk-of-bias assessments using the Cochrane Risk-of-Bias 2 tool. A network meta-analysis using a frequentist random-effects model was performed to integrate direct and indirect comparisons, estimating relative treatment effects (risk ratios with 95% confidence intervals) and generating rankings via the surface under the cumulative ranking curve (SUCRA).

Results: Fourteen RCTs (1983–1996) with 1,788 participants across 27 treatment arms were included. No regimen demonstrated significant superiority over TMP-SMX in direct comparisons, although TMP-SMX outperformed atovaquone and trimetrexate plus folinic acid in reducing treatment failure. In the network analysis, clindamycin–primaquine, intravenous pentamidine, and TMP-SMX all had favorable SUCRA values for preventing treatment failure. For all-cause mortality, dapsone–trimethoprim and intravenous pentamidine ranked highest, while TMP-SMX was better than atovaquone in direct comparison. Notably, for tolerability, all alternative regimens tended to be safer than TMP-SMX, which ranked worst for toxicity. Inhaled pentamidine, trimetrexate plus folinic acid, and atovaquone were the best-tolerated therapies.

Conclusions: These findings suggest that TMP-SMX, although commonly used, might not be universally superior to all other regimens when balancing efficacy and safety in PWH with PCP. When the risk of renal or hematologic complications is high, considering clindamycin–primaquine or intravenous pentamidine may provide comparable efficacy with a more favorable safety profile. Inhaled pentamidine or atovaquone may offer good tolerability but should be carefully assessed for efficacy in moderate-to-severe disease.

Implications for Practice: When managing PCP in PWH, TMP-SMX may not always be the ideal standalone first-line choice, especially in patients at high risk for renal or hematologic complications. Clindamycin–primaquine and intravenous pentamidine could represent viable alternatives for clinicians seeking to balance efficacy with improved safety. Inhaled pentamidine or atovaquone may offer strong tolerability but should be carefully evaluated for their effectiveness in moderate-to-severe disease.

Study Strengths and Limitations: Strengths include a robust search strategy, strict inclusion criteria of RCTs, and the use of a network meta-analysis to integrate direct and indirect comparisons. Limitations involve the older timeframe of the included trials (most conducted before the modern ART era) and heterogeneous definitions of treatment failure, which may limit generalizability to broader contemporary clinical settings. Women and other high-risk populations were underrepresented, presenting another limitation.

Future Research: Contemporary RCTs should address the optimal dose and duration of TMP-SMX and alternative agents, include underrepresented groups (women, older adults, patients with renal impairment), and consider modern management of HIV and critical care practices. Ongoing investigations of novel agents like rezafungin may further refine first-line PCP treatment strategies.

Reference: Hatzl S, Posch F, Scholz L, … Bassetti M, Hoenigl M, Krause R. Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV: a systematic review and network meta-analysis of randomized controlled trials. Clinical Microbiology and Infection, Published online December 26, 2024. DOI: http://doi.org/10.1016/j.cmi.2024.12.024

2024 Focused Guideline Update on Corticosteroid Use in Sepsis, ARDS, and Community-Acquired Pneumonia

13 Jan, 2025 | 11:04h | UTC

Introduction: This summary presents the key points from a 2024 focused update of the guidelines on corticosteroid use for hospitalized adult patients with sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). Developed by a panel of international experts in critical care, endocrinology, and methodology, the update aims to incorporate new evidence into recommendations regarding dosage, duration, and timing of corticosteroid therapy. Pediatric-specific recommendations could not be made due to limited data.

Key Recommendations:

Sepsis and Septic Shock
- Conditional Recommendation: In adult patients with septic shock requiring vasopressor support, the panel suggests administering corticosteroids (typically hydrocortisone 200–300 mg/day IV for about 5–7 days, with or without fludrocortisone).
- Strong Recommendation Against High Dose/Short Duration: High-dose corticosteroids (> 400 mg/day hydrocortisone equivalent given for fewer than 3 days) are not recommended, as they confer increased risk of adverse effects without demonstrating benefit.
Acute Respiratory Distress Syndrome (ARDS)
- Conditional Recommendation: In adult patients hospitalized with ARDS (including those with COVID-19 ARDS), the panel suggests using corticosteroids (e.g., methylprednisolone, dexamethasone, or hydrocortisone) to lower short-term mortality and potentially reduce duration of mechanical ventilation. No specific agent or dosing regimen is mandated; choices should be guided by clinical judgment and patient context.
Community-Acquired Pneumonia (CAP)
- Strong Recommendation (Severe CAP): In adults hospitalized with severe bacterial CAP, the panel recommends corticosteroids (commonly moderate-dose IV hydrocortisone or methylprednisolone for 5–7 days). Recent data indicate a clear mortality benefit in these high-risk patients.
- No Recommendation (Less Severe CAP): For adults with less severe bacterial CAP, current evidence is inconclusive regarding mortality benefit. Although some findings suggest improvements in certain outcomes, the panel reached no consensus on whether corticosteroids should be routinely administered.

Conclusion: These updated guidelines emphasize the overall safety and potential survival benefits of corticosteroids in specific populations with critical illness, particularly those with septic shock, ARDS, or severe CAP. For each condition, the recommendations balance desirable effects—such as reduced mortality, organ dysfunction, and length of hospital stay—against possible harms, including hyperglycemia and neuromuscular weakness. Evidence remains insufficient to support pediatric guidance or clarify whether less severe CAP consistently merits treatment. Future research should address optimal dosing strategies, pediatric outcomes, long-term adverse effects, and potential cost-effectiveness across diverse healthcare settings.

Reference:
Chaudhuri, Dipayan MD, MSc, FRCPC, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Critical Care Medicine 52(5): e219–e233, May 2024. DOI: http://dx.doi.org/10.1097/CCM.0000000000006172

ATS Guidelines on Invasive Pulmonary Aspergillosis and Antifungal Strategies in Critically Ill Adults

7 Jan, 2025 | 12:29h | UTC

Introduction: This summary provides an overview of a recent American Thoracic Society clinical practice guideline addressing two core questions in adult pulmonary and critical care practice. First, it examines whether combination therapy with a mold-active triazole (most data concern voriconazole, though newer agents such as isavuconazole or posaconazole may also be considered) plus an echinocandin (specifically caspofungin, micafungin, or anidulafungin) offers added benefit over mold-active triazole monotherapy for patients with proven or probable invasive pulmonary aspergillosis (IPA). Second, it evaluates whether routine use of prophylactic or empiric antifungal agents against Candida species is advisable in critically ill, nonneutropenic, nontransplant patients at risk of invasive candidiasis (IC). By synthesizing available evidence using the GRADE approach, this guideline aims to support clinicians in optimizing therapeutic strategies and improving patient outcomes in these complex infections.

Key Recommendations:

Initial Combination Therapy vs. Monotherapy for IPA

For patients with proven or probable IPA, the guideline makes a conditional recommendation, meaning the best choice isn’t entirely clear. Both initial combination therapy (mold-active triazole + echinocandin) and monotherapy (mold-active triazole alone) are considered reasonable options.
Evidence stems primarily from studies in hematologic malignancy (HM) or hematopoietic stem cell transplant (HSCT) recipients, with mixed findings in observational cohorts and a key randomized trial favoring combination therapy, particularly in a subgroup diagnosed by positive galactomannan assays.
When critical illness or triazole resistance is a concern, combination therapy may be considered, but there is insufficient evidence to categorically endorse one approach over the other.

Prophylactic or Empiric Antifungal Therapy for Candida in Critically Ill Patients

In nonneutropenic, nontransplant adult ICU patients at risk for IC, the guideline makes a conditional recommendation against routinely using prophylactic or empiric antifungal therapy. This means the benefits of withholding these treatments likely outweigh the risks, but there’s still some uncertainty.
Low-quality evidence from multiple randomized controlled trials showed no significant mortality benefit in administering antifungals prophylactically or empirically compared with placebo.
Although IC carries substantial morbidity and mortality, its overall incidence in this population remains low, and ongoing surveillance or targeted diagnostics may be preferable to universal antifungal administration.

Conclusion: The panel emphasizes that these recommendations should be applied with clinical judgment, especially in patients with severe disease, likely high fungal burden, or concerns for antifungal resistance. Combination therapy for IPA may be particularly relevant when critical illness or limited triazole efficacy is suspected. Meanwhile, prophylactic or empiric anti-Candida therapy in the broader ICU setting does not appear to substantially reduce mortality. Continued advances in rapid diagnostics, close monitoring of local resistance patterns, and new antifungal agents may further refine best practices. Future research should focus on validating these findings in diverse patient populations, exploring novel combination regimens, and establishing more precise risk assessments for IC in the ICU.

Reference: Epelbaum O, Marinelli T, Haydour Q, Pennington KM, Evans SE, Carmona EM, Husain S, Knox KS, Jarrett BJ, Azoulay E, Hope WW, and others. “Treatment of Invasive Pulmonary Aspergillosis and Preventive and Empirical Therapy for Invasive Candidiasis in Adult Pulmonary and Critical Care Patients: An Official American Thoracic Society Clinical Practice Guideline.” American Journal of Respiratory and Critical Care Medicine (2025). https://doi.org/10.1164/rccm.202410-2045ST

RCT: Assessing Procalcitonin-Based Antibiotic Management in Critically Ill Patients With Sepsis

7 Jan, 2025 | 14:00h | UTC

Background: Optimal antibiotic duration for sepsis remains uncertain. Procalcitonin (PCT) and C-reactive protein (CRP) are thought to support shorter courses, but prior research was small-scale or at risk of bias. This multicenter, randomized trial (ADAPT-Sepsis) evaluated whether daily PCT- or CRP-guided protocols could reduce antibiotic use without increasing 28-day all-cause mortality in critically ill adults with suspected sepsis.

Objective: To determine if daily biomarker-guided (PCT or CRP) strategies decrease total antibiotic days among critically ill adults while maintaining acceptable 28-day mortality, compared with standard care.

Methods: From 2018 to 2024 (with enrollment paused March–August 2020 due to COVID-19), 2760 adults (≥18 years) on intravenous antibiotics for suspected sepsis (acute organ dysfunction and presumed infection) and likely to continue antibiotics for at least 72 hours were randomized across 41 UK NHS ICUs within 24 hours of antibiotic initiation. They were assigned in a 1:1:1 ratio to (1) daily PCT-guided advice (n=918), (2) daily CRP-guided advice (n=924), or (3) standard care (n=918). Biomarker results were concealed; clinicians received automated daily prompts recommending continuation or discontinuation. The co-primary outcomes were (1) total antibiotic duration (randomization to day 28) and (2) 28-day all-cause mortality. Secondary measures included antibiotic duration for the initial sepsis episode, 90-day mortality, readmissions, and length of stay.

Results: Among 2760 participants (mean age, 60.2 years; 60.3% men; ~50% with septic shock), over 96% provided 28-day data. Patients in the PCT-guided arm had a statistically significant mean reduction in total antibiotic duration vs standard care (9.8 vs 10.7 days; difference, 0.88 days; 95% CI, 0.19–1.58; p=0.01). The PCT strategy met the prespecified 5.4% noninferiority margin for 28-day mortality (20.9% vs 19.4%; absolute difference, 1.57; 95% CI, –2.18 to 5.32; p=0.02), implying noninferiority but not fully excluding a small risk of excess mortality. CRP-guided protocols did not shorten total antibiotic use (10.6 vs 10.7 days; p=0.79) and were inconclusive for noninferiority regarding mortality (21.1% vs 19.4%; difference, 1.69; 95% CI, –2.07 to 5.45; p=0.03). Notably, 90-day mortality also showed no significant differences. A post-trial commentary (PulmCCM) emphasized that some uncertainty remains with the 5.4% margin and warned that patient-level randomization could subtly discourage earlier antibiotic discontinuation in standard care, which received no explicit “stop” prompts.

Conclusions: In critically ill patients with suspected sepsis, a PCT-guided antibiotic discontinuation protocol shortened overall antibiotic use by nearly one day without exceeding the predefined noninferiority threshold for 28-day mortality. However, the chosen 5.4% margin allows for the possibility of clinically relevant harm. A CRP-guided protocol did not reduce total antibiotic use and showed inconclusive mortality findings.

Implications for Practice: Adopting PCT-based stewardship may modestly decrease antibiotic exposure without a clear short-term mortality penalty, potentially limiting antibiotic resistance. Clinicians should remain vigilant, recognizing the risk tolerance implied by the 5.4% margin. PCT results should complement, not replace, comprehensive clinical judgment.

Study Strengths and Limitations: Strengths include the large sample size, multi-center design, blinded biomarker allocation, and distinct emphasis on both effectiveness and safety outcomes. Limitations include the acceptance of a 5.4% potential excess mortality as the noninferiority threshold, uncertainty about rare but significant harms, and the possibility of bias introduced by patient-level randomization. Generalizability to lower-resource settings may also be limited.

Future Research: Further randomized trials with lower noninferiority margins or cluster-level allocation are needed to better define the safety and efficacy of PCT-guided strategies for reducing antibiotic duration in sepsis. Additional investigations are needed for long-term patient-centered outcomes, cost-effectiveness, and the role of alternative biomarkers or combined strategies in sepsis care.

Reference:

Dark P, Hossain A, McAuley DF, et al. Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial. JAMA. 2024; published online December 9. DOI: http://doi.org/10.1001/jama.2024.26458

PulmCCM Commentary: “Is procalcitonin ‘safe’ to guide antibiotic use in patients with sepsis? ADAPT-Sepsis tests the strategy in the U.K., with global ambitions.” Jan 02, 2025. https://www.pulmccm.org/p/is-procalcitonin-safe-to-guide-antibiotic

Joint ATS/CDC/ERS/IDSA Guideline Recommends Shorter, All-Oral Regimens for Drug-Susceptible and Drug-Resistant TB

5 Jan, 2025 | 11:30h | UTC

Introduction: This summary outlines new clinical practice guidelines from the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America on updated treatment regimens for tuberculosis (TB) in low-incidence settings. These recommendations build on recent clinical trials, World Health Organization (WHO) guidance, and were developed using the GRADE and GRADE-ADOLOPMENT methodology. The guidelines aim to shorten treatment duration, reduce pill burden, and improve patient outcomes for both drug-susceptible (DS) and drug-resistant (DR) TB, and they apply to settings where mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies are routinely available. A separate news release from CIDRAP highlights the significance of these shorter, all-oral regimens for adults and children. Directly observed therapy (DOT) remains the standard of care.

Key Recommendations:

Four-Month Regimen for DS-TB in Adults:

For people aged 12 years or older with isoniazid- and rifampin-susceptible pulmonary TB, a new four-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide (2HPZM/2HPM) is conditionally recommended. This shortened course is based on a large, randomized trial (Study 31/A5349) demonstrating noninferior efficacy compared to the standard six-month regimen (84.6% vs 85.4% cure, respectively), no increase in adverse events, and potential benefits in completion rates. Exclusions include TB meningitis and other complicated forms of extrapulmonary TB, and clinicians should obtain rapid fluoroquinolone susceptibility tests before initiating this regimen.

Four-Month Regimen for DS-TB in Children:

For children and adolescents aged 3 months to 16 years with nonsevere, drug-susceptible pulmonary TB, a four-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for the initial phase, followed by isoniazid and rifampin, is strongly recommended. Evidence from the SHINE trial showed high success (97.1% vs 96.9%) and similar safety with the shorter course compared to the 6-month regimen. Nonsevere TB generally excludes extensive cavitary disease, advanced extrapulmonary TB, or complicated forms. Close clinical and radiographic follow-up is important to confirm effective cure.

Six-Month BPaL Regimen for Rifampin-Resistant, Fluoroquinolone-Resistant or Intolerant TB:

For rifampin-resistant (RR) pulmonary TB with resistance or patient intolerance to fluoroquinolones in adolescents aged 14 and older and adults, a six-month all-oral bedaquiline, pretomanid, and linezolid (BPaL) regimen is strongly recommended, replacing much longer regimens that often included injectables. Clinical trials (Nix-TB, ZeNix) demonstrated higher cure rates and lower toxicity with this regimen compared to longer regimens, though vigilance is needed for linezolid-related adverse events (e.g., neuropathy, myelosuppression). Baseline and monthly lab and ECG checks are advised.

Six-Month BPaLM Regimen for Rifampin-Resistant, Fluoroquinolone-Susceptible TB:

For RR pulmonary TB that remains fluoroquinolone-susceptible in adolescents aged 14 and older and adults, a six-month bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen is strongly recommended over traditional 15-month or longer regimens in patients with MDR/RR-TB. Data from the TB-PRACTECAL trial showed high success rates and fewer serious adverse events. BPaLM is the first-line recommendation for this group. Close monitoring of cardiac status (QTc prolongation) and blood counts is advised.

Both BPaL and BPaLM regimens require detailed drug susceptibility testing and cautious management of potential drug–drug interactions, particularly for patients with comorbidities or HIV infection. Of note, the certainty of evidence for the outcomes in the DR-TB trials was rated as very low, due to multiple factors including bias, small event numbers, lack of blinding, and inconsistent outcomes.

Conclusion: These new recommendations markedly shorten TB treatment courses for adults and children in low-incidence settings with access to appropriate diagnostic tools, while avoiding injectables and reducing serious toxicities. By replacing older, more complex regimens with all-oral, shorter-duration therapy, and using DOT as the standard of care, the guidelines aim to improve adherence, lessen the burden on healthcare systems, and enhance patient quality of life. Ongoing research will further refine dosing, safety for special populations (e.g., pregnant individuals), and the role of advanced drug susceptibility testing.

Reference:

Jussi J. Saukkonen, Raquel Duarte, Sonal S. Munsiff, et al. “Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.” American Journal of Respiratory and Critical Care Medicine, (2025). https://doi.org/10.1164/rccm.202410-2096ST

News release commentary: “New guidelines expand recommendations for shorter, all-oral TB treatments” (CIDRAP). https://www.cidrap.umn.edu/tuberculosis/new-guidelines-expand-recommendations-shorter-all-oral-tb-treatments

Meta-analysis: Therapeutic-Dose Heparin Improves 28-Day Mortality in COVID-19 Hospitalized Patients

6 Jan, 2025 | 12:00h | UTC

Background: High rates of thrombotic events and systemic inflammation among COVID-19 hospitalized patients led researchers to test whether intensified anticoagulation strategies could reduce morbidity and mortality. Previous trials yielded conflicting results, partly due to varying doses of anticoagulants—prophylactic, intermediate, or therapeutic—and heterogeneous patient severity. This comprehensive investigation, conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, aimed to clarify the benefits and risks of escalated anticoagulation dosing in patients hospitalized for COVID-19.

Objective: To estimate whether higher-dose anticoagulation (therapeutic or intermediate) improves 28-day all-cause mortality compared with lower-dose anticoagulation (prophylactic or intermediate), and to evaluate secondary outcomes, including progression to mechanical ventilation, thromboembolic events, and major bleeding.

Methods: This prospective meta-analysis included randomized trials comparing higher- versus lower-dose anticoagulation for hospitalized COVID-19 patients. Investigators collected trial-level summary data, focusing primarily on heparins. Dosing categories—therapeutic, intermediate, and prophylactic—were predefined. The main outcome was 28-day mortality; secondary outcomes included progression to invasive mechanical ventilation (IMV), venous or arterial thrombotic events, and major hemorrhage. Data were analyzed using a fixed-effects model, with odds ratios (ORs) pooled across trials.

Results: Overall, 22 trials (over 11 000 total participants) contributed data, primarily evaluating heparins. For therapeutic versus prophylactic-dose heparin, 28-day mortality was significantly reduced (OR, 0.77; 95% CI, 0.64–0.93), especially among patients requiring low-flow oxygen or no supplemental oxygen. Therapeutic dose reduced thromboembolic events (OR 0.48; 95% CI, 0.36-0.64) but increased major bleeding (OR 1.90; 95% CI, 1.19-3.05) compared to prophylactic dose. In contrast, when therapeutic was compared to intermediate-dose heparin, the summary OR for 28-day mortality was 1.21 (CI, 0.93–1.58), suggesting a potential trend toward higher mortality that did not reach statistical significance. Intermediate versus prophylactic-dose comparisons revealed no conclusive mortality difference (OR, 0.95; CI, 0.76–1.19). Across all higher-dose arms, thromboembolic events decreased, while the risk of major bleeding increased, underscoring the delicate risk–benefit balance. Subgroup analyses by respiratory support level, D-dimer, and baseline severity did not indicate strong interaction effects, although sample sizes were limited in more severe illness subgroups.

Conclusions: Therapeutic-dose heparin reduces 28-day mortality relative to prophylactic-dose in hospitalized patients with COVID-19, mainly among those not requiring invasive ventilation. Mortality was similar or potentially worse when therapeutic was compared to intermediate-dose. Clinicians must weigh the lower rate of thrombotic complications against the higher bleeding risk, particularly in critically ill patients.

Implications for Practice: Although higher anticoagulant dosing appears beneficial for certain hospitalized COVID-19 patients, especially those with mild to moderate respiratory compromise, individualized assessment remains key. Current guidelines broadly recommend prophylactic dosing for the critically ill and suggest considering higher doses only in carefully selected patients. Evolving viral variants and changes in standard of care further complicate direct application of these findings to present-day hospital settings.

Study Strengths and Limitations: Strengths include prospective planning, collaboration with multiple trials, and a large pooled sample. Limitations encompass heterogeneity in dose definitions, partial reliance on published data where individual-level parameters could not be fully harmonized, and potential temporal changes in COVID-19 clinical profiles. Moreover, bleeding severity beyond major hemorrhage was not universally reported, limiting robust safety assessments.

Future Research: Further studies should focus on individualized anticoagulant strategies that consider biomarkers (for example, D-dimer) and evolving treatment protocols. Investigations examining optimal timing, duration, and post-discharge management will help refine anticoagulation practices.

Reference:

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Anticoagulation Among Patients Hospitalized for COVID-19: A Systematic Review and Prospective Meta-analysis. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-00800

Shappell CN, Anesi GL. Anticoagulation for COVID-19: Seeking Clarity and Finding Yet More Gray. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-03244

Avian Influenza A(H5N1) Outbreak Among US Farm Exposures: Clinical Findings and Early Treatment Outcomes

2 Jan, 2025 | 17:01h | UTC

Background: Highly pathogenic avian influenza A(H5N1) has reemerged in the United States with documented infections in poultry and dairy cows since 2021. From March through October 2024, 46 human cases were identified, most of whom were workers engaged in poultry depopulation or dairy-farm activities where infected or presumably infected animals were present.

Objective: To characterize the clinical presentations, exposure settings, and outcomes of individuals with laboratory-confirmed H5N1 infection and to investigate potential routes of transmission, disease severity, and risk to public health.

Methods: Using a standardized case-report form, data were collected on exposure history, symptom onset, and use of personal protective equipment (PPE). Respiratory and conjunctival swabs from symptomatic persons underwent real-time RT-PCR for H5 subtyping at both state laboratories and the Centers for Disease Control and Prevention (CDC). Genetic sequencing was performed on available samples. Investigators also monitored close household contacts to evaluate the risk of secondary transmission. An additional hospitalized patient with no identifiable exposure source was detected through routine influenza surveillance.

Results: Of the 46 adult case patients, 20 were exposed to infected poultry, 25 to infected or presumably infected dairy cows, and 1 had unknown exposure. Among the 45 occupationally exposed patients, illness was mild, with no hospitalizations or deaths. Conjunctivitis was present in 93% of cases; 49% reported fever, and 36% had respiratory symptoms. Fifteen patients had only conjunctivitis, highlighting the utility of conjunctival specimens for detection. Early antiviral therapy with oseltamivir was common, initiated at a median of two days after symptom onset. No additional cases were found among 97 closely monitored household contacts, indicating no evidence of sustained human-to-human transmission. Genetic analyses revealed clade 2.3.4.4b viruses, with some genotypic differences between poultry-related (D1.1 genotype) and cow-related (B3.13 genotype) infections.

Conclusions: In this observational study, H5N1 infections in US adults were generally mild, self-limited, and predominantly associated with conjunctivitis. The absence of critical illness or fatalities contrasts with historical reports of more severe H5N1 disease. Although no ongoing person-to-person transmission was documented, continued vigilance is warranted, given the virus’s potential for rapid adaptation.

Implications for Practice: Occupational health measures, such as consistent PPE use (especially eye protection), timely surveillance, and prompt antiviral treatment, may reduce the impact of H5N1 infections among exposed workers. Clinicians should consider conjunctival sampling for symptomatic patients with relevant animal contact. Policy efforts should focus on improving biosecurity practices in both poultry and dairy settings.

Study Strengths and Limitations: Strengths include systematic surveillance, robust laboratory testing of both respiratory and conjunctival specimens, and early antiviral administration. Limitations involve possible underreporting of mild or asymptomatic cases, incomplete details on exposure duration, and limited data on specific routes of cow-to-human transmission.

Future Research: Further studies should explore viral evolution in cows, the significance of raw milk as a transmission vehicle, and the potential for more severe infections, as highlighted by sporadic reports of severe H5N1 illness worldwide.

Reference: Garg S, Reinhart K, Couture A, Kniss K, Davis CT, Kirby MK, Murray EL, et al. Highly Pathogenic Avian Influenza A(H5N1) Virus Infections in Humans. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2414610

Editorial: Ison MG, Marrazzo J. The Emerging Threat of H5N1 to Human Health. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMe2416323

Management of Adult Sepsis in Resource-Limited Settings: A Global Delphi-Based Consensus

26 Dec, 2024 | 02:06h | UTC

Introduction: This summary presents key points from a recent expert consensus on managing adult sepsis under limited-resource conditions, where patients may lack access to an ICU bed, advanced monitoring technologies, or sufficient staffing. The statements were developed through a Delphi process involving an international panel of clinicians, aiming to complement existing sepsis guidelines by focusing on pragmatic approaches and context-specific adaptations. These consensus statements address unique challenges such as limited diagnostic tests, alternative strategies for hemodynamic monitoring, and management of sepsis in areas with tropical infections.

Key Recommendations:

Location of Care and Transfer
- When an ICU bed is unavailable, care can be provided in a non-ICU setting if minimum monitoring (neurological status, blood pressure, peripheral perfusion) is ensured.
- Before transferring a patient, ensure airway patency, initiate intravenous fluids and antimicrobials, and maintain safe transport conditions.
- Incorporate telemedicine or phone consultation with critical care specialists whenever feasible.
Diagnostic Considerations
- Employ screening tools (e.g., qSOFA) in areas with limited resources, acknowledging its diagnostic constraints.
- Use clinical parameters like altered mental state, capillary refill time (CRT), and urine output to gauge tissue perfusion when lactate measurement is unavailable.
- Insert an indwelling urinary catheter in septic shock to monitor urine output accurately, balancing infection risks against close monitoring needs.
Hemodynamic Management
- Rely on clinical indicators (CRT, urine output) to guide fluid resuscitation when serum lactate is not accessible.
- Use fluid responsiveness tests (e.g., passive leg raising, pulse pressure variation) if advanced hemodynamic monitoring is impractical.
- Consider balanced solutions such as Ringer’s lactate or Hartmann’s solution for fluid resuscitation.
- Recognize that patients with tropical infections (e.g., malaria, dengue) may require cautious fluid volumes to avoid overload.
- Initiate epinephrine if norepinephrine or vasopressin is unavailable, and use vasopressors through peripheral lines if central access cannot be established.
Antimicrobial Therapy
- Administer antibiotics without delay (ideally within one hour) in suspected sepsis or septic shock.
- In severe infections of parasitic origin (e.g., malaria), start antiparasitic agents promptly.
- In settings where laboratory investigations are limited, begin broad-spectrum antimicrobial coverage when infection cannot be ruled out.
- De-escalate or discontinue therapy based on clinical improvement, declining white blood cell counts, and adequate source control.
Respiratory Support
- For acute hypoxemic respiratory failure in septic patients, noninvasive ventilation (NIV) can be used if high-flow nasal oxygen is not available, provided close monitoring for potential failure is ensured.

Conclusion: These consensus-based statements offer practical guidance for clinicians treating sepsis in resource-limited environments. By adapting globally accepted recommendations and incorporating alternative strategies—such as clinical markers of perfusion, use of peripheral vasopressors, and prioritizing immediate antimicrobial therapy—these principles aim to improve patient outcomes where healthcare resources are scarce. Further research and context-specific adaptations will be essential to address remaining uncertainties and refine these expert recommendations.

Reference:
Thwaites, L., Nasa, P., Abbenbroek, B. et al. Management of adult sepsis in resource-limited settings: global expert consensus statements using a Delphi method. Intensive Care Medicine (2024). https://doi.org/10.1007/s00134-024-07735-7

RCT: Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam

24 Dec, 2024 | 12:53h | UTC

Background:
Multidrug-resistant (MDR) and rifampin-resistant tuberculosis pose significant global health challenges. Preventing active disease among contacts exposed to resistant strains is critical, yet limited evidence exists on targeted chemopreventive interventions. This study investigated whether a six-month course of daily levofloxacin could reduce the incidence of bacteriologically confirmed tuberculosis among household contacts of individuals with confirmed MDR or rifampin-resistant tuberculosis in Vietnam.

Objective:
To assess if levofloxacin prophylaxis decreases the 30-month incidence of active tuberculosis among high-risk contacts. Primary endpoints included bacteriologically confirmed disease, and secondary outcomes encompassed adverse events, mortality, and development of fluoroquinolone-resistant Mycobacterium tuberculosis.

Methods:
Researchers conducted a double-blind, placebo-controlled, randomized trial. Eligible participants were household contacts of persons who had started MDR tuberculosis treatment within the previous three months, had a positive tuberculin skin test or immunosuppressive condition, and showed no clinical or radiographic signs of active disease. Enrolled individuals received weight-based oral levofloxacin (up to 750 mg/day) or an identical placebo for 180 days. Monthly visits supported adherence and monitored adverse events. Participants underwent follow-up visits every six months until 30 months for tuberculosis screening, chest radiography, and sputum testing where indicated.

Results:
Of 2041 randomized contacts, 1995 (97.7%) completed 30 months of follow-up or reached a primary endpoint. Confirmed tuberculosis was diagnosed in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% CI, 0.19–1.62), a difference that did not achieve statistical significance. Severe (grade 3 or 4) adverse events were infrequent in both groups, while mild adverse events were more common with levofloxacin (31.9% vs. 13.0%). Acquired fluoroquinolone resistance was not detected.

Conclusions:
Daily levofloxacin for six months showed a numerically lower incidence of tuberculosis than placebo, but the difference was not statistically significant due to lower-than-expected case counts. Treatment was generally well tolerated; however, higher discontinuation rates occurred among levofloxacin recipients, often due to mild musculoskeletal complaints. Further studies may clarify the role of fluoroquinolone-based regimens in preventing MDR tuberculosis across diverse epidemiologic contexts.

Implications for Practice:
These findings suggest that levofloxacin prophylaxis could benefit contacts at high risk of MDR tuberculosis, albeit with caution regarding adherence challenges and low-grade side effects. Broader implementation would require diligent screening, consideration of background fluoroquinolone resistance, and strategies to manage mild adverse events that could undermine treatment completion.

Study Strengths and Limitations:
Strengths include a rigorous double-blind, placebo-controlled design, nearly complete follow-up, and thorough exclusion of prevalent tuberculosis at baseline. Limitations involve an unexpectedly low incidence of confirmed disease, limiting statistical power, and a study population with low HIV prevalence, which may reduce generalizability.

Future Research:
Further research is necessary to confirm these findings in diverse settings, explore alternative or shorter regimens (including newer agents like delamanid), and investigate optimal approaches for patients with fluoroquinolone-resistant strains. The long-term impact on transmission dynamics and microbiome shifts also warrants additional investigation.

Reference:
Fox GJ, Nhung NV, Binh NC, et al. Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam. New England Journal of Medicine. 2024;391:2304-2314. DOI: http://doi.org/10.1056/NEJMoa2314325

Editorial:
Dorman SE. Levofloxacin Preventive Therapy for Persons Exposed to MDR Tuberculosis. New England Journal of Medicine. 2024;391:2376-2378. DOI: http://doi.org/10.1056/NEJMe2413531

Guideline: Doxycycline Postexposure Prophylaxis to Reduce Bacterial STI Incidence in High-Risk Populations

19 Dec, 2024 | 22:32h | UTC

Introduction: This summary presents key recommendations from the 2024 Centers for Disease Control and Prevention (CDC) guidelines on using doxycycline postexposure prophylaxis (doxyPEP) to prevent bacterial sexually transmitted infections (STIs), including syphilis, gonorrhea, and chlamydia. Targeting men who have sex with men (MSM) and transgender women with at least one bacterial STI in the past 12 months, these guidelines aim to reduce recurrence rates and improve sexual health outcomes through timely prophylactic intervention.

Key Recommendations:

Offer doxyPEP counseling to MSM and transgender women with a recent bacterial STI history, addressing the benefits, harms, and uncertainties of prophylactic doxycycline use.
Advise eligible patients to take a single 200 mg dose of doxycycline as soon as possible (ideally within 72 hours) following condomless oral, anal, or vaginal sexual exposure to reduce their subsequent STI risk.
Reinforce periodic screening (every 3–6 months) for STI markers, including syphilis and HIV serologies, as well as nucleic acid amplification tests for gonorrhea and chlamydia at relevant anatomical sites.
Integrate doxyPEP into comprehensive sexual health services that include risk-reduction counseling, condom use, recommended immunizations, and linkage to HIV preexposure prophylaxis (PrEP) or HIV care, thereby enhancing overall prevention strategies.
Consider extending doxyPEP to other high-risk groups, including heterosexual individuals with recurrent STIs, guided by clinical judgment and shared decision-making.
Monitor and address adverse events, particularly gastrointestinal symptoms, and acknowledge the potential for antimicrobial resistance. Continued vigilance is warranted given the risk of resistance in commensal flora and key STI pathogens, such as Neisseria gonorrhoeae.
Assess social and ethical dimensions of doxyPEP implementation, ensuring equitable access and minimizing potential harms, including stigma or intimate partner violence related to prophylaxis disclosure.

Conclusion: Implementing doxyPEP for MSM and transgender women who have experienced a recent bacterial STI can substantially lower the incidence of recurrent infections. By combining prophylactic doxycycline with routine surveillance, comprehensive preventive services, and careful consideration of resistance patterns, clinicians may enhance patient care and strengthen STI control efforts. Further investigation is needed to establish efficacy in cisgender women, transgender men, nonbinary persons, and other populations at risk. Longer-term, population-based studies focused on antimicrobial resistance and community-level effects will help guide sustainable and equitable use of this prevention strategy.

Reference: Flores J, Davis AM, Hazra A. Doxycycline Postexposure Prophylaxis to Prevent Bacterial Sexually Transmitted Infection. JAMA. Published online December 19, 2024. DOI: http://doi.org/10.1001/jama.2024.24540

RCT: A Single Dose of Ceftriaxone Reduces Early Ventilator-Associated Pneumonia in Acute Brain Injury Patients

17 Dec, 2024 | 12:26h | UTC

Background: Patients with acute brain injury are at increased risk for early ventilator-associated pneumonia (VAP), which can worsen their clinical course. Although short-term antibiotic prophylaxis has been considered, its utility remains uncertain. This study evaluated whether a single early dose of ceftriaxone could reduce the incidence of early VAP in these patients.

Objective: To determine if a single 2-g intravenous dose of ceftriaxone administered within 12 hours of intubation reduces the incidence of early VAP (day 2 to day 7 of mechanical ventilation) in comatose adults (Glasgow Coma Scale ≤12) requiring prolonged mechanical ventilation after acute brain injury.

Methods: This multicenter, randomized, double-blind, placebo-controlled, assessor-masked superiority trial was conducted in nine ICUs across eight French university hospitals. Patients with acute brain injury from trauma, stroke, or subarachnoid hemorrhage who required at least 48 hours of mechanical ventilation were enrolled. Participants received either ceftriaxone 2 g or placebo once, early after endotracheal intubation. All patients received standard VAP prevention measures, but no selective oropharyngeal or digestive decontamination. The primary endpoint was the incidence of early VAP confirmed by blinded assessors using standard clinical, radiological, and microbiological criteria.

Results: Among 319 patients included in the analysis (162 ceftriaxone, 157 placebo), early VAP incidence was significantly lower with ceftriaxone (14%) compared to placebo (32%) (HR 0.60 [95% CI 0.38–0.95]; p=0.030). Patients receiving ceftriaxone had fewer overall VAP episodes, fewer ventilator and antibiotic exposure days, shorter ICU and hospital stays, and reduced 28-day mortality (15% vs 25%). No significant increase in resistant organisms or adverse events attributable to ceftriaxone was observed.

Conclusions: A single early dose of ceftriaxone significantly reduced early VAP risk in acute brain injury patients undergoing mechanical ventilation. This prophylactic approach may improve clinical outcomes without evident safety concerns.

Implications for Practice: Incorporating a single early ceftriaxone dose into VAP prevention protocols for brain-injured patients could mitigate early respiratory infections and potentially enhance clinical outcomes. Nonetheless, clinicians should remain cautious, considering overall antibiotic stewardship and the need for further evidence on long-term microbial resistance patterns.

Study Strengths and Limitations: Strengths include a robust, multicenter, double-blind, placebo-controlled design and blinded adjudication of VAP cases. Limitations include the lack of long-term assessment of the intestinal microbiota and antimicrobial resistance. Further investigation is required to confirm the safety profile regarding microbial ecology and to explore neurological outcomes in greater depth.

Future Research: Future studies should examine the long-term effects of this single-dose approach on resistance patterns, microbial flora, and functional neurological recovery.

Reference: Dahyot-Fizelier C, et al. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial. The Lancet Respiratory Medicine. 2024; DOI: http://doi.org/10.1016/S2213-2600(23)00471-X

Management of Adult Sepsis in Resource-Limited Settings: A Global Delphi-Based Consensus

24 Dec, 2024 | 13:35h | UTC

Key Recommendations:

Location of Care and Transfer
- When an ICU bed is unavailable, care can be provided in a non-ICU setting if minimum monitoring (neurological status, blood pressure, peripheral perfusion) is ensured.
- Before transferring a patient, ensure airway patency, initiate intravenous fluids and antimicrobials, and maintain safe transport conditions.
- Incorporate telemedicine or phone consultation with critical care specialists whenever feasible.
Diagnostic Considerations
- Employ screening tools (e.g., qSOFA) in areas with limited resources, acknowledging its diagnostic constraints.
- Use clinical parameters like altered mental state, capillary refill time (CRT), and urine output to gauge tissue perfusion when lactate measurement is unavailable.
- Insert an indwelling urinary catheter in septic shock to monitor urine output accurately, balancing infection risks against close monitoring needs.
Hemodynamic Management
- Rely on clinical indicators (CRT, urine output) to guide fluid resuscitation when serum lactate is not accessible.
- Use fluid responsiveness tests (e.g., passive leg raising, pulse pressure variation) if advanced hemodynamic monitoring is impractical.
- Consider balanced solutions such as Ringer’s lactate or Hartmann’s solution for fluid resuscitation.
- Recognize that patients with tropical infections (e.g., malaria, dengue) may require cautious fluid volumes to avoid overload.
- Initiate epinephrine if norepinephrine or vasopressin is unavailable, and use vasopressors through peripheral lines if central access cannot be established.
Antimicrobial Therapy
- Administer antibiotics without delay (ideally within one hour) in suspected sepsis or septic shock.
- In severe infections of parasitic origin (e.g., malaria), start antiparasitic agents promptly.
- In settings where laboratory investigations are limited, begin broad-spectrum antimicrobial coverage when infection cannot be ruled out.
- De-escalate or discontinue therapy based on clinical improvement, declining white blood cell counts, and adequate source control.
Respiratory Support
- For acute hypoxemic respiratory failure in septic patients, noninvasive ventilation (NIV) can be used if high-flow nasal oxygen is not available, provided close monitoring for potential failure is ensured.

Review: Acute Respiratory Distress Syndrome

28 Nov, 2024 | 13:06h | UTC

Introduction: Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung condition characterized by diffuse alveolar damage, leading to hypoxemia and respiratory failure. Since its initial description in 1967, the understanding and definition of ARDS have significantly evolved, integrating advances in basic science and clinical practice. A newly recommended global definition expands diagnostic criteria to enhance early recognition and management, especially in resource-limited settings. This review summarizes current insights into the epidemiology, pathophysiology, and evidence-based management of ARDS, highlighting key updates and future research priorities.

Key Recommendations:

New Global Definition of ARDS: Adoption of an expanded definition that includes patients receiving high-flow nasal oxygen (HFNO) support and allows diagnosis using pulse oximetry and thoracic ultrasonography. This makes ARDS identification feasible in diverse clinical environments, including those with limited resources.
Established Critical Care Interventions: Emphasis on early implementation of proven strategies such as low tidal volume ventilation (6 mL/kg predicted body weight) with plateau pressures ≤30 cm H₂O, prone positioning for patients with PaO₂/FiO₂ <150 mm Hg, and conservative fluid management after initial resuscitation. These interventions have consistently reduced mortality and are recommended as standard care.
Personalized Approaches and Phenotyping: Recognition of the heterogeneity in ARDS pathophysiology underscores the need for personalized treatment strategies. Identification of hyper-inflammatory and hypo-inflammatory phenotypes may guide targeted therapies and improve outcomes, although prospective validation is required.
Impact of COVID-19 on ARDS: Acknowledgment of the significant increase in ARDS incidence due to the COVID-19 pandemic. While COVID-19 ARDS shares similarities with traditional ARDS, notable differences in endothelial dysfunction and immune response highlight the necessity for tailored management approaches in these patients.
Pharmacologic Interventions: Updated guidelines provide conditional recommendations for the use of corticosteroids in ARDS, particularly in early moderate to severe cases. Ongoing research into pharmacologic agents such as statins, mesenchymal stromal cells, and other cell-based therapies shows potential but requires further clinical trials to establish efficacy.
Future Research Priorities: Identification of key areas for investigation, including the long-term sequelae of ARDS, optimization of non-invasive and invasive ventilation strategies, exploration of genetic and environmental risk factors, and development of rapid biomarker assays for real-time phenotyping and targeted therapy.

Conclusion: The evolving definition and understanding of ARDS aim to improve early detection and standardization of care across various clinical settings. Reinforcing established critical care interventions while advancing personalized and novel therapeutic approaches holds promise for reducing mortality and enhancing long-term patient outcomes. Continuous research into the pathophysiology and management of ARDS, enriched by insights from the COVID-19 pandemic, is essential to address ongoing challenges and improve patient care.

Reference: Wick KD, Ware LB, Matthay MA. Acute respiratory distress syndrome. BMJ. 2024;387:e076612. DOI: http://doi.org/10.1136/bmj-2023-076612

RCT: Twice-Yearly Lenacapavir Reduces HIV Incidence in Men and Gender-Diverse Persons Background

28 Nov, 2024 | 12:38h | UTC

Background: Although preexposure prophylaxis (PrEP) effectively reduces HIV transmission, adherence to daily oral regimens is suboptimal among high-risk populations. Lenacapavir, a long-acting HIV-1 capsid inhibitor administered subcutaneously every six months, has shown efficacy in cisgender women, but its efficacy in men and gender-diverse individuals remains unclear.

Objective: To evaluate the safety and efficacy of twice-yearly subcutaneous lenacapavir compared to background HIV incidence and daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF) in preventing HIV infection among men and gender-diverse persons.

Methods: In this phase 3, double-blind, randomized trial, 3,271 HIV-negative participants were assigned in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral F/TDF, with matching placebos. Participants were cisgender men, transgender women and men, and gender-nonbinary persons aged 16 or older who have sex with male-assigned partners. The primary endpoint compared HIV incidence in the lenacapavir group to background incidence; secondary analysis compared lenacapavir to F/TDF.

Results: In the modified intention-to-treat analysis (n=3,265), HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years) and 9 in the F/TDF group (0.93 per 100 person-years). The background HIV incidence was 2.37 per 100 person-years. Lenacapavir significantly reduced HIV incidence compared to background (incidence rate ratio [IRR], 0.04; 95% CI, 0.01–0.18; P<0.001) and F/TDF (IRR, 0.11; 95% CI, 0.02–0.51; P=0.002). No significant safety concerns emerged. Injection-site reactions led to discontinuation in 1.2% of lenacapavir recipients and 0.3% of F/TDF recipients.

Conclusions: Twice-yearly subcutaneous lenacapavir significantly reduced HIV incidence compared to both the background incidence and daily oral F/TDF among men and gender-diverse persons. These findings support lenacapavir as an effective PrEP option in this population.

Implications for Practice: The introduction of a long-acting, twice-yearly injectable PrEP option like lenacapavir could improve adherence and uptake among populations challenged by daily oral regimens.

Study Strengths and Limitations: Strengths include a large, diverse participant population with significant representation of transgender and gender-nonbinary persons, and the use of an active comparator. The novel counterfactual design estimating background HIV incidence avoided ethical issues of placebo controls but may have limitations in accuracy. Limitations include a relatively short follow-up and potential impact of injection-site reactions on adherence. The emergence of resistance mutations in participants who acquired HIV while on lenacapavir is a concern needing further investigation.

Future Research: Further studies should assess the long-term safety, efficacy, and resistance patterns associated with lenacapavir use. Research into optimizing injection techniques to minimize injection-site reactions and exploring lenacapavir’s applicability in other at-risk populations is recommended.

Reference: Kelley CF, et al. Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons. New England Journal of Medicine. Published November 27, 2024. DOI: http://doi.org/10.1056/NEJMoa2411858

Review: Candida auris Infections

24 Nov, 2024 | 19:50h | UTC

Introduction: Candida auris, first identified in Japan in 2009, has rapidly emerged as a global public health threat due to its multidrug resistance and propensity to cause difficult-to-control outbreaks in healthcare settings. This review by Lionakis and Chowdhary aims to provide clinicians with an in-depth understanding of the mycologic features, immune responses, epidemiology, risk factors, clinical manifestations, diagnosis, antifungal resistance, treatment, and prevention strategies associated with C. auris infections to inform effective patient care and containment measures.

Key Points:

Mycologic Features: C. auris is a budding yeast that thrives in high-salt and high-temperature environments. It is divided into five clades (I–V) with distinct geographic distributions and varying virulence and resistance profiles.
Immune Response: The interleukin-17 pathway is crucial in reducing skin colonization by C. auris, while phagocytes like monocytes, macrophages, and neutrophils are essential for clearing bloodstream and organ infections.
Epidemiology: Reported in over 45 countries, C. auris is known for causing outbreaks in healthcare facilities due to its persistence on skin and surfaces and challenges in accurate identification. The CDC classifies it as an urgent threat, and the WHO places it in the “critical” group of human fungal pathogens.
Risk Factors: Key risk factors include advanced age, indwelling medical devices, immunocompromised states, diabetes, recent surgery, use of broad-spectrum antibiotics or antifungals, prolonged hospitalization, and severe COVID-19.
Clinical Manifestations: Primarily causing invasive infections like candidemia, C. auris is associated with high morbidity and mortality rates (30–60%). Up to 25% of critically ill colonized patients may develop invasive infections.
Diagnosis: Accurate identification is challenging due to misidentification with other Candida species on conventional tests. Reliable methods include MALDI-TOF mass spectrometry, sequencing of rDNA regions, and molecular assays like PCR.
Antifungal Resistance: C. auris exhibits clade-specific multidrug resistance, with most strains resistant to fluconazole and some resistant to echinocandins and amphotericin B. Resistance mechanisms involve mutations in the ERG11 and FKS1 genes.
Treatment: Echinocandins are recommended as first-line treatment for invasive C. auris infections. Close monitoring is essential due to potential treatment failure and emergence of resistance. Amphotericin B formulations may be used in neonates or if echinocandin resistance is present.
Prevention: Strict infection control measures are critical, including contact precautions, environmental cleaning with EPA-registered disinfectants effective against C. auris, surveillance screening, and cohorting of patients to prevent nosocomial transmission.

Conclusion: The rapid global spread of multidrug-resistant C. auris presents significant challenges for clinical management and infection control. Early and accurate diagnosis, appropriate antifungal therapy, and stringent prevention strategies are essential to improve patient outcomes and prevent further dissemination of this pathogen.

Reference: Lionakis MS, Chowdhary A. Candida auris Infections. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMra2402635

RCT: 7-Day Antibiotic Therapy Noninferior to 14-Day for Bloodstream Infections

20 Nov, 2024 | 18:19h | UTC

Background: Bloodstream infections are a significant cause of morbidity and mortality worldwide. Early and appropriate antibiotic therapy is essential, but the optimal duration remains uncertain. Prolonged antibiotic use can lead to adverse events, Clostridioides difficile infection, antimicrobial resistance, and increased healthcare costs.

Objective: To determine whether a 7-day course of antibiotic treatment is noninferior to a 14-day course in hospitalized patients with bloodstream infections regarding 90-day all-cause mortality.

Methods: In this multicenter, noninferiority randomized controlled trial, 3,608 hospitalized patients from 74 hospitals in seven countries were enrolled. Eligible patients had bloodstream infections but were excluded if they had severe immunosuppression, infections requiring prolonged therapy, possible contaminants, or Staphylococcus aureus bacteremia. Participants were randomized to receive either 7 days (n=1,814) or 14 days (n=1,794) of adequate antibiotic therapy, with antibiotic selection at the clinicians’ discretion. The primary outcome was death from any cause by 90 days post-diagnosis, with a noninferiority margin of 4 percentage points.

Results: At 90 days, mortality was 14.5% in the 7-day group and 16.1% in the 14-day group (difference: –1.6 percentage points; 95.7% CI, –4.0 to 0.8), demonstrating noninferiority of the shorter duration. Noninferiority was confirmed in per-protocol and modified intention-to-treat analyses. Secondary outcomes, including relapse rates, adverse events, and hospital length of stay, were similar between groups. Findings were consistent across subgroups based on infection source, pathogen type, and patient characteristics.

Conclusions: A 7-day antibiotic regimen is noninferior to a 14-day regimen for treating hospitalized patients with bloodstream infections, without increasing mortality or relapse rates.

Implications for Practice: Implementing a 7-day antibiotic course could reduce antibiotic exposure, minimize adverse events, and potentially limit antimicrobial resistance development. Clinicians should consider individual patient factors, such as infection severity and comorbidities, before universally adopting shorter treatment durations.

Study Strengths and Limitations: Strengths include a large, diverse patient population and inclusion of critically ill patients, enhancing generalizability. Limitations involve the open-label design and nonadherence to assigned durations in some cases (23.1% in the 7-day group continued antibiotics longer). Exclusion of S. aureus bacteremia limits applicability to that subgroup. The study may not have been powered to detect differences in rare adverse outcomes like C. difficile infection or antimicrobial resistance emergence.

Future Research: Further studies should explore the efficacy of even shorter antibiotic durations, individualized treatment strategies based on patient response, and the long-term impact on antimicrobial resistance and healthcare costs.

Reference: The BALANCE Investigators, for the Canadian Critical Care Trials Group and others. Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections. New England Journal of Medicine. Published November 20, 2024. DOI: http://doi.org/10.1056/NEJMoa2404991

Cohort Study: High Rate of Preventable Adverse Events in Surgical Inpatients

16 Nov, 2024 | 17:29h | UTC

Background: Adverse events during hospital admissions, particularly in surgical settings, remain a significant cause of patient harm despite efforts to improve patient safety since the “To Err is Human” report. Advances in surgical techniques and patient care necessitate an updated assessment of the current state of perioperative safety.

Objective: To estimate the frequency, severity, and preventability of adverse events associated with perioperative care in surgical inpatients and to identify the settings and healthcare professionals involved.

Methods: A multicenter retrospective cohort study was conducted across 11 US hospitals in Massachusetts. A weighted random sample of 1,009 patients was selected from 64,121 adults admitted for surgery in 2018. Trained nurses reviewed electronic health records to identify adverse events, which were then adjudicated by physicians. Adverse events were classified by type, severity, preventability, setting, and professions involved.

Results: Adverse events occurred in 38.0% of patients (95% CI, 32.6–43.4%), with major adverse events in 15.9% (12.7–19.0%). Among 593 adverse events identified, 59.5% were potentially preventable, and 20.7% were definitely or probably preventable. The most common events were surgery-related (49.3%), adverse drug events (26.6%), healthcare-associated infections (12.4%), and patient care events (11.2%). Adverse events most frequently occurred in general care units (48.8%) and involved attending physicians (89.5%) and nurses (58.9%).

Conclusions: More than one-third of surgical inpatients experienced adverse events, with nearly half classified as major and most potentially preventable. These findings highlight the critical need for ongoing improvement in patient safety throughout perioperative care involving all healthcare professionals.

Implications for Practice: Healthcare providers should enhance patient safety protocols across all perioperative settings, not just in operating rooms. Emphasis should be placed on preventing surgery-related complications, adverse drug events, and healthcare-associated infections by fostering teamwork and continuous monitoring.

Study Strengths and Limitations: Strengths include a comprehensive review of medical records and systematic classification of adverse events by trained professionals. Limitations involve the study’s confinement to Massachusetts hospitals in 2018, potential variability in documentation practices, and limited sample size affecting generalizability and specialty-specific estimates.

Future Research: Further studies are needed to assess adverse event rates in diverse geographic locations and healthcare systems, explore effective interventions to reduce preventable harm, and evaluate long-term trends in surgical patient safety.

Reference: Duclos A, Frits ML, Iannaccone C, Lipsitz SR, Cooper Z, Weissman JS, Bates DW. Safety of inpatient care in surgical settings: cohort study. BMJ. 2024; DOI: http://doi.org/10.1136/bmj-2024-080480

Retrospective Cohort Study: Midline Catheters Associated with Lower Major Complications Than PICCs in Outpatient Antimicrobial Therapy

16 Nov, 2024 | 14:35h | UTC

Background: Outpatient parenteral antimicrobial therapy (OPAT) requires reliable vascular access for administering intravenous antibiotics post-hospitalization. Peripherally inserted central catheters (PICCs) are commonly used due to their versatility and ease of placement. Recently, midline catheters have emerged as potential alternatives for OPAT, offering less invasive access. However, limited evidence exists comparing the safety and complication rates of midline catheters versus PICCs in OPAT patients.

Objective: To compare the risk of major and minor device complications associated with midline catheters versus PICCs in patients receiving OPAT.

Methods: This retrospective cohort study analyzed data from 2,824 hospitalized patients across 69 Michigan hospitals who received either a midline catheter (n=1,999) or a PICC (n=825) for OPAT between January 2017 and November 2023. Patients receiving vancomycin were excluded. The primary outcome was major device complications, defined as catheter-related bloodstream infection (CRBSI) or catheter-related venous thromboembolism (CR-VTE). Secondary outcomes included minor device complications (e.g., catheter dislodgement, occlusion) and device failure, defined as catheter removal due to any complication.

Results: Midline catheters were associated with a lower risk of major complications compared to PICCs (0.8% vs 3.4%; adjusted hazard ratio [aHR], 0.46; 95% CI, 0.23-0.91; P < .001). This difference was more pronounced for devices with dwell times of 14 days or fewer (aHR, 0.29; 95% CI, 0.12-0.68). There were no significant differences in minor complications (10.3% vs 13.8%; aHR, 1.07; 95% CI, 0.83-1.38) or device failure rates (9.6% vs 12.1%; aHR, 1.26; 95% CI, 0.96-1.65) between midline catheters and PICCs.

Conclusions: Midline catheters are associated with a lower risk of major complications compared to PICCs in patients receiving OPAT, particularly for treatment durations of 14 days or fewer. These findings suggest that midline catheters are a safe and effective alternative to PICCs for short-term OPAT.

Implications for Practice: Clinicians should consider using midline catheters for OPAT when the anticipated therapy duration is 14 days or less and the infusate is peripherally compatible. This may reduce the risk of major complications such as CRBSI and CR-VTE, potentially improving patient outcomes and reducing healthcare costs.

Study Strengths and Limitations: Strengths of this study include a large, diverse patient population across multiple hospitals and rigorous data collection methods. Limitations include its retrospective design, potential for unmeasured confounding, and exclusion of patients receiving vancomycin, which may limit generalizability. Additionally, complications occurring after 30 days or post-device removal may have been missed.

Future Research: Further studies are needed to evaluate the safety and efficacy of midline catheters for OPAT durations exceeding 14 days and to explore factors influencing long-term device performance and patient outcomes.

Reference: Paje D, et al. Midline vs Peripherally Inserted Central Catheter for Outpatient Parenteral Antimicrobial Therapy. JAMA Internal Medicine. 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.5984

Test-Negative Study: RSV Vaccine May Reduce Hospitalizations and ED Visits in Adults Aged ≥60

16 Nov, 2024 | 14:18h | UTC

Background: Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality among older adults in the USA, with an estimated 100,000–160,000 RSV-associated hospitalizations annually in those aged 60 years and older. In 2023, RSV vaccines were recommended for this population, showing efficacy in clinical trials. However, real-world effectiveness data, particularly against severe outcomes like hospitalizations in high-risk groups, are limited.

Objective: To assess the real-world effectiveness of RSV vaccination against RSV-associated hospitalizations and emergency department (ED) encounters among adults aged 60 years and older during the 2023–24 RSV season in the USA.

Methods: A test-negative design analysis was conducted using data from the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION), encompassing eight states. Adults aged ≥60 presenting with RSV-like illness and tested for RSV from Oct 1, 2023, to Mar 31, 2024, were included. Vaccination status was determined through electronic health records, immunization registries, and medical claims. Vaccine effectiveness (VE) was estimated by comparing the odds of vaccination among RSV-positive cases and RSV-negative controls, adjusting for age, sex, race and ethnicity, comorbidities, and geographic region.

Results: Among 28,271 hospitalizations for RSV-like illness in immunocompetent adults aged ≥60, VE against RSV-associated hospitalization was 80% (95% CI 71–85). VE against RSV-associated critical illness (ICU admission or death) was 81% (95% CI 52–92). In 8,435 hospitalizations among immunocompromised adults, VE was 73% (95% CI 48–85) against RSV-associated hospitalization. Among 36,521 ED encounters in immunocompetent adults, VE against RSV-associated ED visits was 77% (95% CI 70–83). VE estimates were consistent across age groups and vaccine products.

Conclusions: RSV vaccination effectively prevented RSV-associated hospitalizations and ED visits among adults aged ≥60 during the first season post-approval, including those at highest risk due to advanced age or immunocompromise.

Implications for Practice: These findings support recommending RSV vaccination for adults aged ≥60 to reduce severe RSV-related morbidity and mortality. Clinicians should consider advising eligible patients to receive the RSV vaccine to prevent hospitalizations and critical illness.

Study Strengths and Limitations: Strengths include a large, geographically diverse cohort and integrated medical, laboratory, and vaccination data, allowing robust VE estimates across subgroups. Limitations involve potential misclassification of vaccination status, residual confounding, and reliance on clinician-directed RSV testing, which may introduce bias.

Future Research: Further studies are needed to evaluate the duration of vaccine protection over multiple RSV seasons and to assess VE in other high-risk populations and settings.

Reference: Payne AB, et al. Respiratory syncytial virus vaccine effectiveness against RSV-associated hospitalisations and emergency department encounters among adults aged 60 years and older in the USA, October 2023 to March 2024: a test-negative design analysis. The Lancet. Published October 19, 2024. DOI: http://doi.org/10.1016/S0140-6736(24)01738-0

Review: Lung Transplantation

16 Nov, 2024 | 13:33h | UTC

Introduction: Lung transplantation has progressed from experimental to standard therapy for life-threatening lung diseases, offering improved survival and quality of life. Challenges include primary graft dysfunction, chronic lung allograft dysfunction (CLAD), infections, and long-term immunosuppression effects. This review highlights current practices, developments, and opportunities to enhance this transformative therapy.

Key Recommendations

Candidate Selection: Selection criteria have shifted from strict contraindications to a holistic approach emphasizing physiologic age, frailty, and recoverability. Early referral and multidisciplinary assessment are recommended to address barriers and optimize outcomes.
Donor-Lung Utilization: Extended-criteria donors, including older donors and those with smoking histories, are increasingly used. Ex vivo lung perfusion allows detailed lung assessment and reconditioning, while antiviral therapies enable transplantation of lungs from hepatitis C-positive donors.
Lung Allocation: Urgency-weighted scores prioritize factors like medical urgency and post-transplant survival. Recent updates include biologic disadvantages, patient access, and logistical efficiency to improve fairness and outcomes.
Surgical Techniques: Bilateral sequential lung transplantation is standard, with ECMO replacing cardiopulmonary bypass in many cases. Surgical approaches are tailored to individual needs, with options like volume reduction or lobectomy for size mismatches.
Postoperative Management: Primary graft dysfunction affects up to 25% of recipients and is a major early complication. Preventive strategies, ECMO support, and infection management are critical. Attention to airway complications and acute kidney injury further improves recovery.
Immunosuppression: Maintenance therapy typically includes a calcineurin inhibitor, glucocorticoid, and cell-cycle inhibitor. Induction therapy is individualized. Ongoing studies are exploring adjunct therapies like mTOR inhibitors and inhaled immunosuppressants to prevent CLAD.
Management of ALAD and CLAD: Early detection and treatment of acute lung allograft dysfunction are essential. CLAD, affecting half of recipients within 5 years, remains a major challenge. Current therapies slow progression, but further research is needed for targeted prevention and treatment.
Infections: Infections remain a leading cause of morbidity and mortality. Prophylaxis against cytomegalovirus, fungal pathogens, and community-acquired viruses is essential to minimize complications and reduce CLAD risk.
Cancer Risk: Post-transplant cancer risk is elevated due to immunosuppression. Lung cancer and post-transplant lymphoproliferative disease are the most common malignancies, emphasizing the need for routine surveillance and early intervention.
Long-Term Outcomes: Median survival remains limited at 6.7 years. Efforts focus on improving long-term outcomes by balancing graft function maintenance with minimizing adverse effects of immunosuppression. Collaborative research aims to refine diagnostics, personalize therapies, and address CLAD mechanisms.

Conclusion: Enhanced donor utilization, tailored candidate selection, refined perioperative care, and robust long-term monitoring are pivotal to advancing lung transplantation. Ongoing research and collaboration are critical to overcoming challenges like CLAD, improving survival, and enhancing patient quality of life.

Reference: Christie JD, et al. Lung Transplantation. New England Journal of Medicine. 2024. DOI: http://doi.org/10.1056/NEJMra2401039

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