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Global and Humanitarian Medicine

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:

  1. 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.
  2. 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.
  3. 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.
  4. 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

 

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

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

 

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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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:

  1. Offer doxyPEP counseling to MSM and transgender women with a recent bacterial STI history, addressing the benefits, harms, and uncertainties of prophylactic doxycycline use.
  2. 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.
  3. 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.
  4. 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.
  5. Consider extending doxyPEP to other high-risk groups, including heterosexual individuals with recurrent STIs, guided by clinical judgment and shared decision-making.
  6. 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.
  7. 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

 

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

24 Dec, 2024 | 13:35h | 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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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: 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: Chronic Low-Level Lead Poisoning

3 Nov, 2024 | 01:15h | UTC

Introduction: Lead poisoning, historically known as plumbism, remains a significant health concern despite reductions in lead use. Chronic low-level lead exposure has been identified as a critical risk factor for cardiovascular disease in adults and cognitive deficits in children, even at blood lead concentrations previously deemed safe. This review by Lanphear et al. explores the multifaceted effects of chronic, low-level lead poisoning, emphasizing its impact on neurodevelopment, kidney function, and cardiovascular health, and underscores the urgent need for effective prevention strategies.

Key Findings:

  1. Exposure and Absorption: Lead exposure occurs primarily through ingestion and inhalation, with children absorbing lead more readily than adults. Absorption is enhanced in the presence of iron or calcium deficiency. Once absorbed, lead is predominantly stored in the skeleton, and factors altering bone metabolism can mobilize lead back into the bloodstream.
  2. Neurodevelopmental Effects: Lead exposure is linked to preterm birth, cognitive deficits, attention deficit–hyperactivity disorder (ADHD), and behavioral disorders in children. Notably, cognitive deficits are proportionately larger at lower blood lead levels, with significant IQ reductions observed even at the lowest measurable concentrations.
  3. Kidney Disease: Chronic lead exposure is a risk factor for chronic kidney disease. Higher blood lead levels are associated with reduced glomerular filtration rates and an increased risk of developing chronic kidney conditions.
  4. Cardiovascular Disease: Lead induces hypertension and atherosclerosis through mechanisms such as oxidative stress and endothelial dysfunction. It is a leading risk factor for mortality from cardiovascular disease, with substantial risk increases even at low blood lead concentrations. Studies indicate that lead exposure may have contributed to historical trends in coronary heart disease mortality.
  5. Global Burden: In 2019, lead exposure accounted for approximately 5.5 million deaths from cardiovascular disease and the loss of 765 million IQ points in children globally. The economic cost associated with lead-related health outcomes is estimated at $6 trillion annually, representing about 7% of the global gross domestic product.
  6. Screening and Treatment: Screening high-risk populations is recommended, including children in older housing and workers in certain industries. While chelation therapy can reduce body lead burden, its effects on health outcomes are inconsistent, highlighting the importance of primary prevention.
  7. Prevention Strategies: Eliminating environmental sources of lead through government-funded population strategies is essential. This includes replacing lead-containing infrastructure like water service lines, banning leaded aviation fuel, reducing lead in consumer products, and remediating contaminated soils and older housing with lead-based paints.

Conclusion: Chronic low-level lead poisoning continues to pose a significant global health threat, contributing to cardiovascular disease and neurodevelopmental deficits. The disproportionate effects at even the lowest exposure levels underscore the necessity for robust, population-wide prevention strategies. Implementing stringent regulatory actions to eliminate sources of lead exposure is imperative to reduce the substantial morbidity, mortality, and economic burdens associated with lead poisoning.

Reference: Lanphear B, Navas-Acien A, Bellinger DC. Lead Poisoning. New England Journal of Medicine. 2024;391(17):1621–1631. DOI: http://doi.org/10.1056/NEJMra2402527

 

Cluster-Randomized Trial: Twice-Yearly Azithromycin Reduces Mortality in Children Aged 1 to 59 Months in Niger – New England Journal of Medicine

24 Aug, 2024 | 19:44h | UTC

Study Design and Population: This adaptive cluster-randomized trial evaluated the impact of twice-yearly azithromycin distribution on childhood mortality in rural communities in Niger. A total of 1273 communities were assigned to three groups: children aged 1 to 59 months receiving azithromycin, infants aged 1 to 11 months receiving azithromycin and placebo for older children, and a placebo group. The study included 382,586 children and followed mortality over 419,440 person-years.

Main Findings: The study found a significant 14% reduction in mortality among children aged 1 to 59 months in the azithromycin group compared to placebo (11.9 vs. 13.9 deaths per 1000 person-years; P<0.001). However, azithromycin did not significantly reduce mortality in infants aged 1 to 11 months when compared to placebo (22.3 vs. 23.9 deaths per 1000 person-years).

Implications for Practice: Azithromycin distribution to children aged 1 to 59 months effectively reduces mortality in rural sub-Saharan Africa. However, targeting only infants may not yield significant benefits. Continuous monitoring for antimicrobial resistance is essential.

Reference: O’Brien KS, Arzika AM, Amza A, et al. (2024). Azithromycin to reduce mortality — an adaptive cluster-randomized trial. N Engl J Med, 391(8), 699-709. DOI: https://doi.org/10.1056/NEJMoa2312093

 

RCT: Twice-Yearly Lenacapavir Prevents HIV Infections More Effectively Than Daily F/TAF in Women – N Engl J Med

18 Aug, 2024 | 13:56h | UTC

Study Design and Population: This phase 3, double-blind, randomized controlled trial included 5,338 adolescent girls and young women in South Africa and Uganda. Participants were assigned to receive either twice-yearly subcutaneous lenacapavir, daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF) as an active control, with corresponding placebos.

Main Findings: Lenacapavir demonstrated superior efficacy in HIV prevention, with zero infections observed among its recipients. In contrast, the F/TAF group experienced 39 HIV infections (2.02 per 100 person-years), while the F/TDF group had 16 infections (1.69 per 100 person-years). HIV incidence was significantly lower with lenacapavir compared to background incidence and F/TDF, while no significant difference was observed between F/TAF and F/TDF.

Implications for Practice: Twice-yearly lenacapavir could be a more effective and potentially easier-to-adopt HIV prevention strategy than daily oral F/TAF in cisgender women, though considerations of injection-site reactions are necessary. This approach could improve adherence and outcomes in populations with low persistence in daily PrEP use.

Reference: Bekker, L.-G., Das, M., Abdool Karim, Q., Ahmed, K., Batting, J., Brumskine, W., Gill, K., et al. (2024). Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. New England Journal of Medicine, 391(7), 648-659. DOI: 10.1056/NEJMoa2407001.

 

Phase 3 RCT: Butantan-DV Dengue Vaccine is Safe and Shows 67.3% Efficacy Over 3.7 Years in Participants Aged 2–59 Years – Lancet Infect Dis

10 Aug, 2024 | 20:23h | UTC

Study Design and Population: This double-blind, randomized, placebo-controlled, phase 3 trial conducted in Brazil evaluated the efficacy and safety of the Butantan-dengue vaccine (Butantan-DV) in 16,235 healthy participants aged 2–59 years. Participants, who had not previously received a dengue vaccine, were randomly assigned to receive either a single dose of Butantan-DV or a placebo and were followed up for an average of 3.7 years.

Main Findings: The study found that Butantan-DV demonstrated 67.3% efficacy against virologically confirmed dengue (VCD) caused by any dengue virus serotype, with no cases of VCD caused by DENV-3 or DENV-4. The proportions of serious adverse events were similar between the vaccine and placebo groups, indicating that the vaccine was generally well tolerated.

Implications for Practice: The results support the potential of the Butantan-DV vaccine as an effective intervention for preventing symptomatic dengue, particularly from DENV-1 and DENV-2, across a broad age range regardless of dengue serostatus. Continued development and monitoring are warranted to confirm long-term efficacy and safety.

Reference: Nogueira, M. L., et al. (2024). Efficacy and safety of Butantan-DV in participants aged 2–59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil. The Lancet Infectious Diseases. DOI: https://doi.org/10.1016/S1473-3099(24)00376-1.

 

Diagnostic Study: Enhanced prediction of TB progression with IGRAs compared to tuberculin skin test

27 Apr, 2024 | 18:53h | UTC

Study Design and Population:

This prospective diagnostic study analyzed the predictive accuracy of tuberculosis (TB) tests among 22,020 high-risk participants across 10 US sites from 2012 to 2020. Participants included individuals with close contacts to infectious TB cases, those born in or travelers to high-incidence countries, individuals living with HIV, or belonging to locally prevalent high-risk groups. Testing included two interferon-γ release assays (IGRAs), QuantiFERON-TB Gold In-Tube (QFT-GIT) and SPOT.TB (TSPOT), alongside the traditional tuberculin skin test (TST).

 

Main Findings:

The study found that both IGRAs, TSPOT and QFT-GIT, showed significantly superior positive predictive value (PPV) for predicting TB disease progression compared to the TST, with PPV ratios of 1.65 (95% CI, 1.35-2.02) and 1.47 (95% CI, 1.22-1.77) respectively. Additionally, when considering a positive TST result, further positive results from either IGRA significantly increased the PPV, emphasizing the enhanced predictive capability of IGRAs over TST alone.

 

Implications for Practice:

The superior predictive performance of Interferon-γ Release Assays (IGRAs) suggests they should be considered in clinical settings for high-risk populations, if available and feasible, to better identify individuals at increased risk of progressing to active tuberculosis (TB). This enhanced detection capability could guide more targeted preventive treatments, ultimately supporting global efforts toward TB elimination. Clinicians should assess the accessibility and cost-effectiveness of IGRAs to refine decision-making processes in TB prevention strategies, ensuring that the benefits of these advanced diagnostics are balanced against their costs.

 

Reference (free full-text):

Ayers, T. et al. (2024). Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease. JAMA Network Open, 7(4), e244769. DOI: https://doi.org/10.1001/jamanetworkopen.2024.4769.

WHO report on HIV drug resistance – Rising dolutegravir resistance and implications for global care standards

27 Apr, 2024 | 16:08h | UTC

The World Health Organization’s latest HIV Drug Resistance Report highlights both the effectiveness and emerging challenges with dolutegravir (DTG)-based therapies. While there is significant suppression of HIV viral loads in populations treated with DTG, data reveals increasing resistance levels, particularly among those with high viral loads and prior treatment experiences. The report calls for enhanced surveillance and management strategies to address these resistance patterns and maintain treatment efficacy. It also underscores the necessity of robust data systems and proactive healthcare policies to improve the overall quality of HIV treatment and prevent the transmission of resistant HIV strains, aligning with global efforts to combat antimicrobial resistance.

 

Source:

New report documents increase in HIV drug resistance to dolutegravir – World Health Organization

Systematic Analysis: Global Burden and Trends of Nervous System Disorders, 1990–2021

21 Mar, 2024 | 11:10h | UTC

Study Design and Population

This study, a systematic analysis conducted by the Global Burden of Disease Study 2021, aimed to estimate the global, regional, and national health loss attributable to 37 unique nervous system conditions from 1990 to 2021. The researchers estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life years (DALYs) across 204 countries. The analysis included morbidity and deaths directly resulting from damage to the central or peripheral nervous system, as well as neurological health loss from conditions where nervous system morbidity is a secondary outcome.

Main Findings

The collective global burden of these nervous system conditions emerged as the leading cause of DALYs in 2021, affecting approximately 3.40 billion individuals (43.1% of the global population) and resulting in 443 million DALYs. Although global DALY counts for these conditions increased by 18.2% from 1990 to 2021, there was a notable decrease in the age-standardised rates of deaths and DALYs by 33.6% and 27.0%, respectively. The conditions contributing most significantly to the age-standardised DALYs were stroke, neonatal encephalopathy, migraine, and Alzheimer’s disease among others.

Implications for Practice

This analysis underscores the critical need for effective prevention, treatment, and rehabilitation strategies for nervous system disorders, which now lead the global disease burden. Highlighting an 18.2% increase in DALY counts over the study period, it calls for heightened public health attention and resource allocation towards these conditions. The findings support the prioritization of nervous system health on the global health agenda and stress the importance of further research into modifiable risk factors and equitable access to care.

Reference

GBD 2021 Nervous System Disorders Collaborators (2024). Systematic Analysis: Global Burden and Trends of Nervous System Disorders, 1990–2021. The Lancet Neurology, Volume(issue), Pages. DOI: https://doi.org/10.1016/S1474-4422(24)00038-3. Access the study here: Link

Global prevalence, years lived with disability, and trends in anemia burden by severity and cause, 1990–2021

3 Aug, 2023 | 13:43h | UTC

Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990–2021: findings from the Global Burden of Disease Study 2021 – The Lancet Haematology

News Release: New study reveals global anemia cases remain persistently high among women and children. Anemia rates decline for men – Institute for Health Metrics and Evaluation

 

Commentary on Twitter

 

WHO | Seven out of 10 people protected by at least one tobacco control measure

2 Aug, 2023 | 14:14h | UTC

News Release: Seven out of 10 people protected by at least one tobacco control measure – World Health Organization

See also: MPOWER measures

Report: WHO report on the global tobacco epidemic, 2023: protect people from tobacco smoke – World Health Organization

Commentaries:

While Anti-Smoking Policies Cover 70% of Global Population, Taxation is Under-Utilised – Health Policy Watch

Expert reaction to WHO report on the global tobacco epidemic 2023 – Science Media Centre

 

Commentary on Twitter

 

Study | Childhood deaths in high-mortality settings mostly preventable; infection, malnutrition top causes

31 Jul, 2023 | 14:05h | UTC

Causes of Death Among Infants and Children in the Child Health and Mortality Prevention Surveillance (CHAMPS) Network – JAMA Network Open

Invited Commentary: Need for a Structural Approach to Promote Child Survival – JAMA Network Open

News Release: Eight out of ten child deaths in low-income countries could be prevented – Barcelona Institute for Global Health

 

New WHO lists of essential medicines

28 Jul, 2023 | 14:23h | UTC

News Release: WHO endorses landmark public health decisions on Essential Medicines for Multiple Sclerosis – World Health Organization

Lists of Essential Medicines

Model Lists of Essential Medicines – World Health Organization

Model Lists of Essential Medicines for Children – World Health Organization

 

Commentary on Twitter

 

WHO world drowning prevention day 2023

27 Jul, 2023 | 13:12h | UTC

World Drowning Prevention Day 2023 – World Health Organization

Report: Hidden depths: the global investment case for drowning prevention – World Health Organization

Related:

Wilderness Medical Society Clinical Practice Guidelines for the Treatment and Prevention of Drowning: 2019 Update

Tracing the emergence of drowning prevention on the global health and development agenda: a policy analysis – The Lancet Global Health

WHO Guideline on the prevention of drowning through provision of day-care and basic swimming and water safety skills – World health Organization

Wilderness Medical Society Clinical Practice Guidelines for the Treatment and Prevention of Drowning: 2019 Update

Prevention of Drowning – Pediatrics

The burden of unintentional drowning: global, regional and national estimates of mortality from the Global Burden of Disease 2017 Study – Injury Prevention

Preventing drowning: an implementation guide – World Health Organization

Global report on drowning: preventing a leading killer – World Health Organization

Hidden Hazards: An Exploration of Open Water Drowning and Risks for Children – Safe Kids Worldwide

 

Commentary on Twitter (thread – click for more)

 

Global, regional, and national burden of meningitis and its etiologies, 1990–2019

25 Jul, 2023 | 13:55h | UTC

Global, regional, and national burden of meningitis and its aetiologies, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019 – The Lancet Neurology

 

Commentary on Twitter

 

Key factors associated with quality of postnatal care: a pooled analysis of 23 countries

25 Jul, 2023 | 13:50h | UTC

Key factors associated with quality of postnatal care: a pooled analysis of 23 countries – eClinicalMedicine

 

New WHO guidance on the role of HIV viral suppression in improving individual health and reducing transmission

24 Jul, 2023 | 13:17h | UTC

News Release: New WHO guidance on HIV viral suppression and scientific updates released at IAS 2023 – World Health Organization

WHO Guidance: The role of HIV viral suppression in improving individual health and reducing transmission – Word Health Organization

Related WHO Guidelines:

WHO recommends optimizing HIV testing services – World Health Organization

Primary health care and HIV: convergent actions – World Health Organization

 

Systematic Review | Low-level HIV viremia (below 1000 copies/mL) linked to minimal sexual transmission risk

24 Jul, 2023 | 13:15h | UTC

The risk of sexual transmission of HIV in individuals with low-level HIV viraemia – The Lancet

Editorial: HIV is sexually untransmittable when viral load is undetectable – The Lancet

Related: Study: Growing Acceptability of “Undetectable = Untransmittable” but Widespread Misunderstanding of HIV Transmission Risk Persists (several texts on the subject)

 

Commentary on Twitter

 

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