Risk factors for baseline bedaquiline (BDQ) resistance, amplification during treatment, and correlations with treatment outcomes are not fully understood. This cohort included Armenian patients with multidrug-resistant TB predominantly fluoroquinolone-resistant enrolled between 2013 and 2015 in a BDQ compassionate use program. BDQ resistance at baseline and during treatment was assessed using MGIT (pDSTMGIT), minimal inhibitory concentration in 7H11 (MIC7H11), and whole-genome sequencing. Risk factors, such as treatment effectiveness or stage of the disease, were analyzed for association with baseline BDQ resistance, acquired BDQ resistance, and treatment outcome. Among 39 patients, baseline BDQ resistance was 6% (2/33) by pDSTMGIT and 7% (2/29) by MIC7H11. All four baseline isolates with an Rv0678 mutation were phenotypically resistant. During treatment, 48% of the patients acquired BDQ resistance by pDSTMGIT, and 52% acquired mutations at various frequencies (97% in Rv0678). None of the factors significantly contributed to baseline or acquired BDQ resistance. Unfavorable treatment outcome (41%) was more frequent in the presence of acquired Rv0678 mutations [odds ratio (OR) 132, 95% confidence interval (CI) 7.43, 2375], phenotypic BDQ resistance (OR 176, 95% CI 6.48, 2423), or MIC increase above or below the critical concentration (both OR 84.3, 95% CI 2.93, 2423) during treatment. For these highly treatment-experienced patients, low baseline prevalence but high incidence of acquired BDQ resistance was observed. Acquisition of mutations in BDQ candidate resistance genes, regardless of their frequency, or increased MICs during treatment, even below the critical concentration, should be seen as a warning sign of resistance amplification and increased risk of unfavorable treatment outcome.
BACKGROUND
Bedaquiline (BDQ) resistance presents a critical challenge in the fight against tuberculosis (TB), particularly multidrug-resistant (MDR) strains. The emergence of resistance to BDQ, a key drug in treating MDR-TB, poses significant threats to TB treatment effectiveness.
METHODS
The National Institute of Tuberculosis and Respiratory Diseases in Delhi and the Médecins Sans Frontières clinic in Mumbai provide BDQ, delamanid, and carbapenem-based regimens for patients with suspected or confirmed treatment failure. BDQ phenotypic drug-susceptibility testing (DST) was performed for all BDQ-exposed patients. Treatment regimens were individualized based on exposure history, comorbidities, drug interactions, prior adverse drug reactions, and DST results.
RESULTS
Of 117 BDQ-exposed patients from December 2020–December 2022, 42 (36%) exhibited a BDQ-resistant strain. Median (IQR) age was 24 (22–32) years, with 63 (54%) females and 94% with pulmonary TB. Patients with a BDQ-resistant strain were older (median age: 27 vs 23 years; P = .04), more likely to have lung cavities (risk ratio [RR]: 1.8; 95%-CI: 1.1–3.1; P = .02), and be resistant to clofazimine (RR: 2.3; 95%-CI: 1.5–3.6; P = .001). Overall, 102 patients initiated treatment. Patients with BDQ-resistance had higher risk of unfavorable outcomes compared with BDQ-susceptible patients (RR:2.1; 95%-CI: 1.5–2.8; P < .001). Overall, 87% (33/38) of patients with BDQ-resistance experienced unfavorable treatment outcomes: 15 (40%) died, 15 (40%) had treatment failure, and 3 (8%) were lost-to-follow-up.
CONCLUSIONS
The study highlights a concerning rate of BDQ-resistance among previously treated patients, resulting in poor treatment outcomes. To prevent treatment failure, we recommend implementing BDQ-DST, developing affordable and accurate rapid tests for BDQ-resistance, and intensifying research and development efforts for newer TB drugs.
BACKGROUND
Antibiotics are indispensable to modern healthcare, yet their equitable access remains a pressing global challenge. Factors contributing to inequities include insufficient evidence for optimal clinical use, limited registration, pricing for Reserve antibiotics, and supply chain challenges. These issues disproportionately affect low- and middle-income countries, exacerbating antimicrobial resistance burdens.
OBJECTIVES
This paper explores the multifaceted dimensions of inequitable antibiotic access and proposes a comprehensive framework to address the crisis.
SOURCES
Published articles, grey literature analysis, and the authors' own expertise contributed to this article.
CONTENT
While much attention has been paid to push-and-pull incentives for antibiotic development, these interventions are inadequate to reach sustainable and equitable access to antibiotics. Improving equitable antibiotic access requires an ecosystem approach, involving multiple stakeholders and including public–private partnerships. The paper advocates for initiatives spanning research and development, regulatory pathways, procurement strategies, and financing mechanisms and suggests concrete interventions in each of these areas. The specific interventions and mix of public and private actors may vary according to antibiotic, market, and health system context, but must be designed to meet public health needs while also supporting a market that will sustain quality-assured production and delivery of antibiotics.
IMPLICATIONS
Addressing the challenge of equitable antibiotic access requires coordinated efforts across sectors and regions. By embracing an ecosystem approach centred on public health priorities, stakeholders can pave the way for a sustainable supply of antibiotics, and equitable access, safeguarding the future of global healthcare amidst the growing threat of antimicrobial resistance.
BACKGROUND
Only 63% of patients initiating multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment in 2020 were treated successfully. 24-Week all-oral bedaquiline, pretomanid, and linezolid (BPaL)–based regimens have demonstrated higher rates of treatment success and have been recommended by the World Health Organization. Operational research is urgently required to evaluate these regimens in non-trial settings.
METHODS
This was a prospective cohort study of patients with microbiologically confirmed MDR/RR-TB and pre–extensively drug-resistant TB (pre-XDR-TB) initiated on BPaL-based regimens in Belarus and Uzbekistan (February 2022–June 2023). All clinical care and research procedures were delivered by treating physicians. After treatment completion, patients were followed up at 6 and 12 months, including collecting sputum to ascertain recurrence. The primary objective was to estimate the effectiveness (cured or treatment completed) and safety (the occurrence of serious adverse events) of BPaL-based regimens.
RESULTS
A total of 677 patients initiated treatment with BPaL-based regimens during the study. We documented successful treatment outcomes in 95.3% (427/448) of patients with MDR/RR-TB treated with BPaL plus moxifloxacin and 90.4% (207/229) of patients with pre–XDR-TB treated with BPaL plus clofazimine. 10.2% (69/677) experienced serious adverse events including 24 deaths (3.5%), 11 of which occurred during treatment. 83.3% (20/24) of deaths were not related to TB or TB treatment. Of patients who were successfully treated and completed 12-month follow-up, 0.5% (2/383) had recurrence.
CONCLUSIONS
BPaL-based regimens for MDR/RR-TB and pre–XDR-TB are safe and highly effective in non-trial settings. These regimens should be considered for widespread implementation globally, and further research is needed to evaluate their performance in other key populations.
BACKGROUND
While the relationship between conflict-associated injuries and antimicrobial resistance is increasingly being elucidated, data concerning civilian casualties is sparse. This systematic review assesses literature focused on Global Antimicrobial Resistance Surveillance System (GLASS) Priority Pathogens causing infections in civilian wounds and burns in conflict-affected countries within the World Health Organisation's Eastern Mediterranean Region Office (EMRO)
METHODS
A systematic literature review was conducted following Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Five databases and grey literature were searched, identifying studies published from January 2010 to June 2024. Search terms included "wounds", "burns," "antimicrobial resistance", and the twelve countries of interest. Included studies reported resistance of GLASS pathogens. Two reviewers used Covidence to assess papers for inclusion. Data were extracted into a spreadsheet for analysis. Where quantitative data were available, medians, interquartile ranges and percentages were calculated by pathogen and country.
RESULTS
621 records were identified; 19 studies met inclusion criteria. Nine of the papers were from Iraq, three from Libya, three from Lebanon, one each from Yemen and Gaza; two reported on conflict affected refugees in Jordan. A total of 1,942 distinct microbiological isolates were reported, representing all four critical and high priority GLASS pathogen categories. Among the isolates, Staphylococcus aureus was the most prevalent (36.3%). Median resistances identified: Methicillin resistant Staphylococcus aureus (n = 680): 55.6% (IQR:49.65-90.3%); carbapenem resistant Pseudomonas aeruginosa (n = 372): 22.14% (7.43-52.22%); carbapenem resistant Acinetobacter baumannii (n = 366): 60.3% (32.1-85%); carbapenem resistant Klebsiella pneumoniae (n = 75): 12.65% (9.73-34.25%); ceftriaxone resistant Escherichia coli (n = 63): 76% (69-84.65%); ceftriaxone resistant Klebsiella pneumoniae (n = 40): 81.45% (76.73-86.18%). Only three studies had a low risk of bias.
DISCUSSION
Findings imply high rates of GLASS priority pathogens among wounded civilians in conflict-affected EMRO countries. However, evidence was heterogeneous, low quality and sparse in certain countries, highlighting the necessity of effective surveillance including standardised data collection. Improving primary data will facilitate the production of large, high-quality studies throughout the EMRO, including under-represented countries.
Conclusion: Laboratory diagnostic capacity building and improved surveillance in conflict-affected settings in the Eastern Mediterranean Region are required to assess the burden of GLASS priority pathogens in vulnerable non-combatant populations.
BACKGROUND
For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.
METHODS
We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points.
RESULTS
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.
CONCLUSIONS
Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).
INTRODUCTION
Despite global surveillance efforts, antibiotic resistance (ABR) is difficult to address in low- and middle-income countries (LMICs). In the absence of country-wide ABR surveillance data, peer-reviewed literature is the next most significant source of publicly available ABR data. Médecins Sans Frontières conducted this review in hopes of using the pooled findings to inform treatment choices in the studied countries where sufficient local ABR data are unavailable.
METHODS
A systematic literature review reporting ABR rates for six infection sites in nine countries in the Middle East and Southern Asia was conducted. PubMed was used to identify literature published between January 2012 and August 2022. A meta-analysis of the included studies (n = 694) was conducted, of which 224 are reviewed in this paper. The JBI critical appraisal tool was used to evaluate risk of bias for included studies.
RESULTS
This paper focuses on sepsis, burns and wound infections, specifically, with the largest number of papers describing data from Iran, Türkiye and Pakistan. High (>30%) resistance to recommended first-line antibiotics was found. Gram-negative resistance to ceftriaxone, aminoglycosides and carbapenems was high in burn-related infections; colistin resistance among Klebsiella pneumoniae isolates in Pakistan was alarmingly high (81%).
CONCLUSIONS
High-quality data on ABR in LMIC settings remain difficult to obtain. While peer-reviewed literature is a source of publicly available ABR data, it is of inconsistent quality; the field also lacks agreed reporting standards, limiting the capacity to pool findings. Nonetheless, high resistance to first-line antibiotics underscores the need for improved localized surveillance and stewardship.