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
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.
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.
BACKGROUND
The history of conflicts in the Middle East has resulted in a high burden of complications from conflict-related wounds like posttraumatic osteomyelitis (PTO). This is particularly challenging to manage in settings like Mosul, Iraq and Gaza, Palestine, where healthcare systems are weakened. In nonconflict settings, PTO caused by Pseudomonas aeruginosa (PAPTO) can lead to >20% of treatment failures. We aim to describe the clinical characteristics, outcomes, and management, in PAPTO patients admitted to Médecins Sans Frontières (MSF) facilities in Mosul and Gaza between 1 April 2018 and 31 January 2022.
METHODS
We conducted a retrospective cohort study on patients with PAPTO diagnosed with culture of intraoperative bone biopsy, using routinely collected data.
RESULTS
Among 66 PAPTO episodes from 61 enrolled patients, 37.9% had a multidrug-resistant Pseudomonas aeruginosa, with higher antibiotic resistance in Gaza. Polymicrobial infections were prevalent (74.2%), mainly involving Staphylococcus aureus (74.1%), being predominantly methicillin-resistant (95.0%). Overall, 81.7% received appropriate antibiotic treatment, with monotherapy used in 60.6% of episodes and a median treatment duration of 45.5 days. Recurrence was observed in 24.6% of episodes within a median of 195 days (interquartile range, 64-440 days). No significant differences were found in recurrence rates based on the type of antibiotic treatment (mono- or dual therapy) or episode (mono- or polymicrobial).
CONCLUSIONS
Management of PAPTO in the conflict-affected, low-resource settings of Mosul and Gaza achieved a recurrence rate aligned with global reports through appropriate and targeted antibiotic use, primarily in monotherapy, provided over a mean treatment duration of 45.5 days.
OBJECTIVE
The primary objectives of this study were to assess the usefulness of C-reactive protein (CRP) and procalcitonin (PCT) in the diagnosis of bacterial co-infections in coronavirus disease 2019 (COVID-19) and if their incorporation in antimicrobial stewardship (AMS) programs is safe and useful, stratified by severity of disease as level of care, intensive care unit (ICU) or non-ICU. Our secondary objectives were to identify cut-off values for antibiotic decision-making and identify reported results from low- and middle-income countries (LMICs).
DESDIGN
A scoping review of published literature, adhering to the PRISMA statement for Systematic Reviews and Meta-analyses Extension for Scoping Reviews guidelines. The last search was performed in January 2024.
RESULTS
Fifty-nine studies were included in this scoping review: 20 studies reporting predictive values and/or sensitivity/specificity results for PCT, 8 reporting clear objectives on AMS, and 3 studies from LMICs.
CONCLUSION
In the context of non-ICU hospitalized COVID-19 patients in high-income countries, a PCT value below 0.25 mg/L can be a useful tool to rule out bacterial co-infection. The wide range of reported negative predictive values suggests that PCT should be interpreted in the context of other clinical findings. Our results do not support the use of CRP in the same manner as PCT. There is a clear need for more studies in LMICs.