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Some anti-mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life-threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE-PEOPLE trial evaluating the safety of bedaquiline-enhanced post-exposure prophylaxis (bedaquiline and rifampicin, BE-PEP, versus rifampicin, SDR-PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post-exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L-ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L-ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L-ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: To achieve zero leprosy cases in Santa Cruz, Bolivia, we designed a community-based active detection and provision of single-dose rifampicin post-exposure prophylaxis (SDR-PEP) to household contacts with new leprosy patients., Methods: From July to August 2021, we assessed the current knowledge, attitude, and practices through structured interviews and focus group discussions with community representatives and health staff. This was followed by sensitization sessions, the training of health staff, and the reinforcement of referral mechanisms. Teams, including health staff and community volunteers, visited all new leprosy patients detected in 2021-2023 and household contacts., Results: Among 115 community representatives, knowledge about leprosy etiology was attributed to non-biological factors (74%); fear accounted for 77%, and access to care was perceived as weak (74%), but the outlook was improved by SDR-PEP (80%). Among the 217 health staff interviewed, the programmatic barriers identified were a lack of referral feedback (67%), limited supplies for diagnosis and prevention, and ineffective training (64%). We visited 70 new patients and 258 household contacts. The median age in household contacts was 25 years old; 49% were women, 98% were eligible for SDR-PEP, and all who were eligible accepted it. Those who were non-eligible included one tuberculosis patient and six newly detected leprosy patients (23‱)., Conclusions: A community-based intervention was successful in Santa Cruz, Bolivia. Misbeliefs and a lack of knowledge were identified as barriers. Programmatic components should be reinforced for SDR-PEP extension.

Introduction: Senegal is a leprosy low-endemic country with nine villages known to be hyperendemic with a leprosy incidence rate above 1,000 per million inhabitants. We aim to implement a door-to-door screening strategy associated with the administration of a single-dose-rifampicin (SDR) as post-exposure prophylaxis (PEP) to household and social contacts in these villages and to identify spatial clustering and assess the risk of leprosy in population according to the physical distance to the nearest index-case., Methods: From October/2020 to February/2022 active door-to-door screening for leprosy was conducted in nine villages. Using an open-source application, we recorded screening results, demographic and geographic coordinate's data. Using Poisson model we analysed clustering and estimated risk of contracting leprosy in contacts according to the distance to the nearest new leprosy patient., Results: In nine villages, among 9086 contacts listed, we examined 7115. Among 6554 eligible contacts, 97.8% took SDR. We found 39(0.64%) new leprosy cases among 6,124 examined in six villages. Among new cases, 21(53.8%) were children, 10(25.6%) were multibacillary and 05(12.8%) had grade 2 disability. The prevalent risk ratio and 95% confidence intervale(95%CI) adjusted by village were 4.2(95%CI 1.7-10.1), 0.97(95%CI 0.2-4.4), 0.87(95%CI 0.2-25), 0.89(95%CI 0.3-2.6) and 0.70(95%CI 0.2-2.5) for the contacts living in the same household of an index case, 1-25m, 26-50m, 51-75m and 76-100m compared to those living at more than 100m respectively. We identified nine high prevalent clusters including 27/39(69%) of new cases in 490/7,850(6%) inhabitants, with relative risks of 46.6(p-value = 0.01), and 7.3, 42.8, 8.2, 12.5, 11.4, 23.5, 22.3, and 14.6 (non-significant p-values)., Conclusions: Our strategy has proved the feasibility of active screening for leprosy in contacts and the introduction of PEP for leprosy under programmatic conditions. Only individuals living in the same household as the leprosy patient had a significant risk of contracting leprosy. We documented nine clusters of leprosy that could benefit from tailored control activities while optimizing resources., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Batista et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Patients with TB resistant to rifampicin (Rr-TB), and those with additional resistance to fluoroquinolones (pre-XDR-TB), should be treated with bedaquiline-pretomanid-linezolid-moxifloxacin and bedaquiline-pretomanid-linezolid, respectively. However, pretomanid is not yet widely available., Methods: This is a pragmatic prospective single-arm study investigating the efficacy and safety of 9 mo of bedaquiline-delamanid-linezolid-clofazimine in patients with pre-XDR-TB or Rr-TB unresponsive to Rr-TB treatment in Nigeria., Results: From January 2020 to June 2022, 14 of 20 patients (70%) successfully completed treatment, five died and one was lost-to-follow-up. No one experienced a treatment-emergent grade three/four event. Treatment success was higher compared with global pre-XDR-TB treatment outcomes., Conclusions: While pretomanid is unavailable, highly resistant TB can be treated with bedaquiline-delamanid-linezolid-clofazimine., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Leprosy is an infectious neglected tropical disease, which can cause irreversible disabilities if not diagnosed in time. Colombia continues to show high rates of leprosy-related disability, mainly due to a delay in diagnosis. Limited knowledge is available that explains this delay, therefore our study aimed to explore the perceptions and experiences of leprosy health professionals with the delay in leprosy diagnosis in the Cesar and Valle del Cauca departments, Colombia. Nine semi-structured expert interviews with leprosy health professionals were conducted in May-June 2023 in Colombia. Thematic analysis was performed to analyse the interview results. Our analysis highlighted that the main reasons for delay at the health system-level included accessibility issues to obtain a diagnosis, lack of expertise by health staff, and barriers related to the organisation of the care pathway. Individual - and community-level factors included a lack of leprosy awareness among the general population and leprosy-related stigma. Diagnostic delay consists of a fluid interplay of various factors. Structural changes within the health system, such as organising integral leprosy care centres and highlighting leprosy in the medical curriculum, as well as awareness-related interventions among the general population, might help reducing diagnostic delays.

Directly observed treatment (DOT) for tuberculosis (TB) is recommended by the World Health Organization. However, DOT does not always meet patients' preferences, burdens health facilities, and is hard to implement in settings where access to healthcare services is regularly interrupted. A model addressing these limitations of DOT is community-supported self-administered treatment (CS-SAT), in which patients who self-administer TB treatment receive regular visits from community members. Guinea is a country with a high TB burden, recurrent epidemics, and periodic socio-political unrest. We piloted a CS-SAT model for drug-susceptible TB patients in Conakry, led by community volunteers, who also conducted active TB case finding among household contacts and referrals for isoniazid preventive treatment (IPT) in children below 5 years old. We aimed to assess TB treatment outcomes of patients on CS-SAT and describe the number of patients identified with TB case finding and IPT provision. Prospectively enrolled bacteriologically confirmed TB patients, presenting to two facilities, received monthly TB medication. Community volunteers performed bi-weekly (initiation phase) and later monthly (continuation phase) home visits to verify treatment adherence, screen household contacts for TB, and assess IPT uptake in children under five. Among 359 enrolled TB patients, 237 (66.0%) were male, and 37 (10.3%) were HIV-positive. Three hundred forty (94.7%) participants had treatment success, seven (1.9%) died, seven (1.9%) experienced treatment failure, and five (1.4%) were lost-to-follow-up. Among 1585 household contacts screened for TB, 26 (1.6%) had TB symptoms, of whom five (19.2%) were diagnosed with pulmonary TB. IPT referral was done for 376 children from 198 households. In a challenging setting, where DOT is often not feasible, CS-SAT led to successful TB treatment outcomes and created an opportunity for active TB case finding and IPT referral. We recommend the Guinean CS-SAT model for implementation in similar settings.

Background: Pulmonary tuberculosis (PTB) diagnosis relies on sputum examination, a challenge in sputum-scarce patients. Alternative non-invasive sampling methods such as face mask sampling (FMS) have been proposed., Objective: To evaluate the value of FMS for PTB diagnosis by assessing its agreement with sputum samples processed by GeneXpert MTB/RIF (Ultra)(Xpert) testing, and describe FMS sensitivity and specificity., Methods: This was a prospective study conducted at the Carrière TB clinic in Guinea. Presumptive TB patients willing to participate were asked to wear a surgical mask containing a polyvinyl alcohol (PVA) strip for thirty minutes. Subsequently, two spot sputum samples were collected, of which one was processed by microscopy on site and the other by Xpert in Guinea's National Reference Laboratory of Mycobacteriology (LNRM). The first 30 FMS were processed at the Supranational Reference Laboratory in Antwerp, Belgium, and the following 118 FMS in the LNRM., Results: One hundred fifty patients participated, of whom 148 had valid results for both mask and sputum. Sputum smear microscopy was positive for 47 (31.8%) patients while sputum-Xpert detected MTB in 54 (36.5%) patients. Among the 54 patients testing sputum-Xpert positive, 26 (48.1%) yielded a positive FMS-Xpert result, while four sputum-Xpert negative patients tested positive for FMS and 90 patients were Xpert-negative for both sputum and mask samples, suggesting a moderate level of agreement (k-value of 0.47). The overall mask sensitivity was 48.1%, with 95.7% specificity., Conclusion: In our setting, Xpert testing on FMS did not yield a high level of agreement to sputum sample., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Patients with multidrug-resistant tuberculosis (MDR-TB) who have comorbidities, complications, and experience serious adverse events (SAEs) are at substantial risk of having unfavorable hospital outcomes. We assessed characteristics and discharge outcomes of 138 MDR-TB patients hospitalized in the National Referral Center of Bishkek, Kyrgyz Republic, from January 2020 to August 2022. The main clinical characteristics included pulmonary complications (23%), malnutrition (33%), severe anemia (17%), diabetes mellitus (13%), viral hepatitis B and C (5%), and HIV infection (3%). Of those patients, 95% were successfully managed and discharged from hospital. Seven patients had unfavorable discharge outcomes (three patients died and four had a worsened clinical condition). Comorbidities (diabetes, and/or HIV), severe anemia, pulmonary complications, cardiovascular disorders, alcohol abuse, and SAEs were associated with unfavorable discharge outcomes. Sixty-five percent of the patients had SAEs, with electrolyte imbalance (25%), gastrointestinal disease (18%), hepatotoxicity (16%), and anemia (14%) being the most frequent. Successful resolution occurred in 91% of patients with SAEs. In summary, our study documented that sick patients who were hospitalized with MDR-TB were well managed and had good hospital discharge outcomes, despite the fact that they had comorbidities, complications, and SAEs. This information should assist in the referral and management of such patients in the future.

Background: Outcomes of retreatment for rifampicin-resistant tuberculosis (RR-TB) are rarely reported. We report 'definitive outcomes' after a cascade approach to RR-TB treatment. After a bacteriologically adverse outcome for the 9-months fluoroquinolone-based Short Treatment Regimen (STR), patients were retreated with a bedaquiline-based regimen (BDQ-regimen)., Methods: A Retrospective cohort study of RR-TB patients treated with the STR during 2012-2019 and retreated with a BDQ-regimen in case of failure or relapse was conducted. Definitive relapse-free cure took into account BDQ-regimen outcomes., Results: Of 367 patients treated with the STR, 20 (5.4%) experienced failure or relapse. Out of these 20 patients, 14 started a BDQ-regimen, of whom none experienced failure or relapse. Definitive end of treatment outcomes of STR after revising with third-line BDQ-regimen outcomes, 84.7% (311/367) were cured relapse-free, 10.6% (39/367) died during treatment and 3.0% (11/367) were lost to follow-up during treatment with either the STR or BDQ-regimen. Six patients (1.6%; 6/367) with STR failure/relapse died before starting a BDQ-regimen. No patient had definitive treatment failure or relapse and remained without treatment., Conclusions: If fluoroquinolone resistance is excluded or rare, it is beneficial to use fluoroquinolone as the core drug for a first RR-TB treatment regimen and to safeguard bedaquiline for those in need of retreatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Objective: Colistin is an antibiotic of last resort for treating serious Gram-negative bacterial infections. However, the misuse of colistin, especially as an animal growth promoter, has contributed to increasing antimicrobial resistance, mediated mainly through plasmid transfer of the mcr-1 gene. This study assessed the prevalence of phenotypic and molecular colistin resistance in Escherichia coli and Klebsiella pneumoniae in Ecuador in healthy humans and their chickens and pigs., Methods: Fecal samples were collected from humans and their chickens and pigs in two rural coastal and Amazon regions between April and August 2020. Gram-negative bacteria were isolated and identified using conventional techniques. Phenotypic resistance was determined using the broth microdilution technique, and the mcr-1 gene was detected using conventional polymerase chain reaction., Results: A total of 438 fecal samples were obtained from 137 humans, 147 pigs and 154 chickens. The prevalence of E. coli isolates was 86.3% (378/438) and K. pneumoniae , 37.4% (164/438). Overall, the mcr-1 gene was found in 90% (340/378) of E. coli isolates, with higher prevalences found in isolates from coastal regions (96.5%, 191/198), humans (95.6%, 111/116) and chickens (91.8%, 123/134); for K. pneumoniae , the gene was found in 19.5% (32/164) of isolates, with equal distribution between regions and hosts. Only four isolates, two E. coli and two K. pneumoniae , showed phenotypic resistance: mcr-1 was present in both E. coli strains but absent in the K. pneumoniae strains., Conclusions: Despite a low prevalence of phenotypic resistance to colistin, the high prevalence of the mcr-1 gene in E. coli is of concern. Ecuador's ban on using colistin in animal husbandry must be enforced, and continual monitoring of the situation should be implemented.

Whole-genome sequencing is becoming the gold standard for pathogen characterization and offers considerable advantages for understanding the evolution and dissemination of new determinants of antimicrobial resistance. Despite the benefits of whole-genome sequencing for pathogen characterization, implementation costs and lack of expertise may limit its use by public health laboratories. This article reviews the advantages of whole-genome sequencing for pathogen characterization and the current status of the use of whole-genome sequencing for antimicrobial resistance surveillance in Ecuador. A roadmap is suggested for including whole-genome sequencing for pathogen characterization based on the needs of the health reference institutions through alliances with Ecuadorian universities. Establishing a partnership between public health institutions and academia would be valuable for clinicians, policy-makers, and epidemiologists who could then take reasonable measures in those areas and establish a basis for adapting One Health strategies to tackle antimicrobial resistance in Ecuador.

The importance of the One Health concept in attempting to deal with the increasing levels of multidrug-resistant bacteria in both human and animal health is a challenge for the scientific community, policymakers, and the industry. The discovery of the plasmid-borne mobile colistin resistance ( mcr ) in 2015 poses a significant threat because of the ability of these plasmids to move between different bacterial species through horizontal gene transfer. In light of these findings, the World Health Organization (WHO) recommends that countries implement surveillance strategies to detect the presence of plasmid-mediated colistin-resistant microorganisms and take suitable measures to control and prevent their dissemination. Seven years later, ten different variants of the mcr gene ( mcr-1 to mcr-10 ) have been detected worldwide in bacteria isolated from humans, animals, foods, the environment, and farms. However, the possible transmission mechanisms of the mcr gene among isolates from different geographical origins and sources are largely unknown. This article presents an analysis of whole-genome sequences of Escherichia coli that harbor mcr-1 gene from different origins (human, animal, food, or environment) and geographical location, to identify specific patterns related to virulence genes, plasmid content and antibiotic resistance genes, as well as their phylogeny and their distribution with their origin. In general, E. coli isolates that harbor mcr-1 showed a wide plethora of ARGs. Regarding the plasmid content, the highest concentration of plasmids was found in animal samples. In turn, Asia was the continent that led with the largest diversity and occurrence of these plasmids. Finally, about virulence genes, terC, gad, and traT represent the most frequent virulence genes detected. These findings highlight the relevance of analyzing the environmental settings as an integrative part of the surveillance programs to understand the origins and dissemination of antimicrobial resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Calero-Cáceres, Rodríguez, Medina, Medina, Ortuño-Gutiérrez, Sunyoto, Dias, Bastidas-Caldes, Ramírez and Harries.)

Background: Rifampicin-resistant tuberculosis (RR-TB) treatment requires combination treatment, which frequently causes serious adverse events and globally results in not much more than 60% treatment success. In Niger, a high cure rate was obtained with a RR-TB treatment strategy based on a second-line injectable drug (SLID)-containing Short Treatment Regimen (STR), with linezolid replacing the SLID in patients with ototoxicity. Given the availability of novel anti-tuberculosis drugs, WHO recommends all-oral RR-TB treatment. Considering the high level of success with the Niger treatment strategy, it would only be justified to replace it in case robust evidence shows that the WHO all-oral bedaquiline/linezolid (BDQ/LZD)-containing STR (experimental arm) performs better than the Niger RR-TB treatment strategy, (control arm) in terms of safety, effectiveness and adherence., Methods: A pragmatic randomised clinical trial (RCT) using stratified block randomisation, conducted between April 2021 and March 2024, prospectively enrols participants diagnosed with RR-TB in one of the four RR-TB units of the nation. Depending of the month in which patients are diagnosed with RR-TB, patients with FQ-susceptible RR-TB are enrolled in either the experimental arm or control arm., Discussion: To increase the feasibility of conducting a RCT, embedded in routine activities of all Niger's RR-TB Units, we used a creative trial design. We randomised by monthly blocks, whereby the regimen used changes every month, using the month of RR-TB diagnosis as stratifying variable. This approach was deemed feasible for Niger's national tuberculosis programme, as it simplifies the work of the clinicians running the RR-TB units. Our creative design may serve as an example for other national programs. Findings will inform national and international RR-TB treatment guidelines, and will also strengthen the evidence-base on how to develop robust RR-TB treatment regimens., Trial Registration: Pan African Clinical Trial Register PACTR202203645724919 . Registered on 15 March 2022., (© 2022. The Author(s).)

The standard of care for cutaneous leishmaniasis includes the intramuscular/intravenous administration of pentavalent antimonials that are toxic and poorly tolerated. Primary health care usually lacks trained health staff for the diagnosis and treatment of leishmaniasis in Cochabamba Bolivia. Taking these aspects into account, a Bolivian consortium set out to explore the intralesional administration of meglumine antimoniate to treat cutaneous leishmaniasis during primary care under programmatic conditions. A four-step strategy consisting of clinical training for intralesional treatment and the promotion and periodic follow-up of health staff was carried out. The training process was applied in situ to personnel of nine primary health care centres. The intralesional treatment was applied five times every other day. Clinical follow-up after six-months of treatment showed a 77% healing proportion and 5% of therapeutic failure among 152 enrolled patients. The drug volume used in the intralesional procedure was on average 1.7 mL/ulcer treated. In conclusion, the strategy used was successful and effective, accomplishing a healing proportion similar to the long standardized treatment with a reduced time of administration, no severe side effects, and it is feasible to conduct by trained health staff. Our study supports the current PAHO/WHO recommendation for the intralesional administration of pentavalent antimonials for the treatment of cutaneous leishmaniasis.

Background: In India, leprosy clusters at hamlet level but detailed information is lacking. We aim to identify high-incidence hamlets to be targeted for active screening and post-exposure prophylaxis., Methodology: We paid home visits to a cohort of leprosy patients registered between April 1st, 2020, and March 31st, 2022. Patients were interviewed and household members were screened for leprosy. We used an open-source app(ODK) to collect data on patients' mobility, screening results of household members, and geographic coordinates of their households. Clustering was analysed with Kulldorff's spatial scan statistic(SaTScan). Outlines of hamlets and population estimates were obtained through an open-source high-resolution population density map(https://data.humdata.org), using kernel density estimation in QGIS, an open-source software., Results: We enrolled 169 patients and screened 1,044 household contacts in Bisfi and Benipatti blocks of Bihar. Median number of years of residing in the village was 17, interquartile range(IQR)12-30. There were 11 new leprosy cases among 658 household contacts examined(167 per 10,000), of which seven had paucibacillary leprosy, one was a child under 14 years, and none had visible disabilities. We identified 739 hamlets with a total population of 802,788(median 163, IQR 65-774). There were five high incidence clusters including 12% of the population and 46%(78/169) of the leprosy cases. One highly significant cluster with a relative risk (RR) of 4.7(p<0.0001) included 32 hamlets and 27 cases in 33,609 population. A second highly significant cluster included 32 hamlets and 24 cases in 33,809 population with a RR of 4.1(p<0.001). The third highly significant cluster included 16 hamlets and 17 cases in 19,659 population with a RR of 4.8(p<0.001). High-risk clusters still need to be screened door-to-door., Conclusions: We found a high yield of active household contact screening. Our tools for identifying high-incidence hamlets appear effective. Focusing labour-intensive interventions such as door-to-door screening on such hamlets could increase efficiency., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Nimer Ortuño-Gutiérrez is employee of Damien Foundation. Aashish Wagh and Shivakumar Mugudalabetta are employees of Damien Foundation India Trust.

Competing Interests: The authors have declared that no competing interests exist.

Objectives: To identify patterns of spatial clustering of leprosy., Design: We performed a baseline survey for a trial on post-exposure prophylaxis for leprosy in Comoros and Madagascar. We screened 64 villages, door-to-door, and recorded results of screening, demographic data and geographic coordinates. To identify clusters, we fitted a purely spatial Poisson model using Kulldorff's spatial scan statistic. We used a regular Poisson model to assess the risk of contracting leprosy at the individual level as a function of distance to the nearest known leprosy patient., Results: We identified 455 leprosy patients; 200 (44.0%) belonged to 2735 households included in a cluster. Thirty-eight percent of leprosy patients versus 10% of the total population live ≤25 m from another leprosy patient. Risk ratios for being diagnosed with leprosy were 7.3, 2.4, 1.8, 1.4 and 1.7, for those at the same household, at 1-<25 m, 25-<50 m, 50-<75 m and 75-<100 m as/from a leprosy patient, respectively, compared to those living at ≥100 m., Conclusions: We documented significant clustering of leprosy beyond household level, although 56% of cases were not part of a cluster. Control measures need to be extended beyond the household, and social networks should be further explored., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The short treatment regimen (STR) achieves a >80% cure in rifampicin-resistant tuberculosis (RR-TB) patients. However, ototoxicity induced by the injectable is a concern. This is the first study to evaluate the replacement of injectables by linezolid in patients with audiometry abnormalities at baseline or during the treatment.We conducted a retrospective cohort study of all RR-TB patients started on the STR between 2016 and June, 2019, in Niger. Patients underwent audiometry every 2 months in 2016 and every month since 2017.Of 195 patients, 16.9% (33 out of 195) received linezolid from the start (n=17), or switched from injectables to linezolid during treatment (n=16), based on audiometry abnormalities. In 2016, two patients developed severe ototoxicity despite switching to linezolid. Since 2017, no patient developed severe hearing loss or complete deafness. Severe haematological toxicity was observed in 18.1% (six out of 33) of patients on linezolid, none of which was life threatening. The use of linezolid was associated with severe but manageable adverse events (hazard ratio 8.9, 95% CI 2.5-31.5; p=0.001). A total of 90.9% (30 out of 33) of patients on a linezolid-containing STR were cured, and none experienced treatment failure. Three died, but not due to adverse events.Baseline and monthly audiometry monitoring and using linezolid after detection of hearing abnormalities appears effective to prevent severe ototoxicity, while keeping high treatment success and manageable adverse events., Competing Interests: Conflict of interest: M.B. Souleymane has nothing to disclose. Conflict of interest: A. Piubello has nothing to disclose. Conflict of interest: I.M. Mamane-Lawan has nothing to disclose. Conflict of interest: S. Hassane-Harouna has nothing to disclose. Conflict of interest: M.M. Assao-Neino has nothing to disclose. Conflict of interest: A. Soumana has nothing to disclose. Conflict of interest: Z. Hamidou-Harouna has nothing to disclose. Conflict of interest: A. Gagara-Issoufou has nothing to disclose. Conflict of interest: N. Ortuño-Gutiérez has nothing to disclose. Conflict of interest: A. Roggi has nothing to disclose. Conflict of interest: V. Schwoebel has nothing to disclose. Conflict of interest: S. Mamadou has nothing to disclose. Conflict of interest: L. Lynen has nothing to disclose. Conflict of interest: B. De Jong has nothing to disclose. Conflict of interest: A. Van Deun has nothing to disclose. Conflict of interest: T. Decroo has nothing to disclose., (Copyright ©ERS 2021.)

Background: Since a meta-analysis showed little or no effect of second-line injectables on treatment success, and using injectables may induce ototoxicity, injectable-free rifampicin-resistant tuberculosis (RR-TB) treatment regimens are recommended. However, acquired resistance preventing activity was overlooked. No previous study assessed the effect of shortening the duration of kanamycin administration to 2 months during the intensive phase of the RR-TB shorter treatment regimen (STR)., Methods: Retrospective cohort study of the effect of using 2 months of kanamycin instead of the standard 4(+) months (extension if lack of smear conversion at 4 months) on recurrence (either treatment failure or relapse) and fluoroquinolone acquired drug resistance, in patients treated with a gatifloxacin-based STR in Damien Foundation supported clinics in Bangladesh. Logistic regression was used to estimate associations., Results: Five of 52 (9.6%) treated with a STR containing two months of kanamycin had recurrence, compared to 21 of 738 (2.8%) patients treated with the standard STR containing 4(+) months of kanamycin (OR 3.7; 95%CI:1.5-10.3). In those with initially fluoroquinolone-susceptible TB, acquired resistance to fluoroquinolone was detected in none of 639 patients treated with 4(+) months of kanamycin and two (4.5%) of 44 treated with two months of kanamycin (OR 75.2; 95%CI:3.6-1592.1)., Conclusion: Two months of kanamycin was insufficient to prevent recurrence with acquired resistance to gatifloxacin, the core drug of the most effective RR-TB STR. Injectable mediated resistance prevention is important to reach high effectiveness, to safeguard all treatment options after recurrence, and to prevent the spread of resistant TB. Studies on all-oral regimens should also assess the effect of regimen composition on resistance acquisition. Until evidence shows that other drugs can assure at least the same strong resistance preventing activity of the injectables, it seems wise to continue using this group of drugs, and adapt the regimen if any ototoxicity is detected., Competing Interests: The authors have declared that no competing interests exist.

The introduction of the nine-month short-treatment regimen (STR) has drastically improved outcomes of rifampicin-resistant tuberculosis (RR-TB) treatment. Adverse events (AE) commonly occur, including injectable-induced hearing loss. In Burundi we retrospectively assessed the frequency of adverse events and treatment modifications in all patients who initiated the STR between 2013-2017. Among 225 included patients, 93% were successfully treated without relapse, 5% died, 1% was lost-to-follow-up, 0.4% had treatment failure and 0.4% relapsed after completion. AE were reported in 53%, with grade 3 or 4 AE in 4% of patients. AE occurred after a median of two months. Hepatotoxicity (31%), gastro-intestinal toxicity (22%) and ototoxicity (10%) were most commonly reported. One patient suffered severe hearing loss. Following AE, 7% of patients had a dose reduction and 1% a drug interruption. Kanamycin-induced ototoxicity led to 94% of modifications. All 18 patients with a modified regimen were cured relapse-free. In this exhaustive national RR-TB cohort, RR-TB was treated successfully with the STR. Adverse events were infrequent. To replace the present STR, all-oral regimens should be at least as effective and also less toxic. During and after transition, monitoring, management, and documentation of AE will remain essential.

Background: Meta-analyses on impact of isoniazid-resistant tuberculosis informed the World Health Organization recommendation of a levofloxacin-strengthened rifampicin-based regimen. We estimated the effect of initial rifampicin resistance (Rr) and/or isoniazid resistance (Hr) on treatment failure or relapse. We also determined the frequency of missed initial and acquired Rr to estimate the impact of true Hr., Methods: Retrospective analysis of 7291 treatment episodes with known initial isoniazid and rifampicin status obtained from individual patient databases maintained by the Damien Foundation Bangladesh over 20 years. Drug susceptibility test results were confirmed by the programme's designated supra-national tuberculosis laboratory. To detect missed Rr among isolates routinely classified as Hr, rpoB gene sequencing was done randomly and on a sample selected for suspected missed Rr., Results: Initial Hr caused a large recurrence excess after the 8-month regimen for new cases (rifampicin for two months), but had little impact on rifampicin-throughout regimens: (6 months, new cases; 3.8%; OR 0.8, 95%CI:0.3,2.8; 8 months, retreatment cases: 7.3%, OR 1.8; 95%CI:1.3,2.6). Rr was missed in 7.6% of randomly selected "Hr" strains. Acquired Rr was frequent among recurrences on rifampicin-throughout regimens, particularly after the retreatment regimen (31.9%). It was higher in mono-Hr (29.3%; aOR 3.5, 95%CI:1.5,8.5) and poly-Hr (53.3%; aOR 10.2, 95%CI 4.4,23.7) than in susceptible tuberculosis, but virtually absent after the 8-month new case regimen. Comparing Bangladesh (low Rr prevalence) with a high Rr prevalence setting,true Hr corrected for missed Rr caused only 2-3 treatment failures per 1000 TB cases (of whom 27% were retreatments) in both., Conclusions: Our analysis reveals a non-negligible extent of misclassifying as isoniazid resistance of what is actually missed multidrug-resistant tuberculosis. Recommending for such cases a "strengthened" regimen containing a fluoroquinolone provokes a direct route to extensive resistance while offering little benefit against the minor role of true Hr tuberculosis in rifampicin-throughout first-line regimen., Competing Interests: The authors have declared that no competing interests exist.

Background: In Niger, the Shorter Treatment Regimen (STR) has been implemented nationwide for rifampicin resistant tuberculosis (RR-TB), since 2008. No previous publication has shown the results from countrywide programmatic implementation using few exclusion criteria, nor exhaustively assessed the effect of initial resistance to companion drugs on outcomes., Methods: The National Tuberculosis Programme and the Damien Foundation conducted a retrospective observational study to evaluate the management of RR-TB from 2008 to 2016. Baseline resistance to drugs was assessed phenotypically, complemented by screening the inhA, katG and pncA genes. Cured patients were followed-up for a period of one year after cure., Findings: Among 1044 patients tested for rifampicin resistance, mainly previously treated patients, 332 were diagnosed with pulmonary RR/TB, 288 were enrolled on treatment and 255 started on STR. Six patients received a modified STR. Among 249 patients on standardised STR, 207 (83·1%) were cured relapse-free, eight (3·2%) had failure, 23 (9·2%) died, seven (2·8%) were lost to follow-up and four (1·6%) relapsed. The risk of unfavourable outcome was higher in patients with initial resistance to fluoroquinolones (aOR 20·4, 95%CI:5·6-74·6) and very severely underweight (aOR 3·9, 95%CI:1·5-10·1). Successful outcome was not affected by initial resistance to companion drugs. Serious ototoxicity was reported in eight patients (3·2%)., Interpretation: A comprehensive nationwide approach to multidrug-resistant tuberculosis management using the STR was feasible and successful. Outcomes were not affected by initial resistance to companion drugs. Our study confirms the effectiveness and safety of the STR., Funding: Damien Foundation and Institute of Tropical Medicine-Antwerp., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)