"Caught In Each Other's Traps": Factors Perpetuating Incentive-Linked Prescribing Deals Between Physicians and the Pharmaceutical Industry.

BACKGROUND: Despite known adverse impacts on patients and health systems, 'incentive-linked prescribing', which describes the prescribing of medicines that result in personal benefits for the prescriber, remains a widespread and hidden impediment to quality of healthcare. We investigated factors perpetuating incentive-linked prescribing among primary care physicians in for-profit practices (referred to as private doctors), using Pakistan as a case study. METHODS: Our mixed-methods study synthesised insights from a survey of 419 systematically samples private doctors and 68 semi-structured interviews with private doctors (n=28), pharmaceutical sales representatives (n=12), and provincial and national policy actors (n=28). For the survey, we built a verified database of all registered private doctors within Karachi, Pakistan's most populous city, administered an electronic questionnaire in-person and descriptively analysed the data. Semi-structured interviews incorporated a vignette-based exercise and data was analysed using an interpretive approach. RESULTS: Our survey showed that 90% of private doctors met pharmaceutical sales representatives weekly. Three interlinked factors perpetuating incentive-linked prescribing we identified were: gaps in understanding of conflicts of interest and loss of values among doctors; financial pressures on doctors operating in a (largely) privately financed health-system, exacerbated by competition with unqualified healthcare providers; and aggressive incentivisation by pharmaceutical companies, linked to low political will to regulate and an over-saturated pharmaceutical market. CONCLUSION: Regular interactions between pharmaceutical companies and private doctors are normalised in our study setting, and progress on regulating these is hindered by the substantial role of incentive-linked prescribing in the financial success of physicians and the pharmaceutical industry employees. A first step towards addressing the entrenchment of incentive-linked prescribing may be to reduce opposition to restrictions on incentivisation of physicians from stakeholders within the pharmaceutical industry, physicians themselves, and policymakers concerned about curtailing growth of the pharmaceutical industry.

Genomic analysis of clinical Aeromonas isolates reveals genetic diversity but little evidence of genetic determinants for diarrhoeal disease.

Aeromonas spp. are associated with a number of infectious syndromes in humans including gastroenteritis and dysentery. Our understanding of the genetic diversity, population structure, virulence determinants and antimicrobial resistance of the genus has been limited by a lack of sequenced genomes linked to metadata. We performed a comprehensive analysis of the whole genome sequences of 447 Aeromonas isolates from children in Karachi, Pakistan, with moderate-to-severe diarrhoea (MSD) and from matched controls without diarrhoea that were collected as part of the Global Enteric Multicenter Study (GEMS). Human-associated Aeromonas isolates exhibited high species diversity and extensive antimicrobial and virulence gene content. Aeromonas caviae, A. dhankensis, A. veronii and A. enteropelogenes were all significantly associated with MSD in at least one cohort group. The maf2 and lafT genes that encode components of polar and lateral flagella, respectively, exhibited a weak association with isolates originating from cases of gastroenteritis.

Aetiology and use of antibiotics in pregnancy-related infections: results of the WHO Global Maternal Sepsis Study (GLOSS), 1-week inception cohort.

BACKGROUND: Pregnancy-related infections are important contributors to maternal sepsis and mortality. We aimed to describe clinical, microbiological characteristics and use of antibiotics by source of infection and country income, among hospitalized women with suspected or confirmed pregnancy-related infections. METHODS: We used data from WHO Global Maternal Sepsis Study (GLOSS) on maternal infections in hospitalized women, in 52 low-middle- and high-income countries conducted between November 28th and December 4th, 2017, to describe the frequencies and medians of maternal demographic, obstetric, and clinical characteristics and outcomes, methods of infection diagnosis and causative pathogens, of single source pregnancy-related infection, other than breast, and initial use of therapeutic antibiotics. We included 1456 women. RESULTS: We found infections of the genital (n = 745/1456, 51.2%) and the urinary tracts (UTI) (n = 531/1456, 36.5%) to be the most frequent. UTI (n = 339/531, 63.8%) and post-caesarean skin and soft tissue infections (SSTI) (n = 99/180, 55.0%) were the sources with more culture samples taken and microbiological confirmations. Escherichia coli was the major uropathogen (n = 103/118, 87.3%) and Staphylococcus aureus (n = 21/44, 47.7%) was the commonest pathogen in SSTI. For 13.1% (n = 191) of women, antibiotics were not prescribed on the same day of infection suspicion. Cephalosporins (n = 283/531, 53.3%) were the commonest antibiotic class prescribed for UTI, while metronidazole (n = 303/925, 32.8%) was the most prescribed for all other sources. Ceftriaxone with metronidazole was the commonest combination for the genital tract (n = 98/745, 13.2%) and SSTI (n = 22/180, 12.2%). Metronidazole (n = 137/235, 58.3%) was the most prescribed antibiotic in low-income countries while cephalosporins and co-amoxiclav (n = 129/186, 69.4%) were more commonly prescribed in high-income countries. CONCLUSIONS: Differences in antibiotics used across countries could be due to availability, local guidelines, prescribing culture, cost, and access to microbiology laboratory, despite having found similar sources and pathogens as previous studies. Better dissemination of recommendations in line with antimicrobial stewardship programmes might improve antibiotic prescription.

What happens when private general practitioners receive incentivisation offers from pharmaceutical sales representatives? A qualitative study in Pakistan.

OBJECTIVES: Pharmaceutical incentivisation of physicians for profit maximisation is a well-documented health system challenge. This study examined general practitioners' (GPs) reactions to pharmaceutical incentivisation offers in one region in Pakistan. METHODS: We used the Standardised Pharmaceutical Sales Representative (SPSR) method and qualitative interviews with GPs. SPSRs were field researchers representing mock pharmaceutical companies who recorded their observations of 267 GPs' responses to pharmaceutical incentivisation offers. We triangulated SPSR data using qualitative interviews with a subset of the same GPs to gather information about how they interpreted different interaction outcomes. RESULTS: We found four major outcomes for GPs being offered incentives by pharmaceutical companies for prescribing medications. GPs might agree to make incentivisation deals, reject incentivisation offers, disallow PSRs to access them, or remain indeterminate with no clear indication of acceptance or rejection of incentivisation offers. GPs rejecting SPSRs' incentivisation offers indicated having active commitments to other pharmaceutical companies, not being able to work with unheard-of companies, and asking SPSRs to return later. CONCLUSIONS: The GP-pharmaceutical sales representative interaction that centres on profit-maximisation is complex as offers to engage in prescribing for mutual financial benefit are not taken up immediately. The SPSR method helps understand the extent of distortion of practices impacted by incentivisation. Such an understanding can support the development of strategies to control unethical behaviours.

Strain features of pneumococcal isolates in the pre- and post-PCV10 era in Pakistan.

Pakistan is amongst the four countries with the highest number of pneumococcal deaths. While the PCV10 vaccine was introduced in Pakistan in October 2012, data regarding the impact of the vaccine on the population dynamics of Streptococcus pneumoniae in Pakistan remain obscure. Using whole genome sequencing of 190 isolates (nasopharyngeal carriage=75, disease=113, unknown sites=2) collected between 2002 and 2020, this study presents characteristics of pneumococcal strains in Pakistan in the pre- and post-vaccine era. The isolates were characterized on the basis of serotype distribution, genetic lineages (or Global Pneumococcal Sequence Cluster, GPSC) and antibiotic resistance. A high level of diversity in serotype and genetic lineages of pneumococci was observed in Pakistan. Among 190 isolates, we identified 54 serotypes, 67 GPSCs and 116 sequence types (STs) including 23 new STs. The most prevalent GPSCs and their associated serotypes in nasopharyngeal carriage were GPSC54 (expressing serotype 9V), GPSC5 (15A and 7B, and serogroup 24), GPSC25 (15B/15C), GPSC67 (18C) and GPSC376 (6A and 6D). Similarly, among 113 disease-causing isolates, the most prevalent GPSC/serotype combinations were GPSC2 (serotype 1), GPSC10 (serotypes 14, 10A, 19A and 19F), GPSC43 (serotypes 13, 11A, 23B, 35A and 9V), GPSC67 (serotypes 18A and 18C) and GPSC642 (serotype 11A). Of the 190 isolates, the highest levels of resistance were observed against penicillin (58.9 %, n=122), erythromycin (29.5 %, n=56), clindamycin (13.2 %, n=25), co-trimoxazole (94.2 %, n=179) and tetracycline/doxycycline (53.2 %, n=101). A higher proportion of disease-causing isolates were multidrug resistant as compared to carriage isolates (54 % vs 25 %). Our data suggest limited coverage of PCV10 in nasopharyngeal (21.6 %, 16/74) as well as disease-causing (38.1 %, 16/42) isolates among children ≤5 years old; however, higher valent vaccine PCV13 would increase the coverage rates to 33.8 % in nasopharyngeal and 54.8 % in disease-causing isolates, whereas PCV24/25 would offer the highest coverage rates. Owing to the diversity of serotypes observed during the post-vaccine period, the suggested inclusion of serotype in future vaccine formulations will require investigations with larger data sets with an extended temporal window. This article contains data hosted by Microreact.

Cumulative antimicrobial susceptibilities for respiratory clinical isolates of Mycobacterium avium Complex, Mycobacterium kansasii, and Mycobacterium abscessus from Pakistan 2018 to 2022.

Background: Nontuberculous mycobacteria (NTM) are increasingly identified as causes of protracted pulmonary infections. Antibiotic susceptibility testing requires microdilution methods, which are often unavailable in laboratories in resource-poor settings. We report cumulative antibiograms for the most frequently isolated clinical pulmonary NTM from Pakistan to inform empiric antibiotic management of initial NTM infections. Methods: We analyzed data from 2018 to 2022 for the most frequently isolated and clinically relevant NTM isolated from respiratory specimens, i.e., Mycobacterium avium complex (MAC), Mycobacterium abscessus group (MAG), and Mycobacterium kansasii (MK). Antibiograms were developed using the Clinical Laboratory Standards Institute's M39ED5 standard. Percentage susceptibilities and 95% confidence intervals (CI) were calculated. Results: Over 4 years, 529 NTM, comprising 209 MAC, 249 MAG, and 71 MK were analyzed. For MAC and MAG, where clarithromycin (CLR)-based regimens are recommended, CLR was active for 94.8% (95% CI 91.3-96.9), and 77.5% (95% CI 71.4-82.7) isolates, respectively. Combination regimens comprising 3 active drugs CLR + linezolid (LZD) + moxifloxacin for MAC and CLR + LZD + Amikacin for MAG had 98.4% (95% CI 95.9-99.4) and 68.9% (95% CI 62.3-74.8) coverage for pulmonary disease, respectively. For MK, 91.5% (95% CI 82.8-96.1) isolates were susceptible to rifampin (RIF), with a combination of RIF + CLR covering 88.7% (95% CI 79.3-94.2) of MK pulmonary infections, respectively. Conclusions: These data can inform empiric treatment guidance for the most common NTM pulmonary infections, i.e., for MAC, MAG, and MK disease in Pakistan.

Early recognition and management of maternal sepsis in Pakistan: a feasibility study of the implementation of FAST-M intervention.

OBJECTIVE: Maternal sepsis is the third leading cause of maternal mortality globally. WHO and collaborators developed a care bundle called FAST-M (Fluids, Antibiotics, Source identification and treatment, Transfer and Monitoring) for early identification and management of maternal sepsis in low-resource settings. This study aimed to determine feasibility of FAST-M intervention in a low-resource setting in Pakistan. The FAST-M intervention consists of maternal sepsis screening tools, treatment bundle and implementation programme. DESIGN AND SETTING: A feasibility study with before and after design was conducted in women with suspected maternal sepsis admitted at the Liaquat University of Medical and Health Sciences hospital Hyderabad. The study outcomes were compared between baseline and intervention phases. In the baseline phase (2 months), the existing sepsis care practices were recorded, followed by a training programme for healthcare providers on the application of FAST-M tools. These tools were implemented in the intervention phase (4 months) to assess any change in clinical practices compared with the baseline phase. RESULTS: During the FAST-M implementation, 439 women were included in the study. 242/439 were suspected maternal infection cases, and 138/242 were women with suspected maternal sepsis. The FAST-M bundle was implemented in women with suspected maternal sepsis. Following the FAST-M intervention, significant changes were observed. Improvements were seen in the monitoring of oxygen saturation measurements (25.5% vs 100%; difference: 74%; 95% CI: 68.4% to 80.5%; p<0.01), fetal heart rate assessment (58% vs 100%; difference: 42.0%; 95% CI: 33.7% to 50.3%; p≤0.01) and measurement of urine output (76.5% vs 100%; difference: 23.5%; 95% CI: 17.6% to 29.4%; p<0.01). Women with suspected maternal sepsis received all components of the treatment bundle within 1 hour of sepsis recognition (0% vs 70.5%; difference: 70.5%; 95% CI: 60.4% to 80.6%; p<0.01). CONCLUSION: Implementation of the FAST-M intervention was considered feasible and enhanced early identification and management of maternal sepsis at the study site. TRIAL REGISTRATION NUMBER: ISRCTN17105658.

Etiology of Acute Infectious Meningitis and Meningoencephalitis in Karachi, Pakistan: Retrospective Observational Study from a Tertiary Care Center.

Meningoencephalitis (ME) is potentially fatal and is caused by a wide array of pathogens. Diagnostic and health-care access gaps prevent accurate estimation of the pathogen-specific burden in low-resource settings. We present pathogen-specific etiologies among patients hospitalized with ME in Karachi, Pakistan. We performed a retrospective hospital database evaluation of pathogen etiology and outcomes of community-acquired infectious ME at a single tertiary care center in Karachi, Pakistan. Annual rates of hospitalization (ARH) were calculated by adjusting for missed cases and are reported per 100,000 population. From May 2017 to April 2020, 522 episodes of infectious ME were identified in 514 patients. The overall ARH from ME was 5.7/100,000 population (95% CI, 5.1-6.1). Among children younger than 5 years, the ARH was 9.8/100,000 population (95% CI, 8.1-11.8). Unknown causes of ME resulted in the greatest burden, with an ARH of 1.9/100,000 population (95% CI, 1.7-2.2). Among known causes, the greatest burden of hospitalizations resulted from tuberculous ME (0.8/100,000; 95% CI, 0.6-0.97), followed by pneumococcal and enteroviral ME (both 0.6/100,000 population; 95% CI, 0.5-0.8). The burden of ME caused by pathogens preventable through vaccination or public health measures outweighed that of ME from other causes (P = 0.0092, Fisher's exact test). We report a broad range of pathogens causing ME in southern Pakistan and show a high burden of preventable illness. Synergistic actions to improve diagnostic strategies, increase vaccinations, and introduce measures to reduce water-borne and vector-borne diseases are required to reduce the ME burden in Pakistan and prevent future outbreaks.

Incentivisation practices and their influence on physicians' prescriptions: A qualitative analysis of practice and policy in Pakistan.

Focus on profit-generating enterprise in healthcare can create conflicts of interest that adversely impact prescribing and pricing of medicines. Although a global challenge, addressing the impacts on quality of care is particularly difficult in countries where the pharmaceutical industry and physician lobby is strong relative to regulatory institutions. Our study characterises the range of incentives exchanged between the pharmaceutical industry and physicians, and investigates the differences between incentivisation practices and policies in Pakistan. In this mixed methods study, we first thematically analysed semi-structured interviews with 28 purposively selected for-profit primary-care physicians and 13 medical sales representatives from pharmaceutical companies working across Pakistan's largest city, Karachi. We then conducted a content analysis of policies on ethical practice issued by two regulatory bodies responsible in Pakistan, and the World Health Organization. This enabled a systematic comparison of incentivisation practices with what is considered 'prohibitive' or 'permissive' in policy. Our findings demonstrate that incentivisation of physicians to meet pharmaceutical sales targets is the norm, and that both parties play in the symbiotic physician-pharma incentivisation dynamics. Further, we were able to categorise the types of incentive exchanged into one of five categories: financial, material, professional or educational, social or recreational, and familial. Our comparison of incentivisation practices with policies revealed three reasons for such widespread incentivisation linked to sales targets: first, some clear policies were being ignored by physicians; second, there are ambiguous or contradictory policies with respect to specific incentive types; and third, numerous incentive types are unaddressed by existing policies, such as pharmaceutical companies paying for private clinic renovations. There is a need for policies to be clarified and updated, and to build buy-in for policy enforcement from pharmaceutical companies and physicians, such that transgressions on target-driven prescribing are seen to be unethical.

Whole-genome sequencing reveals genotypic resistance in phenotypically susceptible Mycobacterium tuberculosis clinical isolates.

Background: Whole-genome sequencing (WGS) data of Mycobacterium tuberculosis (MTB) complex strains have revealed insights about genetic variants associated with drug resistance (DR). Rapid genome-based diagnostics are being sought for specific and sensitive identification of DR; however, correct prediction of resistance genotypes requires both informatics tools and understanding of available evidence. We analyzed WGS datasets from phenotypically susceptible MTB strains using MTB resistance identification software. Methods: WGS data for 1526 MTB isolates classified as phenotypically drug susceptible were downloaded from the ReSeqTB database. The TB-Profiler software was used to call Single Nucleotide Variants (SNV) associated with resistance to rifampicin (RIF), isoniazid (INH), ethambutol (EMB), pyrazinamide, fluoroquinolone (FLQ), streptomycin (STR), and aminoglycosides. The SNV were further matched against the 2021 World Health Organization (WHO) catalogue of resistance mutations. Results: Genome analysis of 1526 MTB strains susceptible to first-line drugs revealed 39 SNV associated with DR to be present in across 14 genes in 5.9% (n = 90) isolates. Further interpretation of SNV based on the WHO catalog of mutations revealed resistance that 21 (1.4%) MTB isolates were resistant to first-line (4 to RIF, 14 to INH, 3 to EMB) drugs. While, 36 (2.6%) isolates were resistant to second-line (19 to STR, 14 to FLQ, and three to capreomycin) agents. The most frequent predictive SNV were; rpoB Ser450 Leu for RIF; katG Ser315Thr, inhA Ser94Ala, fabG1-15C >T (for INH); gyrA Asp94Gly for FLQ; embB Met306 Leu for EMB; rpsL Lys43Arg for STR; and tlyA Asn236 Lys for Capreomycin. Conclusions: Our study highlights the value of WGS-based sequence data for identifying resistance in MTB. It also shows how MTB strains may be misclassified simply on phenotypic drug susceptibility testing, and that correct genome interpretation is key for correct interpretation of resistance genotypes that can be used to guide clinical treatment.

Laboratory service relocation: experience and lessons learned from relocating a biosafety level-3 clinical mycobacteriology service to a new facility.

Objectives: We recount our experiences of relocating an active mycobacteriology reference level service in Karachi, Pakistan, from an older accredited biosafety level-3 facility to a newly constructed and environmentally validated facility. Methods: The service relocation planning, execution, and verification stages are described in detail. Results: Lessons learned from our experience include establishing a service transfer plan, including relevant service staff, obtaining their buy-in on the plan, arranging backup service facilities or liaisons for the execution phase, and ensuring viable backup arrangements for troubleshooting during the verification phase of services in the new facility. Careful planning and inclusion of all stakeholders are critical to avoid service interruptions. Conclusions: This narrative is expected to support other laboratorians, scientists, and clinicians providing laboratory services to large population sectors who are looking to move their services to a new location while continuing to offer said services in a proficient and reliable manner.

Socioecological factors linked with pharmaceutical incentive-driven prescribing in Pakistan.

Pharmaceutical marketing through financial incentivisation to general practitioners (GPs) is a poorly studied health system problem in Pakistan. Pharmaceutical incentivisation is seen to be distorting GPs prescribing behaviour that can compromise the health and well-being of patients. We draw on a conceptual framework outlined in the ecological system theory to identify multiple factors linked with pharmaceutical incentivisation to GPs in Pakistan. We conducted qualitative interviews with 28 policy actors to seek their views on the health system dynamics, how they sustain pharmaceutical incentivisation and their effect on the quality of care. Our analysis revealed four interlinked factors operating at different levels and how they collectively contribute to pharmaceutical incentivisation. In addition to influences such as the increasing family needs and peers' financial success, sometimes GPs may naturally be inclined to maximise incomes by engaging in pharmaceutical incentivisation. On other hand, the pharmaceutical market dynamics that involve that competition underpinned by a profit-maximisation mindset enable pharmaceutical companies to meet GPs' desires/needs in return for prescribing their products. Inadequate monitoring and health regulations may further permit the pharmaceutical industry and GPs to sustain the incentive-driven relationship. Our findings have important implications for potential health reforms such as introducing regulatory controls, and appropriate monitoring and regulation of the private health sector, required to address pharmaceutical incentivisation to GPs.

The healthcare field as a marketplace: general practitioners, pharmaceutical companies, and profit-led prescribing in Pakistan.

Incentivisation of general practitioners (GPs) by pharmaceutical companies is thought to affect prescribing practices, often not in patients' interest. Using a Bourdieusian lens, we examine the socially structured conditions that underpin exchanges between pharmaceutical companies and GPs in Pakistan. The analysis of qualitative interviews with 28 GPs and 13 pharmaceutical sales representatives (PSRs) shows that GPs, through prescribing medicines, met pharmaceutical sales targets in exchange for various incentives. We argue that these practices can be given meaning through the concept of 'field' - a social space in which GPs, PSRs, and pharmacists were hierarchically positioned, with their unique capacities, to enable healthcare provision. However, structural forces like the intense competition between pharmaceutical companies, the presence of unqualified healthcare providers in the healthcare market, and a lack of regulation by the state institutions produced a context that enabled pharmaceutical companies and GPs to use the healthcare field, also, as space to maximise profits. GPs believed the effort to maximise incomes and meet socially desired standards were two key factors that encouraged profit-led prescribing. We conclude that understanding the healthcare field is an important step toward developing governance practices that can address profit-led prescribing.

Comparative Analysis of Commercially Available Typhoid Point-of-Care Tests: Results of a Prospective and Hybrid Retrospective Multicenter Diagnostic Accuracy Study in Kenya and Pakistan.

Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid, but these methods require infrastructure and skilled staff that are not always available in low- and middle-income countries where typhoid is endemic. The objective of the study is to evaluate the sensitivity and specificity of nine commercially available Salmonella Typhi rapid diagnostic tests (RDTs) using blood culture as a reference standard in a multicenter study. This was a prospective and retrospective multicenter diagnostic accuracy study conducted in two geographically distant areas where typhoid is endemic (Pakistan and Kenya; NCT04801602). Nine RDTs were evaluated, including the Widal test. Point estimates for sensitivity and specificity were calculated using the Wilson method. Latent class analyses were performed using R to address the imperfect gold standard. A total of 531 serum samples were evaluated (264 blood culture positive; 267 blood culture negative). The sensitivity of RDTs varied widely (range, 0 to 78.8%), with the best overall performance shown by Enterocheck WB (72.7% sensitivity, 86.5% specificity). In latent class modeling, CTK IgG was found to have the highest sensitivity (79.1%), while the highest overall accuracy was observed with Enterocheck (73.8% sensitivity, 94.5% specificity). All commercially available Salmonella Typhi RDTs evaluated in the study had sensitivity and specificity values that fell below the required levels to be recommended for an accurate diagnosis. There were minimal differences in RDT performances between regions of endemicity. These findings highlight the clear need for new and more-accurate Salmonella Typhi tests.

Impact of a multifaceted intervention on physicians' knowledge, attitudes and practices in relation to pharmaceutical incentivisation: protocol for a randomised control trial.

INTRODUCTION: In settings where the private sector constitutes a larger part of the health system, profit-gathering can take primacy over patients' well-being. In their interactions with pharmaceutical companies, private general practitioners (GPs) can experience the conflict of interest (COI), a situation whereby the impartiality of GPs' professional decision making may be influenced by secondary interests such as financial gains from prescribing specific pharmaceutical brands. METHODS AND ANALYSIS: This study is a randomised controlled trial to assess the impact of a multifaceted intervention on GPs' medical practice. The study sample consists of 419 registered GPs who own/work in private clinics and will be randomly assigned to intervention and control groups. The intervention group GPs will be exposed to emotive and educational seminars on medical ethics, whereas control group GPs will be given seminars on general medical topics. The primary outcome measure will be GPs' prescribing practices, whereas the secondary outcome measures will be their knowledge and attitudes regarding COI that arises from pharmaceutical incentivisation. In addition to a novel standardised pharmaceutical representatives (SPSR) method, in which field researchers will simulate pharmaceutical marketing with GPs, presurvey and postsurvey, and qualitative interviewing will be performed to collect data on GPs' knowledge, attitudes and practices in relation to COI linked with pharmaceutical incentives. Univariate and multivariate statistical analyses will be performed to measure a change in GPs' knowledge, attitudes and practices, while qualitative analysis will add to our understanding of the quantitative SPSR data. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Pakistan National Bioethics Committee (# 4-87/NBC-582/21/1364), the Aga Khan University (# 2020-4759-1129) and the London School of Hygiene and Tropical Medicine (# 26506). We will release results within 6-9 months of the study's completion. TRIAL REGISTRATION NUMBER: ISRCTN12294839.

Drug-resistant bacterial infections: We need urgent action and investment that focus on the weakest link.

Despite high mortality and morbidity, drug-resistant bacterial infections remain the forgotten pandemic. We argue for strengthening of diagnostics, WASH (water, sanitation, and hygiene) and infection prevention and control to reduce drug-resistant infections, as an integral part of sustainable high-quality health services, particularly in low- and middle-income countries.

Bedaquiline resistant Mycobacterium tuberculosis clinical isolates with and without rv0678 mutations have similar growth patterns under varying BDQ drug pressure.

Resistance associated mutations have been reported to alter the growth of Mycobacterium tuberculosis (MTB) isolates under drug pressure. However, there is little information on the growth characteristics of bedaquiline (BDQ) resistant isolates in the presence of BDQ. To further understand the role of rv0678, we aimed to study whether the presence of rv0678 variants in BDQ resistant isolates alters the killing effect of BDQ. We, therefore, selected BDQ resistant clinical MTB isolates with (n = 6) and without (n = 3) variants in rv0678 gene. Using time kill assays, growth inhibition; taken as the relative change in log average colony forming unit (CFU)/ml at selected time points (24-96 h), was studied at Minimum Inhibitory Concentrations (MICs): 0x, 1x, 2.5x, 5x, 7.5x, 10x for these isolates. Growth inhibition was then analyzed using Kruskal Wallis and Kolmogorov Smirnov tests in PRISM vr.9. During the 24-96 h lag phase isolates with and without variants in rv0678 showed a similar growth inhibition pattern. No difference was noted in growth inhibition between BDQ resistant isolates and H37Rv. These findings suggest that role of alternate mechanisms in contributing to BDQ tolerance needs to be explored.