Isoniazid preventive therapy in child household contacts of adults with active TB in Bamako, Mali.

BACKGROUND AND OBJECTIVE: Isoniazid preventive therapy (IPT) is known to reduce the risk of developing active TB in about 59% in children aged ⩽15 years. We assessed adherence, completion and adverse events among children who were household contacts of a newly diagnosed adult with smear-positive TB in Bamako, Mali. METHODS: Children aged <15 years living in the same house with an adult smear-positive index case were enrolled in the study in the Bamako Region after consent was obtained from the parent or legal guardian. Adherence was assessed based on the number of tablets consumed during 6 months. RESULTS: A total of 260 children aged <15 years were identified as household contacts of 207 adult patients with smear-positive TB during the study period. Among all child contacts, 130/260 (50.0%) were aged 0-4 years and were eligible for IPT; 128/130 (98.5%) were started on IPT and 83/128 (64.8%) completed with good adherence at the end of the 6 months, and without any significant adverse events. CONCLUSION: We successfully implemented IPT with good acceptance, but low completion rate. The Mali National TB Program and partners should expand this strategy to reach more children in Bamako and the whole country and create greater awareness in the population.

CADRE ET OBJECTIF: Le traitement préventif par isoniazide (IPT) réduit le risque de développer une TB active chez environ 59% des enfants ⩽15 ans. Nous avons évalué l'observance, l'achèvement du traitement et les évènements indésirables chez des enfants qui étaient contacts domestiques d'un adulte ayant récemment reçu un diagnostic de TB à microscopie positive à Bamako, Mali. MÉTHODES: Les enfants âgés <15 ans vivant sous le même toit qu'un cas index adulte de TB à microscopie positive ont été inclus dans l'étude dans la région de Bamako, après obtention du consentement des parents ou du tuteur légal. L'observance a été évaluée en fonction du nombre de comprimés consommés au cours d'une période de 6 mois. RÉSULTATS: Au total, 260 enfants âgés <15 ans ont été identifiés comme contacts domestiques de 207 patients adultes atteints de TB à microscopie positive pendant la période d'étude. Parmi tous les contacts pédiatriques, 130/260 (50,0%) étaient âgés de 0­4 ans et étaient éligibles à l'IPT ; 128/130 (98,5%) ont été mis sous IPT et 83/128 (64,8%) ont achevé leur traitement avec une bonne observance à la fin de la période de 6 mois, sans évènement indésirable significatif. CONCLUSION: Nous avons mis en place l'ITP avec succès. L'acceptation était bonne mais le taux d'achèvement du traitement était faible. Le programme national de lutte contre la TB du Mali et ses partenaires devraient élargir cette stratégie afin d'inclure davantage d'enfants de Bamako et du pays, et d'accroître la sensibilisation de la population.

[Drug-resistant tuberculosis with rifampicin in children co-infected with HIV in Bamako]. / Tuberculose resistante a la rifampicine chez un enfant co-infectepar le VIH a Bamako, Mali.

Drug-resistant tuberculosis, especially in children, is a major public health challenge. We report a case with rifampicin resistance diagnosed in an HIV co-infected in Bamako. The history of the disease suggests possible father-to-child transmission. After confirmation, MDR-TB treatment was initiated. Global improvement and normalization of biological parameters and X-Ray was obtained. The identification of this case highlights the need to improve diagnosticand treatment algorithms for rapid confirmation and better management.

La tuberculose pharmaco-résistante surtout de l'enfant représente un défi majeur de santé publique. Nous rapportons un cas avec résistance à la rifampicine chez un enfant séropositif au VIHà Bamako. L'histoire de la maladie suggère une possible transmission du père à l'enfant. Après la confirmation, l'enfant a été mis sous traitement de TB-MR. Une amélioration de son état général et une normalisation des paramètres biologiques et radiologiques a été observée. L'identification de ce patient met en évidence la nécessité d'améliorer les algorithmes de diagnostic et de traitement pour une confirmation rapide et une meilleure prise en charge.

[Contribution of the University Clinical Research Center's laboratoryin the diagnosis of SARS-CoV-2 in Mali]. / Contribution du laboratoire du Centre Universitaire de Recherche Clinique (UCRC) au diagnostic de SRAS-CoV-2 au Mali.

INTRODUCTION: The rapid diagnostic capacities of laboratories in Mali have been an essential element in the response to COVID-19. The University Clinical Research center (UCRC) diagnosed the first cases of Mali COVID-19. OBJECTIVE: The objective was to describe the contribution of the UCRC in the diagnosis of Covid-19 and to clinically and epidemiologically characterize the patients tested in the UCRC laboratory. MATERIALS AND METHODS: A cross-sectional study was conducted during eight months of intense activity. The samples were sent from the National Institute of Public Health (INSP) to the UCRC. RESULTS: The UCRC tested 12,406 contacts and suspected samples and confirmed the diagnosis in 1091 patients, or 9%. The most common symptoms were cough (48.78%), headache (34.14%), fatigue / weakness (34.14%), while (33.33%) of the patients were asymptomatic. The sample positivity rate among new cases decreased from May to September 2020, despite almost 230% of the number of samples tested. CONCLUSION: The laboratory played a major role in the response and there may be a low transmission of the virus in the Malian community.

INTRODUCTION: Les capacités de diagnostic rapide des laboratoires au Mali ont été un élément essentiel dans la riposte contre la COVID-19. Le Centre Universitaire de Recherche Clinique (UCRC)a diagnostiqué les premiers cas du Mali. OBJECTIF: Etait de décrire l'apport de l'UCRC dans le diagnostic de la Covid-19 et de caractériser cliniquement et épidémiologiquement les patients testés au laboratoire de l'UCRC. MATÉRIELS ET MÉTHODES: Une étude transversale a été conduite pendant huit mois d'activité intense. Les échantillons ont été envoyés de l'Institut National de Santé Publique (INSP) à l'UCRC. RÉSULTATS: L'UCRC a testé 12 406 échantillons contacts et suspects et a confirmé le diagnostic chez 1091 patients soit 9%. Les symptômes les plus rencontrés ont été la toux (48,78%), les maux de tête (34,14%), la fatigue/faiblesse (34,14%), tandis que (33,33%) des patients étaient asymptomatiques. Le taux de positivité des échantillons a diminué entre mai et août et avec une légère diminution en septembre 2020,avec près de 230% du nombre d'échantillons testés. CONCLUSION: Le laboratoire a joué un grand rôle dans la riposte et il y'aurait une faible transmission du virus dans la communauté Malienne.

Fluorescein diacetate and rapid molecular testing for the early identification of rifampicin resistance in Mali.

BACKGROUND: Non-conversion on auramine smear microscopy indicates a lack of treatment response, possibly associated with initial rifampicin-resistant tuberculosis (RR-TB). However, dead bacteria still stain positive and may be detected. Fluorescein diacetate smear microscopy (FDA) shows live mycobacteria only. Therefore, we studied the potential of 2-month (2M) FDA for the identification of initial RR-TB.METHODS: Between 2015 and 2018, we enrolled new smear-positive pulmonary TB patients from five local centres in Bamako, Mali. After baseline screening, sputum samples were collected at 1M, 2M, 5M and 18M. We used rpoB sequencing to identify initial RR-TB.RESULTS: Of 1359 patients enrolled, 1019 (75%) had rpoB sequencing results. Twenty-six (2.6%, 95%CI: 1.7-3.7) had mutations conferring rifampicin resistance. Most frequent rpoB mutations were located at the codons Asp435Val (42.4%) and Ser450Leu (34.7%). Among patients with initial RR-TB, 72.2% were FDA-negative at 2M (P = 0.2). The positive and negative predictive value of 5M FDA for culture-based failure was respectively 20.0% and 94.7%.CONCLUSION: FDA did not identify the majority of patients with initial RR-TB or culture-based failure. As the full spectrum of mutations identified on sequencing was identified using Xpert, our data support its rapid universal implementation in Mali.

Diabetes Mellitus among new tuberculosis patients in Bamako, Mali.

INTRODUCTION: Diabetes Mellitus (DM) increases worldwide, mostly in low- and middle-income countries. In Mali, the prevalence in the adult population is estimated at 1.8%, but tuberculosis (TB) patients are not systematically screened. The goal of our study was to determine the prevalence of DM among newly diagnosed TB patients. METHODS: We conducted a cross sectional study and a pilot prospective cohort study in four health centers in Bamako. All patients underwent fasting capillary-blood glucose (FCBG) test at Day 0, and repeated after one-week of TB treatment. Venous FBG test was performed for discrepancies between the two FCBG results. Thereafter, FCBG was performed for pilot study at month-2 (M2) and M5 of TB treatment. RESULTS: Two hundred and one patients were enrolled in this study. Impaired fasting blood glucose was identified in 17 (8.5%), of whom 11 (5.5%) had DM (VFBG >7 mmol/L). Among patients with DM, seven (63.6%) had successful TB treatment outcome, versus 142 (74.7%) of those without DM (p = 0.64), and (OR: 1.69, 95%CI 0.47-6.02). CONCLUSION: The prevalence of DM among TB patients in Bamako exceeds that of the general population and screening at TB diagnosis suffices to identify those with DM. Systematic screening of both diseases will allow better treatment.

In vitro potentiation of carbapenems with tannic acid against carbapenemase-producing enterobacteriaceae: exploring natural products as potential carbapenemase inhibitors.

AIMS: We hypothesized and confirmed that tannic acid (TA) reverses carbapenem resistance by inhibiting carbapenemases in class A and B carbapenemase-producing Enterobacteriaceae. METHODS AND RESULTS: Minimum inhibitory concentrations of carbapenems in the presence and absence of TA and other efflux pump inhibitors, TA-carbapenemases inhibition assays and computational studies showed that TA had the greatest effect on metallo-ß-lactamases (MBLs) followed by class A serine-ß-lactamases (SBLs). TA completely reversed the MICs of MBL producers from between 32 and ≥512 mg l-1 to susceptible values (<4 mg l-1 ) while substantially reducing the MICs of SBLs from between 16 and >512 mg l-1 to <4 to 16 mg l-1 . Tolerable cytotoxic effect was observed for the concentrations tested (8-1024 mg l-1 ). TA inhibited enzymes with a marked difference of ≈50% inhibition (IC50 ) for NDM-1 (270 µmol l-1 ) and KPC-2 (15  µmol l-1 ). CONCLUSION: TA inhibited both MBLs and SBLs by targeting their hydrophobic sites. Moreover, TA had a stronger binding affinity for MBLs than SBLs as the MBLs, specifically VIM-1 (-43·7220 ± 0·4513 kcal mol-1 ) and NDM-1(-44·2329 ± 0·3806 kcal mol-1 ), interact with a larger number of their catalytic active-site residues than that of OXA-48 (-22·5275 ±  0·1300 kcal mol-1 ) and KPC-2 (-22·1164 ± 0·0111 kcal mol-1 ). SIGNIFICANCE AND IMPACT OF THE STUDY: Tannic acid or its analogues could be developed into carbapenemase-inhibiting adjuvants to restore carbapenem activity in CRE infections, save many lives and reduce healthcare associated costs.

Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali.

The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.

Performance of microscopic observation drug susceptibility for the rapid diagnosis of tuberculosis and detection of drug resistance in Bamako, Mali.

OBJECTIVES: In Mali early detection and treatment of multidrug-resistant tuberculosis (MDR-TB) are still challenging due to the cost, time and/or complexity associated with regular tests. Microscopic Observation Drug Susceptibility (MODS) is a low-cost assay validated by WHO in 2010. It is a liquid-culture-based assay to detect the 'cording' characteristic of Mycobacterium tuberculosis complex and to assess susceptibility to both isoniazid and rifampicin defining multidrug-resistant tuberculosis (MDR-TB). In this study we aimed to evaluate the performance of MODS as diagnostic tool compared with a validated method-Mycobacteria Growth Indicator Tube/Antimicrobial Susceptibility Testing/Streptomycin, Isoniazid, Rifampicin and Ethambutol (MGIT/AST/SIRE). METHODS AND RESULTS: Between January 2010 and October 2015 we included 98 patients with suspected TB in an observational cohort study. The sensitivity and specificity of MODS assay for detecting TB were respectively 94.12% and 85.71% compared with the reference MGIT/7H11 culture, with a Cohen κ coefficient of 0.78 (95% CI 0.517-1.043). The median time to culture positivity for MODS assay and MGIT (plus interquartile range, IQR) was respectively 8 days (IQR 5-11) and 6 days (IQR 5-6). In detecting patients with MDR-TB, the sensitivity and specificity of MODS assay were respectively 100% and 95.92%. The positive predictive value and negative predictive value were, respectively, 66.7% and 100%. The median turnaround times for obtaining MDR-TB results using MODS assay and MGIT/AST/SIRE was respectively 9 days and 35 days. Hence, the MODS assay rapidly identifies MDR-TB in Mali compared with the MGIT/AST/SIRE. CONCLUSION: As an easy, simple, fast and affordable method, the MODS assay could significantly improve the management of TB.

In vitro evaluation of metal chelators as potential metallo- ß -lactamase inhibitors.

AIMS: This study aimed at investigating the use of metal chelators as potential metallo-ß-lactamase inhibitors (MBL). METHODS AND RESULTS: The minimum inhibitory concentration (MIC) of meropenem was ascertained alone and in combination with various concentrations of macrocyclic (1,4,7- triazacyclononane-1-glutaric acid-4,7-diacetic acid = NODAGA) peptide derivatives and acyclic (N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine = TPEN and di-(2-picolyl)amine = DPA) metal chelators using the broth microdilution method. MICs of meropenem against carbapenem-resistant enterobacteriaceae (CRE) producing MBLs were decreased to concentrations as low as 0·06 mg l(-1) in the presence of some metal chelators. TPEN at 4 and 8 mg l(-1) showed the best activity by decreasing meropenem MICs to 0·5 and 0·06 mg l(-1) , respectively, for some New Delhi Metallo-beta-lactamase (NDM) and Verona integron-encoded metallo-ß-lactamase (VIM) -producing enterobacteriaceae. DPA at 8 and 16 mg l(-1) was also able to decrease meropenem MICs to 1 and 0·125 mg l(-1) , respectively, for these CREs. NODAGA peptide derivatives showed the least inhibition as 32 mg l(-1) was required for meropenem MICs to be decreased to 0·06 mg l(-1) against an NDM-1 producing isolate. CONCLUSION: The various metal chelators, TPEN, DPA and NODAGA peptide derivatives were able to inhibit the MBLs in decreasing order of activity, rendering CREs susceptible to meropenem. SIGNIFICANCE AND IMPACT OF THE STUDY: In the absence of new antibiotics, this study evaluated metal chelators as potential MBL inhibitors.

Molecular strain typing of Mycobacterium tuberculosis complex in Bamako, Mali.

OBJECTIVE: To identify strains of Mycobacterium tuberculosis complex (MTC) circulating in Bamako and to examine the relationship between the strains and their drug susceptibility profiles. METHODS: Between 2006 and 2010, we conducted a cross-sectional study using spoligotyping to identify strains of MTC recovered from 126 tuberculosis (TB) patients under treatment in Bamako, Mali. RESULT: Three members of the MTC were isolated: M. tuberculosis (71.4%), M. africanum (27.8%) and M. bovis (0.8%). Of these, three strains were found to be the most prevalent: M. tuberculosis T1 (MTB T1; 38.9%), M. africanum F2 (MAF2; 26.2%) and M. tuberculosis Latin American and Mediterranean 10 (MTB LAM 10; 10.3%). MAF2 and MTB LAM 10 strains have a lower risk of multidrug resistance (MDR) than MTB T1 (respectively OR 0.1, 95%CI 0.03-0.4 and OR 0.1, 95%CI 0.01-0.8). Age ≥ 32 years (OR 1.4, 95%CI 0.4-3.9), negative human immunodeficiency virus status (OR 0.4, 95%CI 0.1-2.5) and male sex (OR 4, 95%CI 0.9-16.5) were not associated with MDR. The prevalence of MDR among treatment and retreatment failure patients was respectively 25% and 81.8% compared to new patients (2.9%). CONCLUSION: This study indicates a low level of primary drug resistance in Bamako, affirms the importance of using correct drug regimens, and suggests that the MTB T1 strain may be associated with the development of resistance.