Browsing by Author "Addo, Kennedy"

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Meta-narrative review of molecular methods for diagnosis and monitoring of multidrug-resistant tuberculosis treatment in adults
(PubMed Central, 2019-06-04) Mbelele, Peter; Mohamed, Sagal; Sauli, Elingarami; Mpolya, Emmanuel; Mfinanga, Sayoki; Addo, Kennedy; Heysell, Scott; Mpagama, Stellah
Early and accurate diagnosis and rigorous clinical and microbiological monitoring of multidrug-resistant tuberculosis (MDR-TB) treatment can curb morbidity and mortality. While others are still under evaluation, the World Health Organization has recommended few novel molecular methods for MDR-TB diagnosis only. We present current molecular methods for diagnosis and monitoring of MDR-TB treatment in TB-endemic settings. A systematic meta-narrative review was conducted according to the RAMESES recommendations. Electronic databases were searched for relevant articles published in English language from January 2013 to June 2018. Based on predefined criteria, two independent reviewers extracted the key messages from relevant articles. Disagreement between them was resolved through discussion and the involvement of a third reviewer, if needed. Key messages were synthesized to create the meta-narratives for method's accuracy, drug-susceptibility capability, and laboratory infrastructure required. We included 33 articles out of 1213 records retrieved, of which 16 (48%) and 12 (36%) were conducted in high- and low-TB-endemic settings, respectively. Xpert® MTB/RIF, GenoType MTBDRplus, GenoType MTBDRsl, FlouroType™ MTBDR, TB TaqMan® array card, and DNA sequencers can accurately guide effective treatment regimens. Molecular bacterial load assay quantifies mycobactericidal impact of these regimens. Although they present inherent advantages compared to the current standard of care, they carry important limitations to implementation and/or scale-up. Therefore, considerable effort must now be directed to implementation and health systems research to maximize these forecasted benefits for individual patient's health outcomes.
Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania
(American Society for Microbiology, 2021-02-03) Mbelele, Peter; Mpolya, Emmanuel; Sauli, Elingarami; Mtafya, Bariki; Ntinginya, Nyanda; Addo, Kennedy; Kreppel, Katharina; Mfinanga, Sayoki; Phillips, Patrick; Gillespie, Stephen; Heysell, Scott; Sabiiti, Wilber; Mpagama, Stellah
Rifampin or multidrug-resistant tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component, despite the drug class’ purported bactericidal activity early in treatment. We tested whether Mycobacterium tuberculosis killing rates measured by tuberculosis molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at days 0, 3, 7, and 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable M. tuberculosis 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). M. tuberculosis killing rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures. Thirty-seven patients produced 296 serial sputa and received treatment as follows: 13 patients received an injectable bedaquiline-free reference regimen, 9 received an injectable bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted M. tuberculosis killing of −0.17 (95% confidence interval [CI] −0.23 to −0.12) for the injectable bedaquiline-free reference regimen, the killing rates were −0.62 (95% CI −1.05 to −0.20) log10 eCFU/ml for the injectable bedaquiline-containing regimen (P = 0.019), −0.35 (95% CI −0.65 to −0.13) log10 eCFU/ml for the all-oral bedaquiline-based regimen (P = 0.054), and −0.29 (95% CI −0.78 to +0.22) log10 eCFU/ml for the RHZE regimen (P = 0.332). Thus, M. tuberculosis killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.
TB or not TB? Definitive determination of species within the Mycobacterium tuberculosis complex in unprocessed sputum from adults with presumed multidrug-resistant tuberculosis
(Tropical Medicine and International Health, 2021-06-09) Mbelele, Peter; Sauli, Elingarami; Mpolya, Emmanuel; Mohamed, Sagal; Addo, Kennedy; Mfinanga, Sayoki; Heysell, Scott; Mpagama, Stellah
Objectives Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drug-susceptibility testing to anti-tuberculosis drugs from direct sputum of patients with presumed multidrug-resistant tuberculosis (MDR-TB) by the MTBDRplus/sl reference method. Methods Patients with positive Xpert® MTB/RIF (Xpert) results were consented to provide early-morning-sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi-square or Fisher’s exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. Results Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40–45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31–13.32, P = 0.016), high-quantity MTC by Xpert 3.03 (1.35–6.82, P = 0.007) and sputum smear positivity 1.93 (1.19–3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86–98; κ = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. Conclusions The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR-TB treatment regimens.
TB or not TB? Definitive determination of species within the Mycobacterium tuberculosis complex in unprocessed sputum from adults with presumed multidrug-resistant tuberculosis
(Wiley, 2021-06-09) Mbelele, Peter; Sauli, Elingarami; Mpolya, Emmanuel; Mohamed, Sagal; Addo, Kennedy; Mfinanga, Sayoki; Heysell, Scott; Mpagama, Stellah
Objectives Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drug-susceptibility testing to anti-tuberculosis drugs from direct sputum of patients with presumed multidrug-resistant tuberculosis (MDR-TB) by the MTBDRplus/sl reference method. Methods Patients with positive Xpert® MTB/RIF (Xpert) results were consented to provide early-morning-sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi-square or Fisher’s exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. Results Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40–45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31–13.32, P = 0.016), high-quantity MTC by Xpert 3.03 (1.35–6.82, P = 0.007) and sputum smear positivity 1.93 (1.19–3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86–98; κ = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. Conclusions The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR-TB treatment regimens
TB or not TB? Definitive determination of species within the Mycobacterium tuberculosis complex in unprocessed sputum from adults with presumed multidrug-resistant tuberculosis
(John Wiley & Sons, Inc., 2021-06-09) Mbelele, Peter; Sauli, Elingarami; Mpolya, Emmanuel; Mohamed, Sagal; Addo, Kennedy; Mfinanga, Sayoki; Heysell, Scott; Mpagama, Stellah
objectives Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drugsusceptibility testing to anti-tuberculosis drugs from direct sputum of patients with presumed multidrug-resistant tuberculosis (MDR-TB) by the MTBDRplus/sl reference method. methods Patients with positive Xpert MTB/RIF (Xpert) results were consented to provide earlymorning-sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi-square or Fisher’s exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. results Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40–45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31– 13.32, P = 0.016), high-quantity MTC by Xpert 3.03 (1.35–6.82, P = 0.007) and sputum smear positivity 1.93 (1.19–3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86–98; j = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. conclusions The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR-TB treatment regimens.
Whole genome sequencing-based drug resistance predictions of multidrug-resistant Mycobacterium tuberculosis isolates from Tanzania
(Oxford University Press, 2022-04-21) Mbelele, Peter; Utpatel, Christian; Sauli, Elingarami; Mpolya, Emmanuel; Mutayoba, Beatrice; Barilar, Ivan; Dreyer, Viola; Merker, Matthias; Sariko, Margaretha; Swema, Buliga; Mmbaga, Blandina; Gratz, Jean; Addo, Kennedy; Pletschette, Michel; Niemann, Stefan; Houpt, Eric; Mpagama, Stellah; Heysell, Scott
Background: Rifampicin- or multidrug-resistant (RR/MDR) Mycobacterium tuberculosis complex (MTBC) strains account for considerable morbidity and mortality globally. WGS-based prediction of drug resistance may guide clinical decisions, especially for the design of RR/MDR-TB therapies. Methods: We compared WGS-based drug resistance-predictive mutations for 42 MTBC isolates from MDR-TB pa tients in Tanzania with the MICs of 14 antibiotics measured in the Sensititre™ MycoTB assay. An isolate was phenotypically categorized as resistant if it had an MIC above the epidemiological-cut-off (ECOFF) value, or as susceptible if it had an MIC below or equal to the ECOFF. Results: Overall, genotypically non-wild-type MTBC isolates with high-level resistance mutations (gNWT-R) cor related with isolates with MIC values above the ECOFF. For instance, the median MIC value (mg/L) for rifampicin gNWT-R strains was .4.0 (IQR 4.0–4.0) compared with 0.5 (IQR 0.38–0.50) in genotypically wild-type (gWT-S, P,0.001); isoniazid-gNWT-R .4.0 (IQR 2.0–4.0) compared with 0.25 (IQR 0.12–1.00) among gWT-S (P= 0.001); ethionamide-gNWT-R 15.0 (IQR 10.0–20.0) compared with 2.50 (IQR; 2.50–5.00) among gWT-S (P, 0.001). WGS correctly predicted resistance in 95% (36/38) and 100% (38/38) of the rifampicin-resistant isolates with ECOFFs .0.5 and .0.125 mg/L, respectively. No known resistance-conferring mutations were present in genes associated with resistance to fluoroquinolones, aminoglycosides, capreomycin, bedaquiline, delamanid, linezolid, clofazimine, cycloserine, or p-amino salicylic acid. Conclusions: WGS-based drug resistance prediction worked well to rule-in phenotypic drug resistance and the absence of second-line drug resistance-mediating mutations has the potential to guide the design of RR/MDR-TB regimens in the future.