Browsing by Author "Heysell, Scott"

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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.
Multiple Pathogens Contribute to Human Immunodeficiency Virus-Related Sepsis in Addition to Mycobacterium tuberculosis: A Prospective Cohort in Tanzania
(PubMed Central, 2022-10-20) Tsere, Donatus; Shirima, Gabriel; Grundy, Brian; Heysell, Scott; Mpagama, Stellah; Mziray, Shabani; Mbelele, Peter
Background: Mortality from tuberculosis (TB) sepsis is common among patients living with human immunodeficiency virus (PLHIV). We aimed to detect M. tuberculosis (MTB) and additional sepsis etiologies, and mortality determinants in PLHIV. Methods: This prospective cohort study consented and followed-up PLHIV for 28 days in northern Tanzania. From May through December 2021, patients provided urine and sputum for TB testing in lateral-flow lipoarabinomannan (LF-LAM) and Xpert® MTB/RIF. Bacterial blood culture, cryptococcal antigen, malaria rapid diagnostic, C-reactive-protein (CRP), and international normalized ratio (INR) tests were also performed. Sepsis severity was clinically measured by Karnofsky and modified early warning signs (MEWS) scores. Anti-TB, broad-spectrum antibiotics, and antimalarial and antifungal agents were prescribed in accordance with Tanzania treatment guideline. An independent t-test and Chi-square or Fisher’s exact tests compared means and proportions, respectively. P < 0.05 was statistically significant. Results: Among 98 patients, 59 (60.2%) were female. Their mean (standard deviation) age was 44 (12.9) years. TB detection increased from 24 (24.5%) by Xpert® MTB/RIF to 36 (36.7%) when LF-LAM was added. In total, 23 (23.5%) patients had other than TB etiologies of sepsis, including Staphylococcus aureus, Streptococcus pneumoniae, Cryptococcus spp., and Plasmodium spp. Twenty-four (94.4%) of 36 patients with TB had higher CRP (≥10 mg/l) compared to 25 (40.3%) non-TB patients (P < 0.001). Nine (9.2%) patients died and almost all had INR ≥1.8 (n = 8), Karnofsky score <50% (n = 9), MEWS score >6 (n = 8), and malnutrition (n = 9). Conclusions: MTB and other microbes contributed to sepsis in PLHIV. Adding non-TB tests informed clinical decisions. Mortality was predicted by conventional sepsis and severity scoring, malnutrition, and elevated INR.
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.
Transforming Nursing Practice to Optimize Care of Patients with Tuberculosis and Associated Comorbidities in the Kilimanjaro Region, Tanzania
(The Open Nursing Journal, 2025-01-31) Shayo, Pendo Martha; Zewdie, Elyana; Byashalira, Kenneth; Chamb, Nyasatu; Mbelele, Peter; Bygbjerg, Ib; Lillebaek, Troels; Heysell, Scott; Christensen, Dirk; Mpagama, Stellah
Background: Managing tuberculosis (TB) patients with comorbidities requires a holistic and patient-centered approach. This study evaluated patient-centered care (PCC) experiences among TB patients with multimorbidity under the Adaptive Diseases Control Expert Program in Tanzania (ADEPT), with a focus on the TB/diabetes mellitus (DM) co-epidemic targeted by the program. Methods: A quantitative cross-sectional study was conducted involving TB patients with associated comorbidities receiving care from nurses trained in PCC through the ADEPT program. Patients were assessed for their interpretation of how they received PCC across eight dimensions of care. Results: All 39 participants with TB had at least one comorbidity (100%). The most common multi-morbidities were TB/HIV (59.0%) and TB/DM (12.8%). Evaluation of needs, values, and preferences revealed that participants strongly felt healthcare workers considered these aspects (mean score = 4.53; scale 1 minimum- strongly disagree to 5 maximum- strongly agree). Subsequent analysis showed varying evaluations across dimensions. Patients reported robust endorsement for receiving care that involved family and friends, with mean scores of 4.04, and for access to care, with a mean score of 4.40. However, physical comfort, coordination, continuity of care, education and emotional support received comparatively lower rankings. Conclusion: TB patients with multimorbidity under the ADEPT program experienced PCC. However, certain systemic issues such as physical spaces, coordination, transition of care, and information education did not meet patient's needs in their own assessment, indicating opportunities for further quality improvement. Scaling up the ADEPT program within healthcare systems is likely to enhance care provision for TB patients with multimorbidity through a patient-centered approach.
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.