Please use this identifier to cite or link to this item: http://hdl.handle.net/10125/62202

Drug Resistance in Mycobacterium Tuberculosis: An Investigation of Drug Transporter P-glycoprotein and an Evaluation of Improved Diagnosis of Drug Resistant Tuber- culosis in Cameroonian Pulmonary Tuberculosis Patients.

File Size Format  
2017-05-phd-abanda.pdf 4.65 MB Adobe PDF View/Open

Item Summary

Title:Drug Resistance in Mycobacterium Tuberculosis: An Investigation of Drug Transporter P-glycoprotein and an Evaluation of Improved Diagnosis of Drug Resistant Tuber- culosis in Cameroonian Pulmonary Tuberculosis Patients.
Authors:Abanda, Ngu Njei
Contributors:Biomedical Sciences (Tropical Medicine) (department)
Date Issued:May 2017
Publisher:University of Hawaiʻi at Mānoa
Abstract:Tuberculosis (TB) is a major health problem, especially in Africa and Southeast Asia.
The disease, caused by Mycobacterium tuberculosis, (Mtb) is curable with a multidrug
regimen of Rifampicin (RIF), Isoniazid (INH), Ethambutol and Pyrazinamide. However,
treatment is not always successful, as ~ 2 million patients fail treatment each year, in
part, because the bacterium has become resistant to these drugs. Thus, efficient
diagnosis of drug-resistant Mtb is extremely important. This study sought to determine if
a new molecular assay, the Genotype MTBDRplus, could accurately detect drugresistant
Mtb in Cameroon. When compared to the conventional drug susceptibility
testing assay, the molecular assay identified 98% (48/49) RIF-resistant isolates, 92%
(55/60) INH-resistant isolates, and 94% (46/49) of Mtb resistant to both drugs in
Cameroonian TB patients. Further evaluation of the molecular assay with an additional
50 Mtb isolates, identified 6% (16/275) of isolates with questionable RIF-resistant
results. To determine if these 16 isolates were truly RIF-resistant, the Rifampicin
Resistance-determining Region of the rpoB gene were sequenced. Mutations were
found known as ‘disputed’ RIF mutations, i.e., mutations that are not always associated
with resistance to RIF. Thus, sequencing results confirm that when DNA from Mtb
isolates do not hybridize with the wild-type rpoB probe, it is wise to assume the Mtb
isolate is RIF-resistant and treat accordingly. The Genotype MTBDRplus assay can be
adopted by the government of Cameroon to diagnose drug-resistant TB. In addition to
mycobacterial mutations, host factors that cause sub-therapeutic plasma drug
concentration could lead to treatment failure. One of such host factors could be variation
in the liver efflux pump, P-glycoprotein (p-gp). Therefore, the relative amount of p-gp
V
protein in 87 human liver samples was measured. P-gp was found to be present from
birth reaching 90 % of adult levels by age 5. Since low variability (2.9 + 0.32 fold) in pgp
occurred among individuals, it is unlikely variability in p-gp protein accounts for wide
variation in RIF plasma levels. The data are important because expression p-gp in
children provides a plausible explanation as to why, when given the same dose/kg of
RIF as adults, children clear the drug faster.
Description:Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017.
URI:http://hdl.handle.net/10125/62202
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Biomedical Sciences (Tropical Medicine)


Please email libraryada-l@lists.hawaii.edu if you need this content in ADA-compliant format.

Items in ScholarSpace are protected by copyright, with all rights reserved, unless otherwise indicated.