Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide
Abstract:BackgroundBesides inclusion in 1st line regimens against tuberculosis (TB), pyrazinamide (PZA) is used in 2nd line anti-TB regimens, including in the short regimen for multidrug-resistant TB (MDR-TB) patients. Guidelines and expert opinions are contradictory about inclusion of PZA in case of resistance. Moreover, drug susceptibility testing (DST) for PZA is not often applied in routine testing, and the prevalence of resistance is unknown in several regions, including in most African countries.MethodsSix hundre… Show more
“…The prevalence of pncA mutations among MDR-TB cases from 32 different countries in six WHO regions varied widely ranging from 21.4% in Yunnan Province of China12 and 39.5% in Pakistan7 to 81.3% in Belarus7 and 87.8% in Republic of Korea 38. In addition, the prevalence of pncA mutations among previously treated TB cases from six WHO regions also varied extensively ranging from 4.7% in South Africa,7 8.9% in Pakistan7 and 13.8% in Bangladesh7 to 36.2% in Zunyi, China, 66.7% in Rwanda10 and 70.8% in George 11Table 4The Prevalence Of pncA Mutations In M. tuberculosis Isolates From Six Different WHO Regions And 32 Countries Of The WorldPrevalence Of pncA Gene Mutations, % (Number Of TB Isolates Tested)WHO RegionsMDR/RR CasesNew CasesPT CasesTotal CasesAfrica Burundi965.7% (35)N/AN/AN/A Sub-Sahara Africa (12 countries)1054.3% (573)63.9% (72)49.0% (453)51.0% (525) Cameroon1049.6% (133)55.6% (9)50% (116)50.4% (125) CAR1028.6% (35)N/A23.3% (30)N/A DRC1073.7% (95)75% (16)68.7% (67)69.9% (83) Niger1039.6% (48)N/A39.1% (46)N/A Rwanda1067.3% (101)69.0% (42)66.7% (36)67.9% (78) Senegal1033.3% (39)N/A31.4% (35)N/A…”
BackgroundChina is one of the high-burden countries for multidrug-resistant tuberculosis (MDR-TB), and pyrazinamide is one of the anti-TB drugs used for the shorter MDR-TB treatment regimen. The aim of this study was to determine the correlation between pncA gene mutations and resistance to four first-line anti-TB drugs as well as treatment history in clinical isolates of Mycobacterium tuberculosis.Patients and methodsM. tuberculosis clinical isolates were collected from 318 in-patients with smear-positive TB between October 2008 and September 2016 at a major hospital in Zunyi, Guizhou Province of China, and used for drug susceptibility testing against four first-line anti-TB drugs. Genomic DNA extracted from clinical isolates was used for PCR amplification and DNA sequencing of the pncA gene.ResultsAmong 318 clinical isolates, 129 (40.6%), 170 (53.5%), 66 (20.8%) and 109 (34.3%) were resistant to rifampicin, isoniazid, ethambutol and streptomycin respectively. In addition, 124 clinical isolates were MDR-TB and 71.8% of them were previously treated cases. Sequencing results showed that 46.8% of MDR-TB and 2.2% of drug susceptible isolates harbored a pncA mutation, and 52 types of pncA mutations were detected from 64 isolates. The prevalence of pncA mutations in isolates resistant to first-line anti-TB drugs and previously treated TB cases was significantly higher than that in drug-susceptible isolates and new cases of TB.ConclusionHigh prevalence of pncA mutations in clinical isolates of M. tuberculosis from Zunyi, Guizhou Province of China, is correlated with resistance to four first-line anti-TB drugs, MDR-TB and previously treated TB cases.
“…The prevalence of pncA mutations among MDR-TB cases from 32 different countries in six WHO regions varied widely ranging from 21.4% in Yunnan Province of China12 and 39.5% in Pakistan7 to 81.3% in Belarus7 and 87.8% in Republic of Korea 38. In addition, the prevalence of pncA mutations among previously treated TB cases from six WHO regions also varied extensively ranging from 4.7% in South Africa,7 8.9% in Pakistan7 and 13.8% in Bangladesh7 to 36.2% in Zunyi, China, 66.7% in Rwanda10 and 70.8% in George 11Table 4The Prevalence Of pncA Mutations In M. tuberculosis Isolates From Six Different WHO Regions And 32 Countries Of The WorldPrevalence Of pncA Gene Mutations, % (Number Of TB Isolates Tested)WHO RegionsMDR/RR CasesNew CasesPT CasesTotal CasesAfrica Burundi965.7% (35)N/AN/AN/A Sub-Sahara Africa (12 countries)1054.3% (573)63.9% (72)49.0% (453)51.0% (525) Cameroon1049.6% (133)55.6% (9)50% (116)50.4% (125) CAR1028.6% (35)N/A23.3% (30)N/A DRC1073.7% (95)75% (16)68.7% (67)69.9% (83) Niger1039.6% (48)N/A39.1% (46)N/A Rwanda1067.3% (101)69.0% (42)66.7% (36)67.9% (78) Senegal1033.3% (39)N/A31.4% (35)N/A…”
BackgroundChina is one of the high-burden countries for multidrug-resistant tuberculosis (MDR-TB), and pyrazinamide is one of the anti-TB drugs used for the shorter MDR-TB treatment regimen. The aim of this study was to determine the correlation between pncA gene mutations and resistance to four first-line anti-TB drugs as well as treatment history in clinical isolates of Mycobacterium tuberculosis.Patients and methodsM. tuberculosis clinical isolates were collected from 318 in-patients with smear-positive TB between October 2008 and September 2016 at a major hospital in Zunyi, Guizhou Province of China, and used for drug susceptibility testing against four first-line anti-TB drugs. Genomic DNA extracted from clinical isolates was used for PCR amplification and DNA sequencing of the pncA gene.ResultsAmong 318 clinical isolates, 129 (40.6%), 170 (53.5%), 66 (20.8%) and 109 (34.3%) were resistant to rifampicin, isoniazid, ethambutol and streptomycin respectively. In addition, 124 clinical isolates were MDR-TB and 71.8% of them were previously treated cases. Sequencing results showed that 46.8% of MDR-TB and 2.2% of drug susceptible isolates harbored a pncA mutation, and 52 types of pncA mutations were detected from 64 isolates. The prevalence of pncA mutations in isolates resistant to first-line anti-TB drugs and previously treated TB cases was significantly higher than that in drug-susceptible isolates and new cases of TB.ConclusionHigh prevalence of pncA mutations in clinical isolates of M. tuberculosis from Zunyi, Guizhou Province of China, is correlated with resistance to four first-line anti-TB drugs, MDR-TB and previously treated TB cases.
“…bovis , which is intrinsically PZA resistant due to a lineage wide pncA mutation, L6 is susceptible to PZA. However, L6 grows slower in vitro and is less dependent on aerobic metabolism[28], both of which may increase its tolerance to certain TB drugs like isoniazid that mainly target rapidly dividing bacteria [3,29]. In support of the slower response to TB treatment of L6, a study in The Gambia showed slower immunological recovery of patients treated for L6 relative to L4 [16].…”
ObjectiveAncestral M. tuberculosis complex lineages such as M. africanum are underrepresented among retreatment patients and those with drug resistance. To test the hypothesis that they respond faster to TB treatment, we determined the rate of smear conversion of new pulmonary tuberculosis patients in Bamako, Mali by the main MTBc lineages.MethodsBetween 2015 and 2017, we conducted a prospective cohort study of new smear positive pulmonary tuberculosis patients in Bamako. Confirmed MTBc isolates underwent genotyping by spoligotyping for lineage classification. Patients were followed at 1 month (M), 2M and 5M to measure smear conversion in auramine (AR) and Fluorescein DiAcetate (FDA) vital stain microscopy.ResultAll the first six human MTBc lineages were represented in the population, plus M. bovis in 0.8% of the patients. The most widely represented lineage was the modern Euro-American lineage (L) 4, 57%, predominantly the T family, followed by L6 (M. africanum type 2) in 22.9%. Ancestral lineages 1, 5, 6 and M. bovis combined amounted to 28.8%. Excluding 25 patients with rifampicin resistance, smear conversion, both by AR and FDA, occurred later in L6 compared to L4 (HR 0.80 (95% CI 0.66–0.97) for AR, and HR 0.81 (95%CI 0.68–0.97) for FDA). In addition we found that HIV negative status, higher BMI at day 0, and patients with smear grade at baseline ≤ 1+ were associated with earlier smear conversion.ConclusionThe six major human lineages of the MTBc all circulate in Bamako. Counter to our hypothesis, we found that patients diseased with modern M. tuberculosis complex L4 respond faster to TB treatment than those with M. africanum L6.
“…However, it seemed to have limitations in settings where a "mixture" of MDR strains was present, for instance where there was additional resistance, especially to pyrazinamide, or where it is difficult to obtain a complete resistance profile of isolated strains [16][17][18][19]. Pyrazinamide resistance, however, can often be associated with rifampicin resistance [20].…”
Section: Dots-plusmentioning
confidence: 99%
“…The potential wide use of the regimen will, as for BPaL, be conditional to minimisation of creation of resistance to its new components. Concerningly, the presence of resistance to the fluoroquinolones and pyrazinamide among rifampicin-resistant cases, although frequently low, is already well documented in certain settings [20,21,37].…”
Section: While This Historical Account Summarises the Past And Presenmentioning
Over the past few decades, treatment of multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB) has been challenging because of its prolonged duration (up to 20–24 months), toxicity, costs and sub-optimal outcomes.After over 40 years of neglect, two new drugs (bedaquiline and delamanid) have been made available to manage difficult-to-treat MDR-/XDR-TB cases. World Health Organization (WHO) guidelines published in March 2019 endorsed the possibility of treating MDR-TB patients with a full oral regimen, following previous guidelines published in 2016 which launched a shorter regimen lasting 9–10 months.The objectives of this article are to review the main achievements in MDR-TB treatment through the description of the existing WHO strategies, to discuss the main ongoing trials and to shed light on potential future scenarios and revised definitions necessary to manage drug-resistant TB.
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