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 hundred and twenty-three culture isolates from rifampicin-resistant (RR) patients were collected in twelve Sub-Saharan African countries. Among those isolates, 71% were from patients included in the study on the Union short-course regimen for MDR-TB in Benin, Burkina Faso, Burundi, Cameroon, Central Africa Republic, the Democratic Republic of the Congo, Ivory Coast, Niger, and Rwanda PZA resistance, and the rest (29%) were consecutive isolates systematically stored from 2014–2015 in Mali, Rwanda, Senegal, and Togo. Besides national guidelines, the isolates were tested for PZA resistance through pncA gene sequencing.ResultsOver half of these RR-TB isolates (54%) showed a mutation in the pncA gene, with a significant heterogeneity between countries. Isolates with fluoroquinolone resistance (but not with injectable resistance or XDR) were more likely to have concurrent PZA resistance. The pattern of mutations in the pncA gene was quite diverse, although some isolates with an identical pattern of mutations in pncA and other drug-related genes were isolated from the same reference center, suggesting possible transmission of these strains.ConclusionSimilar to findings in other regions, more than half of the patients having RR-TB in West and Central Africa present concomitant resistance to PZA. Further investigations are needed to understand the relation between resistance to PZA and resistance to fluoroquinolones, and whether continued use of PZA in the face of PZA resistance provides clinical benefit to the patients.

<p>Resistance To First-Line Antituberculosis Drugs And Prevalence Of <em>pncA</em> Mutations In Clinical Isolates Of <em>Mycobacterium tuberculosis</em> From Zunyi, Guizhou Province Of China</p>

“…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…”

Mycobacterium africanum (Lineage 6) shows slower sputum smear conversion on tuberculosis treatment than Mycobacterium tuberculosis (Lineage 4) in Bamako, Mali

“…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].…”

Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives

“…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].…”

“…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].…”