“…3 and 4), suggests that PZA resistant strains are transmissible. Contrary to the majority of first- and second line drug resistance mutations, multiple studies show that neither the fitness nor the virulence are significantly reduced by pncA mutations and data from Quebec moreover show that pncA mutants can maintain virulence and transmit [23, 44, 45]. However, as MIRU-VNTR typing has limited power to discriminate within genetically very similar strains only the comparison of the genomes of the respective strains can confirm our observation and rule out the possibility that the mutations in pncA have not been individually acquired.Fig.…”
BackgroundThe ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region.MethodsPhenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates.ResultsOut of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94–32 and 100–32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region.ConclusionIn this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.
“…3 and 4), suggests that PZA resistant strains are transmissible. Contrary to the majority of first- and second line drug resistance mutations, multiple studies show that neither the fitness nor the virulence are significantly reduced by pncA mutations and data from Quebec moreover show that pncA mutants can maintain virulence and transmit [23, 44, 45]. However, as MIRU-VNTR typing has limited power to discriminate within genetically very similar strains only the comparison of the genomes of the respective strains can confirm our observation and rule out the possibility that the mutations in pncA have not been individually acquired.Fig.…”
BackgroundThe ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region.MethodsPhenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates.ResultsOut of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94–32 and 100–32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region.ConclusionIn this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.
“…The clinical
significance of the rare low level PZA-resistant PZase positive strains is
unclear as they may still respond to PZA treatment in vivo. The virulence and
fitness of PZA-resistant strains with pncA mutations seem to be
unaltered and such strains appear to not only be capable of causing active
transmission of disease (63) but also
seem to be more virulent as shown in a more recent study (68). …”
PZA is a unique anti-tuberculosis drug that plays a key role in
shortening the TB therapy. PZA kills non-replicating persisters that other TB
drugs fail to kill, and thus making it an essential drug for inclusion in any
drug combinations for treating drug susceptible and drug-resistant TB such as
MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple
targets such as energy production, trans-translation and perhaps pantothenate
/coenzyme A required for persister survival. Resistance to PZA is mostly caused
by mutations in the pncA gene encoding pyrazinamidase involved in conversion of
the prodrug PZA to the active form POA. Mutations in the drug target RpsA are
also found in some PZA-resistant strains. The recent finding that panD mutations
are found in some PZA-resistant strains without pncA or rpsA mutations may
suggest a third PZA resistance gene and a potential new target of PZA. Current
phenotype based PZA susceptibility testing is not reliable due to false
resistance, and sequencing of the pncA gene represents a more rapid,
cost-effective and more reliable molecular test for PZA susceptibility testing
and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the
story of PZA has important implications for not only TB therapy but also
chemotherapy in general. PZA serves as a model prototype persister drug and
hopefully a ‘tipping point’ that inspires new efforts at
developing a new type of antibiotics or drugs that target non-replicating
persisters for improved treatment of not only TB but also other persistent
bacterial infections.
“…Moreover, 38% of MDR cases also harbor resistance to PZA, which results from inactivating mutations in the pnc A allele [1], [2]. In a retrospective cohort study spanning 11 years, cases in Quebec infected with PZA monoresistant M.tb were less likely to be categorized as cured after treatment compared to patients infected with pan-susceptible M.tb (adjusted odds ratio [aOR], 0.4; 95% confidence interval [CI], 0.2–0.8) [3]. An improved understanding of PZA monoresistance and its influence on treatment response in other regions is needed as new duration shortened regimens are under development that include PZA as a companion drug [4].…”
BackgroundPyrazinamide (PZA) is a first line agent for the treatment of active tuberculosis. PZA is also considered a potent companion drug for newer regimens under development. There are limited data on the demographic, clinical, and pathogen characteristics of PZA resistant tuberculosis.MethodsUsing a retrospective cohort study design, we evaluated all PZA resistant M. tuberculosis (M.tb) and M. bovis cases reported in San Francisco from 1991 to 2011. Demographic, clinical, and molecular data were analyzed. M.tb lineage was determined for all PZA resistant strains and compared to PZA susceptible strains.ResultsPZA resistance was identified in 1.8% (50 of 2,842) of mycobacterial isolates tested, corresponding to a case rate of 0.3 per 100,000 in the population. Monoresistant PZA infection was associated with the Hispanic population ([OR], 6.3; 95% [CI], 1.97–20.16) and 48% of cases were due to M. bovis. Infection with monoresistant PZA was also associated with extrapulmonary disease ([OR], 6.0; 95% [CI], 2.70–13.26). There was no statistically significant difference between treatment failure and mortality rates in patients infected with PZA monoresistance compared to pansusceptible controls (4% vs. 8%, p = 0.51), or those with PZA and MDR resistance (PZA-MDR) compared to MDR controls (18% vs. 29%, p = 0.40). PZA resistance was not associated with M.tb lineage.ConclusionsAcross two decades of comprehensive epidemiologic data on tuberculosis in San Francisco County, PZA resistance was uncommon. PZA resistance caused predominantly extrapulmonary disease and was more common in Hispanics compared to other ethnicities, with nearly half the cases attributed to M. bovis. No association was found between PZA monoresistance and M.tb lineage. Treatment outcomes were not adversely influenced by the presence of PZA resistance.
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