Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project

Abstract

SummaryBackgroundPyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available.MethodsIn a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system.FindingsPyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0–42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0–16·6% for ofloxacin, to 0·5–12·4% for levofloxacin, and 0·9–14·6% for moxifloxacin when tested at 0·5 μg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 μg/mL was low in all countries.InterpretationAlthough pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19–63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness.FundingBill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…Resistance to the latest generation fluoroquinolones at the clinical breakpoint is still uncommon, a finding supporting current WHO recommendations to use moxifloxacin or gatifloxacin in the treatment of MDR-TB. 36 …”

Preexisting variation in DNA damage response predicts the fate of single mycobacteria under stress

“…The efficacy of fluoroquinolones in bulk assays is inversely proportional to the bacterial metabolic state and cell density, not merely due to target unavailability and decreased permeability (Sarathy et al, 2013;Gutierrez et al, 2017), but also for the ability of both replicating and non-replicating cells to repair DNA (Volzing and Brynildsen, 2015). Conversely, M. tuberculosis expresses relatively low levels of recA, also following exposure to fluoroquinolones, and its mutation rate is generally low (O'Sullivan et al, 2008;Zignol et al, 2016;Gagneux, 2018). In model microorganisms, the formation of cells persistent to fluoroquinolones and increased mutation rate were associated with constitutive induction of the SOS response (Dörr et al, 2009).…”

The shorter multidrug-resistant tuberculosis treatment regimen in Singapore: are patients from South-East Asia eligible?

“…Data from Pakistan and Brazil showed more optimistic eligibility rates of 50% or higher [11,12]. A multicountry population-based survey showed that, although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug might still be effective in 19-63% of patients with rifampicin-resistant TB, and that the worrisome high level of ofloxacin resistance in Pakistan ( probably reflecting extensive, unregulated use of fluoroquinolones in some parts of Asia) was tempered by the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites [13]. To our knowledge, there are to date no publications on the eligibility of this regimen among patients with MDR-PTB from South-east Asia, India and China.…”