Fourth-Generation Fluroquinolones Effective Despite Pyrazinamide-Rifampicin Linked TB Resistance

Pyrazinamide resistance linked with rifampicin resistance in treating TB, however, fourth generation fluoroquinolones are still highly effective.

While Mycobacterium tuberculosis resistance to pyrazinamide has been strongly linked with rifampicin resistance, fourth generation fluoroquinolones are still highly effective in the fight against TB, according to a retrospective, population level study published in The Lancet Infectious Diseases.1

Matteo Zignol, MD, of the Global Tuberculosis Programme at the World Health Organization in Geneva, Switzerland, and colleagues looked at trends of TB resistance in Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa using molecular epidemiology analysis to study TB resistance to pyrazinamide and  fluoroquinolones at the population level.

Researchers collected sputum samples that were tested at the National Tuberculosis Reference Laboratory using the Lowenstein-Jensen (LJ) proportion method for Azerbaijan, Bangladesh, and Pakistan and the Mycobacteria Growth Indicator Tube (MGIT) 960 method for Belarus and South Africa.

Pyrazinamide resistance was examined in 4972 patients using gene sequencing to detect mutations located in the pncA gene that caused resistance to pyrazinamide. Dr Zignol and colleagues used the MGIT system to check for fluoroquinolone resistance in 5015 patients.

For pyrazinamide, researchers reported a wide variation of resistance among populations, ranging between 3% and 42.1%. However, they reported significant association between pyrazinamide resistance and rifampicin resistance. In spite of this, “…this drug may still be effective in 19% to 63% of patients with rifampicin-resistant tuberculosis,” Dr Zignol and colleagues reported.

Researchers said pyrazinamide is essential part of short-term treatment regimens and regimens for drug resistant TB that is recommended by WHO.

While TB has developed resistance to earlier generations of fluoroquinolones, “Resistance to the latest generation of fluoroquinolones (moxifloxacin and gatifloxacin at 2.0 μg/mL) was extremely low in all settings, even among patients with rifampicin resistance. This finding can be partly explained by the still-infrequent use of fourth-generation fluoroquinolones in most countries,” the researchers said.

Dr Zignol and colleagues reported two limitations to their study. First, researchers said that because the research was to examine multi-drug resistant TB, when investigators saw low levels of resistance they said estimates having wide confidence intervals were an issue.

“Although higher levels of resistance to most drugs were evident among rifampicin resistant and previously treated cases, statistically significant differences could not be detected in all settings due to insufficient power,” Dr Zignol and colleagues reported.

Second, researchers reported that WHO’s suggested thresholds of critical concentrations used for phenotypic testing “might not be ideal.”  They went on to explain that the observed lack of TB resistance to moxifloxacin and gatifloxacin could be caused by very high breakpoints. They also said that differences between examining laboratories may have played a part in results.

This retrospective study offers background into current levels of resistance to TB treatments in specific populations and offers guidance in treatment of multi-drug resistant TB.

“These findings are crucial for the design of standard regimens in different settings, guidance to regimen developers and diagnostic manufacturers, and the introduction of existing regimens for the treatment of drug-resistant tuberculosis,” the researchers concluded.

Related Articles


  1. Zignol M, Dean AS, Alikhanova N et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Infect Dis. 2016; 16:1185-1192. doi: 10.1016/S1473-3099(16)30190-6.