Counting Pyrazinamide in Regimens for Multidrug-Resistant Tuberculosis

Franke, Molly F.; Becerra, Mercedes C.; Tierney, Dylan B.; Rich, Michael; Bonilla, César; Bayona, Jaime; McLaughlin, Megan M.; Mitnick, Carole D.

doi:10.1513/annalsats.201411-538oc

Cited by 24 publications

(15 citation statements)

References 25 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of rifampin, a prior study found that phenotypic DST does not capture some clinically relevant resistance conferred by disputed rpoB mutations that had previously been considered of indeterminate significance; these were associated with a rate of failure or relapse of first-line retreatment of 63% (6). For pyrazinamide, only a few studies have directly evaluated the correlation between in vitro resistance with clinical outcomes (12,(29)(30)(31)(32). One of these reported that patients whose isolates had an MIC breakpoint of over 50 mg/liter had poor sputum conversion rates (12).…”

Section: Discussionmentioning

confidence: 99%

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

Velásquez

Calderón

Mitnick

et al. 2016

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

h Phenotypic drug susceptibility testing is the current "gold standard" for detecting Mycobacterium tuberculosis susceptibility to antituberculous drugs. Pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. Here we performed latent class analysis (LCA) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. We then compared this consensus measure to the 2-month culture results for patients with multidrug-resistant tuberculosis (MDR-TB) who were treated for 2 months with first-line antituberculous drugs before their resistance results were known. Among 121 patients with MDR-TB, 60 (49.6%) were resistant to pyrazinamide by the Wayne method (L. G. Wayne, Am Rev Respir Dis 109:147-151, 1974), 71 (58.7%) were resistant by the Bactec MGIT 960 method, and 68 (56.2%) were resistant by pncA sequencing. LCA grouped isolates with positive results by at least two assays into a category which we considered the "consensus gold standard" for pyrazinamide resistance. The sensitivity and specificity for this consensus gold standard were 82.4% and 92.5%, respectively, for the Wayne method; 95.6% and 88.7%, respectively, for the Bactec MGIT 960 method; and 92.6% and 90.6%, respectively, for pncA sequencing. After we adjusted for other factors associated with poor outcomes, including age, sex, alcohol use, and baseline ethambutol resistance, patients whose isolates were resistant by the LCA-derived consensus gold standard were more likely to be culture positive at 2 months with an odds ratio of 1.95 (95% confidence interval, 0.74 to 5.11), but this result was not statistically significant. These findings underscore the need for improved diagnostics for routine use in programmatic settings.

show abstract

Section: Discussionmentioning

confidence: 99%

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

Velásquez

Calderón

Mitnick

et al. 2016

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…[26] In contrast, the risk of mortality is nearly tripled when patients with pyrazinamide-resistant MDR-TB receive a regimen containing four likely effective drugs plus pyrazinamide that is not likely effective. [8] Since efficacy of treatment with pyrazinamide-containing regimens is compromised when pyrazinamide resistance is documented, pyrazinamide DST, even if imperfect, should guide regimen selection for patients with MDR-TB. [27] This is relevant to the current standard of care, including the recently endorsed shortened regimen and the conventional regimen, [9] as well as to new regimens under evaluation.…”

Section: Discussionmentioning

confidence: 99%

“…[6] Questions have emerged about the utility of pyrazinamide in MDR-TB treatment when sensitivity to the drug is not confirmed. [7] The inclusion of pyrazinamide when M. tuberculosis bacilli are pyrazinamide resistant has been associated with higher risk of death, [8] and may be associated with unnecessary toxicity. Consequently, current WHO guidelines recommend that additional drugs should be included in MDR-TB regimens if the effectiveness of pyrazinamide or other core drugs may be compromised by resistance.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of pyrazinamide resistance and Wayne assay performance analysis in a tuberculosis cohort in Lima, Peru

Calderón

Velásquez

Becerra

et al. 2017

int j tuberc lung dis

View full text Add to dashboard Cite

Rationale Multidrug-resistant (MDR) tuberculosis (TB) regimens often contain pyrazinamide, despite the absence of confirmed sensitivity to the drug. This gap is due to limited availability and reliability of pyrazinamide susceptibility testing. Objectives To estimate the prevalence of pyrazinamide resistance by the Wayne assay among TB patients in Lima, Peru; to describe characteristics associated with pyrazinamide resistance; and to compare Wayne performance to BACTEC MGIT 960. Methods In patients diagnosed with culture-positive pulmonary TB from September 2009 to August 2012, we tested pyrazinamide susceptibility using the Wayne assay. We evaluated factors associated with pyrazinamide resistance. In a convenience sample, we compared Wayne assay performance to MGIT 960. Results Pyrazinamide resistance prevalence was 6.6% (95% CI: 5.8%–7.5%) among 3,277 patients and 47.7% (95% CI: 42.7%–52.6%) among the subset of 405 MDR-TB patients. In multivariable analysis, MDR-TB (OR=86.0; 95% CI: 54.0–136.9) and LAM lineage (OR=3.40; 95% CI: 2.33–4.96) were associated with pyrazinamide resistance. The Wayne assay agreed with MGIT 960 in 83.9% of samples (Kappa: 0.66; 95% CI: 0.56–0.76). Conclusion Resistance to pyrazinamide was detected by the Wayne assay in nearly half of MDR-TB patients in Lima. This test can inform selection and composition of regimens, especially those dependent on additional resistance.

show abstract

“…5,6 Treatment approaches for MDR-TB have shown that increasing the number of medications used is more successful than increasing the duration of treatment. [7][8][9] Current treatment regimens have not been able to reduce the number of MDR-TB and XDR-TB infections while achieving reductions in the number of TB infections and death. Despite all this knowledge and notable efforts, only two new anti-TB drugs, bedaquiline and delamanid, were approved for TB therapy in the last halfcentury.…”

Section: Introductionmentioning

confidence: 99%

Some New Hydrazone Derivatives Bearing the 1,2,4-Triazole Moiety as Potential Antimycobacterial Agents

Sari

Tan

Sriram

et al. 2019

tjps

View full text Add to dashboard Cite

Bu çalışma, 1-(4-((2-(4-sübstitüefenil)hidrazono)metil)fenil)-1H-1,2,4-triazol türevlerinin sentezlerini yaparak yapılarını aydınlatmayı ve antimikobakteriyel aktivitelerini incelemeyi amaçlamaktadır. Gereç ve Yöntemler: Bu çalışmada hedef bileşikler (2a-h), 4-(1H-1,2,4-triazol-l-il)benzaldehidin uygun fenilhidrazinlerle kondenzasyonu ile elde edilmiştir. Bileşiklerin yapıları, IR, 1H-NMR ve kütle spektrometrisi ile aydınlatılmıştır. Antimikobakteriyel aktiviteleri, Mycobacterium tuberculosis H37Rv'ye karşı in vitro olarak incelenmiştir. Bulgular: Aktivite sonuçları incelendiğinde, metilsülfonil sübstitüe türevin 2f serinin en aktif üyesi olduğu bulunmuştur. Sonuç: Metilsulfonil sübstitüe türevin dikkate değer antimikobakteriyel aktivite göstermesine rağmen, sentezlenen bileşiklerin hiçbirinin M. tuberculosis'e karşı izoniazit, rifampin, etambutol ve siprofloksazin kadar etkili olmadıkları bulunmuştur. Anahtar kelimeler: Hidrazon, 1,2,4-triazol, antimikobakteriyel aktivite Objectives: The aim of this study was to synthesize, characterize, and screen some new 1-(4-((2-(4-substitutedphenyl)hydrazono)methyl)phenyl)-1H-1,2,4-triazole derivatives for their antimycobacterial activities. Materials and Methods: The target compounds (2a-h) were gained by condensation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde with appropriate phenylhydrazines. Their structures were elucidated by IR, 1 H-NMR, and mass spectrometry. The antimycobacterial activities of the compounds were determined in vitro against Mycobacterium tuberculosis H37Rv. Results: The biological assay results showed that the methylsulfonyl-substituted derivative 2f displayed the highest antimycobacterial activity in this series. Conclusion: Although the methylsulfonyl-substituted derivative exhibited significant antimycobacterial activity, none of the synthesized compounds was as effective as isoniazid, rifampin, ethambutol, and ciprofloxacin against M. tuberculosis.

show abstract

Counting Pyrazinamide in Regimens for Multidrug-Resistant Tuberculosis

Abstract: Mortality may be reduced by the inclusion of five likely effective drugs, including an injectable, during the intensive phase of treatment. If PZA is unlikely to be effective in an individual patient, these results suggest adding a different, likely effective drug.

Cited by 24 publications

References 25 publications

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

Prevalence of pyrazinamide resistance and Wayne assay performance analysis in a tuberculosis cohort in Lima, Peru

Some New Hydrazone Derivatives Bearing the 1,2,4-Triazole Moiety as Potential Antimycobacterial Agents

Contact Info

Product

Resources

About