Pyrazinamide May Improve Fluoroquinolone-Based Treatment of Multidrug-Resistant Tuberculosis

Chang, Kwok Chiu; Leung, Chi Chiu; Yew, Wing Wai; Leung, Eric Chung Ching; Leung, Wai Man; Tam, Cheuk Ming; Zhang, Ying

doi:10.1128/aac.01300-12

Cited by 43 publications

(33 citation statements)

References 33 publications

(37 reference statements)

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“…Indeed, the use of Z throughout largely abrogated the difference observed between MEt and LEt continuation phase regimens. The sterilizing activity of Z under acidic conditions in vitro, in mice, and in humans is well documented (22,42). Indeed, the addition of Z to regimens containing rifampin and H permits shortening the duration of TB treatment from 9 to 6 months and constitutes one basis of modern short-course TB therapy (22,23).…”

Section: Discussionmentioning

confidence: 99%

Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

Ahmad

Tyagi

Minkowski

et al. 2013

Am J Respir Crit Care Med

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Rationale: High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown. Objectives: We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months. Methods: A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ. Measurements and Main Results: After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log 10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log 10 lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment. Conclusions: In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months in fluoroquinolonecontaining second-line regimens, largely compensating for L's weaker activity.

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Section: Discussionmentioning

confidence: 99%

Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

Ahmad

Tyagi

Minkowski

et al. 2013

Am J Respir Crit Care Med

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“…PZA acts synergistically with other TB drugs to accelerate culture conversion and reduce the risk of relapse among patients with drug-susceptible TB (1). In patients with multidrug-resistant (MDR) TB, defined as resistance to at least isoniazid (INH) and rifampin (RIF), inclusion of PZA is recommended to reduce the treatment duration (2,3), while optimizing MDR TB treatment regimens based on PZA susceptibility may improve clinical outcomes (4).…”

mentioning

confidence: 99%

Epidemiologic Correlates of Pyrazinamide-Resistant Mycobacterium tuberculosis in New York City

Verdugo

Fallows

Ahuja

et al. 2015

Antimicrob Agents Chemother

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r was acquired somewhat more frequently via primary transmission than by independent pathways. Our molecular analysis also revealed that several historic M. tuberculosis strains responsible for MDR TB outbreaks in the early 1990s were continuing to circulate in NYC. We conclude that the increasing incidence of PZA r , with clear microbial risk factors, underscores the importance of routine PZA drug susceptibility testing and M. tuberculosis genotyping for the identification, control, and prevention of increasingly resistant organisms.

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“…Recent clinical investigations clarified that PZA resistance has become an underestimated problem, since it may occur in up to 43% of MDR-TB strains (7,17). Additional treatment outcome studies that aimed to address the clinical significance of in vitro PZA resistance have shown that a FQ-based MDR regimen increased early culture conversion and treatment completion by 38% versus a similar treatment without PZA (18,19). Clearly, the consequence of losing PZA for the treatment of MDR-TB is highly significant.…”

Section: (Iii) Is There a Need For A Rapid Screening Test For Pyrazinmentioning

confidence: 99%

“…Clearly, the consequence of losing PZA for the treatment of MDR-TB is highly significant. In comparison, the addition of PZA to INH and RIF for the treatment of susceptible TB increased the 2-month culture conversion by 15 to 20% (18). Therefore, rapid screening of the pncA and rpsA genes for mutations known or likely to be associated with phenotypic PZA resistance is indispensable.…”

Section: (Iii) Is There a Need For A Rapid Screening Test For Pyrazinmentioning

confidence: 99%

Commentary: The Race Is On To Shorten the Turnaround Time for Diagnosis of Multidrug-Resistant Tuberculosis

Somoskövi

2015

J Clin Microbiol

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A ccording to the World Health Organization (WHO), there are many hot spots of multidrug-resistant tuberculosis (MDR-TB), defined as resistance to rifampin (RIF) and isoniazid (INH), in the world. In one of the hot spots, the Russian Federation, a total of 142,500 TB cases, including an estimated 41,000 MDR-TB pulmonary cases in 2013, were reported. Of all new TB cases, 19% were MDR-TB, and among retreated cases, 49% were MDR-TB cases (1). In contrast, the U.S. Centers for Disease Control and Prevention (CDC) reported 9,582 TB cases, including 96 MDR-TB cases in 2014, resulting in 1.3% of all TB cases with available antimicrobial susceptibility test (AST) results (2). The time has come to screen all TB cases in the United States for MDR-TB either at the time a sputum specimen tests positive with a nucleic acid amplification test (NAAT) or when the culture yields a positive result for Mycobacterium tuberculosis complex.The faster turnaround time for diagnosing MDR-TB, enabled by current molecular assays which yield results within hours compared to weeks and months with conventional testing, is needed in order to make up for lost time because of patient and/or health care system delays. An earlier diagnosis of MDR-TB facilitates earlier prescription of an adequate regimen benefiting patients and public health. However, in addition to screening all patients rapidly for MDR-TB, additional information is necessary from molecular assays for the successful management of MDR-TB patients.Besides the presence or absence of M. tuberculosis, the next additional answer from a routine rapid molecular test is whether the patient's specimen contains MDR-TB. In cases where MDR-TB is confirmed, the second question that such an assay will need to rapidly confirm is the presence of extensively drug-resistant tuberculosis (XDR-TB), which is defined as MDR-TB plus resistance to quinolones and second-line injectable drugs. IS RAPID CONFIRMATION OF THE FACT THAT THE PATIENT HAS MDR-OR XDR-TB ENOUGH OR DO WE NEED TO GO BEYOND WITH RAPID MOLECULAR SCREENING?In light of the accumulating evidence on the meaning of molecular mechanisms of different first-and second-line antituberculosis drugs, by appropriate characterization of known and newly identified resistance-associated mutations with quantitative phenotypic susceptibility testing, it is time to raise the question " is rapid detection of MDR and XDR-TB alone enough to successfully win the war on TB or MDR-TB?" Can we extract and utilize more meaningful diagnostic information from currently used molecular tests for our patients?In order to settle this question, we need to keep in mind that molecular markers cannot only rapidly confirm the presence of MDR-TB, they may also provide additional valuable information that can help to predict the level of phenotypic resistance or even cross-resistance to certain first-and second-line antituberculosis drugs. These molecular markers may provide such important additional information as to significantly influence the care of the patient and ultim...

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Pyrazinamide May Improve Fluoroquinolone-Based Treatment of Multidrug-Resistant Tuberculosis

Cited by 43 publications

References 33 publications

Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

Epidemiologic Correlates of Pyrazinamide-Resistant Mycobacterium tuberculosis in New York City

Commentary: The Race Is On To Shorten the Turnaround Time for Diagnosis of Multidrug-Resistant Tuberculosis

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