Limited Tolerance of Ofloxacin and Pyrazinamide Prophylaxis against Tuberculosis

Horn, David L.; Hewlett, Dial; Alfalla, Celia; Peterson, Stephen J.; Opal, Steven M.

doi:10.1056/nejm199404283301718

Cited by 65 publications

(39 citation statements)

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“…The present report is, to the current authors' knowledge, the first to describe a high rate of drug-induced hepatitis in contacts treated in this context with a combination of PZA and EMB. Previous publications have described high rates of drug-induced hepatitis in contacts treated by PZA with either levofloxacin (47%) or ofloxacin (25-41%) [9][10][11]. Median time to peak increase in ASAT and/or ASAT was approximately 4 weeks in these three studies, with a wide variability (drug-induced hepatitis occurring up to 25 weeks after beginning of treatment).…”

Section: Discussionmentioning

confidence: 82%

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High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis: Table. 1—

Rochat²,

Jp³

et al. 2005

Eur Respir J

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Pyrazinamide (PZA) combined with either ethambutol (EMB) or a fluoroquinolone for 6-12 months is one of the treatments recommended for latent tuberculosis infection (LTBI) in contacts exposed to multidrug-resistant tuberculosis (MDR-TB). The aim of the present study was to describe the side effects related to combined PZA and EMB treatment given for LTBI, in contacts previously exposed to MDR-TB.In total, 12 consecutive contacts, all of African origin and aged 38¡5 yrs, were treated with daily PZA (23¡4 mg?kg -1 ) and EMB (17¡4 mg?kg -1) at Geneva University Hospital outpatient clinic (Switzerland), as a result of contact-tracing procedures for two patients with contagious MDR-TB.Clinical status and liver function tests (aspartate aminotransferase (ALAT) and alanine aminotransferase (ASAT)) were monitored monthly. In seven cases (58%) treatment was discontinued after a median of 119 days, due to hepatic toxicity in six cases (ALAT or ASAT elevation more than four times the upper normal limit), and gastrointestinal symptoms in one case.In conclusion, combined pyrazinamide and ethambutol for latent tuberculosis infection may be associated with a high risk of hepatic toxicity, and warrants close monitoring. There is clearly a need for alternative preventive treatments for contacts exposed to multidrug-resistant tuberculosis.

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Section: Discussionmentioning

confidence: 82%

“…Due to the lower hepatic toxicity of RIF alone, rather than that of PZA, the question of the toxicity of PZA and its' acceptability in a prophylactic treatment has been raised [7,8]. To date, information as to the toxicity of PZA in combination with either EMB or a fluoroquinolone is scarce [9][10][11].…”

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confidence: 99%

High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis: Table. 1—

Rochat²,

Jp³

et al. 2005

Eur Respir J

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“…If the clinical situation mirrors our results in mice, susceptibility of the infecting isolate to Z may indicate the potential for short-course therapy of 9 months or less if Z is continued. On the other hand, continuing Z in the face of resistance may not provide any treatment-shortening benefit while increasing the risk of intolerance and/or toxicity, as observed with fluoroquinolone-Z combinations used to treat latent TB infection among MDR-TB contacts (46)(47)(48)(49). Given the favorable interactions between Z and new TB drugs in development and rising concerns over Z resistance among MDR-TB isolates, improved susceptibility testing methods for Z, including genotypic resistance testing, will continue to require attention in the future (50)(51)(52)(53).…”

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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“…Still, the use of MXF alone (or in combination with EMB) for 9 to 12 mo may constitute an efficacious oral regimen for persons intolerant of PZA or ETH. Given the apparent frequency with which PZA and regimens containing PZA have been implicated in causing hepatotoxicity (7,(14)(15)(16)(17)40), such a regimen may provide a valuable alternative regimen for patients with MDR-LTBI.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, in some outbreak settings, combinations of PZA with ofloxacin or levofloxacin have been associated with treatment-limiting hepatotoxicity (14)(15)(16)(17). The paucity of data regarding the efficacy of these or other chemoprophylactic regimens for treatment of MDR-LTBI is of great concern given the increasing prevalence of MDR-TB in many parts of the world and the potential use of MDR-TB strains as agents of bioterrorism.…”

mentioning

confidence: 99%

Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model

Nuermberger

Tyagi

Williams

et al. 2005

Am J Respir Crit Care Med

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Rationale: Priorities for developing improved regimens for treatment of latent tuberculosis (TB) infection include (1 ) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2 ) developing and evaluating regimens that are active against multidrug-resistant organisms. Objectives and Methods: By using a previously validated murine model that involves immunizing mice with Mycobacterium bovis bacillus Calmette-Guérin to augment host immunity before infection with virulent Mycobacterium tuberculosis, we evaluated new treatment regimens including rifapentine and moxifloxacin, and assessed the potential of the Mycobacterium leprae heat shock protein-65 DNA vaccine to augment the activity of moxifloxacin. Measurements: Quantitative spleen colony-forming unit counts, and the proportion of mice with culture-positive relapse after treatment, were determined. Main Results: Three-month, once-weekly regimens of rifapentine combined with either isoniazid or moxifloxacin were as active as daily isoniazid for 6-9 mo. Six-month daily combinations of moxifloxacin with pyrazinamide, ethionamide, or ethambutol were more active than pyrazinamide plus ethambutol, a regimen recommended for latent TB infection after exposure to multidrug-resistant TB. The combination of moxifloxacin with the experimental nitroimidazopyran PA-824 was especially active. Finally, the heat shock protein-65 DNA vaccine had no effect on colony-forming unit counts when given alone, but augmented the bactericidal activity of moxifloxacin. Conclusions: Together, these findings suggest that rifapentine, moxifloxacin, and, perhaps, therapeutic DNA vaccination have the potential to improve on the current treatment of latent TB infection.Keywords: DNA vaccine; latency; moxifloxacin; rifapentine; tuberculosisThe objective of treatment for latent tuberculosis infection (LTBI) is to prevent the development of overt tuberculosis (TB) disease in infected, but asymptomatic, individuals. At present, a 9-mo course of daily isoniazid (INH) is recommended as firstline therapy for LTBI (1). Alternative regimens include a shorter 6-mo course of INH, which is likely inferior to a 9-mo course (2), or a 4-mo course of daily rifampin (RIF), which is largely untested (1, 3). Although it is comparable in efficacy to 6 or 12 mo of INH (4-6), a 2-mo course of RIF plus pyrazinamide (PZA) is no longer recommended for use because of concerns over excessive hepatotoxicity (7). Priorities for developing improved regimens for treatment of LTBI include (1 ) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2 ) developing and evaluating regimens that are active against multidrug-resistant organisms (8).(Received in original form July 6, 2005; accepted in final form September 7, 2005) Supported by the National Institutes of Health (grant AI58993 and supplement to grant AI43846), the Global Alliance for TB Drug Development, and the Potts Memorial Foundation. Regarding the first objective, the l...

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Limited Tolerance of Ofloxacin and Pyrazinamide Prophylaxis against Tuberculosis

Cited by 65 publications

References 0 publications

High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis: Table. 1—

High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis: Table. 1—

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

Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model

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