Limited Tolerability of Levofloxacin and Pyrazinamide for Multidrug‐Resistant Tuberculosis Prophylaxis in a Solid Organ Transplant Population

Lou, Huei-Xin; Shullo, M.; McKaveney, Teresa P.

doi:10.1592/phco.22.9.701.34065

Cited by 48 publications

(30 citation statements)

References 18 publications

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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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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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“…However the optimal duration of fluoroquinolone-containing regimens is unknown. Combined and prolonged use of levofloxacin and pyrazinamide has been associated with poor gastrointestinal tolerance [103,104].…”

Section: Treatment Of Active Tb In Transplant Recipientsmentioning

confidence: 99%

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Bumbăcea

Arend

Eyüboğlu³

et al. 2012

Eur Respir J

232

261

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Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-c based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking. KEYWORDS: Guideline, management, Mycobacterium tuberculosis, transplantation, tuberculosis T uberculosis (TB) is caused by the pathogenic species of the Mycobacterium tuberculosis complex. Only a minority of individuals who develop an adaptive immune response following infection with M. tuberculosis will ever develop TB, with the actual risk depending on the extent to which the host immune system provides a successful or inadequate response [1,2]. Therefore, individuals with impaired immune response, such as solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, are more prone to develop TB than immunocompetent persons. TB in transplant recipients is more frequent compared to the general population (estimates from the last decades state 20-74 times as frequent in SOT [3,4] and twice as frequent in HSCT [5]), and more often fatal (up to 31% in SOT [6] and up to 50% in HSCT recipients [7]), thus adding effectiveness to interventions for its prevention, even in the face of difficulties, with treatment related to adverse drug events and drug-drug interactions. Active TB in transplant recipients can result from latent infection with M. tuberculosis (LTBI) in the transplant candidate or in the donor tissue, or from de novo post-transplant infection. These various scenarios prompt for targeted pre-transplant screening of both recipient and, if possible, donors to allow focused management of recipients selected for preventive intervention in the pre-and/or posttransplant period. The term ''preventive chemotherapy'' is used to denote treatmen...

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“…A report of 48 solid organ transplant recipients who were receiving levofloxacin and pyrazinamide for presumed MDR LTBI revealed that 32 (67%) discontinued therapy prematurely because of adverse events. 151 Gastrointestinal intolerance accounted for more than half of the adverse events. In a case series of 17 persons in Ontario, Canada with suspected MDR LTBI who were treated with levofloxacin and pyrazinamide, all 17 discontinued treatment because of a variety of adverse effects including musculoskeletal, central nervous system, gastrointestinal and dermatologic symptoms.…”

Section: Treatment Of Latent Tuberculosis Infection In Contacts Of Acmentioning

confidence: 99%

Treatment of latent tuberculosis infection: An update

2010

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Isoniazid (INH) has been the mainstay of treatment of latent tuberculosis infection for almost 50 years. The currently recommended preferred regimen is 9 months daily self-administered INH (9H); this has efficacy of more than 90% if completed properly. Unfortunately, INH is associated with serious adverse events, including hepatotoxicity. Although risk factors for this complication are well established, allowing for better selection of candidates for therapy, this complication still occurs, and is occasionally fatal. Hence close follow up of patients is necessary, increasing the cost and complexity of treatment. This problem, plus the lengthy duration, results in poor acceptance by patients and providers, and poor adherence by patients. As a result, many preventable cases of tuberculosis continue to occur, and the public health impact of latent tuberculosis infection treatment is suboptimal. These problems have spurred interest in finding shorter, safer and cheaper alternative regimens, with similar efficacy. Of the many regimens that have been examined, 2 months of rifampin and pyrazinamide has excellent efficacy-in experimental studies in mice and randomized trials, largely in HIV-infected persons. However, while the safety of 2 months of rifampin and pyrazinamide appears acceptable in HIV-infected persons and children, in non-HIV-infected adults this regimen is associated with an unacceptably high rate of severe liver toxicity. Three to four months of INH and rifampin has had equivalent effectiveness as 6 months INH in several randomized trials. However, completion of therapy and toxicity has been the same as with INH-possibly because two drugs are taken rather than one.The fourth commonly studied regimen is 4 months rifampin. This has been found to have significantly better completion than 9H, with significantly less toxicity, especially hepatotoxicity. However, only one trial has evaluated efficacy and effectiveness of mono-rifampin therapy. In this trial, 3 months rifampin had somewhat better efficacy than either 3 months of isoniazid and rifampin (3HR) or 6 months isoniazid. Two large scale trials are ongoing; one is comparing efficacy and effectiveness of 9H with 4 months rifampin (both daily and self-administered), while the second, which is nearing completion, compares daily self-administered 9H with 3 months directly observed once weekly INH combined with rifapentine. The results of these two trials will likely shape future recommendations substantially.r esp_1751 603..622

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Limited Tolerability of Levofloxacin and Pyrazinamide for Multidrug‐Resistant Tuberculosis Prophylaxis in a Solid Organ Transplant Population

Abstract: Prophylaxis of MDRTB with levofloxacin and pyrazinamide was associated with limited tolerability due to the high frequency of adverse events. While we search for a better tolerated prophylactic regimen, close monitoring for adverse reactions is recommended.

Cited by 48 publications

References 18 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

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Treatment of latent tuberculosis infection: An update

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