Aerosolized Gentamicin Reduces the Burden of Tuberculosis in a Murine Model

Roy, Chad J.; Sivasubramani, Satheesh K.; Dutta, Noton K.; Mehra, Smriti; Golden, Nadia; Killeen, Stephanie Z.; Talton, James D.; Hammoud, Badre E.; Didier, Peter J.; Kaushal, Deepak

doi:10.1128/aac.05633-11

Cited by 14 publications

(7 citation statements)

References 14 publications

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“…However, pathological differences between M. tuberculosis-infected mice and humans have raised concerns about the "predictiveness" of mouse models with respect to novel drugs or drug regimens, which require more human-like pathology for optimal activity. Human TB is characterized histologically by the presence of necrotic granulomas, which are absent in BALB/c mice (2,39). Like rabbits and nonhuman primates, guinea pigs infected with M. tuberculosis develop necrotic granulomas characterized by tissue hypoxia (9-14, 25, 38), which is not a feature of mouse granulomas (9-14, 25, 34, 35).…”

Section: Discussionmentioning

confidence: 99%

Potent Rifamycin-Sparing Regimen Cures Guinea Pig Tuberculosis as Rapidly as the Standard Regimen

Dutta

Alsultan

Gniadek

et al. 2013

Antimicrob Agents Chemother

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e Strategies involving new drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug-sensitive or multidrug-resistant (MDR) tuberculosis (TB). We compared the sterilizing activity of the standard first-line antitubercular regimen, rifampin-isoniazid-pyrazinamide (RHZ), with that of the novel regimen PA-824 -moxifloxacin-pyrazinamide (PaMZ), which is currently being studied in clinical trials (NCT01498419), in the guinea pig model of chronic TB infection, in which animals develop necrotic granulomas histologically resembling their human counterparts. Guinea pigs were aerosol infected with ϳ2 log 10 bacilli of wild-type Mycobacterium tuberculosis H37Rv, and antibiotic treatment was initiated 6 weeks after infection. Separate groups of animals received RHZ, PaMZ, or single or two-drug components of the latter regimen administered at human-equivalent doses 5 days/week for a total of 8 weeks. Relapse rates were assessed 3 months after discontinuation of treatment to determine the sterilizing activity of each combination regimen. PaMZ given at human-equivalent doses was safe and well tolerated for the entire treatment period and rendered guinea pig lungs culture negative more rapidly than RHZ did. After 1 month of treatment, 80% and 50% of animals in the RHZ and PaMZ groups, respectively, had lung culture-positive relapse. Both combination regimens prevented microbiological relapse when administered for a total of 2 months. Our data support the use of PaMZ as a novel isoniazid-and rifamycin-sparing regimen suitable for treatment of both drug-sensitive TB and MDR-TB. The increasing global burden of drug-resistant tuberculosis (TB) underscores the need for new drugs but also for shorter, better-tolerated regimens to reduce treatment durations from the current 18 to 24 months for multidrug-resistant TB (MDR-TB) (1, 2). Shorter regimens are expected to improve adherence to treatment, thereby reducing transmission and the emergence of new drug resistance, as well as facilitating coadministration with antiretroviral regimens and curbing costs. As a result of continuing efforts to evaluate novel drug combinations with treatmentshortening potential, several new drugs have been shown to contribute to reducing the time required to achieve a relapse-free state in animal models (3-6).A paradigm shift from "drug development" to "regimen development," wherein the regimen, not an individual drug, is the unit of development, seems a more feasible approach to deliver sufficiently novel combinations more rapidly (1). The novel regimen PaMZ, comprising PA-824 (Pa), moxifloxacin (M), and pyrazinamide (Z), a combination containing neither rifampin (R) nor isoniazid (H), was found to have a sterilizing activity superior to that of the current first-line regimen, RHZ, in mice (3, 7). In addition, studies in the mouse model have revealed synergism between the agents in the novel combination (3, 7). Recently, a phase II clinical study confirmed the potent initial activ...

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Section: Discussionmentioning

confidence: 99%

Potent Rifamycin-Sparing Regimen Cures Guinea Pig Tuberculosis as Rapidly as the Standard Regimen

Dutta

Alsultan

Gniadek

et al. 2013

Antimicrob Agents Chemother

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“…Four groups of 28 male C3HeB/FeJ mice (5-6 wk old) (Jackson Laboratory, Bar Harbor, ME) were infected with approximately 100 CFUs of bacilli via aerosol (17) (Table 1). Initial bacterial deposition was determined by killing four mice from each group at Day 1 (17). Four mice per group were then killed every 4 weeks for CFU count, histopathology, and host immune response assays (Weeks 0, 4, 8, 12, 16, and 20).…”

Section: Mice and Infectionmentioning

confidence: 99%

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

Gautam¹,

McGillivray²,

Mehra

et al. 2015

Am J Respir Cell Mol Biol

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Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the D-dosR, D-dosS, and D-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although D-dosR and D-dosT grew comparably to wild-type Mtb, D-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. D-dosS retained the ability to induce DosR. The D-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice.The attenuation of D-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of D-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.Keywords: Mycobacterium tuberculosis; hypoxia; response regulator; sensor kinase; latency Clinical RelevanceOur research indicates that the C3HeB/FeJ mouse model is appropriate for the study of Mycobacterium tuberculosis pathogenesis because it reveals attenuation in the D-dosS mutation. It appears that this attenuation is not the result of hypoxia in lung granulomas.

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“…We hypothesized that the efficacy of P relative to R may be overrepresented in the murine model of TB, in which the bacilli are almost exclusively located in the intracellular compartment (30). In addition, since human TB is characterized histologically by the presence of necrotic granulomas harboring persistent bacilli (34), which are absent in BALB/c mice (7,17,31), it is possible that penetration of P into such lesions may be limited due to its relatively high protein binding. In the current study, we directly compared the activity of human-equivalent exposures of P and R, both alone and in combination with the first-line drugs isoniazid (H) and pyrazinamide (Z), in a guinea pig model of chronic TB, which is characterized by a predominantly extracellular population of bacilli residing within necrotic lung granulomas histologically resembling their human counterparts (1-5, 18, 19, 21, 23).…”

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Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

Dutta

Illei

Peloquin

et al. 2012

Antimicrob Agents Chemother

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e Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ϳ200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening. R ifapentine (P), a cyclopentyl rifamycin with a much longer half-life than rifampin (R) (10 to 15 h compared to 2 to 5 h, respectively), was developed with the goal of allowing highly active once-weekly therapy for tuberculosis (TB) (37). However, relative to twice-or thrice-weekly rifampin-isoniazid (RH), once-weekly PH during the continuation phase of treatment was associated with greater drug-susceptible relapse among HIV-negative patients with lung cavitation (8) and a significant incidence of acquired rifamycin monoresistance among HIV-positive patients (35). Recent data in a murine model of active TB showed that increasing rifamycin exposure by daily dosing of P in place of R improved sterilizing activity, suggesting that daily P might permit shortening of treatment duration (28-30). These encouraging results prompted a large-scale phase 2 clinical trial conducted by the Tuberculosis Trials Consortium (TBTC study 29) to evaluate the safety and efficacy of a regimen in which P is substituted for R during the initial 8 weeks of treatment (13).P is known to have significantly higher intracellular accumulation relative to R, as the MIC and minimal bactericidal concentration (MBC) of P against Mycobacterium tuberculosis H37Rv within macrophages are 4-fold lower than the corresponding values against extracellular bacilli (22). On the other hand, the MIC and MBC of R against intracellular M. tu...

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Aerosolized Gentamicin Reduces the Burden of Tuberculosis in a Murine Model

Cited by 14 publications

References 14 publications

Potent Rifamycin-Sparing Regimen Cures Guinea Pig Tuberculosis as Rapidly as the Standard Regimen

Potent Rifamycin-Sparing Regimen Cures Guinea Pig Tuberculosis as Rapidly as the Standard Regimen

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

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