Adjunctive Salvage Therapy with Inhaled Aminoglycosides for Patients with Persistent Smear-Positive Pulmonary Tuberculosis

We formulated PA-824, a nitroimidazopyran with promise for the treatment of tuberculosis, for efficient aerosol delivery to the lungs in a dry powder porous particle form. The objectives of this study were to prepare and characterize a particulate form of PA-824, assess the stability of this aerosol formulation under different environmental conditions, and determine the pharmacokinetic parameters for the powder after pulmonary administration. The drug was spray dried into porous particles containing a high drug load and possessing desirable aerosol properties for efficient deposition in the lungs. The physical, aerodynamic, and chemical properties of the dry powder were stable at room temperature for 6 months and under refrigerated conditions for at least 1 year. Pharmacokinetic parameters were determined in guinea pigs after the pulmonary administration of the PA-824 powder formulation at three doses (20, 40, and 60 mg/kg of body weight) and compared to those after the intravenous (20 mg/kg) and oral (40 mg/kg) delivery of the drug. Oral and inhaled delivery of PA-824 achieved equivalent systemic delivery at the same body dose within the first 12 h of dosing. However, animals dosed by the pulmonary route showed drug loads that remained locally in the lungs for 32 h postexposure, whereas those given the drug orally cleared the drug more rapidly. Therefore, we expect from these pharmacokinetic data that pulmonary delivery may achieve the same efficacy as oral delivery at the same body dose, with a potential improvement in efficacy related to pulmonary infection. This may translate into the ability to deliver lower body doses of this drug for the treatment of tuberculosis by aerosol.The global epidemic caused by the infectious disease tuberculosis (TB) has recently garnered attention due to the growing concern over the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), which are caused by Mycobacterium tuberculosis strains that show resistance to multiple first-line drugs or that are virtually untreatable by existing anti-TB antibiotics (7). An investigational nitroimidazopyran, PA-824, is one of the most promising anti-TB drug candidates to have been discovered in 30 years. PA-824 appears to have bactericidal activity against both active replicating and persisting or latent M. tuberculosis strains and has the potential to be used for the treatment of MDR-TB (21). It has been proposed that this activity against static bacilli could help sterilize TB lesions faster (26). Therefore, reduced treatment times may be possible with drug regimens that include PA-824. Any advance in anti-TB therapy that addresses drug-resistant TB and that reduces the frequency of dosing, the dose required, and the duration of treatment has the potential to improve patient treatment.Preclinical evaluation with animal models of PA-824 alone and in combination with moxifloxacin, rifampin (rifampicin), isoniazid, and/or pyrazinamide indicated the potential of the use of PA-824 alone and in combination for...

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confidence: 99%

Dry Powder Nitroimidazopyran Antibiotic PA-824 Aerosol for Inhalation

Sung

García-Contreras

VerBerkmoes

et al. 2009

“…Pulmonary drug delivery for TB treatment has been extensively explored (3,15). Aerosol adjunctive therapy with different aminoglycosides can improve outcomes (15).…”

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confidence: 99%

“…Aerosol adjunctive therapy with different aminoglycosides can improve outcomes (15). Aerosol delivery of gamma interferon (IFN-␥), a key cytokine in the immunological response against M. tuberculosis, as an adjunct to systemic therapy has also been beneficial in particularly refractory cases (3).…”

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confidence: 99%

Aerosolized Gentamicin Reduces the Burden of Tuberculosis in a Murine Model

Roy

Sivasubramani

Dutta

et al. 2012

Tuberculosis (TB) is a major infectious disease problem: 1.7 million people annually die due to TB. Emergence of drug-resistant Mycobacterium tuberculosis and the lack of new antibiotics have exacerbated the situation. There is an urgent need to develop or repurpose drugs against TB. We evaluated inhaled gentamicin as direct respiratory system-targeted therapy in a murine model of TB. Aerosolized-gentamicin-treated mice showed significantly reduced lung M. tuberculosis loads and fewer granulomas relative to untreated controls. These results suggest that direct delivery of antibiotics to the respiratory system may provide therapeutic benefit to conventional treatment regimes for treatment of pulmonary TB.

“…The porous particle system is well suited for efficient delivery to the lungs (1,5,6,21). This high drug load formulation has been shown to maintain physical, aerodynamic, and chemical stability at room temperature for 6 months and under refrigerated conditions for more than 1 year.…”

Section: Discussionmentioning

confidence: 99%

Dry Powder PA-824 Aerosols for Treatment of Tuberculosis in Guinea Pigs

García-Contreras

Sung

Muttil

et al. 2010

Novel treatments for multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), or latent TB are needed urgently. Recently, we reported the formulation and characterization of the nitroimidazo-oxazine PA-824 for efficient aerosol delivery as dry powder porous particles and the subsequent disposition in guinea pigs after pulmonary administration. The objective of the present study was to evaluate the effects of these PA-824 therapeutic aerosols on the extent of TB infection in the low-inoculum aerosol infection guinea pig model. Four weeks after infection by the pulmonary route, animals received daily treatment for 4 weeks of either a high or a low dose of PA-824 dry powder aerosol. Animals received PA-824 cyclodextrin/lecithin suspensions orally as positive controls, and those receiving placebo particles or no treatment were negative controls. The lungs and spleens of animals receiving the high dose of inhaled PA-824 particles exhibited a lower degree of inflammation (indicated by wet tissue weights), bacterial burden, and tissue damage (indicated by histopathology) than those of untreated or placebo animals. Treatment with oral PA-824 cyclodextrin/lecithin suspension resulted in a more significant reduction in the bacterial burden of lungs and spleen, consistent with a dose that was larger than inhaled doses (eight times the inhaled low dose and four times the inhaled high dose). However, histopathological analysis revealed that the extent of tissue damage was comparable in groups receiving the oral or either inhaled dose. The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB.Mortality rates attributed to tuberculosis (TB) worldwide are increasing due to the epidemic of HIV coinfection and the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) mycobacterial strains (20). There is an urgent need for new therapies with (i) activity against MDR/ XDR and latent TB, (ii) shorter treatment duration, and (iii) safe and effective use in HIV-infected TB patients. PA-824, a leading compound in the 4-nitroimidazo-oxazine subclass, has shown promise in all those areas, as demonstrated by efficacy studies in the TB mouse model (11, 16-18, 24, 26). The mechanism of action of PA-824 appears to be the inhibition of the synthesis of protein and cell wall lipid after activation by the Mycobacterium tuberculosis F 420 cofactor (13,28). MIC values of PA-824 against M. tuberculosis range from 0.015 to 0.25 g/ml for drug-sensitive strains and from 0.03 to 0.53 g/ml for drug-resistant strains (9). In addition, this drug is active against nonreplicating anaerobic M. tuberculosis.Pharmacokinetic (PK) studies in rats and mice indicate that when delivered by the oral route, PA-824 has excellent tissue penetration (23); however, its pharmacokinetics appears to be different when given to other species, including guinea pigs, rabbits, and humans (19,25). The disposition, safety, and tolerability of single and multiple escalating doses of...