Deaths Related to Nontuberculous Mycobacterial Infections in the United States, 1999–2014

Vinnard, Christopher; Longworth, Sarah; Mezochow, Alyssa; Patrawalla, Amee; Kreiswirth, Barry N.; Hamilton, Keith

doi:10.1513/annalsats.201606-474bc

Cited by 59 publications

(38 citation statements)

References 16 publications

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“…Recently, COPD has been identified as the most frequent pulmonary comorbid cause of death in NTM-PD-related mortality [18,19]. For that purpose, COPD patients (n=245 218) in the research database were matched with respect to occurrence or non-occurrence of NTM-PD by age, sex and CCI.…”

Section: Mortalitymentioning

confidence: 99%

Burden of non-tuberculous mycobacterial pulmonary disease in Germany

et al. 2017

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The objective of this study was to estimate the burden of disease in incident patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD).A sample of 7 073 357 anonymised persons covered by German public statutory health insurances was used to identify patients with NTM-PD. In total, 125 patients with newly diagnosed NTM-PD in 2010 and 2011 were matched with 1250 control patients by age, sex and Charlson Comorbidity Index, and followed for 39 months.The incidence rate for NTM-PD was 2.6 per 100 000 insured persons (95% CI 2.2-3.1). The mortality rate for patients with NTM-PD and the control group in the observational period was 22.4% and 6%, respectively (p<0.001). Mean direct expenditure per NTM-PD patient was €39 559.60 (95% CI 26 916.49-52 202.71), nearly 4-fold (3.95, 95% CI 3.73-4.19) that for a matched control (€10 006.71, 95% CI 8907.24-11 106.17). Hospitalisations were three times higher in the NTM-PD group and accounted for 63% of the total costs. Attributable annual direct costs and indirect work-loss costs in NTM-PD patients were €9093.20 and €1221.05 per control patient, respectively. Only 74% of NTM-PD patients received antibiotics and nearly 12% were prescribed macrolide monotherapy.Although NTM-PD is considered rare, the attributable mortality and financial burden in Germany are high. Efforts to heighten awareness of appropriate therapy are urgently needed.

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Section: Mortalitymentioning

confidence: 99%

Burden of non-tuberculous mycobacterial pulmonary disease in Germany

et al. 2017

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“…The number of cases is climbing at an alarming rate with an annual increase in NTM isolate prevalence of 8.4% from 1997 through 2003, reaching 50 per 100,000 persons [5][6][7]. In the US, NTM incidence largely surpasses that of TB, and while TBrelated deaths have been decreasing steadily for the past 20 years, NTM-related deaths are on the rise [8]. The annual cost of pulmonary NTM disease in the US was estimated at $815M in 2010 [5].…”

Section: Introductionmentioning

confidence: 99%

Repositioning rifamycins for Mycobacterium abscessus lung disease

Ganapathy

Dartois

Dick

2019

Expert Opinion on Drug Discovery

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Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen. ARTICLE HISTORY

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“…Infections with non-tuberculous mycobacteria (NTM) are increasing in incidence (Falkinham, 2013 ; Prevots and Marras, 2015 ; Strollo et al, 2015 ; Vinnard et al, 2016 ; Prevots et al, 2017 ; Spaulding et al, 2017 ) and are notoriously difficult to treat (Henkle et al, 2017 ; Lande et al, 2018 ). Resistance of NTM to disinfectants may contribute to hospital acquired infections (Caskey et al, 2018 ) especially in cystic fibrosis disease where infection is common as patients age (Nick et al, 2016 ; Martiniano et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Optimization and Lead Selection of Benzothiazole Amide Analogs Toward a Novel Antimycobacterial Agent

et al. 2018

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Mycobacteria remain an important problem worldwide, especially drug resistant human pathogens. Novel therapeutics are urgently needed to tackle both drug-resistant tuberculosis (TB) and difficult-to-treat infections with nontuberculous mycobacteria (NTM). Benzothiazole adamantyl amide had previously emerged as a high throughput screening hit against M. tuberculosis (Mtb) and was subsequently found to be active against NTM as well. For lead optimization, we applied an iterative process of design, synthesis and screening of several 100 analogs to improve antibacterial potency as well as physicochemical and pharmacological properties to ultimately achieve efficacy. Replacement of the adamantyl group with cyclohexyl derivatives, including bicyclic moieties, resulted in advanced lead compounds that showed excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12 μg/mL against M. abscessus (Mabs) and other rapid- growing NTM, 1–2 μg/mL against M. avium complex (MAC), and 0.12–0.5 μg/mL against Mtb. No pre-existing resistance was found in a collection of n = 54 clinical isolates of rapid-growing NTM. Unlike many antibacterial agents commonly used to treat mycobacterial infections, benzothiazole amides demonstrated bactericidal effects against both Mtb and Mabs. Metabolic labeling provided evidence that the compounds affect the transfer of mycolic acids to their cell envelope acceptors in mycobacteria. Mapping of resistance mutations pointed to the trehalose monomycolate transporter (MmpL3) as the most likely target. In vivo efficacy and tolerability of a benzothiazole amide was demonstrated in a mouse model of chronic NTM lung infection with Mabs. Once daily dosing over 4 weeks by intrapulmonary microspray administration as 5% corn oil/saline emulsion achieved statistically significant CFU reductions compared to vehicle control and non-inferiority compared to azithromycin. The benzothiazole amides hold promise for development of a novel therapeutic agent with broad antimycobacterial activity, though further work is needed to develop drug formulations for direct intrapulmonary delivery via aerosol.

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Deaths Related to Nontuberculous Mycobacterial Infections in the United States, 1999–2014

Cited by 59 publications

References 16 publications

Burden of non-tuberculous mycobacterial pulmonary disease in Germany

Burden of non-tuberculous mycobacterial pulmonary disease in Germany

Repositioning rifamycins for Mycobacterium abscessus lung disease

Optimization and Lead Selection of Benzothiazole Amide Analogs Toward a Novel Antimycobacterial Agent

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