Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung disease
Olivier KN, Griffith DE, Eagle G, McGinnis Ii JP, Micioni L, Liu K, Daley CL, Winthrop KL, Ruoss S, Addrizzo-Harris DJ, Flume PA, Dorgan D, Salathe M, Brown-Elliott BA, Gupta R, Wallace RJ Jr. Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung disease. Am J Respir Crit Care Med. 2016 Oct 17. DOI: 10.1164/rccm.201604–0700OC.
Pulmonary nontuberculous mycobacterial infection is a complex disease process that can result in progressive lung damage characterized by necrotizing inflammation, bronchiectasis and cavitory lesions. The resultant irreversible damage can impair pulmonary function and increase mortality. Treatment of patients with pulmonary nontuberculous mycobacterial (NTM) infections involves prolonged duration of multiple antibiotics that are limited by poor efficacy, toxicities and intolerance. Newer drugs and or delivery methods that increase tolerance and reduce systemic toxicities are needed to improve management of these complex patients. In this multicenter clinical trial, investigators studied the efficacy and safety of liposomal amikacin for inhalation in patients who have persistently positive cultures for NTM despite at least 6 months of appropriate multidrug antibiotic regimens as recommended in guidelines.
In this phase 2 double blind, placebo-controlled study, investigators randomly assigned 90 patients to liposomal amikacin for inhalation (LAI) or placebo once daily in addition to their guideline-based multi-drug regimens for 84 days, followed by open label administration of LAI to both groups for additional 84 days. Patients with history of active smoking, forced expiratory volume in 1 s of less than 30%, clinically significant heart, lung, liver or kidney disease, systemic immune deficiency, and malignancy were excluded. The primary end point was change in semi-quantitative scale (to assess relative mycobacterial growth) from baseline day 84.
Modified intent-to-treat analysis included 89 patients. 19% had cystic fibrosis, 64% had predominant growth of M. avium complex and 36% had predominant growth of M. abscesses. The primary end point did not achieve statistical significance but higher proportion of patients in the LAI treatment arm achieved sputum culture negativity at day 84 (32% [14/44] vs. 4%[4/45]; p = 0.006) as compared to those in placebo arm and improvement in 6-min walk test (+ 20.6 vs. −25 m; p = 0.017). Majority of patients who achieved sputum culture negativity (14/18) remained negative at 28 days after discontinuation of the study drug. Investigators noted that non-cystic fibrosis patients with pulmonary Mycobacterium avium complex infections were more likely to achieve sputum culture conversion.
Serious adverse effects such as nephrotoxicity, vestibulotoxicity and ototoxicity limit the use of intravenous aminoglycosides. Novel drug delivery methods to targeted tissues locally have the potential to reduce the likelihood of systemic toxicity. Inhalation of liposomal Amikacin delivers the drug to the targeted pulmonary tissues and is subsequently taken up by pulmonary macrophages, resulting in high intracellular levels of amikacin in the cells that are infected with nontuberculous mycobacteria. This study shows that inhaled liposomal amikacin added to multidrug regimens recommended in guidelines, may achieve earlier and sustained sputum culture negativity in selected patient population with treatment refractory nontuberculous mycobacterial disease and has limited systemic toxicity. As authors note, more research is needed.
Reference
1. Griffith DE, et al. An Official ATS/IDSA statement: Diagnosis, treatment and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416.
Human Tuberculosis caused by Mycobacterium bovis in the United States.
Colleen Scott, Joseph S. Cavanaugh, Robert Pratt, Benjamin J. Silk, Philip LoBue, and Patrick K. Moonan. Human Tuberculosis caused by Mycobacterium bovis in the United States, 2006–2013. Clin Infect Dis, 2016;63(5):594–601.
Mycobacterium tuberculosis complex consists of closely related, pathogenic mycobacteria including Mycobacterium bovis. Humans get infected with M.bovis primarily by ingestion of unpasteurized, raw bovine milk and its products such as queso fresco. Unlike Mycobacterium tuberculosis infection, person-to-person transimission via inhalation of airborne droplet nuclei is uncommon, but has been noted in both immunocompromised and immunocompetent individuals. Clinical presentations of M. bovis and M. tuberculosis infections can be indistinguishable. Since 2004, US Centers for Disease Control and Prevention (CDC) ‘s National Tuberculosis Genotyping Service (NTGS) has been performing genotyping of all culture confirmed human tuberculosis cases to differentiate M. bovis and M.tuberculosis infections. 95% of cultures were genotyped in 2013 as compared to 51% in 2004. In this study, investigators used genotype data from NTGS and patient demographic data from National Tuberculosis Surveillance System (NTSS), to understand and validate the epidemiology of human tuberculosis caused by M.bovis in the United States.
The investigators analyzed all culture-confirmed cases of human tuberculosis that were reported to US CDC during the 8-year study period (2006 – 2013). In 2009, the country of origin of the parent or guardian of patient less than 15 years of age was added as an additional variable. All the culture isolates were genotyped using two standardized methods: 1. Spacer oligonucleotide typing (Spoligotyping) and 2. Mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR). Patients with infections due to M.bovis BCG and other M. tuberculosis complex (M. africanum, M. canetti, M. caprae, M. microti, M. mungi, M.pinipedii, M. suricattae) were excluded. Of the 91,985 cases of human tuberculosis, three-fourth had positive cultures and 85% of culture isolates had genotype results. The final analysis included 862 M bovis cases and 58,411 M tuberculosis cases.
During the study period, the proportion of human tuberculosis cases caused by M. bovis remained in 1.3–1.6% range. The study observed that among human tuberculosis cases in US, Hispanics, children less than 15 years of age, female population, foreign-born patients and patients with extra-pulmonary disease were more likely to have M. bovis infection as compared to M. tuberculosis infection. Patients born in Mexico or children with a parent of Mexican ancestry constituted a significant proportion of M. bovis infection reported in the US. Majority (86%) of children with M. bovis infection were noted to have exclusive extra-pulmonary disease, suggesting ingestion of unpasteurized milk products to be the main mode of transmission. The authors tried to understand the female predilection of M. bovis infection by analyzing the survey data of food exposure from CDC's FoodNet but could not find any difference by gender in consumption of high risk food products such as Mexican queso fresco or other unpasteurized cheese products. Higher incidence of M. bovis infection was noted in patients residing in US-Mexico border region.
An important finding of the study was that more than half (56%) of patients with M.bovis infection had pulmonary involvement and about one-third of patients had exclusive pulmonary infection. This finding raises the possibility of person-to-person transmission via airborne droplet nuclei. For patients with pulmonary involvement, clinicians should institute appropriate infection control precautions in the hospitals and public health officials should identify potential cases of exposure/latent infection by performing contact tracing. As authors have noted, the study is limited by a significant number of cases without positive cultures (about 26%) and incomplete genotyping. Data on HIV was unavailable in survery data, which limited authors to analyze its association with M. bovis infection.
M. bovis is a zoonotic infection which predominantly affects children, foreign-born patients, Hispanics, and females. This study will inform public health officials to target their educational initiatives to high prevalence population and raise awareness of the risks of unpasteurized milk and its products.
References
1. Paula I. Fujiwara and Francisco Olea-Popelka. Why it is important to distinguish Mycobacterium bovis as a causal agent of Human Tuberculosis. Clin Infect Dis 2016;63(5):602–3.
Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluroquinolones: results from a multicountry surveillance project.
Matteo Zignol, Anna S Dean, Natavan Alikhanova, Sonke Andres, Andrea Maurizio Cabibbe, Daniela Maria Cirillo, Andrei Dadu, Andries Dreyer, Michele Driesen, Christopher Gilpin, Rumina Hasan, Zahra Hasan, Sven Hoffner, Ashaque Husain, Alamdar Hussain, Nazir Ismail, Mostofa Kamal, Mikael Mansjo, Lindiwe Mvusi, Stefan Niemann, Shaheed V Omar, Ejaz Qadeer, Leen Rigouts, Sabine Ruesch-Gerdes, Marco Schito, Mehriban Seyfaddinova, Alena Skrahina, Sabira Tasheen, William A Wells, Ya Diul Mukadi, Michael Kimerling, Katherine Floyd, Karin Weyer, Mario C Raviglione. Lancet Infect Dis 2016;16:1185–92.
Tuberculosis remains as one of the major cause of death due to infections worldwide, resulting in 1.5 million deaths in 2014. The global spread of multi-drug resistant strains of M. tuberculosis and the limited availability of therapeutic options form a significant barrier in successful management and control of this complex public health problem. New shorter regimens with drugs that have good tolerability and less adverse effects are important to manage these patients, especially those with multi-drug and extensively drug resistant tuberculosis. In three large trials, the addition of a fourth generation fluroquinolone to reduce the duration of treatment to 4 months was not found to be non-inferior as compared to 6-month standard regimen recommended by WHO (World health Organization). New rifampin-sparing regimens for drug-susceptible tuberculosis and shorter regimens being considered for multi-drug resistant tuberculosis include pyrazinamide and a fourth generation fluroquinolone such as gatifloxacin and moxifloxacin. Before this combination is included in new shorter regimens of tuberculosis control programs, it is important that we have data on prevalence of population-level resistance to these drugs. This information will also help to decide if drug susceptibility testing to these drugs should be included in the control programs. WHO collects reports of levels of resistant to isoniazid and rifampicin from more than 150 countries, obtained via routine surveillance and/or ad-hoc population-based surveys. Since susceptibility testing of isolates to fluroquinolones and rifampicin are not part of surveillance, population level data on resistance to these drugs are unavailable. In this study, investigators used population-based surveys to obtain this data.
Sputum samples were collected from patients who were enrolled in national drug resistance surveys in Azerbaijan, Bangladesh, Pakistan, Minsk city in Belarus and two provinces in South Africa. These countries have high incidence of tuberculosis, with a significant proportion of isolates being resistant to rifampicin. National tuberculosis reference laboratories performed culture and susceptibility testing for first-line tuberculosis drugs using LT proportion method or MGIT 960 (Becton Dickinson, Sparks, MD, USA) and subsequently, WHO tuberculosis reference laboratories performed resistance testing to pyrazinamide (using sequencying for detection of mutation in pncA gene [Rv2043c] and the promotor) and fluroquinolones (MGIT system).
The study included 4972 patients who underwent testing for pyrazinamide resistance and 5015 patients who had testing for fluroquinolone resistance. The rate of pyrazinamide resistance varied widely (3%−42%) among countries and was significantly higher in patients with rifampicin resistance and those with prior treatment for tuberculosis. Among isolates that were tested for fluroquinolone resistance, the rates of resistance varied from 1–16% for ofloxacin, 0.5–12% for levofloxacin and 0.9–15% for moxifloxacin (0.5 mcg/ml). The rate of resistance was much lower for gatifloxacin (0–2.5%) and moxifloxacin at 2 mcg/ml (0–5.1%). Patients with history of prior treatment had higher rates of resistance to fluroquinolones. Another observation was that there was very low cross-resistance between ofloxacin and the fourth generation fluroquinolones.
The study raises the need for rapid molecular tests to identify pyrazinamide resistance to help in the clinical management of patients with rifampicin-resistant tuberculosis. Even though the level of pyrazinamide resistance was lower in Pakistan, the country had very high prevalence of resistance to fluroquinolones, likely resulting from extensive, sometimes unwarranted use of this class of drugs for several infectious syndromes. This finding calls for attention of global public health officials to promote judicious use of antibiotics in humans and regulation of antibiotic use in livestock industry. The low prevalence of resistance to fourth generation fluroquinolones likely represents limited use of these drugs so far in these countries, and will likely increase without responsible use of these antimicrobial drugs. The absence of cross-resistance to fourth generation fluroquinolones supports their utility in the treatment of multi-drug resistant tuberculosis. As authors note, the study is limited by its retrospective design, inability to regrow a significant number of original survey isolates and potential variability in laboratory testing.
This study provides valuable information about prevalence of resistance to pyrazinamide and fluroquinolones among M. tuberculosis isolates in countries with high burden of tuberculosis. This will be helpful for global public health officials to identify best strategy for implementation of new shorter regimens that include these drugs. Widespread availability of molecular techniques to identify resistant to all available anti-tuberculosis drugs will be important in the global fight to treat and prevent the emergence of multi-drug resistant tuberculosis.
With ever increasing and unprecedented trends in global trade and human migration, it is evident that infectious agents and their resistant genes can spread rapidly with relative ease. Antimicrobial resistance and multi-drug resistant tuberculosis are global health problems and are not restricted by borders, requiring a coordinated global effort in the control and prevention.