Open Forum Infectious Diseases BRIEF REPORT are ubiquitous in water and soil, may frequently be isolated Positive Effect of Liposomal Amikacin from residential sources, including showerheads and other for Inhalation on Mycobacterium home water sources [6–8]. In addition, a few studies suggested abcessus in Cystic Fibrosis Patients transmission from tap water and from person-to-person [6–8]. 1,2 1 1 e g Th enus Mycobacterium was introduced in 1896, and a total Davide Caimmi, Nicolas Martocq, Delphine Trioleyre, 1 3 1 1 Catherine Guinet, Sylvain Godreuil, Thomas Daniel, and Raphael Chiron of 169 species and 13 subspecies have been assigned to it . Cystic Fibrosis Center, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Although in the United States, Mycobacterium avium complex Montpellier, Univ Montpellier, France; Epidemiology of Allergic and Respiratory Diseases (MAC), Mycobacterium kansasii, and Mycobacterium abscessus Department (EPAR), Sorbonne Université, French Institute of Health and Medical Research (INSERM), Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France; and are the most frequent pathogens, in Europe, M abscessus seems Department of Microbiology, University Hospital of Montpellier, France to be the main NTM in CF patients [2, 6, 10]. Infections due to M abscessus are associated with poor clinical outcomes and Mycobacterium abscessus is difficult to eradicate. At the accelerated loss of lung function [2, 6]. Montpellier CF Center, we prescribed liposomal amikacin Unfortunately, M abscessus is notoriously difficult to treat for inhalation to 5 patients with M abscessus infection. The 3 because it shows a high level of intrinsic drug resistance to patients who completed the treatment did not have any respira- many antibiotics, due to the presence of an impermeable cell tory exacerbation, showed negative cultures for M abscessus in wall, antibiotic-modifying/inactivating enzymes, biofilms, their sputum, and stabilized their spirometric functions. efflux pumps, and genetic polymorphisms in target genes [2, 3, Keywords: cystic fibrosis; liposomal amikacin; Mycobacterium abscessus; nontuberculous mycobacteria; treatment. 7]. Recent guidelines for the management of M abscessus infec- tion in CF patients recommend a combined treatment with a macrolide, an aminoglycoside, and at least 1 other antibiotic Cystic fibrosis (CF) is the most common, potentially lethal, . Many guidelines recommend to prescribe inhaled amika- autosomal recessive disease in whites . It is mainly character- cin, an aminoglycoside active against Pseudomonas aeruginosa ized by recurrent cycles of airway infections and chronic inflam- as well . Amikacin is available for intravenous (i.v.) admin- mation, eventually leading to permanent lung damage [1, 2]. istration only, and therefore clinicians prescribe the i.v. form as Lung infections with nontuberculous mycobacteria (NTM) are inhaled treatment, which is oen n ft ot well tolerated by patients. emerging as a global threat to individuals with chronic lung Liposomal amikacin for inhalation (LAI) is delivered using an diseases [3, 4]. The increase of NTM infection diagnosis in CF optimized nebulizer, once a day, which allows a rapid delivery of subjects is probably due to greater surveillance, better detection the drug throughout the respiratory tree . Pharmacological techniques, and/or shifts in the lung microbiome due to wide- studies on humans focused on the use of such a drug against spread antibiotic use . P aeruginosa infection, but mouse models showed that LAI is Nontuberculous mycobacteria may infect CF patients at also effective against NTM, as much as higher concentrations all ages, but mycobacterial lung disease most oen o ft ccurs in of free amikacin [2, 12]. In addition, LAI may reach high levels patients older than 15 years, with an estimated incidence of in alveolar macrophages, and it is associated with macrophage 13%–20% [5, 6]. Infection is mostly indolent and generally defects in cytokine signaling or pathogen-killing functions . progresses slowly . However, a serious, life-threatening lung METHODS disease may develop in some patients, and fatal disseminated infections have been reported aer l ft ung transplantation . Two hundred fifteen patients (median age 19.6 years) attend our e s Th ource of these infections is still unclear, but NTM, which pediatric and adult CF center in Montpellier (France). Patients are regularly investigated for microbiological analysis during their follow-up according to recommendations . Currently, Received 13 November 2017; editorial decision 30 January 2018; accepted 15 February 2018. 11 patients are chronically colonized with M abscessus. We Correspondence: D. Caimmi, MD, CRCM, Hôpital Arnaud Villeneuve, CHU de Montpellier; 371, decided to treat 5 of them with LAI because they recently Avenue du Doyen Gaston Giraud, 34090 Montpellier, France (firstname.lastname@example.org). underwent a severe rapid deterioration of their clinical status Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases and respiratory functions. In addition, all 5 of these patients Society of America. This is an Open Access article distributed under the terms of the Creative showed radiological findings compatible with M abscessus dis- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any ease, and other diseases (such as tuberculosis) had already been medium, provided the original work is not altered or transformed in any way, and that the work ruled out. All M abscessus strains were genetically determined is properly cited. For commercial re-use, please contact email@example.com without rrs or erm 41 mutation, demonstrating no resistance DOI: 10.1093/ofid/ofy034 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy034/4868549 by Ed 'DeepDyve' Gillespie user on 16 March 2018 against aminoglycosides, with a minimum inhibitory concen- tration (MIC) <64 μg/mL. All 5 patients were also chronically colonized by P aeruginosa and S aureus. Antibiotic prescription, based on bacteria susceptibility, seemed no longer effective for these patients. In addition, they did not tolerate inhaled amik- acin (i.v. form). To prescribe LAI for M abscessus treatment, we obtained a Temporary Use Authorization, which is an excep- tional permission to prescribe an innovative therapy before marketing authorization in France. Patients (or their parents, if minors) signed an informed consent before starting the pre- scribed therapy. All evaluated patients presented with Mycobacterium absces- sus in their sputum with at least 5 positive cultures, before LAI treatment (Table 1). At inclusion, they all underwent either a 2-week or 3-week treatment of i.v. meropenem at high doses. We administered 590 mg of LAI (70 mg/mL), at 1 daily dose (according to a previous pharmacokinetic/pharmacodynamic study ), every day for 3 months and then every other month. Each patient received clarithromycin as well, as a continuous treatment, during the entire evaluation period. Patients 1, 2, and 4 showed an inducible clarithromycin resistance (MICs ≥16 µg/ mL) associated with T28C substitution. Patients 3 and 5 were not resistant to clarithromycin. Patients received no other inhaled therapy during the month when they were not treated with LAI. RESULTS None of the 5 patients showed any side effect related to the treatment. The prescribed inhaled drug was taken regularly by only 3 of them (ie, patients 1, 3, and 5), whereas the other 2 were not compliant and the prescription was interrupted after the first 3 months of treatment (use of LAI inferior to 4 days per week). The 3 compliant patients did not receive any i.v. antibiotic therapy, during the observational period, besides the meropenem treatment, at inclusion. The clinical evolution and sputum cultures are shown in Table 1. Two to six months after they started the treatment, all 3 compliant patients no longer showed presence of M abscessus in their sputum. No signifi- cant modification was detected on high-resolution computed tomography. Finally, the 3 treated patients showed stabilization or improvement of their pulmonary function test values, and their clinical symptoms improved after treatment. DISCUSSION Mycobacterium abscessus is a rapidly growing, multidrug-re- sistant organism that accounts for more than half of all NTM infection in CF patients . The diagnosis of NTM lung disease is based on the American Thoracic Society’s guidelines, which include a combination of clinical, radiographic, and microbio- logic elements, associated with a longitudinal follow-up of the patient and detection of multiple positive sputum cultures [6, 13]. Once the disease is diagnosed, a specific treatment should be prescribed. In a randomized placebo controlled trial, proposed 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy034/4868549 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Characteristics of the 5 Patients Treated With Liposomal Amikacin for Inhalation Before LAI After LAI (Most Recent Visit) Number of Positive MAB Body Mass VEMS FVC (% of Most Recent Body Mass VEMS FVC Year of First MAB Cultures Before First LAI Treatment Index (% of Predicted Predicted Visit at CF Index (% of Predicted (% of Predicted Positive MAB Negative MAB 2 2 Patient ID Birth Genetic Mutations Infection Treatment Prescription Compliance (kg/m ) Value) Value) Center (kg/m ) Value) Value) Cultures Cultures 1* 2000 DF508/W846 12/2013 7 03/2016 Good 15.9 52% 71% 07/2017 17.4 (+1.5) 71% (+19%) 79% (+8%) 1 since 4 since 09/2016 03/2016 (6 months 0 after treatment) 09/2016 2 1983 DF508/R347P 05/2008 26 03/2016 Drop out after 17.4 27% 56% 06/2017 17.5 (+0.1) 25% (−2%) 51% (−5%) 9 since 0 2 months 03/2016 3* 1959 G542X/3849 + 10kb C > T 02/2011 11 04/2016 Good 18.6 33% 64% 05/2017 20.6 (+2.0) 34% (+1%) 66% (+2%) 1 since 3 since 08/2016 04/2016 (4 months 0 after treatment) 08/2016 4 1995 S364P/S364P 05/2016 14 12/2016 Drop out after 17.1 61% 83% 07/2017 16.8 (−0.3) 56% (−5%) 69% (−14%) 2 since 0 1 month 12/2016 5* 2005 DF508/DF508 05/2016 5 12/2016 Good 14.0 60% 65% 06/2017 16.0 (+2.0) 75% (+15%) 83% (+18%) 1 since 3 since 01/2017 12/2016 (2 months 0 after treatment) 01/2017 Abreviations: CF, cystic fibrosis; FVC, forced expiratory volume in 1 second; ID, indentification; LAI, liposomal amikacin for inhalation; MAB, Mycobacterium abscessus; VEMS, maximum expiratory volume per second. *Patients still under LAI treatment. in a poster at the American Thoracic Society Conference of possibility of reaching a good control of M abscessus infection in 2015, CF subjects with NTM lung disease were assigned to CF patients, with a single daily dose inhaled therapy with lipos- inhaled liposomal amikacin or placebo (64% M avium complex omal amikacin. Further studies are needed to assess the clinical, and 36% M abscessus complex), in addition to their ongoing microbiological and spirometric evolution of these patients, NTM therapy . At the end of the 6-month treatment period, and to propose new guidelines. there was a statistically significant increase in culture negativity Acknowledgments overall and for the MAC group [2, 14]. Potential conifl cts of interest. All authors: No reported conflicts of As survival in cystic fibrosis increases, the emergence of new interest. All authors have submitted the ICMJE Form for Disclosure of and resistant bacterial infections, including NTM, is an increas- Potential Conflicts of Interest. ing concern . To assure active and healthy aging for these References subjects, we should (1) assess new ways to improve patients’ 1. Chiron R, Caimmi D, Valiulis A, et al. A model for active and healthy ageing with compliance and reduce pulmonary infections and (2) deceler- a rare genetic disease: cystic fibrosis. Eur Respir J 2016; 47:714–9. ate the progression of the lung disease. Considering all of the 2. Skolnik K, Kirkpatrick G, Quon BS. Nontuberculous mycobacteria in cystic fibro- sis. Curr Treat Options Infect Dis 2016; 8:259–74. above recommendations, we prescribed the new LAI in 5 of our 3. Aziz DB, Low JL, Wu ML, et al. Rifabutin is active against Mycobacterium absces- patients who suffered from M abscessus infection. We hoped sus complex. Antimicrob Agents Chemother 2017; 61:pii: e00155-17. 4. Prevots DR, Adjemian J, Fernandez AG, et al. Environmental risks for nontu- that the prescription of a single daily dose of nebulized therapy berculous mycobacteria. Individual exposures and climatic factors in the cystic would improve patients’ compliance. This was true for only 3 of fibrosis population. Ann Am Thorac Soc 2014; 11:1032–8. 5. Roux AL, Catherinot E, Soismier N, et al. Comparing Mycobacterium massiliense our 5 patients. In this group, we recorded general improvement and Mycobacterium abscessus lung infections in cystic fibrosis patients. J Cyst in patients’ general status, a stabilization of their pulmonary Fibros 2015; 14:63–9. function tests, an improvement of their body mass index, and 6. Chmiel JF, Aksamit TR, Chotirmall SH, et al. Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, the disappearance of M abscessus in their sputum. and fungi. Ann Am Thorac Soc 2014; 11:1298–306. A limit of our results may be that patients’ improvement 7. Harris KA, Kenna DT. Mycobacterium abscessus infection in cystic fibrosis: molecular typing and clinical outcomes. J Med Microbiol 2014; 63:1241–6. could be due to the activity of LAI against P aeruginosa. 8. Floto RA, Olivier KN, Saiman L, et al. US Cystic Fibrosis Foundation and Nevertheless, M abscessus negative cultures support the fact that European Cystic Fibrosis Society consensus recommendations for the manage- ment of non-tuberculous mycobacteria in individuals with cystic fibrosis: execu- the treatment acted on this germ as well. Another limit of our tive summary. Thorax 2016; 71:88–90. findings is that our patients are still taking the drug; therefore, 9. Wassilew N, Hoffmann H, Andrejak C, Lange C. Pulmonary disease caused by non-tuberculous mycobacteria. Respiration 2016; 91:386–402. we have no information on possible culture conversion at the 10. Bar-On O, Mussaffi H, Mei-Zahav M, et al. Increasing nontuberculous mycobac- end of the therapy with LAI, as highlighted by other authors teria infection in cystic fibrosis. J Cyst Fibros 2015; 14:53–62. . Moreover, our results are not in line with those published 11. Ehsan Z, Clancy JP. Management of Pseudomonas aeruginosa infection in cystic fibrosis patients using inhaled antibiotics with a focus on nebulized liposomal by Olivier et al . In their study of six CF patients with M amikacin. Future Microbiol 2015; 10:1901–12. abscessus infection, only one showed negative cultures aer ft 12. Okusanya OO, Bhavnani SM, Hammel JP, et al. Evaluation of the pharmacokinet- ics and pharmacodynamics of liposomal amikacin for inhalation in cystic fibrosis treatment with LAI. We found no significant reason that could patients with chronic pseudomonal infections using data from two phase 2 clin- explain such discrepancy. ical studies. Antimicrob Agents Chemother 2014; 58:5005–15. 13. Griffith DE, Aksamit T, Brown-Elliott BA, 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. CONCLUSIONS 14. Biller JA, Eagle G, McInnis JP, et al. Efficacy of liposomal amikacin (LAI) in achieving nontuberculous mycobacteria (NTM) culture negativity in The possibility of using a single-dose inhaled antibiotic could patients whose lung function is refractory to guideline based therapy [poster]. be associated to a better patients’ compliance. Also, the fact International Conference of the American-Thoracic Socirty (ATS), Denver (CO), USA; AJRCCM 2015. Poster 611. that LAI is active on both P. aeruginosa and M abscessus could 15. Olivier KN, Griffith DE, Eagle G, et al. Randomized trial of liposomal amikacin make this drug of even greater interest, and allow to modify for inhalation in nontuberculous mycobacterial lung disease. Am J Respir Crit existing guidelines. The present communication highlight the Care Med 2017; 195:814–23. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy034/4868549 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Open Forum Infectious Diseases – Oxford University Press
Published: Mar 1, 2018
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