NON TUBERCULOUS MYCOBACTERIA, M. MASSILIENSE, M. ABSCESSUS

PULMONARY TUBERCULOSIS

[FOR ASPERGILLUS PLEASE SEE SEPARATE “MYCOLOGY” TOPIC]

* Some of these references do not appear in the main text

1980 Boxerbaum B. isolation of rapidly growing mycobacteria in patients with cystic fibrosis. J Pediatr 1980; 96:689-691.[PubMed]
Apparently the first reference to non tuberculous mycobacteris in cystic fibrosis patients.

1984 Efthimiou J, Smith MJ, Hodson ME, Batten JC. Fatal pulmonary infection Mycobacteriumfortuitum in cystic fibrosis. Br J Dis Chest 1984; 78:299-302. [PubMed]
An early report of an atypical Mycobacterium infection in a young adult with cystic fibrosis. The organism was resistant to all antibiotics and the patient died.

–  Atypical mycobacteria were to become an increasing problem in people with CF. In a subsequent paper from Royal Brompton Smith MJ et al (1984 below) made a search to determine the prevalence of atypical mycobacteria in their CF patients – presumably as a result of experience with this patient. (see also Boxerbaum B. Isolation of rapidly growing mycobacteria in patients with cystic fibrosis. J Pediatr 1980; 96:689-691.[PubMed]).

1984 Smith MJ, Efthimiou J, Hodson ME, Batten JC. Mycobacterial isolations in young adults with cystic fibrosis. Thorax 1984; 39:369-375. [PubMed]
Seven of 223 patients with CF admitted to the Brompton Hospital over a six year period had Mycobacteria in their sputum. The organisms isolated were Mycobacterium tuberculosis in three patients, M. chelonei in one, M. fortuitum in one, and unidentified Mycobacteria in two. The diagnosis was not suspected on clinical grounds in any of these patients; in one patient, however, night sweats were a prominent feature before diagnosis. In four of the patients direct sputum smear examination did not reveal the organism, which was grown subsequently in culture.

These were early days for appreciating the role of atypical Mycobacteria in CF and the organisms were present in the sputa of patients with cystic fibrosis more often than previously recognised. Therefore the authors recommended that sputum examination and culture for Mycobacteria should be performed periodically in these patients. Subsequently problems with these organisms would become more widely recognised and occur as a problem sometimes after lung transplantation when the patients were on immunosuppressive therapy.

Probably as there were few adults at that time and so few CF centres for adults, there were no further reports until one from Dublin in 1990 (Mulherin D, et al. Respir Med 1990; 84:273-276. [PubMed]) where the frequency of positive skin reactions was found to be similar as in a control population. One of the 43 patients grew an atypical mycobacterium from the sputum.

1990 Hjelt L, Petrini B, Kallenius G Strandvik B, Prospective study of mycobacterial infections in patients with cystic fibrosis. Thorax 1990; 45:397-400. [PubMed]
Fifty four patients with cystic fibrosis, aged 3-67 years, were studied prospectively for pulmonary mycobacterial infection. Sputum smears and cultures were carried out and intradermal skin tests performed. Mycobacteria were cultured from six patients in association with clinical deterioration; four patients had positive direct smears. Mycobacterium tuberculosis, M. avium intracellulare, M. kansasii, and M. gordonae were isolated. There were no deaths and all improved with chemotherapy. A third of the other 48 patients had positive skin test responses (greater than 6 mm) to purified protein derivative (PPD) tuberculin and 21 to one or more antigens prepared from non-tuberculous mycobacteria. Sensitisation increased with age; before the age of 11 only one patient had a positive response to PPD tuberculin and none to any other antigen. This was less than in healthy control subjects of similar age. After age 11 the reactions in sensitised patients were stronger than in positive healthy control subjects.

The authors suggest that their study indicates that it is important to consider mycobacterial infection in patients with cystic fibrosis who deteriorate without obvious cause

1994 Hjelt K, Hojlyng N, Howitz P, Illum N, Munk E, Valerius NH, Hansen KN, Heltberg I, Koch C. The role of Mycobacteria Other Than Tuberculosis (MOTT) in patients with cystic fibrosis. Scand J Infect Dis 1994; 26:569-576. [PubMed]
The purpose of this study was to estimate the frequency of and evaluate the clinical impact of pulmonary mycobacterial infections among cystic fibrosis (CF) patients. 185 CF patients aged 2.2-38.5 years were screened by sputum samples and by intracutaneous skin tests against tuberculin and sensitins produced from Mycobacterium chelonae subsp. abscessus, M. avium, M. intracellulare and M. scrofulaceum (the MAIS complex). The skin tests towards the sensitins in BCG-vaccinated patients (n = 60) were significantly influenced by the vaccination.

26 of the remaining 125 non-vaccinated patients had one or more positive skin test (95% confidence limits 15-29%). The majority reacted against the MAIS complex. However, the reactions were similar to those of healthy siblings and an age-matched control group. Moreover, the lung function, growth and HbA1c were similar among skin test positive and negative patients.

Three patients had repeated positive sputum cultures, the point prevalence being 1.6% (M. intracellulare, n = 2 and M. chelonae subsp. abscessus, n = 1). During the subsequent 4 years, 4 additional patients with M. chelonae subsp. abscessus were identified. Based on clinical observations, 5 of the infected patients were considered asymptomatic, while 2 might have been symptomatic. In 1 patient, M. chelonae subsp. abscessus disappeared spontaneously.

Despite intensive treatment with new antibiotics against Mycobacteria Other Than Tuberculosis (MOTT) in 4 patients, the mycobacteria were not eradicated.

The authors concluded MOTT infection was rare and the clinical impact difficult to prove. Treatment should focus on clinical improvement in the individual patient suspected of suffering from significant symptomatic infection. Eradication of the bacteria should not be expected.

1996 Tomashefski JF Jr, Stern RC, Demko CA, Doershuk CF. Nontuberculous mycobacteria in cystic fibrosis. An autopsy study. Am J Resp Crit Care 1996;154:523-28.[PubMed]
Lung and hilar lymph nodes were studied at autopsy in 18 patients with cystic fibrosis who had antemortem sputum cultures positive for nontuberculous mycobacteria (NTM). Histologic features were compared with those of 18 patients with CF who had negative antemortem cultures. The most frequent species isolated was M. chelonae group (10 patients). Multiple cultures were positive for NTM in six patients. Three patients were clinically considered to be infected, and two received antimycobacteria drugs. Necrotizing pulmonary granulomas associated with granulomatous organizing pneumonia were found at autopsy in two patients, each of whom had multiple positive sputum cultures and clinical evidence of infection. In one of these, mycobacterial infection was considered to be an important factor in her terminal illness. Neither necrotizing granulomas nor granulomatous organizing pneumonia were seen in the lung tissue of patients whose antemortem cultures were negative for mycobacteria. There was no difference in the prevalence of other granuloma-like lesions between those with and those without positive sputum cultures.

No mycobacteria-related granulomas occurred in hilar lymph nodes, although histoplasma granulomas involved hilar lymph nodes of three patients.

The authors concluded that granulomatous mycobacterial lung disease is present in a minority of patients (two of six patients in this study) who have multiple positive cultures. Histologic evidence of infection was not found in patients who had only one of multiple sputum cultures positive for NTM.

1998 Torrens JK, Dawkins P, Conway SP, Moya E. Non-tuberculous mycobacteria in cystic fibrosis. Thorax 1998 Mar;53(3):182-5. [PubMed]
A retrospective case-control study was performed to assess possible risk factors for non-tuberculous mycobacteria and its impact on clinical status in patients with cystic fibrosis. The records of all patients attending the Leeds cystic fibrosis clinics who were positive for non-tuberculous mycobacteria were examined. Each case was matched with two controls for sex, age, and respiratory function at the time of the first non-tuberculous mycobacteria isolate. Details of respiratory function, nutritional status, antibiotic and corticosteroid therapy, Shwachman-Kulczycki (S-K) score, Northern chest radiographic score, and the frequency of isolation of other bacteria and fungi were collected from two years before to two years after the first non-tuberculous mycobacteria isolate. The patients’ genotype and the presence of diabetes mellitus were also recorded.

Non-tuberculous mycobacteria were isolated from 14 patients out of a cystic fibrosis population of 372 (prevalence = 3.8%). No significant effect of non-tuberculous mycobacteria was seen on respiratory function, nutritional status, or S-K score. There was a significant association with the number of intravenous antibiotic courses received before the first isolate with cases receiving, on average, twice as many courses as controls (cases 6.64, controls 2.86, 95% CI for difference 1.7 to 5.9). No significant difference was seen between cases and controls for Northern scores, previous steroid therapy, or the incidence of diabetes mellitus. Non-tuberculous mycobacteria infection in patients with cystic fibrosis is uncommon and its clinical impact appears to be minimal over a two year period. Frequent intravenous antibiotic usage is a possible risk factor for colonisation with non-tuberculous mycobacteria.

2003 Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH et al. Nontuberculous Mycobacteria in Cystic Fibrosis Study group. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am J Respir Crit Care 2003; 167:828-834.[PubMed]
Nontuberculous mycobacteria (NTM) are potential respiratory pathogens in cystic fibrosis (CF). To assess the species-specific prevalence and risk factors for acquisition, we conducted a prospective, cross-sectional study of the prevalence of NTM and clinical features of patients at 21 U.S. centers. Almost 10% of patients with CF who were 10 years or older were included (n = 986).

The overall prevalence of NTM in sputum was 13.0% (range by center, 7-24%). Mycobacterium avium complex (72%) and Mycobacterium abscessus (16%) were the most common species. When compared with patients with CF without NTM, culture-positive subjects were older (26 vs. 22 years, p < 0.001), had a higher FEV1 (60 vs. 54%, p < 0.01), higher frequency of Staphylococcus aureus (43 vs. 31%, p < 0.01), and lower frequency of Pseudomonas aeruginosa (71 vs. 82%, p < 0.01). Molecular typing revealed that almost all patients within each center had unique NTM strains.

The group showed that NTM are common in patients with CF, but neither person-to-person nor nosocomial acquisition explained the high prevalence. Older age was the most significant predictor for isolation of NTM. The clinical significance of NTM in CF is incompletely defined, but patients with these organisms should be monitored with repeat cultures.

*2003  Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molina PL et al; Nontunberculous Mycobacteria Study Group. Nontuberculous mycobacteria. II: nested-cohort study of impact on cystic fibrosis lung disease. Am J Respir Crit Care 2003; 167:835-840.[PubMed]

Kenneth Olivier

The prevalence of nontuberculous mycobacteria (NTM) is high (approximately 13%) in sputum of patients with cystic fibrosis (CF), but the impact on lung disease is unknown. We followed 60 incident NTM-positive and 99 culture-negative patients with CF for 15 months and assessed clinical impact of NTM by FEV1 and high-resolution computed tomography (HRCT) of the chest. Mycobacterium avium complex was seen in 75% of NTM-positive subjects. The annual rate of decline in FEV1 was not different among control versus NTM-positive subjects who did not, or did, meet American Thoracic Society microbiologic criteria for NTM disease (3 +/- 1, 3 +/- 2, and 5 +/- 2%, respectively). More subjects with three or more positive cultures for NTM had two or more characteristic findings on entry HRCT (60%, 9/15) as compared with subjects with two positive cultures or less (32%) or negative cultures (19%; p < 0.02). All subjects with three or more positive cultures and exit HRCTs (n = 6) showed progression of HRCT findings, whereas only 17% of subjects with two positive cultures or less had progression (p = 0.0006).

In summary, no significant short-term effect on FEV1 was detected in patients with multiple positive NTM cultures, but an abnormal HRCT was predictive of progression. Patients with CF and multiple positive NTM cultures, characteristic HRCT findings, and progression of HRCT changes should be monitored closely and considered for antimycobacterial therapy.

2009 Radhakrishnan DK, Yau Y, Corey M, Richardson S, Chedore P, Jamieson F, Dell SD. Non-tuberculous mycobacteria in children with cystic fibrosis: isolation, prevalence, and predictors. Pediatr Pulmonol 2009; 44:1100-1106. [PubMed]
Screening for non-tuberculous mycobacteria (NTM) is recommended for adults with cystic fibrosis. The relevance of this organism in North American pediatric CF patients is unclear as there is limited NTM prevalence data for children. 6.1% of 98 children at the hospital for Sick Children Toronto were positive for NTM – 2 M. abscessus and 4 M. avium – one with M. abscessus required treatment. As the NTM prevalence rate in children with CF is within the range previously reported in adults and there are no reliable clinical predictors for isolation, annual sputum screening is needed to identify NTM in children. The authors considered further research was needed to determine the best sputum decontamination method for NTM culture in pediatric patients.

–   This is a useful study from Toronto detailing the prevalence of NTM in their paediatric CF population – which they found to be similar to that in adults.

2009 van Ingen J, de Zwaan R, Dekhuijzen RP, Boeree MJ, van Soolingen D. Clinical relevance of Mycobacterium chelonae-abscessus group isolation in 95 patients. J Infect 2009; 59:324-331. [PubMed]

To determine the clinical relevance of Mycobacterium chelonae-abscessus group isolation from clinical samples the authors retrospectively reviewed medical files of all patients from whom these mycobacteria were isolated between January 1999 and January 2005. They applied the American Thoracic Society (ATS) diagnostic criteria to establish clinical relevance. Ninety-five patients were traced (56 M. chelonae, 25 Mycobacterium abscessus, 8 Mycobacterium massiliense, 6 Mycobacterium bolletii). Most isolates were cultured from pulmonary samples in patients with pre-existing pulmonary disease. Among patients with pulmonary isolates, 27% (20/74) meets ATS criteria; M. abscessus is most relevant (50%; 9/18), followed by M. massiliense (29%; 2/7), M. bolletii (20%; 1/5) and M. chelonae (18%; 8/44). Extrapulmonary disease presented as disseminated skin disease, eye disease specific for M. chelonae and otomastoiditis for M. abscessus. Treatment, especially for pulmonary M. abscessus disease, yielded limited results. One-fourth of the patients with pulmonary M. chelonae-abscessus group isolates met the ATS criteria; this percentage differs by species. Species distribution and clinical relevance differ from other regions.

M. abscessus isolation in cystic fibrosis patients warrants special attention. Current ATS criteria might be too lenient to diagnose M. chelonae-abscessus group disease.

There is increasing interest in NTM in CF. This survey gives an idea of the general prevalence of the various NTMs.

2009 Roux AL, Catherinot E, Ripoll F, Soismier N, Macheras E, Ravilly S, Bellis G, Vibet MA, Le Roux E, Lemonnier L, Gutierrez C, Vincent V, Fauroux B, Rottman M, Guillemot D, Gaillard JL, Jean-Louis Herrmann for the OMA Group. Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in France. J Clin Microbiol 2009; 47:4124-4128. [PubMed]
A multicenter prevalence study of nontuberculous mycobacteria (NTM) involving 1,582 patients (mean age, 18.9 years; male/female ratio, 1.06) with cystic fibrosis in France. The overall NTM prevalence (percentage of patients with at least one positive culture) was 6.6% (104/1,582 patients), with prevalences ranging from 3.7% (in the east of France) to 9.6% (in the greater Paris area). Mycobacterium abscessus complex (MABSC; 50 patients) and Mycobacterium avium complex (MAC; 23 patients) species were the most common NTM, and the only ones associated with fulfillment of the American Thoracic Society bacteriological criteria for NTM lung disease. The “new” species, Mycobacterium bolletii and Mycobacterium massiliense, accounted for 40% of MABSC isolates. MABSC species were isolated at all ages, with a prevalence peak between 11 and 15 years of age (5.8%), while MAC species reached their highest prevalence value among patients over 25 years of age (2.2%).

A useful large survey of NTM in France showing an overall prevalence of 6.6%.- very similar to previous reports.

2011 Renna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J, Bowden AR, Newton SM, Kampmann B, Helm J, Jones A, Haworth CS, Basaraba RJ, DeGroote MA, Ordway DJ, Rubinsztein DC, Floto RA. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest 2011; 121:3554-63. [PubMed]
A recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM). This study confirms that long-term azithromycin use by adults with CF is associated with the development of infection with NTM, particularly the multi-drug-resistant species Mycobacterium abscessus, and identifies an underlying mechanism. In primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM in mice. The findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.

Autophagy = “the segregation of part of the cell’s own protoplasmic material within an membrane and its digestion after fusion of the segregated vacuole with a lysosome”. As many people with CF now receive long term azithromycin treatment further information on this association will be awaited with interest.

Subsequent information from the CF Patient Registry did not confirm a relationship between chronic azithromycin use and nontuberculous mycobacterial infection (Binder Am et al. Am J Resp Crit Car 2013 188:807-812.[PubMed]).

2012 Catherinot E, Roux AL, Vibet MA, Bellis G, Ravilly S, Lemonnier L, Le Roux E, Bernede-Bauduin C, Le Bourgeois M, Herrmann JL, Guillemot D, Gaillard JL, for the OMA group.  Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations.J Cyst Fibros 2012 Jul 31. [PubMed]

Clinical observations suggest that Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) may affect cystic fibrosis(CF)patients with different characteristics and risk factors, but this has never been demonstrated within a single prospective cohort. The authors studied 50 MABSC-positive and 23 MAC-positive patients from a French prevalence study of non-tuberculous mycobacteria (NTM) in CF. Risk factors specifically associated with MABSC and MAC were analyzed by nested case-control studies, with two NTM-negative controls matched by age, sex and center for each case.

MAC-positive patients were significantly older than MABSC-positive patients (mean [SD] age, 23.1 [10.2] vs 17.4 [8.3] years, p=0.013), and were also older at CF diagnosis (mean [SD] age, 12.9 [16.1] vs 3.1 [7.7] years, p=0.015); they tended to be less frequent of the ΔF508/ΔF508 genotype (33.3 vs 61.1%, p=0.17) and to use pancreatic extracts less frequently (82.4 vs 97.6%, p=0.07). Risk factors identified by multivariate analysis were: i) in the MAC case-control study, an older age at CF diagnosis (p=0.004); ii) in the MABSC case-control study, at least one course of intravenous antibiotics (p=0.01) and more frequent isolation of Aspergillus (p=0.03).MAC affects adult patients with a mild form of CF, whereas MABSC affects younger patients with more severe CF and more frequent intravenous antimicrobial treatment.

2012 Hill UG, Floto RA, Haworth CS. Non-tuberculous mycobacteria in cystic fibrosis. J R Soc Med 2012;105 (Suppl 2):S14-8. [PubMed]

An up to date review of the subject by Charlie Haworth of Papworth Hospital Cambridge. Overall rates of recovery were 3.7% to 24% depending on location and patient population – in USA overall prevalence 13% (7 – 24%) and in France 6.6% (3.7 – 9.6%).  M. avium complex and M. abscessus complex most frequently isolated. ATS guidelines were published in 2007 but were not specific for CF. (free download available from ATS website)

There follows a detailed review of diagnosis and treatment.

2015 Andres Floto R, Haworth CS. The growing threat of non-tuberculous mycobacteria in CF. J Cyst Fibros 2015; 14(1):1-2. Editorial. [PubMed]
The authors note the recent growing awareness of the threat of non-tuberculous mycobacteria (NTM) to individuals with cystic fibrosis (CF) and an increasing appreciation of the difficulties in screening, diagnosing and treating NTM-pulmonary infection in the context of CF lung disease. They provide a useful summary of the present situation.
There are two main groups of NTM that cause the majority of infections in individuals with CF: the Mycobacterium avium complex (MAC) consisting of M. avium, M. intracellulare and M. chimaera; and the M. abscessus complex (MABSC) made up of three subspecies, M. abscessus spp. abscessus, M. abscessus. spp. massiliense and M. abscessus spp. bolettii. While MAC is the more common infection in the US [PubMed], studies have suggested that MABSC is more frequent in Europe [PubMed] and elsewhere [PubMed]. Moreover, the rates of MABSC infection appear to be rising across the world [PubMed]; CFF Registry 2010]; a positive sputum culture for MABSC is more likely to indicate the presence of NTM-mediated lung damage (termed ‘NTM pulmonary disease’) rather than asymptomatic colonisation [PubMed]; and treatment of MABSC remains extremely difficult.

2015 Bar-On O; Mussaffi H; Mei-Zahav M; Prais D; Steuer G; Stafler P; Hananya S; Blau H.  Increasing nontuberculous mycobacteria infection in cystic fibrosis.   J Cyst Fibros 2015; 14(1):53-62.  [PubMed]
Patient records, 2002-2011, were reviewed for NTM infection. FEV1, pancreatic function, sputum microbiology, and serum cytokines were compared in patients with and without NTM infection.
The incidence of NTM infection increased from nil in 2002 to 8.7% in 2011 (p<0.001). NTM infection prevalence increased 3-fold from 5% (4/79) in 2003 to 14.5% (16/110) in 2011 (p=0.05).  NTM incidence and prevalence have increased dramatically in the CF clinic in the Graub CF Center in Israel, associated with a severe CF genotype and phenotype. M. abscessus, the most prevalent NTM, caused prolonged infection despite therapy. There has been some decrease in the prevalence of NTM lung disease since 2009.

– A useful record of longitudinal experience from a major clinic in Israel documenting the increasing problem of nontuberculous mycobacterial infection.

2015 Roux AL, Catherinot E, Soismier N, Heym B, Bellis G, Lemonnier L, Chiron R, Fauroux B, Le Bourgeois M, Munck A, Pin I, Sermet I, Gutierrez C, Véziris N, Jarlier V, Cambau E, Herrmann JL, Guillemot D, Gaillard JL; OMA group.  Comparing Mycobacterium massiliense and Mycobacterium abscessus lung infections in cystic fibrosis patients. J Cyst Fibros. 2015; 14(1):63-9. doi: 10.1016/j.jcf.2014.07.004. Epub 2014 Jul 30. [PubMed]
This data from a national French survey, show a particular link between M. massiliense and malnutrition specifically in CF patients. Unlike M. abscessus, the bacteriological response of M. massiliense to combination antibiotic therapies containing clarithromycin was excellent. Distinguishing between M. massiliense and M. abscessus has major clinical implications for CF patients.
Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. Infections with a significant impact on rate of decline in % FEV1 were Mycobacterium abscessus complex with -2.22% points per year (95% CI -3.21 to -1.23), Burkholderia cepacia complex -1.95% (95% CI -2.51 to -1.39), Achromobacter xylosoxidans -1.55% (95% CI -2.21 to -0.90), and Pseudomonas aeruginosa -0.95% (95% CI -1.24 to -0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope.

2015 Qvist T, Taylor-Robinson D, Waldmann E, Olesen HV, Hansen CR, Mathiesen IH, Høiby N, Katzenstein TL, Smyth RL, Diggle PJ, Pressler T.  Comparing the harmful effects of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis. J Cyst Fibros. 2015 Oct 5. pii: S1569-1993(15)00215-5. doi: 10.1016/j.jcf.2015.09.007. [Epub ahead of print]   [PubMed]

Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. Infections with a significant impact on rate of decline in % FEV1 were Mycobacterium abscessus complex with -2.22% points per year (95% CI -3.21 to -1.23), Burkholderia cepacia complex -1.95% (95% CI -2.51 to -1.39), Achromobacter xylosoxidans -1.55% (95% CI -2.21 to -0.90), and Pseudomonas aeruginosa -0.95% (95% CI -1.24 to -0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope.

– A helpful record of extensive experience over a considerable time from Copenhagen confirming the more serious consequences of M. abscessus.

2015 Qvist T, Gilljam M, Jönsson B, Taylor-Robinson D, Jensen-Fangel S, Wang M, Svahn A, Kötz K, Hansson L, Hollsing A, Hansen CR, Finstad PL, Pressler T, Høiby N, Katzenstein TL; Scandinavian Cystic Fibrosis Study Consortium (SCFSC).  Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia.  J Cyst Fibros. 2015; 14(1):46-52. doi: 10.1016/j.jcf.2014.08.002. Epub 2014 Aug 30. [PubMed]
Data from Danish, Swedish and Norwegian CF centres between 2000 and 2012 identified 11% (157/1270) patients with at least one positive NTM culture during this period. Higher rates of NTM were detected in larger centres.

2015 Patil N, Marco A, Montales MT, Bhaskar N, Mittadodla P, Mukasa LN. Pulmonary Tuberculosis in a Patient with Cystic Fibrosis. N Am J Med Sci. 2015 May;7(5):233-5. doi: 10.4103/1947-2714.157494.  [PubMed]    Free PMC Article
A 24-year-old CF patient had fever, cough, hemoptysis, and weight loss of 1week duration prior to admission. Past sputum cultures grew methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The patient was treated with broad spectrum antibiotics based on previous culture data, but failed to improve. Chest radiograph and computed tomography (CT) chest revealed chronic collapse of the anterior sub segment of right upper lobe and multiple bilateral cavitary lesions which were worse compared to prior films. Mycobacterium tuberculosis (MTB) was suspected and was confirmed by positive acid-fast bacilli (AFB) smears and cultures. After receiving first-line anti-tuberculous drugs, the patient’s condition markedly improved.

– MTB is an infrequent finding, but considered a potential pathogen in CF patients, and may lead to serious pulmonary complications if there is a delay in diagnosis and treatment. The same group from Arkansas report a 26 year old pregnant CF patient who had recurreent MTB infection (Marco A et al. Respir Med case Rep 2015; 16;57-9. [PubMed]).

2015 Park IK; Olivier KN.  Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis. Respir Crit Care Med 2015; 36(2):217-24. 25826589  [PubMed]
Increasing numbers of CF and non-CF bronchiectasis patients are affected by pulmonary nontuberculous mycobacteria (NTM) infection worldwide. Two species of NTM account for up to 95% of the pulmonary NTM infections: Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC). Diagnosis of pulmonary NTM infection is based on criteria specified in the 2007 American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guidelines.
While many initial positive cultures do not progress to active NTM disease, even a single positive NTM sputum culture obtained from higher risk groups such as classic CF or older women with bronchiectasis and very low body mass index should be closely monitored for progressive disease.
Macrolides remain the most effective agents available against MAC and MABSC. Infection with MABSC may be associated with worse clinical outcomes, as more than half of MABSC isolates have inducible macrolide resistance conferred by an active erm(41) gene.
Of growing concern in CF is that MABSC is becoming more common than MAC, seems to target younger patients with classic CF, and is more difficult to manage, often requiring prolonged courses of intravenous antibiotics. Recurrence rates of NTM after initial successful treatment remain high, likely due to non-modifiable risk factors raising the question of whether secondary prophylaxis is feasible. More rapid and readily available methods for detecting inducible macrolide resistance and better in vitro susceptibility testing methods for other drugs that correlate with clinical responses are needed. This is crucial to identify more effective regimens of existing drugs and for development of novel drugs for NTM infection

– A timely article on an increasing problem in people with CF by experts in this area.

Bryant JM, Grogono DM, Rodriguez-Rincon D, Everall I, Brown KP, Moreno P, et al. Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium. Science. 2016 Nov 11;354(6313):751-757[PubMed]
Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

2016 Floto RA; Olivier KN; Saiman L; Daley CL; Herrmann JL; Nick JA; Noone PG; Bilton D; Corris P; Gibson RL; Hempstead SE; Koetz K; Sabadosa KA; Sermet-Gaudelus I; Smyth AR; van Ingen J; Wallace RJ; Winthrop KL; Marshall BC; Haworth CS; US Cystic Fibrosis Foundation and European Cystic Fibrosis Society.    US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax. 71 Suppl 1:i1-22, 2016 Jan[PubMed

        Andres Floto

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, they have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition.

Andres Floto (figure) is Professor of Respiratory Biology, Cambridge Immunology Network. Research interests include control of antigen processing by Fcgamma receptors and mycobacterial-host reactions

2017 Aziz DB, Low JL, Wu ML, Gengenbacher M, Teo JW, Dartois V, Dick T. Rifabutin Is Active Against Mycobacterium abscessus Complex. Antimicrob Agents Chemother. 2017 Apr 10. pii: AAC.00155-17. doi: 10.1128/AAC.00155-17. [Epub ahead of print] [Pubmed]A collection of more than 2700 approved drugs was screened at a single point concentration against an M. abscessus clinical isolate. Surprisingly, the rifampicin derivative rifabutin had an MIC of 3 ± 2 μM (3 μg/mL) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T and M. abscessus subsp. massiliense CCUG 48898-T, as well as a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin resistant strains.

The authors concluded, rifabutin – in contrast to rifampicin – is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

2017 Bouso JM, Burns JJ, Amin R, Livingston FR, Elidemir O. Household proximity to water and non-tuberculous mycobacteria in children with cystic fibrosis. Pediatr Pulmonol. 2017 Jan 30. doi: 10.1002/ppul.23646. [Epub ahead of print]  [Pubmed]A study to determine if there is an association between household proximity to water and NTM in children with CF. Of the 150 CF patients, 65 met inclusion criteria and 21 (32.3%) tested positive for NTM.

The CF patients who lived within 500 meters of water were 9.4 times more likely to acquire NTM (P = 0.013). Other significant predictors included a history of Aspergillus fumigatus (OR 7.9, P = 0.011) and recent history of Pseudomonas aeruginosa (OR 2.5, P = 0.007).

–    Not sure how this helps in practice although NTM seems to be an increasing problem so all information relating to the infection is valuable perhaps when choosing a new home?

2017 Schwarz C, Brandt C, Whitaker P, Sutharsan S, Skopnik H, Gartner S, Smazny C, Röhmel Invasive Pulmonary Fungal Infections in Cystic Fibrosis. Mycopathologia. 2017 Sep 1. doi: 10.1007/s11046-017-0199-4. [Epub ahead of print] [Pubmed]

     Carsten Schwarz

This case series provides useful multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centres in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500 kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections

Carsten Schwarz (figure) is Director of the Adult CF Centre, Endoscopy and Lung Transplantation Charite Universitatsmedizin, Berlin.

2018 Adjemian JOlivier KNPrevots DR.Epidemiology of Pulmonary Nontuberculous Mycobacterial Sputum Positivity in Patients with Cystic Fibrosis in the United States, 2010-2014.  Ann Am Thorac Soc. 2018 Jun 13. doi: 10.1513/AnnalsATS.201709-727OC. [Epub ahead of print]  [Pubmed]
Pulmonary nontuberculous mycobacterial (NTM) disease represents a significant threat to cystic fibrosis (CF) patients, with an estimated annual prevalence of 12%. Prior studies report an increasing annual NTM prevalence in the general population, though similar trends in persons with CF have not been assessed.  This study aimed to identify the prevalence, geographic patterns, temporal trends and risk factors for NTM positivity by mycobacterial species among persons with CF throughout the United States using annualized CF Patient Registry (CFPR) data from 2010-2014.         Of 16,153 included persons with CF, 3,211 (20%) had a pathogenic NTM species isolated at least once over the 5-year period; 1,949 (61%) had Mycobacterium avium complex (MAC) and 1,249 (39%) M. abscessus. NTM prevalence showed a significant relative increase of 5% per year, from 11.0% in 2010 to 13.4% in 2014 (p=0.0008), although this varied by geographic area. Study participants with either MAC or M. abscessus were significantly more likely to have been diagnosed with CF at an older age (p<0.0001), have a lower BMI (p<0.0001), higher forced expiratory volume in one second (FEV1) percent predicted (p<0.01), and fewer years on chronic macrolide therapy (p<0.0001).

The authors concluded NTM remains highly prevalent among adults and children with CF in the U.S., with one in five affected, and appears to be increasing over time. Variation in prevalence exists by geographic region and by patient-level factors, including older age and receiving an initial CF diagnosis later in life. Routine screening for NTM, including mycobacterial speciation, especially in high-risk geographic areas, is critical for better understanding its epidemiology and changes in prevalence over time.

2018 Schwarz CBrandt CWhitaker PSutharsan SSkopnik HGartner SSmazny CRöhmel JF.  Invasive Pulmonary Fungal Infections in Cystic Fibrosis. Mycopathologia.  2018 Feb;183(1):33-43. doi: 10.1007/s11046-017-0199-4. Epub 2017 Sep 1. [Pubmed]
Pulmonary mycosis is after allergic bronchopulmonary aspergillosis (ABPA) a frequent and severe complication of CF lung disease. Among CF caregivers, there is an insecurity when and how to treat infections of the lung parenchyma caused by different fungi in patients with CF. This case series provides a multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centers in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500 kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections.

2018 Singh ARalhan ASchwarz CHartl DHector A.Fungal Pathogens in CF Airways: Leave or Treat?Mycopathologia. 2018 Feb;183(1):119-137. doi: 10.1007/s11046-017-0184-y. Epub 2017 Aug 2.[Pubmed]
Fungi are frequently detected in CF airways and there is an increasing body of evidence that fungal pathogens might play a role in CF lung disease. Several studies have shown an association of fungi, particularly Aspergillus fumigatus and Candida albicans, with the course of lung disease in CF patients. It remains elusive whether fungi are actively involved in CF lung disease pathologies or whether they rather reflect a dysregulated airway colonization and act as microbial bystanders. A key issue for dissecting the role of fungi in CF lung disease is the distinction of dynamic fungal-host interaction entities, namely colonization, sensitization or infection. This review summarizes key findings on pathophysiological mechanisms and the clinical impact of fungi in CF lung disease.

– An extensively referenced review of the problem (222 references) relating to inhaled antibiotics and fungal infections.

2017 Schwarz CHartl DEickmeier OHector ABenden CDurieu ISole AGartner SMilla CEBarry PJ.Progress in Definition, Prevention and Treatment of Fungal Infections in Cystic Fibrosis.  Mycopathologia. 2018 Feb;183(1):21-32. doi: 10.1007/s11046-017-0182-0. Epub 2017 Jul 31.  [Pubmed]  
The main bacterial species causing infections include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Achromobacter xylosoxidans. In addition to bacteria, fungi are detected in a significant number of patients. Although fungal infections are rare, fungi can cause severe pneumonia requiring appropriate targeted treatment. The most common fungi in respiratory samples of patients with CF are Aspergillus fumigatus, Aspergillus terreus and Scedosporium species for filamentous fungi, and yeasts such as Candida albicans and Candida glabrata. Therapeutic strategies depend on the detected fungus and the underlying clinical status of the patient. The antifungal therapy can range from a simple monotherapy up to a combination of three different drugs. Treatment course may be indicated in some patients for two weeks and in others for up to six months, and in rare cases even longer. New antifungal drugs have been developed and are being tested in clinical studies offering the hope of therapeutic alternatives to existing drugs. Identifying relevant risk factors and diagnostic criteria for fungal colonization and infection is crucial to enabling an adequate prevention, diagnosis and treatment.

2018 Schwarz CBrandt CMelichar VRunge CHeuer ESahly HSchebek MKöster HBouchara JPBiedermann TMeißner PGroße-Onnebrink JSkopnik HHartl DSedlacek L, Tintelnot K.  Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis. J Cyst Fibros. 2018 Oct 5. pii: S1569-1993(18)30794-X. doi: 10.1016/j.jcf.2018.08.012. [Epub ahead of print]  [Pubmed] Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. The authors aimed to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF.

– Useful combined experience for those treating  these relatively uncommon infections.

Singh ARalhan ASchwarz CHartl DHector A.Fungal Pathogens in CF Airways: Leave or Treat?Mycopathologia. 2018 Feb;183(1):119-137. doi: 10.1007/s11046-017-0184-y. Epub 2017 Aug 2.[Pubmed]
Fungi are frequently detected in CF airways and there is an increasing body of evidence that fungal pathogens might play a role in CF lung disease. Several studies have shown an association of fungi, particularly Aspergillus fumigatus and Candida albicans, with the course of lung disease in CF patients. It remains elusive whether fungi are actively involved in CF lung disease pathologies or whether they rather reflect a dysregulated airway colonization and act as microbial bystanders. A key issue for dissecting the role of fungi in CF lung disease is the distinction of dynamic fungal-host interaction entities, namely colonization, sensitization or infection. This review summarizes key findings on pathophysiological mechanisms and the clinical impact of fungi in CF lung disease.

– An extensively referenced review of the problem (222 references) relating to inhaled antibiotics and fungal infections.

Schwarz CHartl DEickmeier OHector ABenden CDurieu ISole AGartner SMilla CEBarry PJ.Progress in Definition, Prevention and Treatment of Fungal Infections in Cystic Fibrosis.  Mycopathologia. 2018 Feb;183(1):21-32. doi: 10.1007/s11046-017-0182-0. Epub 2017 Jul 31.  [Pubmed]  

The main bacterial species causing infections include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Achromobacter xylosoxidans. In addition to bacteria, fungi are detected in a significant number of patients. Although fungal infections are rare, fungi can cause severe pneumonia requiring appropriate targeted treatment. The most common fungi in respiratory samples of patients with CF are Aspergillus fumigatus, Aspergillus terreus and Scedosporium species for filamentous fungi, and yeasts such as Candida albicans and Candida glabrata. Therapeutic strategies depend on the detected fungus and the underlying clinical status of the patient. The antifungal therapy can range from a simple monotherapy up to a combination of three different drugs. Treatment course may be indicated in some patients for two weeks and in others for up to six months, and in rare cases even longer. New antifungal drugs have been developed and are being tested in clinical studies offering the hope of therapeutic alternatives to existing drugs. Identifying relevant risk factors and diagnostic criteria for fungal colonization and infection is crucial to enabling an adequate prevention, diagnosis and treatment.

Schwarz CBrandt CMelichar VRunge CHeuer ESahly HSchebek MKöster HBouchara JPBiedermann TMeißner PGroße-Onnebrink JSkopnik HHartl DSedlacek L, Tintelnot K Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis. J Cyst Fibros. 2018 Oct 5. pii: S1569-1993(18)30794-X. doi: 10.1016/j.jcf.2018.08.012. [Epub ahead of print]  [Pubmed] Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. The authors aimed to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF.

– Useful combined experience for those treating  these relatively uncommon infections.

Adjemian JOlivier KNPrevots DR.Epidemiology of Pulmonary Nontuberculous Mycobacterial Sputum Positivity in Patients with Cystic Fibrosis in the United States, 2010-2014.  Ann Am Thorac Soc. 2018 Jun 13. doi: 10.1513/AnnalsATS.201709-727OC. [Epub ahead of print]  [Pubmed]
Pulmonary nontuberculous mycobacterial (NTM) disease represents a significant threat to cystic fibrosis (CF) patients, with an estimated annual prevalence of 12%. Prior studies report an increasing annual NTM prevalence in the general population, though similar trends in persons with CF have not been assessed.  This study aimed to identify the prevalence, geographic patterns, temporal trends and risk factors for NTM positivity by mycobacterial species among persons with CF throughout the United States using annualized CF Patient Registry (CFPR) data from 2010-2014.         Of 16,153 included persons with CF, 3,211 (20%) had a pathogenic NTM species isolated at least once over the 5-year period; 1,949 (61%) had Mycobacterium avium complex (MAC) and 1,249 (39%) M. abscessus. NTM prevalence showed a significant relative increase of 5% per year, from 11.0% in 2010 to 13.4% in 2014 (p=0.0008), although this varied by geographic area. Study participants with either MAC or M. abscessus were significantly more likely to have been diagnosed with CF at an older age (p<0.0001), have a lower BMI (p<0.0001), higher forced expiratory volume in one second (FEV1) percent predicted (p<0.01), and fewer years on chronic macrolide therapy (p<0.0001).

The authors concluded NTM remains highly prevalent among adults and children with CF in the U.S., with one in five affected, and appears to be increasing over time. Variation in prevalence exists by geographic region and by patient-level factors, including older age and receiving an initial CF diagnosis later in life. Routine screening for NTM, including mycobacterial speciation, especially in high-risk geographic areas, is critical for better understanding its epidemiology and changes in prevalence over time.

Richards CJ, Olivier KN.   Nontuberculous Mycobacteria in Cystic Fibrosis. Semin Respir Crit Care Med. 2019 Oct 28. doi: 10.1055/s-0039-1693706. [Epub ahead of print] [Pubmed]

   Christopher Richards

Over the past decade, the incidence of nontuberculous mycobacterial (NTM) infection has been increasing in cystic fibrosis patients. Along with this have come a host of complications and burdens to patients that threaten longevity and quality of life. The two main constituents of NTM pulmonary disease, Mycobacterium avium complex (MAC) and M. abscessus, are notoriously difficult to treat with suboptimal clinical responses and are accompanied by high treatment burdens for patients. This review aims to summarize the current knowledge of NTM epidemiology, pathogenesis, professional society guidelines for diagnosis and treatment, and the efficacy of current management recommendations, with attention to cystic fibrosis patients. We go on to examine drugs of emerging but unknown efficacy in clinical use to provide a comprehensive assessment of the current state of management of NTM for cystic fibrosis patients.

.Dr Christopher J Richards is an Instructor in Medicine in the Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston.

Ahmed MI, Kulkarni H, Shajpal S, Patel D, Patel P, Claydon A, Modha DE, Gaillard EA. Early detection of non-tuberculous mycobacteria in children with cystic fibrosis using induced sputum at annual review.Pediatr Pulmonol. 2019 Mar;54(3):257-263. doi: 10.1002/ppul.24220. Epub 2018 Dec 18.[Pubmed]

        Erol Gaillard

The authors aimed to test the hypothesis that performing sputum induction at routine annual review results in earlier identification of NTM in non-sputum producing children with CF. They conducted a 5-year prospective observational cohort study involving children with CF aged 5-17 years who had sputum induction with hypertonic saline for microbiological surveillance including NTM at their annual review.

Forty-two children (19 males, mean age 11.4 years ± 3.6, mean FEV1 % predicted 94.7 ± 20.6) participated in the study. Six samples from six children (14% of the cohort) yielded NTM never previously isolated from the patient. We also detected three isolates of Pseudomonas aeruginosa and one isolate each of Burkholderia cepacia complex and Meticillin resistant Staphylococcus aureus (MRSA), all of which were first time isolates.

The author conclude that annual induced sputum for microbiological surveillance is useful for early detection of NTM and other important respiratory pathogens, particularly in non-expectorating children. This may lead to earlier identification and help inform initiation of eradication treatment in children with NTM. Children can also be cohorted earlier, before they potentially infect other children in the clinic.

Dr Erol A Gaillard is Senior Lecturer and lead Paediatric CF Consultant in Leicester

Boyle M, Moore JE, Whitehouse JL, Bilton D, Downey DG. The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice. Med Mycol. 2019 Feb 1;57(2):155-160. doi: 10.1093/mmy/myy014. [Pubmed]

Damion Downey

Damion Downey

The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys

Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019 May;25(5):730-733. doi: 10.1038/s41591-019-0437-z. Epub 2019 May 8.[Pubmed]

Robert Dedrick

A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-

      Helen Spencer

phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules

Dr Robert Dedrick is Professor and Programme Coordinator, College of Education University of South Florida

Dr Helen Spencer is a Respiratory Paediatrician and has been clinical lead for the Lung Transplantation service at Great Ormond Street since 2007 where this patient was treate

For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF.

Doyle RM, Rubio M, Dixon G, Hartley J, Klein N, Coll P, Harris KA. Cross- infection is not the source of new Mycobacterium abscessus infections in a multi-centre cohort of cystic fibrosis patients. Clin Infect Dis. 2019 Jun 19. pii: ciz526. doi: 10.1093/cid/ciz526. [Epub ahead of print] [Pubmed]

Ronan Doyle

Mycobacterium abscessus is an extensively drug resistant pathogen that causes pulmonary disease particularly in cystic fibrosis (CF) patients. Identifying direct patient-to-patient transmission of M. abscessus is critically important in directing infection control policy for the management of risk in CF patients. A variety of clinical labs have used molecular epidemiology to investigate transmission. However there is still conflicting evidence as to how M. abscessus is acquired and whether cross-transmission occurs. Recently labs have applied whole-genome sequencing (WGS) to investigate this further and in this study we investigate whether WGS can reliably identify cross-transmission in M. abscessus. These authors retrospectively sequenced the whole genomes of 145 M. abscessus isolates from 62 patients seen at four hospitals in two countries over 16 years. They showed that a comparison of a fixed number of core single nucleotide variants (SNVs) alone cannot be used to infer cross-transmission in M. abscessus but does provide enough information to replace multiple existing molecular assays. They detected one episode of possible direct patient-to-patient transmission in a sibling pair. We found that patients acquired unique M. abscessus strains even after spending considerable time on the same wards with other M. abscessus positive patients.They concluded this novel analysis has demonstrated that the majority of patients in this study have not acquired M. abscessus through direct patient-patient transmission or a common reservoir. Tracking transmission using WGS will only realise its full potential with proper environmental screening as well as patient sampling.

Dr Ronan Doyle is Assistant Professor in the Department of Clinical Research, the London School of Hygiene and Tropical Medicine.

Gardner AI, McClenaghan E, Saint G, McNamara PS, Brodlie M, Thomas MF. Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry. Clin Infect Dis. 2019 Feb 15;68(5):731-737. doi: 10.1093/cid/ciy531. [PubMed]

Aaron Gardner

Data from 2010-2015 for individuals aged <16 years (23200 observations from 5333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. The significant factors that were identified were used to generate a multivariate logistic regression model that, following step-wise removal, generated a final parsimonious model.The prevalence of individuals with a NTM-positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (odds ratio [OR], 2.66; P = 5.0 × 10-8), age (OR, 1.08; P = 3.4 × 10-10), and intermittent Pseudomonas aeruginosa infection (OR, 1.51; P = .004) were significantly associated with NTM infectio

Dr Aaron Gardner id Research Associate at the Institute of Cellular Medicine, Newcastle University Medcial School Newcastle upon Tyne

Shaw LP, Doyle RM, Kavaliunaite E, Spencer H, Balloux F, Dixon G, Harris KA. Children with cystic fibrosis are infected with multiple subpopulations of Mycobacterium abscessus with different antimicrobial resistance profiles. Clin Infect Dis. 2019 Jan 26. doi: 10.1093/cid/ciz069. [Epub ahead of print] [Pubmed]
Children with cystic fibrosis (CF) can develop life-threatening infections of Mycobacterium abscessus. These present a significant clinical challenge, particularly when the strains involved are resistant to antibiotics. Recent evidence of within-patient subclones of M. abscessus in adults with CF suggests the possibility that within-patient diversity may be relevant for the treatment of pediatric CF patients.

The authors performed whole genome sequencing (WGS) on 32 isolates of M. abscessus from multiple body sites for two patients with CF undergoing treatment at Great Ormond Street Hospital, UK, in 2015. They found evidence of extensive diversity within patients over time. Clustering analysis of single nucleotide variants (SNVs) revealed that each patient harboured multiple subpopulations, which were differentially abundant between sputum, lung samples, chest wounds, and pleural fluid. Sputum isolates did not reflect overall within-patient diversity, including failing to detect subclones with mutations previously associated with macrolide resistance (rrl 2058/2059). Some variants were present at intermediate frequencies before lung transplant. The time of transplant coincided with extensive variation, suggesting that this event is particularly disruptive for the microbial community, but transplant did not clear the M. abscessus infection and both patients died as a result of this infection.

So isolates of M. abscessus from sputum do not always reflect the entire diversity present within the patient, which can include subclones with differing antimicrobial resistance profiles. Awareness of this phenotypic variability, with sampling of multiple body sites in conjunction with WGS, may be necessary to ensure the best treatment for this vulnerable patient group.

Yan JKevat AMartinez ETeese NJohnson KRanganathan SHarrison JMassie JDaley A.     Investigating transmission of Mycobacterium abscessusamongst children in an Australian cystic fibrosis centre.J Cyst Fibros.2019Mar 7. pii: S1569-1993(18)30918-4. doi: 10.1016/j.jcf.2019.02.011. [Epub ahead of print] [Pubmed]

Mycobacterium abscessus is an emerging pathogen in cystic fibrosis (CF) lung disease. Hospital transmission of M. abscessus has been described. This paper details the investigation into possible cross-transmission of M. abscessus locally at our paediatric hospital CF centre, and the subsequent infection control response. Whole genome sequencing (WGS) of M. abscessus respiratory isolates with epidemiological linkage analysis using hospital electronic medical records.

6.7% (22/328) of CF patients had M. abscessus isolated from respiratory specimens. WGS revealed a cluster of three patients with genomically related isolates that differed by <7 single nucleotide polymorphisms (SNPs), suggesting a shared recent ancestor and probable cross-transmission. Epidemiological investigation revealed multiple potential crossovers between patients with genomically similar M. abscessus isolates.

The authors concluded cross-infection of NTM occurs in CF hospital patients and advise that hospital infection control practices should be upgraded to reflect this. Consensus is needed between centres.

From the Department of Microbiology, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia; Department of Infection Prevention and Control, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia.

Paajanen J, Halme M, Palomäki M. Anttila VJ.Disseminated Scedosporium apiospermum central nervous system infection after lung transplantation: A case report with successful recovery. Med Mycol Case Rep. 2019 Mar 16;24:37-40. doi: 10.1016/j.mmcr.2019.03.003. eCollection 2019 Jun. Free PMC Article [Pubmed]

Juuso Paajanen

Scedosporium species are fungal opportunistic pathogens frequently seen in chronic lung diseases such as in cystic fibrosis (CF). They can cause a wide spectrum of diseases mainly in immunodeficient patients. Invasive, disseminated infections with poor prognosis have been described after lung transplantation. We present a CF-patient with disseminated Scedosporium apiospermum infection after lung transplantation. The patient had skin, surgical wound, spinal cord, and brain involvements. She recovered fully after prolonged course of voriconazole treatm

Dr Juuso Paajanen is at the Department of Pulmonary Medicine, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Finland

Lopeman RCHarrison JRathbone DLDesai MLambert PACox JAG.  Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus.  Sci Rep. 2020 Jan 27;10(1):928. doi: 10.1038/s41598-020-57844-8.   [Pubmed] Free PMC Article

Rose Lopeman

Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosispatients. This opportunistic pathogen’s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. Here they report a prospective advance in the treatment of M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. They establish by multiple in vitro methods that this combination works synergistically to inhibit M. abscessus. They also show the direct competitive inhibition of the M. abscessus β-lactamase, BlaMab, using a novel assay, which is validated kinetically using the nitrocefin reporter assay and in silico binding studies. Furthermore, they reverse the susceptibility by overexpressing BlaMab in M. abscessus, demonstrating relebactam-BlaMab target engagement. Finally, they highlight the in vitro efficacy of this combination against a panel of M. abscessus clinical isolates, revealing the therapeutic potential of the amoxicillin-imipenem-relebactam combination

Rose Lopeman is at Department of Medical Sciences Aston University

Low DWilson DAFlume PA. Screening practices for nontuberculous mycobacteria at us cystic fibrosis centers.  J Cyst Fibros. 2020 Mar 13. pii: S1569-1993(20)30060-6. doi: 10.1016/j.jcf.2020.02.013. [Epub ahead of print]  [Pubmed]
Current guidelines recommend at least once yearly screening for nontuberculous mycobacteria (NTM) in Cystic Fibrosis (CF), however screening practices remain widely variable. This study evaluates current practices among United States CF centers with specific focus on clinical predictive factors for NTM screening.

Between 2010 AND 2014 NTM screening practices varied widely among United States CF centers with many centers testing only on clinical changes. With higher rates of testing shown as successful in identifying more patients with NTM, routine screening should be emphasized in CF care going forward.

From the Department of Medicine, University of Colorado, Denver, CO, United States.

Siân Bentley , Jane C Davies Siobhán B Carr Ian M Balfour-Lynn Combination Antifungal Therapy for Scedosporium Species in Cystic Fibrosis. . 2020 Apr 27.doi: 10.1002/ppul.24789. Online ahead of print.  [Pubmed]

       Sian Bentley

A study to evaluate safety and efficacy of oral posaconazole and terbinafine for Lomentospora prolificans and Scedosporium apiospermum in children with cystic fibrosis.  There were five children (four girls), median age 15.0 years; three had S. apiospermum and two had L. prolificans. Treatment duration: median 5 months (range: 5-18 m). In no patient was eradication achieved, with the follow-up range being 6 months to 4 years. Effect on lung function was variable but encouraging. No adverse effects were reported, one child had transient elevation of liver enzymes.
The authors concluded while the combination therapy was well tolerated, it was unsuccessful at eradication.

Sian Bentley is Lead Pharmacist, Paediatrics Royal Brompton and Harefield NHS Foundation Trust, London