There has been an increase in the isolation of NTM bacteria from the respiratory secretions of CF patients [2,3,4,5,6]. Although NTM infection was present in 8.3% of our CF patients during the study period, this value is relatively similar to previous studies [2, 5, 8,9,10,11]; however, this may not reflect the true prevalence. Many of our CF patients rarely underwent mycobacterial analysis and some never underwent any mycobacterial testing. This omission may be due to difficulties with the collection of adequate and appropriate specimens in younger patients, the indeterminate significance of these organisms in the CF population, and a lack of awareness and consistency among providers in obtaining NTM cultures as part of routine CF care .
More than 160 species of NTM have been characterized to date; of which a select few are associated with clinical disease in humans. Each member of this heterogeneous group of organisms has its own microbiological and clinical significance, with equally diverse treatment and resistance profiles . The most common NTM species isolated in our study was MAC, followed by MABSC (Table 1); this observation is consistent with other reports [2, 4, 7, 9, 10, 15, 17, 31]. Catherinot et al.  compared CF patients infected with MAC and MABSC in France and found that MAC was more common in adult patients with mild CF, whereas MABSC more frequently infected younger patients with more severe CF . Our results do not fully confirm the results of Catherinot et al., since the median age was similar between the culture-positive groups (Table 1). Historically, M. gordonae was classified as the most common contaminant NTM species; however, there have been reports of infection with this organism in patients with CF [6, 18].
Our analyses revealed a significant relationship between the patients’ age at CF diagnosis and infection with rapidly growing mycobacteria (Table 1). Early CF diagnosis via newborn screening and recent advances in medical care are expected to facilitate better preventive care and management of CF patients infected with NTM . Delays in the initial diagnosis of CF generally lead to a late start in patient management, potentially resulting in poorer general health, malnutrition, and more advanced lung disease, all of which contribute to infection with rapidly growing mycobacteria [28, 31].
Multiple prospective and retrospective studies have yielded inconsistent results regarding the possible effects of NTM infection on the progression of CF lung disease [7, 10, 14, 17, 20]. To the best of our knowledge, the current investigation is the first single center study in the US to compare the effects of slow- and rapidly-growing NTM on the smaller airways by comparing the FEF25–75 before and after NTM acquisition in CF patients. Previous studies have suggested that FEF25–75 is a sensitive indicator of early disease in children with CF , which our current study further supports. Similarly, Bakker et al.  reported that FEF75 is a more sensitive marker of early CF lung disease than FEV1 and forced vital capacity because abnormalities in FEF75 occur at a younger age and FEF75 decreases more than other pulmonary-function parameters. In the present study, FEV1 as a measure of pulmonary function did not differ before and after NTM acquisition in either infection group; however, we did detect significantly lower FEF25–75 after NTM acquisition in both culture-positive patient groups (Table 2). Patients with more than four cultures positive for rapidly growing NTM were associated with the greatest change in the median FEF25–75 throughout the follow-up period (Table 3; Fig. 2). This is likely because patients with rapidly growing NTM can have more acute and severe clinical symptoms [6, 7]. Our data suggest that NTM infection has a negative impact on small airway function in patients with CF.
Coexisting microbial pathogens have an undetermined role in the development of NTM infection. In the current study, the most common bacterial colonization in both culture-positive groups was P. aeruginosa, followed by S. aureus (Table 4). A variable prevalence of NTM isolation in patients with underlying P. aeruginosa and S. aureus colonization has been reported in multiple studies [10, 14]; however, there is some evidence of a higher prevalence of A. fumigatus colonization among NTM-positive patients [10, 14, 16], as well as an association of NTM with ABPA . Despite these previous reports, we failed to detect a significant relationship between a history of ABPA and NTM acquisition.
Penicillin, beta-lactamase inhibitors, and rifampin use was higher in our patients infected with slow-growing NTM compared to the patients infected with rapidly growing NTM (Table 5). This observation may reflect a decline in patient clinical status that leads to more frequent hospitalization and antibiotic administration in inpatient and ambulatory settings. Many of the antimicrobials used to treat underlying bacterial colonization exhibit some activity against NTM species and may interfere with an accurate diagnosis of the infection and evaluation of subsequent pulmonary function [6, 7]. Unfortunately, inadequate and inappropriate exposure of NTM to antimicrobials can also lead to the development of antibiotic resistance .
The increased use of macrolides following NTM acquisition (Table 5) is rarely a component of a multidrug regimen recommended for the treatment of certain mycobacterial species (e.g., M. absessus). In addition to their antibacterial properties, macrolides (i.e., azithromycin) are most often chosen for their immunomodulatory activity to improve respiratory function and reduce the frequency of pulmonary exacerbations . Screening for an NTM infection in CF patients prior to the initiation of macrolide therapy should be a universal practice. The increased use of macrolides after NTM acquisition may reflect the clinical decline of these patients, which supports the earlier observation of NTM infections in CF patients reported in a two-year cross-sectional study from Israel . There were low treatment numbers for both of the NTM positive groups based on the ATS/ IDSA guidelines . However, increasing knowledge and awareness to NTM infections has led to different management strategies in recent years [6, 7].
This study has several limitations: 1) NTM screening was not routinely practiced at our center during the 10-year study period; however, it may have been performed more often in patients who did not respond satisfactorily to conventional treatments. As a result, our data may not reflect the overall prevalence of these organisms in the study population; 2) our cohort did not have a large variety of CF gene mutation profiles. This is primarily attributed to the predominance of Caucasians in our patient population, which precluded our ability to detect a relationship between ethnicity or genotype and NTM infections; 3) retrospective studies can be limited by ascertainment bias, despite our best efforts to review every available medical record; and 4) a single, tertiary care, referral center study with small sample size may not adequately represent the entire CF population in the US; multiple variables (e.g., race, geography, and practice patterns) may influence the disease presentation and outcome.