Antibody response against Mycobacterium avium complex in cystic fibrosis patients measured by a novel IgG ELISA test.

BACKGROUND: Early signs of Mycobacterium avium complex pulmonary disease can be missed in patients with cystic fibrosis due to subclinical infection or delays in mycobacterial culture. The aim of this study was to determine the diagnostic accuracy of a novel enzyme linked immunosorbent assay for immunoglobulin G against Mycobacterium avium complex, which could help stratify patients according to risk. METHODS: A retrospective cross sectional analysis of serum samples from the Copenhagen Cystic Fibrosis Center was performed. Corresponding clinical data were reviewed and patients with cystic fibrosis were assigned to one of four groups based on their mycobacterial culture results. In addition, anti-Mycobacterium avium complex immunoglobulin G levels were measured longitudinally before and after first positive culture in the period 1984-2015. RESULTS: Three-hundred and five patients with cystic fibrosis were included with a median of five nontuberculous mycobacterial cultures. Four individuals had Mycobacterium avium complex pulmonary disease at the time of cross sectional testing and their median antibody level was 22-fold higher than patients with no history of infection (1820 vs. 80 IgG units; p < 0.001). Test sensitivity was 100% (95% CI 40-100) and specificity 77% (95% CI 72-81). Longitudinal kinetics showed rising antibodies prior to first positive culture suggesting diagnostic delay. CONCLUSIONS: Antibody screening for Mycobacterium avium complex may be used as a supplement to culture. Although confirmation in a larger cohort is needed, our findings suggest that stratifying a cystic fibrosis population into high- and low-risk groups based on antibody levels may help clinicians identify patients in need of more frequent culture.

Individual pharmacokinetic variation leads to underdosing of ciprofloxacin in some cystic fibrosis patients.

BACKGROUND: Ciprofloxacin (CIP) is frequently used when treating cystic fibrose (CF) patients with intermittent Pseudomonas aeruginosa (P. aeruginosa) lung colonization. However, approximately 20% of the patients progress to chronic infection despite early intervention. The aim of this study, was to investigate the pharmacokinetics of CIP, to evaluate if CYP3A4-related metabolism is involved and to find the optimal dose needed to eradicate intermittently colonizing bacteria in the lungs of CF patients. Methods An open-label, prospective pharmacokinetic study was performed. Twenty-two adult CF-patients were each given 500 mg CIP orally. One blood sample was taken at t = 0, and the following 12 hr, nine blood samples were collected. The optimal dose and interval was then calculated by Monte Carlo simulation. CYP3A4-activity was mesured using the Erythromycin Breath Test (ERMBT). Results A 14-fold variation in AUC for the 500 mg CIP (median 473.5 µg/ml × min), and a 30-fold variation in Cmax for CIP (median 2 µg/ml) was found. For CYP3A4-activity the variation was 8-fold. No correlation was found between the CYP3A4-activity and CIP-concentrations. The probability of eradicating intermittent P. aeruginosa colonization in the lungs of CF patients was found to be 57% (3 doses/day), when 500 mg CIP was given. It was calculated to be 89% (2 doses/day) and 94% (3 doses/day), respectivly if 750 mg CIP had been given. Conclusion A large pharmacokinetic difference of CIP in CF patiens was found, not explained by CYP3A4 variation. CIP should be given at 750 mg two or three times daily to adult CF patients with intermittently colonization. Pediatr Pulmonol. 2017;52:319-323. © 2016 Wiley Periodicals, Inc.

Associations between adherence, depressive symptoms and health-related quality of life in young adults with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a life shortening disease, however prognosis has improved and the adult population is growing. Most adults with cystic fibrosis live independent lives and balance the demands of work and family life with a significant treatment burden. The aim of this study was to examine the relationships among treatment adherence, symptoms of depression and health-related quality of life (HRQoL) in a population of young adults with CF. METHODS: We administered three standardized questionnaires to 67 patients with CF aged 18-30 years; Morisky Medication Adherence Scale, Major Depression Inventory, and Cystic Fibrosis Questionnaire-Revised. RESULTS: There was a response rate of 77 % and a majority of the young adults (84 %) were employed or in an education program. Most participants (74 %) reported low adherence to medications. One third (32.8 %) of the participants reported symptoms of depression. HRQoL scores were especially low on Vitality and Treatment Burden, and symptoms of depression were associated with low HRQoL scores (p < 0.01) with medium to large deficits across on all HRQoL domains (Cohen's d 0.60-1.72) except for the domain treatment burden. High depression symptom scores were associated with low adherence (r = -0.412, p < 0.001). CONCLUSIONS: Despite improved physical health, many patients with CF report poor adherence, as well as impaired mental wellbeing and HRQoL. Thus, more attention to mental health issues is needed.

Sinus surgery postpones chronic Gram-negative lung infection: cohort study of 106 patients with cystic fibrosis.

BACKGROUND: In patients with cystic fibrosis (CF) the sinuses are a bacterial reservoir for Gram-negative bacteria (GNB). From the sinuses the GNB can repeatedly migrate to the lungs. In a one-year follow-up study, endoscopic sinus surgery (ESS) with adjuvant therapy reduced the frequency of pulmonary samples positive for GNB. We investigated whether the effect is sustained. METHODOLOGY: We report the effect of ESS and adjuvant therapy three years postoperatively in a CF cohort participating in this prospective clinical follow-up study. The primary endpoint was the lung infection status defined by Leeds criteria. RESULTS: One hundred and six CF patients underwent ESS; 27 had improved lung infection status after three years. The prevalence of patients free of lung colonization with GNB significantly increased from 16/106 patients (15%) preoperatively to 35/106 patients (33%) after three years. The total cohort had decreasing lung function during follow-up; however, in 27 patients with improved lung infection status lung function was stable. Revision surgery was performed in 31 patients (28%). CONCLUSION: ESS with adjuvant therapy significantly improves the lung infection status for at least three years in our cohort of patients with CF and may postpone chronic lung infection with GNB and thus stabilize lung function.

Erratum to: Associations between adherence, depressive symptoms and health-related quality of life in young adults with cystic fibrosis.

[This corrects the article DOI: 10.1186/s40064-016-2862-5.].

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen.

Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by persisting mucoid biofilms in hypoxic endobronchial mucus. These biofilms are surrounded by numerous polymorphonuclear leucocytes (PMNs), which consume a major part of present molecular oxygen (O(2)) due to production of superoxide (O(2)(-)). In this study, we show that the PMNs also consume O(2) for production of nitric oxide (NO) by the nitric oxide synthases (NOS) in the infected endobronchial mucus. Fresh expectorated sputum samples (n = 28) from chronically infected CF patients (n = 22) were analysed by quantifying and visualizing the NO production. NO production was detected by optode measurements combined with fluorescence microscopy, flow cytometry and spectrophotometry. Inhibition of nitric oxide synthases (NOS) with N(G) -monomethyl-L-arginine (L-NMMA) resulted in reduced O(2) consumption (P < 0·0008, n = 8) and a lower fraction of cells with fluorescence from the NO-indicator 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM) (P < 0·002, n = 8). PMNs stained with DAF-FM and the superoxide indicator hydroethidine (HE) and host cells with inducible NOS (iNOS) were identified in the sputum. In addition, the production of the stable end-products of NO in CF sputum was correlated with the concentration of PMNs; NO(3)(-) (P < 0·04, r = 0·66, n = 10) and NO(2)(-) (P< 0·006, r = 0·78, n = 11). The present study suggests that besides consumption of O(2) for production of reactive oxygen species, the PMNs in CF sputum also consume O(2) for production of NO.

Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis.

BACKGROUND: To investigate the correlation between CYP3A4/5 activity and clarithromycin metabolism, and between CYP3A activity and CYP3A genotype. METHODS: This is an open-label, prospective pharmacokinetic study evaluating CYP3A activity using The Erythromycin Breath Test. Eight blood samples were collected within 12h after clarithromycin 500 mg was administered orally. The clarithromycin concentrations were measured by liquid chromatography-tandem mass spectrometry. AUC, Tmax and Cmax were calculated. Selected Single Nucleotide polymorphisms in CYP3A4/5 genes were assessed by PCR and single base extension. RESULTS: Twenty-one chronically infected patients were included. An 8-fold variation in the CYP3A4 activity, 10-fold variation in AUC for clarithromycin (median 881 µg/mL × min), and a 16-fold variation in Cmax for clarithromycin (median 3.4 µg/mL) were found. A linear correlation between the CYP3A4-activity and clarithromycin metabolism was demonstrated (P < 0.05). CONCLUSION: The large variation in the clarithromycin pharmacokinetics in cystic fibrosis patients may cause treatment failure. The Erythromycin Breath Test could be valuable in identifying cystic fibrosis patients in risk of treatment failure/drug toxicity.

Clinical effects of sinus surgery and adjuvant therapy in cystic fibrosis patients - can chronic lung infections be postponed?

BACKGROUND: The paranasal sinuses can be a bacterial reservoir for pulmonary infections in patients with cystic fibrosis (CF) METHODOLOGY: In this prospective, non-randomised, uncontrolled, intervention cohort study, the clinical effect of sinus surgery followed by two weeks` intravenous antibiotics, 6 months` antibiotic nasal irrigations was assessed in 106 CF patients. RESULTS: One year after sinus surgery, the prevalence of intermittently colonised patients had decreased by 38%, while the prevalence of non-colonised patients had increased by 150%. The frequency of pulmonary samples with CF pathogens was reduced after surgery. Specific IgG against P. aeruginosa decreased after six months. Additionally, the self reported symptoms of chronic rhinosinusitis and quality of life improved. CONCLUSION: Combined sinus surgery and postoperative systemic and topical antibiotic treatment significantly reduced the frequency of pulmonary samples positive for CF pathogens in the first year after sinus surgery.

Achromobacter species in cystic fibrosis: cross-infection caused by indirect patient-to-patient contact.

BACKGROUND AND METHODS: Achromobacter species leads to chronic infection in an increasing number of CF patients. We report 2 cases of Achromobacter ruhlandii cross-infection between patients after well-described indirect contact. RESULTS: Both cases were young, stable, CF patients without chronic infections and with normal FEV1, but experienced clinical deterioration after visits to the home of a CF patient with A. ruhlandii infection and after sharing facilities with an A. ruhlandii infected CF patient on a skiing vacation, respectively. Both cases became positive for A. ruhlandii in airway secretions and were colonized with A. ruhlandii in their sinuses. Aggressive, long-term antibiotic treatment led to clinical stability. One of the cases developed chronic A. ruhlandii infection. CONCLUSION: A. species can cause cross-infection even after a short period of indirect contact between infected and non-infected CF patients. Patients should be followed closely for several months before the possibility of cross-infection is ruled out.

Early treatment with inhaled antibiotics postpones next occurrence of Achromobacter in cystic fibrosis.

OBJECTIVES: In this nationwide retrospective study, we analysed species distribution, antimicrobial susceptibility and time to next occurrence of Achromobacter in Danish cystic fibrosis (CF) patients from 2000 to 2011. METHODS: Thirty-four primary isolates were identified to species level and subjected to antimicrobial susceptibility testing. Effectiveness of early antimicrobial treatment was assessed by a Kaplan-Meier estimation of time to recurrence. RESULTS: Achromobacter xylosoxidans accounted for 13 (38%) of the isolates, and an unnamed species accounted for 11 (32%) of the isolates. Meropenem, piperacillin-tazobactam and trimethoprim-sulfamethoxazole were highly active against chemotherapy-naïve Achromobacter, while ceftazidime, colistin and tobramycin were judged adequate for inhalation therapy. Fifty-five percent of 25 patients treated with inhaled ceftazidime, colistin, or tobramycin remained free of Achromobacter three years after acquisition, in contrast to 17% of 22 patients who did not receive inhaled antibiotics (P<0.01). CONCLUSIONS: Early treatment with inhaled antibiotics may prevent or postpone chronic infection with Achromobacter in CF patients.

Nontuberculous mycobacterial disease is not a contraindication to lung transplantation in patients with cystic fibrosis: a retrospective analysis in a Danish patient population.

Whether nontuberculous mycobacterial (NTM) disease is a contraindication to lung transplantation remains controversial. We conducted a nationwide study to evaluate the clinical importance of NTM infection among lung transplant patients with cystic fibrosis (CF) in Denmark and to determine if NTM infection poses a contraindication to lung transplantation. All CF patients with current or prior NTM who had undergone lung transplantation were identified. Out of 52 lung transplant patients with CF 9 (17%) had NTM disease. Five patients had known infection at the time of transplantation. Two of these died of non-NTM-related causes whereas two developed deep Mycobacterium abscessus wound infections and one was transiently culture negative until M abscessus was reactivated. One patient was subsequently cured; the other two remained on therapy with good performance status. The study supports the contention that CF patients with prior or active NTM can undergo lung transplantation although postoperative complications can be expected.

Extensive endoscopic image-guided sinus surgery decreases BPI-ANCA in patients with cystic fibrosis.

Antineutrophil cytoplasm autoantibodies (ANCA) directed against bactericidal/permeability-increasing protein (BPI) are common in patients with cystic fibrosis (CF), and serum levels are correlated with lung colonization by Pseudomonas aeruginosa and the severity of lung damage. The production of BPI-ANCA may be due to the costimulation of BPI when mounting an immune response against P. aeruginosa. The effect of surgery aiming to eradicate bacteria and infected tissue on BPI-ANCA levels is sparsely described. A cohort of patients with CF were included: 53 patients having extensive image-guided sinus surgery (EIGSS) with topical postoperative antibiotic treatment, 131 non-operated controls and 36 who had double lung transplantation (LTX). In all 219 patients, serum samples before and after surgery or at similar intervals were analysed for IgG and IgA BPI-ANCA. The EIGSS group showed a highly significant decrease in both IgA and IgG BPI-ANCA levels compared with their own preoperative values and control group values (P < 0.001-0.02). The LTX patients also showed a highly significant decrease in both IgA and IgG BPI-ANCA levels (P < 0.001). EIGSS and LTX decrease IgA and IgG BPI-ANCA levels in patients with CF, indicating that extensive removal of infected tissue influences the pathogenic process of autoantibody production. The results shown herein are in favour of applying EIGSS in selected patients with CF and for using BPI-ANCA as a surrogate marker for guiding further therapeutic interventions.

Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study.

AIMS/HYPOTHESIS: Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis-related glucose intolerance. METHODS: We enrolled 898 cystic fibrosis patients from Sweden, Norway and Denmark. Vitamin D intake was assessed using a seven-day food record. Serum 25-hydroxyvitamin D (s25OHD) and HbA(1c) were measured, and an OGTT was carried out. Multiple linear and logistic regressions were used for HbA(1c) and cystic fibrosis-related diabetes/OGTT result as outcome variables, respectively. Each model was controlled for country, and for known cystic fibrosis-related diabetes risk factors: age, sex, genotype, liver dysfunction, long-term corticosteroid treatment, and lung and pancreatic function. RESULTS: Degree of vitamin D insufficiency (OR 1.36; p = 0.032) and s25OHD < 30 nmol/l (OR 1.79; p = 0.042) were significant risk factors for cystic fibrosis-related diabetes. Accordingly, HbA(1c) value was positively associated with s25OHD < 30 nmol/l and < 50 nmol/l, as well as with degree of vitamin D insufficiency (adjusted R (2) = 20.5% and p < 0.05 in all). In subgroup analyses, s25OHD < 30 nmol/l determined the HbA(1c) value in paediatric patients (adjusted R (2) = 20.2%; p = 0.017), but not in adults. CONCLUSIONS/INTERPRETATION: Vitamin D status is associated with HbA(1c) and diabetes in cystic fibrosis, particularly in children. The study justifies prospective studies on the proposed role of vitamin D deficiency in the pathophysiology of diabetes mellitus.

Chronic Pseudomonas aeruginosa infection definition: EuroCareCF Working Group report.

Chronic pulmonary infection with P. aeruginosa develops in most patients with cystic fibrosis (CF); by adulthood 80% of patients are infected and chronic P. aeruginosa infection is the primary cause of increased morbidity and mortality in CF. Chronic infection is preceded by an intermittent stage of infection. The initial stage is characteristically followed by the gradual emergence of mucoid variants of the colonizing strains and a rise in anti-Pseudomonas antibodies. In addition to optimizing existing therapeutic strategies, effective new agents need to be identified. Studies in patients with CF are particularly challenging: the progressive nature of the disease and the wide variation in severity influence considerably the outcome of drug testing. A validated, universally accepted, and clinically useful classification of patients infected with P. aeruginosa, particularly those chronically infected, is needed that can be used as both a criterion for patient selection for clinical trials and as a study endpoint.

Chronic pulmonary infection with Stenotrophomonas maltophilia and lung function in patients with cystic fibrosis.

BACKGROUND: The clinical consequences of chronic Stenotrophomonas maltophilia infection in cystic fibrosis (CF) patient are still unclear. METHOD: All patients treated in the Copenhagen CF centre (N=278) from 1 January 2008 to 31 December 2009 were included. Each patient chronically infected with S. maltophilia for at least 2 years without any other chronic Gram-negative infection were matched to two non-infected CF controls. RESULTS: Twenty-one patients were chronically infected with S. maltophilia during the 2-year study period. Fifteen were infected for at least 2 years. The patients in the S. maltophilia group had a steeper decline (-3.2%/year vs. -0.3%/year) in FEV(1) compared to the non-infected CF controls (P=0.03). The rate of decline was the same as observed 3 years before the patients became chronically infected. DISCUSSIONS: Chronic infection with S. maltophilia does not lead to a steeper decline in lung function when compared to the period before chronic infection.

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study.

BACKGROUND/OBJECTIVES: The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, we aimed to assess the relationship between vitamin D and IgG levels. SUBJECTS/METHODS: Eight hundred and ninety-six CF patients were included (0.53-65.9 years) from seven centers in Denmark, Norway and Sweden. Serum 25-hydroxyvitamin D (25OHD) and total IgG were measured, spirometry was carried out and vitamin D intake data were gathered using a 7-day dietary food record. Multiple linear regression analyses were performed for IgG and forced expiratory volume in 1λs (FEV1) as dependent variables, and serum 25OHD, daily food and supplemented vitamin D sources of intake as independent variables. The model was controlled for age, gender, genotype, CF-related diabetes, season, infection/colonization status, long-term oral corticosteroid treatment, long-term treatment with macrolide antibiotics, pancreatic insufficient phenotype and body mass index z-score. RESULTS: Serum total IgG levels were negatively associated with serum 25OHD (adjusted R (2) = 0.376; beta = -0.02; P<0.001), supplemented vitamin D intake per kg bodyweight (adjusted R (2) = 0.375; beta = -0.82; P < 0.001) and total vitamin D intake per kg bodyweight (adjusted R (2) = 0.398; beta = -0.60; P = 0.002). Serum 25OHD was positively associated with FEV1 (adjusted R (2) = 0.308; beta = 0.0007; P = 0.025). CONCLUSIONS: Increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies.

Inflammation in Achromobacter xylosoxidans infected cystic fibrosis patients.

BACKGROUND: Achromobacter xylosoxidans infection may cause conspicuous chronic pulmonary inflammation in cystic fibrosis (CF) patients similar to Pseudomonas aeruginosa and the Burkholderia cepacia complex (Bcc). Evolution in lung function was compared in chronically infected patients. Cytokine concentrations in CF patients with and without chronic infection were compared to healthy controls. METHODS: Cytokines in serum and sputum were measured using multiplex bead based immunoassay. RESULTS: Sixty CF patients, 11 with A. xylosoxidans, 11 with Bcc, 21 with P. aeruginosa and 17 non-infected CF patients were compared to 11 healthy controls. A. xylosoxidans patients were younger, but had a FEV(1) decline similar to P. aeruginosa patients. Bcc patients had the steepest decline in FEV(1). Serum levels of G-CSF, IL-6 and TNF-alpha were significantly higher in CF patients compared to healthy controls. Chronically infected CF patients had significantly higher serum levels of IFN-gamma and IL-6 compared to non-infected CF patients. Bcc patients had significantly lower serum G-CSF and A. xylosoxidans patients had significantly higher sputum TNF-alpha compared to the other groups of chronically infected patients. CONCLUSION: A. xylosoxidans can cause a level of inflammation similar to P. aeruginosa in chronically infected CF patients. A. xylosoxidans is a clinically important pathogen in CF and should be treated accordingly.

Co-morbidity of cystic fibrosis and celiac disease in Scandinavian cystic fibrosis patients.

BACKGROUND: The co-morbidity of cystic fibrosis (CF) and celiac disease (CD) has been reported sporadically since the 1960s. To our knowledge, this is the first time a systematic screening is performed in a large cohort of CF patients. METHODS: Transglutaminase-IgA (TGA), endomysium-IgA (EMA) and total IgA in serum were measured in 790 CF patients (48% females, 86% with pancreatic insufficiency). Six patients were diagnosed with CD prior to the study, all receiving a gluten-free diet. Patients with elevated TGA (>50 Units/mL) and a positive EMA test were offered a gastroscopy obtaining mucosal biopsies from the duodenum. RESULTS: Four new cases of CD were diagnosed. Two additional patients had positive serological tests, but normal biopsies. In total, 10 cases of CD (1.2%, 1:83) indicate a prevalence rate about three times higher than the general prevalence of CD in Norway and Sweden. No CD patients were detected in the Danish CF cohort. Patients diagnosed with untreated CD reported symptoms typical of both CF and CD (poor weight gain, loose and/or fatty stools, fatigue, irritability, abdominal pain). They improved after introduction of a gluten-free diet. CONCLUSIONS: Systematic screening for CD in a Scandinavian cohort of CF patients revealed a higher prevalence of CD than in the general population. Clinical signs of CD are difficult to differentiate from CF with malabsorption, and patients may go undiagnosed for a long time. In a population where CD is common we recommend screening for CD in patients with CF.

Long-term, low-dose azithromycin treatment reduces the incidence but increases macrolide resistance in Staphylococcus aureus in Danish CF patients.

BACKGROUND: Since 2001, long-term, low-dose azithromycin treatment has been used for CF patients chronically infected with Pseudomonas aeruginosa in the Copenhagen CF centre. Our study investigates changes in incidence of colonization with Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis and changes in macrolide sensitivity in these microorganisms during azithromycin treatment. METHODS: CF patients treated continuously with azithromycin for at least 3 months were included. Results of microbiological examination, including phage typing results of S. aureus, obtained during treatment were compared to results obtained 2 years before treatment. RESULTS: 70 patients (median age 29.1 years) treated for a median of 4 years (range 0.7-5.1) were included. Before treatment, 44 patients had at least one culture positive for S. aureus compared to 25 patients during treatment (p<0.01). Mean percentage of sputum samples with growth of S. aureus decreased from 12.1% (range 0-82.6%) before treatment to 6.1% (range 0-93.2) during treatment (p<0.0006). Prevalence's of H. influenzae and S. pneumoniae also decreased significantly. Fifteen of 214 isolates (7%) of S. aureus were macrolide resistant before treatment, increasing to 95 of 181 isolates (52.5%) during treatment (p<0.001). Macrolide resistant strains were found in 3 of 44 S. aureus colonized patients before treatment and in 11 of 25 patients at some time during treatment (p<0.03), all belonging to different phage types. First resistant S. aureus isolate was isolated after a median treatment duration of 1.5 years (range 0.3-2.9). No MRSA were isolated. Only 1 macrolide resistant isolate of M. catarrhalis was found during treatment. No macrolide resistance was found in H. influenzae or S. pneumoniae. CONCLUSION: Long-term, low-dose treatment with azithromycin in CF patients leads to reduced prevalence of S. aureus, S. pneumoniae, and H. influenzae, but increased macrolide resistance in S. aureus. Reduction in the prevalence of S. aureus will make increasing macrolide resistance clinically insignificant in these patients.