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. Author manuscript; available in PMC: 2020 Aug 1.
Published in final edited form as: Pediatr Pulmonol. 2019 Apr 22;54(8):1200–1208. doi: 10.1002/ppul.24341

Pathogen Acquisition in Patients with Cystic Fibrosis Receiving Ivacaftor or Lumacaftor/Ivacaftor

Sachinkumar B Singh 1, Amanda J McLearn-Montz 2, Francesca Milavetz 3, Levi K Gates 3, Christopher Fox 3, Logan T Murry 3, Ashley Sabus 3, Harry S Porterfield 4, Anthony J Fischer 1
PMCID: PMC6641998  NIHMSID: NIHMS1025714  PMID: 31012285

Abstract

Background:

The CFTR modulators ivacaftor and lumacaftor/ivacaftor improve the status of existing infections in patients with cystic fibrosis (CF). It is unknown how well these drugs protect patients against incident infections. We hypothesized that CFTR modulator treatment would decrease new infections with Pseudomonas aeruginosa or Staphylococcus aureus.

Methods:

We retrospectively studied a single-center cohort of patients with CF during two time periods (2008 – 2011, Era 1) and (2012 – 2015, Era 2) based on the January 2012 approval of ivacaftor. Using Kaplan-Meier analysis, we compared the time to any new infection with P. aeruginosa, methicillin-resistant S. aureus (MRSA), or methicillin-sensitive S. aureus (MSSA) that was absent during a two-year baseline. We stratified the analysis based on whether patients received ivacaftor or lumacaftor/ivacaftor during Era 2. We used the log-rank test and considered P < 0.05 statistically significant.

Results:

For patients receiving ivacaftor or lumacaftor/ivacaftor in Era 2, there was a statistically significant delay in the time to new bacterial acquisition in Era 2 vs. Era 1 (P = 0.008). For patients who did not receive CFTR modulators, there was a trend toward slower acquisition of new bacterial infections in Era 2 compared to Era 1, but this was not statistically significant (P = 0.10).

Conclusions:

Patients receiving ivacaftor or lumacaftor/ivacaftor for CF had significantly delayed acquisition of P. aeruginosa and S. aureus after these drugs were released. This method for analyzing incident infections may be useful for future studies of CFTR modulators and bacterial acquisition in CF registry cohorts.

Keywords: Ivacaftor, Lumacaftor, CFTR, Cystic Fibrosis, Staphylococcus aureus, Pseudomonas aeruginosa

Introduction

Patients with cystic fibrosis (CF) have defective host defense against bacterial pathogens, resulting in susceptibility to Staphylococcus aureus and Pseudomonas aeruginosa airway infections. These infections are risk factors for subsequent disease progression, resulting in bronchiectasis and respiratory failure.1–3 Why people with CF develop these infections remains incompletely understood. Recent advances in animal models of CF implicate CFTR-dependent impairment of mucus clearance and bacterial killing.4–7 These studies predict that restoration of CFTR function would diminish these host defense defects and prevent new bacterial infections.

In 2012, the first CFTR modulator drug, ivacaftor, was introduced for patients with a G551D CFTR mutation.8 In patients with this mutation, there is abundant evidence that biologic function of CFTR is restored. Ivacaftor decreases sweat chloride by 50 mEq/L, improves FEV1 by 10% of predicted, and increases weight by 3 kg.8 Subsequently, lumacaftor/ivacaftor was introduced for F508del homozygous patients in 2015 and ivacaftor-tezacaftor was introduced in 2017 for patients who are homozygous for F508del or have F508del and a residual function mutation.9–11 The bioelectric and clinical effects of these medications vary by genotype. Currently, CFTR modulators are available for 39 unique genotypes: nine class III mutations, the homozygous F508del mutation, 23 residual function mutations, five splice mutations, and one conduction mutation. Together, these genotypes constitute 50–60% of all patients with CF.12

CFTR modulator drugs may improve the status of existing infections in patients with CF.13,14 The GOAL study showed decreased prevalence of both mucoid and non-mucoid P. aeruginosa in patients with G551D treated with ivacaftor for one year.13 However, interpreting these studies is complicated when considering recent changes in the epidemiology of CF infections.15 Highly effective inhaled antibiotic treatments are available for both early and chronic P. aeruginosa, resulting in substantial microbiologic and clinical benefit for patients.16–21 Treatments for S. aureus are under development, but lag behind treatment options for P. aeruginosa.22,23 Over the past decade, patients with CF have had increasing prevalence of methicillin resistant S. aureus (MRSA) and decreasing prevalence of P. aeruginosa in respiratory cultures.15 Indeed, infections with MRSA and methicillin sensitive S. aureus (MSSA) remained unchanged in the G551D patients examined in the GOAL study.13

In this study, we assessed the impact of CFTR modulators on the time for patients to acquire new CF respiratory infections. We focused on P. aeruginosa and S. aureus due to their pathogenic relevance24,25 and the changing epidemiology of infections.13,15,26,27 We studied two groups of patients: patients who received ivacaftor or lumacaftor/ivacaftor (which we refer to as the treatment theratype) and patients who did not receive these drugs (control). We hypothesized that the theratype of CF patients receiving ivacaftor or lumacaftor/ivacaftor would have significantly longer durations free of new respiratory infections compared with the same theratype in an earlier era when CFTR modulators were not available as treatment. In untreated controls, we predicted similar biologic susceptibility to new infections in the eras before and after the approval of CFTR modulators.

We tested this hypothesis using a single-center retrospective longitudinal cohort that was divided into two time eras. The first era (January 1, 2008 – December 31, 2011) facilitated assessment of pathogen acquisition rates prior to the introduction of CFTR modulators. Similarly, we analyzed acquisition of these same pathogens during the CFTR modulator era (January 1, 2012 – December 31, 2015), which included the times that ivacaftor and lumacaftor/ivacaftor were introduced.

Methods

Ethics statement.

The Institutional Review Board (IRB) of the University of Iowa approved this study and granted a waiver of informed consent due to the study being retrospective and minimal risk. The authors have no conflicts of interest regarding this work.

Subjects.

We included patients with a diagnosis of CF28 who were active patients at the University of Iowa adult or pediatric CF center, born prior to the year 2005, and cared for in the center between the years 2006 and 2015 (Figure 1). Patients born in 2005 or after were not included because younger patients were not initially approved for use of CFTR modulators. The subjects were analyzed in two separate time periods. The pre-modulator period (Era 1) was defined as January 1, 2008 – December 31, 2011. The CFTR modulator period (Era 2) was defined as January 1, 2012 – December 31, 2015. We excluded patients who lacked a baseline respiratory culture in the two years that preceded these eras or who did not have a respiratory culture during the era. We also excluded patients who received a lung transplant during either era, patients who participated in blinded studies of ivacaftor during Era 1, patients whose only use of CFTR modulators was in the context of clinical studies of tezacaftor/ivacaftor during Era 2, or if there was conflicting documentation of CFTR modulator use. Many patients were represented in both Era 1 and Era 2 (Supplemental Table 1).

Figure 1.

Figure 1

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Study Design

Case/Control Definition.

Cases were defined as patients prescribed ivacaftor or lumacaftor/ivacaftor for clinical indications at any point during Era 2. Controls were patients with CF who did not receive ivacaftor or lumacaftor/ivacaftor in Era 2.

Baseline measurements.

We obtained baseline information for each patient from electronic medical records, including genotype, spirometry, and radiology reports. For patients old enough to complete spirometry, we determined baseline FEV1 % predicted as the best value obtained in the year prior to the start of each era. We defined bronchiectasis by the radiologist’s final diagnosis on CT reports dated prior to the January 1, 2008 (Era 1) or January 1, 2012 (Era 2). Pancreatic insufficiency was defined by abnormally low stool elastase or use of pancreatic enzyme replacement therapy.

Respiratory cultures.

We examined microbiology data from electronic medical records to document infection status with MSSA, MRSA, and P. aeruginosa. Because our goal was to assess for incident infections, we focused on subjects who may be naïve for at least one of MSSA, MRSA, or P. aeruginosa based on the absence of these organisms from respiratory cultures obtained during a two-year baseline period. Any positive respiratory culture (including oropharyngeal swab, expectorated sputum, or bronchoalveolar lavage) in the two years preceding the era was assumed to represent a baseline intermittent or chronic infection. We examined all subsequent respiratory cultures to determine the time to acquisition of a new pathogen, defined as the first positive respiratory culture for MSSA, MRSA, or P. aeruginosa that was not present at baseline. MRSA and MSSA appear to cause stable long-term infections and can be distinguished on the basis of genetic markers.26,29,30 Within our population, MRSA and MSSA have distinct pulse-field gel electrophoresis types (data not shown). Therefore, we assumed that MSSA and MRSA infected patients as distinct organisms, rather than MRSA evolving from MSSA in vivo.

Medications.

Because CF-specific medications are proxy for disease severity, we determined baseline prescriptions for dornase alfa, hypertonic saline, ibuprofen, and prednisone/prednisolone. Since chronic antibiotics may influence acquisition of pathogens, we determined baseline use of three times weekly azithromycin and tobramycin inhalation as documented on the clinic visit immediately prior to January 1, 2008 (Era 1) or January 1, 2012 (Era 2). We did not assess short-term antibiotic courses given for exacerbations or pathogen eradication due to their intended short-term use and because of changes in electronic prescription practices between Era 1 and Era 2.

Statistical Analysis.

Statistical comparisons for baseline conditions were made using the unpaired t-test for continuous variables. For categorical data, chi-square test or Fisher’s exact test were used when appropriate. The time to new bacterial acquisition was compared between both eras in the CFTR modulator treated and untreated groups using Kaplan-Meier analysis. The log-rank test was used for this comparison and P < 0.05 was considered statistically significant. We used odds ratios and 95% confidence intervals to compare the baseline, incident, and final infection status for each pathogen in both eras. Statistical analyses were performed using SAS (version 9.4; SAS Institute, Cary, North Carolina, USA), R Statistical Software (version 3.4.0; R Foundation for Statistical Computing, Vienna, Austria), and Prism (version 8.0.1; GraphPad Software, La Jolla California USA).

Results

Baseline characteristics.

Because CFTR modulator therapy relies upon the expression of endogenous CFTR, it is possible that patients who receive modulator therapies have greater residual CFTR function and milder baseline disease manifestations. Additionally, CF lung disease progresses over time in individual patients. Therefore, we compared baseline characteristics for patients in CFTR modulator treatment and control theratypes in each era. Between Era 1 and Era 2, the baseline age increased in both cohorts (Table 1). A larger decrease in baseline FEV1 was observed in the CFTR modulator group. The proportion of patients with bronchiectasis increased between Era 1 and Era 2 in both groups, consistent with disease progression. Pancreatic insufficiency was similar between the study eras in both groups and did not change over time. Comparing treatment groups, genotypes were different in both eras and FEV1 % predicted was higher in the CFTR modulator group compared to the control group in Era 1 (Supplemental Table 2). There was a trend toward younger age in the CFTR modulator group in both eras.

Table 1.

Baseline Characteristics of Study Subjects

Characteristic Control CFTR Modulator
Era 1 (N = 67) Era 2 (N = 80) P Era 1 (N = 21) Era 2 (N = 25) P
Ivacaftor*, N 0 0 4 4
Lumacaftor/Ivacaftor*, N 0 0 17 21
No CFTR Modulator, N 67 80 0 0
Female, % 41.8 45.0 0.70 38.1 28.0 0.47
Genotype
Homozygous F508del, % 50.7 46.3 0.89 † 81.0 84.0 1.00 †
Heterozygous F508del, % 47.8 51.3 14.3 12.0
No F508del, % 1.5 2.5 4.8 4.0
Age, years, Mean ± SD 21.4 ± 12.1 26.5 ± 12.1 0.01 16.8 ± 13.5 22.0 ± 14.3 0.22
Best FEV1 % Predicted in Previous Year, Mean ± SD 83.1 ± 22.7 (N = 53) 79.8 ± 22.3 (N = 65) 0.43 99.2 ± 16.4 (N = 17) 82.7 ± 23.7 (N = 21) 0.02
Bronchiectasis on CT, % 68.3 (N = 60) 87.0 (N = 77) 0.008 52.4 (N = 21) 80.0 (N = 25) 0.05
Pancreatic Insufficiency, % 98.3 (N = 59) 97.3 (N = 73) 1.00 † 94.7 (N = 19) 95.8 (N = 24) 1.00 †
Oral corticosteroid, % 14.9 12.5 0.67 4.8 0 0.46 †
Ibuprofen, % 19.4 11.3 0.17 33.3 36.0 0.85
Inhaled tobramycin, % 26.9 22.5 0.54 19.0 16.0 1.00 †
Chronic azithromycin, % 58.2 56.3 0.81 38.1 56.0 0.23
Dornase alfa, % 14.9 23.8 0.18 23.8 24.0 0.99
Hypertonic saline, % 17.9 31.3 0.06 4.8 24.0 0.11 †
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Baseline values are as of January 1, 2008 (Era 1) and January 1, 2012 (Era 2).

*

Subjects who received a prescription for the medication listed between January 1, 2012 and December 31, 2015. SD = standard deviation. P values were calculated using chi-square test or

†

Fisher’s exact test for categorical variables and unpaired t-test for continuous variables. Some totals may exceed 100% due to rounding.

Medications.

Chronic antibiotic therapy could potentially block new infections. There were no significant differences in the use of inhaled tobramycin between the two eras in either treatment group (Table 1). There was a trend toward increased chronic azithromycin use in the CFTR modulator group in Era 2, but this was not statistically significant. The use of dornase alfa was also comparable between the two eras in both groups. There was a trend toward increased use of hypertonic saline in both groups in Era 2. Aside from CFTR modulators, the only baseline medication that was significantly different between the two treatment groups was ibuprofen in Era 2 (Supplemental Table 2).

Baseline infections.

We determined the baseline infection status for patients in the two years preceding each era (2006–7 and 2010–11). Because increased surveillance could increase detection of baseline infections, we determined the number of baseline cultures obtained for each subject. The median number of cultures obtained during these baseline periods was similar between treatment groups and over time (Supplemental Table 3). Between the baseline periods, the prevalence of P. aeruginosa and MSSA was stable in both treatment and control groups (Table 2). Consistent with a recent nation-wide epidemiologic report in CF,15 we observed a trend toward increased MRSA prevalence in Era 2. Comparing the two treatment groups, we observed no statistically significant differences in the baseline prevalence of the three organisms prior to either era.

Table 2.

Baseline Infection Status

Baseline Infection Status – Control Baseline Infection Status – CFTR Modulator
Pathogen Era 1 Total = 67 N (%) Era 2 Total = 80 N (%) OR CI Era 1 Total = 21 N (%) Era 2 Total = 25 N (%) OR CI
P. aeruginosa 52 (77.6) 61 (76.3) 0.93 0.45 – 2.00 17 (81.0) 17 (68.0) 0.5 0.15 – 1.99
MSSA 36 (53.7) 40 (50.0) 0.86 0.44 – 1.67 16 (76.2) 13 (52.0) 0.34 0.10 – 1.31
MRSA 9 (13.4) 20 (25.0) 2.15 0.93 – 5.08 0 (0) 6 (24.0) - > 1.78
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Baseline Period for Era 1: January 1, 2006 – December 31, 2007; Era 2: January 1, 2010 – December 31, 2011; OR = odds ratio. Values > 1 indicate increased risk of positive culture in baseline for Era 2 vs. Era 1 for the organism listed within that treatment group. CI = 95% confidence interval.

We considered patients to be susceptible to incident infections with MSSA, MRSA, or P. aeruginosa if at least one of these organisms was not identified during the baseline period. Many patients had baseline infections with one or two of these pathogens. Patients having baseline infections with multiple pathogens would be susceptible to fewer pathogens as incident infections. Therefore, we counted the number of pathogens (among P. aeruginosa, MRSA, and MSSA) that were identified in individual patients during the baseline period (Supplemental Table 4). There were no significant differences between Era 1 and Era 2 in the total number of baseline S. aureus and P. aeruginosa infections per patient within either treatment group. Comparing the two treatment groups, we observed no statistically significant differences in the total number of baseline S. aureus and P. aeruginosa infections per patient within either era (Supplemental Table 4 and Supplemental Figure 1).

Incident Infections.

Using the baseline infection data, we determined the number of patients susceptible to new infections with MRSA, MSSA, or P. aeruginosa in each era. Because detection of incident infections may depend on the frequency of testing, we determined the number of follow up cultures obtained during these four-year eras (Supplemental Table 3). The number of cultures obtained was similar between eras and treatment groups.

Incident infections were detected for each of the organisms in both treatment groups and in both eras. The rate of incident infections declined for each of the pathogens between Era 1 and Era 2 in both treatment groups. There was a statistically significant decrease in incident MSSA infections in both treatment and control groups (Table 3). Because individual patients have different baseline infections and are susceptible to different incident infections, we calculated a composite endpoint for incident infections, defined as an infection with any of P. aeruginosa, MSSA, or MRSA that was not present at baseline. In Era 2, 20% of patients receiving CFTR modulators developed a new infection, compared to 52% of the patients with this theratype in Era 1 (P = 0.02; OR = 0.23, 95% CI = 0.06 – 0.78), indicating a reduced risk of incident infections for patients starting CFTR modulators in Era 2. Patients in the control group had relatively less protection from new infections in Era 2. 34% of control patients developed a new infection in Era 2 compared with 49% in Era 1 (P = 0.06, OR = 0.53, 95% CI = 0.27 – 1.04).

Table 3.

Incident Infections by Pathogen

Control CFTR Modulator
Era 1 N = 67 Era 2 N = 80 OR CI Era 1 N = 21 Era 2 N = 25 OR CI
P. aeruginosa 0.86 0.20 – 3.15 0.43 0.02 – 10.70
Susceptible 15 19 4 8
Infected 10 12 1 1
% Infected 66.7% 63.2 % 25.0% 12.5 %
MSSA 0.24 0.08 – 0.67 0.06 0.004 – 0.71
Susceptible 31 40 5 12
Infected 17 9 3 1
% Infected 54.8% 22.5% 60.0% 8.33%
MRSA 0.71 0.29 – 1.78 0.53 0.15 – 2.16
Susceptible 58 60 21 19
Infected 14 11 7 4
% Infected 24.1% 18.3% 33.3% 21.1%
Composite: At least one of P. aeruginosa, MSSA, or MSSA 0.53 0.27 – 1.04 0.23 0.06 – 0.78
Susceptible 67 80 21 25
Infected 33 27 11 5
% Infected 49.3% 33.8% 52.4% 20.0%
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Era 1: January 1, 2008 – December 31, 2011; Era 2: January 1, 2012 – December 31, 2015; OR = odds ratio. Values > 1 indicate increased risk of incident infection during Era 2 vs. Era 1 for the organism listed within that treatment group. CI = 95% confidence interval.

Time to Pathogen Acquisition.

Control Group.

After assessing the baseline infection status of each study subject and identifying incident infections, we measured the time to the first acquisition of P. aeruginosa, MRSA, or MSSA that was not documented in the 2-year baseline period before each era. We compared the time to new pathogen acquisition for Era 1 versus Era 2 for subjects in the control group (Figure 2A). There was a trend toward slower acquisition of pathogens in Era 2 vs. Era 1 (P = 0.10), but this did not reach statistical significance.

Figure 2.

Figure 2

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Time to acquisition of new bacterial pathogens before and after the introduction of CFTR modulator drugs. Data show the time to the first new infection with MSSA, MRSA, or P. aeruginosa during Era 1 (January 1, 2008 – December 31, 2011, black) or Era 2 (January 1, 2012 – December 31, 2015, gray). A. Control Group. B. CFTR Modulator Group. The number of susceptible subjects in each group is given at yearly intervals above each graph. P values were calculated using the log-rank test.

CFTR Modulator Group.

We performed a similar analysis for the CFTR modulator group, comparing the time to new pathogen acquisition between Era 1 and Era 2 (Figure 2B). The time for patients to acquire a new CF pathogen was significantly prolonged in Era 2 vs. Era 1 (P = 0.008). Thus, exposure to CFTR modulators in Era 2 was associated with a significantly lower risk of incident infection.

Persistence of Baseline Pathogens.

Our definition of baseline infection included some subjects with intermittent infections and others with chronic infections. To assess the persistence of baseline infections, we determined whether patients with baseline cultures positive for P. aeruginosa, MSSA, or MRSA maintained these infections during the subsequent era. For each of the pathogens studied, > 80% of subjects with a baseline infection had at least one positive culture during the 4-year era that followed (Table 4). Compared to subjects who had negative baseline cultures (Table 3), subjects who had baseline infections for these three pathogens were more likely to culture positive during the following era. Many subjects with positive baseline cultures grew the same organism repeatedly during the study (Supplemental Figure 2).

Table 4.

Persistence of Baseline Infections During Follow Up

Control Era 1 Era 2
Pathogen Baseline Infected N Any Culture Positive N (%) Final Culture Positive N (%) Baseline Infected N Any Culture Positive N (%) Final Culture Positive N (%) OR CI
P. aeruginosa 52 49 (94.2) 36 (69.2) 61 54 (88.5) 42 (68.9) 0.98 0.45 – 2.27
MSSA 36 34 (94.4) 19 (52.8) 40 33 (82.5) 19 (47.5) 0.81 0.34 – 1.96
MRSA 9 9 (100.0) 5 (55.6) 20 20 (100.0) 14 (70.0) 1.87 0.44 – 8.25
CFTR Modulator Era 1 Era 2
Pathogen Baseline Infected N Any Culture Positive N (%) Final Culture Positive N (%) Baseline Infected N Any Culture Positive N (%) Final Culture Positive N (%) OR CI
P. aeruginosa 17 15 (88.2) 9 (52.9) 17 16 (94.1) 11 (64.7) 1.63 0.38 – 5.95
MSSA 16 13 (81.3) 3 (18.8) 13 12 (92.3) 4 (30.8) 1.93 0.41 – 8.93
MRSA 0 - - 6 6 (100.0) 4 (66.7) - -
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Era 1: January 1, 2008 – December 31, 2011; Era 2: January 1, 2012 – December 31, 2015; OR = Odds ratio. Values > 1 indicate increased risk of the final culture being positive in Era 2 vs. Era 1 for the organism listed. CI = 95% Confidence interval. Percentages were calculated using the number of patients who were initially infected as the denominator.

CFTR modulators may help clear existing infections.13 To determine whether CFTR modulator use protected subjects with baseline infections from positive cultures, we examined the final culture of each era. For the control group, the probability of the final culture being positive did not change between Era 1 and Era 2 for any of the three pathogens (Table 4). Similarly, CFTR modulator use in Era 2 was not associated with reduced risk of a positive final culture for P. aeruginosa or MSSA. The change in persistence of baseline MRSA could not be evaluated in the CFTR modulator group due to the absence of any baseline MRSA infections in Era 1.

Discussion

Patients with CF are susceptible to respiratory infections with S. aureus and P. aeruginosa. These organisms are highly prevalent in patients with CF at the beginning of the CFTR modulator era. Despite the use of antibiotics, airway clearance, and recent implementation of infection control guidelines, children and adults with CF in this center continue to experience new infections with S. aureus and P. aeruginosa.

Ivacaftor and lumacaftor/ivacaftor increase CFTR activity in vivo.8,9 This may improve endogenous host defense mechanisms, including mucociliary transport.31 Ivacaftor may also possess direct antimicrobial activity toward S. aureus and to a lesser extent, P. aeruginosa.32 We hypothesized that augmenting host defense by increasing endogenous CFTR activity would decrease the incidence of new infections with S. aureus and P. aeruginosa. We found that patients who did not receive ivacaftor or lumacaftor/ivacaftor had similar susceptibility to new S. aureus and P. aeruginosa infections in both eras, although there was a trend towards delayed infections in the second era. For patients receiving ivacaftor or lumacaftor/ivacaftor, new infections with S. aureus or P. aeruginosa were less common and were significantly delayed in Era 2 compared with Era 1. This is consistent with a decreased susceptibility to infection after introduction of CFTR modulators. Patients in this group did not receive these medications for the entire duration of Era 2. Thus, the effect of these CFTR modulators on pathogen acquisition could be underestimated by this analysis.

Previous investigators have focused on the effect of CFTR modulators on the prevalence of infections.9,13 In the GOAL study, the prevalence of P. aeruginosa decreased after initiation of ivacaftor.13 Because S. aureus and P. aeruginosa are versatile opportunistic pathogens, they are capable of producing persistent infections through genetic and phenotypic modification33–35, biofilm formation36, and immune modulation.37 Although some patients with CF can clear existing infections,13 we and others observed baseline infections often persist after initiation of CFTR modulator therapy.38 In our study, we did not classify baseline infections as intermittent or chronic. Intermittent infections are potentially more susceptible to treatment after CFTR modulator therapy,13 whereas chronically infecting bacteria adapt to the host airway and could be more difficult to clear compared to initial infections by S. aureus and P. aeruginosa.

Advantages

An advantage of our approach is that we evaluated longitudinal microbiology cultures during the study period to identify incident infections with P. aeruginosa, MSSA, and MRSA. Using a composite endpoint for new infections allowed inclusion of a larger number of subjects compared with focusing on a single microorganism, thus increasing statistical power in this analysis. Because using a composite endpoint excluded fewer subjects, the cohorts within this study may represent our center population better than if we had selected a single organism such as P. aeruginosa.

Observational studies of CFTR modulators require control groups, which have inherent limitations. Untreated controls with CF may have different endogenous CFTR function and disease severity, altering their risk of acquiring new infections. Historical controls with similar genotypes experienced different environmental exposures. We used both historical and untreated controls in this study. For future studies addressing this question, there may be fewer untreated control subjects available as CFTR modulator therapy expands. By using two different eras and two different populations, we could examine CFTR-dependent and independent effects on bacterial acquisition.

Limitations

This study has limitations. The single center represents a small sample of the CF population and has a small number of patients receiving CFTR modulators. However, focusing on a single center allows for common exposures that may be risk factors for acquisition and transmission of infections.39 We selected fixed time intervals for both eras since infections may fluctuate with time.40 We were not able to control for some potential confounding variables. Many patients receiving CFTR modulators initiated them later in Era 2, and we did not assess medication compliance. New antibiotics prescribed after the beginning of each era could also affect the acquisition of new pathogens.

Given the number of study subjects, particularly in the CFTR modulator group, we did not examine the association of CFTR modulators with acquisition of other CF pathogens, including Stenotrophomonas, Achromobacter, Burkholderia, and nontuberculous mycobacteria. Finally, we did not determine the potential effects of CFTR modulator therapy on younger children.

In summary, ivacaftor and lumacaftor/ivacaftor may protect against new infections with important CF pathogens. Larger studies are needed to confirm this hypothesized effect. Prevention of new respiratory infections remains an important goal in CF care.

Supplementary Material

Figure 1

Supplemental Figure 1. Number of baseline CF pathogens present per subject. Symbols represent mean and standard deviation. Pathogens included in the count were P. aeruginosa, MRSA, and MSSA. The baseline period for Era 1 was January 1, 2006 – December 31, 2007; the baseline for Era 2 was January 1, 2010 – December 31, 2011.

Figure 2

Supplemental Figure 2. Persistence of baseline cultures. Data represent longitudinal culture results during Era 2. Individual subjects are shown in rows and sorted by their baseline culture status for Pseudomonas aeruginosa (A), MSSA (B), or MRSA (C) between Jan 1, 2010 and Dec 31, 2011. In each panel, subjects are reordered. Subjects with negative baseline cultures are indicated with circles; subjects with baseline infections are indicated with squares. Positive cultures for the organism listed at the top of the panel are marked red. Subjects positive at baseline for a given pathogen often had repeated positive cultures for the same organism. N = 105 subjects, including 25 who received CFTR modulator treatment. N = 78 with baseline P. aeruginosa, 53 with MSSA, 26 with MRSA.

Table 1
Table 2
Table 3
Table 4

Acknowledgement

We acknowledge Benjamin Doyle and Renae Juska for technical assistance. This work was supported in part by startup funds from University of Iowa Stead Family Department of Pediatrics, NIH K12 HD027748-23, NIH K08 HL136927, and the Cystic Fibrosis Foundation FISCHE16I0.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure 1

Supplemental Figure 1. Number of baseline CF pathogens present per subject. Symbols represent mean and standard deviation. Pathogens included in the count were P. aeruginosa, MRSA, and MSSA. The baseline period for Era 1 was January 1, 2006 – December 31, 2007; the baseline for Era 2 was January 1, 2010 – December 31, 2011.

NIHMS1025714-supplement-Figure_1.pdf (48.5KB, pdf)
Figure 2

Supplemental Figure 2. Persistence of baseline cultures. Data represent longitudinal culture results during Era 2. Individual subjects are shown in rows and sorted by their baseline culture status for Pseudomonas aeruginosa (A), MSSA (B), or MRSA (C) between Jan 1, 2010 and Dec 31, 2011. In each panel, subjects are reordered. Subjects with negative baseline cultures are indicated with circles; subjects with baseline infections are indicated with squares. Positive cultures for the organism listed at the top of the panel are marked red. Subjects positive at baseline for a given pathogen often had repeated positive cultures for the same organism. N = 105 subjects, including 25 who received CFTR modulator treatment. N = 78 with baseline P. aeruginosa, 53 with MSSA, 26 with MRSA.

NIHMS1025714-supplement-Figure_2.pdf (878.9KB, pdf)
Table 1
NIHMS1025714-supplement-Table_1.pdf (42.2KB, pdf)
Table 2
NIHMS1025714-supplement-Table_2.pdf (903.2KB, pdf)
Table 3
NIHMS1025714-supplement-Table_3.pdf (56.9KB, pdf)
Table 4
NIHMS1025714-supplement-Table_4.pdf (235.8KB, pdf)

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