Grand round

Cystic fibrosis pulmonary exacerbations

Control of pulmonary exacerbations (PEs) is highly important in the treatment of cystic fibrosis (CF). Given the evidence of the extra skeletal properties of vitamin D, this study aimed to evaluate the effect of supplementation with an extra dose of vitamin D on CF PEs.

This is a randomized crossover clinical trial conducted in Brazil. Subjects were randomly allocated to receive vitamin D (5,000-10,000 IU/day, liquid, or gelatin capsules) followed by standard treatment (400-2,000 IU/day of vitamin D), or standard treatment followed by vitamin D for three months, with 9-month washout separating each treatment period. The primary endpoint was the number of PEs during the intervention period. In addition, a 6-month period following the use of the extra dose and the regular dose were assessed. Secondary outcome included change in serum 25(OH)D after the end of supplementation.

34 subjects completed the study (16 received vitamin D first, and 18 received standard treatment first; median age: 5.16 years (1.74:8.07)). A significant statistical reduction in pulmonary exacerbations with the use of the extra dose of vitamin D was not detected (P = 0.10). No effect of vitamin D on PEs was observed after the end of supplementation. More than half of the subjects had suboptimal levels of 25(OH)D pre-supplementation and only 58% achieved desirable levels of the vitamin.

Our findings reinforce the high prevalence of hypovitaminosis D in subjects with CF, despite routine supplementation. Further robust evidence is needed to analyze the possible effect of vitamin D in reducing CF pulmonary exacerbations.

Methicillin-resistant Staphylococcus aureus infections are increasing in prevalence in patients with cystic fibrosis (CF) and are associated with worsening lung function and increased mortality. Lefamulin is a pleuromutilin antimicrobial approved to treat community-acquired bacterial pneumonia based on potent in vitro activity and clinical efficacy. This Phase I, open-label, randomized crossover study assessed the safety and pharmacokinetic profile of oral and intravenous (IV) lefamulin in adults with CF.

The study comprised 2 dosing periods in which adults with CF (N = 13) received a single dose of lefamulin via a 150-mg IV infusion or 600-mg immediate-release orally administered tablet, separated by a 4- to 7-day washout period. Pharmacokinetic and safety parameters were assessed after lefamulin treatment.

Single doses of lefamulin administered via oral tablet or IV infusion resulted in comparable drug exposure, and sputum analysis suggested rapid penetration of lefamulin into the lung. Comparison of the present results with those obtained from prior single-dose studies of healthy volunteers indicate no meaningful difference in the pharmacokinetic properties of lefamulin in patients with CF. Treatment-emergent adverse events were consistent with previous reports, and the majority were mild in severity.

These results show similar lefamulin pharmacokinetic and safety profiles between patients with CF and healthy volunteers receiving the same oral and IV doses, suggesting no need for lefamulin dose adjustment in patients with CF and indicating the potential of lefamulin as therapy for lung infections in patients with CF. ClinicalTrials.gov identifier: NCT05225805.

CF registry pulmonary exacerbation (PEx) analyses have employed “before and after” spirometry recovery, where the best percent predicted forced expiratory volume in 1 s (ppFEV₁) prior to PEx (“baseline”) is compared to the best ppFEV₁ <3 months post-PEx. This methodology lacks comparators and ascribes recovery failure to PEx.

Herein, we describe 2014 CF Foundation Patient Registry PEx analyses including a comparator: recovery around nonPEx events, birthdays. 49.6% of 7357 individuals with PEx achieved baseline ppFEV₁ recovery while 36.6% of 14,141 achieved baseline recovery after birthdays; individuals with both PEx and birthdays were more likely to recover baseline after PEx than after birthdays (47% versus 34%); mean ppFEV₁ declines were 0.3 (SD=9.3) and 3.1 (9.3), respectively. Post-event measure number had more effect on baseline recovery than did real ppFEV₁ loss in simulations, suggesting that PEx recovery analyses lacking comparators are prone to artifact and poorly describe PEx contributions to disease progression.

No data exist to guide antibiotic selection among people with CF (PwCF) with respiratory cultures positive for multiple CF-related bacteria (polymicrobial infections). This study aimed to describe the number of polymicrobial in-hospital treated pulmonary exacerbations (PEx), to determine the proportion of polymicrobial PEx where antibiotics were prescribed with activity against all bacteria detected (termed complete antibiotic coverage), and to determine clinical and demographic factors associated with complete antibiotic coverage.

Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System dataset. Children aged 1–21 years with an in-hospital treated PEx from 2006 to 2019 were eligible for inclusion. Bacterial culture positivity was based on any positive respiratory culture in the 12 months prior to a study PEx.

A total of 4,923 children contributed 27,669 total PEx of which 20,214 were polymicrobial; of these, 68% of PEx had complete antibiotic coverage. In regression modeling, a prior PEx with complete antibiotic coverage for MRSA was associated with a higher likelihood of having complete antibiotic coverage at a subsequent study PEx (OR (95% CI) 3.48 (2.50, 4.83)).

The majority of children with CF hospitalized for polymicrobial PEx were prescribed complete antibiotic coverage. Prior PEx treatment with complete antibiotic coverage predicted complete antibiotic coverage at a future PEx for all bacteria studied. Studies are needed comparing outcomes of polymicrobial PEx treated with different antibiotic coverages to optimize PEx antibiotic selection.

Limited data exist to inform antibiotic selection among people with cystic fibrosis (CF) with airway infection by multiple CF-related microorganisms. This study aimed to determine among children with CF co-infected with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pa) if the addition of anti-MRSA antibiotics to antipseudomonal antibiotic treatment for pulmonary exacerbations (PEx) would be associated with improved clinical outcomes compared with antipseudomonal antibiotics alone.

Retrospective cohort study using data from the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. The odds of returning to baseline lung function and having a subsequent PEx requiring intravenous antibiotics were compared between PEx treated with anti-MRSA and antipseudomonal antibiotics and those treated with antipseudomonal antibiotics alone, adjusting for confounding by indication using inverse probability of treatment weighting.

943 children with CF co-infected with MRSA and Pa contributed 2,989 PEx for analysis. Of these, 2,331 (78%) PEx were treated with both anti-MRSA and antipseudomonal antibiotics and 658 (22%) PEx were treated with antipseudomonal antibiotics alone. Compared with PEx treated with antipseudomonal antibiotics alone, the addition of anti-MRSA antibiotics to antipseudomonal antibiotic therapy was not associated with a higher odds of returning to ≥90% or ≥100% of baseline lung function or a lower odds of future PEx requiring intravenous antibiotics.

Children with CF co-infected with MRSA and Pa may not benefit from the addition of anti-MRSA antibiotics for PEx treatment. Prospective studies evaluating optimal antibiotic selection strategies for PEx treatment are needed to optimize clinical outcomes following PEx treatment.

In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital.

Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location.

In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV₁ improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only.

Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.