Pseudomonas aeruginosa eradication therapy predicts the hazard of having Aspergillus Fumigatus positive culture in early life of children with CF

Aims: To describe the hazard of having Aspergillus fumigatus positive cultures in young children (≤ 5 years of age) with cystic fibrosis (CF) and to investigate the predictive factors influencing the hazard, specifically the influence of prior Pseudomonas aeruginosa positive culture.Methods: Data on repeated Aspergillus fumigatus and Pseudomonas aeruginosa cultures were obtained from 80 children in the Australasian Cystic Fibrosis Bronchoalveolar lavage (BAL) study (1). A repeated time to event (RTTE) model was developed to describe the hazard of Pseudomonas aeruginosa and Aspergillus fumigatus positive culture events by fitting a parametric hazard model using NONMEM version 7.2. The predicted probability of having a Pseudomonas aeruginosa positive culture prior to the time of having an Aspergillus fumigatus positive culture was tested as an influence on the hazard of having an Aspergillus fumigatus positive culture. Other time varying ( e.g. number of antibiotic therapy courses received prior the event) and time constant covariates (e.g. sex and meconium ileus) were also tested.Results: The median age of having the first positive culture was 2.38 years for Pseudomonas aeruginosa and 3.69 years for Aspergillus fumigatus. The baseline hazard of having recurrent Pseudomonas aeruginosa and Aspergillus fumigatus positive cultures in the first five years of life of children with CF increased with time and was described by a Gompertz model. The hazard of Pseudomonas aeruginosa events doubled after the first event. The hazard of recurrent Aspergillus fumigatus events was found to be increased by the use of combination treatment with intravenous and inhalation tobramycin to eradicate Pseudomonas aeruginosa infection (Table 1). The probability of having Pseudomonas aeruginosa events had no detectable influence on the hazard of having Aspergillus fumigatus events.

Table 1: Hazard estimates and their uncertainty from a combined Pseudomonas aeruginosa and Aspergillus fumigatus positive culture repeated time to event model

 

 

 

Pseudomonas aeruginosa

positive culture

Aspergillus fumigatus

positive culture

 

 

Final model estimate

Bootstrap

Final model estimate

Bootstrap

Median

95% CI

Median

95% CI

Parameter

Units

 

 

 

 

 

 

Hazard of first event

year-1

0.13

0.13

0.08-0.19

0.03

0.02

0.01-0.05

Hazard of subsequent  event

year-1

0.25

0.25

0.12-0.39

βTime

(half-life)*

year-1

   year

0.13

(0.19)

0.13

(0.19)

0.01-0.32

(0.01-0.46)

0.35

(0.50)

0.35

(0.50)

0.16-0.53

(0.23-0.77)

βeradication therapy

(hazard ratio)#

 

1.29

(3.63)

1.32

(3.74)

0.66-2.16

(1.93-8.69)

* Gompertz parameter converted to half-life by dividing the estimate into ln (2)

# Hazard ratio calculated from exp (βeradication therapy)

Conclusion: Eradication therapy for Pseudomonas aeruginosa infection was a more important influence on the hazard of having a  Aspergillus fumigatus positive culture than the probability of having a Pseudomonas aeruginosa positive culture itself. However, because eradication therapy is important in children with CF, stopping the treatment is not clinically feasible in order to reduce the risk of Aspergillus fumigatus positive culture. Further studies to determine the effect of antifungal treatment on the hazard of having Aspergillus fumigatus positive culture and the impact of Aspergillus fumigatus positive culture on disease progression are warranted.

References:1. Wainwright CE, Vidmar S, Armstrong DS, Byrnes CA, Carlin JB, Cheney J, et al. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA : the journal of the American Medical Association. 2011;306(2):163-71.