Long Use of Inhaled Antibiotics to Treat P. aeruginosa in Children May Raise Risk of Fungal Infection

Long-term use of inhaled antibiotics, given to treat lung infections caused by the bacteria Pseudomonas aeruginosa  in people with cystic fibrosis (CF), can for young children raise the risk of a new infection by Aspergillus fungi, a study suggests.

The study, “Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis,” was published in the journal Thorax.

Lung infections linked to P. aeruginosa are common among CF patients and their treatment includes weeks of inhaled antibiotics. But their use is associated with the development and spread of other potentially harmful microorganisms in the lungs, such as Aspergillus fungi, and poorer lung function.

In adults and older children with CF, long-term use of antibiotics and corticosteroids has been identified as key risk factors for persistent Aspergillus infection. But whether this treatment contributes to Aspergillus lung infections in children age 5 or younger is not known.

A team led by researchers in Australia analyzed data on 156 children — ages 6 months to 5 years old — who participated in the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL, ACTRN12605000665639) study, a randomized trial into treatment approaches taken to eradicate P. aeruginosa infections that ran from 1999 to 2009.

Bronchoalveolar lavage (BAL) fluid collection, a procedure used to collect samples of lung tissue, cells, and microorganisms living in the lungs, was given to children in the ACFBAL study.

The team evaluated all 156 BAL fluid samples and found 28 of them (17.9%) positive for Aspergillus. In 26.7% of these cases, the children had previously been treated with a combination of antibiotics — a regimen called eradication therapy — for P. aeruginosa. Their eradication therapy involved two weeks of treatment with intravenous antibiotics, followed by four weeks of oral antibacterial Cipro (ciprofloxacin), and eight weeks of inhaled tobramycin (another antibiotic, marketed under brand names such as Tobi).

“The type of eradication therapy varies in different settings from 1 month of either inhaled tobramycin alone or combined with oral ciprofloxacin, through to 3 months of combination oral and inhaled therapy, to regimens that include intravenous antibiotics. The optimal eradication therapy is unknown,” the study noted.

“Eradication therapy in the ACFBAL study was for 10 weeks and included 8 weeks of inhaled tobramycin compared with the 4-week courses of inhaled tobramycin that are now recommended by some authorities,” it continued. “This longer course of inhaled antibiotic may have increased the risk of acquiring Aspergillus.”

P. aeruginosa was first detected in the children at a median age of 2.38 years, and Aspergillus at 3.69 years. Each eradication course for P. aeruginosa was associated with 1.6-times higher risk of Aspergillus infection in these children by age 5, the researchers found.

“This suggests that either eliminating or suppressing P. aeruginosa may be the key reason for acquiring Aspergillus, rather than the recent suggestion of each promoting the other’s growth,” the team wrote. Previous studies support this suggestion, finding that P. aeruginosa released chemical molecules, called phenazines, that appeared to inhibit Aspergillus growth.

Researchers next determined the risk of recurrent Aspergillus infections by analyzing patients’ BAL cultures in the first five years of life.

Results showed a very low risk in the first year of study participation. However, a first infection with Aspergillus or P. aeruginosa raised the risk of a subsequent infection. While the risk of reinfection by P. aeruginosa was almost null immediately after finishing an eradication therapy regimen, the risk for Aspergillus infection was 2.75 times higher. 

No link between P. aeruginosa and a subsequent Aspergillus infection was evident after two weeks of intravenous antibiotics alone, suggesting that the“inhaled [tobramycin] therapy may pose the greater risk,” the researchers said.

Still, they noted these findings cannot be generalized to all forms of eradication therapy, and emphasized that “eradicating P. aeruginosa remains an integral part of clinical care.”

Overall, “the risk of recurrent Aspergillus events in children with CF was very low in the first year after enrolment into the study and increased after completing P. aeruginosa eradication therapy and once children had an Aspergillus event,” the study concluded.

Future studies are needed to determine whether infection by Aspergillus is simply a sign of imbalance in the microbe species linked with CF that colonize the lungs (dysbiosis), or a cause of progressive lung injury.