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Drug Resistance in Cystic Fibrosis Lung Infections Associated With Pseudomonas Bacteriophages

NEW YORK (GenomeWeb) – Bacteria involved in infecting the lungs of cystic fibrosis (CF) patients may get a boost from filamentous viruses found within them, according to new research from scientists at Stanford University and elsewhere.

As they reported online today in Science Translational Medicine, the researchers used DNA sequence or quantitative PCR data to profile bacteria in lung or sputum samples from 110 children or adults with CF from Denmark or the US, identifying filamentous bacteriophages (Pf phages) that were overrepresented in a significant proportion of older CF patients and patients carrying  Pseudomonas aeruginosa bacteria that are drug resistant.

The team suspects that the phages help Pseudomonas bugs in CF patient lungs, perhaps by boosting biofilm production and making it more likely that Pseudomonas will establish chronic infections in the lungs.

"We saw that phage infection of the lung bacteria is associated with more antibiotic resistance in patients," first author Elizabeth Burgener, a pulmonary biology researcher at Stanford, said in a statement.

"If we're able to confirm these results, it may affect how we choose antibiotic therapy for patients who have CF and Pseudomonas," Burgener said, noting the team hopes to find strategies for preventing Pseudomonas infections.

In animal models, P. aeruginosa virulence has previously been linked to Pf phage contributions, the team noted. Other past studies described similar filamentous bacteriophages in P. aeruginosa biofilms, in general, and in the lung infections from some CF patients. The researchers suspected that the phages may have an important role in the pathogenesis of the P. aeruginosa in chronic lung infections in CF patients.

"We hypothesized that Pf phage is widespread in the CF patient population and that higher Pf phage concentrations are associated with features of advanced lung disease in CF," the authors wrote.

"To test this hypothesis, we explored the prevalence of Pf prophage in P. aeruginosa isolates in an online dataset and in a previously described cohort of Danish patients with CF," they explained. "We then performed a prospective cross-sectional cohort study at the Stanford CF Center to evaluate Pf phage concentrations in sputum and clinical outcomes in patients with CF."

Specifically, the researchers began by tapping into available P. aeruginosa sequence data for more than 2,200 isolates in the Pseudomonas Genome Database, identifying Pf phage sequences in more than half of those P. aeruginosa representatives. From there, they scrutinized genome sequences for 474 P. aeruginosa isolates from 34 Danish CF patients that were assessed for a past study, identifying Pf phages in 211 — or nearly 45 percent — of those isolates.

The isolates corresponded with 21 of the CF cases, including nine individuals who had Pf phages in their P. aeruginosa isolates across the sampling period considered. Most of those patients were older than their Pf phage-free counterparts, the team noted.

The researchers went on to test for P. aeruginosa and Pf phage infections with qPCR assays on sputum samples from 76 CF patients treated at Stanford. Among the 58 patients who tested positive for P. aeruginosa, they picked up Pf phages in 21.

Along with enhanced levels of P. aeruginosa in the CF patients carrying Pf phages, the team saw signs that the filamentous bacteriophages again tended to turn up in older patients and those carrying antibiotic-resistant forms of P. aeruginosa.

"Because antibiotic therapy is an important component of CF care," the authors wrote, "these data suggest that an association with heightened antibiotic resistance may contribute to the link between Pf phage status and increased lung disease pathogenicity in CF."

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