Antipseudomonal Bacteriophage Reduces Infective Burden and Inflammatory Response in Murine Lung.

As antibiotic resistance increases, there is a need for new therapies to treat infection, particularly in cystic fibrosis (CF), where Pseudomonas aeruginosa is a ubiquitous pathogen associated with increased morbidity and mortality. Bacteriophages are an attractive alternative treatment, as they are specific to the target bacteria and have no documented side effects. The efficacy of phage cocktails was established in vitro. Two P. aeruginosa strains were taken forward into an acute murine infection model with bacteriophage administered either prophylactically, simultaneously, or postinfection. The infective burden and inflammation in bronchoalveolar lavage fluid (BALF) were assessed at various times. With low infective doses, both control mice and those undergoing simultaneous phage treatment cleared P. aeruginosa infection at 48 h, but there were fewer neutrophils in BALF of phage-treated mice (median, 73.2 × 10(4)/ml [range, 35.2 to 102.1 × 10(4)/ml] versus 174 × 10(4)/ml [112.1 to 266.8 × 10(4)/ml], P < 0.01 for the clinical strain; median, 122.1 × 10(4)/ml [105.4 to 187.4 × 10(4)/ml] versus 206 × 10(4)/ml [160.1 to 331.6 × 10(4)/ml], P < 0.01 for PAO1). With higher infective doses of PAO1, all phage-treated mice cleared P. aeruginosa infection at 24 h, whereas infection persisted in all control mice (median, 1,305 CFU/ml [range, 190 to 4,700 CFU/ml], P < 0.01). Bacteriophage also reduced CFU/ml in BALF when administered postinfection (24 h) and both CFU/ml and inflammatory cells in BALF when administered prophylactically. A reduction in soluble inflammatory cytokine levels in BALF was also demonstrated under different conditions. Bacteriophages are efficacious in reducing both the bacterial load and inflammation in a murine model of P. aeruginosa lung infection. This study provides proof of concept for future clinical trials in patients with CF.

Bacteria in sputum of stable severe asthma and increased airway wall thickness.

BACKGROUND: Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness. METHODS: In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (WT) and area (WA) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels. RESULTS: Positive bacterial cultures were obtained in 29 patients, with H. influenzae, P. aeruginosa and S. aureus being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in WA (67.5 ± 5.4 vs 66.4 ± 5.4) and WT/D (21.6 ± 2.7 vs 21.3 ± 2.4) between the culture negative versus positive groups. Similarly, in airways (≤ 2 mm), there were no significant differences in these parameters. The ratio of √wall area to Pi was negatively correlated with FEV1% predicted (p < 0.05). CONCLUSIONS: Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness.