In this pilot study of polymyxin B PK in adults with CF, the PK parameters of polymyxin B were mostly similar to adults without CF. We observed a potential association between CrCL and polymyxin B clearance, which stands in contrast to the general adult population. However, this observation requires further study. Additional studies focusing on optimal and safe polymyxin B dosing in CF are needed. This article is protected by copyright. All rights reserved.

Pseudomonas aeruginosa (PA) from acute and chronic (e.g. cystic fibrosis [CF]) infections differ in several respects though they can worsen prognosis in each context. Factors that facilitate conversion from an acute to chronic phenotype are poorly understood. Type III (T3) secretion proteins are virulence factors associated with poorer outcomes in acute infections, but little is known about their role in CF. We wished to characterize T3 secretion in CF PA isolates and examine its role in clinical outcomes. One-hundred fourteen CF subjects were divided into 3 cohorts: 1 st infected individuals, chronically infected (CI) children, and adults. Serial respiratory cultures were analyzed for T3 secretion. Serial spirometry and exacerbation data were prospectively collected. In 1 st infection, 45.2% +/− 9.1% of PA isolates secreted T3 proteins compared to 29.1% +/− 4.2% and 11.5% +/− 3.0% in CI children and CI adults, respectively (p<0.001). There was an inverse correlation between duration of PA infection and percent T3 positive isolates (r=−0.32, p<0.001). Overall there was no association between T3 secretion and pulmonary outcomes, but in the subgroup of subjects who had at least one T3 positive organism, T3 secretion was inversely correlated with FEV 1 decline (r=−0.35, p=0.02). In 1 st infection, 82% of cultures grew either all or no T3 positive organisms. In these patients, T3 secretion was associated with greater risk of subsequent PA isolation (p<0.001). In CF, PA T3 secretion decreases with residence time in lung, may predict FEV 1 decline in patients who have detectable T3 organisms, and may facilitate persistence following 1 st infection.

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Rationale Aminoglycoside (AG) resistance by Pseudomonas aeruginosa in Cystic Fibrosis is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children, and children with new infection. Measurements One P. aeruginosa isolate from each patient was analyzed for mexZ mutations, mexY mRNA expression, and amikacin resistance. Main Results Fifty-six CF patients were enrolled: 21 children with new P. aeruginosa infection, 18 CI children, and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33%, and 65% in children with new infection, CI children, and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin- resistant compared to 18% of isolates with non-synonymous mutations. The doubling rate for amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusion P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

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