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Patients with cystic fibrosis are living longer with chronic pulmonary bacterial infections. One consequence of antibiotic treatment of these chronic infections has been the increasing prevalence of antibiotic resistance seen in bacterial isolates recovered from patients with cystic fibrosis.Bacteria such as Pseudomonas aeruginosa and Burkholderia cepacia are able to acquire antibiotic resistance by either spontaneous mutation or gene transfer via plasmids or integrins. In addition, bacteria survive by forming antibiotic-resistant biofilms within the airways of patients with cystic fibrosis. Therapeutic approaches to dealing with antibiotic-resistant bacterial pulmonary infections include the use of in vitro synergy testing to determine optimal double antibiotic combinations or multiple-combination bactericidal testing to determine bactericidal double and triple antibiotic combinations to use against the bacteria in the clinical setting of acute exacerbations.Therapy for antibiotic-resistant bacterial infections in cystic fibrosis involves the use of new laboratory methods (synergy testing or multiple-combination bactericidal testing) to optimize antibiotic treatment strategies. Clinical trials are required to address whether treatment guided by susceptibility testing improves clinical outcomes. Future novel approaches will likely include drugs that can disrupt bacterial biofilm formation and the use of cationic peptide antimicrobial compounds.