Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90 We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function
Methicillin-resistant Staphylococcus aureus (MRSA) is an important infectious human pathogen responsible for diseases ranging from skin and soft tissue infections to life-threatening endocarditis in both hospital and community settings. -Lactam resistance in MRSA involves the acquisition of penicillin-binding protein 2a (PBP 2a), which has a low affinity for -lactams and can mediate cell wall assembly when the normal staphylococcal penicillin-binding proteins (PBPs 1 to 4) are inactivated by these agents [1]
Susceptibility of cystic fibrosis patient-derived MRSA/methicillin-susceptible S. aureus (MSSA) strains to telavancin
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. In patients with CF, chronic pulmonary infections with MRSA and their exacerbations were shown to be associated with a decline in lung function and a clinical outcome worse than that in non-CF patients [9] In this context, additional data regarding the antibiotic susceptibility of strains from CF patients are urgently needed to enhance treatment options against multidrug-resistant strains and to try to eradicate MRSA from their lungs. Clinical data on TLV activity against MRSA strains isolated from patients with chronic diseases, such as cystic fibrosis, are not yet available These strains are well-known to have an altered metabolism and possess multidrug resistance due to their chronic habitation of the CF patient lung and prolonged, repeated exposures to antibiotic treatments in the CF lung environment [15]
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