Heterogeneity of genetic pathways toward daptomycin nonsusceptibility in Staphylococcus aureus determined by adjunctive antibiotics.
Daptomycin is increasingly used in combination with other antibiotics to enhance antimicrobial efficacy and/or to mitigate the emergence of daptomycin nonsusceptibility (DNS). This study used a clinical methicillin-resistant Staphylococcus aureus (MRSA) strain in which DNS emerged upon therapy to examine the influence of antibiotic combinations on the development of mutations in specific genes (mprF, rpoBC, dltA, cls2, and yycFG) previously associated with DNS. Whole genomes of bacteria obtained following 28 days of in vitro exposure to daptomycin with or without adjunctive clarithromycin, linezolid, oxacillin, or trimethoprim-sulfamethoxazole were sequenced, and the sequences were compared to that of the progenitor isolate. The addition of oxacillin to medium containing daptomycin prevented the emergence of mprF mutation but did not prevent rpoBC mutation (P < 0.01). These isolates maintained susceptibility to daptomycin during the combined exposure (median MIC, 1 mg/liter). Daptomycin plus clarithromycin or linezolid resulted in low-level (1.5 to 8 mg/liter) and high-level (12 to 96 mg/liter) DNS, respectively, and did not prevent mprF mutation. However, these same combinations prevented rpoBC mutation. Daptomycin alone or combined with linezolid or trimethoprim-sulfamethoxazole resulted in high-level DNS and mutations in mprF plus rpoBC, cls2, and yycFG. Combining daptomycin with different antimicrobials alters the mutational space available for DNS development, thereby favoring the development of predictable collateral susceptibilities.
University of Wisconsin-Madison School of Pharmacy, Pharmacy Practice Division, Madison, Wisconsin, USA.
Andrew D
AD
Berti
Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia Microbiology and Infectious Diseases Departments, Austin Health, Melbourne, Victoria, Australia.
Sarah L
SL
Baines
Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia Microbiology and Infectious Diseases Departments, Austin Health, Melbourne, Victoria, Australia Department of Microbiology, Monash University, Melbourne, Victoria, Australia.
Benjamin P
BP
Howden
University of California San Diego School of Medicine, La Jolla, California, USA.
George
G
Sakoulas
University of California San Diego School of Medicine, La Jolla, California, USA.
Victor
V
Nizet
Departments of Medical Microbiology/Immunology and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Richard A
RA
Proctor
University of Wisconsin-Madison School of Pharmacy, Pharmacy Practice Division, Madison, Wisconsin, USA warren.rose@wisc.edu.
Warren E
WE
Rose
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D017576:Daptomycin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017576:Daptomycin