title: Reversible antibiotic tolerance induced in Staphylococcus aureus by concurrent drug exposure.
abstract: Resistance of Staphylococcus aureus to beta-lactam antibiotics has led to increasing use of the glycopeptide antibiotic vancomycin as a life-saving treatment for major S. aureus infections. Coinfection by an unrelated bacterial species may necessitate concurrent treatment with a second antibiotic that targets the coinfecting pathogen. While investigating factors that affect bacterial antibiotic sensitivity, we discovered that susceptibility of S. aureus to vancomycin is reduced by concurrent exposure to colistin, a cationic peptide antimicrobial employed to treat infections by Gram-negative pathogens. We show that colistin-induced vancomycin tolerance persists only as long as the inducer is present and is accompanied by gene expression changes similar to those resulting from mutations that produce stably inherited reduction of vancomycin sensitivity (vancomycin-intermediate S. aureus [VISA] strains). As colistin-induced vancomycin tolerance is reversible, it may not be detected by routine sensitivity testing and may be responsible for treatment failure at vancomycin doses expected to be clinically effective based on such routine testing.
  
  
  OBJECTIVE
  Commonly, antibiotic resistance is associated with permanent genetic changes, such as point mutations or acquisition of resistance genes. We show that phenotypic resistance can arise where changes in gene expression result in tolerance to an antibiotic without any accompanying genetic changes. Specifically, methicillin-resistant Staphylococcus aureus (MRSA) behaves like vancomycin-intermediate S. aureus (VISA) upon exposure to colistin, which is currently used against infections by Gram-negative bacteria. Vancomycin is a last-resort drug for treatment of serious S. aureus infections, and VISA is associated with poor clinical prognosis. Phenotypic and reversible resistance will not be revealed by standard susceptibility testing and may underlie treatment failure.
authors.forename: Jakob
authors.initials: J
authors.lastname: Haaber
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Friberg
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: McCreary
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA sncohen@stanford.edu hi@sund.ku.dk.
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Cohen
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark sncohen@stanford.edu hi@sund.ku.dk.
authors.forename: Hanne
authors.initials: H
authors.lastname: Ingmer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology*; D006801:Humans; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology*; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D014640:Vancomycin; D003091:Colistin