title: Early in vitro and in vivo development of high-level daptomycin resistance is common in mitis group Streptococci after exposure to daptomycin.
abstract: The development of high-level daptomycin resistance (HLDR; MIC of ≥ 256 mg/liter) after exposure to daptomycin has recently been reported in viridans group streptococcus (VGS) isolates. Our study objectives were as follows: to know whether in vitro development of HLDR after exposure to daptomycin was common among clinical isolates of VGS and Streptococcus bovis; to determine whether HLDR also developed during the administration of daptomycin to treat experimental endocarditis caused by the daptomycin-susceptible, penicillin-resistant Streptococcus mitis strain S. mitis 351; and to establish whether combination with gentamicin prevented the development of HLDR in vitro and in vivo. In vitro studies were performed with 114 VGS strains (mitis group, 92; anginosus group, 10; mutans group, 8; and salivarius group, 4) and 54 Streptococcus bovis strains isolated from 168 consecutive patients with infective endocarditis diagnosed between 1995 and 2010. HLDR was only observed after 24 h of exposure to daptomycin in 27% of the mitis group, including 27% of S. mitis isolates, 47% of S. oralis isolates, and 13% of S. sanguis isolates. In our experimental model, HLDR was detected in 7/11 (63%) and 8/12 (67%) isolates recovered from vegetations after 48 h of daptomycin administered at 6 mg/kg of body weight/24 h and 10 mg/kg/24 h, respectively. In vitro, time-kill experiments showed that daptomycin plus gentamicin was bactericidal against S. mitis 351 at tested concentrations of 0.5 and 1 times the MIC and prevented the development of HLDR. In vivo, the addition of gentamicin at 1 mg/kg/8 h to both daptomycin arms prevented HLDR in 21 out of 23 (91%) rabbits. Daptomycin plus gentamicin was at least as effective as vancomycin plus gentamicin. In conclusion, HLDR develops rapidly and frequently in vitro and in vivo among mitis group streptococci. Combining daptomycin with gentamicin enhanced its activity and prevented the development of HLDR in most cases.
authors.affiliation: Infectious Diseases Service, University of Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: García-de-la-Mària
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pericas
authors.forename: Ana
authors.initials: A
authors.lastname: Del Río
authors.forename: Ximena
authors.initials: X
authors.lastname: Castañeda
authors.forename: Xavier
authors.initials: X
authors.lastname: Vila-Farrés
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Armero
authors.forename: Paula A
authors.initials: PA
authors.lastname: Espinal
authors.forename: Carlos
authors.initials: C
authors.lastname: Cervera
authors.forename: Dolors
authors.initials: D
authors.lastname: Soy
authors.forename: Carlos
authors.initials: C
authors.lastname: Falces
authors.forename: Salvador
authors.initials: S
authors.lastname: Ninot
authors.forename: Manel
authors.initials: M
authors.lastname: Almela
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Mestres
authors.forename: Jose M
authors.initials: JM
authors.lastname: Gatell
authors.forename: Jordi
authors.initials: J
authors.lastname: Vila
authors.forename: Asuncion
authors.initials: A
authors.lastname: Moreno
authors.forename: Francesc
authors.initials: F
authors.lastname: Marco
authors.forename: Jose M
authors.initials: JM
authors.lastname: Miró
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013045:Species Specificity; D013290:Streptococcal Infections / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D034366:Streptococcus anginosus / Q000187:drug effects / Q000502:physiology; D016985:Streptococcus bovis / Q000187:drug effects / Q000502:physiology; D034361:Streptococcus mitis / Q000187:drug effects* / Q000502:physiology; D013295:Streptococcus mutans / Q000187:drug effects / Q000502:physiology; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D014640:Vancomycin; D017576:Daptomycin