Enhancement of bactericidal activity against group B streptococci with reduced penicillin susceptibility by uptake of gentamicin into cells resulting from combination with β-lactam antibiotics.
Combined effects of penicillin (PEN) and gentamicin (GM) against Streptococcus agalactiae, i.e. group B streptococci (GBS), are known to occur, but synergy has not been examined in strains with reduced PEN susceptibility, usually called PEN-resistant GBS (PRGBS). We therefore studied combined effects of β-lactam antibiotics and GM in cultures of 3 PRGBS strains belonging to serotype Ia or III that were isolated from Japanese adults with invasive infections. Killing kinetics were determined at 2-h intervals from 0 to 6 h after exposure to ampicillin (AMP) or cefotaxime (CTX) combined with GM. Concentrations of GM in bacterial cells were measured by liquid chromatography-tandem mass spectrometry. Morphologic changes after exposure to agents were observed by transmission electron microscopy. Combining AMP or CTX with GM synergistically increased bactericidal activity against PRGBS beyond that of either β-lactam alone. GM concentrations in bacterial cells increased 5- to 8-fold when GM was combined with AMP or CTX. Electron microscopically, bacterial cells showed aggregates of strands and ribosomal damage most likely reflecting enhanced GM uptake into bacterial cells. This uptake appeared to result from cell wall damage caused by β-lactam antibiotics. This study suggests that combining β-lactam antibiotics with GM might be useful against severe PRGBS infection.
Department of Laboratory Medicine, Keio University, School of Medicine, Tokyo, Japan; Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan.
Yoshifumi
Y
Ebara
Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan.
Miyuki
M
Morozumi
Laboratory of Electron Microscopy, Japan Women's University, Tokyo, Japan.
Mamiko
M
Sato
Laboratory of Electron Microscopy, Japan Women's University, Tokyo, Japan.
Nobuko
N
Moritoki
Department of Pediatrics, Yokohama Rosai Hospital, Yokohama, Japan.
Meiwa
M
Toyofuku
Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan.
Misako
M
Takata
Department of Laboratory Medicine, Keio University, School of Medicine, Tokyo, Japan.
Mitsuru
M
Murata
Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan.
Kimiko
K
Ubukata
Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan. Electronic address: siwata@a8.keio.jp.
Satoshi
S
Iwata
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D010406:Penicillins / Q000494:pharmacology*; D013290:Streptococcal Infections / Q000188:drug therapy*; D013292:Streptococcus agalactiae / Q000187:drug effects*; D047090:beta-Lactams / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010406:Penicillins; D047090:beta-Lactams; D000667:Ampicillin
Antibiotic combinations; Bactericidal effect; Group B streptococci; Reduced penicillin susceptibility; Streptococcus agalactiae; Synergistic effect