title: Synergy between amoxicillin and gentamicin in combination against a highly penicillin-resistant and -tolerant strain of Streptococcus pneumoniae in a mouse pneumonia model.
abstract: In vivo synergy with beta-lactam antibiotics and aminoglycosides has been studied only with penicillin-susceptible Streptococcus pneumoniae strains. We evaluated the interaction between amoxicillin (AMX) and gentamicin (GEN) on the basis of in vitro checkerboard and time-kill curves and of findings in a mouse model of acute bacteremic pneumonia due to a highly penicillin-resistant and -tolerant S. pneumoniae strain of serotype 19 (penicillin and AMX MICs of 4 micrograms/ml; gentamicin MIC of 16 micrograms/ml). Checkerboard results at 18 h of incubation showed indifference. With regard to AMX alone, in vitro time-kill curves demonstrated synergy between AMX (1 microgram/ml) and GEN (16 micrograms/ml) at 5 and 8 h of incubation and for AMX (16 micrograms/ml) in combination with GEN (16 micrograms/ml) at 3, 5, and 8 h of incubation. In leukopenic mice, pulmonary killing curves after a single drug injection demonstrated that AMX (100 mg/kg of body weight) with GEN (16 mg/kg) was more effective than AMX alone (P = 10(-4). With repeated-dose treatment, a synergy was apparent at 8 h after four injections with AMX (100 mg/kg) in combination with GEN (8 or 16 mg/kg) (P < or = 0.05). The cumulative survival rate with AMX (100 mg/kg) every 8 h, combined with GEN (4 or 8 mg/kg) every 8, 12, or 24 h, was better than with AMX alone. Combined use of AMX and GEN may be a valuable therapeutic alternative for pneumococcal pneumonia due to highly penicillin-resistant S. pneumoniae strains.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale U 13, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Darras-Joly
authors.forename: J P
authors.initials: JP
authors.lastname: Bédos
authors.forename: C
authors.initials: C
authors.lastname: Sauve
authors.forename: P
authors.initials: P
authors.lastname: Moine
authors.forename: E
authors.initials: E
authors.lastname: Vallée
authors.forename: C
authors.initials: C
authors.lastname: Carbon
authors.forename: E
authors.initials: E
authors.lastname: Azoulay-Dupuis
mesh_terms: D000658:Amoxicillin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005839:Gentamicins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D007279:Injections, Subcutaneous; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance; D010406:Penicillins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010406:Penicillins; D000658:Amoxicillin