Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase.
We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.
Institut National de la Santé et de la Recherche Médicale U:13, Hôpital Claude Bernard, Paris, France.
B
B
Fantin
B
B
Pangon
G
G
Potel
F
F
Caron
E
E
Vallée
J M
JM
Vallois
J
J
Mohler
A
A
Buré
A
A
Philippon
C
C
Carbon
D000818:Animals; D002443:Ceftriaxone / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004697:Endocarditis, Bacterial / Q000188:drug therapy*; D004926:Escherichia coli / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D008826:Microbial Sensitivity Tests; D009428:Netilmicin / Q000627:therapeutic use; D011817:Rabbits; D013407:Sulbactam / Q000008:administration & dosage / Q000627:therapeutic use*; D065093:beta-Lactamase Inhibitors
D004338:Drug Combinations; D065093:beta-Lactamase Inhibitors; D009428:Netilmicin; D002443:Ceftriaxone; D013407:Sulbactam