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.
Fantin
B
B
Institut National de la Santé et de la Recherche Médicale U:13, Hôpital Claude Bernard, Paris, France.
Pangon
B
B
Potel
G
G
Caron
F
F
Vallée
E
E
Vallois
J M
JM
Mohler
J
J
Buré
A
A
Philippon
A
A
Carbon
C
C
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