BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin-and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10 Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.

To investigate if the characteristics of human intestinal Escherichia coli are changing with the environment of the host, we studied intestinal E. coli from subjects having recently migrated from a temperate to a tropical area. We determined the phylogenetic group, the prevalence of the antibiotic resistance, the presence of integrons and the strain diversity in faecal isolates from 25 subjects originally from metropolitan France and expatriated to French Guyana. These characteristics were compared with those of 25 previously studied Wayampi Amerindian natives of French Guyana and from 25 metropolitan French residents. The three groups of subjects were matched for age and sex, had not taken antibiotics for at least 1 month, nor had been hospitalized within the past year. In all, the characteristics of intestinal E. coli from Expatriates were intermediate between those found in residents from metropolitan France and those found in natives of French Guyana. Prevalence of carriage of resistant Gram-negative bacteria in Expatriates was intermediate between French residents and Wayampi as were the prevalence of integrons in E. coli (12.3% versus 16.3% and 7.8% respectively), and the intra-host diversity of E. coli (2.3 strains/subject versus 1.9 and 3.1, respectively); lastly, in Expatriates, the prevalence of carriage of phylogenetic group B2 strains was lower than in French residents (16% versus 56%, P = 0.005), while carriage of phylogenetic group A strains was lower than in Wayampi (56% versus 88%, P = 0.03). Our results suggest that the composition of the commensal intestinal flora of humans is not static but changes dynamically in response to new environmental conditions.

We studied the efficacy of sulbactam, a j8-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum ,-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 ,ug/ml with 5 x 105 and 5 x i07 CFU of inoculum per ml, respectively). Sulbactam inhibited the P-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 log1o CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactani-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 loglo CFU/g of vegetation greater than that produced by single-drug therapy (P < 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P < 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 ,ug/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.The therapeutic use of broad-spectrum cephalosporins that are relatively resistant to hydrolysis by P-lactamases such as ceftriaxone has been initially associated with the emergence of resistant clinical isolates with an overproduction of chromosomal ,B-lactamase among members of the family Enterobacteriaceae (Enterobacter cloacae, Proteus vulgaris, Citrobacterfreundii, and Serratia marcescens) (19,20). The mechanism of resistance, involving the overproduction of class 1 P-lactamase as a result of mutation, is spontaneously nontransferable. More recently, strains of Klebsiella pneumoniae and Escherichia coli resistant to cefotaxime and ceftriaxone have been reported (2,22). The mechanism of ,-lactam resistance involved is a new, plasmid-mediated P-lactamase called SHV-2 (10). A similar type of resistance, related to another new, plasmid-mediated ,-lactamase called CTX-1 or TEM-3, has been described in multiresistant K. pneumoniae causing outbreaks of nosocomial infections (3, 23 However, no in vivo data are available on the activity of a P-lactamase inhibitor in combination with a broad-spectrum cephalosporin for the treatment of an infect...