Efficacy of BAL5788, a prodrug of cephalosporin BAL9141, in a mouse model of acute pneumococcal pneumonia

Abstract

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(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. 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.

FIG. 1.

Activity of BAL9141 against pneumococcal strains. (A) Cumulative 10-day survival of mice challenged with Pen^s Cro^S Ctx^s strain P-52181 and treated with BAL5788 3 × q12h (BAL9141 equivalents, 1.05 or 2.1 mg/kg). (B) Cumulative 10-day survival of mice challenged with Pen^r Cro^s Ctx^s strain P-15986 and treated with BAL5788 3 × q12h (BAL9141 equivalents, 2.1, 4.2, or 8.4 mg/kg). (C) Cumulative 10-day survival of mice challenged with Pen^r Cro^r Ctx^r strain P-40422 and treated with BAL5788 3 × q12h (BAL9141 equivalents, 17 or 25 mg/kg) or 3 × q8h (BAL9141 equivalents, 37.5 mg/kg). (D) Cumulative 10-day survival of mice challenged with Pen^r Cro^r Ctx^r strain P-40984 and treated with BAL5788 3 × q12h (BAL9141 equivalents, 17 or 25 mg/kg) or 3 × q8h (BAL9141 equivalents, 37.5 mg/kg). Peni, penicillin; CRO, ceftriaxone; BAL, BAL5788.

FIG. 2.

Mean concentration-time profiles of BAL9141 (25 mg/kg administered s.c. as BAL5788) in the sera and lungs of uninfected immunocompetent Swiss albino female mice (n = 6).