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.