Cephamycin derivatives: comparison of the in vitro and in vivo antibacterial activities of SQ 14,359, CS-1170, and cefoxitin.

SQ 14,359 is a new cephamycin-type (7alpha-OCH3) antibiotic belonging to a series containing a 7alpha-ureidoacetyl substituent. The compound is the most potent extended spectrum derivative of this type yet reported, surpassing CS-1170 and cefoxitin by a wide margin. This activity in vitro which extends throughout the Enterobacteriaceae is particularly prominent against Gram-negative organisms that are producers of "cephalosporinase-type" beta-lactamases such as Enterobacter, Serratia, Citrobacter and indole-positive Proteus species. Superior activity also is demonstrated in vitro against streptococci, beta-lactamase-producing staphylococci, Haemophilus influenzae, Neisseria gonorrhoeae, and many Gram-negative pathogens resistant to aminoglycoside antibiotics. Experimental chemotherapeutic studies have confirmed these observations in wound and selected systemic infections in mice as well as acute pyelonephritis and meningitis in rats. The pharmacokinetics for each drug including antibiotic bound to serum was similar in both mice and rats. The pharmacokinetic profile in blood and cerebrospinal fluid favored SQ 14,359.

Diastereomeric 7-ureidoacetyl cephalosporins. III. Contribution of D- and L-isomers to the growth inhibiting activities of 7alpha-H and 7alpha-OCH3 derivatives for gram-positive and gram-negative bacteria.

A series of 7beta-ureidoacetyl, 7alpha-H and 7alpha-OCH3 cephalosporin antibiotics have shown broad-spectrum antibacterial activity in vitro. In the 7alpha-H but not in the 7alpha-OCH3 series, contrary to experience in the antibiotic field, the L-isomers were substantially more active than the D-isomers both in vitro and in vivo particularly, but not exclusively, against Enterobacteriaceae that produce potent chromosomal cephalosporinases. Enhanced resistance to and inhibition of beta-lactamase (s) appeared to be responsible for this effect. Studies in vitro specifically with 7beta-thienylureidoacetyl derivatives showed that D-isomers interacted with L-isomers in the 7alpha-OCH3 series in a synergistic manner against "cephalosporinase-type" enzyme producers while isomers in the 7alpha-H series did not. Examples were presented in which this favorable event resulted in improved efficacy of the racemic mixture over the pure D- or L-isomer alone in appropriate experimental infections.