In vitro activity of CP-65,207, a new penem antimicrobial agent, in comparison with those of other agents

Abstract

CP-65,207 is a new parenteral penem antibiotic with a broad spectrum that includes gram-positive, gram-negative, and anaerobic microorganisms, with MICs for 90% (MIC90s) of the majority of 1,101 clinical pathogens tested being '1 ,ig/ml. The compound was from 10-to 100-fold more active than cefoxitin and broad-spectrum cephalosporins against gram-positive bacteria and anaerobes. CP-65,207 was less active than imipenem for staphylococci, group A streptococci, and Enterococcus faecalis. Against members of the family Enterobacteriaceae, CP-65,207 was in general 100-fold more active than cefoxitin, 5-to 10-fold more active than broad-spectrum cephalosporins, and 2-fold more active than imipenem. Fresh clinical isolates that were resistant to broad-spectrum cephalosporins were highly susceptible to 207 and imipenem (MIC90,1 ,ug/ml). Isolates of Enterococcusfaecalis, Serratia marcescens, and anaerobic Peptococcus spp. had MIC9,s of 8, 2, and 3.12 ,ug/mI, respectively. CP-65,207 was not very active against methicillin-resistant staphylococci or Pseudomonas aeruginosa. Killing kinetics showed that against some strains CP-65,207 is rapidly bactericidal at concentrations well below those required to achieve a similar degree of killing with cefotaxime, ceftazidime, and ceftriaxone. CP-65,207 was only slightly susceptible to hydrolysis by type I cephalosporinases and TEM-1, SHV-1, and PSE-2 plasmid-encoded enzymes. It had the highest affinity for penicillin-binding proteins 2, 1A, 1B, and 3 in cell-free preparations of Escherichia coli W-7.Penems are synthetic beta-lactams that, as a class, possess a number of interesting properties which include a broad antibacterial spectrum and low susceptibility to hydrolysis by ,B-lactamases but, at the same time, are inactivated by renal dipeptidases found in the brush border of the kidney (20). A number of novel penems have been evaluated in the past decade; SCH-29482 and SCH-34343 (2, 10, 11) have rivaled carbapenems like imipenem in antibacterial activity, yet in clinical trials they were found to have undesirable side effects. The broad antibacterial spectrum of penems, however, has encouraged continued research in order to find clinically useful compounds. Two of these penems, FCE-22101 and SUN-5555, are in clinical trials (20). 207 ( Fig. 1) is a new parenteral penem that demonstrates high activity against gram-positive, gram-negative, and anaerobic bacteria that in some itistances is significantly imtproved over cefoxitin and the broad-spectrum cephalosporins. The current study characterizes the in vitro activity of CP-65,207 compared with those of both cephalosporins and imipenem.( Susceptibility studies. Antibiotic susceptibility studies were performed in microdilution trays containing 0.2 ml of unsupplemented Mueller-Hinton broth (MHB) per well with twofold dilutions of antibiotic (3). Inocula were grown overnight in MHB and diluted in broth to give a final inoculum of approximately 7.5 x 105 CFU/ml. Inoculated plates were incubated at 37°C in air for 18 h.

Antianaerobic Activity of Sulopenem Compared to Six Other Agents

“…Gootz and coworkers (13) in their 1989 study on CP-65,207, reported on its activity against 84 anaerobes, many of which have since been reclassified. Excluding Peptococcus spp., which are no longer included among clinically significant anaerobic gram-positive cocci in standard manuals (16), their results were similar to those obtained in our study.…”

“…CP-65,207, whose in vitro activity was published in 1989 (13), is a diastereomeric mixture of two isomers, the active component of the two being sulopenem. Sulopenem development was put on hold in the 1990s as discovery/development efforts were focused on gram-positive organisms.…”

Extrusion of Penem Antibiotics by Multicomponent Efflux Systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa

“…MexXY-OprM and MexCD-OprJ extrude most penicillins but not carbenicillin, sulbenicillin, various cephems, and many carbapenems. Penem antibiotics display potent activities against a variety of gram-positive and gram-negative bacteria but not against P. aeruginosa (2,3,4,13,15,16,17,21,24). Studies with mutants that overproduce or lack MexAB-OprM demonstrated that this efflux system extrudes penem antibiotics (18).…”

Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

“…infusions of 1 g of CP-65,207-S produce concentrations in serum in excess of 1.0 jig/ml, the MIC for 90% of over 1,000 hospital pathogens (8), for approximately 3.5 h. Since CP-65,207 (and presumably the single isomers) produce very rapid killing of bacteria (8), the results suggest that 1-g doses of CP-65,207-S may be effective against many infections. The oral prodrug CP-65,207-POM produces appreciable concentrations of both isomers of CP-65,207 in serum.…”

“…CP-65,207 (2) is a potent broad-spectrum antibacterial agent with activity comparable to that of imipenem, with the exception that it has significantly lower activity against Pseudomonas aeruginosa (8). The MIC for 90% of over 1,000 hospital pathogens was approximately 1.0 jig/ml (8).…”