Controlled experiments were conducted to determine the in-vitro postantibiotic effect (PAE) of meropenem and imipenem on ten selected bacteria representative of medically important species: Staphylococcus aureus (2). Pseudomonas aeruginosa (4), Escherichia coli (1), Serratia marcescens (1), Morganella morganii (1), and Providencia stuartii (1). The PAE was determined by comparing serial colony counts of cultures recovering from exposure to drug concentrations at 4 x MIC for 1.5 h with the counts of drug-free controls. A PAE was observed with both meropenem and imipenem when tested against four strains of Ps. aeruginosa (meropenem PAE = 0.8-2 h; imipenem PAE = 1.2-2.5 h) and two strains of Staph. aureus (meropenem PAE = 0.7, 1.7 h; imipenem PAE = 1.7, 1.8 h). In addition, a PAE was observed with meropenem on two of four Enterobacteriaceae, E. coli ATCC 25922 (0.8 h) and Prov. stuartii (1.2 h), but not with one strain each of M. morganii and Ser. marcescens. A PAE was not observed when imipenem was tested against the four Enterobacteriaceae. Studies are suggested to investigate further the PAE of meropenem on additional strains of Enterobacteriaceae.

A neutralizer system was developed and validated for use in the in vitro bactericidal evaluation of three commonly used antiseptics, namely, Hibiclens (4% [wt/vol] chlorhexidine gluconate), Betadine (7.5% [wt/vol] povidone-iodine), and pHisoHex (3% [wt/vol] hexachlorophene). The neutralizer finally selected after a screening of 12 potential candidates consisted of 3% Asolectin, 10% Tween 80, and 0.3% sodium thiosulfate in diluent, and 0.3% Asolectin, 1% Tween 80, and 0.3% sodium thiosulfate in the recovery agar. This neutralizer system was tested and validated for its neutralizing capacity for the three antiseptics, as well as for its lack of inherent bactericidal action against Staphylococcus aureus and a number of gram-negative bacteria of clinical significance. With no more than a 10-fold dilution of the antiseptic, the selected neutralizer system was 100% effective in neutralizing all the bacteriostatic carry-over of the three antiseptics and was also completely without any inherent bactericidal action against all the test organisms used. Sodium sulfite (considered to be a potential inactivator for iodophores such as Betadine), even in concentrations as low as 0.1%, was found to be ineffective or inherently bactericidal, whereas 0.3% sodium thiosulfate, in combination with Asolectin and Tween 80, was adequate (effective as well as nonbactericidal) and was considered to be essential for the neutralization of the three test antiseptics, namely, Hibiclens, Betadine, and pHisoHex.Chemical agents commonly known as inactivators or neutralizers are often used for (i) the bactericidal evaluation of antimicrobial agents, antiseptics, and disinfectants; (ii) the evaluation of preservative efficacy in many pharmaceuticals, toiletries, and cosmetic products; and (iii) the microbial limit testing ofproducts containing antimicrobial agents. The need for an adequate neutralizer in some of these applications is well documented and rightfully stressed (2-4, 11-14). The selected neutralizer should not only be able to completely inactivate all of the bacteriostatic activity of the residual antimicrobial agent likely to be carried over into recovery media, but also be inherently non-bactericidal to the test organisms (4).As

The in vitro activity of meropenem was compared with those of six other antimicrobials against up to 1,182 clinical isolates of Pseudomonas aeruginosa from 16 North American centers by means of standardized controlled methods. Meropenem was the most active drug. These isolates were less frequently resistant to meropenem (4.2%) than to imipenem (12.5%), ceftazidime (15.6%), piperacillin (21%), ciprofloxacin (16%), tobramycin (26%), or gentamicin (29.8%). Of 147 imipenem-resistant P. aeruginosa isolates, 43.8% were susceptible to meropenem, and 26.9% additional isolates were moderately susceptible to meropenem. Of 49 meropenem-resistant (MIC, > or = 16 micrograms/mL) isolates, 85.7% were also imipenem-resistant, and 24% to 79% were resistant to other antimicrobials. Meropenem MICs were lower than imipenem and ceftazidime MICs for 92 P. aeruginosa isolates from meropenem clinical trials. Carbapenem MICs of > or = 16 micrograms/mL for selected P. aeruginosa isolates from meropenem clinical trials were associated with loss of the approximately 45-kD outer-membrane protein and/or production of type I beta-lactamases. No metallo-beta-lactamases (e.g., "efficient" carbapenemases) were detected.

Meropenem body fluid and tissue concentration data from both published studies and samples obtained during efficacy evaluation have been compiled and presented according to a consistent format to facilitate comparison. The concentration data have been compared with the mode MIC data available for the pathogens isolated during the clinical evaluation of meropenem. These data support the widespread and rapid penetration of meropenem into the interstitial fluid of those tissues not protected by a tight epithelial barrier. Furthermore, they suggest that the proposed dosages of meropenem 500 mg or 1 g tds would provide an adequate duration of cover at tissue sites for the treatment of a range of commonly occurring pathogens. A higher dosage of 40 mg/kg or 2 g in adults given tds would be recommended for meningitis based on the penetration of meropenem into CSF. Overall, the tissue and body fluid data presented confirm the expectation, based on the plasma concentrations and theoretical arguments, that meropenem is rapidly and readily distributed into the interstitial fluid, thereby producing concentrations in tissues likely to be clinically effective. This is consistent with the available clinical data on the therapeutic efficacy of meropenem.

The antibacterial activity of meropenem and comparative agents against approximately 1,000 anaerobes was determined using the disk dilution methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The organisms represented 27 species of six genera and included the most common pathogens. Meropenem and imipenem were the most active drugs and were comparable in overall activity, generally exhibiting an MIC90 of < or = 1 micrograms/mL. In contrast, the MICs of cefoxitin, clindamycin, and metronidazole were 32, 16, and 2 micrograms/mL, respectively. Meropenem was two- to fourfold more active than imipenem against selected Bacteroides species, Clostridium species, and Fusobacterium species. At a concentration of 1 microgram/mL, meropenem was more active than imipenem against cefoxitin-resistant Bacteroides fragilis or Bacteroides thetaiotaomicron. At a concentration of < or = 0.5 micrograms/mL, meropenem was more active than imipenem against clindamycin-resistant Bacteroides distasonis. At a concentration of 2 micrograms/mL, meropenem was more active than imipenem against cefoxitin-resistant or clindamycin-resistant Clostridium difficile. Thus, meropenem's high potency and broad-spectrum activity against common, rare, and drug-resistant anaerobes confirms its utility in the treatment of mixed anaerobic and aerobic infections.