In the course of clinical studies with the investigational streptogramin antimicrobial dalfopristin-quinupristin, isolates of vancomycin-resistant Enterococcus faecium were referred to our laboratory from across the United States. Seventy-two percent of the strains were of the VanA type, phenotypically and genotypically, while 28% were of the VanB type. High-level resistance to streptomycin or gentamicin was observed in 86 and 81%, respectively, of the VanA strains but in only 69 and 66%, respectively, of the VanB strains. These enterococci were resistant to ampicillin (MIC for 50% of the isolates tested [MIC50] and MIC90, 128 and 256 μg/ml, respectively) and to the other approved agents tested, with the exception of chloramphenicol (MIC90, 8 μg/ml) and novobiocin (MIC90, 1 μg/ml). Considering all of the isolates submitted, dalfopristin-quinupristin inhibited 86.4% of them at concentrations of ≤1 μg/ml and 95.1% of them at ≤2 μg/ml. However, for the data set comprised of only the first isolate submitted for each patient, 94.3% of the strains were inhibited at concentrations of ≤1 μg/ml and 98.9% were inhibited at concentrations of ≤2 μg/ml. Multiple drug resistance was very common among these isolates of vancomycin-resistant E. faecium, while dalfopristin-quinupristin inhibited the majority at concentrations that are likely to be clinically relevant.

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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.

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.