Comparison of antibacterial activities of meropenem and six other antimicrobials against Pseudomonas aeruginosa isolates from North American studies and clinical trials.

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.

Comparative in vitro activity of meropenem versus other extended-spectrum antimicrobials against randomly chosen and selected resistant clinical isolates tested in 26 North American centers.

The in vitro antibacterial activity of meropenem and up to nine other antimicrobials was compared in studies at 26 North American centers from 1989 to 1992 with use of standardized and controlled procedures for determining minimal inhibitory concentrations (MICs) against 12,483 recent clinical isolates and additional drug-resistant strains. Overall, carbapenems were the most active drugs. The antibacterial activity of meropenem was consistent against random isolates in all centers; however, inclusion of large proportions of multidrug-resistant gram-negative aerobes by some centers did increase MICs of meropenem and the comparators. Meropenem was 4-64 times more active than imipenem against gram-negatives, including Enterobacteriaceae organisms, Pseudomonas aeruginosa, Burkholderia cepacia, Neisseria meningiditis, and Haemophilus influenzae. Imipenem was up to 2-4 times more active than meropenem against some gram-positive cocci, including Enterococcus faecalis. Carbapenems were similarly active against anaerobes, and resistant strains were rarely encountered. Meropenem, unlike imipenem or ceftazidime, was bactericidal for all strains of Enterobacteriaceae, P. aeruginosa, and gram-positive cocci tested at < or = 8 times the MIC. A lack of antibiotic cross-resistance was frequently observed between comparator-resistant strains and meropenem. These data suggest the potential utility of meropenem as a monotherapeutic agent against a broad range of pathogens.

A compilation of meropenem tissue distribution data.

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.

Comparison of the activity of meropenem with that of other agents in the treatment of intraabdominal, obstetric/gynecologic, and skin and soft tissue.

Meropenem, a new carbapenem with improved stability in the presence of human dehydropeptidase-I[1], was evaluated in three prospective, multicenter, randomized, controlled clinical trials in North America. We compared the in vitro activity of meropenem and conventional antimicrobial agents for the treatment of intraabdominal, obstetric/gynecologic, and skin or soft tissue infections as well as the responses of pathogens to all of these agents. The trials of the drug for intraabdominal infection were double blind, and those for the obstetric/gynecologic and soft tissue infections were open labeled. Overall, MICs of meropenem for pathogens were lower, and the pathogen response rates were at least comparable to those for the following comparative agents: clindamycin plus tobramycin (for intraabdominal infections); clindamycin plus gentamicin (for obstetric/gynecologic infections); and imipenem and cilastatin (for skin or soft tissue infections). Meropenem has high in vitro potency and covers a broad spectrum of anaerobic and aerobic pathogens.

Comparison of sensititre broth microdilution and agar dilution susceptibility testing techniques for meropenem to determine accuracy, reproducibility, and predictive values.

The stability, accuracy, reproducibility, and predictive value of Sensititre MIC panels containing meropenem (Merrem) were evaluated by using National Committee for Clinical Laboratory Standards (NCCLS)-recommended American Type Culture Collection (ATCC) strains and 110 selected strains of rapidly growing and fastidious aerobes and anaerobes with various degrees of susceptibility to meropenem. The NCCLS-recommended agar dilution method was used as a standard reference method. Meropenem-containing Sensititre MIC panels were monitored for their stabilities at room temperature and reproducibilities over 24 months by using six ATCC strains. Ninety-nine percent of the MICs of both meropenem and imipenem obtained for NCCLS-recommended ATCC strains were within the established ranges after 2 years. The overall agreement (+/- 1 twofold dilution) between the Sensititre and the agar dilution meropenem MICs was greater than 93%. The predictive value of meropenem MICs for indicating suspeptibility or resistance obtained by the Sensititre method was greater than 90%. No major or very major interpretive errors were observed, and only 5% of meropenem MICs were associated with minor interpretive errors. Problematic organisms were not observed. The Sensititre MIC panels containing meropenem offer a convenient and valid alternative to the NCCLS reference method for the susceptibility testing of potential pathogens likely to be recovered from mixed infections.

A comparison of the in vitro postantibiotic effect of meropenem and imipenem versus selected enterobacteriaceae and other pathogens.

The in vitro postantibiotic effect (PAE) of meropenem (Merrem or SM-7338) and imipenem was determined by using 12 strains of clinically important pathogens. A PAE of > or = 1/2 h duration was observed more frequently with strains tested against meropenem than with imipenem.

Antibacterial activity of meropenem and selected comparative agents against anaerobic bacteria at seven North American centers.

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.

Lack of predictability of cefotetan in vitro susceptibility tests against cefotetan-resistant anaerobic bacteria in determining clinical and bacteriologic efficacies.

Interpretive criteria for cefotetan in vitro susceptibility testing appear to be clinically relevant when applied to aerobic bacteria. To determine whether the same was true for anaerobic bacteria, we conducted a retrospective analysis of intraabdominal, gynecologic, and skin and skin structure infections treated with cefotetan. Of the infections, 202 contained at least one anaerobe isolate. Of the 51 patients, 47 (92.9%) from whom one or more cefotetan-resistant anaerobes were isolated were clinically cured or showed improvement. Similarly, cefotetan was efficacious for 95.4% of the patients harboring only cefotetan-susceptible anaerobes. Favorable bacteriologic responses were observed in 94.1% and 97.4% of these patient groups, respectively. The data suggests that the therapeutic utility of cefotetan against anaerobic bacteria cannot be accurately predicted on the basis of in vitro susceptibility test results alone but may be explained by a variety of factors, as discussed in this report.

The postantibiotic effect of meropenem and imipenem on selected bacteria.

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.

Development of a meropenem susceptibility disc: drug content, preliminary interpretive and quality control criteria and potency bioassay.

Laboratory studies were conducted to develop an appropriate susceptibility disc for meropenem. Laboratory-prepared paper discs containing 5, 10, and 20 micrograms of meropenem were investigated. Agar dilution MICs and agar disc diffusion tests were performed with 367 rapidly growing clinical isolates by methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Agar disc diffusion tests with 10 micrograms meropenem discs acceptably defined organisms as susceptible or resistant. The preliminary interpretive zone size criteria for 10 micrograms meropenem discs were: susceptible, greater than or equal to 14 mm, and resistant, less than or equal to 10 mm, by application of the NCCLS imipenem MIC interpretive susceptible and resistant breakpoints to the meropenem data. A total of 270 agar disc diffusion assays were performed with each of four ATCC reference strains, using prototype discs (Becton Dickinson (BBL] containing 10 micrograms meropenem. The preliminary quality control limits for agar disc diffusion tests with these discs are: Escherichia coli ATCC 25922, 28-32 mm; Pseudomonas aeruginosa ATCC 27853, 26-31 mm; Staphylococcus aureus ATCC 25923, 33-39 mm; and Enterococcus faecalis ATCC 29212, 19-23 mm. Further studies are necessary to re-evaluate both the preliminary interpretive and quality control criteria before definitive limits can be established. A reproducible, large plate bioassay with Enterococcus faecalis ATCC 29212 was developed to monitor meropenem disc potency.

Quality control guidelines for testing cefotetan in the reference agar dilution procedure for susceptibility testing of anaerobic bacteria.

Reference values for quality control of in vitro susceptibility tests with cefotetan against anaerobic bacteria were determined in two independent multilaboratory studies with the approved National Committee for Clinical Laboratory Standards agar dilution method and three control strains (Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29741, and Clostridium perfringens ATCC 13124). The results of the two studies were in agreement. The recommended MIC control limits for B. fragilis ATCC 25285 and B. thetaiotaomicron ATCC 29741 are 4.0 to 16 micrograms/ml and 32 to 128 micrograms/ml, respectively. MICs for C. perfringens ATCC 13124 were too variable to be useful for controlling tests with cefotetan.

A multicenter study of the in vitro antianaerobic activity of cefotetan compared with other antimicrobial agents.

The in vitro antianaerobic activity of cefotetan was compared with that of chloramphenicol, clindamycin, cefoxitin, and penicillin in a multicenter study. Both agar dilution and broth microdilution testing procedures, as described by the National Committee for Clinical Laboratory Standards (NCCLS), were employed; a total of 1,377 strains were examined. Results were interpreted using the U.S. Food and Drug Administration- and NCCLS-recommended criteria. This study indicates that Bacteroides fragilis, Clostridium difficile, and most other clinically significant anaerobic bacteria are susceptible to cefotetan.

A new selective medium for isolating Pseudomonas spp. from water.

A new medium, pseudomonas selective isolation agar, was developed to isolate Pseudomonas spp. from water. It consists of 350 micrograms of nitrofurantoin per ml and 2 micrograms of crystal violet per ml in a nutrient agar base. It is more selective for Pseudomonas spp. than are available commercial media. Its ingredients are inexpensive and readily available, and it is easy to prepare.

Percutaneous biliary drainage in acute suppurative cholangitis.

One hundred and sixteen percutaneous drainage procedures of the biliary system were performed in a 2-year period. Eight of 9 acutely ill patients with the diagnosis of acute suppurative cholangitis were successfully treated nonoperatively. They represented 26% of all patients with benign or postsurgical obstruction referred for biliary decompression. Conversely, acute suppurative cholangitis only occurred in 2.3% of patients with underlying malignant disease. These observations are considered most relevant in predicting the purulent nature of the disease, with further implications for patient management. Early recognition and prompt decompression of the biliary system are mandatory, along with the appropriate antibiotic coverage. Our experience compares favorably with surgical results and the procedure is proposed as the method of choice for the initial treatment of acute suppurative cholangitis.

Subacute and chronic bone infections: diagnosis using In-111, Ga-67 and Tc-99m MDP bone scintigraphy, and radiography.

The usefulness of indium-111 white blood cell scintigraphy in the diagnosis of subacute or chronic bone infection was examined in 21 orthopedic patients. In-111 WBC imaging was compared with gallium-67 and technetium-99m methylene diphosphonate skeletal scintigraphy and bone radiography, all studies being performed within 1 week. In-111 WBC scintigraphy showed no definite advantage over Ga-67 scintigraphy in the identification of chronic bone infection. The two tests had the same sensitivity (80%) and similar specificity (In-111 WBC 75%, Ga-67 83%; difference not significant). Bone radiography had a sensitivity of 60% and a specificity of 67%. A negative Tc-99m MDP bone scintigram ruled out infection (sensitivity 100%), but because of low specificity (25%), final evaluation required performance of Ga-67 or In-111 WBC scintigraphy.

Tc-99m glucoheptonate scintigraphy in a case of renal vein thrombosis.

Tc-99m glucoheptonate flow and static studies with computer-assisted analysis provided specific diagnostic information in unilateral renal vein thrombosis complicating a case of nephrotic syndrome. Decreased flow with congestion, a large kidney with parenchymal thickening, pelvocalyceal thinning, good function, and no obstruction in the proper clinical settings indicated the diagnosis of a chronic form of renal vein thrombosis with compensating collateralization. The differential diagnosis is discussed.

Evaluation of an immunoradiometric assay specific for the CK-MB isoenzyme for detection of acute myocardial infarction.

Clinical evaluation of patient's symptoms, electrocardiographic changes and increased serum enzyme levels, specifically creatine kinase (CK)-MB by electrophoresis, are established as the primary diagnostic indicators for myocardial infarction (MI). Two hundred fifteen patients were evaluated in this study. Of these patients, 102 were admitted to the coronary care unit and 113 were admitted to the emergency room and screened for possible MI. The immunoradiometric assay used in this study was a double antibody "sandwich" technique, which utilizes antibody to the M and B monomers of the CK isoenzymes. This assay is specific for the CK-MB isoenzyme, which is present in increased levels in MI. The intraassay coefficients of variation for 30 samples were 11.7% (mean 4.1 equivalent units [EU]/liter) and 8.4% (mean 15.4 EU/liter) and the interassay coefficients of variation for 30 samples were 11.1% (mean 2.6 EU/liter) and 8.1% (mean 13.6 EU/liter). The diagnostic sensitivity, specificity and accuracy in this study was 100%, respectively. The CK-MB by the immunoradiometric assay was found to be significantly more accurate than electrophoresis and, therefore, a reliable and also technically simpler replacement for electrophoresis.

Diagnosing myocardial infarction with a radioimmunoassay for the B-monomer of the creatine phosphokinase isoenzymes.

A diagnosis of myocardial infarction (MI) is usually established by the evaluation of clinical symptoms, electrocardiographic changes, and serum enzyme levels, specifically creatine phosphokinase, subunit MB (CK-MB), by electrophoresis. A total of 215 patients were evaluated in this study. One hundred two of them were admitted to the coronary care unit and 113 to the emergency room, where they were screened for possible MIs. The radioimmunoassay (RIA) used in this study determines levels of the CK-MB isoenzyme by detecting the B monomer, which also has 100% cross-reactivity with the CK-BB isoenzyme. The intra-assay coefficients of variability (CVs) for 30 samples were 22% (means = 7.0 ng/ml) and 11% (means = 47.3 ng/ml), and the interassay CVs for 30 samples were 17% (means = 7.1 ng/ml) and 9.2% (means = 49.3 ng/ml). Of the 215 patients evaluated, 21 had myocardial infarction by the criteria in the study. The diagnostic sensitivity, specificity, and accuracy were 100.0%, 92.8%, and 93.5% respectively. These values increased to 100.0%, 96.9%, and 97.2% when only coronary care unit patients were considered. The CK-MB RIA was found to be a reliable replacement for electrophoresis, but it was nonspecific in some patients.