Comparison of the in vitro activity of and pathogen responses to sparfloxacin with those of other agents in the treatment of respiratory tract, urinary tract, and skin and skin-structure infections.

The in vitro activity of and pathogen responses to sparfloxacin were compared with those of standard therapies for the treatment of patients with community-acquired pneumonia, complicated skin or skin-structure infections, urinary tract infections, acute bacterial exacerbations of chronic bronchitis, and acute maxillary sinusitis in 7 multicenter controlled trials in North America. Sparfloxacin was administered orally as a 400-mg loading dose followed by 200 mg once daily for up to 10 days. The bacteriologic efficacy of sparfloxacin (84% to 95%) was comparable to that of comparator drugs (77% to 100%). Sparfloxacin was generally 2 to 8 times more active (minimum inhibitory concentration for 90% of strains tested [MIC90]: 0.03 to 0.5 microg/mL) than comparators against common pathogens isolated in community-acquired infections, especially Streptococcus pneumoniae, including penicillin-resistant strains; Moraxella catarrhalis; Haemophilus influenzae; Streptococcus pyogenes; and Staphylococcus aureus. Sparfloxacin was also effective against Chlamydia and Mycoplasma species. The emergence of resistance was uncommon during sparfloxacin therapy (0.3% of 1100 cases). Higher area under the plasma concentration-time curve/MIC and maximum plasma concentration/MIC ratios for sparfloxacin were associated with clinical and bacteriologic efficacy, whereas lower ratios were associated with clinical and bacteriologic failure. The clinical efficacy of sparfloxacin (80% to 95%) was comparable to that obtained with the comparator drugs (71% to 92%). In addition, sparfloxacin was well tolerated and had an overall frequency of related adverse events similar to that of the comparators. There was a higher frequency of photosensitivity reactions but a lower level of digestive adverse events with sparfloxacin compared with comparators. Sparfloxacin is a suitable therapeutic alternative for the empiric treatment of respiratory tract infections owing to its favorable pharmacokinetic profile and activity against typical and atypical respiratory tract pathogens, even in geographic areas with a high incidence of penicillin resistance.

Practical approach to the identification of clinically relevant Enterococcus species.

Enterococci have become important nosocomial pathogens, with Enterococcus faecalis and then Enterococcus faecium predominating. Because of the emergence of glycopeptide (vancomycin and teicoplanin) resistance in enterococci, laboratories have been required to screen for resistant strains and to identify them to the species level. This has resulted in the need for accurate identification of species less commonly associated with clinical infections, such as Enterococcus casseliflavus and Enterococcus gallinarum, which are inherently resistant to the glycopeptides. Studies evaluating commonly used commercial identification systems, have found error rates for enterococcal species identification of 2-21% for E. faecalis, 5-9% for E. faecium, and 14-79% for other species. Reporting errors may have adverse effects on the management of clinical infections, as well as in the control of multidrug-resistant strain outbreaks. The purpose of this document is to present a simplified approach to the identification of Enterococcus species that uses a combination of rapid, readily available, and inexpensive tests.

Evaluation of in vitro activity of quinupristin/dalfopristin and comparator antimicrobial agents against worldwide clinical trial and other laboratory isolates.

This report summarizes the activities of quinupristin/dalfopristin (Q/D) and appropriate comparator antibiotics, including ciprofloxacin, erythromycin, gentamicin, rifampin, teicoplanin, and vancomycin, against selected gram-positive pathogens, including Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus agalactiae, and Streptococcus pyogenes. The study pathogens were obtained from 2 sources: (1) clinical isolates taken from patients participating in Q/D worldwide Phase III comparative and noncomparative (emergency-use program) clinical trials; and (2) other isolates collected from the laboratories of 45 geographically distinct medical centers around the world. Q/D was highly active, with minimum inhibitory concentrations (MICs) < or = 1.0 microg/mL against most isolates, including those known to be resistant to methicillin, vancomycin, or erythromycin. Q/D was active (MICs < or = 1 microg/mL) against 95% of the vancomycin-resistant E. faecium strains, for example, whereas ciprofloxacin was active against 6%. Q/D was equally active against methicillin-susceptible or -resistant S. aureus strains (MIC90=1 microg/mL), as was vancomycin (MIC90=2 microg/mL), whereas ciprofloxacin was much less active against methicillin-resistant strains than against methicillin-susceptible strains (MIC90=32 vs 1 microg/mL). Given its spectrum of activity, Q/D may provide a viable option for the treatment of severe respiratory and skin and skin-structure infections caused by gram-positive bacteria, especially when strains with known or suspected resistance to other commonly used antibiotics are present.

Characterization of vancomycin-resistant Enterococcus faecium isolates from the United States and their susceptibility in vitro to dalfopristin-quinupristin.

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 microg/ml, respectively) and to the other approved agents tested, with the exception of chloramphenicol (MIC90, 8 microg/ml) and novobiocin (MIC90, 1 microg/ml). Considering all of the isolates submitted, dalfopristin-quinupristin inhibited 86.4% of them at concentrations of < or = 1 microg/ml and 95.1% of them at < or = 2 microg/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 < or = 1 microg/ml and 98.9% were inhibited at concentrations of < or = 2 microg/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.

A review of in-vitro antibacterial activity of quinupristin/dalfopristin against methicillin-susceptible and -resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) presently represents approximately 30% of clinical isolates of S. aureus in the USA. Many strains are additionally resistant to erythromycin, 15- and 16-membered macrolides (e.g. azithromycin, spiramycin), clindamycin, aminoglycosides and/or quinolones. A review of the literature shows that quinupristin/dalfopristin, a semisynthetic derivative of pristinamycin, exhibits good in-vitro activity against methicillin-sensitive S. aureus and MRSA (mean MIC90 0.25-1.0 and 0.5-2.0 mg/L, respectively). Its in-vitro bacteriostatic activity is also unaffected by resistance phenotypes for erythromycin, ciprofloxacin, rifampicin or gentamicin. Among erythromycin-resistant MRSA strains, those with constitutive (macrolide and lincosamide) resistance are only 2-fold less sensitive as strains with inducible (14- and 15-membered macrolide only) resistance (MICs 0.5-1.0 and 0.25-1.0 mg/L, respectively). Quinupristin/dalfopristin is at least as active as vancomycin and more active than ciprofloxacin and erythromycin against MRSA. It generally has a more rapid bactericidal action than vancomycin and oxacillin against many strains of MRSA. The bactericidal activity of quinupristin/dalfopristin may be affected by macrolide resistance phenotype: S. aureus strains susceptible or inducibly resistant to macrolides are killed within 6 h, whereas a number of strains constitutively resistant to macrolides remain viable after 12 h. The clinical significance of this laboratory phenomenon requires investigation, possibly in additional animal models of infection.

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.

Hawkinsinuria in two families.

Hawkinsinuria, a disorder of tyrosine metabolism has been documented in two families in the United States, in one of which there was clear evidence of autosomal dominant inheritance. Metabolic acidosis and failure to thrive appear to be confined to infancy. Tyrosyl metabolites and 5-oxoproline are also found only in infancy, while 4-hydroxycyclohexylacetic acid was present only with time. The disease may be detected by organic acid analysis or by staining an electropherogram for sulfur containing compounds.

Comparison of electronic and viability counting methods for determination of postantibiotic effect of oxacillin on Staphylococcus aureus.

The postantibiotic effect of oxacillin on Staphylococcus aureus ATCC 6538P was determined under different test conditions by reference (viability counting) and semiautomated (electronic counting) methods. Differences in durations of the postantibiotic effect obtained with the two counting methods were not statistically significant. The semiautomated method provided a more rapid and convenient alternative to viability counting.

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.

Ultrasonographic prenatal diagnosis and fetal pathology of Langer mesomelic dwarfism.

In a family at risk for Langer mesomelic dwarfism, we document the onset of disproportionate growth in the second trimester by sonographic biometry. Midtrimester pathologic correlation of this condition demonstrates primary changes in the growthplate in the regions of proliferating cartilage and hypertrophic and degenerative chondrocytes.