In vitro and in vivo antibacterial activities of BO-2727, a new carbapenem.

BO-2727, a new injectable carbapenem, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of biapenem, meropenem, imipenem, cefpirome, and ceftazidime. BO-2727 had activity comparable to that of imipenem against methicillin-susceptible staphylococci and streptococci, with MICs at which 90% of strains tested (MIC90s) are inhibited being equal to 0.5 microgram/ml or less. Against methicillin-resistant staphylococci, BO-2727 was the most active among the antibiotics tested, with MIC90s ranging from 4 to 8 micrograms/ml. BO-2727 was highly active against members of the family Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis, with MIC90s ranging from 0.006 to 2 micrograms/ml. BO-2727 was also highly active against Pseudomonas aeruginosa (imipenem-susceptible strains), for which the MIC90 was 2 micrograms/ml, which was lower than those of imipenem, cefpirome, and ceftazidime and comparable to those of biapenem and meropenem. Differences in activity between BO-2727 and the other carbapenems against imipenem-resistant P. aeruginosa were particularly striking (MIC90, 8 micrograms/ml). Furthermore, BO-2727 displayed a high degree of activity against many of the ceftazidime-, ciprofloxacin-, and/or gentamicin-resistant isolates of P. aeruginosa. The in vivo efficacy of BO-2727 against experimental septicemia caused by gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and imipenem-resistant P. aeruginosa, reflected its potent in vitro activity and high levels in plasma.     

Argentinean collaborative multicenter study on the in vitro comparative activity of piperacillin-tazobactam against selected bacterial isolates recovered from hospitalized patients

The in vitro activity of piperacillin-tazobactam and several antibacterial drugs commonly used in Argentinean hospitals for the treatment of severe infections was determined against selected but consecutively isolated strains from clinical specimens recovered from hospitalized patients at 17 different hospitals from 9 Argentinean cities from different geographic areas during the period November 2001-March 2002. Out of 418 Enterobacteriaceae included in the Study 84% were susceptible to piperacillin-tazobactam. ESBLs putative producers were isolated at an extremely high rate since among those isolates obtained from patients with hospital acquired infections 56% of Klebsiella pneumoniae, 32% of Proteus mirabilis and 25% Escherichia coli were phenotypically considered as ESBLs producers Notably P.mirabilis is not considered by for screening for ESBL producers. ESBLs producers were 100% susceptible to imipenem and 70% were susceptible to piperacillin-tazobactam whereas more than 50% were resistant to levofloxacin. The isolates considered as amp C beta lactamase putative producers showed 99% susceptibility to carbapenems while 26.7% were resistant to piperacillin-tazobactam and 38.4% to levofloxacin. Noteworthy only 4% of the Enterobacteriaceae isolates were resistant to amikacin. Piperacillin-tazobactam was the most active agent against Pseudomonas aeruginosa isolates (MIC(90): 128 microg/ml; 78% susceptibility) but showed poor activity against Acinetobacter spp (MIC(90):>256 microg/ml; 21.7% susceptibility). Only 41.7% Acinetobacter spp isolates were susceptible to ampicillin-sulbactam. Piperacillin-tazobactam inhibited 100% of Haemophilus influenzae isolates (MIC(90) < 0.25 microg/ml) but only 16.6% of them were ampicillin resistant. The activity of piperacillin-tazobactam against oxacillin susceptible Staphylococcus aureus or coagulase negative staphylococci was excellent (MIC(90) 2 microg/ml; 100% susceptibility). Out of 150 enterococci 12 isolates (8%) were identified as E.faecium and only three isolates (2%), 2 E.faecium and 1 E.faecalis were vancomycin resistant. All the enterococci isolates were susceptible to linezolid. Piperacillin-tazobactam showed excellent activity (MIC(90) 2 microg/ml; 92% susceptibility). Regarding pneumococci all the isolates showed MICs of 16 microg/ml for piperacillin-tazobactam. Among 34 viridans group streptococci only 67% were penicillin susceptible and 85.2% ceftriaxone susceptible whereas piperacillin-tazobactam was very active (MIC(90) 4 microg/ml).Piperacillin-tazobactam is therefore a very interesting antibacterial drug to be used, preferably in combination (IE: amikacin-vancomycin) for the empiric treatment of severe infections occurring in hospitalized patients in Argentina. Caution must be taken for infections due to ESBL producers considering that the inoculum effect MICs can affect MIC values.     

In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90) of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 microg/ml, respectively, whereas they were 0.5 and 0.5 microg/ml, respectively, for methicillin-susceptible S. aureus. The MIC(50) and MIC(90) were 1 and 4 microg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 microg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 microg/ml, respectively. The MIC(50) and MIC(90) of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 microg/ml, respectively, but they were 4 and 8 microg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC(90)s of RWJ-54428 were 0.03, 0.25, and 0.5 microg/ml, respectively, with the highest MIC for a pneumococcus being 1 microg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 microg/ml. MICs for Lancefield group A, B, C, and G streptococci were < or =0.008 microg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.     

In vitro activities of RWJ-54428 (MC-02,479) against multiresistant gram-positive bacteria

RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC at which 90% of isolates are inhibited (MIC(90)) of 2 microg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times more active than imipenem, with an MIC(90) of 2 microg/ml. RWJ-54428 was active against S. aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus isolates with reduced susceptibility to glycopeptides (RWJ-54428 MIC range, < or = 0.0625 to 1 microg/ml). RWJ-54428 was eight times more potent than methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC(90), 0.5 microg/ml). For ampicillin-susceptible Enterococcus faecalis (including vancomycin-resistant and high-level aminoglycoside-resistant strains), RWJ-54428 had an MIC(90) of 0.125 microg/ml. RWJ-54428 was also active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs ranged between < or = 0.0625 and 1 microg/ml for ampicillin-susceptible strains and 0.125 and 8 microg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains of Streptococcus pneumoniae (MIC(90)s, 0.25, 0.125, and < or = 0.0625 microg/ml, respectively). RWJ-54428 was only marginally active against most gram-negative bacteria; however, significant activity was observed against Haemophilus influenzae and Moraxella catarrhalis (MIC(90)s, 0.25 and 0.5 microg/ml, respectively). This survey of the susceptibilities of more than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428 indicates that this new cephalosporin has the potential to be useful in the treatment of infections due to gram-positive bacteria, including strains resistant to currently available antimicrobials.     

In Vitro Antibacterial Activity of LJC 11,036, an Active Metabolite of L-084, a New Oral Carbapenem Antibiotic with Potent Antipneumococcal Activity

LJC 11,036 is the active metabolite of L-084, a novel oral carbapenem that exhibits potent broad-spectrum activity. Antibacterial activities of LJC 11,036 against clinical isolates from respiratory infections, such as Streptococcus pneumoniae (n = 52), Streptococcus pyogenes (n = 19), Haemophilus influenzae (n = 50), Klebsiella pneumoniae (n = 53), and Moraxella catarrhalis (n = 53), and from urinary-tract infections, such as Escherichia coli (n = 53) (MICs at which 90% of the isolates were inhibited [MIC(90)s], 0.1, 相似文献   

In vitro antibacterial activities of DQ-113, a potent quinolone, against clinical isolates

The antibacterial activity of DQ-113, formerly D61-1113, was compared with those of antibacterial agents currently available. MICs at which 90% of the isolates tested are inhibited (MIC90s) of DQ-113 against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and methicillin-susceptible and -resistant coagulase-negative staphylococci were 0.03, 0.008, 0.03, and 0.06 microg/ml, respectively. Moreover, DQ-113 showed the most potent activity against ofloxacin-resistant and methicillin-resistant S. aureus, with a MIC90 of 0.25microg/ml. DQ-113 inhibited the growth of all strains of Streptococcus pneumoniae, including penicillin-resistant strains, and Streptococcus pyogenes at 0.06 microg/ml, and DQ-113 was more active than the other quinolones tested against Enterococcus faecalis and Enterococcus faecium with MIC90s of 0.25 and 2 microg/ml, respectively. Against vancomycin-resistant enterococci, DQ-113 showed the highest activity among the reference compounds, with a MIC range from 0.25 to 2 microg/ml. DQ-113 also showed a potent activity against Haemophilus influenzae, including ampicillin-resistant strains (MIC90, 0.015 microg/ml), and Moraxella catarrhalis (MIC90, 0.03 microg/ml). The activity of DQ-113 was roughly comparable to that of levofloxacin against all species of ENTEROBACTERIACEAE: The MICs of DQ-113 against ofloxacin-susceptible Pseudomonas aeruginosa ranged from 0.25 to 2 microg/ml, which were four times higher than those of ciprofloxacin. From these results, DQ-113 showed the most potent activity against gram-positive pathogens among antibacterial agents tested.     

Role of penicillin-binding protein 5 in expression of ampicillin resistance and peptidoglycan structure in Enterococcus faecium

The contribution of penicillin-binding protein 5 (PBP 5) to intrinsic and acquired beta-lactam resistance was investigated by constructing isogenic strains of Enterococcus faecium producing different PBP 5. The pbp5 genes from three E. faecium clinical isolates (BM4107, D344, and H80721) were cloned into the shuttle vector pAT392 and introduced into E. faecium D344S, a spontaneous derivative of E. faecium D344 highly susceptible to ampicillin due to deletion of pbp5 (MIC, 0.03 microg/ml). Immunodetection of PBP5 indicated that cloning of the pbp5 genes into pAT392 resulted in moderate overproduction of PBP 5 in comparison to wild-type strains. This difference may be attributed to a difference in gene copy number. Expression of the pbp5 genes from BM4107 (MIC, 2 microg/ml), D344 (MIC, 24 microg/ml), and H80721 (MIC, 512 microg/ml) in D344S conferred relatively low levels of resistance to ampicillin (MICs, 6, 12, and 20 microg/ml, respectively). A methionine-to-alanine substitution was introduced at position 485 of the BM4107 PBP 5 by site-directed mutagenesis. In contrast to previous hypotheses based on comparison of nonisogenic strains, this substitution resulted in only a 2.5-fold increase in the ampicillin MIC. The reversed-phase high-performance liquid chromatography muropeptide profiles of D344 and D344S were similar, indicating that deletion of pbp5 was not associated with a detectable defect in cell wall synthesis. These results indicate that pbp5 is a nonessential gene responsible for intrinsic resistance to moderate levels of ampicillin and by itself cannot confer high-level resistance.     

Worldwide assessment of dalbavancin activity and spectrum against over 6,000 clinical isolates

Continuing emergence of new antimicrobial resistance mechanisms and the increased frequency of existing resistances, requires the development of alternative antimicrobial agents. Dalbavancin is an amide glycopeptide derivative with a markedly extended serum elimination half-life. Dalbavancin and selected comparators were tested against 6,339 recent clinical isolates (2002) from the Americas and Europe using reference susceptibility testing methods. The general characteristics of this Gram-positive organism collection were: oxacillin (OXA)-resistant Staphylococcus aureus (ORSA) at 39% of strains; vancomycin-resistant enterococci (VRE) at 10%; and penicillin-nonsusceptible pneumococci at 28%. The overall distribution of dalbavancin minimum inhibitory concentration (MIC) values ranged from < or = 0.015 to > 32 microg/ml, but > 99% of MIC results were at < or =1 microg/ml. S. aureus and coagulase-negative staphylococci were extremely susceptible to dalbavancin (MIC90, 0.06 microg/ml) despite resistance patterns to other agents. Dalbavancin was the most potent compound (by weight) against vancomycin-susceptible Enterococcus faecalis and E. faecium (MIC90, 0.06 and 0.12 microg/ml, respectively); however, VRE strains showed decreased dalbavancin susceptibility (MIC50, 4 or 8 microg/ml). All streptococcal isolates were inhibited at < or =0.25 microg/ml of dalbavancin. This reported dalbavancin activity indicates that the new glycopeptide has significant activity, superior to available agents in the class, and a potency that was uniform across geographically sampled organisms. Some VRE were inhibited by very low dalbavancin concentrations (< or = 1 microg/ml; Van B phenotypes). Further clinical development seems warranted for this once-weekly administered agent.     

In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia

Ertapenem (MK-0826, L-749,345) is a 1-beta-methyl carbapenem with a long serum half-life. Its in vitro activity was determined by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone, and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the family Enterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC(90)s) of < or =1 microg/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci, and anaerobes, but its MIC(90)s for these groups remained < or =0.5 microg/ml. Acinetobacter spp. and Pseudomonas aeruginosa were also much less susceptible to ertapenem than imipenem, and most Enterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of > or =16 microg/ml, was seen in only 3 of 1,611 strains of the family Enterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1 Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of < or =2 microg/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were as high as 2 microg/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 microg/ml and one required an MIC of 4 microg/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 microg/ml. These streptococci also had diminished susceptibilities to other beta-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results in good agreement with those of the broth microdilution method for ertapenem.     

In vitro activity of linezolid against key gram-positive organisms isolated in the united states: results of the LEADER 2004 surveillance program

Since the approval of linezolid in 2000, sporadic reports of resistance have been given and a greater understanding of the underlying mechanisms of resistance has been gained. However, since these developments, an updated status of the in vitro activity of linezolid against gram-positive organisms from the United States has not been reported. The LEADER 2004 surveillance initiative was undertaken to obtain current and representative data on the activity of linezolid against key species, including isolates with significant resistance phenotypes. Organisms were isolated during 2004 and included 2,872 Staphylococcus aureus, 496 coagulase-negative staphylococcus (CNS), 428 Enterococcus faecalis, 196 Enterococcus faecium, and 422 Streptococcus pneumoniae isolates. All S. aureus isolates (54.2% oxacillin resistant) were susceptible to linezolid (MIC90 = 2 microg/ml); MIC distributions were consistent, regardless of oxacillin or multidrug resistance status. For CNS, one nonsusceptible isolate was encountered (Staphylococcus epidermidis; MIC = 32 microg/ml), but overall, the MIC(90) (1 microg/ml) was lower than that obtained with S. aureus. For E. faecalis and E. faecium, 99.5% and 96.4% of isolates, respectively, were linezolid susceptible. Both species had an MIC90 of 2 microg/ml, and MIC distributions did not vary with the vancomycin susceptibility status of the populations analyzed. Linezolid nonsusceptibility was not encountered among the S. pneumoniae isolates. These findings indicate that linezolid nonsusceptibility has remained rare among staphylococci and uncommon and sporadic among enterococci. Nonetheless, careful and ongoing monitoring of the in vitro effectiveness of linezolid will be needed so that any changes to the current status may be detected as soon as possible.     

Therapeutic efficacy of BO-3482, a novel dithiocarbamate carbapenem, in mice infected with methicillin-resistant Staphylococcus aureus.

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15.9 mg/kg for imipenem. BO-3482 was also as effective as vancomycin in an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0.001). These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal than vancomycin in local-tissue infections. The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.     

Antimicrobial susceptibilities of clinical Desulfovibrio isolates

The antimicrobial susceptibilities of 16 clinical isolates of Desulfovibrio spp. were determined. All or most isolates were susceptible to imipenem (MIC(90) [MIC at which 90% of the isolates tested were inhibited], 0.5 microg/ml), metronidazole (MIC(90), 0.25 microg/ml), clindamycin (MIC(90), 4 microg/ml), and chloramphenicol (MIC(90), 16 microg/ml) but were resistant or intermediate to penicillin G (MIC(90), 64 microg/ml), piperacillin (MIC(90), 256 microg/ml), piperacillin-tazobactam (MIC(90), 256 microg/ml), cefoxitin (MIC(90), >256 microg/ml), and cefotetan (MIC(90), 64 microg/ml). Among isolates with decreased susceptibility to beta-lactams (n = 15), only six were beta-lactamase positive and susceptible to amoxicillin-clavulanate and ticarcillin-clavulanate.     

Inhibitory and bactericidal effects of telithromycin (HMR 3647, RU 56647) and five comparative antibiotics, used singly and in combination, against vancomycin-resistant and vancomycin-susceptible enterococci

The inhibitory and bactericidal effects of telithromycin (HMR 3647, RU 66647) were compared with those of gentamicin, ampicillin, erythromycin, azithromycin and vancomycin against 74 strains of enterococci (34 Enterococcus faecalis and 40 Enterococcus faecium) by agar dilution, broth dilution, time kill assays and postantibiotic effect (PAE). The telithromycin MIC(90) for vancomycin-sensitive (VSE) E. faecalis strains tested using the agar dilution method was 8 microg/ml. For a different group of VSE E. faecalis strains tested using the broth dilution method it was 0.06 microg/ml The telithromycin MIC(90)s for vancomycin-resistant (VRE) and VSE E. faecium strains, determined using the agar dilution method, were 4 and 8 microg/ml, respectively, while for a different set of VRE and VSE E. faecium strains tested using the broth macrodilution method, they were 32 and 16 microg/ml, respectively. Telithromycin MBC(90)s for E. faecalis were 4-6 tubes higher and for E. faecium 3-5 tubes higher, respectively, than the MIC(90)s. In time kill assays, telithromycin had bactericidal activity against only 1 of 7 E. faecium strains; for all other E. faecium and E. faecalis strains, only inhibitory activity was demonstrated. Neither synergy nor drug interference was observed when telithromycin was used in combination with ampicillin, vancomycin or gentamicin. At 10 times the MIC, the PAE of telithromycin against E. faecalis was 2.8 h, while for E. faecium it was 1.6 h. Telithromycin should be evaluated for therapy of enterococcal infections, including those caused by VRE organisms. However, because of the strain-to-strain variability in susceptibility to telithromycin, MIC determinations are important, especially for erythromycin-resistant strains.     

Oritavancin activity against vancomycin-susceptible and vancomycin-resistant Enterococci with molecularly characterized glycopeptide resistance genes recovered from bacteremic patients, 2009-2010

Oritavancin exhibited potent activity against vancomycin-susceptible (MIC(50) and MIC(90), 0.015/0.03 μg/ml) and vanB-carrying E. faecalis isolates (MIC(50) and MIC(90), 0.015 and 0.015 μg/ml). Higher (16- to 32-fold) MIC(50)s and MIC(90)s for vanA-harboring E. faecalis were noted (MIC(50) and MIC(90), 0.25 and 0.5 μg/ml), although oritavancin inhibited all strains at ≤ 0.5 μg/ml. Vancomycin-susceptible and vanB-carrying E. faecium strains (MIC(50) and MIC(90), ≤ 0.008 and ≤ 0.008 μg/ml for both) were very susceptible to oritavancin, as were VanA-producing isolates (MIC(50) and MIC(90), 0.03 and 0.06 μg/ml). Oritavancin exhibited good in vitro potency against this collection of organisms, including vancomycin-resistant enterococci.     

In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem

SM-216601 is a novel parenteral 1beta-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC(90)) was 2 microg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC(90) = 8 microg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC(90)s of less than 0.5 microg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.     

In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms.

The in vitro activity of RP59500, a streptogramin antibiotic, against 146 clinical isolates of vancomycin-resistant gram-positive bacteria was examined. Five strains of the species Enterococcus casseliflavus and Enterococcus gallinarum, for which the MIC of vancomycin was 8 micrograms/ml, were also studied. Twenty-eight vancomycin-susceptible strains of Enterococcus faecalis and Enterococcus faecium were included for comparison. The drug was highly active against Leuconostoc spp., Lactobacillus spp., and Pediococcus spp. (MICs, < or = 2 micrograms/ml). RP59500 was more active against vancomycin-susceptible strains of E. faecium than E. faecalis (MICs for 90% of the strains [MIC90s], 1.0 versus 32 micrograms/ml). Vancomycin-resistant strains of E. faecalis were as resistant to RP59500 as vancomycin-susceptible strains (MIC90, 32 micrograms/ml), but some vancomycin-resistant E. faecium strains were relatively more resistant to the new agent (MIC90, 16; MIC range, 0.5 to 32 micrograms/ml) than were vancomycin-susceptible organisms of this species.     

Influence of erythromycin resistance, inoculum growth phase, and incubation time on assessment of the bactericidal activity of RP 59500 (quinupristin-dalfopristin) against vancomycin-resistant Enterococcus faecium.

RP 59500, a mixture of two semisynthetic streptogramin antibiotics (quinupristin and dalfopristin), is one of a few investigational agents currently in clinical trials with inhibitory activity against multiple-drug-resistant strains of Enterococcus faecium. We evaluated the bactericidal activity of this antimicrobial against 30 recent clinical isolates of vancomycin-resistant E. faecium, including 23 erythromycin-resistant (MIC, >256 microg/ml) and 7 erythromycin-intermediate (MIC, 2 to 4 microg/ml) strains. All isolates were inhibited by RP 59500 at 0.25 to 1.0 microg/ml. The bactericidal activity of RP 59500 was markedly influenced by the erythromycin susceptibility of the strains and by several technical factors, such as inoculum growth phase and time of incubation of counting plates. As determined by time-kill methods, RP 59500 at a concentration of 2 or 8 microg/ml failed to kill erythromycin-resistant organisms under any conditions. Bactericidal activity was observed against all seven erythromycin-intermediate isolates when log-phase inocula were used and the cells were counted after 48 h of incubation (mean reductions in viable bacteria for RP 59500 at concentrations of 2 and 8 microg/ml, 3.45 and 3.50 log10 CFU/ml, respectively), but killing was diminished when the plates were examined at 72 h (mean killing, 3.06 and 2.95 log10, CFU/ml, respectively). No bactericidal activity was observed when stationary-phase cultures were used. On the basis of these data, we expect that bactericidal activity of RP 59500 against the multiple-drug-resistant E. faecium strains currently encountered would be distinctly uncommon.     

Comparison of in vitro activities of ABT-773 and telithromycin against macrolide-susceptible and -resistant streptococci and staphylococci

The activity of a new ketolide, ABT-773, was compared to the activity of the ketolide telithromycin (HMR-3647) against over 600 gram-positive clinical isolates, including 356 Streptococcus pneumoniae, 167 Staphylococcus aureus, and 136 Streptococcus pyogenes isolates. Macrolide-susceptible isolates as well as macrolide-resistant isolates with ribosomal methylase (Erm), macrolide efflux (Mef), and ribosomal mutations were tested using the NCCLS reference broth microdilution method. Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.002 to 0.03 microg/ml for ABT-773 and 0.008 to 0.06 microg/ml for telithromycin. ABT-773 had increased activities against macrolide-resistant S. pneumoniae (Erm MIC90, 0.015 microg/ml; Mef MIC90, 0.12 microg/ml) compared to those of telithromycin (Erm MIC90, 0.12 microg/ml; Mef MIC90, 1 microg/ml). Both compounds were active against strains with rRNA or ribosomal protein mutations (MIC90, 0.12 microg/ml). ABT-773 was also more active against macrolide-resistant S. pyogenes (ABT-773 Erm MIC90, 0.5 microg/ml; ABT-773 Mef MIC90, 0.12 microg/ml; telithromycin Erm MIC90, >8 microg/ml; telithromycin Mef MIC90, 1.0 microg/ml). Both compounds lacked activity against constitutive macrolide-resistant Staphylococcus aureus but had good activities against inducibly resistant Staphylococcus aureus (ABT-773 MIC90, 0.06 microg/ml; telithromycin MIC90, 0.5 microg/ml). ABT-773 has superior activity against macrolide-resistant streptococci compared to that of telithromycin.     

Comparative in vitro activities of carbapenem L-749,345 and other antimicrobials against multiresistant gram-negative clinical pathogens.

Carbapenems L-749,345 and imipenem had the lowest MICs at which 90% of isolates were inhibited (0.5 microg/ml) of 14 antimicrobial agents tested against 76 multiresistant gram-negative clinical isolates with TEM- or SHV-type extended-spectrum beta-lactamases and chromosomal or plasmid-determined AmpC beta-lactamases, but the MIC of L-749,345 for one isolate of Klebsiella pneumoniae was 16 microg/ml.     

Comparative activity of cefoxitin, ampicillin/sulbactam, and imipenem against clinical isolates of Escherichia coli and Klebsiella pneumoniae

The in vitro activities of cefoxitin, ampicillin/sulbactam, and imipenem were determined by the standard twofold agar dilution method against 62 strains of Escherichia coli and 40 strains of Klebsiella pneumoniae isolated from patients in intensive care units. Judging from the concentrations required to inhibit at least 90% of the test isolates, imipenem (MIC90 less than or equal to 0.125 micrograms/ml) was markedly more active than cefoxitin (MIC90 = 4 micrograms/ml) and ampicillin/sulbactam (MIC90 = 32 micrograms/ml) against both bacterial genera. Cefoxitin, therefore, was more active than ampicillin/sulbactam against these organisms. Breakpoints specified in the prescribing information are less than or equal to 4 micrograms/ml for imipenem, less than or equal to 16 micrograms/ml for cefoxitin, and less than or equal to 8 micrograms/ml for ampicillin/sulbactam. At these breakpoints all organisms were susceptible to imipenem and cefoxitin, while 73% of E coli and 78% of K pneumoniae were susceptible to ampicillin/sulbactam. At recommended susceptible MIC breakpoints of the National Committee for Clinical Laboratory Standards (less than or equal to 4 micrograms/ml for imipenem, less than or equal to 8 micrograms/ml for cefoxitin, and less than or equal to 4 micrograms/ml for ampicillin/sulbactam) all the isolates tested were susceptible to imipenem, while 98% and 73% of the E coli isolates were susceptible to cefoxitin and ampicillin/sulbactam, respectively, and 100% and 78% of the K pneumoniae isolates were susceptible to cefoxitin and ampicillin/sulbactam, respectively. Approximately 14% of E coli and 17% of K pneumoniae isolates were resistant to ampicillin/sulbactam (MIC greater than or equal to 32/16 micrograms/ml).