Vancomycin-gentamicin synergism revisited: effect of gentamicin susceptibility of methicillin-resistant Staphylococcus aureus.

Vancomycin monotherapy of deep-seated staphylococcal infection may be associated with poor bacteriological response. We evaluated 24 unique patient isolates of methicillin-resistant Staphylococcus aureus (MRSA) for vancomycin-gentamicin synergism by determining time-kill curves for vancomycin at 10 micrograms/ml and gentamicin at 1 microgram/ml. Nine MRSA strains showed high-level gentamicin resistance (HLGR) (MIC, > 500 micrograms/ml), and 15 did not. Vancomycin-gentamicin demonstrated synergism against none of the HLGR strains. For the non-HLGR strains, gentamicin agar dilution MICs ranged from 0.5 to > 128 micrograms/ml. Vancomycin-gentamicin demonstrated synergism against six of these strains and indifference against nine of them. There was no relationship between the agar dilution MIC of gentamicin and the occurrence of synergism against non-HLGR strains. We conclude that a gentamicin MIC of > 500 micrograms/ml predicts a lack of vancomycin-gentamicin synergism for strains of MRSA. For non-HLGR strains, synergism is not predictable from the gentamicin MIC.     

Comparative in vitro activities of ampicillin, BMY 28142, and imipenem against Mycobacterium avium complex

The in vitro activity of ampicillin, BMY 28142, and imipenem was evaluated against 21 clinical isolates of Mycobacterium avium complex by both a broth and an agar dilution method. The MIC90 by broth dilution for ampicillin, BMY 28142, and imipenem was 16 micrograms/ml, 8 micrograms/ml, and greater than 32 micrograms/ml, respectively. The MIC90 by agar dilution for ampicillin and BMY 28142 was 16 micrograms/ml.     

In vitro activity of LY146032 against gram-positive bacteria

The activity of LY146032 (LY) was evaluated against 269 clinical isolates: 150 Staphylococcus spp. (Staph), 45 enterococci, 51 Clostridium spp., and 23 peptostreptococci. LY was compared to penicillin, metronidazole, imipenem, clindamycin, oxacillin, ciprofloxacin, vancomycin, and ampicillin. LY and oxacillin were tested against Staph by microdilution in cation-supplemented Mueller-Hinton broth (CSMHB), and in unsupplemented Mueller-Hinton broth (MHB). For LY, the MIC 90s in CSMHB were 16-32 dilutions lower. Among the Staph, the MIC 90s for LY, vancomycin, and ciprofloxacin were 4 micrograms/ml, 4 micrograms/ml, and 2 micrograms/ml respectively. The MIC 90s for enterococci by agar dilution were as follows: LY 8 micrograms/ml; ampicillin 4 micrograms/ml; imipenem 4 micrograms/ml; vancomycin 4 micrograms/ml; and ciprofloxacin 2 micrograms/ml. Clindamycin and penicillin were the most effective drugs against peptostreptococci and Clostridia spp., but LY was the most active drug against Clostridium difficile. The bactericidal activity of LY was determined by 24-hr time-kill curves in MHB. These showed a bactericidal effect against enterococci, and a bacteriostatic effect against three of four strains of Staph. Synergy was demonstrated against enterococci and Staph when LY was tested with aztreonam, ceftriaxone, or tobramycin. LY is a promising new agent against gram-positive bacteria, including methicillin resistant strains of staphylococci and enterococci.     

In vitro activity of the trinem sanfetrinem (GV104326) against gram-positive organisms.

The in vitro activity of the trinem sanfetrinem (formerly GV104326) (GV) was compared with that of vancomycin, ampicillin, and/or nafcillin against 287 gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and multiresistant enterococci, by the agar and microbroth dilution methods. GV demonstrated 2 to 16 times more activity than ampicillin and nafcillin against the majority of these organisms. The MIC range of GV was 16 to 64 micrograms/ml for 19 Enterococcus faecium strains that were highly resistant to ampicillin (ampicillin MIC range, 64 to 512 micrograms/ml) and vancomycin resistant and 0.25 to 32 micrograms/ml for resistant Rhodococcus spp. Similar activities (+/-1 dilution) were observed by either the agar or the broth microdilution method. GV demonstrated bactericidal activity against a beta-lactamase-producing Enterococcus faecalis strain and against two methicillin-susceptible Staphylococcus aureus strains in 10(5)-CFU/ml inocula. Synergy between GV and gentamicin was observed against an E. faecalis strain that lacked high-level gentamicin resistance. The activity of GV suggests this compound warrants further study.     

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).     

Effects of combinations of beta-lactams, daptomycin, gentamicin, and glycopeptides against glycopeptide-resistant enterococci.

Activities of combinations of beta-lactams, daptomycin, gentamicin, teicoplanin, and vancomycin against 11 clinical isolates of Enterococcus faecium highly resistant to glycopeptides, three plasmid-cured derivatives, eight E. faecalis and E. faecium transconjugants, and two susceptible recipient strains were tested. A marked synergy between penicillins or imipenem and glycopeptides against the glycopeptide-resistant strains but not against the glycopeptide-susceptible strains was observed by the double-disk agar diffusion assay. The synergy of combinations of amoxicillin, imipenem, penicillin G, or piperacillin with vancomycin or teicoplanin against resistant strains was confirmed by the checkerboard technique. The fractional inhibitory concentration indexes were generally below 0.25, except for one strain of E. faecium resistant to high levels of penicillin G. However, the combinations were not bactericidal as tested by time-killing experiments, and high concentrations (64 micrograms/ml) of amoxicillin, penicillin G, or piperacillin combined with 8 micrograms of vancomycin or teicoplanin per ml tended to be antagonistic. Addition of 4 micrograms of gentamicin per ml to these combinations enhanced their bactericidal effect, but they occasionally remained slightly less effective than beta-lactams associated with gentamicin. The combination of 10 micrograms of daptomycin per ml with gentamicin was bactericidal after 6 h against 11 glycopeptide-resistant strains.     

Antimicrobial susceptibilities of enterococci isolated from hospitalized patients.

One hundred and one isolates of Enterococcus species isolated recently from hospitalized patients were evaluated in vitro for antibiotic susceptibility. Teicoplanin and mideplanin were the most active agents, followed by ramoplanin, vancomycin, ciprofloxacin, ampicillin, and imipenem. High-level resistance to gentamicin (MIC > 500 micrograms/ml) and/or streptomycin (MIC > 2,000 micrograms/ml) was found in 60 isolates. High-level resistance to ampicillin (MIC > or = 16 micrograms/ml) was found in 17 isolates. MBC studies revealed that ramoplanin possesses significant bactericidal activity.     

In vitro activities of aztreonam, imipenem, and amoxycillin-clavulanate against ampicillin-resistant Haemophilus influenzae.

Two hundred and fifty-seven ampicillin-resistant clinical isolates of Haemophilus influenzae were tested by disk diffusion and MIC determination for susceptibility to aztreonam, imipenem, and amoxycillin combined with clavulanate. The modal MICs and MICs for 50 and 90% of isolates of all three antimicrobial agents for the 157 beta-lactamase-positive strains did not differ significantly from figures obtained with 2,201 ampicillin-susceptible H. influenzae by the same methods. Aztreonam and amoxycillin-clavulanate were less active, as reflected by an increase in these parameters, against 38 beta-lactamase-negative isolates requiring greater than or equal to 4 micrograms of ampicillin per ml for inhibition and 62 strains considered to have an intermediate degree of nonenzymic (intrinsic) resistance to ampicillin (zone diameters of less than 20 mm with 2-micrograms ampicillin disks and MICs of 1 or 2 micrograms/ml). There was no detectable difference in imipenem activity against these 100 strains compared with that observed against the ampicillin-susceptible group. Of the 24 strains requiring at least 4 micrograms of imipenem per ml for inhibition, 13 also showed reduced susceptibility to ampicillin (5 beta-lactamase-positive and 8 beta-lactamase-negative isolates). A lack of correlation between reduced susceptibility to imipenem and the other beta-lactams was observed.     

Activities and Time-Kill Studies of Selected Penicillins, β-Lactamase Inhibitor Combinations, and Glycopeptides against Enterococcus faecalis

The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, vancomycin, and teicoplanin were tested against 212 Enterococcus faecalis strains (9 β-lactamase producers) by standard agar dilution MIC testing (10⁴ CFU/spot). The MICs at which 50 and 90% of the isolates were inhibited (MIC₅₀s and MIC₉₀s, respectively) were as follows (μg/ml): piperacillin, 4 and 8; piperacillin-tazobactam, 4 and 8; ticarcillin, 64 and 128; ticarcillin-clavulanate, 64 and 128; ampicillin, 2 and 2; ampicillin-sulbactam, 1 and 2; vancomycin, 1 and 4; and teicoplanin, 0.5 and 1. Agar dilution MIC testing of the nine β-lactamase-positive strains with an inoculum of 10⁶ CFU/spot revealed higher β-lactam MICs (piperacillin, 64 to >256 μg/ml; ticarcillin, 128 to >256 μg/ml; and ampicillin, 16 to 128 μg/ml); however, MICs with the addition of inhibitors were similar to those obtained with the lower inoculum. Time-kill studies of 15 strains showed that piperacillin-tazobactam was bactericidal (99.9% killing) for 14 strains after 24 h at four times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Ampicillin gave 99.9% killing of 14 β-lactamase-negative strains after 24 h at eight times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Killing by ticarcillin-clavulanate was slower than that observed for piperacillin-tazobactam, relative to the MIC. For the one β-lactamase-producing strain tested by time-kill analysis with a higher inoculum, addition of the three inhibitors (including sulbactam) to each of the β-lactams resulted in bactericidal activity at 24 h at two times the MIC. For an enzyme-negative strain, addition of inhibitors did not influence kinetics. Kinetics of vancomycin and teicoplanin were significantly slower than those of the β-lactams, with bactericidal activity against 6 strains after 24 h at eight times the MIC, with 90% killing of 12 and 14 strains, respectively, at four times the MIC. Slower-kill kinetics by both glycopeptides were observed at earlier periods.     

The bactericidal activity of ampicillin, daptomycin, and vancomycin against ampicillin-resistant Enterococcus faecium.

Ampicillin, daptomycin, and vancomycin, alone and in combination with gentamicin, were examined for bactericidal effects on ampicillin-resistant Enterococcus faecium using broth dilution minimum inhibitory concentrations (MICs) and time-kill studies. We tested 12 ampicillin-resistant isolates and demonstrated the following MICs and MBCs, respectively: ampicillin, greater than or equal to 32 micrograms/ml and greater than 256 micrograms/ml; daptomycin, less than or equal to 4 micrograms/ml and less than or equal to 16 micrograms/ml; and vancomycin, less than or equal to 4 micrograms/ml and greater than 64 micrograms/ml. Time-kill studies demonstrated that daptomycin alone had marked activity against the ampicillin-resistant E. faecium and that the addition of gentamicin resulted in synergistic killing. In addition, ampicillin and vancomycin were not bactericidal for the ampicillin-resistant isolates without the addition of gentamicin. The present study supports the consideration of daptomycin alone or in combination with an aminoglycoside as an alternative therapy for ampicillin-resistant enterococci, although additional clinical experience is now necessary.     

Comparison of Inhibitory and Bactericidal Activities and Postantibiotic Effects of LY333328 and Ampicillin Used Singly and in Combination against Vancomycin-Resistant Enterococcus faecium

One hundred ninety-five individual vancomycin-resistant Enterococcus faecium (VRE) isolates from five upstate New York hospitals were studied for antimicrobial susceptibilities to LY333328, quinupristin-dalfopristin, teicoplanin, ampicillin, and gentamicin. LY333328 was the most active antibiotic against VRE. The effect of media and methods on the antibacterial activity of LY333328, its synergy with ampicillin, and the postantibiotic effects (PAE) of LY333328 and ampicillin were evaluated. In microdilution tests, the MIC of LY333328 at which 90% of the isolates were inhibited (MIC₉₀) was 2 μg/ml in Mueller-Hinton II (MH II) broth and 1 μg/ml in brain heart infusion (BHI) broth. In contrast, on MH II agar the MIC₉₀ was 4 μg/ml and on BHI agar it was >16 μg/ml. Bactericidal activity was observed for most strains at concentrations from 8 to ≥133 times the MIC of the tube macrodilution in MH II broth. A bactericidal effect of LY333328 plus ampicillin was demonstrated in time-kill studies, but there was great strain-to-strain variability. By the MH II agar dilution method, bacteristatic synergy (defined as a fractional inhibitory concentration of <0.5) with LY333328 and ampicillin was demonstrated for 61% of the strains tested. Under similar conditions, there was synergy with LY333328 and quinupristin-dalfopristin or gentamicin for 27 and 15% of the strains tested, respectively. The PAE of LY333328 was prolonged (23.0 h at 10 times the MIC). However, 50% normal pooled human serum decreased the PAE to 12.2 h at 10 times the MIC. Test conditions and media had a considerable effect on VRE susceptibilities to LY333328. The prolonged PAE of LY333328, a potent new bactericidal glycopeptide, and its synergy with ampicillin in a large proportion of strains suggest that further evaluation of this drug in pharmacokinetic studies and experimental infections, including those with VRE, is warranted.     

Antipneumococcal activities of gemifloxacin compared to those of nine other agents

The activities of gemifloxacin compared to those of nine other agents was tested against a range of penicillin-susceptible and -resistant pneumococci by agar dilution, microdilution, time-kill, and post-antibiotic effect (PAE) methods. Against 64 penicillin-susceptible, 68 penicillin-intermediate, and 75 penicillin-resistant pneumococci (all quinolone susceptible), agar dilution MIC(50)s (MICs at which 50% of isolates are inhibited)/MIC(90)s (in micrograms per milliliter) were as follows: gemifloxacin, 0.03/0.06; ciprofloxacin, 1.0/4.0; levofloxacin, 1.0/2. 0; sparfloxacin, 0.5/1.0; grepafloxacin, 0.125/0.5; trovafloxacin, 0. 125/0.25; amoxicillin, 0.016/0.06 (penicillin-susceptible isolates), 0.125/1.0 (penicillin-intermediate isolates), and 2.0/4.0 (penicillin-resistant isolates); cefuroxime, 0.03/0.25 (penicillin-susceptible isolates), 0.5/2.0 (penicillin-intermediate isolates), and 8.0/16.0 (penicillin-resistant isolates); azithromycin, 0.125/0.5 (penicillin-susceptible isolates), 0. 125/>128.0 (penicillin-intermediate isolates), and 4.0/>128.0 (penicillin-resistant isolates); and clarithromycin, 0.03/0.06 (penicillin-susceptible isolates), 0.03/32.0 (penicillin-intermediate isolates), and 2.0/>128.0 (penicillin-resistant isolates). Against 28 strains with ciprofloxacin MICs of >/=8 microg/ml, gemifloxacin had the lowest MICs (0.03 to 1.0 microg/ml; MIC(90), 0.5 microg/ml), compared with MICs ranging between 0.25 and >32.0 microg/ml (MIC(90)s of 4.0 to >32.0 microg/ml) for other quinolones. Resistance in these 28 strains was associated with mutations in parC, gyrA, parE, and/or gyrB or efflux, with some strains having multiple resistance mechanisms. For 12 penicillin-susceptible and -resistant pneumococcal strains (2 quinolone resistant), time-kill results showed that levofloxacin at the MIC, gemifloxacin and sparfloxacin at two times the MIC, and ciprofloxacin, grepafloxacin, and trovafloxacin at four times the MIC were bactericidal for all strains after 24 h. Gemifloxacin was uniformly bactericidal after 24 h at 相似文献   

Synergy of daptomycin with oxacillin and other beta-lactams against methicillin-resistant Staphylococcus aureus

We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of > or =128 microg/ml), we looked for synergy between daptomycin and other beta-lactams against 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca2+/liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of > or =256 microg/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 microg/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 microg/ml alone or in combination with oxacillin at a fixed concentration of 32 microg/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 microg of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other beta-lactams. In this approach, daptomycin was incorporated into Ca(2+)-supplemented Mueller-Hinton agar at subinhibitory concentrations, and synergy was screened by comparing test antibiotic Kirby-Bauer disks on agar with and without daptomycin. By this method, daptomycin with ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam showed synergy comparable to or greater than daptomycin with oxacillin. For seven of the eight strains tested, time-kill studies confirmed synergy between daptomycin and ampicillin-sulbactam with ampicillin in the range of 2 to 8 microg/ml. The combination of daptomycin and beta-lactams may be useful for the treatment of MRSA infection, but further studies are needed to elucidate the mechanisms and to determine the in vivo efficacy of the combination.     

Bactericidal activities of chloramphenicol and eleven other antibiotics against Salmonella spp.

The bactericidal activity of chloramphenicol against 27 strains of Salmonella typhi and 33 strains of S. enteritidis was compared with those of 11 other antibiotics. The geometric mean bactericidal concentrations of chloramphenicol against susceptible strains (36.10 and 43.13 micrograms/ml for S. typhi and S. enteritidis, respectively) far exceeded those of the other 11 antibiotics, with cephalothin having the next highest values (2.67 and 8.66 micrograms/ml) and moxalactam (0.09 and 0.28 micrograms/ml), cefotaxime (0.08 and 0.28 micrograms/ml), ceftriaxone (0.07 and 0.16 micrograms/ml), norfloxacin (0.06 and 0.10 micrograms/ml), and aztreonam (0.05 and 0.20 micrograms/ml) having the lowest values. The results for imipenem (0.24 and 0.81 micrograms/ml) and ceftazidime (0.22 and 0.75 micrograms/ml) were lower than those noted for trimethoprim-sulfamethoxazole (1.20 and 5.56 micrograms/ml), cefamandole (0.62 and 3.29 micrograms/ml), and ampicillin (0.55 and 2.78 micrograms/ml). The MBC of chloramphenicol for some isolates decreased with increased incubation times such that the proportion of susceptible isolates killed by chloramphenicol at concentrations within achievable levels in blood increased from 10% after 24 h to 26% after 48 h of incubation. Although the MBC of the other 11 antibiotics for some isolates were also lowered by prolonged incubation, all 24-h values were within achievable levels in blood. The data indicate that chloramphenicol is not uniformly bacteriostatic against S. typhi and S. enteritidis. The in vivo significance of demonstrating delayed killing by chloramphenicol is, however, uncertain.     

Lomefloxacin, a new fluoroquinolone. Studies on in vitro antimicrobial spectrum, potency, and development of resistance

Lomefloxacin (NY-198; SC-47111), a potent new difluoroquinolone, was studied to compare its in vitro activity with that of other antimicrobials against 2194 clinical isolates. Lomefloxacin showed excellent inhibitory and bactericidal activity against strains of Enterobacteriaceae and inhibited greater than 99% of the isolates at a concentration of 4 micrograms/ml or less. Lomefloxacin exhibited good-to-moderate activity against strains of Acinetobacter (MIC90 4 micrograms/ml) and Pseudomonas aeruginosa (MIC90 8 micrograms/ml), but poor activity for Pseudomonas cepacia (MIC90 greater than 16 micrograms/ml). Staphylococcus aureus, and Staphylococcus epidermidis isolates, both oxacillin-susceptible and -resistant strains, were susceptible (MIC90 1 micrograms/ml) to lomefloxacin and the other fluoroquinolones. Strains of Haemophilus influenzae, (MIC90 less than or equal to 0.13 micrograms/ml) Neisseria gonorrhoeae (MIC90 less than or equal to 0.03 micrograms/ml), and Branhamella catarrhalis (MIC90 less than or equal to 0.03 micrograms/ml) were highly susceptible to lomefloxacin. Streptococcal isolates, especially viridans streptococci, were considerably less susceptible to the fluoroquinolones. Overall, lomefloxacin had comparable activity to norfloxacin, fleroxacin, and ofloxacin, and against many facultative anaerobes lomefloxacin was more active than imipenem, cefotaxime, ceftazidime, ticarcillin/clavulanic acid, aztreonam, trimethoprim/sulfamethoxazole and gentamicin. Development of resistance to lomefloxacin by spontaneous mutation was low and comparable to that of other fluoroquinolones. Growth in subinhibitory concentrations resulted in increased resistance to fluoroquinolones for selected test strains.     

Influence of high-level gentamicin resistance and beta-hemolysis on susceptibility of enterococci to the bactericidal activities of ampicillin and vancomycin.

The bactericidal activities of ampicillin and vancomycin against 40 recent isolates of Enterococcus faecalis were examined by kill-kinetic studies at concentrations of 4 x the MIC and 20 micrograms/ml. Greater killing was seen with ampicillin (3.57 +/- 0.87 and 2.50 +/- 1.09 log10 CFU/ml, respectively; mean +/- standard deviation) than with vancomycin (1.23 +/- 0.65 and 1.05 +/- 0.57 log10 CFU/ml, respectively). Highly gentamicin-resistant strains showed a tendency toward reduced susceptibility to killing; beta-hemolytic strains were more susceptible than nonhemolytic strains when exposed to ampicillin at 20 micrograms/ml. Within each group, individual isolates demonstrated great variability in susceptibility to killing by the drugs.     

Susceptibility patterns of enterococci causing infections

Enterococci are among the common organisms associated with hospital-acquired infections. We examined in vitro activities of different antibiotics to 103 enterococcal isolates. Minimal inhibitory concentrations (MICs) of penicillin G, ampicillin, gentamicin, ciprofloxacin, ofloxacin, levofloxacin, grepafloxacin, trovafloxacin and gemifloxacin were determined by broth microdilution testing method. Among the isolates 71 (69%) were identified as E. faecalis and 32 (31%) as E. faecium. While over 75% of E. faecium isolates were resistant to penicillin and ampicillin, approximately 25% of E. faecalis isolates were resistant to penicillin and ampicillin. None of the E. faecalis and E. faecium isolates were resistant to vancomycin. While 17 (52%) of E. faecium isolates exhibited high-level gentamicin resistance (HLGR), high level streptomycin resistance (HLSR) was detected in 24 (74%) of the isolates. In contrast, HLGR and HLSR rates for E. faecalis were 14 (20%) and 22 (31%), respectively. Both HLGR and HLSR were detected with higher frequency in ampicillin resistant isolates. Among fluoroquinolones, gemifloxacin and trovafloxacin were the most potent antibiotics tested. There was no increase in MIC90 values of the fluoroquinolones in ampicillin resistant isolates in comparison with ampicillin susceptible isolates. Our data suggest newer fluoroquinolones would be good alternative agents to use especially for combination drug therapy where enterococci with ampicillin resistance and HLAR are prevalent.     

In vitro activity of LY264826, a new glycopeptide antibiotic, against gram-positive bacteria isolated from patients with cancer.

The in vitro activity of LY264826, a novel glycopeptide antibiotic produced by Amycolatopsis orientalis, was compared with those of vancomycin, teicoplanin, and oxacillin against 311 gram-positive clinical isolates from patients with cancer, LY264826 had lower MICs for 90% of isolates (MIC90) than vancomycin for all species tested. It was active against oxacillin-resistant isolates including Staphylococcus aureus (MIC90, 0.5 micrograms/ml), Staphylococcus haemolyticus (MIC90, 2.0 micrograms/ml), Enterococcus spp. (MIC90, 0.5 micrograms/ml), Bacillus cereus (MIC90, 0.25 micrograms/ml), and Corynebacterium jeikeium (MIC90, 0.12 micrograms/ml). For S. aureus, including oxacillin-resistant isolates, the MICs of LY264826 were similar to those of teicoplanin. For coagulase-negative staphylococci, however, LY264826 had MICs that were 4- to 32-fold lower than those of teicoplanin. Against most streptococcal species the activities of LY264826 and teicoplanin were similar. Bactericidal activity against Staphylococcus spp. and most Streptococcus pyogenes isolates was less than or equal to 1 dilution of the MIC. One isolate of S. pyogenes and all Enterococcus faecalis strains tested were tolerant of LY264826, with MBCs greater than or equal to 32-fold greater than the MICs. The addition of 50% human serum resulted in a significant increase in activity only against Staphylococcus epidermidis. Variations in pH from 6.4 to 8.4 and in inoculum from 10(3) to 10(7) CFU/ml did not significantly affect the activity of LY264826.     

In vitro interactions between different beta-lactam antibiotics and fosfomycin against bloodstream isolates of enterococci.

The effects of 16 different beta-lactam-fosfomycin combinations against 50 bloodstream enterococci were compared by a disk diffusion technique. Cefotaxime exhibited the best interaction. By checkerboard studies, the cefotaxime-fosfomycin combination provided a synergistic bacteriostatic effect against 45 of the 50 isolates (MIC of cefotaxime at which 90% of the isolates were inhibited, >2,048 micrograms/ml; MIC of fosfomycin at which 90% of the isolates were inhibited, 128 micrograms/ml; mean of fractional inhibitory concentration indexes, 0.195). By killing curves, cefotaxime (at 64 micrograms/ml) combined with fosfomycin (at > or = 64 micrograms/ml) was bactericidal against 6 of 10 strains tested.     

Pseudomonas aeruginosa: in vitro susceptibility to antimicrobial drugs, single and combined, with and without defibrinated human blood

Twelve clinical isolates of Pseudomonas aeruginosa of distinct pyocin type varied in susceptibility to 14 of 17 antimicrobial drugs. The 2 x MIC concentrations of 16 antimicrobial drugs combined with 55% (v/v) of fresh, defibrinated human blood yielded additive effects. Additive effects were noted with blood plus the MIC concentrations of all drugs tested except cefoperazone, gentamicin, and netilmicin. Blood combined with subinhibitory (1/2 MIC) concentrations of aztreonam, ceftazidime, ciprofloxacin, fleroxacin, imipenem, and tobramycin, respectively, yielded additive effects; indifferent effects were observed with the remaining 10 blood plus 1/2 MIC drug combinations. The following drug combinations additively augmented the antibacterial activity of 65% (v/v) of human blood against two selected isolates of P. aeruginosa: tobramycin (1 microgram/ml) plus the MIC or 2 x MIC concentrations of azlocillin, aztreonam, ceftazidime, ciprofloxacin, imipenem, norfloxacin, ofloxacin, piperacillin, and ticarcillin, respectively. Imipenem (8 micrograms/ml) combined with ceftazidime, cefoperazone, and piperacillin, but not aztreonam, enhanced the bactericidal activity of human blood. Rifampin (2 micrograms/ml) plus tobramycin (0.5-1 microgram/ml) combined with 8 or 16 micrograms/ml of azlocillin, aztreonam, cefoperazone, ceftazidime, imipenem, and piperacillin, respectively, enhanced blood-mediated killing of three representative multiple-drug-resistant P. aeruginosa isolates. Additional effective triple-drug combinations with human blood were rifampin + tobramycin + polymyxin B, rifampin + ciprofloxacin + imipenem, and rifampin + amikacin + imipenem. Ciprofloxacin (2 micrograms/ml) was the most potent intraphagocytic bactericidal drug of 16 tested agents (greater than or equal to 2 x MBC concentrations) against P. aeruginosa control strain ATCC 27853.