In vitro activity of ramoplanin against vancomycin-resistant gram-positive organisms.

In vitro activity of ramoplanin, a cyclic lipoglycopeptide, against 92 vancomycin-resistant gram-positive organisms was evaluated. Ramoplanin demonstrated potent activity against many highly vancomycin-resistant organisms including enterococci (MICs for 90% of strains tested of 0.5 micrograms/ml) and against Lactobacillus spp., Leuconostoc spp., and Pediococcus spp., all of which were inhibited at concentrations of < or = 0.25 micrograms/ml. This drug or a derivative compound merits further investigation as a potential therapeutic agent for infections due to vancomycin-resistant enterococci.     

In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci, and enterococci.

The in vitro activity of RP 59500, a semisynthetic pristinamycin, was compared with the activities of vancomycin, oxacillin, ampicillin, gentamicin, ciprofloxacin, and rifampin against five Staphylococcus species, five Streptococcus species, and four Enterococcus species. For staphylococci, MICs were 0.13 to 1 microgram/ml and the MICs for 90% of the strains tested (MIC90s) were 0.13 to 0.5 microgram/ml; there were no differences between oxacillin-susceptible and -resistant strains. For streptococci, MICs were 0.03 to 4 micrograms/ml and MIC90s were 0.25 to 2 micrograms/ml; viridans group streptococci were the least susceptible streptococci. For enterococci, MICs were 0.25 to 32 micrograms/ml and MIC90s were 2 to 4 micrograms/ml; Enterococcus faecalis was the least susceptible. Vancomycin was the only comparative drug with consistent activity against all species of gram-positive cocci. With RP 59500, raising the inoculum 100-fold, lowering the pH of cation-adjusted Mueller-Hinton broth to 5.5, or omitting cation supplementation had little effect on MICs, but 50% serum increased MICs 2 to 4 dilution steps. The differences between MBCs and MICs were greater for staphylococci and enterococci than for streptococci. Time-kill studies with 24 strains indicated that RP 59500 concentrations 2-, 4-, and 16-fold greater than the MICs usually killed bacteria of each species at similar rates; reductions in CFU per milliliter were less than those observed with oxacillin or vancomycin against staphylococci and less than those observed with ampicillin against enterococci. RP 59500 antagonized the bactericidal activities of oxacillin and gentamicin against Staphylococcus aureus ATCC 29213 and that of ampicillin against E. faecalis ATCC 29212. Against the latter, combination with gentamicin was indifferent. RP 59500 has a broad spectrum of in vitro activity against gram-positive cocci; combining it with other drugs is not advantageous.     

In vitro antistaphylococcal activity and testing of RP 59500, a new streptogramin, by two methods.

The in vitro antistaphylococcal activity of RP 59500, a new streptogramin, was comparable to those of vancomycin and teicoplanin against Staphylococcus aureus, and RP 59500 was the most active agent against coagulase-negative staphylococci. All staphylococcal strains were inhibited by 4 micrograms of RP 59500 per ml, including multiply resistant strains. Broth microdilution and agar dilution testing gave comparable results in 97% of the tests with RP 59500.     

In vitro activity of an oral streptogramin antimicrobial, XRP2868, against gram-positive bacteria

The comparative in vitro potency of XRP2868, a new oral semisynthetic streptogramin antibiotic, was evaluated against gram-positive bacteria. XRP2868 inhibited all staphylococci at < or = 1 microg/ml and all non-pneumococcal streptococci at < or = 0.25 microg/ml and was fourfold more potent than quinupristin-dalfopristin against Staphylococcus aureus and Enterococcus faecium.     

Comparative in-vitro activity of azithromycin, macrolides (erythromycin, clarithromycin and spiramycin) and streptogramin RP 59500 against oral organisms.

The in-vitro activities of azithromycin, clarithromycin, spiramycin and RP 59500 were compared with erythromycin against a wide range of oral organisms which have been implicated in oral infections and/or endocarditis (clindamycin was included for oral streptococci). All compounds tested showed good activity against many of these organisms, although some variation was observed with different species. Clarithromycin was the most active of the antibiotics tested against Gram-positive anaerobes, including Actinomyces spp., Propionibacterium spp., Lactobacillus spp. and Bifidobacterium dentium. Azithromycin was slightly less active than erythromycin against these species. In general, RP 59500 had higher MICs than the macrolides, other than spiramycin, against these organisms, but was superior in activity against Peptostreptococcus spp., inhibiting all isolates at 2 mg/L. Azithromycin was, in general, the most active antibiotic tested against the Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp., Wolinella spp., Actinobacillus actinomycetemcomitans, Selenomonas spp. and Mitsuokella multiacida, including those isolates which were insusceptible to erythromycin. Clarithromycin showed similar activity to erythromycin against most Gram-negative species, but was superior against Capnocytophaga ochraceus and Eikenella corrodens. RP 59500 was less active than the macrolides against most Gram-negative anaerobes, but was superior to erythromycin and clarithromycin against Fusobacterium spp. and Leptotrichia buccalis, some strains of which were moderately resistant to erythromycin. The macrolides and clindamycin were about equally active against the oral streptococci, whereas RP 59500 showed lower inhibitory activity. The in-vitro results suggest that azithromycin and clarithromycin may be of value in the treatment of dental sepsis and the prophylaxis of endocarditis. RP 59500 showed useful activity against Gram-positive anaerobes and, because of its bactericidal activity against oral streptococci, may also prove to have a role in these areas.     

In vitro activities of a streptogramin (RP59500), three macrolides, and an azalide against four respiratory tract pathogens.

Broth microdilution tests were carried out with 2,671 respiratory tract isolates from 19 medical centers throughout the continental United States. The tests compared a streptogramin (RP59500) to erythromycin, dirithromycin, clarithromycin, and azithromycin against Streptococcus pneumoniae, S. pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Against macrolide-susceptible strains, the potency of RP59500 was similar to that of the macrolides: the azalide, azithromycin, was two to four times more potent against H. influenzae. The azalide and three macrolides showed nearly complete cross-resistance. At 2.0 micrograms/ml or less, the streptogramin, RP59500, was active against both macrolide-resistant and -susceptible strains of S. pneumoniae (MIC for 50% of the strains tested, 0.25 microgram/ml; MIC for 90% of the strains tested, 0.5 microgram/ml).     

In vitro activity of quinupristin/dalfopristin (Synercid, RP 59500) against Legionella spp

The activities of quinupristin/dalfopristin (Synercid), erythromycin and azithromycin against 22 Legionella spp. isolates were measured by a microbroth dilution method. The MICs that inhibited 90% of strains tested were 0.5, 0.35, and 0.5 microg/mL for quinupristin/dalfopristin, erythromycin, and azithromycin, respectively. Quinupristin/dalfopristin was only partially active against intracellular L. pneumophila at high (2 microg/mL), but not low (1 microg/mL) concentration. Activity of the drug in a guinea pig model of Legionnaires' disease could not be accurately determined because of drug toxicity for the guinea pig, although there was evidence that the drug has in vivo activity.     

In vitro activity of RU 64004, a new ketolide antibiotic, against gram-positive bacteria.

The comparative in vitro activity of RU 64004 (also known as HMR 3004), a new ketolide antibiotic, was tested by agar dilution against approximately 500 gram-positive organisms, including multiply resistant enterococci, streptococci, and staphylococci. All streptococci were inhibited by < or = 1 microg of RU 64004 per ml. The ketolide was more potent than other macrolides against erythromycin A-susceptible staphylococci and was generally more potent than clindamycin against erythromycin A-resistant strains susceptible to this agent. Clindamycin-resistant staphylococci (MIC, > 128 microg/ml) proved resistant to the ketolide, but some erythromycin A- and clindamycin-resistant enterococci remained susceptible to RU 64004.     

In vitro activity of LY146032, a new lipopeptide antibiotic, against gram-positive cocci.

The activity of LY146032, a new lipopeptide antibiotic, was compared in vitro with those of vancomycin, oxacillin, and ampicillin against 261 staphylococcal and 154 streptococcal isolates. The MICs of LY146032 and vancomycin were similar, but the bactericidal activity and killing kinetics of LY146032 were more pronounced.     

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.     

In vitro and in vivo antibacterial activities of quinupristin-dalfopristin, a novel injectable streptogramin, against gram-positive cocci and gram-negative respiratory tract pathogens

Quinupristin-dalfopristin, a novel injectable streptogramin, was evaluated for both in vitro and in vivo antibacterial activities in comparison with those of erythromycin, azithromycin, clindamycin, vancomycin, ampicillin, imipenem, and ciprofloxacin. Quinupristin-dalfopristin had high activity against staphylococci and streptococci, including methicillin-resistantStaphylococcus aureus (MRSA), and penicillin-resistantStreptococcus pneumoniae, with MICs at which 90% of strains tested are inhibited (MIC₉₀) equal to 1 μg/mL or less. AgainstEnterococcus spp, quinupristin-dalfopristin was less active than vancomycin with an MIC₉₀ of 32 μg/mL, while againstHaemophilus influenzae, Moraxella (B) catarrhalis andBordetella pertussis, the MIC₉₀s of quinupristin-dalfopristin were 4.0, 1.0, and 0.1 μg/mL, respectively. The minimal bactericidal concentration (MBC) values of quinupristin-dalfopristin against methicillin-susceptible staphylococci, penicillin-resistantS. pneumoniae andH. influenzae were similar to the MIC values, while the MBCs for MRSA andE. faecalis were at least 8-fold greater than the corresponding MIC values. In a murine lung infection model using penicillin-resistantS. pneumoniae, treatment with quinupristin-dalfopristin resulted in a significant reduction in the number of organisms in the lungs compared with that in untreated animals or erythromycin-treated mice (P<0.05). The in vivo efficacy of quinupristin-dalfopristin against experimental septicemia caused by penicillin-sensitiveS. pneumoniae and MRSA was less than that using vancomycin and imipenem-cilastatin, even though it had higher in vitro activity.     

In vitro activity of a new cyclic lipopeptide antibiotic, LY146032, against gram-positive clinical bacteria.

The in vitro activity of LY146032, a novel cyclic lipopeptide antibiotic, was tested against different gram-positive clinical isolates. The activity of LY146032 was clearly higher than that of vancomycin against all isolates tested. However, in some instances rifampin and imipenem showed higher activity than did LY146032.     

In vitro activity of RP 74501-RP 74502, a novel streptogramin antimicrobial mixture, against clinical isolates of Legionella species.

Agar and broth microdilution MICs of RP 74501-RP 74502, a mixture of streptogramin antimicrobial agents that inhibited 90% of 22 Legionella strains tested, were 0.64 and 0.08 microgram/ml, respectively; respective erythromycin values were 1.0 and 0.12 microgram/ml. RP 74501-RP 74502 at 1 microgram/ml was more active than the same erythromycin concentration in a macrophage system for both L. pneumophila strains studied but at a lower concentration (0.25 microgram/ml) was much less active than erythromycin.     

In vitro activities of daptomycin and other antimicrobial agents against vancomycin-resistant gram-positive bacteria.

A comparative evaluation of daptomycin and eight other antimicrobial agents was performed by the agar dilution technique with 56 strains of vancomycin-resistant gram-positive bacteria, including Leuconostoc, Lactobacillus, and Pediococcus spp. Erythromycin, deptomycin, clindamycin, and gentamicin exhibited the greatest activities, whereas penicillin, ampicillin, and cefotaxime showed moderate activities. The organisms were all highly resistant to vancomycin and cefoxitin.     

In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci.

The emergence of resistance in gram-positive bacteria has necessitated a search for new antimicrobial agents. Linezolid is an oxazolidinone, a new class of antibacterial agents with enhanced activity against pathogens. We compared the activity of linezolid to those of other antimicrobial agents against 3,945 clinical isolates. Linezolid demonstrated potent activity against all isolates tested. For all vancomycin-susceptible enterococci, staphylococci, and streptococci, the activity of linezolid was comparable to that of vancomycin. Against oxacillin-resistant staphylococci and vancomycin-resistant enterococci, linezolid was the most active agent tested. In summary, linezolid appears to be a promising new antimicrobial agent for the treatment of gram-positive infections.     

In vitro activity of levofloxacin against gram-positive bacteria

The in vitro activity of levofloxacin was investigated against 256 clinical strains of four gram-positive genera (Staphylococcus, Streptococcus, Enterococcus, and Listeria). Ofloxacin and ciprofloxacin were used as comparators. Uniform susceptibility to levofloxacin was recorded among methicillin-susceptible staphylococci, streptococci other than Streptococcus agalactiae, regardless of their being susceptible, intermediate, or resistant to penicillin (S. pneumoniae) or erythromycin (S. pyogenes and S. pneumoniae), in enterococci other than Enterococcus faecalis and E. faecium, and in Listeria monocytogenes isolates. Moreover, 1 of 22 S. agalactiae isolates and 1 of 19 E. faecium isolates was resistant, and 2 of 19 were intermediate. Resistances to levofloxacin with MIC90s in the resistance range were only observed in methicillin-resistant staphylococci and E. faecalis isolates. In any case, the MICs of ofloxacin and ciprofloxacin were usually 2-4 times higher than those of levofloxacin. In time-kill assays using three test strains (a methicillin-susceptible Staphylococcus aureus isolate, a penicillin-susceptible Streptococcus pneumoniae isolate, and an E. faecalis isolate), the bactericidal activity of levofloxacin was greater than that of ciprofloxacin. Copyright Copyright 1999 S. Karger AG, Basel.     

Pharmacodynamic interaction between RP 59500 and gram-positive bacteria infecting fibrin clots.

The fibrin clot penetration and in vivo bactericidal activity of RP 59500, a new semisynthetic streptogramin, for two Staphylococcus aureus strains (one methicillin resistant and the other methicillin susceptible), two Staphylococcus epidermidis strains (one methicillin resistant and the other methicillin susceptible), and one Enterococcus faecalis strain were evaluated. The clots, inserted subcutaneously, were infected with a mean of 10(8) CFU of the pathogen per g. For each strain, groups of four rabbits received a single intravenous injection of 50 mg of RP 59500 per kg of body weight over 30 min. The mean peak level of RP 59500 in serum in the infected rabbits was 61.9 +/- 6.3 micrograms/ml. The drug was detectable in serum at a level of 0.8 micrograms/ml up to 4 h after administration. The mean peak fibrin clot drug level at 1 h was 3.3 +/- 0.1 micrograms/g. At 6 h, the level in clots was 1.2 +/- 0.1 micrograms/g. The mean half-life in serum in infected rabbits was 0.34 +/- 0.01 h, while in clots the drug exhibited a longer half-life of 3.8 +/- 0.4 h. In vivo, this new streptogramin sterilized the clots infected with the two S. aureus strains studied in less than 1 h and induced a marked reduction in colony counts of the two S. epidermidis strains studied for up to 24 h. The activity of the streptogramin against E. faecalis was limited. These results suggest that RP 59500 should be further evaluated for the treatment of infection with methicillin-resistant staphylococci.     

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 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 activities of an investigational quinolone, glycylcycline, glycopeptide, streptogramin, and oxazolidinone tested alone and in combinations against vancomycin-resistant Enterococcus faecium.

We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopristin, and eperezolid (formerly known as U-100,592) against four strains of enterococci. All regimens tested resulted in the growth inhibition of each isolate. Against the three clinafloxacin-susceptible strains, clinafloxacin tested alone was the most active treatment, decreasing the bacterial inoculum by more than 3 log10 CFU/ml after 24 h in time-kill curve studies.