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.

LY146032 is a new lipopeptide antibiotic with a spectrum of activity that is limited to gram-positive organisms. It is the semisynthetic N-decanoyl derivative of A21978C1 a cyclic polypeptide antibiotic containing a fatty acid side chain.
The original sUbstance A21978C1, from which LY146032 was derived, has been shown to inhibit the peptidoglycan synthesis in Staphylococcus aureus and Streptococcus faecalis; and the activity of the drug apparently depends on the calcium content of the medium (1).
In this study I evaluate the in vitro activity of LY146032 against staphylococci, including oxacillin-resistant isolates, and against a variety of streptococci, in comparison with vancomycin, oxacillin, and ampicillin. The antibiotics were gifts from the manufacturers. LY146032 and vancomycin were obtained from Eli Lilly & Co., Indianapolis, Ind.; oxacillin and ampicillin were obtained from Beecham Laboratories, Betchworth, England.
The in vitro activity of LY146032 was tested by the agar dilution method in Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, Md.) in comparison with vancomycin and oxacillin against staphylococci and with ampicillin against streptococci. Mueller-Hinton agar was supplemented with 5% lysed horse blood to support the growth of streptococci. The antibiotic dilutions (final concentrations, between 32 and 0.03 mg/liter) were prepared fresh daily.
The strains were recent isolates from clinical specimens: Staphylococcus aureus (186 isolates), Staphylococcus epidermidis (75 isolates), Streptococcus faecalis (40 isolates), Streptococcus pneumoniae (20 isolates), Streptococcus pyogenes (20 isolates), Streptococcus agalactiae (20 isolates), and viridans group streptococci (S. sanguis, 17 isolates; S. milleri, 12 isolates; S. mitis, 10 isolates; S. salivarius, 10 isolates; S. mnutans, 5 isolates). The strains were cultured overnight in Trypticase soy broth (BBL) and properly diluted in fresh broth to give a final inoculum of between 10i and 101 CFU per spot. Spots were applied with a multipoint inoculator. The MIC was determined as the lowest concentration which did not allow visible growth after incubation for 24 h at 36°C for streptococci and at 30°C for staphylococci. and other antibiotics. The activity of LY146032 against Staphylococcus aureus and Staphylococcus epidermidis was similar, regardless of their susceptibility or resistance to penicillin and oxacillin. LY146032 was comparable in activity to vancomycin against Staphylococcus aureus but was twice as active as vancomycin against Staphylococcus epidermidis. LY146032 was also similar in activity to vancomycin against Streptococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae, and viridans group streptococci o ,   but was more active against Streptococ( However, both compounds were substan than ampicillin against susceptible nonente cocci. Penicillin-resistant viridans group s inhibited by LY146032 at the same conc penicillin-susceptible isolates. The  cus pneumoniae. studied on the same organisms with an inoculum of approxtially less active imately 106 CFU/ml in MHB-CMS. Overnight cultures in ,rococcal strepto-Trypticase soy broth were properly diluted in prewarmed treptococci were MHB-CMS (37°C), and the antibiotics were added after entrations as the preincubation for 30 min to reach logarithmic growth. Viable counts were made at time zero and after 2, 4, 6, 8, and 24 h ycin against one of contact with concentrations corresponding to 4x MICs vlococcus aureus, and to 16x MICs of each antibiotic against the different reus, oxacillin-isolates. id Streptococcus The killing kinetics of LY146032 and vancomycin are *oth (MHB) and in shown in Fig. 1. The bactericidal effect of LY146032 was L2 (MHB-CMS) to more pronounced and appeared earlier than that of vanco-VOL. 31, 1987