In Vitro Activities of the Glycylcycline GAR-936 against Gram-Positive Bacteria

Abstract

The in vitro activities of GAR-936, the 9-t-butylglycylamido derivative of minocycline, were compared with those of doxycycline, minocycline, and tetracycline against 527 gram-positive clinical isolates. GAR-936 inhibited all strains, including those resistant to other tetracyclines, at concentrations of <2 g/ml, except two strains of JK diphtheroids for which the MIC was 4 g/ml.Although tetracyclines remain valuable therapeutic agents for a variety of infections, resistance to this class limits their use against many important gram-positive bacterial pathogens. For example, only 33% of enterococci recovered at our hospital during 1997 to 1999 were susceptible to tetracycline. The glycylcyclines are novel tetracycline analogs that have activity against organisms resistant to older compounds of this class (5,14). They inhibit protein synthesis on wild-type ribosomes and on TetM-protected, tetracycline-resistant ribosomes (15). These compounds also inhibit organisms with tetracycline efflux determinants (14). GAR-936, the 9-t-butylglycylamido derivative of minocycline, appears to be both better tolerated by hosts and more active against tetracycline-resistant strains than earlier glycylcyclines (14). The present study examined the in vitro activities of GAR-936 against gram-positive bacteria, including strains resistant to ␤-lactams, glycopeptides, and other tetracyclines.Routine clinical isolates collected at the Beth Israel Deaconess Medical Center were included regardless of tetracycline resistance patterns. Staphylococci and most pneumococci were recovered in 1998. Strains with unusual resistance traits, including glycopeptide-resistant or ␤-lactamase-producing enterococci and ␤-lactam-resistant streptococci, had been referred to our laboratory from various sources over several years (2,4,16). Wyeth-Ayerst Laboratories, Pearl River, N.Y., kindly provided GAR-936. Tetracycline, minocycline, and doxycycline were purchased from Sigma Chemical Company, St. Louis, Mo.Activities of the antimicrobials were determined by agar dilution methods on Mueller-Hinton II agar (12). Media were supplemented with 5% sheep blood for testing streptococci and corynebacteria. Inocula of approximately 10 4 CFU were applied to the surfaces of plates and were incubated for 16 to 20 h at 35°C in air or in 5% CO 2 (for Lactobacillus spp., Leuconostoc spp., Streptococcus spp., Pediococcus spp., and diphtheroids). Pneumococci were also tested by broth microdilution (12).The results of susceptibility studies are shown in Table 1. GAR-936 was four times less active than minocycline against oxacillin-susceptible and -resistant strains of Staphylococcus aureus, according to a comparison of MICs at which 90% of the isolates tested were inhibited (MIC 90 s). However, isolates intermediately susceptible or resistant to the other compounds were inhibited by GAR-936 at Յ1 g/ml. GAR-936 inhibited two strains of vancomycin-intermediate S. aureus (resistant to tetracycline and minocycline) at concentrations of 1 and 2 g/ml.Against coagulase-negative s...

In Vitro Activities of Tigecycline (GAR-936) against Recently Isolated Clinical Bacteria in Spain

“…The MIC 50 s and MIC 90 s of tigecycline for enterococcal isolates ranged from 0.125 to 0.25 g/ml. These values are similar to those reported previously (3,6,20). None of the E. faecium strains produced ␤-lactamase, although for 74.5% of these organisms ampicillin MICs were 64 g/ml.…”

Effect of Medium Age and Supplementation with the Biocatalytic Oxygen-Reducing Reagent Oxyrase on In Vitro Activities of Tigecycline against Recent Clinical Isolates

“…Overall, when compared to prior published data (1,5,7,10), tigecycline was generally 1 to 2 dilutions more active when tested in fresh MHB. In addition, the use of Oxyrase to reduce the oxygen content in aged media is a viable alternative to using fresh media.…”

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

“…In addition, 9-(t-butylglycylamido)-minocycline (tigilcycline; GAR-936) ( Tables 1 and 2) could have therapeutic potential in cystic fibrosis patients infected with P. aeruginosa (113). More recently, 1,730 clinical isolates were examined in two studies with tigilcycline and older tetracyclines (22,80). In general, the glycylcycline was 2-to 4-fold more active than minocycline and 2-to 16-fold more active than tetracycline against the Enterobacteriaceae.…”

“…where the tigilcycline MIC against 90% of isolates was Ն8 g/ml (80). Tigilcycline was active against virtually all gram-positive clinical isolates including those resistant to earlier tetracyclines (22). Surveillance studies have not so far identified any naturally occurring high-level glycylcycline-resistant strains among human clinical isolates (113).…”