Antimicrobial activity of MDL 63,246, a new semisynthetic glycopeptide antibiotic

Abstract

MDL 63,246 is a semisynthetic derivative of the naturally occurring glycopeptide antibiotic MDL 62,476 (A40926). It was more active in vitro against Staphylococcus aureus and coagulase-negative staphylococci than MDL 62,476, teicoplanin, and vancomycin and was more active than mideplanin (MDL 62,873) against some isolates. MDL 63,246 had excellent activity against streptococci and teicoplanin-susceptible enterococci, and it also had in vitro activity against some VanA enterococcal isolates. It was more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It was highly efficacious in reducing the bacterial load in the hearts of rats in staphylococcal endocarditis experiments and the bacterial load of Staphylococcus epidermidis in a thigh infection model in neutropenic mice. The excellent in vivo activity of MDL 63,246 appears to correlate both with its in vitro antibacterial activity and with its long half-life in rodents.Glycopeptide antibiotics are an important part of the armamentarium against gram-positive infections, particularly those caused by enterococci and methicillin-resistant staphylococci. Acquired high-level resistance to glycopeptides in enterococci is an emerging problem (8,13,16,17,23,25), and intermediate susceptibility or resistance to teicoplanin, and occasionally to vancomycin, occurs in methicillin-resistant coagulase-negative staphylococci (1,12,14,20,24).Some amide derivatives of teicoplanin, such as mideplanin (MDL 62,873), have been demonstrated to have better activity than teicoplanin against coagulase-negative staphylococci (2-4, 14). We have recently turned our attention to chemical derivatives of MDL 62,476 (A40926), a glycopeptide antibiotic whose antibacterial activity is similar to that of teicoplanin except for its additional activity against Neisseria gonorrhoeae (11). We present data on the in vitro activity and efficacy in animal infection models of a new amide derivative of this antibiotic, MDL 63,246 (Fig. 1). MATERIALS AND METHODSAntimicrobial agents. Teicoplanin, mideplanin (MDL 62,873), MDL 62,476 (A40926), and MDL 63,246 were provided by the Lepetit Research Center. The structures of these compounds are given in Fig. 1. Vancomycin, tetracycline, penicillin G, clindamycin, and erythromycin were obtained from Sigma Chemical Co. (St. Louis, Mo.).MIC determination. Isolates were obtained from various clinical sources. The set of staphylococci used for these experiments was biased to include a high proportion of strains for which teicoplanin MICs were known to be high. The three Staphylococcus aureus isolates for which teicoplanin MICs were 8 to 16 g/ml were kindly provided by J. Acar, G. Kaatz, and G. C. Schito. The enterococci included vancomycin-resistant isolates belonging to various phenotypic classes. MIC determinations were performed by the broth microdilution methodology with inocula of approximately 5 ϫ 10 5 CFU/ml (18). The media used included Iso-Sensitest broth (Oxo...

Structural modifications of glycopeptide antibiotics

“…In addition to excellent activity against vancomycin-susceptible enterococci and vancomycin-resistant VanB isolates, they were significantly more active than teicoplanin or vancomycin against a number of staphylococcal isolates, including MRSA and coagulase-negative staphylococci. 71,72 Although the antistreptococcal activity of teicoplanin is excellent, these compounds were generally even more active than teicoplanin and much more active than vancomycin against streptococci, including penicillin-resistant S. pneumoniae.…”

In Vitro Activities of Dalbavancin and Nine Comparator Agents against Anaerobic Gram-Positive Species and Corynebacteria

“…Dalbavancin (BI 397) is a novel semisynthetic amide derivative of the glycopeptide MDL 62,476 that has enhanced activity against aerobic gram-positive species (2,4,5). Due to its very long half-life (9 to 12 days), it is under investigation at a dosage interval of 1 week.…”

Pharmacokinetics of MDL 63,246, a new semisynthetic glycopeptide antibiotic, in the rat

“…A relatively small amount of drug, the fraction not bound to plasma protein, is available at all times for distribution and elimination (6,12,13). This may not be of practical importance, because the drug was very efficacious in experimental infections (8). An attempt to determine the level of plasma protein binding was carried out by ultrafiltration (cutoff, 30.000 D) of rat and rabbit plasma samples.…”

“…1). MDL 63,246 has better in vitro activity than MDL 62,476, teicoplanin, and vancomycin, particularly against Staphylococcus aureus and coagulase-negative staphylococci (8,10). It also has excellent activity against streptococci and teicoplanin-susceptible enterococci and against some VanA enterococcal isolates.…”

“…The compound is more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It is highly efficacious in reducing the heart bacterial load in staphylococcal endocarditis experiments in rats and the bacterial load of Staphylococcus epidermidis in a thigh infection model in neutropenic mice (8). We present preliminary data on the kinetics in plasma, distribution in tissue, and excretion of MDL 63,246 in the rat following intravenous (i.v.)…”