Roberto Scotti

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

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 epidermis in a high 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.

In vitro antimicrobial activity of a new antibiotic, MDL 62,879 (GE2270 A).

MDL 62,879 (GE2270 A) is a new peptide antibiotic that inhibits protein synthesis through an interaction with elongation factor Tu. MDL 62,879 was very active against gram-positive clinical isolates, particularly staphylococci and enterococci, for which MICs for 90% of isolates were < or = 0.13 micrograms/ml. It was equally active against isolates resistant to beta-lactams, erythromycin, gentamicin, and glycopeptides. It also had activity against Mycobacterium tuberculosis. MDL 62,879 had moderate bactericidal activity against staphylococci.

In vitro activity of A-16686, a potential antiplaque agent.

A-16686, a new glycoproteide antibiotic from Actinoplanes sp., was evaluated as a potential antiplaque agent in comparison with chlorhexidine, benzalkonium chloride, and cetylpyridinium chloride. A-16686 had good activity against gram-positive organisms associated with dental plaque (various streptococci, Streptococcus mutans in particular, lactobacilli, Actinomyces viscosus, and Actinomyces naeslundii); most of the strains tested were clinical isolates. It was bactericidal for streptococci (MBC/MIC ratio of less than or equal to 8 for 92% of the strains) and for growing cells of S. mutans briefly exposed to antibiotic (99.9% killing within 5 min of contact with 200 micrograms of A-16686 per ml). It also inhibited the in vitro plaque formation by S. mutans and had good activity against preformed plaques. For most cases, its activity was comparable to those of chlorhexidine, benzalkonium chloride, and cetylpyridinium chloride. A-16686 appears to be a promising antiplaque agent because of the following attributes: narrow spectrum of activity, rapid bactericidal action, lack of selection of resistant mutants, absence of cross-resistance with clinically used antibiotics, nonabsorption by oral route, good tolerability by the oral mucosa (rats and dogs), and physical characteristics (white powder, soluble in water).

Antimicrobial activity of MDL 62,873, a semisynthetic derivative of teicoplanin, in vitro and in experimental infections.

MDL 62,873 is an amide derivative of teicoplanin A2-2. Like those of natural glycopeptides, its antibacterial activity is mediated by inhibition of cell wall peptidoglycan synthesis. Against streptococci and enterococci, the in vitro activity of MDL 62,873 was similar to that of teicoplanin and greater than that of vancomycin. Against staphylococci, it has activity similar to that of vancomycin, and it was significantly more active than teicoplanin against coagulase-negative isolates. Like teicoplanin and vancomycin, MDL 62,873 had slow but significant bactericidal activity (99 to 99.9% killing in 24 h) against staphylococci at concentrations near the MIC. In murine septicemia studies with Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, the 50% effective doses were lower than those of vancomycin. In staphylococcal endocarditis in rats, MDL 62,873 at 20 mg/kg of body weight and vancomycin at 40 mg/kg, both doses given intravenously twice daily, had similar efficacies in reducing the heart bacterial load. These results probably reflect the longer half-life of MDL 62,873, which has a pharmacokinetic profile in rats similar to that of teicoplanin.

Effect of protein on ramoplanin broth microdilution minimum inhibitory concentrations

Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria. We observed that microdilution minimum inhibitory concentrations (MICs) were higher than those obtained in glass tubes or by agar dilution. Initial studies showed that these differences disappeared when 30% bovine serum was added to the broth. Further studies showed that addition of 0.01% bovine serum albumin (BSA) to the broth lowered the microdilution MICs for staphylococci, streptococci, and enterococci by four- to 32-fold. This phenomenon occurred in several commonly used growth media and in different types of commercially available microtiter trays. Precoating of the microtiter wells with a dilute solution of BSA (0.02%) had the same effect. It seems likely that ramoplanin adsorbs to plastic surfaces and is lost from solution, and that protein masks the sites of adsorption. Ramoplanin MICs may be reliably determined by broth microdilution if a small amount of protein is added to the diluent.

Activity of rifampin plus trimethoprim againstHaemophilus influenzae

The activity of the combination rifampin plus trimethoprim againstHaemophilus influenzae was studied from the point of view of synergism, bactericidal activity, and inhibition of the selection of rifampin-resistant cells. At concentrations of the two drugs that are easily attainable in human serum after oral treatment with 600 mg of rifampin plus 160 mg of trimethoprim, the combination acted synergistically on all of the strains tested, was remarkably bactericidal, and inhibited the selection of rifampin-resistant cells.