Glycylcyclines: a new generation of tetracyclines

Tally, F. T.; Ellestad, George A.; Testa, R. T.

doi:10.1093/jac/35.4.449

Cited by 44 publications

(26 citation statements)

References 13 publications

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“…No correlation between any combination of resistance determinants and the MICs of tigecycline and minocycline was observed, although isolates carrying one or more of these determinants showed higher MICs on average than isolates that lacked these determinants. These data are in accordance with initial reports that efflux mechanisms encoded by tet(A) to tet(D) are not efficient for glycyl-cyclines (9). The presence of tet(B) or tet(C) in E. coli has also been reported to have no effect on the MICs of tigecycline.…”

Section: The Tet(a) To Tet(e) and Tet(k) Determinants Encode Effluxsupporting

confidence: 92%

Presence of Tetracycline Resistance Determinants and Susceptibility to Tigecycline and Minocycline

Fluit

Florijn

Verhoef

et al. 2005

Antimicrob Agents Chemother

105

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Section: The Tet(a) To Tet(e) and Tet(k) Determinants Encode Effluxsupporting

confidence: 92%

Presence of Tetracycline Resistance Determinants and Susceptibility to Tigecycline and Minocycline

Fluit

Florijn

Verhoef

et al. 2005

Antimicrob Agents Chemother

105

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“…Their activity remains bacteristatic. Preclinical toxicological studies have shown qualitatively similar profiles to those noted with minocycline and tetracycline (243). If they are effective clinically, the glycylcyclines will be important drugs for the treatment of infections caused by resistant gram-positive bacteria, but they are still a long way from being marketed (99,243).…”

Section: Treatmentmentioning

confidence: 84%

Vancomycin-Resistant Enterococci

Çetinkaya

Falk

Mayhall

2000

Clinical Microbiology Reviews

642

344

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“…The early glycylcyclines N,N-dimethylglycylamido-9-aminominocycline and 9-amino-6-demethyl-6-deoxytetracycline exhibited potent activity against many gram-positive and gram-negative aerobic and anaerobic bacteria (reviewed by Tally et al [9]). It was especially encouraging that the early glycylcyclines were active in vitro against tetracycline-resistant bacteria due to efflux-based as well as ri- The present study extends the early in vitro findings to the in vivo situation against minocycline-sensitive and -resistant bacteria.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacodynamic Activities of Two Glycylcyclines (GAR-936 and WAY 152,288) against Various Gram-Positive and Gram-Negative Bacteria

Ogtrop

Andes

Stamstad³

et al. 2000

Antimicrob Agents Chemother

160

124

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The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, or Klebsiella pneumoniae. Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters studied. These parameters were time above 0.03 to 32 times the MIC, area under the concentration-time curve (AUC), and maximum concentration of drug in serum (C max ). The bacteriostatic dose remained essentially the same, irrespective of the dosing frequency, for S. pneumoniae 1199 (0.3 to 0.9 mg/kg/day). For E. coli ATCC 25922 and K. pneumoniae ATCC 43816, however, more frequent dosing led to lower bacteriostatic doses. Pharmacokinetic studies demonstrated dose-dependent elimination half-lives of 1.05 to 2.34 and 1.65 to 3.36 h and serum protein bindings of 59 and 71% for GAR-936 and WAY 152,288, respectively. GAR-936 and WAY 152,288 were similarly effective against the microorganisms studied, with small differences in maximum effect and 50% effective dose. The glycylcyclines were also similarly effective against tetracycline-sensitive and tetracycline-resistant bacteria. Time above a certain factor (range, 0.5 to 4 times) of the MIC was a better predictor of in vivo efficacy than C max or AUC for most organism-drug combinations. The results demonstrate that in order to achieve 80% maximum efficacy, the concentration of unbound drug in serum should be maintained above the MIC for at least 50% of the time for GAR-936 and for at least 75% of the time for WAY 152,288. The results of these experiments will aid in the rational design of dose-finding studies for these glycylcyclines in humans. 288 are members of the class of glycylcyclines, a new group of antibiotics derived from minocycline. These drugs have potent activity against a variety of tetracycline-sensitive and tetracycline-resistant bacteria (1-3, 5, 8, 10, 14, 15).The objective of the present study was to determine the effects of various dosing regimens on the in vivo efficacy of GAR-936 and WAY 152,288 and identify which pharmacokinetic or pharmacodynamic parameter best correlated with efficacy. The in vivo antibacterial activities of GAR-936 and WAY 152,288 against several isolates of common human pathogens (Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, ...

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Glycylcyclines: a new generation of tetracyclines

Cited by 44 publications

References 13 publications

Presence of Tetracycline Resistance Determinants and Susceptibility to Tigecycline and Minocycline

Presence of Tetracycline Resistance Determinants and Susceptibility to Tigecycline and Minocycline

Vancomycin-Resistant Enterococci

In Vivo Pharmacodynamic Activities of Two Glycylcyclines (GAR-936 and WAY 152,288) against Various Gram-Positive and Gram-Negative Bacteria

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