Comparative in vitro study of teichomycin A2

The activity of teichomycin A2 was compared with that of vancomycin in vitro against clinical isolates of staphylococci and enterococci. Teichomycin A2 was more active than vancomycin against all isolates tested. Synergistic studies also demonstrated that teichomycin A2 combined with rifampin is more active than vancomycin combined with rifampin against Staphylococcus aureus and Staphylococcus epidermidis isolates. Teichomycin A2, either singly or in combination with an aminoglycoside, was more active against Streptococcus faecalis isolates.Teichomycin A2, a glycopeptide antibiotic, resembles vancomycin in its spectrum of activity and its mode of action, which is via inhibition of cell wall synthesis (8).There is a need for additional agents which are effective for the therapy of patients with serious staphylococcal infections, particularly when methicillin-resistant strains are responsible; there is also a need for additional agents for serious enterococcal diseases (2, 3, 9, 10).The present study examines the in vitro activity of teichomycin A2 against clinical isolates of Staphylococcus aureus (methicillin susceptible and methicillin resistant), Staphylococcus epidermidis, and Streptococcus faecalis. The in vitro interactions of teichomycin A2 and rifampin were compared with those of vancomycin and rifampin against S. aureus, S. epidermidis, and S. faecalis strains. In addition, the activity of vancomycin combined with aminoglycosides was compared with that of teichomycin A2 combined with aminoglycosides in vitro against S. faecalis isolates. MATERIALS AND METHODSThirty-two S. aureus strains (10 methicillin-susceptible isolates from patients with endocarditis, 10 methicillin-resistant isolates from patients with endocarditis, and 12 methicillin-resistant isolates from patients with localized infections such as wound, skin, eye, and ear infections), 10 S. epidermidis strains isolated from patients with endocarditis and osteomyelitis, and 10 S. faecalis strains isolated from patients with endocarditis or septicemia were studied. The methicillin-resistant S. aureus isolates were kindly provided by Dennis Schaberg, University of Michigan, Ann Arbor, and Charles Zierdt, National Institutes of Health, Bethesda, Md. All organisms were maintained on blood agar plates throughout the course of this study. The S. aureus (methicillin susceptible and methicillin resistant) and S. epidermidis isolates were identified by standard microbiological techniques. S. faecalis isolates were identified with bile esculin and arginine hydrolysis and growth at 45°C and in 6.5% NaCl.The following reference standard antibiotics were supplied by the indicated manufacturers and dissolved according to * Corresponding author. their instructions: rifampin, CIBA Pharmaceutical Co.; vancomycin hydrochloride, tobramycin, and streptomycin sulfate, Eli Lilly & Co.; gentamicin sulfate, Schering Corp.; and teichomycin A2, Dow Chemical Co. Rifampin concentrations ranged from 0.25 to 0.0019 ,ug/ml, vancomycin and teichomycin A2 concentrations ranged f...

Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Comparative in vitro activities of teichomycin and vancomycin alone and in combination with rifampin and aminoglycosides against staphylococci and enterococci

Tuazon¹,

Miller²

1984

“…Like vancomycin, it is active against gram-positive aerobic and anaerobic bacteria, including methicillin-resistant staphylococci (6,8,9,21,(24)(25)(26). The in vivo activity of teicoplanin for serious staphylococcal infections has been established in experimental animal models (5,10,23).…”

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confidence: 99%

Teicoplanin pharmacokinetics in intravenous drug abusers being treated for bacterial endocarditis

Rybak

Lerner

Levine

et al. 1991

The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.Teicoplanin is an investigational glycopeptide which is chemically related to vancomycin. Like vancomycin, it is active against gram-positive aerobic and anaerobic bacteria, including methicillin-resistant staphylococci (6,8,9,21,(24)(25)(26). The in vivo activity of teicoplanin for serious staphylococcal infections has been established in experimental animal models (5,10,23). Clinical evaluations of teicoplanin for serious infections caused by gram-positive bacteria have demonstrated the potential efficacy of the drug, although clinical failures with low-dosage regimens have contributed to doubts regarding its ultimate utility (4, 13, 17, 28). Unlike vancomycin, teicoplanin can be administered intramuscularly, and it has a long terminal elimination half-life which permits extended dosing intervals. Furthermore, teicoplanin may have a lower toxicity profile (2,4,26).In a preliminary comparative efficacy trial of teicoplanin versus vancomycin for intravenous drug abuse (IVDA)-associated bacterial endocarditis at Detroit Receiving Hospital, teicoplanin concentrations in serum were consistently lower than expected based on the pharmacokinetics of teicoplanin in normal healthy volunteers (Fig. 1). As a result of this observation, we determined the pharmacokinetics of teicoplanin in IVDA-associated bacterial endocarditis, in order to explore the possible mechanisms responsible for these findings.( After entry into the study, continuation in the protocol required isolation in blood culture of a gram-positive pathogen (methicillin-susceptible or methicillin-resistant staphylococcus, or streptococcus) which was susceptible to teicoplanin. The exclusion criteria were compromised renal function (serum creatinine level, >1.5 mg%), elevated liver transaminase (more than four times normal), pregnancy or lactation, known hypersensitivity to vancomycin, or concomitant antibiotic use. Dosage administration. Teicoplanin (10 to 1...

“…Teicoplanin is a parenteral glycopeptide antibiotic with an antibacterial spectrum like that of vancomycin (1,9). Unlike vancomycin, teicoplanin is well tolerated after intramuscular administration.…”

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confidence: 99%

Effects of dosage, peak and trough concentrations in serum, protein binding, and bactericidal rate on efficacy of teicoplanin in a rabbit model of endocarditis

Chambers

Kennedy

1990

The effect of dosage and the relative importance of peak and trough concentrations in serum for efficacy of teicoplanin were examined in a rabbit model of aortic valve endocarditis. Concentrations of teicoplanin in serum exceeded the MIC by several hundredfold, yet teicoplanin was less rapidly bactericidal than penicillin both in vitro and for endocarditis caused by a strain of Streptococcus sanguis. Because Teicoplanin is a parenteral glycopeptide antibiotic with an antibacterial spectrum like that of vancomycin (1, 9). Unlike vancomycin, teicoplanin is well tolerated after intramuscular administration. Its half-life in humans is 32 h or longer (14). Because of its long half-life, once-daily dosing may be possible for treatment of serious infections.In clinical trials employing relatively low doses of 200 to 400 mg once daily, however, teicoplanin was less effective for treatment of serious staphylococcal infections than was a standard regimen (3). Treatment failures have occurred in open trials (2, 10), and inability to achieve adequate concentrations in serum with recommended dosages has been implicated as a cause of failure (11). Recently, a multicenter study comparing teicoplanin with vancomycin for treatment of staphylococcal bacteremia and endocarditis was halted when interim analysis suggested that teicoplanin was less effective than vancomycin (D. N. Gilbert, C. A. Wood, R. Bracis, R. C. Kimbrough, and the Infectious Diseases Consortium of Oregon, Program Abstr. 28th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 935, 1988).In an effort to understand factors that might contribute to therapeutic failure, the experiments described below were conducted to examine the relationship between concentrations of teicoplanin in serum and efficacy of the drug in a rabbit model of aortic valve endocarditis. MATERIALS AND METHODSBacterial strains. Streptococcus sanguis Poise and methicillin-resistant Staphylococcus aureus 67-0 (4) were used to establish endocarditis.In vitro susceptibility. MICs were determined by macrodilution (12) in Todd-Hewitt broth for the streptococcal strain and in Mueller-Hinton broth for the staphylococcal strain with inocula of approximately 2 x 105 CFU/ml. MICs were read after the strains were incubated at 37°C for 24 h. MBCs were determined by quantitative culture of broth at each * Corresponding author.concentration that showed no visible growth. The MBC was defined as the concentration yielding a 99.9% reduction in the number of viable counts.Time-kill studies were performed at 37°C in 10 ml of Trypticase (BBL Microbiology Systems) soy broth (TSB) and in TSB plus 50% pooled rabbit serum, with inocula of 3 x 105 CFU/ml. An antibiotic concentration four times the MIC was used. Samples (100 ,u) were taken at 0, 4, and 24 h and quantitatively subcultured onto blood agar. Colonies were counted after a 24-h incubation at 37°C.Protein binding. Binding of teicoplanin to serum proteins was determined by ultrafiltration centrifugation (6). Pooled rabbit serum was spiked with either 5...