In vitro studies of the pharmacodynamics of teicoplanin against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium

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1 ORIGINAL ARTICLE In vitro studies of the pharmacodynamics of teicoplanin against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium I. Odenholt, E. LoÈwdin and O. Cars Antibiotic Research Unit, Department of Infectious Diseases and Clinical Microbiology, University Hospital, Uppsala, Sweden Objective To investigate the basic pharmacodynamic properties of teicoplanin in vitro for Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium. Methods The following experiments were performed: (1) bacterial killing by teicoplanin at different concentrations; (2) bacterial killing by teicoplanin at 8 MIC against the same strains with inocula of , and CFU/mL; (3) studies of the postantibiotic effect (PAE) and the postantibiotic sub-mic effect (PASME) of teicoplanin; (4) studies of the killing by teicoplanin in an in vitro kinetic model following exposure to simulated human serum pharmacokinetic concentrations (6 mg/kg OD at steady state). Results Concentration-dependent killing was noted against S. epidermidis,witha>4 log 10 difference in CFUs between 2 MIC and 64 MIC at 24 h. Also, against S. aureus there was slight concentration-dependent killing, which, however, did not reach 2 log 10 CFU/ ml. Teicoplanin exerted a similar killing rate at all inocula for S. epidermidis, except for slower initial killing up to 6 h at the highest inoculum. In contrast, overall slower killing at all inocula was seen for S. aureus, where an inoculum effect was noted at the highest inoculum. For E. faecium, only a bacteriostatic effect was noted at all concentrations and inocula. No or very short PAEs were noted for the investigated strains. However, when the strains in the postantibiotic phase were exposed to 0.1, 0.2 and 0.3 MIC of teicoplanin (PASME), substantial prolongation of the PAEs was seen. Although no signi cant killing was achieved in our kinetic model for any of the strains, regrowth of S. epidermidis was noted rst after 8 h, despite a T > MIC 24 of only 5% (1.2 h), illustrating the long post-mic effect for this strain. For S. aureus, T > MIC was 38%, and regrowth occurred later than for S. epidermidis. Neither killing nor regrowth was seen for E. faecium with a T > MIC 24 of 27%. Conclusion Teicoplanin exerted a concentration-dependent bactericidal effect against S. epidermidis, a less notable one against S. aureus, and a bacteriostatic effect against E. faecium. A reduced killing rate with increasing inocula was seen for S. aureus and also for S. epidermidis at the highest inoculum. No or very short PAEs were noted for the investigated strains, but were substantially prolonged with the addition of subinhibitory concentrations. When human pharmacokinetics was simulated (6 mg/kg OD at steady state) in the kinetic model, no net bactericidal effect was noted for any of the strains at 24 h. Keywords Teicoplanin, pharmacodynamics, in vitro kinetic model Clin Microbiol Infect 2003; 9: 930±937 Corresponding author and reprint requests: Inga Odenholt, Department of Infectious Diseases, University Hospital MAS, MalmoÈ, Sweden Tel: Fax: inga.odenholt@inf.mas.lu.se INTRODUCTION Results from in vitro studies and studies in animals have shown that different classes of antibiotics behave differently with respect to their ß 2003 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Odenholt et al Pharmacodynamics of teicoplanin 931 pharmacodynamics [1±4]. Basic pharmacodynamic properties such as the rate of bacterial killing at different concentrations and different inocula, the postantibiotic effect (PAE), the postantibiotic sub- MIC effect (PASME) and the killing and regrowth pattern after a single-dose exposure to simulated human pharmacokinetics (post-mic effect; PME) are helpful to determine the pharmacokinetic/ pharmacodynamic indices that are correlated with ef cacy [3,5±8]. The pharmacodynamic properties of several classes of antibiotics, e.g. b-lactam antibiotics, uoroquinolones and aminoglycosides, are fairly well characterized [2,3,9±11]. There is, however, less information regarding the basic pharmacodynamic properties of glycopeptides. For vancomycin, it has been shown that the rate of killing is concentration independent, which would indicate that the ef cacy of this compound may be related to T > MIC [7,12]. However, long PAEs and PASMEs have also been documented [5,7,8], which may allow for longer antibiotic-free intervals. For teicoplanin, only scanty pharmacodynamic information is available. The aim of the present investigation was to describe the in vitro pharmacodynamic properties of teicoplanin: killing dynamics at different concentrations and different inocula, the PAE, the PASME and the killing and regrowth following exposure to teicoplanin simulating human pharmacokinetics (PME). Determination of MICs The MICs of teicoplanin and vancomycin for the strains investigated were determined in uid media by a macrodilution technique according to the National Committee for Clinical Laboratory Standards [13]. Two-fold serial dilutions of the antibiotics were added to broth, inoculated with a nal inoculum of approximately CFU of the test strain per ml, and incubated at 37 8C for 22±24 h. Measurements were done in triplicate on different occasions. The MIC was de ned as the lowest concentration of the antibiotic that allowed no visible growth. Owing to a high total bacterial number in the in vitro kinetic model (volume 108 ml, which, with a starting inoculum of CFU/mL, gives a total number of CFUs of ), MICs were also performed by the plate-dilution method with inoculaof and CFU/mL. The MICs of teicoplanin were also determined in the BioScreen C [14,15]. Two-fold serial dilutions of teicoplanin inbrothwere madeinmicroplatescontaining400-ml wells, and the test strains were added to give a bacterial density of approximately 10 5 CFU/mL. The plates were then incubated in the BioScreen C. The MIC determinations were done in triplicate. The MIC was de ned as the lowest concentration that prevented growth, as measured by optical density (OD). The lowest detectable level of OD for the strains corresponded to approximately CFU/mL. MATERIALS AND METHODS Antibiotic Teicoplanin was provided by Aventis, Romainville, France. The antibiotic was obtained as a reference powder with known potency. The substance was dissolved in 1 ml of phosphate-buffered saline (PBS) and thereafter diluted in Todd± Hewitt broth. Fresh solutions were made on the days of the experiments. Bacterial strains and media The following strains were studied: S. aureus ATCC (American Type Culture Collection) 29213, S. epidermidis ATCC 29886, and Enterococcus faecium CCUG (Culture Collection University of Gothenburg). The strains were grown in Todd±Hewitt broth for 6 h at 37 8C, resulting in approximately CFU/mL. Determination of teicoplanin concentrations The concentrations of teicoplanin during the in vitro kinetic experiments were determined by a microbiological agar diffusion method. Plates were seeded with Bacillus subtilis ATCC as the test organism. A standardized inoculum of bacterial suspension was poured over plates with IsoSensitest agar (Oxoid, Basingstoke, UK). After drying of the plates, 0.03-mL volumes of all samples and standards diluted in Todd±Hewitt broth were placed in agar wells, and the plates were then incubated overnight at 37 8C. The limit of detection was 0.5 mg/l. The correlation coef cient for the standard curves was always >0.99. All assays were made in triplicate. Bacterial killing at different static concentrations Tubes containing Todd±Hewitt broth were inoculated with the different strains, yielding a bacterial

3 932 Clinical Microbiology and Infection, Volume 9 Number 9, September 2003 density of approximately CFU/mL. Teicoplanin was added at concentrations corresponding to 2, 4, 8, 16 and 64 MIC, respectively. A growth control was also included. The tubes were then incubated at 37 8C, and samples for viable counting were drawn at 0, 2, 4, 6, 8, 12 and 24 h, and, if necessary, diluted in PBS. At least three dilutions of each sample were spread on blood agar plates (Colombia agar base with 5% horse blood), incubated at 37 8C, and counted after 24 h. The detection limit was CFU/mL. All experiments were performed in triplicate. Bacterial killing at different inocula In the second set of experiments, the strains at three different inocula (approximately , and CFU/mL) were exposed to teicoplanin at a concentration of 8 MIC for each strain. The tubes were then incubated at 37 8C, and samples for viable counting were drawn at 0, 3, 6, 9, 12 and 24 h, and diluted and counted as described above. The experiments were performed in triplicate for all strains. The postantibiotic effect and the postantibiotic sub-mic effect of teicoplanin in BioScreen C The BioScreen C (Laboratory Systems, Helsinki, Finland) is a computerized incubating turbidometric reader, where growth curves are monitored continuously, which is useful for following bacterial regrowth in the PAE and PASME determinations. The machine can process 200 wells simultaneously. The PAEs and PASMEs of the strains were investigated in the BioScreen C. After incubation for 6 h, the strains were diluted in order to obtain an inoculum of approximately CFU/mL at the beginning of the experiments. The strains were then exposed to 10 MIC (as measured in BioScreen C) of the antibiotics for 2 h at 37 8C. To eliminate the antibiotic, the strains were washed three times, centrifuged each time for 5 min at 1400g and diluted in fresh medium. The unexposed control strains were washed similarly but were diluted 10 2,10 3,10 4 and 10 5 in order to obtain an inoculum as close to the exposed strains as possible. Viable counts of the exposed cultures were measured before antibiotic exposure, after 2 h of induction, and after washing. Viable counts of the controls were also measured at the start of the experiments, and at 2 h before and after washing and dilution. Both the exposed strains and the different dilutions of the controls were then transferred in volumes of 40 ml inoculated into microtiter wells with 360 ml of Todd± Hewitt broth, and incubated in the BioScreen C at 35 8C. Growth was measured automatically as OD at 540 nm every 10 min for 20 h, and curves were drawn by the computer. Earlier experimental studies [14] have shown that the growth of controls with different inocula is parallel. In the experiments where viable counts of the exposed culture and the control did not quite match in the inoculum, a corrected control curve for each strain and experiment could therefore be constructed. The PAE was calculated as the difference in time required for the exposed cultures and the corresponding control to grow to a de ned point (A 50 ) on the OD curve, where A 50 is de ned as 50% of the maximal OD of the control [14,15]. The PASMEs for the same strains were determined as follows. The postantibiotic phase was induced as described above, and the controls were diluted (10 2,10 3,10 4 and 10 5 ) in the same way as in the PAE experiments. Viable counts were also used as described above. The strains in the postantibiotic phase were then exposed to 0.1, 0.2 and 0.3 MIC of teicoplanin in Todd±Hewitt broth and incubated in the BioScreen C. Growth curves were monitored automatically for 20 h. The PASME was de ned as the difference in time required for the cultures exposed to subinhibitory concentrations in the postantibiotic phase and the corresponding control with the same inoculum as the pre-exposed culture to reach A 50 (de ned as described above) [14,15]. All experiments were performed in triplicate. Killing and regrowth following exposure to teicoplanin concentrations simulating human pharmacokinetics (PME) The studies were performed in an in vitro kinetic model consisting of a spinner ask, where the base is separated from the rest of the ask [6,7]. A perforated metal support is tted between the two parts, on which a lter membrane and a pre lter are placed. A magnetic stirrer in the center ensures homogeneous mixing of the culture and prevents membrane pore blockage. Medium is drawn from the culture vessel through the lter, at different rates to obtain the desired time±concentration pro le of the antibiotic. The apparatus

4 Odenholt et al Pharmacodynamics of teicoplanin 933 Figure 1 The concentrations of teicoplanin simulating human pharmacokinetics. Mean of nine experiments SD. was placed in a thermostatic room at 37 8C during the experiments. In these experiments, the three different bacterial strains were exposed to an initial concentration of 10 mg/l of teicoplanin, corresponding to the maximal free serum concentration achieved in humans following intravenous administration of 6 mg/kg at steady state. The concentrations then declined according to human pharmacokinetics [16] (Figure 1). Repeated samplings for antibiotic concentrations were performed at 0, 2, 4, 6, 8, 12 and 24 h. The PME was de ned as the difference in time required for the bacteria to grow by 1 log 10 CFU in the model calculated from the numbers at the MIC level and the time for a control culture to increase by 1 log 10 CFU [6]. RESULTS MICs The MICs determined by macrodilution were 1 mg/l for S. aureus ATCC 29213, 8 mg/l for S. epidermidis ATCC 29886, and 2 mg/l for E. faecium CCUG These MIC values were used in experiments 1 and 2. The MICs of vancomycin were 2 mg/l for all strains. The MICs of teicoplanin at the higher inoculum ( ) were one dilution step higher for S. aureus and E. faecium. These MIC values (2 mg/l and 4 mg/l, respectively) were used to calculate the pharmacokinetic/ pharmacodynamic parameters in experiment 4. The MIC values of teicoplanin in the BioScreen C were 0.5 mg/l, 4 mg/l and 1 mg/l for S. aureus ATCC 29213, S. epidermidis ATCC and E. faecium CCUG 33573, respectively. These values were used in experiment 3. Antibiotic concentrations The concentrations of teicoplanin simulated in the in vitro kinetic model are shown in Figure 1. Bacterial killing at different static concentrations Concentration-dependent killing was noted against S. epidermidis ATCC At 24 h, there was a >4 log 10 difference in CFUs between 2 MIC and 64 MIC (Figure 2a). For S. aureus ATCC 29213, there was slight concentrationdependent killing, with a 1±1.5 log 10 difference in CFUs for the highest and lowest concentrations at 12 h and 24 h, respectively (Figure 2b). Only a bacteriostatic effect was noted against E. faecium CCUG at all concentrations (Figure 2c). Bacterial killing at different inocula Teicoplanin exerted a similar killing rate at all inocula for S. epidermidis ATCC 29886, with the exception of slower initial killing at the highest inoculum. In comparison, overall slower killing at all inocula was seen against S. aureus ATCC 29213, for which an inoculum effect was noted at the highest inoculum. No killing was achieved with E. faecium CCUG for any inoculum (Table 1). Postantibiotic effects and postantibiotic sub- MIC effects of teicoplanin Only short or negative PAEs were seen for the investigated strains. The PASMEs at 0.3 MIC

5 934 Clinical Microbiology and Infection, Volume 9 Number 9, September 2003 PME could therefore be calculated. No regrowth was noted for this strain with a T > MIC 24 of 22%, AUC/MIC 24 of 26 and a peak/mic of 2.5 (Figure 3). DISCUSSION Figure 2 (a) Killing by teicoplanin at different concentrations against (a) S. epidermidis ATCC 29886, (b) S. aureus ATCC 29213, and (c) E. faecium CCUG Mean values of three experiments. for the investigated strains were, however, rather long, and varied between 3 h and 6 h (Table 2). Killing and regrowth following exposure to teicoplanin concentrations simulating human pharmacokinetics (PME) Teicoplanin exerted a long PME of 14.5 h against S. epidermidis, and regrowth was noted rst after 8 h, despite a T > MIC of only 5% (1.2 h) of 24 h. The AUC/MIC 24 and peak/mic for this strain were 13.1 and 1.3, respectively. For S. aureus, a PME of 8.6 h was noted, and regrowth started close to the time when the concentration reached the MIC (T > MIC 24 ˆ 38%). The AUC/MIC 24 and peak/ MIC were 52 and 5, respectively. As seen in the static experiments, teicoplanin exerted only a bacteriostatic effect against E. faecium, and no In the present investigation, concentration-dependent killing by teicoplanin was shown against S. epidermidis, with a >4 log 10 difference in CFU at 24 h between the highest and lowest concentrations. Also, against S. aureus there was slight concentration-dependent killing after 12 h, which, however, did not reach 2 log 10 CFU/mL. Bailey et al. also showed an increase in the bactericidal rate of teicoplanin against S. aureus up to a concentration of 90 mg/l [17]. Other authors studying S. aureus have, however, most often described teicoplanin as a non-concentration-dependent drug against this pathogen [18±21]. For vancomycin, concentration-dependent killing for the same strains of S. aureus and S. epidermidis was not demonstrated in an earlier study [7]. Teicoplanin exerted similar killing rates against S. aureus, but somewhat slower killing of S. epidermidis, as compared with vancomycin. Neither teicoplanin nor vancomycin [7] exerted a bactericidal effect on E. faecium. In our study, no inoculum effect was noted for S. epidermidis at 24 h, but one was noted for S. aureus at the higher inoculum, which was in accordance with the higher MIC value found at the inoculum of CFU/mL. No bactericidal effect at any inoculum was seen against E. faecium. An increase in MIC for teicoplanin at high inocula has previously been described [19,22]. A PAE of approximately 1 h was seen for S. aureus measured in the BioScreen. In our earlier study of vancomycin, a similar value was found against the same strain [7]. Other authors have reported a PAE of 1±2 h for methicillin-sensitive S. aureus measured with viable counts, but consistently longer PAEs for the methicillin-resistant strains (3±4 h) [23]. In the present study, a negative PAE of teicoplanin was seen against S. epidermidis ATCC 29886, which can be compared to a PAE of 4.8 h earlier found for vancomycin [7]. Cooper et al. could only detect a PAE against S. epidermidis with high doses of teicoplanin [23]. In our study, a PAE of 0.9 h was noted against E. faecium. Cooper et al. reported a PAE of 10 h against strains of E. faecium with viable counts, but only with high concentrations [23]. At 0.3 MIC, PASMEs of 3 h and 4 h

6 Odenholt et al Pharmacodynamics of teicoplanin 935 Table 1 Bacterial killing by teicoplanin at different inocula (D log 10 CFU from initial inoculum) Staphylococcus epidermidis ATCC Staphylococcus aureus ATCC E. faecium CCUG Strain h h h Table 2 The postantibiotic effects and the postantibiotic sub-mic effects of teicoplanin: mean of three experiments (range) PA SME (h) Bacterial strain PAE (h) 0.1 MIC 0.2 MIC 0.3 MIC 0.4 MIC Staphylococcus aureus ATCC (0.7±1.2) (1.2±2.0) (1.8±2.9) (2.9±4.4) (3.7±7.0) Staphylococcus epidermidis ATCC ( 0.7 to 3.2) ( 0.4 to 2.4) ( 0.6±3.0) (2.2±7.2) (4.3±9.6) Enterococcus faecium CCUG (0.8±1.0) (1.0±1.5) (1.9±4.2) (4.3±8.1) (7.4±12.5) Figure 3 Killing by teicoplanin in the in vitro kinetic model. Mean of three experiments SD. were noted for S. aureus and S. epidermidis, compared with 8 h and >12 h for the same strains induced by vancomycin [7]. The longest PASME (6 h) was seen for E. faecium, which might explain why no regrowth was noted for this strain. There are a few studies on the ef cacy of teicoplanin in relation to its pharmacodynamics. In a study of teicoplanin in a rabbit endocarditis model with S. aureus, doses were given intravenously or intramuscularly. A statistically signi cant reduction in the numbers of CFUs in the valve vegetations was seen with the intramuscular regimen, which gave a lower peak but a longer T > MIC compared with the intravenous regimen [24]. In another study, a maximum killing effect in neutropenic mice with a thigh infection was achieved during the time when the free serum concentration was above the MIC for teicoplanin [20]. Dahl- Knudsen et al., using a mouse peritonitis model, showed that T > MIC and high peak concentrations were the most important parameters for teicoplanin in ensuring survival of the animals infected with S. aureus and Streptococcus pneumoniae, in contrast to vancomycin, where peak/mic and AUC/MIC were the most important indices [25]. In clinical trials on endocarditis and Grampositive bacteremia, Rybak et al found a signi cant correlation between serum trough concentrations of teicoplanin and the number of days required for eradication of bacteremia, the number of days of fever, and also days when therapy could be ended [26]. These ndings are in accordance with a study of Harding et al., who showed that clinical outcome in S. aureus septicemia was signi cantly correlated with mean pre-dose serum concentration [27]. In our in vitro kinetic model simulating the free concentrations of teicoplanin reached in humans at steady state [16], no bactericidal effect was reached for any of the investigated strains. Our results can be compared with the ndings of Schaad et al., who, in a chronic tissue cage model in rats infected with methicillin-resistant S. aureus, were unable to show any signi cant reduction in viable counts during 7-day high-dose therapy (30 mg/kg OD) with teicoplanin, in contrast to a 2 log 10 kill seen with teicoplanin in combination

7 936 Clinical Microbiology and Infection, Volume 9 Number 9, September 2003 with rifampicin [28]. Even though no signi cant killing was achieved in our kinetic model for any of the strains, regrowth of S. epidermidis was noted rst after 8 h, despite a T > MIC 24 of only 5% (1.2 h), illustrating the long PME for this strain. For S. aureus, T > MIC was 38% and regrowth occurred later than for S. epidermidis. Neither killing nor regrowth was seen for E. faecium with a T > MIC 24 of 27%. In conclusion, we have shown that teicoplanin exerted a concentration-dependent effect against S. epidermidis, a less notable effect for S. aureus, and a bacteriostatic effect against E. faecium. An inoculum effect was seen against S. aureus and S. epidermidis. No or very short PAEs were noted for the investigated strains. However, when the strains in the postantibiotic phase were exposed to subinhibitory concentrations, a substantial prolongation of the PAEs was seen. When human pharmacokinetics was simulated (6 mg/kg OD at steady state) in the kinetic model, no net bactericidal effect was noted for any of the strains at 24 h. ACKNOWLEDGMENTS This study was supported by a grant from Aventis, Stockholm, Sweden. REFERENCES 1. Cars O. Efficacy of beta-lactam antibiotics: integration of pharmacokinetics and pharmacodynamics. Diagn Microbiol Infect Dis 1997; 27: 29± Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. J Pediatr Infect Dis 1996; 15: 255±9. 3. Craig WA. Pharmacokinetic/pharmacodynamic parameters. Rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1± Vogelman B, Gudmundsson S, Turnidge J, Legget J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988; 158: 831± Craig WA, Gudmundsson S. The postantibiotic effect. In: Lorian V, ed. Antibiotics in laboratory medicine, 4th edn. Baltimore: Williams & Wilkins, 1996: 296± LoÈwdin E, Odenholt I, Bengtsson S, Cars O. Pharmacodynamic effects of sub-mics of benzylpenicillin against Streptococcus pyogenes in a newly developed in vitro kinetic model. Antimicrob Agents Chemother 1996; 40: 2478± LoÈwdin E, Odenholt I, Cars O. In vitro studies of pharmacodynamic properties of vancomycin against Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother 1998; 42: 2739± Odenholt I, LoÈwdin E, Cars O. Postantibiotic sub- MIC effects of vancomycin, roxithromycin, sparfloxacin and amikacin. Antimicrob Agents Chemother 1992; 36: 1852±8. 9. Dagan R, Klugman KP, Craig WA, Baquero F. Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy. J Antimicrob Chemother 2001; 47: 129± Drusano GL, Johnson DE, Rosen M, Standiford HC. Pharmacodynamics of fluoroquinolone antimicrobial agents in a neutropenic rat model of pseudomonas sepsis. Antimicrob Agents Chemother 1993; 37: 483± Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37: 1073± Ackerman BH, Vannier AM, Eudy EB. Analysis of vancomycin time±kill studies with Staphylococcus species by using a curve stripping program to describe the relationship between concentration and pharmacodynamic response. Antimicrob Agents Chemother 1992; 36: 1766± National Committee for Clinical Laboratory Standards. Methods for determiningbactericidal activity of antimicrobial agents. Tentative Guideline M26-T. Villanova, Pa: NCCLS, LoÈwdin E, Odenholt I, Cars O. A new method to determine the postantibiotic effects and the effects of subinhibitory antibiotic concentrations. Antimicrob Agents Chemother 1993; 37: 2200± Odenholt I. The postantibiotic effect and the postantibiotic sub-mic effect of meropenem measured with two different methods. J Antimicrob Chemother 1993; 31: 881± Verbist L, Tjandragma B, Hendrickx B et al. In vitro activity and human pharmacokinetics of teicoplanin. Antimicrob Agents Chemother 1984; 26: 881± Bailey EM, Rybak MJ, Kaatz GW. Comparative effect of protein binding on the killing activities of teicoplanin and vancomycin. Antimicrob Agents Chemother 1991; 35: 1089± Greenberg RN, Benes CA. Time±kill studies with oxacillin, vancomycin and teicoplanin versus Staphylococcus aureus. J Infect Dis 1990; 161: 1036± Maple PAC, Hamiton-Miller JMT, Brumfitt W. Comparative in-vitro activity of vancomycin, teicoplanin, ramoplanin, Palimycin, DuP 721 and DuP 105 against methicillin and gentamicin resistant Staphylococcus aureus. J Antimicrob Chemother 1989; 23: 517± Peetermans WE, Hoogeterp JJ, Hazekampvan-Dokkum A-M, van den Broek P, Mattie H.

8 Odenholt et al Pharmacodynamics of teicoplanin 937 Antistaphylococcal activities of teicoplanin and vancomycin in vitro and in an experimental infection. Antimicrob Agents Chemother 1990; 34: 1869± Ravizzola G, Pirali F, Turano A. Comparison of the in vitro antibacterial activity of teicoplanin and vancomycin against gram-positive cocci. Drugs Exp Clin Res 1987; XIII: 225± Greenwood D, Bidgood K, Turner M. A comparison of the responses of staphylococci and streptococci to teicoplanin and vancomycin. J Antimicrob Chemother 1987; 20: 155± Cooper MA, Jin YF, Ashby JP, Andrews JM, Wise R. In vitro comparison of the post-antibiotic effect of vancomycin and teicoplanin. J Antimicrob Chemother 1990; 26: 203± Chambers HF, Kennedy S. Effects of dosage, peak, trough concentrations in serum, protein binding and bactericidal rate on efficacy of teicoplanin in a rabbit model of endocarditis. Antimicrob Agents Chemother 1990; 34: 510± Dahl KnudseÂn J, Fuursted K, Raber S, Espersen F, Frimodt-MoÈller N. Pharmacodynamics of glycopeptides in the mouse peritonitis model of Streptococcus pneumoniae or Staphylococcus aureus infection. Antimicrob Agents Chemother 2000; 44: 1247± Rybak MJ, Cappelletty DM, Kang SL, Levine DP, Levison ME. Pharmacodynamic evaluation of teicoplanin versus vancomycin in the treatment of Gram-positive bacteremia and endocarditis [abstract A36]. In: 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, LA. Washington, DC: American Society for Microbiology, 1996: Harding I, MacGowan AP, White LO, Darley ESR, Reed V. Teicoplanin therapy for Staphylococcus aureus septicemia: relationship between pre-dose serum concentrations and outcome. J Antimicrob Chemother 2000; 45: 835± Schaad HJ, Chuard C, Vaudaux P, Waldvogel FA, Lew DP. Teicoplanin alone or combined with rifampicin compared with vancomycin for prophylaxis and treatment of experimental foreign body infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1994; 38: 1703±10.