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Antimicrobial Agents and Chemotherapy, February 2006, p. 770-773, Vol. 50, No. 2
0066-4804/06/$08.00+0 doi:10.1128/AAC.50.2.770-773.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Department of Internal Medicine, Inselspital, Bern, Switzerland,1 Clinical of Pneumology, Inselspital, Bern, Switzerland,2 Clinical of Internal Medicine, Spital Bern-Ziegler, Bern, Switzerland3
Received 17 June 2005/ Returned for modification 1 August 2005/ Accepted 31 October 2005
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into noninflamed meninges after two intravenous injections (30 mg/kg of body weight). In experimental meningitis, telavancin was significantly superior to vancomycin combined with ceftriaxone against a penicillin-resistant pneumococcal strain. Against a methicillin-sensitive staphylococcal strain, telavancin was slightly but not significantly superior to vancomycin. |
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Telavancin is a recently developed lipoglycopeptide with excellent and rapid bactericidal activity against the most relevant gram-positive microorganisms (10). The aim of this study was to evaluate the activities of telavancin against a penicillin-resistant pneumococcal strain and a methicillin-sensitive staphylococcal strain in experimental meningitis and to determine the kinetic parameters of its penetration into the CSF.
Pneumococcal strain. Pneumococcal strain WB4 (a penicillin-resistant serotype 6 strain; MIC, 4 mg/liter) was isolated from the blood of a patient at the Inselspital in Bern, Switzerland, and was provided by the Institute for Infectious Diseases at the University of Bern. This strain was grown in Muller-Hinton broth (MHB) to a density of approximately 108 CFU/ml and was then diluted to circa 106 CFU/ml for in vivo experiments. The MICs were determined in liquid cultures; and growth was controlled after 6, 12, and 24 h because of the spontaneous autolysis of the pneumococci. The MICs were as follows: ceftriaxone, 0.5 mg/liter, vancomycin, 0.12 mg/liter; and telavancin, 0.06 mg/liter.
Staphylococcal strain. Methicillin-susceptible S. aureus strain 1112 was kindly provided by José Entenza, Department of Infectious Diseases, University Hospital Lausanne. This strain has routinely been used in experimental models of endocarditis (4). The strain was grown in MHB to a density of approximately 108 CFU/ml and was then diluted for in vivo experiments. The MICs were determined in liquid cultures. The MICs were as follows: vancomycin, 1 mg/liter; and telavancin, 2 mg/liter.
Experimental meningitis model. The experimental rabbit meningitis model described by Dacey and Sande (2) was used in this project. The experimental protocols were approved by the federal veterinary office of the County of Bern.
Pathogen-free New Zealand rabbits (weight, 2.5 to 3 kg) were provided by the Zentraltierställe der Medizinischen Fakultät der Universität Bern, where all the experiments were performed.
One day before an experiment, the rabbits were anesthetized by intramuscular injection of a combination of ketamine and xylazine to fit a prosthesis on the calvaria to facilitate subsequent placement within a stereotactic frame. On the day of the experiment, the rabbits received 1.75 g/kg of body weight ethylcarbamate (urethane) subcutaneously and then 10 mg/kg pentobarbital intravenously to induce deep anesthesia. The animals were fixed in stereotactic frames, and a 3.5-in. (25-gauge) spinal needle was introduced into the cisterna magna. Following the withdrawal of 0.2 ml of CSF, either pneumococci or staphylococci (1 x 105 CFU in 0.2 ml of saline solution) were injected into the subarachnoid space. After inoculation, the animals were placed back in their cages for the night. The next day, the rabbits were again fitted in the frames by using the techniques and anesthesia described above. A catheter was fixed in the femoral artery for serum sampling. A spinal needle was again fixed in the subarachnoid space. Antibiotics were injected intravenously at the doses described in the literature (12, 13): ceftriaxone at 100 mg/kg and vancomycin at 20 mg/kg for the group infected with pneumococci and vancomycin at 20 mg/kg for the group infected with staphylococci. The ceftriaxone and vancomycin doses were the standard doses used for rabbits.
Telavancin was administered at a dose (twice at 30 mg/kg) that mimics the levels measured in the serum of humans. Vancomycin and telavancin were given at hours 0 and 4 and ceftriaxone was given at hour 0, according to their pharmacokinetic properties. CSF (0.2 ml) was sampled at 0, 1, 2, 4, 5, 6, and 8 h after the initiation of therapy. Blood samples were collected at 0.25, 0.5, 1, 2, 3, 4, 4.25, 4.5, 5, 6, 7, and 8 h after the initiation of therapy. Each group included untreated controls, which received a comparable volume of saline.
Determination of antibiotic levels and CFU titers. The free telavancin concentrations in serum and CSF were determined by high-performance liquid chromatography (kindly performed by Theravance Company). The numbers of CFU were measured by serial dilution of CSF, which was plated on agar plates (S. aureus) or on agar plates with 5% sheep blood (Streptococcus pneumoniae) and incubated overnight at 37°C in 5% CO2.
Statistical analysis. The Student t test and one-way analysis of variance (Newman-Keuls multiple-comparisons test) were used for parametric data. Positive and negative cultures were compared by the two-tailed Fisher exact test. A P value of <0.05 was considered significant.
The kinetics of the free (non-protein-bound) telavancin (administered twice at 30 mg/kg) are presented in Fig. 1A and B. After one injection, serum telavancin levels peaked at about 200 mg/liter and slowly decreased to 50 mg/liter 4 h later. The second injection led to peak levels from 160 to 200 mg/liter and decreased to 70 to 50 mg/liter at the end of the treatment period (Fig. 1A). The dose used in this study (two doses of 30 mg/kg) corresponded approximately to the dose of 15 mg/kg recently tested in humans (15). The peak levels in serum were similar in both species, i.e., 210 to 213 mg/kg in rabbits and 203 mg/kg in humans. Because of the shorter half-life of telavancin in rabbits (4 h in rabbits versus 8 h in humans), a second dose was injected into the rabbits after 4 h in order to mimic the kinetics of telavancin in the serum of humans. In the CSF, the first injection of telavancin produced a peak level of 1.8 mg/liter in inflamed meninges and remained stable without a significant decrease during the next 4 h. In contrast, the second injection led to a progressive increase to 3.8 mg/liter at the end of the experimental period (Fig. 1B). As known from a previous study (5), vancomycin, when it is used at standard doses (twice at 20 mg/kg) in rabbits, produces CSF levels (1.5 to 4.0 mg/liter). Similar to those produced by telavancin. During the entire treatment period, the telavancin CSF levels remained above the MIC for both strains, leading to CSF/MIC ratios that ranged from 30 to 63 for the pneumococcal strain and from 0.9 to 1.9 for the staphylococcal strain. The penetration of unbound telavancin into inflamed meninges was about 2%, whereas that into noninflamed meninges was negligible and was lower than 1. However, due to the high level of protein binding (ca. 93%) (15), the real penetration of telavancin into inflamed meninges might be much higher. The pharmacokinetic parameters are summarized in Table 1.
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log10 CFU/ml · h]) and produced a decrease in the viable cell count of 6.12 log10 at the end of the treatment period, managing to sterilize the CSF from 6 of 10 rabbits. The standard regimen based on a combination of vancomycin with ceftriaxone produced a less rapid decrease in the bacterial titer (–0.61 ± 0.13 versus –0.84 ± 0.23 log10 CFU/ml · h for telavancin; P < 0.01) and was significantly less efficacious after 8 h. The CSF from 4 of 10 of rabbits was sterile at the end of the experimental period when the standard regimen was used. The high degree of efficacy of telavancin against pneumococci is based on its high intrinsic bactericidal activity due to the unique dual mechanism of action of telavancin and on the high CSF/MIC ratios (from 30 to 63), which seems to be the major pharmacodynamic parameter of telavancin (16). Addition of a cephalosporin, e.g., ceftriaxone, as used in the standard regimen, might increase the efficacy of telavancin, in analogy to the synergy between ß-lactam and glycopeptide antibiotics.
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Two factors are probably responsible for the relatively reduced activity of telavancin against staphylococci. First, the low CSF/MIC ratio of from 0.9 to 1.9 and the lower starting bacterial titer before the initiation of therapy may explain the lower decrease in the viable cell count after 8 h, although the number of CSF samples that were sterile was similar in both groups (staphylococci and pneumococci). Two of the four CSF samples from rabbits infected with Staphylococcus aureus that were not sterilized contained the lowest levels of telavancin. A higher dosage of telavancin will probably be more efficacious for the treatment of staphylococcal meningitis, mainly by increasing the CSF/MIC ratio. We are aware that vancomycin is not the standard regimen for the treatment of methicillin-sensitive staphylococcal meningitis, but the aim of this study was to compare telavancin to a standard glycopeptide antibiotic.
In summary, despite its relatively low level of penetration into inflamed meninges, telavancin was a very efficacious monotherapy against a penicillin-resistant pneumococcal strain and was even superior to the standard regimen (vancomycin plus ceftriaxone). Higher dosages of telavancin for the treatment of staphylococcal meningitis should be tested.
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