Linezolid against penicillin-sensitive and -resistant pneumococci in the rabbit meningitis model

Cottagnoud, Philippe

doi:10.1093/jac/46.6.981

Cited by 64 publications

(33 citation statements)

References 11 publications

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“…In a study with a rabbit meningitis model, the authors noted that linezolid showed good penetration into the cerebrospinal fluid of rabbits (mean Ϯ SD, 38% Ϯ 4%) (8). In a limited study of CSF penetration in patients with ventricular-peritoneal shunts and noninflamed meninges, the CSF concentration/plasma concentration ratio was 0.7:1.0 after multiple linezolid doses (18).…”

Section: Discussionmentioning

confidence: 99%

Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

Myrianthefs

Markantonis

Vlachos

et al. 2006

Antimicrob Agents Chemother

103

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Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens commonly responsible for central nervous system (CNS) infections in neurosurgical patients hospitalized in intensive care units. In order to study the penetration of this antimicrobial into the cerebrospinal fluid (CSF) of such patients, the disposition of linezolid in serum and CSF was studied in 14 neurosurgical patients given linezolid at 600 mg twice daily (1-h intravenous infusion) for the treatment of CNS infections caused by gram-positive pathogens or for prophylactic chemotherapy. Serum and CSF linezolid steady-state concentrations were analyzed by high-pressure liquid chromatography, and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters. The mean ؎ standard deviation (SD) linezolid maximum and minimum measured concentrations were 18.6 ؎ 9.6 g/ml and 5.6 ؎ 5.0 g/ml, respectively, in serum and 10.8 ؎ 5.7 g/ml and 6.1 ؎ 4.2 g/ml, respectively, in CSF. The mean ؎ SD areas under the concentration-time curves (AUCs) were 128.7 ؎ 83.9 g · h/ml for serum and 101.6 ؎ 59.6 g · h/ml for CSF, with a mean penetration ratio for the AUC for CSF to the AUC for serum of 0.66. The mean elimination half-life of linezolid in CSF was longer than that in serum (19.1 ؎ 19.0 h and 6.5 ؎ 3.6 h, respectively). The serum and CSF linezolid concentrations exceeded the pharmacodynamic breakpoint of 4 g/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. These findings suggest that linezolid may achieve adequate concentrations in the CSF of patients requiring antibiotics for the management or prophylaxis of CNS infections caused by gram-positive pathogens.Linezolid is the first member of a new synthetic class of antimicrobials, the oxazolidinones, to be used in clinical practice. It acts by selectively inhibiting the initiation of bacterial protein synthesis with a unique mechanism that precludes cross-resistance to currently available agents (10). In vitro and in vivo studies have demonstrated that linezolid has significant bacteriostatic activity against multiresistant gram-positive pathogens, such as coagulase-negative Staphylococcus species, Staphylococcus aureus, vancomycin-resistant enterococci, and Streptococcus pneumoniae, with MIC 90 s generally ranging from 0.5 to 4 g/ml (5, 26).Gram-positive cocci, mainly staphylococci, are the most frequent pathogens involved in central nervous system (CNS) postneurosurgical infections (26). Severe CNS infections caused by gram-positive pathogens may also be related to head trauma with skull fracture in neurosurgical patients, especially in the presence of an external drainage or ventriculoperitoneal shunt. Thus, these patients require antibiotics either for the management of infections or for prophylaxis against such infections. The frequency of CNS infections subsequent to neurosurgical procedures is estimated to be ϳ4% (25). As the epidemiology of CNS infection in neurosurgical patients evolves and the pr...

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Section: Discussionmentioning

confidence: 99%

Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

Myrianthefs

Markantonis

Vlachos

et al. 2006

Antimicrob Agents Chemother

103

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“…The use of this model greatly helped the understanding of several aspects of pneumococcal meningitis, including bacterial replication in the CSF, host defenses and inflammation, BBB alteration, and also the systemic effects of meningitis on animal respiration and circulation (236). Numerous studies have been undertaken to evaluate antibiotic efficacy (34,64,73,85,172,189,203,226,231) and the role of host and bacterial factors in disease pathogenesis (10,36,247). Interestingly, the effectiveness of a bactericidal but nonbacteriolytic antibiotic, such as daptomycin, in clearing pneumococcal infection from the CSF and in reducing inflammation was proven by means of both this rabbit model (226) and a previously described rat model (94).…”

Section: Rat and Rabbit Modelsmentioning

confidence: 99%

Animal Models ofStreptococcus pneumoniaeDisease

2008

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SUMMARY Streptococcus pneumoniae is a colonizer of human nasopharynx, but it is also an important pathogen responsible for high morbidity, high mortality, numerous disabilities, and high health costs throughout the world. Major diseases caused by S. pneumoniae are otitis media, pneumonia, sepsis, and meningitis. Despite the availability of antibiotics and vaccines, pneumococcal infections still have high mortality rates, especially in risk groups. For this reason, there is an exceptionally extensive research effort worldwide to better understand the diseases caused by the pneumococcus, with the aim of developing improved therapeutics and vaccines. Animal experimentation is an essential tool to study the pathogenesis of infectious diseases and test novel drugs and vaccines. This article reviews both historical and innovative laboratory pneumococcal animal models that have vastly added to knowledge of (i) mechanisms of infection, pathogenesis, and immunity; (ii) efficacies of antimicrobials; and (iii) screening of vaccine candidates. A comprehensive description of the techniques applied to induce disease is provided, the advantages and limitations of mouse, rat, and rabbit models used to mimic pneumonia, sepsis, and meningitis are discussed, and a section on otitis media models is also included. The choice of appropriate animal models for in vivo studies is a key element for improved understanding of pneumococcal disease.

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“…A recent study using the rabbit meningitis model studied the efficacy of linezolid against penicillin-sensitive and penicillin-resistant pneumococci (41). The authors noted that linezolid showed good penetration into the cerebrospinal fluid of rabbits (mean [ϮSD], 38% Ϯ 4%).…”

Section: Reviewmentioning

confidence: 99%

Linezolid: The First Oxazolidinone Antimicrobial

2003

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Linezolid is the first of a new class of antimicrobial agents, the oxazolidinones, to be approved for clinical use in the United States and elsewhere. The drug is a totally synthetic compound, which lessens the likelihood of naturally occurring resistance mechanisms. It has excellent activity against virtually all important gram-positive pathogens, including methicillin-resistant staphylococci, penicillin-resistant pneumococci, macrolide-resistant streptococci, and vancomycin-resistant enterococci. Development of resistance to the compound has been infrequent thus far. Linezolid is 100% bioavailable, so it can be given in equal doses orally or parenterally. Its elimination half-life allows dosing twice per day, and alteration of drug dosage is not required in patients with impaired renal or hepatic function. Linezolid has approved indications for skin and soft tissue infections; lower respiratory tract infections; and vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia. The drug has an acceptable profile of adverse events, but reversible myelosuppression has occurred in patients receiving high doses for more than 2 weeks.

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Linezolid against penicillin-sensitive and -resistant pneumococci in the rabbit meningitis model

Cited by 64 publications

References 11 publications

Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

Animal Models ofStreptococcus pneumoniaeDisease

Linezolid: The First Oxazolidinone Antimicrobial

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