In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model

Moine, Pierre; Vallée, E; Azoulay-Dupuis, E.; Bourget, Philippe; Bédos, J P; Bauchet, Jacqueline; Pocidalo, J J

doi:10.1128/aac.38.9.1953

Cited by 54 publications

(43 citation statements)

References 28 publications

(28 reference statements)

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“…Typically, strains of capsular serotypes 2, 3, 4, 5, and 6 are virulent in mice, whereas strains of types 14, 19, and 23 are relatively avirulent (21,39). The low virulence of many pneumococcal strains in rodents can be balanced by either using larger challenge doses (40) or neutropenic hosts (19,49,169,221,223).…”

Section: Considerations Of Animal and Pneumococcal Strainsmentioning

confidence: 99%

“…They have widely been used for analyzing pathogenicity mechanisms of pneumonia (50,58,114,120,125,131), sepsis (109,131,251), and meningitis (59,95,160,268). In addition, outbred mice have also been employed to evaluate active and passive protection against pneumonia and sepsis (4, 115, 163) and the efficacy of antibiotic therapy against invasive pneumococcal disease (13,141,169,220,223). The host genetic factors controlling the response to infection by S. pneumoniae are still unknown.…”

Section: Considerations Of Animal and Pneumococcal Strainsmentioning

confidence: 99%

“…model of penicillin-resistant pneumococcal pneumonia in immunocompetent CBA/J mice (234). This experimental system represents the first example of penicillin-resistant pneumonia in uncompromised mice, which are generally quite insensitive to infection by penicillin-resistant strains (169). The last model was employed both for therapeutic studies (229,233) and for analyzing the host inflammatory response during pneumonia (228).…”

Section: Mouse Modelsmentioning

confidence: 99%

“…The oropharynges were transilluminated, and the tracheas were cannulated with needles attached to microliter syringes containing the pneumococcal suspension (12). This model is still used in several studies on drug efficacy, host response to infection, and the role of pneumococcal virulence factors in the disease (1,11,19,168,169,208,237). Another i.t.…”

Section: Mouse Modelsmentioning

confidence: 99%

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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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Section: Considerations Of Animal and Pneumococcal Strainsmentioning

confidence: 99%

Section: Considerations Of Animal and Pneumococcal Strainsmentioning

confidence: 99%

Section: Mouse Modelsmentioning

confidence: 99%

Section: Mouse Modelsmentioning

confidence: 99%

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Animal Models ofStreptococcus pneumoniaeDisease

2008

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“…While it is impossible and unrealistic to link in vivo model outcomes to clinical situations, it is important to design an experiment that allows investigators to obtain a reasonable estimation of drug activity during a specific form of infection, e.g., in pneumonia. It is well documented that mice are not susceptible to any but the most virulent strains of S. pneumoniae (2); therefore, immunosuppression is required in order to induce lethal infection (13,24). Recently, one strain of mouse, CBA/J, has been found to be susceptible to strains of S. pneumoniae without the use of immunosuppressive agents and has been used successfully in a pneumonia model (21).…”

mentioning

confidence: 99%

Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal Pneumonia

Tessier¹,

Kim²,

Wei³

et al. 2002

Antimicrob Agents Chemother

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The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10 8 -CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentrationtime curve from 0 to 24 h (AUC 0-24 ) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r 2 ‫؍‬ 0.72 to 0.82), median survival (r 2 ‫؍‬ 0.93 to 0.94), and total percent survival (r 2 ‫؍‬ 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC 0-24 /MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were >4 g/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 g/ml.

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Effect of ABCC2 and ABCG2 Gene Polymorphisms and CSF‐to‐Serum Albumin Ratio on Ceftriaxone Plasma and Cerebrospinal Fluid Concentrations

Allegra

Cardellino

Fatiguso

et al. 2018

The Journal of Clinical Pharma

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We measured ceftriaxone pharmacokinetics in patients' plasma and cerebrospinal fluid (CSF) and assessed the influence of biometric, demographic, genetic (ABCB1, ABCC2, ABCB11, ABCG2, and SLCO1A2 polymorphisms) and pathological features. Adult patients with signs and symptoms of central nervous system infections, receiving intravenous ceftriaxone, were enrolled. Ceftriaxone plasma and CSF concentrations were measured by high-precision liquid chromatographic methods; allelic discrimination was performed by real-time polymerase chain reaction. Forty-three patients were included: median ceftriaxone maximal concentration was 15,713 ng/mL in plasma and 3512 ng/mL in CSF with a CSF-to-plasma ratio of 0.3. ABCC2 1249 rs2273697 (P = .027) and ABCG2 1194+928 rs13120400 (P = .015) variants were significantly associated with CSF concentrations and CSF-to-plasma ratios. At linear regression analysis, CSF-to-serum albumin ratio was an independent predictor of ceftriaxone CSF concentrations (P = .001; also in those with intact blood-brain barrier: P = .031) and CSF-to-plasma ratio (P = .001; also in those with blood-brain barrier impairment: P = .040). We here report the role of transporters' genetic variants as well as of blood-brain barrier permeability in predicting ceftriaxone exposure in the central nervous system.

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In vivo efficacy of a broad-spectrum cephalosporin, ceftriaxone, against penicillin-susceptible and -resistant strains of Streptococcus pneumoniae in a mouse pneumonia model

Cited by 54 publications

References 28 publications

Animal Models ofStreptococcus pneumoniaeDisease

Animal Models ofStreptococcus pneumoniaeDisease

Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal Pneumonia

Effect of ABCC2 and ABCG2 Gene Polymorphisms and CSF‐to‐Serum Albumin Ratio on Ceftriaxone Plasma and Cerebrospinal Fluid Concentrations

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