Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis

C. Mccoig, L. Wubbel, I. Lutsar, I. R. Friedland, R. Bastero, H. Jafri, S. Shelton, K. Olsen, G. H. Mccracken

Research output: Contribution to journalArticle

Abstract

The antibacterial activity of quinolones in serum is concentration-dependent, but this has not been shown in cerebrospinal fluid (CSF). The aim of this study was to characterize the pharmacodynamic profile of trova in CSF in experimental cephalosporin-resistant (MBC ceftriaxone = 4 μg/ml; trova = 0.125 μg/ml) pneumococcal meningitis, to determine whether the activity is concentration- or time-dependent, and to suggest a treatment regimen for children with meningitis. Using the rabbit meningitis model we gave dosages of 10-20 mg/kg of trova in one or multiple IV doses. CSF was obtained to determine pharmacokinetic indices and bacterial concentrations for a period up to 24 h. Pharmacokinetic indices and bacterial killing in CSF after a single dose were as follows for 6 h: Dosage AUC Cpeak t1/2 (h) Bact. Killing Rate (mg/kg) (μg/ml · hr) (μg/ml) (Δlog CFU/ml/h) 10 1.93 plusmn; 0.14 0.60 plusmn; 0.12 1.33 plusmn; 0.21 0.38 15 2.60 plusmn; 0.06 0.68 plusmn; 0.04 1.79 plusmn; 0.07 0.55 20 3.92 plusmn; 0.05 1.18 plusmn; 0.07 1.41 plusmn; 0.04 0.73 During the first 6 h a concentration-dependent reduction in bacterial concentration was seen. From 6 to 12 h bacterial regrowth occurred in all dosage groups. Using a four dose regimen administered every half-life of trova in CSF (20 mg/kg loading, 10 mg/kg q2h X 3), 74% of CSF cultures were sterile after 24 h. Conclusions: 1) The Cpeak, AUC, and bacterial killing in CSF were directly related. 2) In CSF trova exhibits a concentration-dependent bacterial killing. 3) Trova is a potentially useful agent for therapy of highly beta-lactam-resistant pneumococcal meningitis when administered every half life.

Original languageEnglish (US)
Pages (from-to)486
Number of pages1
JournalClinical Infectious Diseases
Volume25
Issue number2
StatePublished - 1997

Fingerprint

Pneumococcal Meningitis
Cephalosporins
Cerebrospinal Fluid
Meningitis
Area Under Curve
Half-Life
Pharmacokinetics
Ceftriaxone
trovafloxacin
Quinolones
beta-Lactams
Rabbits

ASJC Scopus subject areas

  • Immunology

Cite this

Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis. / Mccoig, C.; Wubbel, L.; Lutsar, I.; Friedland, I. R.; Bastero, R.; Jafri, H.; Shelton, S.; Olsen, K.; Mccracken, G. H.

In: Clinical Infectious Diseases, Vol. 25, No. 2, 1997, p. 486.

Research output: Contribution to journalArticle

Mccoig, C, Wubbel, L, Lutsar, I, Friedland, IR, Bastero, R, Jafri, H, Shelton, S, Olsen, K & Mccracken, GH 1997, 'Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis', Clinical Infectious Diseases, vol. 25, no. 2, pp. 486.
Mccoig, C. ; Wubbel, L. ; Lutsar, I. ; Friedland, I. R. ; Bastero, R. ; Jafri, H. ; Shelton, S. ; Olsen, K. ; Mccracken, G. H. / Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis. In: Clinical Infectious Diseases. 1997 ; Vol. 25, No. 2. pp. 486.
@article{20ed4222f72f412fa1a7af6a829bde35,
title = "Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis",
abstract = "The antibacterial activity of quinolones in serum is concentration-dependent, but this has not been shown in cerebrospinal fluid (CSF). The aim of this study was to characterize the pharmacodynamic profile of trova in CSF in experimental cephalosporin-resistant (MBC ceftriaxone = 4 μg/ml; trova = 0.125 μg/ml) pneumococcal meningitis, to determine whether the activity is concentration- or time-dependent, and to suggest a treatment regimen for children with meningitis. Using the rabbit meningitis model we gave dosages of 10-20 mg/kg of trova in one or multiple IV doses. CSF was obtained to determine pharmacokinetic indices and bacterial concentrations for a period up to 24 h. Pharmacokinetic indices and bacterial killing in CSF after a single dose were as follows for 6 h: Dosage AUC Cpeak t1/2 (h) Bact. Killing Rate (mg/kg) (μg/ml · hr) (μg/ml) (Δlog CFU/ml/h) 10 1.93 plusmn; 0.14 0.60 plusmn; 0.12 1.33 plusmn; 0.21 0.38 15 2.60 plusmn; 0.06 0.68 plusmn; 0.04 1.79 plusmn; 0.07 0.55 20 3.92 plusmn; 0.05 1.18 plusmn; 0.07 1.41 plusmn; 0.04 0.73 During the first 6 h a concentration-dependent reduction in bacterial concentration was seen. From 6 to 12 h bacterial regrowth occurred in all dosage groups. Using a four dose regimen administered every half-life of trova in CSF (20 mg/kg loading, 10 mg/kg q2h X 3), 74{\%} of CSF cultures were sterile after 24 h. Conclusions: 1) The Cpeak, AUC, and bacterial killing in CSF were directly related. 2) In CSF trova exhibits a concentration-dependent bacterial killing. 3) Trova is a potentially useful agent for therapy of highly beta-lactam-resistant pneumococcal meningitis when administered every half life.",
author = "C. Mccoig and L. Wubbel and I. Lutsar and Friedland, {I. R.} and R. Bastero and H. Jafri and S. Shelton and K. Olsen and Mccracken, {G. H.}",
year = "1997",
language = "English (US)",
volume = "25",
pages = "486",
journal = "Clinical Infectious Diseases",
issn = "1058-4838",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis

AU - Mccoig, C.

AU - Wubbel, L.

AU - Lutsar, I.

AU - Friedland, I. R.

AU - Bastero, R.

AU - Jafri, H.

AU - Shelton, S.

AU - Olsen, K.

AU - Mccracken, G. H.

PY - 1997

Y1 - 1997

N2 - The antibacterial activity of quinolones in serum is concentration-dependent, but this has not been shown in cerebrospinal fluid (CSF). The aim of this study was to characterize the pharmacodynamic profile of trova in CSF in experimental cephalosporin-resistant (MBC ceftriaxone = 4 μg/ml; trova = 0.125 μg/ml) pneumococcal meningitis, to determine whether the activity is concentration- or time-dependent, and to suggest a treatment regimen for children with meningitis. Using the rabbit meningitis model we gave dosages of 10-20 mg/kg of trova in one or multiple IV doses. CSF was obtained to determine pharmacokinetic indices and bacterial concentrations for a period up to 24 h. Pharmacokinetic indices and bacterial killing in CSF after a single dose were as follows for 6 h: Dosage AUC Cpeak t1/2 (h) Bact. Killing Rate (mg/kg) (μg/ml · hr) (μg/ml) (Δlog CFU/ml/h) 10 1.93 plusmn; 0.14 0.60 plusmn; 0.12 1.33 plusmn; 0.21 0.38 15 2.60 plusmn; 0.06 0.68 plusmn; 0.04 1.79 plusmn; 0.07 0.55 20 3.92 plusmn; 0.05 1.18 plusmn; 0.07 1.41 plusmn; 0.04 0.73 During the first 6 h a concentration-dependent reduction in bacterial concentration was seen. From 6 to 12 h bacterial regrowth occurred in all dosage groups. Using a four dose regimen administered every half-life of trova in CSF (20 mg/kg loading, 10 mg/kg q2h X 3), 74% of CSF cultures were sterile after 24 h. Conclusions: 1) The Cpeak, AUC, and bacterial killing in CSF were directly related. 2) In CSF trova exhibits a concentration-dependent bacterial killing. 3) Trova is a potentially useful agent for therapy of highly beta-lactam-resistant pneumococcal meningitis when administered every half life.

AB - The antibacterial activity of quinolones in serum is concentration-dependent, but this has not been shown in cerebrospinal fluid (CSF). The aim of this study was to characterize the pharmacodynamic profile of trova in CSF in experimental cephalosporin-resistant (MBC ceftriaxone = 4 μg/ml; trova = 0.125 μg/ml) pneumococcal meningitis, to determine whether the activity is concentration- or time-dependent, and to suggest a treatment regimen for children with meningitis. Using the rabbit meningitis model we gave dosages of 10-20 mg/kg of trova in one or multiple IV doses. CSF was obtained to determine pharmacokinetic indices and bacterial concentrations for a period up to 24 h. Pharmacokinetic indices and bacterial killing in CSF after a single dose were as follows for 6 h: Dosage AUC Cpeak t1/2 (h) Bact. Killing Rate (mg/kg) (μg/ml · hr) (μg/ml) (Δlog CFU/ml/h) 10 1.93 plusmn; 0.14 0.60 plusmn; 0.12 1.33 plusmn; 0.21 0.38 15 2.60 plusmn; 0.06 0.68 plusmn; 0.04 1.79 plusmn; 0.07 0.55 20 3.92 plusmn; 0.05 1.18 plusmn; 0.07 1.41 plusmn; 0.04 0.73 During the first 6 h a concentration-dependent reduction in bacterial concentration was seen. From 6 to 12 h bacterial regrowth occurred in all dosage groups. Using a four dose regimen administered every half-life of trova in CSF (20 mg/kg loading, 10 mg/kg q2h X 3), 74% of CSF cultures were sterile after 24 h. Conclusions: 1) The Cpeak, AUC, and bacterial killing in CSF were directly related. 2) In CSF trova exhibits a concentration-dependent bacterial killing. 3) Trova is a potentially useful agent for therapy of highly beta-lactam-resistant pneumococcal meningitis when administered every half life.

UR - http://www.scopus.com/inward/record.url?scp=33748138584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748138584&partnerID=8YFLogxK

M3 - Article

VL - 25

SP - 486

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

IS - 2

ER -