Pharmacodynamics of trovafloxacin in experimental pneumococcal meningitis: basis for dosage selection in children with meningitis.
Trovafloxacin is a recently approved fluoroquinolone with excellent activity against gram-positive and gram-negative organisms that offers a potential alternative for treatment of beta-lactam-resistant pneumococcal meningitis. Using the rabbit meningitis model, we sought to characterize the pharmacodynamic properties of trovafloxacin in the cerebrospinal fluid (CSF). Animals were given single doses of trovafloxacin of 10, 15, 20 or 30 mg/kg; 1 h after Infusion mean CSF concentrations were 0.59+/-0.18, 0.74+/-0.14, 1.12+/-0.12 and 1.07+/-0.35 mg/L, respectively. The bacterial killing rate Increased with increasing dosages of trovafloxacin, indicating that its activity is concentration dependent. All three pharmacodynamic Indices (area under the concentration curve (AUC)/MBC, peak concentration (Cmax)/MBC, and time above MBC (T > MBC)) correlated with bacterial killing; however, AUC/MBC correlated best (r = 0.71). In a second experiment we found comparable bacterial killing with multiple doses of trovafloxacin given either every serum half-life or every two serum half-lives. In both experiments bacterial regrowth occurred when the concentration of trovafloxacin in CSF fell below the MBC. These data have been used in formulating an appropriate regimen for trovafloxacin treatment of bacterial meningitis in children.
McCoig
C C
CC
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
Wubbel
L
L
Jafri
H S
HS
Lutsar
I
I
Bastero
R
R
Olsen
K
K
Shelton
S
S
Friedland
I R
IR
McCracken
G H
GH
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002555:Cerebrospinal Fluid / Q000382:microbiology; D004195:Disease Models, Animal; D024841:Fluoroquinolones; D006207:Half-Life; D006801:Humans; D007223:Infant; D008297:Male; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010403:Penicillin Resistance; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; C080163:trovafloxacin