Premium
A novel PD model for gatifloxacin (GF) vs. salmonella typhi (ST) in timed kill curves (KC)
Author(s) -
Okusanya O. O.,
Booker B. M.,
Forrest A.,
Smith P. F.,
Bhavnani S. M.,
Ambrose P. G.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.159
Subject(s) - gatifloxacin , salmonella , growth model , mathematics , biology , microbiology and biotechnology , levofloxacin , bacteria , antibiotics , genetics , mathematical economics
Quinolones are the mainstay of treatment for ST infections but there is growing concern about resistance to older quinolones & poor understanding of quinolone/ST PD. We have developed a new approach to modelling KC data & have applied it to describing the PD of GF vs. ST. Log‐phase cultures (10 7–8 CFU/mL) of ST (MIC=0.5 mg/L) were exposed to GF at 0, 0.5, 1, 2, 4 & 8xMIC; bacterial counts (CFU) were measured serially over 24h. Timecourse of CFU were fit to a PD model with capacity‐limited bacterial growth, 1st‐order rate constant for death (Kd) & a Hill‐type function in which GF enhances Kd. The total CFU was represented by a mixture model, with up to 4 sub‐populations (SP) differing in GF susceptibility. Each KC was fit individually & later simultaneously, using Adapt II. AIC was used to determine the number of SP & which parameters would be allowed to vary between KC. The final model had inter‐KC variance in maximum velocity of growth & 4 SP. The 1st 2 SP were 99.99% of the initial CFU with sensitivities <1xMIC & the other 2 SP were each <0.01% of total CFU, with sensitivities of 2.3 & 4.4xMIC. The GF Emax was a 37‐fold increase in Kd. Goodness of fit was excellent with an overall r=0.96 (Observed=1.01Fit−0.15). This approach to PD modelling of in vitro data will give better insight into the activity of GF vs. different ST SP & aid in determining regimens which minimize therapeutic failure due to the development of resistance. Clinical Pharmacology & Therapeutics (2004) 75 , P42–P42; doi: 10.1016/j.clpt.2003.11.159