The VADS system
approach to pharmacodynamics of fluoroquinolones
In the event that
pharmacodynamic relationships have been shown with experimental data generated
in domestic species with veterinary pathogens using veterinary-approved
antimicrobials, those relationships will be used to generate dose
recommendations. In the absence of that information, data from laboratory
animal and human retrospective and prospective studies (including neutropenic
models) will be used to extrapolate the relationship.
For therapy with fluoroquinolone
antimicrobials, the preponderance of evidence suggests that there is a linear
relationship between clinical or bacteriological cure (or log reduction in
bacterial count in vitro) and the ratio of the area under the serum concentration-time
curve (AUC) for 24 hours and the MIC of the pathogen. Based on the references
below, it is suggested that the AUC(24):MIC ratio be >100. Some references
also report that a ratio of Cmax:MIC should be greater than or equal to 8,
particularly to prevent the selection of resistant isolates.
Since the extralabel use of
fluoroquinolones in food animals is specifically prohibited by U.S. law, the VADS system will not model doses to fit these pharmacodynamic parameters.
However, the following references are provided in the interest of completeness.
|
AUC:MIC ratio
|
Cmax:MIC ratio
|
Drugs
|
Pathogens
|
RefID
|
|
>100 for gram-negative
(may be as low as >40 for some gram-positives)
|
>8-10
|
multiple human drugs
|
Review article; multiple
human pathogens
|
8340
|
|
>100 associated with
almost no mortality
|
|
multiple human drugs
|
Review article; multiple
humanpathogens
|
3873
|
|
>100 provided best
correlation with positive outcome
|
>8
|
multiple human drugs
|
Meta-analysis of 19 trials
(8 fluoroquinolones) with induced endocarditis models with MRSA, MSSA, MR Staphylococcus
epidermidis, streptococci and Pseudomonas aeruginosa
|
5725
|
|
>125 (but >250
results in more rapid eradication in some cases)
|
|
multiple human drugs
|
Multiple human pathogens
(review article)
|
4106
|
|
22.6 for bacteriostatic
activity, 29.6 for bactericidal activity, and 52.4 for complete clearance of
bacteria
|
|
danofloxacin
|
Mannheimia haemolytica in goats
|
5791
|
|
|
4x MIC was almost equal in
effectiveness to 8 x MIC
|
danofloxacin
|
M.haemolytica, P.
multocida, Actinobacillus pleuropneumoniae, E. coli
|
5312
|
|
>100 for 50%, >244
for 80% of the response
|
|
danofloxacin
|
Tissue cage model with M.haemolytica
|
6578
|
