The VADS system approach to pharmacodynamics of tetracyclines
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.
There is a distinct lack of data related to the
pharmacodynamics of the tetracyclines, whether in vitro or in vivo, in animal
models or animal or human trials. Some experts recommend time>MIC since
most tetracyclines are bacteriostatic. However, in some cases, tetracyclines
have been shown to be bacteriocidal, so this may not hold true for all
drug-pathogen combinations. Other recommendations are to maximize AUC.
We have elected to use a time above MIC of 100% of the
dosing interval, due to lack of consistency of literature reports. Dosing of
tetracyclines in food animals tends to be once-a-day or less frequently, in
which case, a PAE of a few hours would not make much of a difference in
efficacy.
TETRACYCLINE/OXYTETRACYLCINE/CHLORTETRACYCLINE
PAE
Unpublished (?) lab data:
tetracycline and Staph. aureus: 2 ½ - 4 hrs. 6740.
1-3 hrs. tetracycline and Bacilllus
anthracis; J anti chemo, Athamna, 2004 Apr
53(4):609-15.
1-2.5 hrs. tetracycline and E.
coli. 1060.
2.4 hrs. for tetracycline and Staph
aureus. 8041.
Unreferenced
data (from the authors’ lab?): tetracycline and E. coli, PAE rose from 0.5 hr.
(0.5X MIC) to 4 hrs. (8X MIC), but appeared to plateau with no increase in PAE
from 8X to 64X MIC. 8042.
E. coli, K. pneumonia
for 2.1h; Streptococcus: 1.8-6.1h. 550.
DOXYCYCLINE
Therapy of septicemia and wound infections failed if peak
titer was </= 1:8 (80% success rate with peak >/=1:8). This also
appeared to be true if trough serum antibacterial bacteriocidal titer was <
1:8, although this was not specifically discussed by the authors. High peaks
correlated with improved success. Time above MIC was not measured or
calculated. 6687.
PAE: 2.1-4.2 hrs for E. coli, Staph
aureus, Pasteurella multocida, Strep. pneumoniae. When
conc. 2-4x MIC: time dependent; at 8-10X MIC: concentration dependent.
(Reference was made to clinical dosing in humans, which result in serum
concentration remaining above the MIC for the entire dosing interval.) 6018.
TIGECYCLINE
T>MIC for 50% of dosing interval for 80% efficacy, for Strep.
pneumoniae (T>MIC); E. coli (T>0.5X MIC); Klebsiella
pneumoniae (T>0.5X MIC). (AUC24 was also predictive, but
with a lower R2.) 5946.
T>MIC of 50% just as effective as T>MIC 100% for Enterococcus.
Lefort A, Massias L, Saleh-Mghir A, et al. Pharmacodynamics of GAR 936 (GAR) in
experimental endocarditis due to VanA- type Enterococcus faecium. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy; 2000 Sep 17-20; Toronto.
PAE: Staph. aureus,
E. coli: need to see article for numbers (minocycline < tigecycline
but hours not in abstract) Projan SJ. Preclinical pharmacology of GAR-936, a
novel glycylcycline antibacterial agent.
Pharmacotherapy 2000; 20 (9 Pt 2): 219S-23S
