The VADS system approach to pharmacodynamics of
macrolides
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 macrolide antimicrobials, the evidence
supports differing pharmacodynamic parameters for various drugs within the
class.
For erythromycin, the evidence suggests that there is
a linear relationship between clinical or bacteriological cure (or log
reduction in bacterial count in vitro) and the percentage of the dosing
interval that the serum concentration of the antimicrobial remains above the
MIC of the pathogen. In addition, while PAEs have been shown for some human
pathogens, they are relatively short (3-6 hrs for most pathogens) compared to
the twice a day or once a day dosing interval typically expected for food
animal regimens.
For tilmicosin, there is little direct evidence to
support selection of any of the commonly used pharmacodynamic parameters. In
addition, there is considerable evidence that the use of tilmicosin results in
clinical cures even when serum concentrations do not remain above the MIC of
the pathogen for any significant amount of time. The reasons for this are not
completely clear, although there is a suggestion that tissue concentrations are
more important than serum concentrations.
The pharmacodynamics parameters associated with the use of clarithromycin,
telithromycin (a ketolide), and azithromycin may be useful only in
the sense that they provide support for other macrolides, since they are rarely
if ever used in food animal medicine.
We have selected the following generalizations to apply to
our pharmacokinetic modeling:
For all pathogens treated with macrolides, the time that
serum concentration of the antimicrobial needs to remain above the MIC of the
pathogen is 100% of the dosing interval.
References on which these recommendations were made follow
below:
T>MIC
|
% OF DOSING INTERVAL
|
DRUG(S)
|
PATHOGEN(S)
|
RefID
|
|
No difference in bacterial killing among 1x – 10x MIC
|
azithromycin
|
Listeria monocytogenes
|
8035
|
|
PAEs in vivo: drug levels above MIC for 2.5-5 hrs: 11.0
hrs. for SP; 13.1 hrs for SA; in vitro PAE for H. influenzae = 1.7-2.7 hrs.
|
azithromycin
|
Strep. pneumoniae, Staph aureus,
Haemophilus influenzae
|
750*
|
|
2x (S.pneum.) or 10x MIC:
|
azithromycin
|
Strep. pyogenes, Strep. pneumoniae, H. influenzae
|
8054
|
|
Azithromycin effective when tissue concentrations exceeded
MIC for substantial portion of treatment period (24-72 hrs. post-infection),
but serum concentrations never exceeded MIC
|
azithromycin
|
E. coli, H. influenzae
|
6851
|
|
Erythromycin ineffective when serum and/or tissue
concentrations did not reach MIC
|
erythromycin
|
E. coli, H. influenzae
|
6851
|
|
T>MIC of 100% resulted in 100% success (but no
breakpoint suggested)
|
clarithromycin
|
Strep. pneumoniae
|
6709
|
|
2x (S.pneum.) or 10x MIC:
|
clarithromycin
|
Strep. pyogenes, Strep. pneumoniae, H. influenzae
|
8054
|
|
T>MIC 60%
|
clarithromycin
|
|
6752 (citing 8039)
|
|
PAE > 4 hrs. for Staph., 1 ½-2 ½ hrs for Haemophilus
|
erythromcyin
|
Staph. aureus, Haemophilus influenzae
|
6740 (p. 838, unpublished data from their lab)
|
|
No difference in survival between same dose given once or
in 4 divided doses: suggests importance of T>MIC, but not enough
information to suggest % of dosing interval
|
erythromcyin
|
Strep. pneumoniae
|
4120
|
|
PAE after 10X MIC = 3.8 hrs
|
erythromycin
|
Strep. pyogenes
|
8036
|
|
PAEs in vivo: drug levels above MIC for 2.5-5 hrs: 5.6
hrs. for SP; 6.8 hrs for SA; in vitro PAE for H. influenzae = 1.7-2.7 hrs.
|
erythromycin
|
Strep. pneumoniae, Staph aureus, Haemophilus
influenzae
|
750*
|
|
T>MIC increases linearly up to 100% (with some efficacy
at 20%); T>MBC increases linearly up to 60%, then slope changes
(decreases) but increases up to 100%
|
erythromycin
|
Strep. pneumoniae
|
549*
|
|
Failure of therapy when T>MIC is less than 20%
|
erythromycin
|
Haemophilus influenzae
|
145 (referenced in 6709)
|
|
T>MIC of 88% resulted in 93% success (but no breakpoint
suggested)
|
erythromycin
|
Strep. pneumoniae
|
6709
|
|
T>MIC 60%
|
erythromycin
|
|
6752 (citing 8039)
|
|
Bactericidal activity, but no difference in 4x or 8x MIC
(suggested no concentration-dependent activity). Bacteriostatic against P.
multocida, suppressed growth against E. coli.
|
erythromycin
|
P. haemolytica, A. pleutropneumonia.
|
5312
|
|
T>MIC 40-50% (citing other research, but it’s not
obvious where those numbers came from)
|
macrolides
|
“respiratory pathogens”
|
4156
|
|
Their analysis of PK literature and efficacy studies (145,
6787, 8037, 8076): T>MIC 40-50% = 80-85% efficacy, T>MIC 60-70%
approached 100% efficacy
|
macrolides and other drugs – macrolides alone not teased
out
|
otitis media pathogens
|
6701
|
|
2x (S.pneum.) or 10x MIC:
|
roxithromycin
|
Strep. pyogenes, Strep. pneumoniae, H. influenzae
|
8054
|
|
Bactericidal all bugs at 4 and 8 x MIC.
|
tilmicosin
|
P.haemolytica, P. multocida, Actinobacillus
pleuropneumoniae, E. coli
|
5312
|
|
PAE: 6.8 hours for Staph., 5.4-5.6 for Strep.
|
erythromycin
|
Staph. aureus, Strep. pyogenes and S.
pneumoniae
|
550
|
|
No increase in killing with concentrations over 2X MIC
(non-concentration dependent)
|
telithromycin
|
Strep. pneumoniae, Haemophilus influenzae and
S. pyogenes
|
6847
|
|
|
erythromycin
|
Strep. pneumoniae
|
8106*
|
|
1/11 mice treated with a dose of E which resulted in
T>MIC of less than 66% of dosing interval recovered
|
erythromycin
|
Strep. pnuemoniae
|
8058
|
*neutropenic or immunocompromised patients
OTHER PARAMETERS
Parameters such as AUC24/MIC or Cmax/MIC
have been shown to be important for the efficacy of azithromycin,
clarithromycin and telithromycin, according to some studies. However, there is
little evidence that these parameters are applicable to the more typically used
macrolides (e.g., erythromycin). Therefore, references are merely provided for
review purposes.
|
PARAMETER
|
VALUE
|
DRUG
|
PATHOGEN
|
RefID
|
|
Cmax (AUC/MIC was not correlated)
|
Not optimized, but higher survival at 135 vs. 19, which
resulted in 50% death
|
clarithromycin
|
Strep. pneumoniae
|
8106*
|
|
Cmax; however, AUC was not determined in the
in vivo experiment, and maximal bacterial kill was at 4x MIC
|
Estimated at 16-32x MIC
|
azithromycin
|
Strep. pneumoniae
|
4120
|
|
AUC/MIC
|
25-30
|
azithromycin
|
respiratory pathogens
|
4156
|
|
AUC24/MIC
|
>100
|
azithromycin
|
Strep. pneumoniae
|
Graphed in 6752, original work in 750
|
|
24-hr AUC/MIC for free drug correlated best with efficacy
(R2 = 90%, compared to 70% for peak/MIC and 46% for T>MIC)
|
none stated
|
telithromycin
|
Strep. pneumoniae
|
8055*
|
|
Peak/MIC was approximately equal to AUC/MIC
|
Breakpoint of 0.19 for Peak/MIC
|
telithromycin
|
community acquired pneumonia in human patients – organisms
not identified
|
8056
|
*neutropenic or immunocompromised patients
