The VADS system
approach to pharmacodynamics of aminoglycosides
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.
It should be understood
clearly that the use of non-approved aminoglycosides in ruminants should be
considered only under special circumstances. Numerous veterinary groups have
recommended a voluntary moratorium on non-approved aminoglycosides in ruminants
due to the extended meat withdrawal times necessary (in excess of 18 months).
For aminoglycosides, the two
parameters that have most consistently been associated with efficacy are
AUC:MIC and Cmax:MIC.
Selection for resistant
organisms can be reduced, according to several studies, by selecting a dose
that will result in a Cmax:MIC ratio of 8-10.
Once-daily dosing:
For all pathogens treated
with aminoglycosides, the Cmax will be optimized to 10 times the MIC
of the pathogen. In addition, once daily dosing will be used.
References on which this
recommendation is made are listed below. This is not meant to be a
comprehensive review of the literature but rather a selected bibliography.
AUC
|
Drug
|
Value
|
Pathogens
|
Reference
|
|
tobramycin
|
No optimal value given; log10AUC
confounded with T>MIC
|
Pseudomonas aeruginosa
|
549*
|
|
gentamicin
|
No optimal value given; log10AUC
confounded with T>MIC
|
E. coli
|
549*
|
|
gentamicin netilmicin
|
log10AUC
for regimens q1-6hr thigh models, and for all dosing intervals for lung models
|
Klebsiella pneumoniae
|
6959
|
|
netilmicin, tobramycin
|
log10AUC
|
Pseudomonas aeruginosa
|
4134*
|
|
tobramycin
|
log10AUC
|
Pseudomonas aeruginosa
|
6762*
|
|
multiple
|
|
Review
article
|
(Drusano,GL, 1988: Ref ID: 112)
|
|
amikacin
|
Increase in killing as Cmax:MIC
increases up to 32X
|
|
6774
|
|
tobramycin
|
Zhi model
|
|
4119
|
Cmax
|
|
Cmax:MIC
|
Pathogens
|
|
|
netilmicin
|
8
|
Pseudomonas aeruginosa,
E. coli, Staph. aureus, Klebsiella pneumoniae
|
42
|
|
amikacin, gentamicin,
tobramycin
|
8-10 for >80% clinical
response; maximal response at ≥10X
|
multiple gram-negative
pathogens
|
383
|
|
gentamicin
|
13X resulted in increased
bactericidal effect compared to 2, 4 and 7X (all regimens had same AUC)
|
Pseudomonas aeruginosa
|
6761
|
|
gentamicin, netilmicin
|
Shape of AUC curve
important: high peak more important than T>MIC; optimal ratio not
determined
|
Pseudomonas aeruginosa
|
6707
|
|
amikacin
|
Increase in killing as Cmax:MIC
increases up to 32X
|
Pseudomonas aeruginosa, Klebsiella
pneumoniae, E. coli, Serratia marcescens
|
6774
|
|
amikacin, gentamicin,
tobramycin
|
Greater survival in
patients with peaks greater than 7 (gentamicin, tobramycin) or 28 (amikacin)
mcg/ml (MICs not reported)
|
Gram-negative pneumonia
(most commonly Klebsiella pneumoniae and Pseudomonas aeruginosa)
|
6770
|
|
amikacin
|
Faster bacterial kill with same
total dose given once as compared to twice a day (although all treated
animals survived). AUC confounded with peak. Cmax:MIC = 6.4 vs. 12
|
Pseudomonas aeruginosa
|
100
|
|
gentamicin
|
Breakthrough growth in
vitro when 2X but not 10X; similar results in vivo
|
Pseudomonas aeruginosa
|
6764*
|
|
gentamicin
tobramycin
amikacin
|
Cmax:MIC
> 4 as well as other parameters (AUC, AUC >MIC, etc.) all associated
with clinical success; Cmax:MIC reported as easiest to measure
|
Multiple etiologies
|
6759
|
|
multiple
|
|
Review
article
|
(Drusano,GL, 1988: Ref ID: 112)
|
|
multiple
|
|
Review
article
|
(Craig 1995)
|
|
|
Concentration
Independent Activity
|
|
|
|
|
Other
|
|
|
|
spectino-mycin
|
Parameter associated with
efficacy unknown, since Cmax, AUC ratios and T>MIC were not predictive of
efficacy.
|
BRD in cattle
|
3670
|
|
|
Dosing Interval
|
|
|
|
|
|
|
8110
|
|
amikacin
|
Same total dose given once
or twice a day: q24h dosing resulted in faster bacterial kill
|
Pseudomonas aeruginosa
|
100
|
|
gentamicin netilmicin
|
Lung model: no increase in
total dose needed as dosing interval increased from 1 to 12 hrs (but large
increase in dose needed in thigh model at q12h)
|
Klebsiella pneumoniae
|
6959*
|
|
gentamicin
|
Same total dose less
frequently resulted in better bacterial kill (q1h compared to q3h)
|
Pseudomonas aeruginosa
|
6764
|
|
gentamicin
|
Same AUC but higher peak
due to decreased dosing frequency resulted in higher bacterial kill
(experiment run up to 24h)
|
Pseudomonas aeruginosa
|
6761
|
|
gentamicin, netilmicin
|
Peak-dependence verified,
but not optimized
|
Pseudomonas aeruginosa
|
6706*
|
|
gentamicin tobramycin
|
Frequency of administration
(up to q12h) had little effect on dose needed for efficacy (dose needed at
q24h was about 3X needed at q12h for tobramycin)
|
Pseudomonas aeruginosa, Klebsiella
pneumoniae, E. coli
|
354*
|
|
tobramycin
|
Same total dose q4h or
q24h: at 72h, lower bacterial titers for q24h in nonneutropenic animals;
neutropenic animals had regrowth to pre-treatment levels with q24h dosing; no
resistance observed post-treatment although resistance was defined only as
growth at 4 mcg/ml (combination with mezlocillin required to completely
eradicate in all animals)
|
Pseudomonas aeruginosa
|
6771*
|
|
gentamicin
|
Same doses (5 mg/kg at each
time interval) separated by 6, 8, 12 or 24 hrs showed similar efficacy until
24hr between doses (Cmax:MIC = 35)
|
Klebsiella pneumoniae
|
6773
|
|
gentamicin
|
Once-daily administration
appeared to result in clinical cure rates similar to multiple times a day
|
multiple pathogens
|
8112
|
|
multiple
|
|
|
(Powell SH, Thompson WL, Luthe MA, Stern RC,
Grossniklaus DA, Bloxham DD. ;1983)
|
|
|
T>MIC
|
|
|
|
gentamicin
netilmicin
|
T>MIC for regimens
q6-12hr (but log10AUC for q1-6, and for all lung infection models; see
above)
|
Klebsiella pneumoniae
|
6959
|
|
amikacin
|
T>MIC was important in
regimens in renally sufficient mice, although Cmax was important in renally impaired
mice (see above)
|
Pseudomonas aeruginosa, Klebsiella
pneumoniae, E. coli, Serratia marcescens
|
6774
|
|
gentamicin
tobramycin
amikacin
|
Cmax:MIC
> 4 as well as other parameters (AUC, AUC >MIC, T>MIC, etc.) all
associated with clinical success; Cmax:MIC reported as easiest to measure
|
Multiple etiologies
|
6759
|
|
Acquisition of
Resistance
|
|
multiple
|
|
Review
article
|
(Craig 1993d)
|
|
netilmicin
|
At 4X MIC, regrowth
occurred; at ≥8X MIC,
|
Klebsiella pneumoniae,
Pseudomonas aeruginosa, E. coli, Staph. aureus
|
42
|
|
gentamicin
|
Prevention of regrowth
required addition of ticarcillin
|
Pseudomonas aeruginosa
|
6705
|
|
gentamicin
|
|
|
(Gerber AU, Wipractchtiger P,
Stettler-Spichtiger U and Lebeck G; 1982a)
|
|
multiple
|
|
|
(Daikos GL, Jackson GG, Lolans
VT, Livermore DM 1990)
|
|
multiple
|
|
|
(Powell SH, Thompson WL, Luthe MA, Stern RC,
Grossniklaus DA, Bloxham DD.,1983; Ref ID 6763)
|
