Ob. Samuelsen et al., PHARMACOKINETIC AND EFFICACY STUDIES ON BATH-ADMINISTERING POTENTIATED SULFONAMIDES IN ATLANTIC HALIBUT, HIPPOGLOSSUS-HIPPOGLOSSUS L, Journal of fish diseases, 20(4), 1997, pp. 287-296
The uptake, metabolism, tissue distribution and excretion of four sulp
honamides and trimethoprim following bath treatment of Atlantic halibu
t, Hippoglossus hippoglossus L., were studied. Bath treatment using a
concentration of 200 mu g ml(-1) for 72 h resulted in peak sulphadimid
ine concentrations in muscle and abdominal organ homogenates of 32.6 a
nd 68.2 mu g g(-1), respectively. The corresponding values were 24.4 a
nd 73.4 mu g g(-1) for sulphaguanidine, 6.1 and 45.1 mu g g(-1) for su
lphamethoxazole, 2.1 adn 15.1 mu g g(-1) for for trimethoprim. After a
72-h treatment, approximately 90% of the sulphadimethoxine and sulpha
methoxazole present in tissues was found as the N-4-acetylated metabol
ite, whereas for sulphadimidine and sulphaguanidine, the N-4-acetylati
ons were from 9 to 23%. Based on these preliminary absorption studies,
sulphadimidine was chosen as the companion sulphonamide to trimethopr
im. Using a combination of 500 mu g ml(-1) sulphadimidine and 100 mu g
ml(-1) trimethoprim in the bath for 72 h, peak muscle and liver conce
ntrations of 262 and 312 mu g g(-1), respectively, for sulphadimidine
and 32.8 and 83.6 mu g g(-1), respectively, for trimerhoprim were achi
eved. Elimination hall-lives (t(1/2)beta) for sulphadimidine were calc
ulated to be 35 and 48 h for muscle and liver, respectively. The corre
sponding values for for trimethoprim were 98 and 116 h. Using the 95%
confidence limit for single observations (95% prediction limit) and a
maximum residue limit (MRL) value of 0.05 mu g g(-1) for trimethoprim
and 0.1 mu g g(-1) for sulphadimidine, the elimination times (E-t95) f
or muscle and liver were calculated to be 18 and 26 days, respectively
, for sulphadimidine and 40 and 55 days, respectively, for trimethopri
m. Minimum inhibitory concentrations (MIC) values against selected str
ains of Vibrio sp. were equal to or above 128 mu g ml(-1) for sulphadi
midine, between 0.25 and 4.00 mu g ml(-1) for trimethoprim and between
0.4 and 8.8 mu g ml(-1) for various ratios of the sulphadimidine:trim
ethoprim combination. In the tested ratios, the combined antimicrobial
action of trimethoprim and sulphadimidine were synergistic, as reveal
ed by their fractional inhibitory concentration (FIC) indices. In gene
ral, the 1:5 trimethoprim sulphadimidine ratio showed the highest degr
ee of synergism. Using a combination of 500 mu g ml(-1) sulphadimidine
and 100 mu g ml(-1) trimethoprim in the bath for 72 h, concentrations
greater than a MIC value of 0.8 mu g ml(-1) were maintained for 22 da
ys in muscle and 29 days in liver. In a laboratory challenge experimen
t using Vibrio anguillarum strain HI 11347, a significantly lower mort
ality was observed in the drug-treated group (40%) compared to the unt
reated control group (93%).