Comparison Of Antibacterial Activity,ototoxicity And Nephrotoxicity Of Amikacin Between Once-daily And Twice-daily Regimen In The Guinea Pig

Objective The purpose of our study was to compare thebactericidal efficacy of the single large daily regimen of amikacinwith that of twice daily regimen for treating experimentalP.aeruginosa pneumonia in guinea pigs. Moreover, the presentstudy was designed to determine whether the nephrotoxicity andototoxicity were related to the dosing schedule and whether theycan be minimized by the administration of a single daily dose.Method 1. Guinea pigs were lightly anesthetized with an ipinjection of urethane(l.25g/kg), then infected by intratrachealinstillation of 2.5 ×l0～7cfu of Ｐ.aeruginosa and randomly assignedto one of the following treatment groups(all drugs wereadministered im):(1)saline once a day (control);(2) 50mg ofamikacin/kg twice a day (BID);(3)100mg of amikacin /kg once aday(OD). The therapy was initiated sixteen hours after inoculaton.Before inoculation,therapy and after 72h of therapy, thetemperature,heart rate and body weight were recorded, and thewhite blood cell as well as C-response protein(CRP) weremeasured. After 72h's therapy, both lungs were aseptcallyremoved, weighed and homogenized. The homogenate wasquantatively cultured onto MH agar plates, which were incubatedat 35°C for l8h. The bacteria were calculated and expressed aslgcfu per lung.2. The guinea pigs were divided into 3 groups of 85N^+1 H h4t4kb#@&*$k$M*Na$#Nk4. .gi'ItltbRanimals each. One grouP received amikacin l00mg/kg im tWice aday (BID). The othr tWo grouPs were given either amikacin200mg/kg or saline im once a day (OD and control). All treaunentslasted 28 days. Kidney functions were evaluated via the serumbiochemistry tests, the urinny assays and the histopathologicalstUdies. At the baseline. the second and forth week, the blood ureanitrogen (BU''N')' creatinine (Cr)' the urea N-acetyl- 0-D-glucosaminidase (NAG)' creatinine and 24 h endogenouscreatinine clearance were measured and the urinny volumes wererecorded,. When treatmellt ended, the kidneys were removed andobserved by ligh microscoPy and transmission eleCtrOnmicroscopyAt the baseline. 2 weeks during the treaAnent and after thetreatffient auditOry function was evaluated by measuring theauditory brainstem response (ABR). The damage to the inner earwas also evaluated by morphological technique (surfacepreParations in SDH stain and scanning electronmicroscoPy) afterthe 4 weeks' theraPyRe8uIt l' After the inoculation, the animals' tCmPerthees' hewtrates rose significanly and the body weighs lost gradually After72 hours' tretheellt, the tCmPeramres' heat ratCs' the loss of bodyweighs and blood white cells in the control grouP were 38.85 l0.23C' 298.67 l 8.29bPm. 128.75 l l9.78g. 19.37 t 2.36 x 1091respectively and were significantly higher than those in OD andBID grouPs (38.l6 l 0.48 oC and 38.33 t 0.57 oC' 28l.00 l1l.01bPm and 286.75 f ll.79bpm. 106.25 l 15.53g and l08.75 ll6.20g. l4.73 t 3.24 x l0o1 and l5.70 t 3.28 x l091 resPectively,P < 0.05). The levels of CRP in OD and BID grOuPs were 0.334 l60.l44mg/dl and 0.408 l 0.245 mg/dl respectively Both of them..were significantly lower than that in cOlltrl grouP(0.662 l 0.326mg/dl, P < 0.05). Howevee there was not significant differencebetWeen the OD and BID grOuP. The numbers of bactCria per lungin OD and BID grouPs were 4.3l l 0.65 lg cfu and 5.l9 l 0.96 lgcfu respectively and were both significanly lower than that in thecontrol grouP (6.57 l 1.18 lg cfu, P < 0.05). But there was nosignificant difference between the tWo exPerimental grouPs.2' The plasma levels of urea nitrogen and creatinine in theOD and BID grouP rose gradually By the forth week the ureanitrogen were l6.18 l 1.84 mmoim and 17.96 t l.16 mmol1resPectively and the former was significatly lower than thelatter(P < 0.05) and both of them were significantly higher than thatin control grouP(ll.09 t l.97 nunol1, P < 0.05). After 2 and 4weeks' treatthefit, there was a signific...