a Section of Gastroenterology and b Infectious Diseases Unit, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil
Sir,
In vitro studies have shown increases in the rate of bacterial killing as aminoglycoside concentrations increase.1 In animal experiments, aminoglycoside efficacy correlates to the ratios of peak concentration of the drug (Cmax) or area under the curve (AUC) to the MIC of the infecting organism.2 These pharmacodynamic properties are in contrast to those of ß-lactam antibiotics, whose efficacy correlates best with time above MIC.3 In addition, aminoglycoside antibiotics have a potent post-antibiotic effect, which results in continued suppression of bacterial growth when concentrations fall below the MIC.1,4,5 These pharmacodynamic characteristics favour the use of once-daily dosing regimens in aminoglycoside therapy.
Since aminoglycosides are commonly used in the treatment of biliary tract infections caused by Gram-negative organisms,6 the use of once-daily dosing could result in higher biliary concentrations and possibly improved clinical efficacy. The purpose of the current study was to measure the concentration of gentamicin in bile in patients on once-daily versus multiple-daily dosing prophylactic regimens of gentamicin for endoscopic retrograde cholangiopancreatography (ERCP) for presumed choledocholithiasis.
Twenty patients who underwent ERCP were randomized to receive an iv 24 h prophylactic regimen of either gentamicin 4 mg/kg od plus ampicillin (2 g/day), or gentamicin 1.3 mg/kg q8h plus ampicillin (2 g/day). Bile was collected over an 18 h period through a catheter inserted in the common bile duct. Between 3 and 4 mL of bile was transported on ice for assay. Bile gentamicin concentra-tions were measured by fluorescence polarization immunoassay (Abbott TDX/FLX, Abbott Park, IL, USA). These were performed before initiating gentamicin therapy, and then at intervals of 30 min for 18 h after initiation. The assay was validated for bile by recovery experiments from drug-free bile spiked at 0.5, 1, 4 and 8 mg/L and by determining the s.d. (n = 10) at each concentration. Performance characteristics were similar to those seen with serum assays (data not shown).
Mean values were compared by paired Student's test and MannWhitney tests for paired and unpaired data. For all comparisons, a P value of <0.05 indicated statistical significance. Statistical analyses were performed with the Sigmastat Statistical Software Package (version 2.0; Jandel Scientific, San Rafael, CA, USA).
Ten patients were treated with gentamicin od and 10 patients with gentamicin thrice daily dosing; their characteristics are listed in the Table. There were no significant differences between the once-daily and multiple-daily dosing group patients including pathological states of altered volume of distribution such as ascites, pancreatites and septic shock. Patients in neither group had adverse reactions. The mean pharmacokinetic profiles of gentamicin in the two groups are shown in the Figure
. The mean concentration of gentamicin in bile 1 h post-dose in patients treated with once-daily dosing was approximately twice the mean concentration in the multiple-daily dosing group (mean ± s.d. 2.88 ± 0.56 versus 1.77 ± 0.38, P < 0.05). The mean gentamicin concentrations in patients treated with once-daily dosing was still >2 mg/L and higher than patients treated with multiple-daily dosing 10 h after injection (mean ± s.d. 2.00 ± 0.31 versus 1.35 ± 0.20, P < 0.05).
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Our results indicate that once-daily gentamicin dosing is associated with a higher ratio of gentamicin Cmax to the MIC of Gram-negative bacillary organisms in the bile compared with multiple-daily dosing, which could result in improved therapeutic efficacy. The potential cost savings and the possible decrease in nephrotoxicity or ototoxicity associated with once-daily administration makes this approach appealing in prophylactic and therapeutic regimens for biliary tract infection.
Acknowledgments
This study was supported by a grant from FIPE (Hospital de Clínicas de Porto Alegre) and CNPq, Brazil.
Notes
* Correspondence address. Serviço de Medicina Interna, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350 90035-002, Porto Alegre RS, Brazil. Tel/Fax: +55-51-3168676; E-mail: Lgoldani{at}vortex.ufrgs.br
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