Gentamicin concentration in bile after once-daily versus thrice-daily dosing of 4 mg/kg/day

Roberto Reckziegela, Ismael Maguilnika and Luciano Z. Goldanib,*

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 Mann–Whitney 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 TableGo. 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 FigureGo. 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).


View this table:
[in this window]
[in a new window]
 
Table. Characteristics of patients with suspected choledocholithiasis who were randomized to receive as prophylaxis once-daily or thrice-daily dosing of gentamicin 4 mg/kg/day
 


View larger version (15K):
[in this window]
[in a new window]
 
Figure. Mean concentration of gentamicin in bile of patients treated with once-daily ({square}) and thrice-daily ({blacksquare}) dosing of gentamcin (4 mg/kg/day). {blacktriangledown} = q8h infusion.

 
Our study was designed to compare concentrations of gentamicin in the bile of patients treated with oncedaily versus multiple-daily dosing. In keeping with the pharmacodynamic characteristics of aminoglycosides in the prophylaxis or treatment of biliary tract infections, once-daily dosing should ensure a high Cmax/MIC ratio in the bile for the pathogen being treated, and ensures that trough concentrations are low enough to permit the loss of adaptive resistance.2,5 The MIC of gentamicin ranged from 0.5 to 1.2 mg/L for most enteric Gram-negative bacilli (including Pseudomonas aeruginosa) found in infection of the biliary tract at our institution (data not shown); the bile concentrations of gentamicin would barely exceed these MICs in the bile for patients treated with multiple-daily dosing of gentamicin 4 mg/kg/day, as shown in this study. In contrast to the patients treated with multiple daily dosing, the mean bile concentration of gentamicin in the once-daily group exceeded these MICs approximately three- to six-fold for a prolonged period of time.

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 Back

References

1 . Kapusnik, J. E., Hackbarth, C. J., Chambers, H. F., Carpenter, T. & Sande, M. A. (1988). Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental Pseudomonas pneumonia. Journal of Infectious Diseases 158, 7–12.[ISI][Medline]

2 . Craig, W. A., Redington, J. & Ebert, S. C. (1991). Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections. Journal of Antimicrobial Chemotherapy 27, Suppl. C, 29–40.[Abstract]

3 . Vogelman, B., Gudmundsson, S., Leggett, J., Turnidge, J., Ebert, S. & Craig, W. A. (1988). Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. Journal of Infectious Diseases 158, 831–47.[ISI][Medline]

4 . Craig, W. A. & Vogelman, B. (1987). The postantibiotic effect. Annals of Internal Medicine 106, 900–2.[ISI][Medline]

5 . Fantin, B., Ebert, S., Leggett, J., Vogelman, B. & Craig, W. A. (1991). Factors influencing the duration of in-vivo postantibiotic effect for aminoglycosides against Gram-negative bacilli. Journal of Antimicrobial Chemotherapy 27, 829–36[Abstract]

6 . Pitt, H. A, Postier, R. G. & Cameron, J. C. (1982). Biliary bacteria: significance and alteration after antibiotic therapy. Archives of Surgery 117, 445–9.[Abstract]





This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Reckziegel, R.
Articles by Goldani, L. Z.
PubMed
PubMed Citation
Articles by Reckziegel, R.
Articles by Goldani, L. Z.