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Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 May;40(5):1164–1169. doi: 10.1128/aac.40.5.1164

In vivo antibacterial effects of simulated human serum profiles of once-daily versus thrice-daily dosing of amikacin in a Serratia marcescens endocarditis experimental model.

D Bugnon 1, G Potel 1, Y Q Xiong 1, J Caillon 1, M F Kergueris 1, P Le Conte 1, D Baron 1, H Drugeon 1
PMCID: PMC163284  PMID: 8723459

Abstract

Once-daily dosage of aminoglycosides is currently under consideration. The lower toxicity of this regimen has been clearly established, but there are conflicting experimental and clinical data concerning its efficacy. It is inadvisable to optimize human therapy by extrapolation from experimental studies since animal and human pharmacokinetics differ. The simulation of human pharmacokinetics in experimental infectious models would seem to offer a more rational approach. We used computer-controlled infusion of amikacin at a variable flow rate to simulate human pharmacokinetics in a Serratia marcescens rabbit endocarditis model and to compare two therapeutic regimens (once-daily versus thrice-daily doses). The doses corresponded to simulations of 15 and 30 mg/kg of body weight per day in humans, and antibacterial activity was measured in vegetations (Veg) after 24 h of treatment. The results show that the dose corresponding to 15 mg/kg/day failed to produce a significant reduction of CFU (6.8 +/- 0.9 and 6.4 +/- 0.8 log10 CFU/g of Veg, respectively, for once-daily and thrice-daily doses versus 7.6 +/- 1.0 for controls). A significant reduction was observed only for the dose corresponding to 30 mg/kg/day in humans (5.2 +/- 1.5 and 5.4 +/- 1.1 log10 CFU/g of Veg, respectively, for the two regimens). With this model, the efficacy of amikacin was similar for both regimens after 24 h of treatment simulating human pharmacokinetics.

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Selected References

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  1. Begg E. J., Peddie B. A., Chambers S. T., Boswell D. R. Comparison of gentamicin dosing regimens using an in-vitro model. J Antimicrob Chemother. 1992 Apr;29(4):427–433. doi: 10.1093/jac/29.4.427. [DOI] [PubMed] [Google Scholar]
  2. Bennett W. M., Plamp C. E., Gilbert D. N., Parker R. A., Porter G. A. The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis. 1979 Oct;140(4):576–580. doi: 10.1093/infdis/140.4.576. [DOI] [PubMed] [Google Scholar]
  3. Blaser J. Efficacy of once- and thrice-daily dosing of aminoglycosides in in-vitro models of infection. J Antimicrob Chemother. 1991 May;27 (Suppl 100):21–28. doi: 10.1093/jac/27.suppl_c.21. [DOI] [PubMed] [Google Scholar]
  4. Boxenbaum H. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokinet Biopharm. 1982 Apr;10(2):201–227. doi: 10.1007/BF01062336. [DOI] [PubMed] [Google Scholar]
  5. Confesson M. A., Barbaut X., Maire P., Vergnaud J. M., el Brouzi A., Jelliffe R. W. Concentrations calculées en aminoside dans des végétations d'endocardites. Relations avec les pratiques cliniques lors du traitement d'endocardites infectieuses par l'amikacine. Therapie. 1994 Jan-Feb;49(1):27–34. [PubMed] [Google Scholar]
  6. Craig W. A., Redington J., Ebert S. C. Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections. J Antimicrob Chemother. 1991 May;27 (Suppl 100):29–40. doi: 10.1093/jac/27.suppl_c.29. [DOI] [PubMed] [Google Scholar]
  7. Daikos G. L., Jackson G. G., Lolans V. T., Livermore D. M. Adaptive resistance to aminoglycoside antibiotics from first-exposure down-regulation. J Infect Dis. 1990 Aug;162(2):414–420. doi: 10.1093/infdis/162.2.414. [DOI] [PubMed] [Google Scholar]
  8. Fan S. T., Lau W. Y., Teoh-Chan C. H., Lau K. F., Mauracher E. H. Once daily administration of netilmicin compared with thrice daily, both in combination with metronidazole, in gangrenous and perforated appendicitis. J Antimicrob Chemother. 1988 Jul;22(1):69–74. doi: 10.1093/jac/22.1.69. [DOI] [PubMed] [Google Scholar]
  9. Fantin B., Ebert S., Leggett J., Vogelman B., Craig W. A. Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli. J Antimicrob Chemother. 1991 Jun;27(6):829–836. doi: 10.1093/jac/27.6.829. [DOI] [PubMed] [Google Scholar]
  10. Fluckiger U., Moreillon P., Blaser J., Bickle M., Glauser M. P., Francioli P. Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats. Antimicrob Agents Chemother. 1994 Dec;38(12):2846–2849. doi: 10.1128/aac.38.12.2846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gerber A. U., Brugger H. P., Feller C., Stritzko T., Stalder B. Antibiotic therapy of infections due to Pseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics. J Infect Dis. 1986 Jan;153(1):90–97. doi: 10.1093/infdis/153.1.90. [DOI] [PubMed] [Google Scholar]
  12. Gerber A. U., Wiprächtiger P., Stettler-Spichiger U., Lebek G. Constant infusions vs. intermittent doses of gentamicin against Pseudomonas aeruginosa in vitro. J Infect Dis. 1982 Apr;145(4):554–560. doi: 10.1093/infdis/145.4.554. [DOI] [PubMed] [Google Scholar]
  13. Giamarellou H., Yiallouros K., Petrikkos G., Moschovakis E., Vavouraki E., Voutsinas D., Sfikakis P. Comparative kinetics and efficacy of amikacin administered once or twice daily in the treatment of systemic gram-negative infections. J Antimicrob Chemother. 1991 May;27 (Suppl 100):73–79. doi: 10.1093/jac/27.suppl_c.73. [DOI] [PubMed] [Google Scholar]
  14. Hollender L. F., Bahnini J., De Manzini N., Lau W. Y., Fan S. T., Hermansyur K., Benny P., Husni A. N., Sutjipto, Lorber R. R. A multicentric study of netilmicin once daily versus thrice daily in patients with appendicitis and other intra-abdominal infections. J Antimicrob Chemother. 1989 May;23(5):773–783. doi: 10.1093/jac/23.5.773. [DOI] [PubMed] [Google Scholar]
  15. Jolley M. E., Stroupe S. D., Wang C. H., Panas H. N., Keegan C. L., Schmidt R. L., Schwenzer K. S. Fluorescence polarization immunoassay. I. Monitoring aminoglycoside antibiotics in serum and plasma. Clin Chem. 1981 Jul;27(7):1190–1197. [PubMed] [Google Scholar]
  16. Kapusnik J. E., Hackbarth C. J., Chambers H. F., Carpenter T., Sande M. A. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis. 1988 Jul;158(1):7–12. doi: 10.1093/infdis/158.1.7. [DOI] [PubMed] [Google Scholar]
  17. Leggett J. E., Fantin B., Ebert S., Totsuka K., Vogelman B., Calame W., Mattie H., Craig W. A. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis. 1989 Feb;159(2):281–292. doi: 10.1093/infdis/159.2.281. [DOI] [PubMed] [Google Scholar]
  18. Maller R., Ahrne H., Eilard T., Eriksson I., Lausen I. Efficacy and safety of amikacin in systemic infections when given as a single daily dose or in two divided doses. Scandinavian Amikacin Once Daily Study Group. J Antimicrob Chemother. 1991 May;27 (Suppl 100):121–128. doi: 10.1093/jac/27.suppl_c.121. [DOI] [PubMed] [Google Scholar]
  19. Marik P. E., Havlik I., Monteagudo F. S., Lipman J. The pharmacokinetic of amikacin in critically ill adult and paediatric patients: comparison of once- versus twice-daily dosing regimens. J Antimicrob Chemother. 1991 May;27 (Suppl 100):81–89. doi: 10.1093/jac/27.suppl_c.81. [DOI] [PubMed] [Google Scholar]
  20. Marik P. E., Lipman J., Kobilski S., Scribante J. A prospective randomized study comparing once- versus twice-daily amikacin dosing in critically ill adult and paediatric patients. J Antimicrob Chemother. 1991 Nov;28(5):753–764. doi: 10.1093/jac/28.5.753. [DOI] [PubMed] [Google Scholar]
  21. Moore R. D., Smith C. R., Lietman P. S. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis. 1984 Mar;149(3):443–448. doi: 10.1093/infdis/149.3.443. [DOI] [PubMed] [Google Scholar]
  22. Mordenti J. Man versus beast: pharmacokinetic scaling in mammals. J Pharm Sci. 1986 Nov;75(11):1028–1040. doi: 10.1002/jps.2600751104. [DOI] [PubMed] [Google Scholar]
  23. Nicolau D. P., Freeman C. D., Belliveau P. P., Nightingale C. H., Ross J. W., Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995 Mar;39(3):650–655. doi: 10.1128/AAC.39.3.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nordström L., Ringberg H., Cronberg S., Tjernström O., Walder M. Does administration of an aminoglycoside in a single daily dose affect its efficacy and toxicity? J Antimicrob Chemother. 1990 Jan;25(1):159–173. doi: 10.1093/jac/25.1.159. [DOI] [PubMed] [Google Scholar]
  25. Pechère M., Letarte R., Pechère J. C. Efficacy of different dosing schedules of tobramycin for treating a murine Klebsiella pneumoniae bronchopneumonia. J Antimicrob Chemother. 1987 Apr;19(4):487–491. doi: 10.1093/jac/19.4.487. [DOI] [PubMed] [Google Scholar]
  26. Perlman B. B., Freedman L. R. Experimental endocarditis. II. Staphylococcal infection of the aortic valve following placement of a polyethylene catheter in the left side of the heart. Yale J Biol Med. 1971 Oct;44(2):206–213. [PMC free article] [PubMed] [Google Scholar]
  27. Potel G., Caillon J., Le Gallou F., Bugnon D., Le Conte P., Raza J., Lepage J. Y., Baron D., Drugeon H. Identification of factors affecting in vivo aminoglycoside activity in an experimental model of gram-negative endocarditis. Antimicrob Agents Chemother. 1992 Apr;36(4):744–750. doi: 10.1128/aac.36.4.744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Powell S. H., Thompson W. L., Luthe M. A., Stern R. C., Grossniklaus D. A., Bloxham D. D., Groden D. L., Jacobs M. R., DiScenna A. O., Cash H. A. Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin. J Infect Dis. 1983 May;147(5):918–932. doi: 10.1093/infdis/147.5.918. [DOI] [PubMed] [Google Scholar]
  29. Prins J. M., Büller H. R., Kuijper E. J., Tange R. A., Speelman P. Once versus thrice daily gentamicin in patients with serious infections. Lancet. 1993 Feb 6;341(8841):335–339. doi: 10.1016/0140-6736(93)90137-6. [DOI] [PubMed] [Google Scholar]
  30. Queiroz M. L., Bathirunathan N., Mawer G. E. Influence of dosage interval on the therapeutic response to gentamicin in mice infected with Klebsiella pneumoniae. Chemotherapy. 1987;33(1):68–76. doi: 10.1159/000238477. [DOI] [PubMed] [Google Scholar]
  31. Sturm A. W. Netilmicin in the treatment of gram-negative bacteremia: single daily versus multiple daily dosage. J Infect Dis. 1989 May;159(5):931–937. doi: 10.1093/infdis/159.5.931. [DOI] [PubMed] [Google Scholar]
  32. Van der Auwera P., Meunier F., Ibrahim S., Kaufman L., Derde M. P., Tulkens P. M. Pharmacodynamic parameters and toxicity of netilmicin (6 milligrams/kilogram/day) given once daily or in three divided doses to cancer patients with urinary tract infection. Antimicrob Agents Chemother. 1991 Apr;35(4):640–647. doi: 10.1128/aac.35.4.640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Viganò A., Principi N., Brivio L., Tommasi P., Stasi P., Villa A. D. Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children. Antimicrob Agents Chemother. 1992 Jul;36(7):1499–1503. doi: 10.1128/aac.36.7.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vogelman B., Gudmundsson S., Leggett J., Turnidge J., Ebert S., Craig W. A. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988 Oct;158(4):831–847. doi: 10.1093/infdis/158.4.831. [DOI] [PubMed] [Google Scholar]
  35. Vogelman B., Gudmundsson S., Turnidge J., Leggett J., Craig W. A. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis. 1988 Feb;157(2):287–298. doi: 10.1093/infdis/157.2.287. [DOI] [PubMed] [Google Scholar]

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