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. 1990 Dec;34(12):2387–2391. doi: 10.1128/aac.34.12.2387

Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis.

B Fantin 1, C Carbon 1
PMCID: PMC172066  PMID: 2128443

Abstract

The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However, the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin, alone or in combination with various dosing regimens of netilmicin, for the treatment of experimental left-sided Enterococcus faecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h), netilmicin at a high dose (4 mg/kg every 8 h), or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 micrograms/ml and 8 and 8 micrograms/ml for penicillin and netilmicin, respectively. A netilmicin concentration of 4 micrograms/ml was the lowest concentration that achieved synergism with penicillin, as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg), 9.8 (netilmicin at 4 mg/kg), and 20.6 (netilmicin at 12 mg/kg) micrograms/ml. Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P less than 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin. Our data suggest that prolonged levels of aminoglycoside in serum might be important to exhibit the greatest in vivo efficacy of the combination against E. faecalis. They also indicate that use of a reduced total daily dose of aminoglycoside or an increase in the interval between each dose might reduce the efficacy of therapy in animals with this type of infection.

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Selected References

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  1. 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]
  2. Brion N., Barge J., Godefroy I., Dromer F., Dubois C., Contrepois A., Carbon C. Gentamicin, netilmicin, dibekacin, and amikacin nephrotoxicity and its relationship to tubular reabsorption in rabbits. Antimicrob Agents Chemother. 1984 Feb;25(2):168–172. doi: 10.1128/aac.25.2.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carrizosa J., Kaye D. Antibiotic synergism in enterococcal endocarditis. J Lab Clin Med. 1976 Jul;88(1):132–141. [PubMed] [Google Scholar]
  4. Carrizosa J., Kaye D. Penicillin and netilmicin in treatment of experimental enterococcal endocarditis. Antimicrob Agents Chemother. 1978 Mar;13(3):505–508. doi: 10.1128/aac.13.3.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carrizosa J., Levison M. E. Minimal concentrations of aminoglycoside that can synergize with penicillin in enterococcal endocarditis. Antimicrob Agents Chemother. 1981 Sep;20(3):405–409. doi: 10.1128/aac.20.3.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Contrepois A., Brion N., Garaud J. J., Faurisson F., Delatour F., Levy J. C., Deybach J. C., Carbon C. Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans. Antimicrob Agents Chemother. 1985 Apr;27(4):520–524. doi: 10.1128/aac.27.4.520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eliopoulos G. M., Eliopoulos C. T. Therapy of enterococcal infections. Eur J Clin Microbiol Infect Dis. 1990 Feb;9(2):118–126. doi: 10.1007/BF01963636. [DOI] [PubMed] [Google Scholar]
  8. Fantin B., Pangon B., Potel G., Caron F., Vallée E., Vallois J. M., Mohler J., Buré A., Philippon A., Carbon C. Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase. Antimicrob Agents Chemother. 1990 Apr;34(4):581–586. doi: 10.1128/aac.34.4.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fantin B., Pangon B., Potel G., Vallois J. M., Caron F., Bure A., Carbon C. Ceftriaxone-netilmicin combination in single-daily-dose treatment of experimental Escherichia coli endocarditis. Antimicrob Agents Chemother. 1989 May;33(5):767–770. doi: 10.1128/aac.33.5.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Frame P. T., Phair J. P., Watanakunakorn C., Bannister T. W. Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits. J Infect Dis. 1977 Jun;135(6):952–956. doi: 10.1093/infdis/135.6.952. [DOI] [PubMed] [Google Scholar]
  11. Henry N. K., Wilson W. R., Geraci J. E. Treatment of streptomycin-susceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin. Antimicrob Agents Chemother. 1986 Nov;30(5):725–728. doi: 10.1128/aac.30.5.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hessen M. T., Pitsakis P. G., Levison M. E. Postantibiotic effect of penicillin plus gentamicin versus Enterococcus faecalis in vitro and in vivo. Antimicrob Agents Chemother. 1989 May;33(5):608–611. doi: 10.1128/aac.33.5.608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kahlmeter G., Dahlager J. I. Aminoglycoside toxicity - a review of clinical studies published between 1975 and 1982. J Antimicrob Chemother. 1984 Jan;13 (Suppl A):9–22. doi: 10.1093/jac/13.suppl_a.9. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Korzeniowski O. M., Wennersten C., Moellering R. C., Jr, Sande M. A. Penicillin-netilmicin synergism against Streptococcus faecalis. Antimicrob Agents Chemother. 1978 Mar;13(3):430–434. doi: 10.1128/aac.13.3.430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Lewis C. M., Zervos M. J. Clinical manifestations of enterococcal infection. Eur J Clin Microbiol Infect Dis. 1990 Feb;9(2):111–117. doi: 10.1007/BF01963635. [DOI] [PubMed] [Google Scholar]
  18. Matsumoto J. Y., Wilson W. R., Wright A. J., Geraci J. E., Washington J. A., 2nd Synergy of penicillin and decreasing concentration of aminoglycosides against enterococci from patients with infective endocarditis. Antimicrob Agents Chemother. 1980 Dec;18(6):944–947. doi: 10.1128/aac.18.6.944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moellering R. C., Jr, Wennersten C., Medrek T., Weinberg A. N. Prevalence of high-level resistance to aminoglycosides in clinical isolates of enterococci. Antimicrob Agents Chemother (Bethesda) 1970;10:335–340. [PubMed] [Google Scholar]
  20. Murray B. E. The life and times of the Enterococcus. Clin Microbiol Rev. 1990 Jan;3(1):46–65. doi: 10.1128/cmr.3.1.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pearson R. D., Steigbigel R. T., Davis H. T., Chapman S. W. Method of reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother. 1980 Nov;18(5):699–708. doi: 10.1128/aac.18.5.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pierre C., Blanchet F., Seta N., Chaigne P., Labarre C., Sterkers O., Amiel C., Carbon C. Tolerance of once-daily dosing of netilmicin and teicoplanin, alone or in combination, in healthy volunteers. Clin Pharmacol Ther. 1988 Oct;44(4):458–466. doi: 10.1038/clpt.1988.180. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Sanders C. C. Synergy of penicillin-netilmicin combinations against enterococci including strains highly resistant to streptomycin or kanamycin. Antimicrob Agents Chemother. 1977 Aug;12(2):195–200. doi: 10.1128/aac.12.2.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Standiford H. D., De Maine J. B., Kirby W. M. Antibiotic synergism of enterococci. Relation to inhibitory concentrations. Arch Intern Med. 1970 Aug;126(2):255–259. [PubMed] [Google Scholar]
  26. 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]
  27. Weinstein A. J., Moellering R. C., Jr Penicillin and gentamicin therapy for enterococcal infections. JAMA. 1973 Feb 26;223(9):1030–1032. [PubMed] [Google Scholar]
  28. Wood C. A., Norton D. R., Kohlhepp S. J., Kohnen P. W., Porter G. A., Houghton D. C., Brummett R. E., Bennett W. M., Gilbert D. N. The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess. J Infect Dis. 1988 Jul;158(1):13–22. doi: 10.1093/infdis/158.1.13. [DOI] [PubMed] [Google Scholar]
  29. Wright A. J., Wilson W. R., Matsumoto J. Y., Washington J. A., 2nd, Geraci J. E. Influence of gentamicin dose size on the efficacies of combinations of gentamicin and penicillin in experimental streptomycin-resistant enterococcal endocarditis. Antimicrob Agents Chemother. 1982 Dec;22(6):972–975. doi: 10.1128/aac.22.6.972. [DOI] [PMC free article] [PubMed] [Google Scholar]

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