Single and combination antibiotic therapy of Staphylococcus aureus experimental endocarditis: emergence of gentamicin-resistant mutants.
The efficacy of nafcillin and gentamicin used alone and in combination at doses giving serum concentrations comparable to those achieved in patients was studied in rabbits with experimental Staphylococcus aureus endocarditis. The organism used was a penicillinase-producing, methicillin-susceptible, clinical isolate. The addition of gentamicin to nafcillin significantly increased the rate of killing of organisms in valvular vegetations, compared to the effect of nafcillin alone. Gentamicin alone delayed mortality but was not effective in reducing the bacterial populations of the vegetations. Bacteremia persisted in the animals treated with gentamicin alone, in contrast to the groups treated with nafcillin or the combination. Selection of a subpopulation of aminoglycoside-resistant small-colony variants occurred in animals treated with gentamicin alone. This variant was subsequently employed in the rabbit model and produced endocarditis, metastatic infection, and bacteremia comparable to those caused by the parent strain. Animals with infection produced by the variant died later than animals infected by the parent strain. Nafcillin was equally effective in reducing the population of both parent and variant strains in vitro and in therapy of the infected animals. Population studies showed the variant to be a mutant emerging at a rate of 1.9 x 10(-7). It was shown to differ from the parent strain in coagulase and hemolysin production, colonial morphology, and aminoglycoside susceptibility, but was similar by light and electron microscopy and in phage type, pigmentation of colonies, deoxyribonuclease production, mannitol fermentation, and growth rate.
D000818:Animals; D004697:Endocarditis, Bacterial / Q000188:drug therapy*; D005839:Gentamicins / Q000627:therapeutic use*; D009254:Nafcillin / Q000627:therapeutic use*; D010403:Penicillin Resistance; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects
D005839:Gentamicins; D009254:Nafcillin
Genetics. 1943 Nov;28(6):491-511
17247100
Bull Johns Hopkins Hosp. 1963 Jan;112:31-47
13949384
J Clin Invest. 1954 Dec;33(12):1611-22
13211817
J Bacteriol. 1952 Mar;63(3):399-406
14927572
Lancet. 1976 Dec 18;2(7999):1347-8
63814
Antimicrob Agents Chemother. 1977 Aug;12(2):163-77
143238
Antimicrob Agents Chemother. 1977 Oct;12(4):513-7
921246
J Infect Dis. 1977 Sep;136(3):360-9
903674
Am J Med Sci. 1977 Mar-Apr;273(2):133-9
871133
Antimicrob Agents Chemother. 1977 Jan;11(1):47-50
836013
Antimicrob Agents Chemother. 1976 Aug;10(2):258-64
984767
Antimicrob Agents Chemother. 1976 Sep;10(3):519-25
984794
J Clin Microbiol. 1976 Oct;4(4):343-8
977733
Ann Med Interne (Paris). 1972 Mar;123(3):225-8
4649708
Lancet. 1969 Dec 27;2(7635):1425-6
4188305
N Engl J Med. 1975 Nov 6;293(19):964-70
1101062
Lancet. 1976 Feb 28;1(7957):464-6
55729
Lancet. 1976 Jan 3;1(7949):20-1
54520
Antimicrob Agents Chemother. 1974 Dec;6(6):802-6
4451352
Br J Exp Pathol. 1972 Feb;53(1):44-9
5014243
J Lab Clin Med. 1971 Sep;78(3):457-63
4999161
Antimicrob Agents Chemother. 1976 Jun;9(6):928-38
820248
Am J Med Technol. 1975 Mar;41(3):99-105
1090163
J Lab Clin Med. 1976 Jul;88(1):118-24
1047088
J Infect Dis. 1975 Apr;131(4):367-75
1117194
J Infect Dis. 1975 Mar;131(3):245-51
1127254
Yale J Biol Med. 1971 Oct;44(2):206-13
5123055
J Med Microbiol. 1969 Aug;2(3):187-97
5404799
Yale J Biol Med. 1969 Apr;41(5):394-403
5780692