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Antimicrobial Agents and Chemotherapy, September 2000, p. 2435-2441, Vol. 44, No. 9
Istituto di Malattie Infettive e Medicina
Pubblica1 and Centro Interdipartimentale
di Epidemiologia, Biostatistica e Informatica
Medica,3 Università degli Studi di Ancona,
Ancona, and Dipartimento di Farmacologia Preclinica e Clinica,
Università degli Studi di Firenze,
Florence,2 Italy
Received 11 February 2000/Returned for modification 12 May
2000/Accepted 6 June 2000
The interaction of amphotericin B (AmB) and azole antifungal agents
in the treatment of fungal infections is still a controversial issue. A
checkerboard titration broth microdilution-based method that adhered to
the recommendations of the National Committee for Clinical Laboratory
Standards was applied to study the in vitro interactions of AmB with
fluconazole (FLC), itraconazole (ITC), and the new investigational
triazole SCH 56592 (SCH) against 15 clinical isolates of
Cryptococcus neoformans. Synergy, defined as a fractional
inhibitory concentration (FIC) index of
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Interactions between Triazoles and Amphotericin B
against Cryptococcus neoformans
0.50, was observed for 7% of
the isolates in studies of the interactions of both FLC-AmB and ITC-AmB
and for 33% of the isolates in studies of the SCH-AmB interactions;
additivism (FICs, >0.50 to 1.0) was observed for 67, 73, and 53% of
the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB
interactions, respectively; indifference (FICs, >1.0 to 2.0) was
observed for 26, 20, and 14% of the isolates in studies of the
FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively. Antagonism
(FIC >2.0) was not observed. When synergy was not achieved, there was
still a decrease, although not as dramatic, in the MIC of one or both
drugs when they were used in combination. To investigate the effects of
FLC-AmB combination therapy in vivo, we established an experimental
model of systemic cryptococcosis in BALB/c mice by intravenous
injection of cells of C. neoformans 2337, a clinical
isolate belonging to serotype D against which the combination of FLC
and AmB yielded an additive interaction in vitro. Both survival and
tissue burden studies showed that combination therapy was more
effective than FLC alone and that combination therapy was at least as
effective as AmB given as a single drug. On the other hand, when cells
of C. neoformans 2337 were grown in FLC-containing medium,
a pronounced increase in resistance to subsequent exposures to AmB was
observed. In particular, killing experiments conducted with
nonreplicating cells showed that preexposure to FLC abolished the
fungicidal activity of the polyene. However, this apparent antagonism
was not observed in vivo. Rather, when the two drugs were used
sequentially for the treatment of systemic murine cryptococcosis, a
reciprocal potentiation was often observed. Our study shows that (i)
the combination of triazoles and AmB is significantly more active than
either drug alone against C. neoformans in vitro and (ii) the concomitant or sequential use of FLC and AmB for the
treatment of systemic murine cryptococcosis results in a positive interaction.
*
Corresponding author. Mailing address: Istituto di
Malattie Infettive e Medicina Pubblica, Università degli Studi di
Ancona, Ospedale Umberto I°, Largo Cappelli 1, 60121, Ancona Italy.
Phone: 39. 71. 5963467. Fax: 39. 71. 5963468. E-mail:
cmalinf{at}popcsi.unian.it.
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