Synergistic interaction between voriconazole and amphotericin B against Aspergillus fumigatus in a pharmacokinetic/pharmacodynamic (PK/PD) model simulating free drug concentrations achieved in human serum

Ref ID: 19435

Author:

M. Siopi, A. Elefanti, N. Siafakas, L. Zerva and J. Meletiadis

Author address:

Clinical Microbiology Laboratory, Attikon University Hospital,
Athens, Greece

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Objectives Voriconazole is often combined with amphotericin B for
the management of refractory invasive aspergillosis. The potential
treatment benefit of polyene-triazole combination therapy is contro-
versial because of conflicting in vitro and in vivo studies. However,
in these studies pharmacodynamic effects were not assessed at clini-
cally relevant concentrations since in vitro and in vivo studied did
not simulated human serum concentration time profiles. We there-
fore investigated the efficacy of voriconazole in combination with
amphotericin B against A. fumigatus simulating free drug concentra-
tions achieved in human serum with a new in vitro PK/PD model.
Methods The A. fumigtaus isolate ATCC MYA-3626 with voriconaz-
ole and amphotericin B CLSI MICs of 0.5 and 1 mg/L, respectively,
was used. Voriconazole and conventional amphotericin B human
standard dosages of 4 mg/kg bid and 1 mg/kg od, respectively were
simulated in a newly developed in vitro PK simulation model. The in
vitro model consists of an internal compartment (IC, a 10 mL dialysis
tube made out of semi-permeable cellulose membrane allowing the
free diffusion of molecules smaller than 20kD) placed inside an exter-
nal compartment (EC, a 700 mL glass beaker) whose content is
diluted with a peristaltic pump at the same rate as the clearance of
the drug in human plasma. The IC was inoculated with a conidial
suspension (103 CFU/mL) and incubated at 37°C for 72 hours, while
voriconazole and amphotericin B were injected alone and in combi-
nation in both compartments every 12 h and 24 h, respectively at
maximum concentrations corresponding to the maximum concentra-
tions of unbound drugs in human serum (fCmax) of 1.7 mg/l and
0.1 mg/l, respectively. Voriconazole and amphotericin B fCmax were
determined based on the 58% and 95% protein binding and the
mean maximum concentrations of total drugs of 4 mg/l and 2 mg/l
achieved in human serum, respectively (Purkins et al AAC 2002,
Ayastraran et al AAC 1996). Drug levels were determined by micro-
biological afar diffusion assays and fungal growth by measuring the
galactomannan production in the IC using a commercially available
sandwich-ELISA. The% of fungal growth was calculated based on the
area under the galactomannan-time curve. The interactions were
analyzed based on the Bliss independence model where the observed
growth EOBS was compared the theoretical ETHE if the two drugs were
acting independently as EVORxEAMB where EVOR and EAMB are the% of
voriconazole and amphotericin B alone, respectively. Synergy was
concluded when EOBS < ETHE (t test p < 0.05). All experiments were repeated two times. Results The model simulated well voriconazole and amphotericin B human pharmacokinetics as drug concentration-time profiles corre- sponded to those observed in human serum. Both monotherapies of amphotericin B and voriconazole resulted in 86  8% and 40  3.6%fungal growth indicating that drug concentrations were suboptimal. The two-drug combination resulted in 8.6  1% growth with Bliss interaction analysis showing a synergistic effect of 25.8  2.5% (p < 0.05). Conclusion The double combination of voriconazole plus amphoteri- cin B may be synergistic against A. fumigatus at clinically achievable serum concentrations, enhancing the overall efficacy of poly- ene+azole combination therapy particularly in patients with subopti- mal drug concentrations.

Abstract Number: p306

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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