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Antimicrobial Agents and Chemotherapy, October 2000, p. 2728-2732, Vol. 44, No. 10
Division of Clinical Pharmacokinetics,
Department of Clinical Pharmacology,1 and
Division of Infectious Diseases and Chemotherapy, Department of
Internal Medicine I,3 University of Vienna
Medical School, Vienna, and Department of Pharmacology and
Toxicology, Karl-Franzens-University Graz,
Graz,2 Austria
Received 31 January 2000/Returned for modification 10 May
2000/Accepted 10 July 2000
Fosfomycin is a broad-spectrum antibiotic which is established as
therapy for uncomplicated lower urinary tract infections. In addition,
preliminary data indicate that fosfomycin has a potential role in the
treatment of soft tissue infections. However, the use of fosfomycin has
not been established for this condition, and it is unclear whether the
level of fosfomycin penetration into human soft tissues is high enough
to eradicate relevant pathogens. To better characterize the antibiotic
potential of fosfomycin, we applied a combined in vivo
pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For
this purpose fosfomycin concentrations in vivo in the fluid of the
interstitial space of human soft tissues were measured by microdialysis
following intravenous infusion of 4 or 8 g of fosfomycin
(n = 6). Subsequently, bacterial isolates with
relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high
degree of soft tissue penetration for fosfomycin, with ratios of the
area under the concentration-time curve from 0 to 8 h for muscle
(AUC0-8muscle)/AUC0-8serum
of 0.48 ± 0.08 and 0.53 ± 0.04 and ratios of
AUC0-8adipose
tissue/AUC0-8serum of 0.74 ± 0.12 and 0.71 ± 0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with
selected isolates of Staphylococcus aureus,
Enterobacter cloacae, and Serratia marcescens
for which MICs were 16 µg/ml, organisms were undetectable after a
single dosing interval. Fosfomycin exhibits a strong ability to
penetrate into the fluid of the interstitial space of soft tissues and
reaches levels sufficient to substantially inhibit the growth of
relevant bacteria at the target site. We therefore conclude that
fosfomycin might qualify as an alternative candidate for the therapy of
soft tissue infections.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Distribution and Antimicrobial Activity of
Fosfomycin in the Interstitial Fluid of Human Soft Tissues
Antimicrobial Agents and Chemotherapy, October 2000, p. 2728-2732, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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