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Antimicrobial Agents and Chemotherapy, May 2009, p. 1874-1883, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01605-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Intracellular Activity of Antibiotics against Staphylococcus aureus in a Mouse Peritonitis Model {triangledown}

Anne Sandberg,1* Jonas H. R. Hessler,1 Robert L. Skov,1 Jens Blom,2 and Niels Frimodt-Møller1

National Center for Antimicrobials & Infection Control, Statens Serum Institut, 5 Artillerivej, Copenhagen S DK-2300, Denmark,1 Department of Virology, Statens Serum Institut, 5 Artillerivej, Copenhagen S DK-2300, Denmark2

Received 14 December 2007/ Returned for modification 25 February 2008/ Accepted 2 February 2009

Antibiotic treatment of Staphylococcus aureus infections is often problematic due to the slow response to therapy and the high frequency of infection recurrence. The intracellular persistence of staphylococci has been recognized and could offer a good explanation for these treatment difficulties. Knowledge of the interplay between intracellular antibiotic activity and the overall outcome of infection is therefore important. Several intracellular in vitro models have been developed, but few experimental animal models have been published. The mouse peritonitis/sepsis model was used as the basic in vivo model exploring a quantitative ex vivo extra- and intracellular differentiation assay. The intracellular presence of S. aureus was documented by electron microscopy. Five antibiotics, dicloxacillin, cefuroxime, gentamicin, azithromycin, and rifampin (rifampicin), were tested in the new in vivo model; and the model was able to distinguish between their extra- and intracellular effects. The intracellular effects of the five antibiotics could be ranked as follows as the mean change in the log10 number of CFU/ml ({Delta}log10 CFU/ml) between treated and untreated mice after 4 h of treatment: dicloxacillin (3.70 {Delta}log10 CFU/ml) > cefuroxime (3.56 {Delta}log10 CFU/ml) > rifampin (1.86 {Delta}log10 CFU/ml) > gentamicin (0.61 {Delta}log10 CFU/ml) > azithromycin (0.21 {Delta}log10 CFU/ml). We could also show that the important factors during testing of intracellular activity in vivo are the size, number, and frequency of doses; the time of exposure; and the timing between the start of infection and treatment. A poor correlation between the intracellular accumulation of the antibiotics and the actual intracellular effect was found. This stresses the importance of performing experimental studies, like those with the new in vivo model described here, to measure actual intracellular activity instead of making predictions based on cellular pharmacokinetic and MICs.

* Corresponding author. Mailing address: National Center for Antimicrobials & Infection Control, Statens Serum Institut, 5 Artillerivej, Building 47, Room 201, Copenhagen S DK-2300, Denmark. Phone: 45 3268 8425. Fax: 45 3268 3132. E-mail: asa{at}ssi.dk

{triangledown} Published ahead of print on 17 February 2009.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1874-1883, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01605-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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