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Antimicrobial Agents and Chemotherapy, December 2008, p. 4370-4373, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00922-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Minocycline against Staphylococcus aureus in an In Vitro Pharmacokinetic Model{triangledown}

Karen E. Bowker,* Alan R. Noel, and Alasdair P. MacGowan

Bristol Centre for Antimicrobial Research and Evaluation, Department of Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom

Received 16 July 2007/ Returned for modification 24 September 2007/ Accepted 26 May 2008

Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log10-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (P < 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with r2 of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and –1-log-unit, –2-log-unit, and –3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.

* Corresponding author. Mailing address: Bristol Centre for Antimicrobial Research and Evaluation, Department of Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. Phone: 44 1179 9595654. Fax: 44 117 9593217. E-mail: karen.bowker{at}nbt.nhs.uk

{triangledown} Published ahead of print on 2 June 2008.

Antimicrobial Agents and Chemotherapy, December 2008, p. 4370-4373, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00922-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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