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Pharmacodynamic and response surface analysis of linezolid or vancomycin combined with meropenem against Staphylococcus aureus

Abstract

Purpose

To systematically assess the impact of pharmacodynamic interactions when adding either linezolid or vancomycin to meropenem on the antibacterial activity against methicillin-susceptible Staphylococcus aureus (MSSA). These regimens are frequently used in empiric therapy when risk factors for MRSA are present, but MSSA will often turn out as pathogen.

Methods

Checkerboard and time-kill curve studies were performed against three strains of MSSA covering clinically relevant concentrations of all antibiotics. We newly elaborated a response surface analysis (RSA) to quantify the extent of the pharmacodynamic interactions.

Results

The most prominent result was that linezolid fully antagonised the rapid (4–6 h) bactericidal effect of meropenem against MSSA to bacteriostasis at clinically relevant concentrations of both drugs. This interaction was invisible in the conventional checkerboard analysis (insensitive turbidity threshold). RSA quantified a 1.5–3.2 log10-fold higher bacterial load compared to expected additivity for linezolid and meropenem. Vancomycin and meropenem interacted partly synergistic (subinhibitory) or additive (inhibitory combinations) being bactericidal after 24 h.

Conclusions

Standard doses of linezolid and meropenem will provide inhibitory concentrations and thus pharmacodynamic antagonism throughout the whole dosing interval for MSSA. Further data is required to assess the clinical significance of this interaction.

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Abbreviations

ATCC:

American type culture collection

BI:

Bliss independence

C:

Drug concentration

CaMHB:

Cation-adjusted Mueller Hinton broth

CFU:

Colony forming unit

E:

Antibacterial effect

EC50 :

Drug concentration at which the half-maximum effect is observed

Emax:

Maximum drug effect

GC:

Growth control

H:

Hill factor expressing the steepness of the concentration-effect relationship

IE:

Intensity of the antibacterial effect

LZD:

Linezolid

MER:

Meropenem

MIC:

Minimal inhibitory concentration

MRSA:

Methicillin-resistant Staphylococcus aureus

MSSA:

Methicillin-sensitive Staphylococcus aureus

PD:

Pharmacodynamic

PK:

Pharmacokinetic

RSA:

Response surface analysis

T>MIC :

Time period that drug concentrations exceed the minimal inhibitory concentration

TKC:

Time-kill curve

VAN:

Vancomycin

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank PD Dr. Thomas Adam (Institute of Microbiology and Hygiene, Charité University Hospital, Berlin/Germany) for providing the clinical isolates of S. aureus and Iris K. Minichmayr (Institute of Pharmacy, Dept. of Clinical Pharmacy and Biochemistry, Freie Universitaet Berlin/Germany) for her critical review of the manuscript.

Part of this work has been presented as a poster (P1592) at the 23rd European Congress of Clinical Microbiology and Infectious Diseases in Berlin/Germany, 27–30 April 2013.

This study was funded by sources from the institution (Freie Universitaet Berlin, Germany). The authors declare no conflicts of interest.

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Correspondence to Charlotte Kloft.

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Wicha, S.G., Kees, M.G., Kuss, J. et al. Pharmacodynamic and response surface analysis of linezolid or vancomycin combined with meropenem against Staphylococcus aureus. Pharm Res 32, 2410–2418 (2015). https://doi.org/10.1007/s11095-015-1632-3

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KEY WORDS

  • antibiotic combination therapy
  • checkerboard
  • pharmacodynamic drug-drug interactions
  • response surface analysis
  • time-kill curve studies