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Antimicrobial pharmacodynamics of vancomycin and disulfiram (Antabuse®) in Staphylococcus aureus

Hasitha Chavva1, Yogesh Meka1, Timothy E Long1,2

  • 1Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, WV, United States.

Frontiers in Microbiology
|January 23, 2023
PubMed
Abstract

Insights

Disulfiram (DSF) enhances vancomycin (VAN) killing of methicillin-resistant Staphylococcus aureus (MRSA) in vitro. However, DSF antagonizes vancomycin

Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • Intravenous vancomycin (VAN) is the primary treatment for systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA).
  • Achieving pharmacokinetic/pharmacodynamic (PK/PD) targets for VAN is challenging for MRSA with minimum inhibitory concentrations (MICs) > 1 µg/mL.
  • Vancomycin-intermediate Staphylococcus aureus (VISA) presents a significant therapeutic challenge.

Purpose of the Study:

  • To investigate the in vitro antimicrobial pharmacodynamic (PD) interaction of disulfiram (DSF) with VAN.
  • To evaluate DSF as a potential adjuvant therapy for MRSA infections, particularly those with reduced vancomycin susceptibility.
  • To assess the combined effect of VAN and DSF on VISA strains.

Main Methods:

  • Checkerboard titration testing to determine MIC and minimum bactericidal concentration (MBC) of VAN and DSF combinations.
  • Time-kill studies and flow cytometry to assess bactericidal activity and cellular effects.
  • Post-antibiotic effect (PAE) experiments to evaluate the duration of bacterial suppression after drug removal.

Main Results:

  • DSF demonstrated synergistic or additive effects, lowering VAN's MIC and MBC against a panel of MRSA strains.
  • A VAN/DSF combination (4/8 µg/mL) showed optimal bactericidal effects and suppressed VISA Mu50 growth more effectively than individual drugs.
  • Flow cytometry confirmed enhanced killing, but DSF antagonized VAN's PAE on the VISA Mu50 strain.

Conclusions:

  • DSF exhibits additive to synergistic killing activity with VAN against MRSA in vitro.
  • DSF may counteract specific resistance mechanisms in VISA strains, as suggested by flow cytometry data.
  • While DSF enhances direct killing, its effect on the post-antibiotic effect of VAN requires further investigation.
Keywords:
VISAdisulfiram (Antabuse®)methicillin-resistant Staphylococcus aureuspharmacodynamicssynergyvancomycin

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