Minimum Inhibitory Concentration

OVERVIEW

• Minimum Inhibitory Concentration (MIC) is lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism following overnight incubation, usually reported as mg/L
• A related concept is the minimum bactericidal concentrations (MBCs), which is the lowest concentration of antimicrobial that will prevent the growth of an organism after subculture on to antibiotic-free media
• Infections in the ICU are often caused by pathogens with higher MICs compared with other clinical settings
• Regular surveillance of MICs is required due to a continuing decrease in susceptibility to the commonly used antibiotics in critically ill patients

IMPORTANCE

• defines the drug exposure necessary to ensure a patient achieves a predefined PK/PD target that is associated with maximal efficacy
• research tool to determine the in vitro activity of new antimicrobials and determine ‘MIC breakpoints’
• monitor resistance to antimicrobial agents

DETERMINATION

• by agar or broth dilution methods
• strips with graded changes in antibiotic concentrations provided
  • when placed on plates the point at which the bacterial inhibition intersects with strip is the MIC

CLINICAL APPLICATION

• generally drug concentrations need to be 4-5x the MIC to ensure that an antibiotic is effective
• different antibiotics depend on Cmax, AUC above MIC and time above MIC for maximal effect
• most laboratories routinely report susceptibility with the classification ‘S, I and R’ (Susceptible, Intermediate-Susceptible and Resistant) based on MIC breakpoints
  • The breakpoint is the chosen concentration of an antibiotic which defines whether a species of bacteria is susceptible or resistant to the antibiotic
  • If the MIC is less than or equal to the susceptibility breakpoint the bacteria is considered susceptible to the antibiotic
  • MIC breakpoints published at www.eucast.org and www.clsi.org

PROS AND CONS OF USING THE MIC

Advantages

• Easy to perform
• Familar and widely used
• usually automated
• highly reproducible (due to simplicity and automation)
• Rapid turnaround of results

Disadvantages

• MIC can vary greatly with minor variations in methodology can result in large variations of the MIC.
  • e.g. prolonged incubation may increase the apparent MIC
  • e.g. smaller inoculum concentrations may decrease the apparent MIC
  • e.g. MIC may change with freezer storage of samples
• Comparisons between laboratories are hindered by differences in techniques used
• inhibition of visible growthdoes not mean the organisms were killed (cf. minimum bactericidal concentration)
• MIC is not truly a single number, but a range depending on the dilution series used during its determination
• MIC does not necessarily equate with in vivo efficacy, for example:
  • an antibiotic will be ineffective if it does not penetrate the affected tissues
  • antibiotics with high MICs may still be effective if concentrated at the site of infection (e.g. treatment of UTI with gentamicin, which concentrates in the urine)
  • antibiotic kill characteristics are important (e.g. concentration versus time dependent killing)
  • critically ill patients may have altered pharmacodynamics and pharmacokinetics
  • ‘breakpoints’ are often subjective and may not correlate with clinical outcomes

EVIDENCE

Kalil et al, 2014 meta-analysis of mortality from S. aureus bacteremia (SAB) with  high-MIC (≥1.5 mg/L) versus low-MIC (<1.5 mg/L)

• systematic review and meta-analysis
• 38 included studies that involved 8291 episodes of SAB
• overall mortality was 26.1%
• no statistically significant differences in the risk of death
• Commentary and criticisms:
  • do high-MIC strains have lower virulence?
  • lack of mortality benefit may be related to limitations of MIC in predicting in vivo efficacy discussed above
  • outcome may be confounded by other factors (e.g. are high MIC-strains more likely to have prompt optimsation of source control or other aspects of management that affect outcomes?)
  • this study cannot exclude definitively higher mortality with high-MIC and did not assess non-mortality patient outcomes
  • the use of alternative anti-staphylococcal agents may not be required for S aureus isolates with elevated but susceptible vancomycin MIC values

References and links

LITFL

• CCC — Antimicrobial Dosing and Kill Characteristics

Journal articles

• Andrews JM. Determination of minimum inhibitory concentrations. The Journal of antimicrobial chemotherapy. 48 Suppl 1:5-16. 2001. [pubmed] [free full text]
• Kalil A et al. Association Between Vancomycin Minimum Inhibitory Concentration and Mortality Among Patients With Staphylococcus aureus Bloodstream Infections A Systematic Review and Meta-analysis. JAMA 2014; 312(15):1552-64. [pubmed]
• Lambert RJ, Pearson J. Susceptibility testing: accurate and reproducible minimum inhibitory concentration (MIC) and non-inhibitory concentration (NIC) values. Journal of applied microbiology. 88(5):784-90. 2000. [pubmed]
• Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. The Lancet. Infectious diseases. 14(6):498-509. 2014. [pubmed] [free full text]