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

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]

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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