Interpreting minimum inhibitory concentrations

Several previous discussions have dealt with the concept of the minimum inhibitory concentration (MIC) such as extended-infusion piperacillin/tazobactam (Zosyn) and vancomycin dosing in hemodialysis.  Though this concept was learned at some point, questions occasionally arise as to what these numbers represent and what to make of them when they show up on a culture and sensitivity result.  This post will discuss the MIC and hopefully address some common misconceptions.  For the take home points, skip down to the bullets at the end.

How is the MIC determined? (the lab portion)

The MIC is an in vitro test that determines the lowest concentration of antibiotic that inhibits the growth of an organism.  There are a number of ways to determine the MIC but I'll described the commonly used microdilution test.  The culture from a patient is adjusted to a standard (ie. 5 x 10⁵ cfu/mL) which is placed in a series of microdilution wells in a tray.  These trays are inexpensive and commercially available and contain preset rows of antibiotics.  Each row of wells contains two-fold increasing concentrations of antibiotics (ie. 0.25, 0.5, 1, 2, 4, 8, 16, 32 mcg/mL though it will be different for each antibiotic) and the tray is then incubated at a prespecified temperature for a prespecified amount of time (ie. 35 degrees Celsius for 18 hours).  

At this point they are inspected visually for growth.  Hopefully, many of the wells will have no visible growth.  The well with the lowest concentration of antibiotic that has no visible growth is the resultant MIC for this specific organism-antibiotic pair.  You want the MIC to be as low as possible because this hopefully translates to requiring less antibiotic to eradicate the bacteria in vivo.

How does the MIC translate to 'sensitive', 'intermediate', or 'resistant'?

Whether a lab uses the microdilution test described above or any other number of tests, the result is a MIC concentration which alone doesn't tell us very much.  A clinician is not going to be able to use their knowledge of pharmacokinetics and pharmacodynamics alone to figure out something like, "If I give X amount of drug it will likely achieve X mg/L concentration at the site of infection for X amount of time which will provide a sufficient percentage of time greater than the MIC throughout the dosing interval (as is desirable for beta-lactams) which is needed to ensure microbial eradication".  To translate these numbers to meaningful data, a source such as the Clinical and Laboratory Standards Institute (CLSI) publishes the interpretation of MICs of relevant antibiotics for most bacteria.  

For example, for a given antibiotic-bacteria pair, a MIC of 2 mcg/mL may be defined as 'sensitive' by the CLSI because treating with the usual doses of that medication will be sufficient to treat the usual types of infections caused by that organism.  If the MIC returns as 4 mcg/mL and that is the CLSI breakpoint to define 'resistant', this means that the concentration needed for a clinical cure is likely to exceed that which we usually administer to patients.

An important concept to point out is that each individual bacteria-antibiotic pair has a different set of thresholds for 'sensitive', 'intermediate', and 'resistant'.  This means that MICs cannot be compared across drugs or across bacteria.  For example, if a urine culture grows out e. coli that is sensitive to all antibiotics tested, you cannot simply look down the list and decide that the antibiotic with the lowest MIC will be most effective.  The 'best' MIC is relative to the prespecified 'sensitive' breakpoint and the best antibiotic choice includes a number of variables such as the ability to reach the site of infection, allergy profile, drug-interactions, cost, adverse effect profile, available routes of administration, dosing schedule, and clinical studies. 

Take home points:

• MIC is the minimum concentration to inhibit in vitro growth of bacteria
• Thresholds defining what is 'sensitive' are standardized by an organization such as the CLSI
• Each bacteria-antibiotic has a unique set of MIC breakpoints defining 'sensitive', 'intermediate', and 'resistant' bacteria - so don't compare them across drugs
• MICs, even when categorized as 'sensitive' occasionally may have different treatment implications so consult an infectious disease specialist if you are uncertain

References:
Jorgensen JH, Ferraro MJ.  Antimicrobial susceptibility testing: a review of general principles and contemporary practice.  Clin Infect Dis  2009;49(11):1749-55.

photo by Iqbal Osman1