Minimal Inhibitory Concentrations and Antimicrobial Dosing: How are they related?

Microbiology laboratories use clinical breakpoints to categorize microorganisms as susceptible, intermediate, or resistant. These breakpoints help guide the selection of antimicrobial therapy having a high likelihood of achieving therapeutic success in patients. One in vitro marker of antimicrobial activity is the minimal inhibitory concentration (MIC), the lowest concentration of antibiotic that prevents visible growth of a standard bacterial inoculum. National committees, such as the Clinical Laboratories Standards Institute (CLSI), Food and Drug Administration (FDA), and The European Committee on Antimicrobial Susceptibility Testing (EUCAST) define clinical practice breakpoint MIC values for each bacterial genus. These defined values are determined using wild type value distributions in relation to what serum drug levels are achievable with standard antimicrobial dosing.

All drugs have individual pharmacokinetic properties such as absorption, volume of distribution, and rate of elimination. These factors contribute to what concentration of drug will be achieved at a certain site of infection. A good index of overall antibiotic exposure in a patient is the serum area-under-the-curve (AUC), which is influenced directly by the drug dose and clearance. Antibiotics also have pharmacodynamic properties, which relate to the drug’s effect on the microorganism over time. There are two main groups of pharmacodynamic characteristics seen with antimicrobial agents: time-dependent bactericidal action (Figure 1) and concentration-dependent bactericidal action (Figure 2). The clinical efficacy of an antibiotic is related to the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters of a drug and the MIC of the specific organism. Bacterial strains with an increase in MIC may exhibit relative resistance by in vitro laboratory standards, but because there is no increase in the PK/PD parameters, the increased MIC can sometimes be overcome by altering dosing regimens to optimize the drug concentrations achieved.

For example, β-lactam antibiotics exhibit time-dependent killing activity, so dosing regimens which maximize duration of exposure to drug concentrations above the MIC of the organism are particularly effective for treating bacteria with this this class of antibiotics. Prolonged infusion times and smaller fractions of total daily doses given more frequently are two strategies through which this can be achieved. For drugs exhibiting concentration-dependent killing, such as aminoglycosides, dosing regimens can be optimized by giving a higher dose in order to achieve higher peak concentrations. The pharmacokinetic properties of drug can also be used to overcome elevated MICs for some organisms depending on the site of the infection. A good example of this would be urinary tract infections. Antibiotics that achieve high concentrations in the urine, such as aminoglycosides, can be used to successfully treat organisms with elevated MICs. Therefore, while healthcare providers utilize breakpoint MIC values to select antimicrobial regimens, understanding characteristics of an antimicrobial, including PK/PD parameters and tissue distribution, along with taking into account the site of infection and the MIC of the infecting organism, can provide the opportunity for optimization of antimicrobial dosing strategies.

Figure 1. For antibiotics which confer time-dependent antimicrobial activity, microbial killing is optimized when the concentration of antibiotic is above the MIC for as long of a time period as possible.

Figure 2. For antibiotics which confer concentration-dependent antimicrobial activity, microbial killing is optimized when a high peak concentration of antimicrobial is achieved.

References:

1. Mouton JW, Brown DFJ, Apfalter P et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect. 2012;18:E37-E45.
2. Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am. 2009;23(4):791-vii.
3. MacGowen AP. Role of pharmacokinetics and pharmacodynamics: does the dose matter? CID. 2001;33(suppl 3):S238-239.
4. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012;56(6):2795-2805.

-Alaina Burns, PharmD, is a PGY-2 Pediatric Pharmacy Resident at Children’s Health, Children’s Medical Center in Dallas, Texas.