Question 24.1

College Answer

a)  What does “A” represents, name one antibiotic for which this is important with regards to dosing?
C MAX: Maximum concentration 
Aminiglycosides

b)  What does “B” represents, name one antibiotic for which this is important with regards to dosing?
AUC > MIC: Area under the curved where drug concentration is greater than MIC Quinilones

c)  What does “C” represents, name one antibiotic for which this is important with regards to dosing?
T>AUC above MIC: Time greater than Area under the curved where concentration is greater than MIC

Penicillins, Carbenepenems

Discussion

This question is based on Table 72.2 from Oh's Manual, "Pharmacodynamic properties of selected antibiotics". It can be found on page 739 of the new edition. The table, in turn, is based on a 2009 article by Roberts and Lipman. The article even has a graph of concentration over time, which resembles the graph in the question. It was published one year after this college paper. In it, an excellent section entitled "Kill characteristics of antibiotics" describes the below concepts very well. This article, in turn, draws on material from an even earlier article from 2003 by William A. Craig, which is even more detailed. For the time-poor exam candidate, a brief summary of antibiotic kill characteristics is compiled in the Required Reading section.

At a basic level, the activity of antibiotics is described by three statements, according to the most important factor in their pharmacokinetics:

• Time dependent killing
  • This refers to the time spent marinading in a concentration over MIC - the "C" on the college graph
  • The antibiotics most affected by this are those which kill bacteria most effectively when the bacteria are about to divide.
  • Examples of this include β-lactams, carbapenems, monobactams, linezolid, linocosamides like clindamycin, and erythromycin.
• Concentration dependent killing
  • This refers to the highest concentration reached.
  • Concentration dependent killing is a property of antibiotics which disable some sort of crucial step in bacterial metabolism or protein synthesis. The higher the concentration reached, the more synthetic enzyme molecules are inhibited.
  • Examples include aminoglycosides, metronidazole, daptomycin, and quinupristin/dalfopristin.
  • Maximum concentration is also important for fluoroquinolones.
• Time and concentration dependent killing
  • This refers to antibiotics which rely on both time and concentration to kill bacteria - it is a property of those drugs which inhibit steps in DNA synthesis or replication, or other bacterial components which are crucial to cellular division.
  • Time is important because the inhibited enzymes are most active during cell division, and one must spend some time immersed in the drug in order to catch a large enough proportion of the bacteria at the point of replication.
  • Concentration is important because higher concentrations disable more of the target cell components.
  • Examples include fluoroquinolones, azithromycin, tetracyclines, glycopeptides, tigecycline, and to some extent linezolid.

Oh's Intensive Care Manual: Chapter 72  (pp. 738)  Principles  of  antibiotic  use  by Jeffrey  Lipman

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Craig, William A. "Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid." Infectious disease clinics of North America 17.3 (2003): 479-501.