Pharmacodynamics

Pharmacodynamics parameters are a measure of the ability of an antimicrobial to kill or inhibit the growth of the infecting organism. Pharmacodynamics parameters include the following:

• The time for which the serum concentration of a drug remains above the minimum inhibitory concentration (MIC) for a dosing period T (T > MIC). This is the most important parameter for time-dependent antimicrobials.
• The ratio of the maximum (peak) antimicrobial concentration, C_max, to MIC (C_max/MIC). This is the most relevant measure for antimicrobials whose efficacy depends on reaching a specific concentration.
• The ratio of the area under the curve (AUC) during a 24-hour period to MIC (AUC24/MIC). This can be a useful parameter for both time and concentration dependent antimicrobials.
• The post-antibiotic effect (PAE); that is, where antibiotics continue to be effective after treatment.

Figure 6 illustrates the pharmacodynamics parameters with examples of relevant antimicrobials.

Figure 6 Concentration versus time-dependent killing with MIC superimposed, and pharmacokinetic and pharmacodynamics markers (Al-Dorzi et al., 2013).

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A graph, labelled ‘Antibiotic serum concentration’ on the y-axis and ‘Time after antibiotic administration’ on the x-axis. The highest point of the curve is labelled ‘C_max’; below that are lines for AUC and MIC. A box labels C^max/MIC as aminoglycosides and fluoroquinolones; AUC/MIC as vancomycin, azithromycin, fluoroquinolones, aminoglycosides, tigecycline and linezolid; and T > MIC as β-lactams, vancomycin, macrolides and clindamycin.

Figure 6 Concentration versus time-dependent killing with MIC superimposed, and pharmacokinetic and pharmacodynamics markers (Al-Dorzi et...

To determine the appropriate dosing levels and frequency for any antimicrobial, it is necessary to understand which parameter correlates with the efficacy of the antimicrobial. For example, the efficacy of aminoglycosides (antimicrobials that inhibit protein synthesis) correlates with AUC/MIC and also C_max/MIC. This implies concentration-dependent killing, which means that larger doses will have an optimal effect.

β-lactams, on the other hand, require dosing to maintain the concentration above the MIC for longer periods for maximum efficacy. However, it is not that simple, as we need to understand the relationship between the therapeutic and toxic effect of drugs.

Figure 7 shows that the dose of a drug can be increased progressively until a desired response is achieved; however, if it is further increased, no additional desired effects are achieved, and unwanted effects can be seen. The orange line shows an optimal dose, above which toxicity occurs.

Figure 7 Concentration-dependent efficacy and toxicity: the concentration of drug should be chosen to deliver effective therapeutic benefit and to avoid toxicity (Padmanabhan, 2014).

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A graph, labelled ‘Efficacy’ on the y-axis and ‘Concentration’ on the x-axis. Two lines are on the graph, labelled ‘Efficacy’ and ‘Toxicity’, and a line for the optimal dose, which starts at ~75% efficacy and drops to ~5%.

Figure 7 Concentration-dependent efficacy and toxicity: the concentration of drug should be chosen to deliver effective therapeutic ...

Depending on the drug it will be necessary to consider other factors such as other medications, renal function or weight.

Pharmacodynamically, the rate and extent of the bactericidal activity of an antimicrobial agent depend on:

• drug concentration at the site of infection
• bacterial load
• phase of bacterial growth
• the MIC for the pathogen.

It follows that a change in any of these factors will alter the activity of the antimicrobial agent against a particular pathogen, and may affect the outcome of therapy.