Pharmacokinetics and pharmacodynamics of antibacterial agents

Abstract

This article reviews pharmacodynamics of antibacterial drugs, which can be used to optimize treatment strategies, prevent emergence of resistance and rationalize the determination of antimicrobial susceptibility. Important pharmacodynamic concepts include the requirements for bactericidal therapy for endocarditis and meningitis, for synergistic combinations to treat enterococcal endocarditis or to shorten the course of antimicrobial therapy, for obtaining maximal plasma concentration/minimal inhibitory concentration (MIC) ratios that are greater than 10 or 24 hour-area under the plasma concentration curve (AUC)/MIC ratios that are greater than 100-125 for concentration-dependent agents against gram-negative bacilli and 25-35 against Streptococcus pneumoniae, and for obtaining percent of time that drug levels are greater than the MIC that is at least 40% to 50% of the dosing interval for time-dependent agents.

Fig.1

A typical example of a plot of the log plasma concentration (Cp) curve over time that may be measured in plasma after administration of a single IV infusion or oral administration of an antimicrobial drug.

Fig. 2

A plot of the log plasma concentration (Cp) over time after rapid IV infusion. The linear beta-phase elimination curve has been extrapolated to the y-intercept to obtain the Cpo, which is the hypothetical zero-time drug concentration.

Fig. 3

A plot of the log plasma concentration (Cp) over time.

Fig. 4

Antibiotic pharmacodynamics. A, time during which free-drug levels at the site of infection exceed the MBC; B, time during which free-drug levels at the site of infection are less than the MBC but exceed the MIC; C, persistent antimicrobial effects (postantibiotic effect, postantibiotic leukocyte enhancement, and minimal antibacterial concentration) when free-drug levels at the site of infection are less than the MIC; D, regrowth of residual bacteria. (From Levison ME. Pharmacodynamics of antimicrobial agents: bactericidal and postantibiotic affects. Infect Dis Clin N Am 1995;9:483–95.)

Fig. 5

A, time during which free-drug levels at the site of infection exceed the MBC; B, time during which free-drug levels at the site of infection are less than the MBC but exceed the MIC; C, persistent antimicrobial effects (PAE, MAC, and PALE) when free-drug levels at the site of infection are less than the MIC; D, regrowth of residual bacteria, with (a) and without (a’) adequate host defenses. Inadequate host defenses at the site of infection may result in a higher residual bacteria population at the time the next dose is given (a’). (From Levison ME. Pharmacodynamics of antimicrobial agents: bactericidal and postantibiotic affects. Infect Dis Clin N Am 1995;9:483–95.)

Fig. 6

A, time during which free-drug levels at the site of infection exceed the MBC; B, time during which free-drug levels at the site of infection are less than the MBC but exceed the MIC; C, persistent antimicrobial effects (PAE, MAC, and PALE) when free-drug levels at the site of infection are less than the MIC; D, regrowth of residual bacteria; E, bactericidal effect following the next dose. If the next dose is given before significant regrowth occurs, multiple doses can eventually clear bacteria from the site of infection. (From Levison ME. Pharmacodynamics of antimicrobial agents: bactericidal and postantibiotic affects. Infect Dis Clin N Am 1995;9:483–95.)

Fig. 7

A, time during which free drug levels at the site of infection exceed the MBC; B, time during which free drug levels at the site of infection are less then the MBC, but exceed the MIC; C, persistent antimicrobial effects (PAE, MAC, and PALE) when free drug levels at the site of infection are less than the MIC; D, regrowth of residual bacteria. Regrowth as a result of a longer dosing interval, which compromises drug efficacy. (From Levison ME. Pharmacodynamics of antimicrobial agents: bactericidal and postantibiotic affects. Infect Dis Clin N Am 1995;9:483–95.)

Fig. 8

A, time during which free drug levels at the site of infection exceed the MBC; B, time during which free drug levels at the site of infection are less than the MBC, but exceed the MIC; C, persistant antimicrobial effects (PAE, MAC, and PALE) when free drug levels at the site of infection are less than the MIC; D, regrowth of residual bacteria. The effect of more rapid and extensive bactericidal action (a’) on the residual bacterial population despite prolongation of the dosing interval. (From Levison ME. Pharmacodynamics of antimicrobial agents: bactericidal and postantibiotic affects. Infect Dis Clin N Am 1995;9:483–95.)