Frequency of dosing

‘Pharmacology of antimicrobials for clinicians, part 2.’

In the previous segment, we reviewed the basic concepts of pharmacokinetics and pharmacodynamics of antimicrobials, and the bioavailability of these drugs. Now, let’s turn our attention to another key pharmacology concept.

Recall that pharmacodynamics refers to what the drug does to both the human and the microorganism. A critical aspect of antibiotic efficacy is the rate of bacterial kill, and the effect of increasing drug concentrations and/or prolonged exposure on that rate. This determines whether bacterial killing by an antibiotic is concentration-dependent or time-dependent. Some antimicrobials also exhibit post-antibiotic effects: the persistent inhibition of bacterial replication after removal of the antibiotic from the system.

Knowing these properties, in turn, enables clinicians to understand and use a dosing regimen that maximises an antimicrobial’s effect. Aminoglycosides and fluoroquinolones, for example, demonstrate concentration-dependent killing over a great range of concentrations, and have post-antibiotic effects. With such antibiotics, the appropriate strategy is the administration of large, infrequent doses. Thus, the higher dose maximises killing, while at the same time, the persistent post-antibiotic effects help to maintain the antibacterial activity between doses.

The practise of once-daily dosing of aminoglycosides and some fluoroquinolones is built around this principle. Beta-lactam antibiotics, in contrast, exhibit time-dependent activity, with limited post-antibiotic effects once exposure to the antibiotic has ended. In this circumstance, the goal is to optimise the duration of exposure of the pathogen to effective concentrations of the beta-lactam antibiotic.

One microbiology concept is important to introduce before moving on. The minimum inhibitory concentration, or MIC, is the lowest concentration of an antimicrobial that inhibits visible growth in vitro, or in other words, of an organism on a plate of culture media. This is determined by testing serial concentrations of an antimicrobial in assessing for the inhibition of bacterial growth. Reference microbiology organisations, like CLSI or EUCAST, provide interpretive guidelines using these MICs to predict clinical outcomes. These organisations provide MIC breakpoints to classify organisms isolated in culture as susceptible or resistant to a particular antimicrobial. CLSI also includes breakpoints that are interpreted as intermediate susceptibility; however, EUCAST does not. For those who would like to learn more, we direct them to this video that provides guidance on reading breakpoint tables.

Let’s return to beta-lactams. Given the pharmacodynamic properties of this class of antibiotics, the goal is to optimise the pathogen’s duration of exposure to beta-lactam concentrations in excess of the MIC of that pathogen. While there is variation between different beta-lactam antibiotics and different target bacteria, a drug concentration of greater than four times the MIC for 40–60% of the dosing interval is generally sufficient to reach this goal. This prolonged exposure can be achieved by a strategy of frequent, extended,or continuous infusions. This critical concept allows us to effectively use antimicrobials, despite some marginal degrees of antimicrobial resistance; for example, organisms with an MIC just above the resistance threshold.

Let’s apply this concept to another urine culture, which also grew E. coli. But in this case, the organism was resistant to ampicillin, fluoroquinolones, trimethoprim-sulfamethoxazole and ceftriaxone. The E. coli isolates MIC to one commonly used beta-lactam, piperacillin tazobactam, is 8. According to EUCAST, this MIC is considered the upper limit of susceptibility.

However, you know that piperacillin tazobactam is a time-dependent antimicrobial. You typically dose piperacillin tazobactam every eight hours, with doses administered over 30 minutes for non-pseudomonal infections. As depicted in this figure, intermittent dosing provides an adequate time above MIC, represented by the yellow arrow, to be effective against highly susceptible organisms with quite low MICs.

However, for susceptible organisms, with higher MICs, this dosing strategy less reliably provides sufficient time for which the serum concentration of the antibiotic is above the MIC, compromising piperacillin tazobactam’s efficacy. So instead, you consider administering each drug over four hours, instead of over 30 minutes, in order to increase the time above MIC, and thus, optimising the likelihood of achieving the pharmacodynamics target and enhancing piperacillin tazobactam’s efficacy.