Pkpd Characteristicsmagnitude Of Measure Predictive Of Activity

Knowing which pharmacodynamic measure is representative of the antimicrobial activity of a drug allows an optimal dosing strategy to be devised. For example, because the peak/MIC ratio best describes activity of drugs from the aminoglycoside class, large, infrequent, even once-daily administrations can be adopted. On the other hand, with beta-lactam antibiotics, the goal of dosing would be to optimize duration of drug exposure;

more frequent administration or even continuous drug infusion strategies may be implemented (19,26,31).

Pharmacodynamic study analyses, however, have also been useful for determining the amount of drug necessary for efficacy in treatment against a number of microbial species, including drug-resistant strains. Both nonclinical (in vitro and animal infection models) and clinical trials have allowed the identification of a pharmacodynamic magnitude or target required for efficacy (4,9,12,17,32-37). For example, a study in an animal model with the penicillin derivative amoxicillin observed bacteriologic efficacy when dosing regimens produced a %T>MIC of 40 to 50 in treatment against a large number of Streptococcus. pneumoniae isolates (4,6,38). This T>MIC target was similar regardless of the MIC of the organism. So, for example, against an organism with a MIC of 1 pg/mL, serum levels of amoxicillin had to remain above a concentration of 1 pg/mL for at least 2.5 hours of the 6-hour dosing interval, or 40% of the dosing interval. For most drug-pathogen combinations, the magnitude of the parameter required for treatment success is most often similar among different microbiologic species (1,4,24,25,27). For example, studies with numerous beta-lactam antibiotics in a murine infection model against a variety of gram-positive and gram-negative bacteria produced maximal bacterial killing when the free-drug T>MIC exceeded 50% of the dosing interval (24,25). These studies included both susceptible and resistant strains. A large number of similar studies have also shown that the pharmacodynamic target or magnitude predictive of efficacy is similar for drugs within the same class (1,4,8,22,27). So, for example, the T>MIC needed for efficacy of penicillin is relatively similar to the T>MIC necessary for efficacy of the cephalosporin ceftriaxone, as long as free drug concentrations are considered. Protein binding limits distribution of antibiotics to the site of infection and binding to microbial drug targets, thus only unbound or free concentrations are available for microbiologic activity at the site of infection (8,39,40). Thus, it is critical that protein binding be taken into consideration when comparing potency among drugs. This is particularly important for drugs with a high degree of binding (e.g., greater than 80%).

A variety of experiments have also demonstrated that the pharmacodynamic target is similar in treatment of infections at different sites of infection and for different infecting microbial species (1,4,6,24,25,38). For example, Leggett et al. (25) demonstrated that the 24 h AUC/MIC of the fluoroquinolone ciprofloxacin necessary for efficacy (1 to 2 log reduction in bacterial numbers) against a species of Klebsiella pneumoniae and Pseudomonas aeruginosa, in both a thigh sepsis and pneumonia models was similar (approximately 24 h AUC/MIC 100). Most importantly, the pharmacodynamic target associated with outcome has been shown to be similar among different animal species, including humans. For example, study T>MIC needed for efficacy with amoxicillin against pneumococci has been shown to be 40% to 50% in mice, rats, children with otitis media, and adults with sinusitis (4,6,12,36-38). The concordance of this pharmacodynamic target among animal species is not surprising, as the receptor (e.g., penicillin-binding protein, ribosome, DNA gyrase) for the antimicrobial agent is associated with pathogen and not the host.

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