Limited-Sampling Strategies for Anti-Infective Agents: DISCUSSION part 2
It is difficult to draw conclusions from the limited- sampling strategies that have been described in the literature to date, given their methodologic flaws and limitations. As well, discrepancies in results between studies may be attributable to the differences between the patient subpopulations being studied. For example, in addition to pathophysiologic parameters (e.g., age, sex, disease states), results for limited- sampling strategies may vary according to dosing schedules, drug bioavailability, and other pharmacokinetic parameters such as elimination half-life. More importantly, there is a lack of evidence supporting the need for therapeutic drug monitoring for the majority of anti-infectives for which limited-sampling strategies have been developed. In other words, even if clinical efficacy and AUC are related, a limited-sampling strategy may be of limited clinical utility. For example, concentrations of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and efavirenz are not routinely monitored in practice, because clinicians are able to monitor efficacy and toxicity clinically and the evidence related to therapeutic drug monitoring for these agents is conflicting. Therapeutic drug monitoring of the nucleoside reverse transcriptase inhibitors, such as didanosine, stavudine, zidovudine, and lamivudine, is also not routine practice. These agents require intracellular activation, and the intracellular concentration of active drug does not correlate well with the plasma concentration of the parent compound.
Although correlation between pharmacokinetic— pharmacodynamic data and microbiological cure has been demonstrated in vitro and in animal models, there are limited prospective human data correlating pharmacokinetic-pharmaco- dynamic parameters with clinical outcomes. For the fi-lactam anti-infectives, such as ceftazidime and meropenem, which were included in this review, it appears that time above MIC (t > MIC) is actually the pharmacokinetic-pharmacodynamic parameter that correlates best with microbiological and clinical efficacy. The t > MIC parameter represents the time that the antibiotic concentration remains above a certain threshold concentration, usually a concentration 4 to 5 times greater than the MIC. These data are again based largely on animal and in vitro data. However,, if t > MIC is the parameter that correlates best with efficacy, as has been traditionally thought for the time- dependent fi-lactams, determining the AUC would not be required. Therefore, limited-sampling strategies for the fi-lactam anti-infectives would not be necessary.
Two studies included in this review describe limited- sampling strategies for vancomycin. Although vancomycin peak and trough concentrations have been routinely monitored for years, there are limited human data to support an association between concentration and efficacy or toxicity. The AUC/MIC has been correlated with improved outcome in animal models and one human study, but other unpublished human data indicate no relationship between the pharmacokinetic—pharmacodynamic parameters and efficacy.
Plasma concentrations of protease inhibitors may be associated with efficacy and toxicity. However, 2 of the protease inhibitors included in studies of limited-sampling strategies may now be less frequently used in practice. It is now known that ethyl methanesulfonate, an animal carcinogen and teratogen, is released in small amounts during the manufacturing of nelfinavir. This has led to an advisory against using nelfinavir in pregnancy and withdrawal of the drug from the market in some countries. Saquinavir may also be used less frequently than other protease inhibitors because of a greater “pill burden” and the requirement for twice-daily dosing. In addition, the efficacy and toxicity of these agents can be monitored clinically, on the basis of viral load, CD4 count, physical symptoms, and laboratory parameters, as is the case of the NNRTIs. This may limit the utility of therapeutic drug monitoring for these agents.
Data also suggest that AUC/MIC and peak/MIC may be correlated with the efficacy of the fluoroquinolones. These data have been derived mostly from animal and in vitro modelling, but a few retrospective and observational human studies support these findings as well. However, therapeutic drug monitoring is not routine practice for the fluoroquinolones, because the efficacy and toxicity of these drugs can be monitored clinically.
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Suggestions for Future Studies
To date, AUC/MIC has been suggested to correlate with clinical efficacy for a limited number of anti-infective agents (e.g., fluoroquinolones, quinupristin-dalfopristin). Ideally, limited- sampling strategies would be developed only for those drugs for which the need for therapeutic drug monitoring has been clearly demonstrated. Alternatively, any limited-sampling strategies that are developed should be assessed to determine if their use results in better clinical outcomes than usual practice (i.e., no monitoring). Optimally, limited-sampling strategies should be prospectively evaluated in a large number of patients randomly assigned to either an index group or a validation group, to determine the validity of the model. Blood sampling in the index group would need to be sufficient to adequately characterize the AUC. Then, all possible combinations of limited sampling at convenient times, using 3 or fewer samples, would be tested to determine the optimal sampling times to characterize AUC or other pharma- cokinetic parameters. In addition, the characteristics of the included patients should be clearly outlined to establish general- izability. If it is desirable to use the limited-sampling strategy in a population other than the one studied, the method must first be validated in the new population.
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To our knowledge, this is the first systematic review of limited-sampling strategies for anti-infective agents. The findings indicate that although a number of such strategies have been developed, the important link between limited-sampling strategies and clinical outcomes has not yet been established. Despite the identification of 6 level I studies in this review, it is difficult to draw conclusions from the majority of studies of limited-sampling strategies that have been reported in the literature to date, given their methodologic flaws and the limited data correlating pharmacokinetic-pharmacodynamic monitoring with clinical outcomes of anti-infective therapy. Future studies should first determine if monitoring pharmacokinetic- pharmacodynamic parameters yields better predictions of efficacy and/or toxicity of an anti-infective agent than no monitoring at all. Once an association between AUC monitoring and clinical outcomes has been clearly established, it may be worthwhile to prospectively develop and evaluate a limited- sampling strategy for the particular anti-infective agent in a similar population.