Designing a dosing regimen based on time vs. concentration dependency: a dynamic challenge (Proceedings)
Dosing regimens for antimicrobials exemplify the integration of pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body). For antimicrobial therapy, the "body" is the microbe. Integration is based upon what is needed to achieve the pharmacodynamic response – in this case, the minimum inhibitory concentration of the drug of interest for the infecting microbe – and comparing it with what will be achieved at the chosen dose. For this discussion, we will build a dose around a desired pharmacodynamic index (PDI). If the MIC of the infecting is not known, then the MIC 90 is a reasonable surrogate. The MIC90 is the MIC at or below which 90% of the isolates is an sample population of the organism is inhibited. However, a couple of terms need to be defined and addressed first.
Bactericidal versus bacteriostatic drugs
The term "bactericidal" is so often abused that the distinction from bacteriostatic should be underemphasized. Although it is appropriate for clinicians to reach for a drug that is "cidal" rather than "static", it is not appropriate to assume that the ability of that drug to kill rather than simply inhibit an organisms will enhance therapeutic efficacy. This may be true, but only if concentrations of the drug achieved at the site of infection are sufficient to kill the microbe. The term "bactericidal" is an in vitro definition and is based on killing rates (eg, 99.9% reduction in bacterial inoculum within a 24 hr period of exposure) as well as the proximity of the minimum bactericidal concentration (MBC) of a drug to the MIC. The MBC is determined based on kill curves, or following tube dilution procedures: tubes with no observable growth are inoculated on agar gel. If no organism grows on the agar, the organisms were killed in the test tube. The tube with the lowest concentration of drug that yields no growth on the agar gel contains the MBC of drug. For drugs considered "bactericidal", the MBC is within one tube dilution of the MIC, meaning, the organisms were not simply inhibited, but rather, were killed. For "bacteriostatic" drugs, growth on the agar plate will occur for several tube dilutions above the MIC, indicating that organisms were not killed. However, bacteriostatic drugs are capable of killing (eg, some organisms are exquisitely sensitive to the effects of selected drugs; some "static" drugs are acculumulated to concentrations that are likely to be cidal [eg, macrolides and lincosamides in phagocytes; urine concentration). However, killing concentrations are generally more likely to be achieved for a cidal drugs compared to a static concentration. On the other hand, a "cidal" drug may not kill if concentrations are not sufficient, or if condictions preclude its actions (eg, slow growth in an anerobic environment; combination with growth inhibitors). Thus, cidal effects will occur only if adequate concentrations (ie, MIC/MBC) are achieved at the site. The bactericidal nature of a drug often reflects its mechanism of action. Drugs which target ribosomes (eg, tetracyclines, macrolides, lincosamides, chloramphenical) often simply inhibit the growth of the organism, and, because a much higher drug concentration is necessary to kill the organism, in vitro, the MIC is distant from the MBC. Clinically, host defenses must eradicate the infection following treatment with these drugs unless exceptionally high concentrations (ie, the MBC) of these drugs are achieved in tissues. An exception is made for aminoglycosides, whose ribosomal inhibition is so effective that the organism dies. Drugs which target cell walls (beta lactams including penicllins and cephalosporins; vancomycin), cell membranes (bacitracin, polymixin and colistin), and DNA (enrofloxacin, metronidazole), RNA (rifampin) are defined in vitro as bactericidal. Combinations of static drugs can often result in cidal actions. For example, sulfonamides (which target folic acid synthesis) are static, but when used in combination with diaminopyramidines (eg, trimethoprim), the combination is defined in vitro as cidal. Attaining bactericidal concentrations of an antimicrobial is critical for those infections for which host killing is likely to be impaired. These include but are not limited to infections in immune compromised animals (eg, viral infections [parvovirus, panleukopenia, FIV, FeLV), patients receiving glucocorticoids), or in systems characterized by derangements in local immunity (ie, CNS infection for which an marked inflammatory response can be life threatening; osteomyelitis; peritonitis, bacteremia/sepsis, many chronic infections).Relationship between MIC, Plasma and tissue Drug Concentrations
The parameters that are most predictive of antimicrobial efficacy and lack of resistance are the ratio of Cmax / MIC, the area under the inhibitory curve (AUC/MIC); and the percent time that PDC are above the MIC [T> MIC]. Based on these relationships, two generally categories of drugs have been described. Exceeding the efficacy targets decreases resistance. Dosing regimens can be designed based on population statistics, using MIC 90 (eg, packaged inserts) as a surrogate indicator of what is needed, or using MIC data from a culture report. The design of the dosing regimen depends upon the drug and its relationship between plasma drug concentrations, the MIC of the infecting organisms and whether or not the drug has a substantial post antibiotic effect (PAE). Postantibiotic Effect: The post antibiotic effect (PAE) describes the continued inhibition of microbial growth after a short exposure of the organisms to the drug. The impact of the PAE on antimicrobial efficacy can be profound, particularly for concentration-dependent drugs. It is the PAE that allows some of these drugs to be administered at long intervals. The PAE may be absent for some organisms or some patients (e.g., some immunocompromised patients). In general, concentration- dependent drugs appear to exhibit longer PAE; further, the duration of the PAE may vary with the magnitude of the peak PDC (ie, longer with higher PDC) and is enhanced by combination antimicrobial therapy. PAEs vary with each drug and each organism.