New Antibiotics in Pulmonary and Critical Care Medicine

†, * University of the Pacific, School of Pharmacy Stockton, California, and Kendle International, Inc.;   †Maine Medical Center, Portland, Maine, and University of Vermont, College of Medicine, Burlington, Vermont

Semin Respir Crit Care Med. 2000;21(1) 

In This Article

Pharmacodynamic Concepts

Since the dawn of penicillin therapy in the 1940s, controversy has existed as to the most appropriate method to administer antibiotics to maximize the killing of microorganisms while minimizing toxicity. Almost 50 years ago, Eagle et al [1,2,3] demonstrated that in the syphilitic infection of rabbits and streptococcal infection in mice and rabbits the total dose of penicillin G could be less if it were administered continuously, rather than intermittently. Additionally, it was observed that maximal bacterial killing plateaus when penicillin concentrations were three times the minimum inhibitory concentration (MIC) for the microorganism.[1] These data contrasted sharply with observations made about aminoglycosides, in which the magnitude of the concentration rather than the duration that effective concentrations were maintained was found to be the determinant of efficacy.[1] Contemporary scientific data have emerged over the past decade that have confirmed and expanded on Eagle's original observations. Today, data from animal models of infection and toxicity, in vitro pharmacodynamic studies, and human trials enable us to establish the best mode of antibiotic administration to maximize clinical efficacy while minimizing toxicity.

Mathematically, bacterial killing may be described as a function of drug concentration (Cp max ) and time of exposure. The product of these two pharmacokinetic measures is the correlated parameter, the area under the concentration-time curve (AUC). Over clinically obtainable drug concentrations, simplifying assumptions can be made so that either drug concentration or time of drug exposure is of primary importance. When these assumptions cannot be made, however, both concentration and time of drug exposure must be considered (e.g., the AUC).

Like penicillin, all ß-lactam (e.g., cephalo-sporin, cephamycin, carbapenem, monobactam) glycopeptide, and macrolide antibiotics kill bacteria in a similar time-dependent fashion.[4] Once the concentration exceeds two to four times above the MIC for a given organism, killing occurs at a zero order rate, and increasing drug concentration does not change the microbial death rate.[5] Under these conditions, there is little correlation between peak serum concentration and the rate or extent of bacterial killing. In brief, these antibiotics exhibit time-dependent or concentration-independent killing over the usual therapeutic concentration range. Consequently, the duration of the concentration of these drugs above their MIC for the microorganism is the best predictor of clinical outcome.

On the other hand, aminoglycosides, fluoro-quinolones, metronidazole, and amphotericin B kill most rapidly when their concentrations are appreciably above the MIC of the targeted microorganism.[6,7,8,9] Hence, their type of killing is referred to as concentration- dependent or dose-dependent killing. It has been shown that aminoglycosides and fluoroquinolones eradicate organisms best at levels approximately 10 to 12 times above the microbe's MIC (Fig. 1).[6,7,10]

Pharmacodynamic relationship: Peak to MIC ratio

Although fluoroquinolones exhibit concentration- dependent killing, unfortunately, excessively high concentrations of these agents can be associated with seizures and other potentially serious adverse reactions in the central nervous system. An integration of the area AUC with the MIC has been used to produce the pharmacodynamic relationship of AUC:MIC ratio to predict clinical outcomes with fluoroquinolones (Fig. 2). Data obtained from animal models of sepsis, in vitro pharmacodynamic experiments, and clinical outcome studies indicate that the magnitude of the AUC:MIC ratio can be used to predict clinical response. Forrest et al [11] demonstrated that an AUC:MIC ratio of ≥ 125 was associated with the best clinical cure rates in the treatment of infections caused by gram-negative enteric pathogens. However, for gram-positive bacteria, it appears the AUC:MIC ratio can be appreciably lower. For instance, against Streptococcus pneumoniae, an in vitro model of infection in our laboratory demonstrated that for levofloxacin and ciprofloxacin an AUC:MIC ratio of approximately 30 was associated with a four-log kill; whereas ratios less than 30 were associated with a significantly reduced extent of bacterial killing and in some instances bacterial regrowth.[12] This observation is supported by data from non-neutropenic animal models of infection, in which maximal survival was associated with a AUC:MIC ratio of 25 against the pneumococcus.[13] These data are further supported clinically by the observation that there has been a significant number of treatment failures and superinfections involving meningeal seeding from S. pneumoniae in patients receiving ciprofloxacin, for which the AUC:MIC ratio is approximately 12.[14] Conversely, similar treatment failures or superinfections have not occurred with quinolones for which the AUC:MIC ratios against this bacterium are greater than 30.[15]

Pharmacodynamic relationship: AUC:MIC ratio


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