In this next module, we will review specific antibiotics and their pharmacokinetic and pharmacodynamic parameters, and how these parameters influences the way pathogens respond to certain regimens, and the various dosing methods developed to optimize the antimicrobial activity of an antibiotic. The three most common PKPD indices used to predict drug response are: one, ratio of maximum free drug concentration to MIC; two, the duration of time where free drug concentration remains above the MIC; and three, MIC ratio of free area under the concentration time curve to the MIC. For concentration dependent antibiotics, the goal of this pattern of activity is to maximize the concentration, obtain the highest possible antimicrobial concentration, at the site of infection because higher drug concentration results in a greater rate and extent of microbial killing. The major pharmacodynamic parameter that correlates with clinical and bacteriologic efficacy of these drugs is peak drug concentration to MIC ratio. Antimicrobial classes that exhibit this pattern of antimicrobial activity include aminoglycosides, fluoroquinolones, daptomycin, and Metronidazol. Aminoglycosides are a class of antibiotic that display concentration dependent killing. High peak aminoglycosides concentrations to MIC ratios are correlated with clinical response. Parental aminoglycosides particularly gentamicin, tobramycin and amikacin have long been used in apparently for the treatment of febrile neutropenia or patients with life threatening nosocomial infections. Aminoglycosides are commonly utilized with cell wall active agents for synergistic activity for gram-positive infections. For the treatment of gram-negative infections, there are two methods of aminoglycosides dosing. The older of the two approach is to minister multiple doses usually 1.7 mg/kg every eight hours for gentamicin and tobramycin. It has long been recognized that ototoxity and nephrotoxicity are potential complications of aminoglycoside therapy. Application of pharmacodynamic principles maybe another method to reduce ototoxicity of aminoglycosides. Recent data have suggested that toxicity is related to drug accumulation within the air and not peak concentrations. When considering the pharmacodynamic profile of aminoglycosides, there are distinct advantages of using high-dose extended interval. First, giving aminoglycosides as a single dose as opposed to conventional strategies provide the opportunity to maximize the peak concentration to MIC ratio, resulting in bactericidal activity. Second, high-dose extended interval dosing minimizes drug accumulation within the inner area in kidney and therefore minimize the potential for toxicity. Also of consideration is the post antibiotic effect which allows for longer periods of bacterial suppression during the dosing interval. Finally, dosing aminoglycosides with high dose extended interval may prevent the development of bacterial resistance. The Hartford nomogram is a commonly used high-dose extended interval dosing method for aminoglycosides. This method aims at optimizing the peak/MIC ratio by administering a dose of 7mg/kg of either gentamicin or tobramycin. Based on renal function, the dose requires modification in order to minimize drug accumulation. Due to the high peak concentrations obtained, and the drug free period at the end of each dosing interval, this nomogram eliminated the need to draw standard peaks and troughs levels, rather a single random blood sample is obtained between 6-14 hours after the administration of the aminoglycoside. The serum concentration obtained is then plotted on the nomogram to determine the appropriate dosing interval. Fluoroquinolones are another class of antibiotics that display concentration dependent activity. The PKPD parameter for flouroquinolones is the 24 hour AUC to MIC ratio, and AUC to MIC ratio of greater than 125 correlates with optimal clinical and micrbiologic outcomes in seriously ill patients infected with enteric gram-negative pathogens. The fluoroquinolone goal AUC to MIC ratio can vary depending on the target organism. For respiratory tract infections involving Streptococcus pneumonia, the free drug 24 hour AUC to MIC ratio associated with high probability of bacterial eradication is around 30, which is significantly lower than the goal AUC to MIC involving gram-negative microorganisms. The second pattern of killing is characterized by time dependent killing which refers to the time it takes for a pathogen to be killed by exposure to an antimicrobial agent. The goal of time-dependent killing is to optimize the duration of exposure. This pattern is most commonly observed with beta-lactam antibiotics. Within each class of beta-lactam antibiotics, the optimal time over MIC varies for different bulk drug combinations. Bacteriostatic effects are typically observed when the free drug concentration exceeds the MIC for 35-40% of the dosing interval for cephalosporins, 30% for penicillins and 20% for carbapenems. To achieve maximal bactericidal affect, the drug concentration has to be above the MIC 60-70% of the dosing interval for cephalosporins, 50% for penicillins and 40% for carbapenems. We can apply these principles to Piperacillin-tazobactam. Piperacillin-tazobactam is a commonly used first-line agent especially for nosocomial infections due to its wide spectrum of activity and safety profile. At the initiation of empiric therapy, the MICs of the organism are often not available and clinicians must rely on the patient's clinical history as well as the institute's local anti-biogram to select an agent that will be active against the likely pathogen. In the setting of healthcare associated infections, it is critical to select an agent and regimen that has a high probability of achieving the pharmacodynamic target for efficacy. For Piperacillin-tazobactam, its activity is optimized when free drug concentration exceeds the MIC for 50% of the dosing interval. In order to maximize time over MIC, we could either administer a higher dose, increase the dosing frequency or increase the duration of infusion. If the MIC of the pathogen is 32 milligrams per liter, the Piperacillin-tazobactam regimen of 3.375 grams every six hours has approximately 30% chance of attaining the target goal, which is free drug above the MIC for 50% of the dosing interval. In order to meet the pharmacodynamic target for maximizing time above MIC, let me consider increasing the dose to 4.5 grams every six hours. However, the probability of target team is still only about 50%. When you prolonged infusion of 4.5 grams every six hours to be administered over four hours, the probability of target attainment is increased significantly, upwards of 90%. This method of prolonging or continuous infusion of time-dependent antibiotics allow for a higher probability of achieving the goal pharmacodynamic target, compared to intermittent dosing and can be especially beneficial in the critically ill population and those infected with organisms that have a higher MIC. Here is an example of bactericidal effect of varying drug concentrations for a concentration dependent antibiotic compared to a time-dependent antibiotic on a strain of Pseudomonas aeruginosa. As shown in the first two graphs, tobramycin and ciprofloxacin display a concentration dependent pattern of bactericidal activity. As tobramycin and ciprofloxacin concentrations above the MIC increases, the rate and extent of bacterial killing also increases as well. In contrast, ticarcillin displays a time-dependent pattern. As seen on the right, increasing concentration results in an increased bacterial kill, however not to the same extent. The additional bacterial killed between concentrations four times over the MIC compared to 64 times over the MIC for ticarcillin are minimal compared to the concentration dependent activity of tobramycin. As mentioned earlier, another important consideration is the post-antibiotic effect, and reflects the time it takes for an organism to recover from the effects of an exposure to an anti-microbial and resume normal growth and also the sub-MIC effect which is the effect of antibiotics at concentrations below the MIC. By adding consideration of the post-antibiotic effect, antibiotic activity can be divided into three rather than two patterns of activity to summarize the three major patterns of antimicrobial activity. Aminoglycosides and fluoroquinolones demonstrate concentration dependent killing over great range of concentrations and have prolonged post antibiotic effects. With such antibiotics, the appropriate strategy is the administration of large infrequent doses, thus high peak drug concentration, maximizing killing while at the same time the persistent post antibiotic effects helps to maintain the antibacterial activity between doses. In contrast, beta-lactam antibiotics exhibit time dependent activity, as well as saturable microbial killing, with only little to moderate persistent effects once exposure to the antibiotic has ended. In this circumstance, the goal is to optimize the duration of exposure of the pathogen to concentrations of antibiotics in excess of the MIC. With other antibiotics such as vancomycin, AUC to MIC, which contains elements of both concentration and time dependent killing, is predictive of optimal, clinical and microbiological outcomes. Understanding the exposure relationship between bug drug combinations is critical when designing an antibiotic dosing regimen. Pharmacokinetic and pharmacodynamic characteristics are major determinant of efficacy for antimicrobial therapy and is essential for rational determination of clinically relevant susceptibility breakpoints. For concentration dependent antimicrobials, the pharmacodynamic goals to maximize antibiotic drug concentration at the site of infection. For time dependent anti-microbials, prolonged or continuous infusion regimens are associated with improved probability of target attainment, especially in the critically ill or patients infected with high MIC or reduce susceptibility pathogens. The role of antimicrobial stewardship is to consider the pharmacokinetics and pharmacodynamics of each antimicrobial class and promote the use of optimal dosing regiments for maximal bacterial eradication as well as preventing the development of resistance on therapy.
