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1 Pharmacodynamic Properties of Antibiotics: Application to Drug Monitoring and Dosage Regimen Design Author(s): Steven C. Ebert and William A. Craig Source: Infection Control and Hospital Epidemiology, Vol. 11, No. 6 (Jun., 1990), pp Published by: The University of Chicago Press Stable URL: Accessed: 18/03/ :58 Your use of the JSTOR archive indicates your acceptance of JSTOR's Terms and Conditions of Use, available at JSTOR's Terms and Conditions of Use provides, in part, that unless you have obtained prior permission, you may not download an entire issue of a journal or multiple copies of articles, and you may use content in the JSTOR archive only for your personal, non-commercial use. Please contact the publisher regarding any further use of this work. Publisher contact information may be obtained at Each copy of any part of a JSTOR transmission must contain the same copyright notice that appears on the screen or printed page of such transmission. JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org. The University of Chicago Press is collaborating with JSTOR to digitize, preserve and extend access to Infection Control and Hospital Epidemiology.

2 Clinical Pharmacology of Antibiotics edited by W. Michael Scheld, MD Pharmacodynamic Properties of Antibiotics: Application to Drug Monitoring and Dosage Regimen Design Steven C. Ebert, PharmD; William A. Craig, MD The goal of antimicrobial chemotherapy is to effectively eradicate pathogenic organisms while minimizing the likelihood of drug-related adverse effects. In this era of cost containment, consideration should also be given to performing this task with the smallest total dose of drug and the shortest duration of therapy. Determination of the appropriate dose and dosing interval of an antimicrobial requires knowledge and integration of both its pharmacokinetic and pharmacodynamic properties. The pharmacokinetic properties of a drug describe its disposition within the body, and include the processes of drug absorption, distribution, metabolism and excretion. Pharmacokinetic parameters that characterize the time course of antibiotic concentration in serum include the area under the serum concentration-time curve (AUC), peak serum concentration and half-life. In addition, the duration of time serum concentrations exceed a threshold value, usually the minimum inhibitory concentration (MIC) or T>MIC, is often described.1 While half-life is a constant, the AUC, peak level and T>MIC will change, depending on the dose and frequency of drug administration. For a given total daily dose of drug, the 24-hour AUC From the University of Wisconsin (Dr. Ebert) and the Department of Medicine, William S. Middleton Memorial Veterans Hospital (Dr. Craig), Madison, Wisconsin. Address reprint requests to William A. Craig, MD, Associate Chief of Staff for Education, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI Ebert SC, Craig WA. Pharmacodynamic properties of antibiotics: application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol. 1990;11: will be constant, regardless of the administration schedule. Administering the daily dose via large individual doses at longer intervals will result in high peak concentrations but smaller T>MIC values. The opposite will occur when smaller doses are administered more frequently. The differences observed with different dosing schemes will be most marked for drugs with short half-lives. Measurement of one or more of these values (AUC, peak, T>MIC) may be important in individualizing dosing regimens of certain antimicrobials. Pharmacodynamic properties of drugs are concerned with the relationship between concentration and some effect. In the case of antibiotics, this usually involves the relationships between concentration and antimicrobial activity or toxicity. The pharmacodynamic parameters most often used to characterize antimicrobial activity are the MIC and the minimum bactericidal concentration (MBC). Unfortunately, these measures of activity are inadequate to completely characterize an antibiotic's pharmacodynamic properties. The MIC and MBC reflect net drug effect following a fixed time of incubation of drug and organism and are often viewed as "all or none" (growth versus no growth, killing versus no killing) phenomena. These parameters, therefore, do not account for the time course of antimicrobial activity. For example, use of the MIC as an endpoint obscures the fact that a substantial proportion of a population of bacteria may be inhibited or killed at concentrations below this value. The MBC does not reflect the rate at which bacteria are killed, and does not offer insight as to whether or not bactericidal activity is further enhanced at higher concentrations. Furthermore, MICs and MBCs are determined after exposure to INFECT CONTROL HOSP EPIDEMIOL 1990/Vol. 11, No

3 Table Postantibiotic Antibiotic Penicillins Cephalosporins Imipenem Vancomycin Tetracyclines Chloramphenicol Rifampin Macrolides Trimethoprim Aminoglycosides Quinolones Effects for Various Antimicrobials Against Gram-Positive and Gram-Negative Bacteria Staphylococci 2-6 hrs. 2-6 hrs. 4-6 hrs. 4-6 hrs. 4-6 hrs. Streptococci <1/2-2 hrs. <1/2-2 hrs. * 4-6 hrs. Enterobacteriaceae <1/2-2 hrs. <1/2-2 hrs. 1/1-2 hrs. 1/2-2 hrs hrs. Pseudomonas <1/2 hr. <1/2 hr hrs. * Not done constant concentrations of drug, ignoring the fact that concentrations in vivo are changing throughout the dosing interval. As was mentioned previously, design of antimicrobial dosing regimens should integrate both the pharmacokinetic and pharmacodynamic properties of the agent in question. The use of the MIC and MBC as the only measures of antimicrobial activity has led to two generalizations in dosing regimen design. One is that in order to achieve an optimal therapeutic effect, antibiotic concentrations must exceed the MIC for the majority of the dosing interval to prevent organism regrowth. In fact, it has been demonstrated by many investigators that for certain antibiotic/pathogen pairs, growth of organisms does not resume immediately after antibiotic concentrations have declined to sub-mic levels. This phenomenon has been termed the postantibiotic effect (PAE).2-6 The PAE is therefore another important pharmacodynamic parameter to consider in dosing regimen design, and one not directly related to the MIC or MBC. Another generalization applied to the design of antimicrobial dosing regimens has been that an increase in drug concentration will invariably result in greater antibacterial activity. This has led to the use of measures such as the serum concentration:mic ratio and serum bactericidal titer (SBT) to estimate the relative in vivo activity of antimicrobials and to predict their clinical efficacy.7-10 Different classes of antimicrobials often are compared in this respect, despite evidence that the relationship between antibiotic concentration and bactericidal activity may not be linear for all drugs. A number of published reports demonstrate a correlation between higher antibiotic serum concentrations and increased efficacy However, these reports fail to consider the interdependence of the aforementioned pharmacokinetic parameters, each of which may influence outcome. For example, while higher concentration:mic ratios may be achieved in patients who were treated successfully, the T>MIC is also likely to be greater in these patients. One is therefore unable to retrospectively determine if the favorable outcome was because of high serum antibiotic concentrations, longer periods of antibacterial activity or both. Characterization of the concentration/bactericidal activity relationship of an antibiotic may offer insight into determining which parameter is most important. PAE The PAE is usually defined as the difference in the time required for the number of organisms previously exposed to an antibiotic to increase by tenfold minus the time for control organisms to increase by a similar amount.2 The PAE occurs both in vitro and in vivo, and is a feature of nearly all antimicrobials. Initially described for penicillin G in the 19405,18 it was later characterized for a variety of antibiotics against both gram-positive and gram-negative bacteria.2-5,19,2o The Table summarizes current information on the PAE. Antibiotics acting to inhibit cell wall synthesis (plactams, glycopeptides) exhibit prolonged PAEs in vivo against staphylococci, but not with streptococci or gram-negative bacteria. An exception is imipenem, which demonstrates a long PAE against Pseudomonas.19,2o In contrast, antimicrobials that act by inhibiting DNA, RNA or protein synthesis, such as quinolones, rifampin and aminoglycosides, exert prolonged PAEs against most bacteria. The duration of the PAE is influenced to some extent by the duration of antimicrobial exposure (i.e., larger doses may result in longer PAEs).5 INFLUENCE OF CONCENTRATION ON CIDAL ACTIVITY As was mentioned previously, it frequently is assumed that increasing antibiotic concentrations above the MIC will result in a concomitant increase in bactericidal rate. On the contrary, numerous investigators have demonstrated that the rate at 320 Pharmacology of Antibiotics/Ebert & Craig

4 which P-lactam and glycopeptide antibiotics kill bacteria is saturable with respect to concentration; the maximal killing rate in vitro is usually observed at concentrations of four to eight times the MBC.6,21-25 Higher concentrations do not enhance rate of killing, and may be deleterious in some models (i.e., the Eagle Effect). On the other hand, aminoglycosides, quinolones, metronidazole and some lipopeptides (daptomycin) demonstrate marked concentration-dependent bactericidal activity, suggesting that serum concentrations in excess of the MBC are desirable and may result in greater efficacy. 6,22-26 THEORETICAL IMPLICATIONS FOR DOSING REGIMEN DESIGN From the discussion above, one can conclude that different classes of antimicrobials vary in their pharmacodynanic properties, and that the MIC and MBC are insufficient in describing these differences. The particular pharmacodynamic properties (presence or absence of a PAE, concentrationdependent or -independent bactericidal activity) of an antibiotic should aid in the determination of dosing regimens that should result in the greatest efficacy. In cases where a PAE would be expected (Table), transient sub-mic levels that occur as a result of infrequent dosing would not be expected to cause a reduction in efficacy. On the other hand, serum concentrations continuously in excess of the MIC would appear to be desirable for p-lactams against gram-negative bacilli, as almost no PAE is observed in these cases. In addition, because the bactericidal rate of p-lactam antibiotics is saturable with respect to concentration, it would appear to be more important to maximize the duration of time for which concentrations exist at the saturation level (i.e., T>MIC) rather than the intensity of exposure, because increasing concentrations above this saturation level would show no benefit. Therefore, the most "efficient" method for administering a given daily dose of a p-lactam would be to divide the dose into smaller units and employ administration at short enough intervals to ensure continuous antibacterial activity. The ultimate extension of this would be continuous infusion of drugs. In particular, p-lactam antibiotics with short serum halflives would be expected to be more efficacious when dosed in this fashion. In contrast, for drugs exerting a concentrationdependent bactericidal activity, such as aminoglycosides and quinolones, both the duration and intensity of exposure would appear to be important in determining efficacy. Dosing by continuous infusion would yield a constant effect over time, whereas a bolus injection would yield a greater early bactericidal effect and a smaller late effect. Although the net effect for both means of admini- stration would be expected to be similar over the period for which active levels of drug exist in serum, intermittent injections yielding higher initial peak concentrations may be preferable to ensure activity against any less-susceptible subpopulations of bacteria in infected foci. In fact, emergence of low-level resistance may be encountered during therapy with aminoglycosides and quinolones, which supports the use of less-frequent administration of large doses. In contrast with therapeutic effects, the rate of renal cortical uptake for aminoglycosides, a prerequisite for nephrotoxicity, appears to be saturable with respect to concentration Similar results have been observed for the rate of uptake of aminoglycosides into the endolymph of the inner ear.29 To theoretically minimize nephro- and ototoxicity, one should therefore administer the entire daily dose as a single injection to minimize exposure time. Avoidance of toxicity provides additional incentive for less-frequent administration of aminoglycosides. INFLUENCE OF DOSING REGIMENS ON ANTIBIOTIC EFFICACY Investigators have employed a variety of methods by which to study the effect of dosing regimen on the antibiotic-pathogen interaction. The most common methodology has been the direct comparison of different dosing schedules in in vitro dilution models and in the treatment of infections in animals and humans. In addition, attempts have been made to characterize specific laboratory parameters that determine the outcome of treatment of infections. Each of these methods has inherent advantages and disadvantages in its application. The role of dosing regimen in determining the efficacy of antibiotics as it pertains to each method will be discussed separately for 13-lactams and for aminoglycosides and quinolones. p-lactams: In Vitro Models Numerous in vitro models have been developed to study the activity of antimicrobials using fluctuating concentrationsimilar to those observed in vivo. However, few of these studies varied dosing regimens to examine the impact of pharmacokinetic and pharmacodynamic properties of antibiotics on therapeutic outcome Grasso modified the peak concentration and elimination half-life of cefazolin to determine the impact of each on the rate and extent of bactericidal activity against Escherichia coli and Klebsiella pneumoniae.3o Increasing peak concentrations exerted little influence on the extent of bactericidal activity, consistent with observations of others that 13-lactams do not exhibit concentration-dependent bactericidal activity. However, increasing the half-life (and therefore the duration of exposure to active drug concentrations) resulted in a pronounced increase INFECT CONTROL HOSP EPIDEMIOL 1990/Vol. 11, No

5 in bactericidal effect. These observations were confirmed in a later study with ampicillin against E coli by White and Toothaker.33 Klaus and associates reported no difference in efficacy between simulated concentrations of amoxicillin (750 mg given three times daily and 1000 mg twice daily against E coli).34 The two regimens were comparable in the amount of time concentrations exceeded the MIC, although both allowed regrowth of resistant subpopulations of bacteria. Zinner and colleagues studied the impact of dose and dose interval of cefoperazone in an in vitro capillary model using four different bacterial strains.35 At a total daily dose of 4 g, cefoperazone was equally effective against E coli and K pneumoniae whether given as a single daily dose or divided and given every 12 hours. Because of the exquisite sensitivity of these two strains to cefoperazone, concentrations in this model were in excess of the MIC for over 20 hours for both regimens. In contrast, when tested against less-sensitive Staphylococcus aureus and Pseudomonas aeruginosa, the divided dose regimen was much more effective in preventing regrowth of resistant organisms because of more marked differences in T>MIC between the two regimens. 13-lactams: Animal Models Many studies of antimicrobial efficacy have been performed in animals to characterize the impact of dosing frequency on therapeutic outcome Experimental designs that vary the total daily dose, dosing interval and (to a lesser extent) organism susceptibility of antibiotics must be used to independently vary the pharmacokinetic parameter's AUC, peak level and T>MIC in order to determine which parameter(s) are important for outcome. Early studies by Eagle and colleagues concluded that the aggregate time active concentrations were maintained in serum was the most important determinant of efficacy for penicillin G.36'37 This finding has been confirmed by Vogelman, et al.38 and Frimodt-Moller, et al.39,4o using other 13-lactam antibiotics. For infections caused by gram-negative bacteria that do not exhibit a PAE with 13-lactams, optimal dosing was achieved at T>MIC approaching 100% of the dosing interval.38 On the other hand, infections caused by staphylococci that do exhibit a PAE were effectively treated with 13- lactam regimens achieving a T>MIC of about 50% of the dosing interval.38 Other investigators have specifically examined the influence of dosing intervals on the in vivo cumulative dose/efficacy relationship of antibiotics Using a murine bacterial pneumonia model, Leggett and colleagues demonstrated that the cumulative dose of antimicrobial required to produce 50% of the maximal reduction in bacterial counts increased markedly with longer dosing intervals for ceftazidime, cefazolin and imipenem.42 Bakker-Woudenberg and colleagues, using a similar model in neutropenic rats, showed the dose of drug protecting 50% of infected animals from death was higher for p-lactams when administered at intermittent schedules than by continuous infusion Continuous infusion or frequent dosing of p-lactams has also resulted in improved efficacy over intermittent injection in animal models of peritonitis and endocarditis lactams: Studies in Humans The goals of pharmacodynamic studies of antibiotics in humans should be to confirm the impact of dosing frequency of antibiotics that has been observed in animal studies, to determine what (if any) laboratory test(s) should be used to adjust dosing regimens in order to increase the likelihood of efficacy and to determine what the critical value for this test(s) should be. Schentag and colleagues analyzed the role of pharmacokinetic parameters (AUC, T>MIC, peak level) in predicting efficacy of cefmenoxime in treating nosocomial bacterial pneumonia.49 In this study, the cefmenoxime AUC was reported as being the most important parameter correlating with eradication of pathogens, but the correlation with T>MIC was equally as strong. A subset of 18 patients was studied in which cefmenoxime regimens were adjusted prospectively to ensure success; 23 of 31 pathogens were eradicated from the sputum. Twenty-two of 23 organisms for which T>MIC for cefmenoxime was 100% were eradicated, compared with only 1 of 8 organisms for which T>MIC was less than 100%.49 In the late 1970s, Bodey and colleagues cornpared the efficacy of continuous versus intermittent infusions of various antibiotics, including cefamandole, in febrile neutropenic patients For patients who were infected with cefamandolesusceptible organisms, especially those with persistent neutropenia, those who received cefamandole by continuous infusion fared better than patients receiving intermittent injections.50 Since the report by Bodey, only a few investigators have examined the impact of dosing frequency on efficacy of P-lactams in humans. Daenen and De Vries-Hospers reported successful use of ceftazidime via continuous infusion in treatment of Pseudomonas bacteremia in a patient in whom intermittent therapy was unsuccessful.53 However, comparative studies have not been performed. The facts that dosing frequency appears to be the primary determinant for the efficacy of 13-lactam antibiotics and they do not exert a PAE against gram-negative bacteria suggest the need to maintain serum concentrations of [3-lactams above inhibitory levels at all times. Consequently, achieving therapeutic predose (trough) serum concentrations would appear to be the most important means of ensuring success of therapy. Due to ethical 322 Pharmacology of Antibiotics/Ebert & Craig

6 Ceftozidime Gentamicin Ciprofloxacin 60 Survival Precent 0 Continuous Infusion 6-Hourly Daily Dose (mg/kg) Figure. Dose-survival relationships for ceftazidime, gentamicin and ciprofloxacin administered for four days by continuous infusion versus six hourly intermittent injections in neutropenic rats with pneumonia caused by K pneumoniae. concerns arising from the administration of potentially ineffective regimens, few rigorous studies addressing this issue have been performed in humans. The majority of studies have been retrospective in nature and have attempted to correlate certain laboratory parameters with likelihood of a favorable outcome. Use of the SBT has been described in treatment of febrile episodes in neutropenic patients, endocarditis and osteomyelitis Klastersky and colleagues reported that peak SBTs greater than 1:8 were associated with a favorable outcome in infected neutropenic patients treated with 13-lactams.13,14 However, one of these studies also showed that the trough SBT was predictive of efficacy.13 The inability to effectively distinguish between peak and trough SBT in predicting outcome also exists for studies of patients with endocarditis and osteomyelitis.11,12 This is because of the interdependence of pharmacokinetic parameters inherent whenever a fixed dosing interval is used; higher serum concentrations and/or more sensitive organisms translate both into higher peak and trough SBTs. In summary, although results from studies in in vitro and animal models suggest that frequent dosing with p-lactams to maintain continuous antibacterial in serum will contribute to efficacy, few confirmatory studies have been performed in humans. The higher intrinsic activity and longer serum half-lives of newer 13-lactams have permitted successful use of intermittent schedules with these agents, so that continuous infusion of islactams is usually unnecessary. However, the MIC still serves as a useful endpoint by which to judge the maximum dosing interval that may be used. Consequently, the potential for failure still exists when p-lactams are administered at intervals that allow for sustained periods of subinhibitory activity (i.e., use of very long intervals or conventional intervals for moderately susceptible bacteria). Aminoglycosides and Quinolones: In vitro Models In vitro dilution models have also been used extensively to study the role of dosing regimen in efficacy of the aminoglycosides and quinolones. Gerber and colleagues demonstrated that continuous infusion of a given dose of gentamicin over a 24-hour period against P aeruginosa was of equal efficacy to the same dose divided and given as three injections every eight hours.54 Similar findings for netilmicin were reported by Blaser, who noted equal efficacy whether the drug was administered as a continuous infusion, divided into eight hourly injections or administered as a single injection.55,56 These studies suggest that the AUC is the most important determinant of efficacy for aminoglycosides, and that dosing frequency plays a minor role. Later studies by Blaser, with netilmicin and enoxacin, demonstrated better results with single compared with multiple daily injections, suggesting that achieving a certain peak serum concentration may also be important.56 The major contribution of higher peak concentrations was the prevention of regrowth of resistant organisms; this is a common problem with in vitro models, but may also occur in vivo.41,55 Aminoglycosides and Quinolones: Animal Models As with the p-lactams, numerous investigators have studied the impact of dosing regimens on efficacy of aminoglycosides and quinolones in animal models. 38,41,42,45,57-61 Results of studies have demonstrated that the AUC is the most important pharmacokinetic parameter correlated with efficacy, as long as dosing intervals are not extended beyond T>MIC plus the duration of the PAE.38 The length of the dosing interval exerts minimal influence on the cumulative dose/efficacy relationship for aminoglycosides and quinolones, unless very long dosing intervals are used.38,41,42,45,57-61 INFECT CONTROL HOSP EPIDEMIOL 1990/Vol. 11, No

7 The Figure illustrates findings by Bakker- Woudenberg and colleagues regarding the impact of dosing interval on the efficacy of ceftazidime, gentamicin and ciprofloxacin in preventing mortality of neutropenic rats with K pneumoniae pneumonia. As mentioned previously, continuous infusion of ceftazidime resulted in greater in vivo potency than intermittent injections. However, the dosing interval had little influence on the potency of gentamicin and ciprofloxacin.45 These findings have been confirmed by Leggett and colleagues.42 Aminoglycosides and Quinolones: Studies in Humans Based on findings from in vitro and animal models, one would predict that frequency of administration would have little impact on the therapeutic efficacy of aminoglycosides and quinolones in infections in humans. Bodey and colleagues compared the efficacy of intermittent injection and continuous infusion of aminoglycosides in febrile neutropenic patients, but determined no differences in outcome between groups.51,52 Powell observed no differences in efficacy or toxicity in cystic fibrosis patients who were treated for lower respiratory tract infection with gentamicin either by continuous infusion or as a single daily dose.59 Based on the concentration-dependent bactericidal activity and postantibiotic effects observed with aminoglycosides and quinolones, it would appear that attaining adequate peak concentrations of these agents would be of more importance for efficacy than the need to maintain active predose (trough) serum concentrations. Human studies performed to determine optimal dosing regimens of aminoglycosides and quinolones have attempted to define the appropriate serum concentration values needed for efficacy, but have been retrospective in design. Moore and colleagues and others have examined the role of serum concentrations of aminoglycosides in predicting therapeutic outcome. In patients with gram-negative bacteremia, peak gentamicin or amikacin levels greater than 5 or 20 mcg/ml, respectively, are associated with a higher response rate.15 For gram-negative bacterial pneumonia, critical values are greater than 7 or 28 mcg/ml, respectively.16 Later studies have concluded a peak concentration:mic ratio of greater than 8:1 for aminoglycosides is predictive of success.17,62 The problems associated with these studies have again been associated with the interdependence of pharmacokinetic parameters. Because the aminoglycoside dosing interval was fixed at eight hours in the studies by Moore and colleagues, higher peak concentrations were likely to be associated with higher trough and AUC values as well, obscuring which parameter is of primary importance. In addition, these serum concentration guidelines reflect the use of aminoglycosides as monotherapy to treat gram-negative bacterial in- fections in these studies; it is conceivable that lower concentrations of aminoglycosides could be efficacious when used in combination with p- lactams. Finally, while the relationship of serum concentration to bacterial sensitivity is addressed in these studies, no consideration is given to the type of organism being treated, which may also be an important variable in determining response. Schentag and colleagues retrospectively analyzed the role of pharmacokinetic parameters in predicting efficacy of ciprofloxacin in treating nosocomial bacterial pneumonia.63 In this study, T>MIC was cited as being the most important parameter associated with eradication of organisms. However, AUC and peak concentration were also highly correlated with outcome, therefore preventing identification of any one important parameter. While it appears that a certain level of antimicrobial activity in serum is necessary to ensure efficacy of aminoglycosides and quinolones, the lack of data demonstrating superiority of continuous versus intermittent schedules suggests that dosing frequency is of much lesser importance for these agents than for the 13-lactams. One of the most promising applications of basic studies in antibiotic pharmacodynamics has been the increasing use of once-daily aminoglycoside dosing Many investigators are now reporting results of studies comparing conventional dosing regimens (every eight or 12 hours) of aminoglycosides with regimens administering the same total daily dose as a single injection. These studies have demonstrated equal efficacy and similar or less toxicity with the once-daily regimens. The majority of these studies have been performed in nonneutropenic patients and have involved combination therapy with 13-lactams. However, additional clinical trials, including those in neutropenic patients, are currently in progress. It is anticipated that as newer dosing regimens of antimicrobials gain popularity, additional investigations will be necessary to define appropriate laboratory parameters to ensure their safe and effective use. Studies With Other Antimicrobials Recently, investigators have begun to examine the use of different modes of administration for other classes of antibiotics, albeit often in an anecdotal and uncontrolled fashion. Pizzo and colleagues7o and Fletcher and associates71 have reported therapeutic success with use of continuous infusions of the antiviral compounds zidovudine and acyclovir, respectively; the latter used to treat patients with Herpes zoster infection that had been unresponsive to intermittent therapy. However, the total daily dose of acyclovir that was used with continuous infusion was higher than for previous regimens, so determining the role of dosing frequency alone was not possible. Whether or not the antiviral compounds exhibit concentration-depend- 324 Pharmacology of Antibiotics/Ebert & Craig

8 ent antimicrobial activity or a PAE is not known. Because of the narrow therapeutic window of many antiviral compounds, these agents may very well serve as the next target for pharmacodynamic studies leading to safer, more effective dosing regimens. REFERENCES 1. Craig WA, Vogelman B. Changing concepts and new applications of antibiotic pharmacokinetics. Am J Med. 1984;77(suppl): Bundtzen RW, Gerber AU, Cohn D, Craig WA. Postantibiotic suppression of bacterial growth. Rev Infect Dis. 1981;3: Vogelman B, Craig WA. Postantibiotic effects. J Antimicrob Chemother. 1985;15(suppl A): Vogelman B, Gudmundsson S, Turnidge J, Leggett J, Craig WA. In vivo postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis. 1988;157: Craig WA, Vogelman B. The postantibiotic effect. Ann Intern Med. 1987;106: VogelmainB, Craig WA. Kinetics of antimicrobial activity. J Pediatr. 1986;108: McCormack JP, Schentag JJ. 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J Antimicrob Chemother. 1989;24: Grasso S, Menardi G, De Carneri I, et al. New in vitro model to study the effect of antibiotic concentration and rate of elimination on antibacterial activity. Antimicrob Agents Chemother. 1978;13: Toothaker RD, Welling PG, Craig WA. An in vitro model for the study of antibacterial dosage regimen design. J Pharm Sci. 1982;71: Zinner SH, Husson M, Klastersky J. An artificial capillary in vitro kinetic model of antibiotic bactericidal activity. J Infect Dis. 1981;144: White CA, Toothaker RD. Influence of ampicillin elimination halflife on in vitro bactericidal effect. J Antimicrob Chemother. 1985;15(suppl A): Klaus U, Henninger W, Jacobi P, Wiedemann B. Bacterial elimination and therapeutic effectiveness under different schedules of amoxicillin administration. Chemotherapy. 1981;27: Zinner SH, Dudley MN, Gilbert D, Bassignani M. Effect of dose and schedule on cefoperazone pharmacodynamics in an in vitro model of infection in a neutropenic host. 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