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Pharmacodynamic Properties of Antibiotics: Application to Drug Monitoring and DosageRegimen DesignAuthor(s): Steven C. Ebert and William A. CraigSource: Infection Control and Hospital Epidemiology, Vol. 11, No. 6 (Jun., 1990), pp. 319-326Published by: The University of Chicago PressStable URL: http://www.jstor.org/stable/30145492Accessed: 18/03/2010 18:58

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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 short- est 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 de- scribe its disposition within the body, and include the processes of drug absorption, distribution, me- tabolism 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 Depart- ment 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 53705.

Ebert SC, Craig WA. Pharmacodynamic properties of antibiotics: application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol. 1990;11:319-326.

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. Meas- urement 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 con- cerned 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 inad- equate 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. 6 319

Table Postantibiotic Effects for Various Antimicrobials Against Gram-Positive and Gram-Negative Bacteria Antibiotic

Penicillins

Cephalosporins Imipenem Vancomycin Tetracyclines Chloramphenicol Rifampin Macrolides

Trimethoprim Aminoglycosides Quinolones

Staphylococci 2-6 hrs. 2-6 hrs. 2-4 hrs. 4-6 hrs. 4-6 hrs. 4-6 hrs. >6 hrs. >6 hrs. 2-4 hrs. 2-4 hrs. 2-4 hrs.

Streptococci <1/2-2 hrs. <1/2-2 hrs.

ND* ND

4-6 hrs. ND ND

>6 hrs. ND ND ND

Enterobacteriaceae

<1/2-2 hrs. <1/2-2 hrs. 1/1-2 hrs.

ND 2-4 hrs. 2-4 hrs. >6 hrs.

ND 1/2-2 hrs. 4->6 hrs. 2-6 hrs.

Pseudomonas

<1/2 hr. <1/2 hr. 2-4 hrs.

ND ND ND

>6 hrs. ND ND

4->6 hrs. 2-6 hrs.

* Not done

constant concentrations of drug, ignoring the fact that concentrations in vivo are changing through- out 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.11-17 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. Anti- biotics acting to inhibit cell wall synthesis (p- lactams, 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

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, concentration- dependent 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 half- lives would be expected to be more efficacious when dosed in this fashion.

In contrast, for drugs exerting a concentration- dependent 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 ini- tial 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 prereq- uisite for nephrotoxicity, appears to be saturable with respect to concentration.27-29 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 fluctu- ating concentrations similar 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.30-35 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 In- creasing peak concentrations exerted little influence on the extent of bactericidal activity, consis- tent 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


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 compara- ble 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 Staphylo- coccus 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.35-48 Ex- perimental designs that vary the total daily dose, dosing interval and (to a lesser extent) organism susceptibility of antibiotics must be used to inde- pendently 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 approach- ing 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.41-45 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.43-45 Continuous infusion or frequent dosing of p-lactams has also resulted in improved efficacy over intermittent injection in animal models of peritonitis and endocarditis.46-48

13-lactams: Studies in Humans The goals of pharmacodynamic studies of antibi-

otics 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 corn- pared the efficacy of continuous versus intermittent infusions of various antibiotics, including cefamandole, in febrile neutropenic patients.50-52 For patients who were infected with cefamandole- susceptible organisms, especially those with persis- tent 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


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.

Ceftozidime Gentamicin Ciprofloxacin 100

80

60

40

20

0

Continuous Infusion

6-Hourly

0.47 1.88 7.5 30 120 0.47 1.88 7.5 30 1.88 7.5 30 120

Daily Dose (mg/kg)

concerns arising from the administration of poten- tially 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.11-14 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 permit- ted successful use of intermittent schedules with these agents, so that continuous infusion of is- lactams 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 subinhib- itory 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 contribu- tion of higher peak concentrations was the preven- tion 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 ani-

38,41,42,45,57-61 mal models. 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


Precent

Survival

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. Be- cause 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.64-69 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 nonneu- tropenic 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 pop- ularity, 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 anec- dotal and uncontrolled fashion. Pizzo and col- leagues7o 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-


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):24-28. 2. Bundtzen RW, Gerber AU, Cohn D, Craig WA. Postantibiotic sup-

pression of bacterial growth. Rev Infect Dis. 1981;3:28-37. 3. Vogelman B, Craig WA. Postantibiotic effects. J Antimicrob Che-

mother. 1985;15(suppl A):37-46. 4. 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;157:287-298.

5. Craig WA, Vogelman B. The postantibiotic effect. Ann Intern Med. 1987;106:900-902.

6. VogelmainB, Craig WA. Kinetics of antimicrobial activity. J Pediatr. 1986;108:835-840.

7. McCormack JP, Schentag JJ. Potential impact of quantitative susceptibility tests on the design of aminoglycoside dosing regimens. Drug Intell Clin Pharm. 1987;21:187-191.

8. Schumacher GE. Comparison of antibiotic dosage regimens using pharmacokinetic and microbiologic factors. Clin Pharm. 1987;6:59- 68.

9. Drusano GL, Ryan PA, Standiford HC, Moody MR, Schimpff A. Integration of selected pharmacologic and microbiologic properties of three new 13-lactam antibiotics: a hypothesis for rational comparison. Rev Infect Dis. 1984;3:357-363.

10. Barriere SL, Ely E, Kapusnik JE, et al. Analysis of a new method of assessing activity of combinations of antimicrobials: area under the bactericidal curve. J Antimicrob Chemother. 1985;16:49-59.

11. Weinstein MP, Stratton CW, Ackley A, et al. Multicenter collaborative evaluation of a standardized serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med. 1985;78:262-269.

12. Weinstein MP, Stratton CW, Hawley HB, Ackley A, Reller LB. Multicenter collaborative evaluation of a standardized serum bactericidal test as a predictor of therapeutic efficacy in acute and chronic osteomyelitis. Am J Med. 1987;83:218-222.

13. Klastersky J, Daneau D, Swings G, et al. Antibacterial activity in serum and urine as a therapeutic guide in bacterial infections. J Infect Dis. 1974;129:187-193.

14. Sculien JP, Klastersky J. Significance of serum bactericidal activity in gram-negative bacillary bacteremia in patients with and without granulocytopenia. Am J Med. 1984;76:429-435.

15. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in gram-negative bacteremia. J Infect Dis. 1984;149:443-448.

16. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med. 1984;77:657-662.

17. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155:93-99.

18. Parker RF, Luse S. The action of penicillin on staphylococcus: further observations on the effect of a short exposure. J Bacteriol. 1948;56:75-84.

19. Gudmundsson S, Vogelman B, Craig WA. The in vivo postantibiotic effect of imipenem and other new antimicrobials. J Antimicrob Chemother. 1986;18(suppl E):67-73.

20. Bustamante CI, Drusano GL, Tatem BA, et al. Postantibiotic effect of imipenem on Pseudomonas aeruginosa. Antimicrob Agents Che- mother. 1984;26:678-682.

21. Bergan T, Carlsen IB. Bacterial kill rates of amoxycillin and ampicillin at exponentially diminishing concentrations simulating in vivo conditions. Infection. 1980;8:S103-S108.

22. Shah PM, Ghahremani M, Gorres F-J, et al. Bactericidal activity of antimicrobials in the dynamic kill-curve model. Journal of Drug Development. 1988;1(suppl 3):35-47.

23. Garrett ER. Kinetics of antimicrobial action. Scand J Infect Dis. 1978;14:54-85.

24. Navashin SM, Fomina IP, Firsov AA, Chernykh VM, Kuznetsoua SM. A dynamic model for in vitro evaluation of antimicrobial action by simulation of the pharmacokinetic profiles of antibiotics. J Antimi- crob Chemother. 1989;23:389-399.

25. Briceland LL, Pasko MT, Mylotte JM. Serum bactericidal rate as a

measure of antibiotic interactions. Antimicrob Agents Chemother. 1987;31:679-685.

26. Tisdale JE, Pasko MT, Mylotte JM. Antipseudomonal activity of simulated infusions of gentamicin alone or with piperacillin assessed by serum bactericidal rate and area under the killing curve. Antimi- crob Agents Chemother. 1989;33:1500-1505.

27. Giuliano RA, Verpooten GA, Verbist L, Wedeen RR, De Broe ME. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther. 1986;236:470-475.

28. Verpooten GA, Giuliano RA, Verbist L, Estermans G, De Broe ME. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin. Clin Pharmacol Ther. 1989;45:22-27.

29. Mattie H, Craig WA, Pechere JC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother. 1989;24:281- 293.

30. 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;13:570- 576.

31. Toothaker RD, Welling PG, Craig WA. An in vitro model for the study of antibacterial dosage regimen design. J Pharm Sci. 1982;71:861- 864.

32. Zinner SH, Husson M, Klastersky J. An artificial capillary in vitro kinetic model of antibiotic bactericidal activity. J Infect Dis. 1981;144:583-587.

33. White CA, Toothaker RD. Influence of ampicillin elimination half- life on in vitro bactericidal effect. J Antimicrob Chemother. 1985;15(suppl A):257-260.

34. Klaus U, Henninger W, Jacobi P, Wiedemann B. Bacterial elimination and therapeutic effectiveness under different schedules of amoxicillin administration. Chemotherapy. 1981;27:200-208.

35. 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. Am J Med. 1988;85(suppl 1A):56-58.

36. Eagle H, Fleischman R, Musselman AD. Effect of schedule of administration on the therapeutic efficacy of penicillin. Am J Med. 1950;9:280-299.

37. Eagle, H, Fleischman R, Musselman AD. The effective concentrations of penicillin in vitro and in vivo for streptococci, pneumococci, and treponema pallidum. J Bacteriol. 1950;59:625-643.

38. Vogelman B, Gudmundsson S, Leggett J, et al. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831-847.

39. Frimodt-Moller N, Bentzon MW, Thomsen VF. Experimental infection with Streptococcus pneumoniae in mice: correlation of in vitro activity and pharmacokinetic parameters with in vivo effect for 14 cephalosporins. J Infect Dis. 1986;154:511-517.

40. Frimodt-Moller NM, Bentzon MW, Thomsen VF. Experimental pneumococcus infection in mice: comparative in vitro and in vivo effects of cefuroxime, cefotaxime, and ceftriaxone. Acta Path Micro- biol Immunol Scand. 1987;95:261-267.

41. Gerber AU, Craig WA, Brugger HP, Feller C, Vastda AP, Brandel J. Impact of dosing intervals on activity of gentamicin and ticarcillin against Pseudomonas aeruginosa in granulocytopenic mice. J Infect Dis. 1983;147:910-917.

42. Leggett JE, Fantin B, Ebert S, et al. Comparative antibiotic dose- effect relationships at several dosing intervals in murine pneumoni- tis and thigh-infection models. J Infect Dis. 1989;159:281-292.

43. Bakker-Woudenberg IAJM, van den Berg JC, Fontijne P, et al. Efficacy of continuous versus intermittent administration of penicillin G in Streptococcus pneumoniae pneumonia in normal and immu- nodeficient rats. Eur J Clin Microbiol Infect Dis. 1984;3:131-135.

44. Roosendaal R, Bakker-Woudenberg IAJM, van den Berghe JC, Michel MF. Therapeutic efficacy of continuous versus intermittent administration of ceftazidime in an experimental Klebsiella pneumoniae pneumonia in rats. J Infect Dis. 1985;152:373-378.

45. Roosendaal R, Bakker-Woudenberg IAJM, van den Berghe-van Raffe M, et al. Impact of the dosage schedule on the efficacy of ceftazidime, gentamicin, and ciprofloxacin in Klebsiella pneumoniae pneumonia and septicemia in mice. Eur J Clin Microbiol Infect Dis. 1989;8:878- 887.

46. Ingerman MJ, Pitsakis PG, Rosenberg AF, Levison ME. The importance of pharmacodynamics in determining dosing interval in therapy for experimental Pseudomonas endocarditis in the rat. J Infect Dis. 1986;153:707-714.

47. Mordenti JJ, Quintiliani R, Nightingale CH. Combination antibiotic therapy: comparison of constant infusion and intermittent bolus dosing in an experimental animal model. J Antimicrob Chemother. 1985;15(suppl A):313-321.

48. Thauvin C, Eliopoulos GM, Willey S, Wennersten C, Moellering RC. Continuous-infusion ampicillin therapy of enterococcal endocarditis in rats. Antimicrob Agents Chemother. 1987;31:139-143.


49. Schentag JJ, Smith IL, Swanson DJ, et al. Role of dual individualiza- tion with cefmenoxime. Am J Med. 1984;77(suppl 6A):43-50

50. Bodey GP, Ketchel SJ, Rodriguez V. A randomized study of carbeni- cillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. Am J Med. 1979;67:608-616.

51. Bodey G, Valdivieso M, Yap BS. The role of schedule in antibiotic therapy of the neutropenic patient. Infection. 1980;8(suppl 1):S75- S81.

52. Feld R, Valdivieso M, Bodey GP, et al. A comparative trial of sisomicin therapy by intermittent versus continuous infusion. Am J Med Sci. 1977;274:179-188.

53. Daenen S, De Vries-Hosper H. Cure of Pseudomonas aeruginosa infection in neutropenic patients by continuous infusion of ceftazidime. Lancet. 1988;1:937.

54. Gerber AU, Wiprachtiger P, Stettler-Spichiger U, I ebek G. Constant infusions vs. intermittent doses of gentamicin against Pseudomonas aeruginosa in vitro. J Infect Dis. 1982;145:554-560.

55. Blaser J, Stone BB, Groner MC, et al. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob Agents Chemother. 1987;31:1054-1060.

56. Blaser J, Stone BB, Zinner SH. Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model. Antimicrob Agents Chemother. 1985;27:343-349.

57. Kapusnik JE, Hackbarth CJ, Chambers HF, Carpenter T, Sande MA. Single, large daily dosing vs intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis. 1988;158:7-12.

58. Pechere M, Letarte R, Pechere JC. Efficacy of different dosing schedules of tobramycin for treating a murine Klebsiella pneumoniae bronchopneumonia. J Antimicrob Chemother. 1987;19:487-491.

59. Powell SH, Thompson WL, Luthe MA, et al. Once-daily vs continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin and tobramycin. J Infect Dis. 1983;147:918-932.

60. Queiroz MLS, Bathirunathan N, Mawer GE. Influence of dosage interval on the therapeutic response to gentamicin in mice infected with Klebsiella pneumoniae. Chemotherapy. 1987;33:68-76.

61. Wood CA, Norton DR, Kohlhepp SJ, et al. The influence of tobramy-

cin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess. J Infect Dis. 1988;158:13-22.

62. Deziel-Evans LM, Murphy JE, Job ML. Correlation of pharmacokinetic indices with therapeutic outcome in patients receiving aminoglycosides. Clin Pharm. 1986;5:319-324.

63. Peloquin CA, Cumbo TJ, Nix DE, et al. Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections: impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication. Arch Intern Med. 1989;149:2269-2273.

64. DeVries PJ, Leguit P, Verkooyen RP, et al. Toxicity of once daily netilmicin in patients with intraabdominal infections. Abstract 608. Program and Abstracts, 27th Interscience Conference for Antimicro- bial Agents and Chemotherapy. New York, NY: American Society for Microbiology; 1987.

65. Fan ST, Lau WY, Thah-Chan, et al. Once daily administration of netilmicin compared with thrice 'daily, both in combination with metronidazole, in gangrenous and perforated appendicitis. J Antimi- crob Chemother. 1988;22:69-74.

66. Maller R, Isaksson B, Nilsson L, et al. A study of amikacin given once versus twice daily in serious infections. J Antimicrob Chemother. 1988;22:75-79.

67. Hollender LF, Bahnini J, DeManzini N, et al. A multicentric study of netilmicin once daily versus thrice daily in patients with appendicitis and other intraabdominal infections. J Antimicrob Chemother. 1989;23:773-783.

68. Sturm AW. Netilmicin . in the treatment of Gram-negative bacteremia: single daily versus multiple daily dosage. J Infect Dis. 1989;159:931-937.

69. Tulkens PM, Clerckx-Braun F, Donnez J, et al. Safety and efficacy of aminoglycosides once-a-day: experimental data and randomized, controlled evaluation in patients suffering from pelvic inflammatory disease. Journal of Drug Development. 1988;1(suppl 3):71-82.

70. Pizzo PA, Eddy J, Falloon J, et al. Effect of continuous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med. 1988;319:889-896.

71. Fletcher CV, Englund JA, Bean B, et al. Continuous high-dose acyclovir for serious herpesvirus infections. Antimicrob Agents Che- mother. 1989;33:1375-1378.


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