THE POSTANTIBUYfIC EFFECT: A REVIEW OF INVITRO AND INVIVO DATA George G. Zhanel, Daryl J. Hoban, and Godfrey K.M. Harding

ABSTRACT: The term postantibioticeffect (PAE)refers to a period of time after complete removalof an antibioticduring which there is no growthof the target organism. The PAEappears to be a featureof most antimicrobial agentsand has been documentedwith a variety of commonbacterial pathogens. Severalfactors influencethe presenceor durationof the PAEincludingthe type of organism, type of antimicrobial, concentration of antimicrobial,durationof antimicrobial exposure, and antimicrobial combinations. In vitro, beta-lactam antimicrobials demonstratea PAEagainst gram-positivecocci but fail to producea PAEwith gram-negative bacilli. Antimicrobials that inhibitRNA or protein synthesisproducean in vitro PAEagainst gram positivecocci and also produce a PAEagainst gram-negative bacilli. In vitro methods used to determine the PAEinclude colony counts, optical density,and measurementof adenosinetriphosphatein bacteria. The exact mechanismsby which antimicrobials induce the PAEhave not been clearly delineated. Animalstudies reveal in vivo PAEsin accordancewith PAEsobtained in vitro for most organism! antimicrobial combinations. The clinical relevance of the PAEis probablymost important when designingdosage regimens. The presenceof a long PAEallows aminoglycosides to be dosed infrequently; the lack of an in vivo PAEsuggeststhat beta-lactam antimicrobials require frequentor continuous dosing. Important questionsremain to be answeredconcerning the PAE.

otcr Ann Pharmacother 1991 ;25:153-63. POSTANTIBIOTIC EFFECT (PAE) is a period of time after com-

plete removal of an antibiotic during which there is no growth of the target organism. This suppression of bacterial growth following short exposure to antimicrobial agents has been observed since the early investigations with penicillin. r-s Parker and Marsh demonstrated in 1946 that staphylococci exposed to penicillin G for 30 minutes and then transferred to a penicillin-free medium did not resume normal growth for three hours. These investigators noted that there appeared to be a time-concentration relationship in the production of this effect. Higher concentrations of penicillin and/or longer organism exposure to the antibiotic resulted in greater bacterial kill and a longer time for resumption of normal growth." In an attempt to explain the suppression of bacterial growth after exposure to penicillin G, Parker and Luse reported that this effect was not due to selective killing of dividing cells, leaving resting cells GEORGE G. ZHANEL, Phann.D., is a PostdoctoralResearchFellow,Departmenlof Medical Microbiology,sponsored by the Phannaceutical ManufacturersAssociation of Canada Health Research Foundation, and Medical Research Council of Canada, and AssistantProfessor,Facultyof Phannacy, Universityof Manitoba;DARYL J. HOBAN, Ph.D., is the Assistant Director of Clinical Microbiology, Health Sciences Centre, and Assistant Professor.Department of MedicalMicrobiology, Universityof Manitoba; and GODFREY K.M. HARDING, M.D., is the Head, Section of Infectious Diseases, St. Boniface General Hospital, and Professor,Department of Medical Microbiology, Universityof Manitoba andthe SI. BonifaceGeneral HospilalResearchInstitute. Reprints: George G. Zhanel, Phann.D., Clinical Microbiology, MS-6, Health Sciences Centre, 820 Sherbrook St., Winnipeg, Manitoba, Canada R3A lR9.

unaffected, because the effect was as apparent when there was no change in the viable cell count after penicillin treatment as when the population was moderately reduced. The exact mechanism as to how penicillin induced this lag period on staphylococcal growth after only a brief exposure could not be found. 3 Eagle subsequently demonstrated that penicillin induced a PAE against various gram-positive cocci and that these organisms, after exposure to penicillin, were extraordinarily susceptible to the defense mechanisms of the body. 4 Even at this early stage, researchers postulated that the PAE of penicillin would greatly increase the knowledge of the theoretical basis for the practice of chemotherapeutics.v' Know ledge of the PAE of penicillin against grampositive cocci was thought to bethe beginning of answering such questions as: Are intermittent bolus injections of penicillin better than continuous infusions? What are the most appropriate doses of penicillin? Can the serum concentration of penicillin fall below the minimum inhibitory concentration (MIC) of the organism during treatment without resulting in clinical failure? With its potential for increasing the knowledge of chemotherapeutics, it is surprising that this important research was not extended to antibiotics other than penicillin or to organisms other than gram-positive cocci. In fact, it was not until the past 10-15 years that researchers extended these observations to other antimicrobials and to gram-negative bacteria.v" The purpose of this article is to review the available data on the PAE. Methods of determining the PAE will be discussed along with the existing in vitro and in vivo data.

Factors Affecting Postantibiotic Effect The PAE appears to be a feature of most antimicrobial agents and has been documented with a variety of common bacterial pathogens. However, several factors influence the presence or duration of the PAE including type of organism, type of antimicrobial, concentration of antimicrobial, duration of antimicrobial exposure, and antimicrobial combinations. TYPE OF ORGANISM

Studies have most commonly used Staphylococcus aureus as the test organism; however, data are also available for streptococci and enterococci including S. pneumoniae, Enterococcus faecalis, S. agalactiae and S. pyogenes (Table 1).23 The majority of published data with gram-negative bacilli have been performed with Escherichia coli and

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Pseudomonas aeruginosa; however, data are also available for Haemophilus injluenzae, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, and Acinetobacter calcoaceticus (Table 2). Data regarding the PAE for organisms other than aerobic gram-positive cocci and gram-negative bacilli are limited. Experiments with gram-negative bacillary anaerobes such as Bacteroidesjragilis demonstrate no PAE with cefoxitin, but PAEs lasting several hours have been observed with c1indamycin, metronidazole, and chlorarnphenicol." Studies with antituberculous agents indicate a several-day PAE for Mycobacterium tuberculosis with isoniazid.P Limited studies with antifungal agents show significant PAEs produced by amphotericin Band flucytosine with various Candida species and one strain of Cryptococcus

neoformans. In contrast, minimal or no PAE was observed with imidazole agents ketoconazole or miconazole." TYPE OF ANTIMICROBIAL

Various antimicrobials consistently demonstrate a PAE with gram-positive bacteria. I-7,9,IO,u-22 Aminoglycosides tested against gram-positive cocci produce a short ( 3V2 h. MRSA = methicillin-resistant Staphylococcus aureus; MSSA

= methicillin-susceptible S. aureus; NO = no data; PAE = postantibiotic effect.

Table 2. Maximum In Vitro Postantibiotic Effect for Antimicrobials with Gram-Negative Bacilli ORGANISM

P. AERUGINOSA E. COLI K. PNEUMONIAE P. MlRABILlS

ANTIMICROBIAL

H. INFLUENZA

Aminoglycosides Aztreonam Cephalosporins

NO NO NO

§III NO *

Chloramphenicol Clindamycin Erythromycin Imipenem Penicillins

NO NO § NO */t

F1uoroquinolones Rifampin Sulfonamides Tetracycline Trimethoprim Vancomycin

NO NO NO NO NO NO

E. CLOACAE

A. CALCOACETICUS

REF

§/II */t */t

:j: NO */t

NO NO */t

§III NO */t

II NO */t

NO NO NO :j:/§ *

:j:/§ NO NO :j: */t

§ NO NO t */t

t NO NO NO */t

NO NO NO :j: *

NO NO NO

:j:/§ §III NO NO NO NO

:j:/§

NO §III NO NO t NO

NO § NO NO t NO

NO NO NO NO NO NO

NO NO NO NO NO NO

7,9,10,12,24-29 30 7,9,10,12,13, 17,24,30 7,9,10,17 7,9,10,14 7,9,10,14,16 10,12,24,26,30 7,9,10,17,19, 20,27,29-31 10,27 7,9,10,17 10 7,9,10,17 7,9,10 7,9,10

II NO §III */t NO

*PAE3V2 h. NO = no data; PAE = postantibiotic effect.

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Postantibiotic Effect

glycosides, antimicrobials that inhibit RNA or protein synthesis (e.g., chloramphenicol, macrolides, rifampin, tetracycline, and vancomycin hydrochloride [also inhibits cell wall synthesis)) tend to produce a longer PAE with gram-positive cocci than do beta-lactam antibiotics (Table I). DNA-gyrase inhibitors (fluoroquinolones) produce a slightly longer PAE than do beta-lactam antibiotics, and folate-synthesis inhibitors (e.g., trimethoprim) produce a PAE against gram-positive cocci similar to that of beta lactam antibiotics. No published data are available for sulfonamides. It should be noted that vancomycin and fiuoroquinolones have been documented to produce a PAE against both methicillin-susceptible and methicillin-resistant S. aureusF" In contrast to the data regarding gram-positive cocci, marked differences in PAE are observed for different antimicrobials with gram-negative bacilli (Table 2). Penicillins and cephalosporins, along with aztreonam, tend to produce a minimal or even negative PAE (the culture exposed to antimicrobial regrows faster than the growth control).7,9,IO,I3,16,17,19,27,30,31 These antimicrobials may induce a negative PAE against gram-negative bacilli because filamentous forms, induced by exposure to beta-lactams, divide faster than control organisms soon after drug removal." Imipenem, however, consistently demonstrates a PAE with gram-negative bacilli. 24,26 Antimicrobials that inhibit RNA or protein synthesis (e.g., chloramphenicol, erythromycin, rifampin, tetracycline, and aminoglycosides) also demonstrate significant PAE with gram-negative bacilli (Table 2). With respect to aminoglycosides, the slower killing of gram-negative bacilli, unlike gram-positive cocci, leaves sufficient organisms to accurately follow regrowth (using viable counts) and thus quantitate the PAE. Fluoroquinolone antimicrobials demonstrate prolonged PAE with both P. aeruginosa and E. coli.27 ,28 Three classes of antimicrobials (penicillins, cephalosporins, and aminoglycosides) will be discussed in detail. It should be noted that minor differences in PAE exist within antimicrobial classes probably because of the lack of a standardized research technique to perform and assess the PAE. Within the penicillin class of antimicrobials, penicillin G demonstrates the longest PAE compared with ampicillin and isoxazolyl penicillins with penicillin-sensitive S. 00-

reus (Table 3), No data are available regarding the antipseudomonal penicillins with S. aureus. Ampicillin and azlocillin consistently demonstrate minimal or no PAE with E. COli. 7,17,I9,31 Ampicillin produces minimal or no PAE when tested with K. pneumoniae (Table 3), and no data are available with ureidopenicillins. The ureidopenicillins (e. g. , carbenicillin, ticarcillin, piperacillin) demonstrate no or even a negative PAE with P. aeruginosa. 9 ,IO,32 Within the class of cephalosporins, cephalothin sodium displays the longest PAE with S. aureus (Table 4). The second-generation cephalosporin cefamandole and the thirdgeneration cephalosporins cefotaxime and cefoperazone sodium demonstrate a PAE of approximately two hours. Ceftriaxone sodium and moxalactam disodium induce a short PAE with S. aureus." All of the cephalosporins tested demonstrate minimal or no PAE when tested with E. coli,6,7,13,17 Neither cephalothin sodium nor cefamandole produces a significant PAE with K. pneumoniae. 10,13 When tested with strains of P. aeruginosa, cefoperazone, ceftazidime, cefotaxime, and moxalactam induced no or even a negative PAE.IO,28 Gentamicin sulfate is the only aminoglycoside that has been documented to produce a PAE with S, aureus (Table 5). The rapid and complete bactericidal activity of gentamicin against S, aureus makes it difficult to quantitate a PAE for this organism/antimicrobial combination. All of the aminoglycosides tested (amikacin, gentamicin, netilmicin sulfate, and tobramycin) produce a long (>3 h) PAE when tested with E, coli and P. aeruginosa (Table 5),28,32 Finally, for K. pneumoniae, gentamicin consistently induces a long PAE.7,9,10 CONCENTRATIONOF~CROBML

It has been suggested through bacterial time-kill studies that antimicrobials belong in three categories: (1) those with little concentration-dependent bactericidal activity, (2) those with marked concentration-dependent bactericidal activity, and (3) those that are predominantly bacteriostatic. 32 Analysis of these studies provides insight into the PAE. The majority of data with beta-lactam antibiotics indicate little concentration-dependent bactericidal activity,4,5,33,34 In vitro kinetic models using cephalosporins

Table 3. Maximum In Vitro Postantibiotic Effect for Penicillins with the Most Commonly Tested Gram-Positive and Gram-Negative Bacteria ORGANISM PENICILLIN Penicillin G Ampicillin Cloxacillin Dicloxacillin Nafcillin Methicillin Carbenicillin Ticarcillin Azlocillin Piperacillin

S. AUREUS'

E. COLI

K. PNEUMON1AE

P. AERUG1NOSA

REF

NO NO NO NO NO NO t t NO t

2-7,9,10,17,20,21 7,10,12,17-19,27,29,3 I 7,10 7,10 10 7,10 10 7,10 10,29,31 10,12,18,30

§III

NO

NO

tl§

tit

tit

§ § § § NO NO NO NO

NO NO NO NO NO NO t NO

NO NO NO NO NO NO NO NO

'Penicillin-sensitive. tPAE3V2 h. NO = no data; PAE = postantibiotic effect.

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Postantibiotic Effect

sure to penicillin G and erythromycin, respectively." Bundtzen et al. stated that the duration of PAE (for both aminoglycosides and beta-lactams) is related to the area under the curve, i.e., both the concentration of antimicrobial and the duration of exposure, up to a point of maximal response." Several investigators report that the concentration of antimicrobial and duration of exposure may have equal importance in determining the PAE. 6.7 ANTIMICROBIAL COMBINATIONS

9

-,7

E

:3 u.

~6

~

5

Several researchers have studied whether antimicrobial combinations are synergistic, indifferent, or antagonistic with regard to the PAE.IO.18.26.37.38 Craig and Gudmundsson documented indifference between rifampin and trimethoprim against Enterococcus coli and S. aureus." Fuursted investigated the effect of various antimicrobials combined with streptomycin on strains of Enterococcus faecalis and Enterococcus faecium, documenting no prolongation in PAE with streptomycin-resistant strains with any antimicrobial combination." However, using streptomycin-sensitive strains, synergistic increases in the PAE were noted with streptomycin in combinations with ampicillin, vancomycin, imipenem, or piperacillin. Antagonistic decreases in the PAE were observed with the combination of ciproftoxacin and streptomycin. 20 Hessen et al. documented enhancement of the PAE with the combination of gentamicin and imipenem against P. aeruginosa:" Zuccarelli et al. demonstrated that antimicrobial combinations of ciproftoxacin/fosfomycin and ciproftoxacinlvancomycin were indifferent or antagonistic with regard to the PAE when tested against strains of E.faecalis. 38 Finally, many parameters that may affect the PAE have been poorly studied and require further investigation. These parameters include the method used to analyze the PAE, the size of the bacterial inoculum, the type of medium used, the method of shaking cultures, and the growth phase of the organism.

In Vitro Methods to Determine Postantibiotic Effect The PAE has been determined by several in vitro methOdS. 2,3,6,7,IO,19,29,33,34 It should be mentioned that the lack of a "gold standard" method to determine the PAE has provided confusion for researchers and clinicians. All techniques involve determining bacterial growth patterns after the removal of the antimicrobial. The majority of investigators examine the PAE in vitro by exposing a broth culture in logarithmic growth to an antimicrobial concentration above the MIC for at least one hour. The drug is then removed by one of several techniques. The most commonly employed methods of rapid drug removal are repeated washing, drug inactivation, or a 100- to lOOO-fold dilution into fresh media. 2,3.6,7,lo,19 After drug removal, serial samples are taken to define the rate of regrowth. The advantage of using repeated washing or dilution is that it can be applied to all antimicrobials. Drug inactivation with penicillinase, however, has primarily been studied with penicillin G. 10 Although several methods have been used to follow bacterial growth kinetics following drug removal, the PAE is best quantitated by calculating from growth curves the difference in time required for the number of antimicrobialexposed and unexposed organisms (cfu/rnl.) to increase one loglo above the number present immediately after completion of the drug removal technique. The viability

4

3 O,!;-'-+-+----;!:-----:8~' --,!.IO

O~--:!~,....--f---:!--+--,!.

TIME (hours)

Figure I. The in vitro PAE of penicillin G (0.05 ILg/mL) after a two-hour exposure in hroth against Staphylococcus aureus ATCC 6538P. Drug removal to inactive concentrations was performed by repeated washing, a 10-' (I: IOOO) dilution. or addition of penicillinase. Reprinted with permission from Reference 10.

curves of a standard staphylococcus during a two-hour exposure to penicillin G and after drug removal by either washing, dilution, or inactivation are illustrated in Figure I. The PAE is quantified by the following equation: PAE=T-C Eq. I where T is the time needed for the bacterial count (cfu/ml.) in the test culture to increase one loglo above the count observed immediately after drug removal, and C is the time required for the count in an untreated control culture to increase by one loglo above the count observed just after completion of the same procedure used on the test culture. 6,7 Note that what is being measured is the time to reach logarithmic growth. Other methods have been used to measure bacterial growth and quantitate PAE including optical density and a bioluminescent assay of bacterial adenosine triphosphate. 25,39 These methods need to be studied to determine how they compare with results obtained using viable counts. Other in vitro methods used to determine PAE involve models that simulate in vivo drug kinetics with first-order reduction of antimicrobial concentrations. 29,33,34.39 The advantage of these systems is that the organisms are exposed to fluctuating concentrations of antimicrobial, thus more closely simulating in vivo conditions. These models, however, suffer from the disadvantage of not being able to separate subinhibitory antimicrobial effects from the PAE.

Mechanism of Postantibiotic Effect Although the mechanism(s) by which antimicrobials induce the PAE have not been clearly delineated, it is suspected that more than one mechanism exists. The two most commonly proposed mechanisms are drug-induced nonlethal damage and persistence of antimicrobial at the bacterial binding site. 3,6.7,9-U.16.19,25 Drug-induced nonlethal damage is probably the mechanism by which aminoglycosides and beta-Iactams exert their PAE. Aminoglycosides probably cause irreversible binding of sublethal amounts of drug to the ribosomes leading to disruption of protein synthesis." The PAE may represent the time needed for resynthesis of ribosomal proteins. Beta-Iactam antimicrobials are known to alter bacterial cell structure and bind

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covalently to penicillin-binding proteins, many of which are enzymes involved in cell-wall synthesis." The PAE of these drugs may reflect the time required by the bacteria to synthesize new enzymes. Tuomanen described the rapid resynthesis of penicillin-binding proteins and immediate gram-negative bacillary regrowth after drug removal. 40 This phenomenon would explain the lack of PAE with betalactams against gram-negative bacilli. The persistence of antimicrobial at the bacterial binding site is probably the mechanism by which chloramphenicol, clindamycin, erythromycin, and tetracycline exert their PAE.7,16 These antimicrobials reversibly bind to specific subunits of susceptible bacterial ribosomes and thus the PAE may represent the time it takes for the antibiotic to diffuse from the ribosomes. 10 Another factor in the mechanism of the PAE is the postantibiotic leukocyte effect (PALE).41 This refers to the enhanced phagocytosis and intracellular killing of bacteria during the drug-free period following brief exposure to an antibiotic. Gerber and Craig demonstrated that the PALE is an in vivo phenomenon as well. Finally, limited data suggest that organisms are less susceptible to the bactericidal activity of certain antimicrobials during the PAE phase." The ultimate significance of all these observations can only be determined during in vivo studies.

Experimental Infections Although considerable data are available reporting the PAE in vitro, less data are available describing in vivo (animal or human) PAE. The majority of investigators performing animal experiments have used either the thigh infection in neutropenic mice model or the rabbit meningitis model (Table 6).49,50 Two other animal models (pneumonia in guinea pigs and endocarditis in rats) assessing the PAE in vivo have also been described. 26,28,47,48 Craig has performed the majority of the work with the thigh infection in neutropenic mice model. 16,50 The advantages of this model are that mice are relatively inexpensive, the thigh muscle of mice can be easily inoculated and removed from the pelvis and femur and homogenized, and the state of neutropenia minimizes the interaction of leukocytes with bacteria. 50 It should be noted that the PAE in vivo has been proven not to be the result of the persistence of active drug in tissues." Gerber and Craig have described the PAE for erythromycin in neutropenic mice. These investigators reported that the in vivo PAE was similar to the in vitro PAE (approximately 3 h) (Table 6). Gudmundsson et al. evaluated the in vivo PAE of imipenem, cefoperazone, and moxalactam against various organisms. 46 Imipenem induced an in vivo PAE against P. aeruginosa of similar duration to the in vitro PAE (Table 6).24 The third-generation cephalosporins induced insignificant or negative PAEs in vivo against gram-negative bacilli. In contrast, both cefoperazone and moxalactam induced PAEs lasting several hours when tested against S. aureus. It should be noted that these in vivo PAEs were considerably longer than those demonstrated in vitro (Table 6). Vogelman et al. outlined the in vivo (neutropenic mice) PAEs for several beta-lactam antimicrobials as well as for protein and nucleic acid synthesis inhibitors against various organisms. 50 With one exception, all drugs tested induced an in vivo PAE with grampositive cocci in accordance with in vitro findings. The

158 • Dlep, TheAnnalsofPhannacotherapy •

exception was penicillin, which induced a several-hour PAE against S. pneumoniae and S. pyogenes in vitro (Table I), but failed to produce a PAE in neutropenic mice. These results are in conflict with previously published results in non-neutropenic mice. 21,42,43 This may be explained, however, by the presence of leukocytes in the non-neutropenic mice, thus prolonging the PAE.2 The in vivo results observed with gram-negative bacilli closely parallel in vitro data. Beta-lactam antimicrobials failed to induce a PAE with any of the organisms tested. Inhibitors of protein or nucleic acid synthesis produced a PAE against all gramnegative bacilli tested. 50 Aminoglycosides consistently demonstrated a longer PAE in vivo than in vitro against gram-negative bacilli. A possible reason for this discrepancy may be that the bactericidal activity of aminoglycosides is slower in vivo and thus higher concentrations may be used to induce longer in vivo PAEs. Sande et aI., using the rabbit meningitis model, documented no rebound in bacterial titers for several hours despite sub-MIC cerebrospinal fluid (CSF) antimicrobial concentrations. In this model, ampicillin induced a considerably longer PAE versus S. pneumoniae in vivo (6-12 h) than has been reported in vitro (Table 1).44.51 It should be noted that penicillinase was not injected into the CSF during the PAE phase and thus this apparent in vivo PAE may have resulted from residual sub-MIC ampicillin concentrations. Tauber et al. and others have extended Sande's observations in this animal model and documented similar resultS.45,52 These investigators noted in vivo PAEs ranging from 2.5 to 18 hours in rabbit CSF infected with S. pneumoniae. However, upon administration of intravenous and intracisternal beta-lactamase, the in vivo PAE was reversed. These data indicate that the in vivo PAE observed with ampicillin in the rabbit model with S. pneumoniae meningitis is not a true PAE, but rather the consequence of the presence of small residual amounts of antimicrobial in the CSF. These results are in agreement with other researchers who have also reported the absence of an in vivo PAE with ampicillin or penicillin G versus S. pneumoniae.IO,21 However, these data are in conflict with recent studies demonstrating an in vivo PAE despite the addition of beta-lactamase. 53 Tauber et al. have documented dose-dependent bactericidal activity with ampicillin using the rabbit meningitis model. 54 These investigators reported greater bactericidal activity and higher cure rates upon administering higher doses of ampicillin at a fixed interval of 24 hours. This effect is unlike the in vitro data with beta-lactams that suggest a lack of dose dependency at concentrations above the minimum bactericidal concentration (MBC), whereas such an effect is well described for aminoglycosides." Thus this study suggests that in the treatment of meningitis, beta-lactam antimicrobials display characteristics that appear similar to those of aminoglycosides in other infections. Other animal models describing the PAE in vivo include the rat endocarditis model and guinea pig pneumonia model. 26,28,47.48 Hessen et al., using a P. aeruginosa endocarditis rat model, failed to induce a PAE in vivo with imipenem alone or in combination with gentamicin, despite the presence of a several-hour PAE in vitro. 26 Ingerman et al. also used a P. aeruginosa endocarditis rat model, and failed to obtain a PAE in vivo with ceftazidime, but did induce a several-hour PAE with ciprofloxacin." The in vivo PAE ob-

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Postantibiotic Effect

tained with ciprofloxacin correlated well with the in vitro PAE for P. aeruginosa. Hessen et al. recently described the lack of an in vivo PAE again using the rat endocarditis model. These investigators induced E. faecalis endocarditis in rats and assessed the PAE of the combination of penicillin G and gentamicin. Although they obtained a PAE of several hours with both penicillin G and gentamicin alone and in combination in vitro, these researchers failed to induce an in vivo PAE with this combinatlon." Finally, Kapusnik et al. used P. aeruginosa in a pneumonia model in guinea pigs and failed to observe an in vivo PAE with mezlocillin; however, tobramycin did induce a PAE. 4 7

In summary, these animal data indicate that with the neutropenic mice model, the PAEs obtained in vivo for various organism/antimicrobial combinations are in accordance with PAEs obtained in vitro. The exceptions to this statement are penicillin G against S. pneumoniae and S. pyogenes where a PAE is consistently demonstrated in vitro but not in vivo. The other exception is with aminoglycosides and gram-negative bacilli where the PAE in vivo is consistently longer than the in vitro PAE. Consistent findings between the in vitro and in vivo PAE in the other animal models have not been demonstrated. The reasons for these discrepancies are unclear."

Table 6. Postantibiotic Effect in Animal Models MODEL

MICROORGANISM

Mouse thigh infection S. S. S. Mouse thigh infection S. Mouse thigh infection S. Mouse thigh infection S.

Rabbit meningitis Rabbit meningitis

agalactiae pyogenes pneumoniae agalactiae pyogenes pneumoniae

S. pneumoniae S. pneumoniae

Mouse thigh infection E. coli

K. pneumoniae

S. aureus P. aeruginosa

Rat endocarditis

P. aeruginosa

ANTIBIOTIC

P. aeruginosa

E. faecalis

(h)

COMMENTS

REF

0.2-4.5 0.6-5.0 0.2-4.5 0.2-4.0 0.3-4.5

1.0-4.0 1.5-3.5 0.0-4.0 1.0-4.0 0.5-2.7 2.5->3.0

t

21

cefoperazone

50 mg/kg sc

moxalactam cefoperazone moxalactam cefoperazone moxalactam cefoperazone imipenem ciprofloxacin

50 mg/kg sc 40-300 mg/kg sc 50-100 rng/kg sc 50-300 mg/kg sc 100 mg/kg sc 400-1200 mg/kg sc 50-200 mg/kg sc 20 mg/kg im q8hx5 d 20 rng/kg im q8hx5 d 5 mg/kg q4h 30 rng/kg q4h

2.6 1.2-1.8 2.7-2.9 1.3-1.8 1.9 1.1-2.6 1.7-2.4 3-6 §

300 mg/kg q4h (duration of therapy 4-72 h) 120 rng/kg im

3

tobramycin

imipenem imipenem

Rat endocarditis

PAE

(h)

ampicillin ampicillin

mezlocillin

Rat endocarditis

TIME ABOVE MIC

0.15-200 mg/kg im 0.15-200 mg/kg im 0.15-200 mg/kg im 0.05-200 rng/kg im 0.05-200 mg/kg im in vitro exposure to 5-10 times MIC for one hour 3.25-62.5 mg/kg iv 2.0-62.5 mg/kg iv

penicillin G penicillin G penicillin G penicillin G penicillin G erythromycin

ceftazidime Guinea pig pneumonia P. aeruginosa

DOSE'

120 mg/kg im q3-6h (1-5 doses) 120 mg/kg im 3 mg/kg im

imipenem gentamicin (administered together) penicillin G 50 mg/kg im and gentamicin 4 mg/kg im

6-12 2.5-18

-0.1

1.7

1-2 § 4 20

t t Bacteria brought into a PAE phase in vitro and then injected into thigh :j:

Ampicillin inactivated by injection of beta-Iactamaser Animals killed at various times and thigh homogenates assessed for bacterial growth

-0.5 -0.5-0.3 0.7 4.6-5.6 2.1 -1.2 to -1.3 0.9, 1.4-4.6 yes Animals killed at various times and cardiac vegetano tions assessed for bacterial growth yes Animals killed at various times and lung homogenates assessed for bacterial growth no

3-4 §

no

3-4 §

no

3-4 § I

no

0-3§

0

42 43 16

44 45

46

28

47

Animals killed at various times and cardiac vegetations assessed for bacterial growth

26

Animals killed at various times and valvular vegetations assessed for bacterial growth

48

*Unless stated, doses were administered only once. tPAE defined as the time interval from the serum antibiotic concentration falling below the MIC of the organism to the time that the bacterial titer (cfu/ml.) increased by one log,o. tpAE defined at the time interval from the cerebrospinal fluid antibiotic concentration falling below the MIC of the organism to the time that the bacterial titer (cfu/ml.) increased by one log,o. §Time above the MIC in cardiac vegetation. MIC = minimum inhibitory concentration; PAE = postantibiotic effect.

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Human Data The clinical relevance of the PAE is probably most important when designing dosage regimens. The presence of a PAE should permit serum and tissue antimicrobial concentrations to fall below the MIC for considerable time intervals without allowing bacterial regrowth and loss of drug efficacy. In contrast, the lack of a PAE may imply that dosage regimens should continuously maintain antimicrobial concentrations above the MIC. Otherwise stated, the presence of a PAE should allow for infrequent, intermittent dosing and the lack of a PAE may require shorter dosing intervals or continuous dosing to ensure drug efficacy and the prevention of bacterial regrowth. Although antimicrobials have been in use for over 40 years, many questions remain concerning the design and practice of antimicrobial dosing regimens. 8,32,55,56 Present dosing regimens are usually designed to maintain antimicrobial serum concentrations above the MIC of common organisms within its spectrum of activity for the majority of the dosing interval. 32,56 Although these empiric dosing schemes (designed from research performed more than 40 years ago with penicillin G) work fairly well in practice, they are not optimal in terms of efficacy, toxicity, or cost. 42,43,56 The majority of human data discussing the clinical relevance of the PAE has focused on the use of aminoglycosides. 57-63 The traditional aminoglycoside (gentamicin or tobramycin) dosing of 1-2 mg/kg administered every eight hours in patients with normal renal function has been challenged,57,59,64-67 because aminoglycosides display concentration-dependent killing and a long PAE against gramnegative bacilli. 32,58,63 Other researchers state that aminoglycoside dosage regimens should be designed to maximize the area under the curve, and doses should be administered at intervals equal to the time that antimicrobial concentrations exceed the MIC plus the duration of the PAE.68,69 These concepts were initially tested in vitro and in animal models and the results obtained proved that infrequent dosing of aminoglycosides was usually better (i.e. reduced bacterial counts or increased animal survival) than frequent or continuous dosing, in terms of efficacy. SO,57,68,7~72 The results of these animal experiments, coupled with data suggesting that high-dose intermittent dosing results in higher tissue antimicrobial concentrations when compared with low-dose frequent or continuous antimicrobial dosing, led to human trials. 61,73-76 The results suggest that once-daily dosing with aminoglycosides (gentamicin, tobramycin, netilmicin, amikacin) is not only as or more efficacious than frequent dosing, but it may actually be less ototoxic and less nephrotoxic. 57,64-67,77,78 Doses of gentamicin, tobramycin, and netilmicin have ranged from 3.1-15 mg/kg administered as a once-daily dose. 57,65-67 One study reported the use of amikacin administered once daily at dosages of 11 or 15 mg/kg." Although the results of these clinical trials are encouraging in terms of efficacy and toxicity, patient populations have been small. Also, studies have been performed in patients with normal immunologic status. Caution is advised against extrapolating these results to immunocompromised patients, as breakthrough bacteremias have been documented in patients with subinhibitory aminoglycoside serum concentrations.Pv" Clinical trials demonstrating that less frequent dosing may be as efficacious as more frequent 160 •

Dlep, The Annals ofPharmacotherapy •

dosing with protein synthesis inhibitors other than aminoglycosides are rare but have been published with regard to clindamycin." In contrast to aminoglycosides, beta-Iactam antimicrobials do not exhibit concentration-dependent bactericidal activity.32 With beta-Iactam antimicrobials, the extent of bactericidal activity depends primarily on duration of exposure.P-" although other factors such as the state of bacterial growth are important." Also, because the betalactam antimicrobials do not induce a PAE against grampositive cocci (in vivo) or gram-negative bacilli (in vitro and.in vivo), it has been suggested that beta-Iactam dosage regimens be selected to maximize the duration of time that antimicrobial concentrations exceed the MIC or MBC. Thus, these antimicrobials probably should be administered at intervals no greater than the duration of time the serum concentration exceeds the MIC. 68 Animal studies report increased efficacy (i.e., reduced bacterial counts or increased survival) with frequent or continuous dosing of penicillins or cephalosporins when compared with intermittent dosing. 57,70,83-85 Human data are also available documenting that continuous administration may be more efficacious than intermittent dosing with beta-Iactam antimicrobials. Bodey et al. reported that a subset of febrile neutropenic patients who had infections caused by gramnegative bacilli responded better to continuous administration of beta-Iactam antimicrobials. A statistically significant difference in positive outcome (74 percent for continuous administration vs. 59 percent for intermittent therapy) was reported, In addition, continuous administration of a beta-Iactam antimicrobial was significantly (statistically) more efficacious (65 vs. 21 percent) than intermittent therapy in patients whose peripheral neutrophil counts were

The postantibiotic effect: a review of in vitro and in vivo data.

The term postantibiotic effect (PAE) refers to a period of time after complete removal of an antibiotic during which there is no growth of the target ...
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