What

Preclinical Data Once-Daily Michel

G. Bergeron,

Are Needed Therapy? MD,

to Justify

FRCP

applying in clinical practice once-daily dosing of antimicrobials, one must take into consideration several factors that may influence the pharmacodynamic interaction between antimicrobials and microbes at the site of infection. The ideal agent should demonstrate rapid concentration-dependent killing activity and a postantibiotic effect that could allow for a clinically significant delay with levels below the minimal inhibitory concentration before regrowth of the microorganism. The pharmacokinetic properties of the antibiotic should allow for a good therapeutic ratio (concentration/MIC) at the site of infection. To evaluate the importance of dosage schedule on outcome, investigators have to use animal models where peak levels, half-life, area under the curve, time above MIC in interstitial fluid or infected tissues, and other pharmacodynamic properties can be evaluated simultaneously. The pharmacodynamics of several antibiotics administered at different dosing interval is compared using an animal model of infected jibrin clots. In this model, once-daily therapy resulted in better killing than other modes of administration. Aminoglycosides and quinol ones may be better suited for once-daily therapy than /3-lactams unless these latter agents have a long half-life. Before

A

lthough once-daily therapy is commonly used with antimicrobials that, like ceftriaxone, have a long half-life, single daily dosing with drugs that have a much shorter half-life or that exhibit a postantibiotic effect (PAE) is still controversial.1’2 Some investigators have suggested that the most effective mode of treatment should provide tissue concentrations of antibiotic continuously in excess of the minimal concentration inhibiting the pathogen (MIC) Continuously maintained bactericidal levels are particularly important in cases of invasive infections such as bacterial endocarditis,5 meningitis,6 or infections in neutropenic or cancer patients,7-1#{176}in whom host defenses may be impaired. Other investigators have demonstrated that these constant bactericidal levels of drug may not be necessary,11-13 and that once-daily therapy or frequent administration of antibiotics at short intervals is as effective as constant infusion, because it results in sigFrom the Department of Microbiology, Faculty of Medicine, Laval University and Le Centre de Recherche du CHUL, Laboratoire et Service d’lnfectiologie, Le Centre Hospitalier de ‘Universit#{233}Laval (CHUL), 2705, Bout. Laurier, Qu#{233}bec, Qu#{233}bec, Canada. Address for reprints: Professor Michel G. Bergeron, MD, FRCP, Chairman, Department of Microbiology Faculty of Medicine, and of Laboratoire et Service d’Infectiologie, CHUL, 2705 Boul. Laurier, Quebec, P.Q., Canada, G1V 4G2.

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nificant accumulation of drugs in interstitial fluid14 and tissues.15’16 Any mode of administration producing higher penetration into extravascular sites may be clinically advantageous, because most infections occur outside the bloodstream. It is likewise difficult to define the influence of the concentration obtained in the extravascular compartment on the bactericidal activity of antibiotics because most investigators have only evaluated the pharmacology of antibiotics2’17’18 or have studied the bacteriologic outcome of therapy4’7’9 without specifically analyzing tissue penetration of drugs and the kinetics of bacterial killing at the site of infection. Before applying in clinical practice once-daily dosing of antimicrobials, one must take into consideration preclinical data that may influence the interaction between antimicrobials and microbes at the site of infection. These factors include the intrinsic in vitro activity of the antibiotic determined by its MIC, by its minimum bactericidal activity, or by in vitro timed killed curves. The presence or absence of a PAE of the drug used may also play a determinant role on the in vivo activity of an agent.19 The pharmacokinetics of antibiotics and their tissue distribution also determine outcome. Key factors include peak and trough serum and tissue levels, serum and tissue half-lives, area under the curve (AUC), time over the

ONCE-DAILY

minimum inhibitory concentration, volume of distribution, protein binding, and the renal and liver function, which may greatly influence the pharmacology of antibiotics. Although knowledge of the in vitro and pharmacokinetics of antibiotics is determinant in the proper use of antimicrobial agents, pharmacodynamics, which can be defined as the composite action of the pharmacologic properties of the antibiotics and of its intrinsic antibacterial activity at the site of infection, is of greatest importance for the determination of dosing interval in the treatment of infectious diseases.19 Preclinical data on pharmacodynamics of antimicrobial agents are thus needed to justify once-daily therapy with antibiotics.20’21 To investigate the question of once-daily therapy with antibiotics, we have evaluated the pharmacodynamics of several antibiotics using a rabbit model involving the insertion of preformed infected fibrin clots into subcutaneous tissues. Antibacterial

Activity

of Antibiotics

Based on the intrinsic killing activity of antibiotics, the ideal drug for single daily dosing should be able to kill pathogens rapidly, should have an activity that is concentration dependent, and should demonstrate a PAE. Bactericidal Activity of Antibiotics. Several factors, including the size of the inoculum and the growth phase of the pathogens, affect the in vitro activity of antibiotics. In general, aminoglycosides are minimally affected by inoculum size and can also kill pathogens that are not actively multiplying, whereas 13-lactams, whose activity is on the bacterial cell wall, are in general effective as long as bacteria are actively multiplying. Minimum inhibitory concentration and minimum bactericidal activity of these latter agents usually increase as the inoculum size rises. Quinolones are less affected than the 3-lactams by the inoculum size and the growth phase of the microorganism. Aminoglycosides kill pathogens extremely rapidly, and their bactericidal activity is concentration dependent, meaning that the rate and extent of the antibacterial activity increase as the concentration of the drug increases. Quinolones exhibit also a concentration-dependent activity, and the onset of their killing activity manifests itself within 15 minutes to 2 hours of exposure to the microbes. With 3-lactams and vancomycin, the extent and rate of bacterial killing depend more on the time of

SYMPOSIUM

ON ONCE-DAILY

ORAL ANTIMICROBIAL

THERAPY

THERAPY

exposure than on the concentration of antibiotics, although one may observe with these antibiotics an earlier onset and a rise in killing activity up to concentrations four to eight times the MIC. Postantibiotic Effect. On theoretical ground, the PAE can be defined as the persistence of an antibiotic effect for a variable period after cessation of exposure of microorganism to an effective antibiotic. This PAE has been demonstrated in vitro and in animal models of infection. The presence of a PAE also offers a reasonable rationale for the use of single-daily dosing. The duration of the PAE depends on the nature of the microorganism, the type of antibiotic, the concentration, and the duration of exposure of the bacteria to the agent.19 Against gram-positive cocci, most antimicrobial agents can induce a PAE of several hours. Against gram-negative pathogens, including Enterobacteriaceae and Pseudomonas, -lactam antibiotics induce a very limited PAE or have no effect. Imipenem appears as an exception to this rule, with a PAE of several hours against P. aeruginosa. Aminoglycosides, quinolones, and other agents that inhibit protein and nucleic acid synthesis can induce a PAE that may last several hours. For aminoglycosides, the duration of PAE against gram-negative bacteria differs from that observed with $-lactam antibiotics and may last up to 10 hours. Although the in vivo significance of this phenomenon is not completely known, it is apparent that good tissue concentrations and a prolonged PAE may be critical to a good therapeutic outcome and may justify once-daily therapy with some antibiotics.

Pharmacodynamic Therapy

Rationale

for Once-daily

Although a wealth of literature has been published on the issue of whether or not antibiotics should be given once daily or by other modes of administration, it is extremely hard to draw any conclusion. In fact, besides modes of administration, other factors, including the physicochemical properties of antibiotics, blood supply to the site of infection, binding of drugs to proteins in serum, interstitial fluid or tissue, membrane permeability, and active transport, might influence tissue distribution of antibiotics. The inflammatory process and the presence of enzymes from bacteria, which may locally destroy antibiotics, should always be remembered as factors that also may influence positively or negatively the concentration of drugs in tissues and modify the outcome of therapy.

699

BERGERON

The experimental model used, the animal species, the type of microorganisms, the status of the host, the dosage regimen, and even the metabolic transformation of antibiotics are all factors that may affect tissue distribution and outcome. For example, rabbits desacetylate antibiotics to a greater degree than humans, so the metabolized antibiotic, which might not be as active as the nontransformed antibiotic, might be less effective in rabbits than in humans.22 All of the above factors must thus be taken into consideration before drawing any conclusion on the role of once-daily dosing in the treatment of infectious diseases. Animal

Model

The model used is extremely important when studying the effect of modes of administration on antibiotic penetration into tissues and their efficacy. The fibrin clot model was developed by Weinstein and subsequently used by several investigators.15 Fibrin clots infected with a pathogen are prepared in vitro and then subcutaneously placed into rabbits. The pharmacokinetics of antibiotics in blood, interstitial fluid, and fibrin clots, and the pharmacodynamic interaction between antibiotics and pathogens at the site of infection can be studied simultaneously in this model. The fibrin clot model may be a relevant model because bacteria interact in vivo with substances involved in clot formation and, hence, tissue repair. For example, the clumping factor of Staphylococcus aureus adheres to fibrinogen, which is converted to the insoluble fibrous protein fibrin during clotting. Dextran produced by certain strains of streptococci also can bind to fibrinogen. Furthermore, bacteria can interact with both platelets and fibronectin. S. aureus binds to fibronectin, as does lipoteichoic acid of Streptococcus pyogenes. Fibronectic, in addition, binds to fibrinogen and platelets, assisting in their aggregation. Dosing Regimens. By using the fibrin effects of four different intravenous mens have been studied:

clot model, the antibiotic regi-

Once-daily therapy (100 mg/kg over 30 minutes strictly a fast infusion) Continuous infusion (100 mg/kg over 24 hours) Bolus followed by continuous infusion (25 mg/kg over 30 minutes, then 75 mg/kg over 23 hours 30 minutes) Intermittent bolus (25 mg/kg over 30 minutes every 6 hours over 24 hours). -

This last dosing regimen is particularly the clinical situation because it is the

700

#{149} J Clin Pharmacol

1992;32:698-705

relevant usual way

to in

which most antibiotics are administered for the treatment of severe infections. Antibiotic levels in serum, insterstitial fluid, and fibrin clots were measured at regular intervals for 48 hours after initiation of antibiotic administration. At similar time intervals, the number of bacteria still present in the infected clots was determined.

HOW DOES SINGLE DAILY DOSING INFLUENCE THE PHARMACOKINETICS AND TISSUE DISTRIBUTION? Levels

of Drugs

Using aztreonam as an example, the effects ent dosing regimens were evaluated.

of differ-

Once-daily Therapy. When aztreonam was given as a single daily dose, serum antibiotic concentrations decreased rapidly, and no antibiotic could be detected after 12 hours.16 Aztreonam was also rapidly detected in interstitial fluid and the fibrin clot. Measurable aztreonam levels were still present in interstitial fluid after 12 hours and in the fibrin clot after 24 hours (Figure Ia). Continuous Infusion. Continuous infusion resulted in clinically significant aztreonam levels, although lower than after bolus injection, being reached relatively rapidly in serum and interstitial fluid (Figure ib). It took about 12 hours, however, for comparable levels to be reached in the fibrin clot. Thereafter, antibiotic levels at all three sites remained constant. Bolus and Continuous Infusion. Using a combination of bolus and continuous infusion, aztreonam levels in serum and interstitial fluid rose quicky and, although levels were lower, followed a pattern similar to that of bolus injection in the first hours (Figure ic). But, unlike bolus infusion, antibiotic levels in the fibrin clot did not decline. The pattern in fibrin clots was unlike that found after continuous infusion; maximum levels were reached after 6 hours using the bolus-plus-infusion combination, whereas comparable levels were reached 12 hours after the start of continuous infusion. Administration. When aztreonam was given intermittently every 8 hours, peak serum levels reached after each injection were lower than after a single daily injection and rose and fell after each injection (Figure id). A similar oscillatory pattern was detected for interstitial fluid concentrations Intermittent

ONCE-DAILY

THERAPY

but, in the fibrin clot, the aztreonam crease slightly after each injection.

(I)(b)

-

Snm Ij*entitial FIbflncIos

--

0.I

Time

12

IS

24

(h)

(c)

to in-

Area Under Concentration-Time Curves. It is valuable to consider the AUCs for the three sites (serum, interstitial fluid, and fibrin clots) and the four different modes of administration (Table I). For serum and interstitial fluid, AUCs for once-daily dosing, continuous, and bolus plus infusion were not significantly different, whereas the AUC was higher in interstitial fluid when aztreonam was given intermittently. In the fibrin clot, the AUC was high and identical to those in serum and interstitial fluid when the drug was given as a single daily injection compared with the three other modes of administration. These results suggest that much higher tissue levels should be observed after a single daily injection. In fact, this was the case for most antibiotics that we have been evaluating over the last 10 years, including penicillins, aminoglycosides, and cephalosporins.

fluid

l0

0246

tended

(d)

I0

AT THE SITE OF THE INFECTION PROCESS, HOW DOES SINGLE DAILY DOSING MODULATE THE PHARMACODYNAMIC INTERACTION BETWEEN THE ANTIBIOTIC AND THE MICROBES?

‘:

0.I 0246

12

18

This potential therapeutic advantage of single daily dosing was confirmed when the effect of the different modes of administration on the number of bacteria (using a f.-lactamase-negative Haemophilus influenzae ATCC 10211) present in the clot was evaluated (Figure 2). The bacteria were killed most effectively with the single daily dose, and the four intermittent injections were almost as effective. Conversely, continuous infusion and bolus plus infusion were relatively ineffective. Antibiotics that are given rapidly thus have a better chance of penetrating rap-

24 Time(h)

Figure 1. Mean concentrations fluid, and fibrin clots after (a) injected iv over 30 minutes; (b) sion of 100 mg/kg; (c) during minutes followed by an infusion after intermittent injections of hours. Adapted with permission

of aztreonam in’serum, interstitial once-daily therapy of 100 mg/kg during a 24-hour continuous infuan injection of 25 mg/kg over 30 of 75 mg/kg over 24 hours; and (d) 25 mg/kg every 8 hours over 24 from Lavoie GY. and Bergeron MG

1985)6

TABLE Effect

of Mode

of Administration

I

on Tissue

Penetration

of Aztreonam AUC (h-tg/mL)

Mode of Administration Once-daily

300 170 219 216

therapy

Continuous Boius + infusion Four intermittent

SYMPOSIUM

Serum

injections

ON ONCE-DAILY

over 24 hours

ORAL

ANTIMICROBIAL

THERAPY

interstitial Fluid

232 160 212 369

FIbrIn Clots

294 102 113 106

701

BERGERON

9

-8---

8

-

Control

-o

Once

-

7

-

6

daily

therapy

Continuous

-“D-’-

-#{149}-

-

Bolus

+ infusion

Intermittent

3

2

0 Time

(h)

Figure 2. Relationship between colony-forming units (cfu) in fibrin clots and modes of administration of aztreonam. Adapted with permission from Lavoie GY and Bergeron MG 1985,16

idly through the fibrin clots and induce greater killing. Using the same approach, the penetration and efficacy of cefuroxime and ampicillin were compared with those of the aztreonam (Table II).16 For aztreonam, the killing index (i.e., the AUC for bacteria killed versus time) was high when the drug was given as single daily dose or intermittently, but was low when given continuously or as a bolus injection plus infusion. When cefuroxime was given as single

daily dose, the time above the MIC was shorter than with a single daily dose of aztreonam and the killing index was lower. The combination of bolus plus infusion of cefuroxime produced a relatively high killing index, however, and cefuroxime compared favorably with aztreonam. For ampicillin, single daily dose or bolus plus infusion dosing was more efficacious than the other two modes of administration. Table II shows that several factors, including peak levels of antibiotics in serum and tissue, AUC, and time above MIC, which is greatly influenced by the intrinsic activity of the antibiotic against the pathogens and its half-life, may influence the activity of antibiotics at the site of infection. In our experience with the 3-lactams, AUC in tissue/AUC in serum ratio combined with time above MIC are the most determinant factors of efficacy, whereas peak levels in tissues or serum do not correlate with efficacy. Drugs with long half-lives are more effective when given in a large bolus. Antibiotic

of Mode

of Administration

on Penetration

over

over

Site

of Infection

and Efficacy

II of Antibiotics

in H. influenzae-Infected Time MIC (hr)

FIbrin Clots Killing Index (%)

AUC Clot: Serum

Peak Level Clot: Serum

0.10 0.60 0.11 0,10

24.0

76.6

23,0

33.2

24 hours

0.98 0,61 0.51 0.49

24.0 24,0

47.5 72.5

24 hours

0,43 0.17 0.34 0.15

0.05 0.16 0,05 0.04

12.0 23.0 24,0 24.0

35,2 13.7 46,8 55.2

0.36 0.20

0.05 0.02

14.4

59.4

22.2

0.21

0.02

22.9

0.06

0.02

Mode of Administration Aztreonam Once-daily therapy Continuous Bolus + infusion Four intermittent injections Cefuroxime Once-daily therapy Continuous Bolus + infusion Four intermittent injections

at the

To evaluate antimicrobial metabolism at the site of infection, residual ampicillin activity was compared after administration by the four different dosing regimens, using clots that had been infected with either H. influenzae C158 (which secretes a j3-lactamase and therefore destroys ampicillin) or H. influenzae ATCC 10211 (which does not produce a j3-lactamase).

TABLE Effect

Destruction

>

Ampicillin

Once-daily therapy Continuous Bolus + infusion Four intermittent injections

702

#{149} J Clin Pharmacol

over 24 hours

1992;32:698-705

1.2

4.6 47.6

20.8

ONCE-DAILY

THERAPY

(b)

(at

80

6O

I

.3

I.

4o

0, -10

10 Banenal

Time

load

-

IO

(cfu/g)

104

Bacterial

load

(cfu/g)

Figure 4. Influence of bacterial load on (a) cefoperazone tions in jibrin clots, and (b) on antibacterial efficacy.

concentra-

destruction of the $-lactam in vivo and the mode of drug administration can affect how many bacterial cells are killed. This appears to be important when treating acute severe infections, because the survival of the infected patients is probably dependent on how they are treated in the first 24 hours.

.3 C

8. E

Bacterial

‘C

0.5

I

2

3

4

6

Inoculum

Using the fibrin clot model, it has been shown that the number of microorganisms present in the clot can affect the concentration of the antibiotic (in this case cefoperazone given by continuous infusion). By reducing the bacterial load of H. influenzae present in fibrin clots from iO colony-forming units per

12 24 Time(h)

Figure 3. Residual ampicillin concentration in fibrin clots infected with H. influenzae C158 (a /3-lactamase producing strain) compared with clots infected with H. influenzae ATCC 102 11(a 3-lactamase negative strain) following (a) once daily therapy; (b) continuous infusion; (c) bolus injection followed by infusion; and (d) intermittent injections. Adapted with permission from Lavoie GY and Bergeron MG, lg85’

Ampicillin was detected for at least 4 hours in clots infected with either H. influenzae strain when a single daily dose was given (Figure 3a); thus, ampicillin penetration outstripped j3-lactamase production by H. influenzae C158. When ampicillin was given by continuous infusion, however, no antibiotic was detected in the clot infected with j3-lactamase-positive strain (Figure 3b). Either bolus plus infusion (Figure 3c) or intermittent ampicillin (Figure 3d) resulted in a gradual destruction of the antibiotic when the enzyme-producing strain was present in the clot. It therefore can be concluded that there is local

SYMPOSIUM

ON ONCE-DAILY

ORAL

ANTIMICROBIAL

THERAPY

-4---o

Ce

Control Once daily

-

Q,., -

-

dosing

Continuous -

Bolus

+

infusion

Intermittent

---#{149}-

--

24 Time

0246

12

18

24

(hi

Figure 5. Comparative in viva efiicacies of (a) cefuroxime, and (b) ampicillin against f3-lactamase positive H. influenzae C158 by different modes of administration. Adapted with permission from Lavoie GY and Bergeron MG.’6

703

BERGERON

gram to iO colony-forming units per gram, a high antibiotic concentration was achieved in the clots (Figure 4a) and, at the same time, the efficacy against H. influenzae increased (Figure 4b). In this case, insufficient bacteria were present to produce sufficient enzyme to convert the drug to an inactive metabolite. In serious infections, the number of microorganisms is likely to be above iO colony-forming units per gram, and local destruction may explain some of the failures observed in practice. This local destruction can be overcome by administering large doses. Whether single daily dosing may prevent inactivation of antibiotics by hemoglobin, which binds penicillins and tetracyclines, inflammatory cells, calcium and magnesium, and anaerobic environment that neutralizes aminoglycoside, is not known. In a recent review on once-daily aminoglycoside therapy, it was shown that the efficacy of aminoglycosides in animal models of infection was the greatest with therapeutic regimen that resulted in the highest peak concentration in serum and the largest AUC, suggesting that with aminoglycosides, which have one of the longest PAE, once-daily dosing may be acceptable. Using an animal model of E. coli endocarditis, it was shown that the killing rate, defined as the reduction of the inoculum within 3 hours after exposure to drug, was the major factor determining the minimal effective dose in milligrams per kilogram administered to animals. Although the half-life of the agent did improve the predictive value of the killing rate, protein binding, MIC, and minimum bactericidal activity did not. With aminoglycosides and quinolones, which had the highest killing rates, the minimal effective dose was lower than with /-lactams, which had a low killing rate. Single daily dosing might thus be possible with aminoglycosides and quinolones.23 To further complicate the issue of such daily dosing, it was demonstrated in a model of Serratia marcescens endocarditis that gentamicin was much more effective when administered as a bolus injection than after a continuous infusion, whereas amikacin, which had a much less impressive concentration-dependent activity than gentamicin against that pathogen, was more effective when given as a continuous infusion.24 These studies further emphasize the

fact that multiple variables have to be taken into account before drawing any conclusion on the efficacy of single daily dosing of antibiotics. With /3-lactam antibiotics, which have limited PAE, one has to emphasize the critical role of a long half-life for those antibiotics that might be used once daily. This is well demonstrated in the following example:

704

#{149} J CIin Pharmacol

1992;32:698-705

Cefuroxime has a short half-life and therefore remains active in serum and tissue for only a short time when administered once daily (Table II). Furthermore, this agent has no PAE. Consequently, once the cefuroxime concentration falls below the MIC, there is a rapid regrowth of the j3-lactamase-positive H. influenzoe (Figure 5a), which was not seen with aztreonam (Figure 2). As expected, there was no suppression of bacterial growth when ampicillin was used as control against the fl-lactamase-positive strain (Figure 5b). Therefore, the reason why aztreonam was so effective when given as a single daily dose was that the AUG was higher and the duration above the MIC was much greater than those observed with cefuroxime.

CONCLUSION On the basis of the pharmacodynamics of an antibiotic, it is possible to choose which compounds are suitable for once-daily therapy. For aminoglycosides and quinolones, where the killing is rapid and dose dependent, and there is a PAE, the pharmacodynamic objective is to maintain the tissue levels way above the MIC for a short period. This can be achieved by giving single bolus doses at long time intervals. With 3-lactams, however, which have a slow, time-dependent antibacterial effect and do not display a PAE, the aim is to keep the antibiotic level above the MIC for the duration of therapy. Consequently, if the drug has a long half-life, single doses at long intervals can be given. If the half-life is short, however, the antibiotic should be given frequently, thus ensuring that the j3-lactam is maintained at concentrations above the MIC at all times in infected tissues. Large doses in general improve the tissue penetration and efficacy of antibiotics in infected tissue like fibrin, where diffusion of antibiotics is limited. REFERENCES 1.

Gilbert

Agents

D:

Chemot

Once-daily her 1991;

aminoglycoside 35:399-405.

therapy.

Antimicrob

Bergeron MG, Beauchamp D, Poirier A, Bastille A: Continuous vs intermittent administration of antimicrobial agents: Tissue penetration and efficacy in vivo. Rev Infect Dis 1981;3:84-97. 3. Eagle H. Fleischman R, Levy M. “Continuous” vs discontinuous therapy with penicillin. The effect of the interval between injections on therapeutic efficacy. N EngI I Med 1953; 248:4871-488. 4. McCracken GH, Jr. Nelson JO, Grimm L: Pharmacokinetics and bacteriological efficacy of cefoperazone, cefuroxime, ceftriaxone, and moxalactam in experimental Streptococcus pneumoniae and 2.

THERAPY

ONCE-DAILY

Haemophilus influenzae meningitis. Antimicrob mother 1982;21:262-267. 5. Weinstein MP, Reller LB: Clinical importance through bacteremia.” Am I Med 1984;76:715.

Agents of

Che“break-

Plorde JJ, Garcia M, Petersdorf RG: Studies on pathogenesis of meningitis. IV. Penicillin levels in the cerebrospinal fluid in experimental meningitis. I Lab Clin Med 1964:960-969.

6.

7. Bodey

GP,

Ketchel

SJ, Rodriguez

V: A randomized

carbenicillin plus cefamandole or tobramycin febrile episodes in cancer patients. Am I 8.

Bodey,

GP,

Valdivieso

M, Yap

BS: The

in the

study

of

treatment

of

Med 1979;67:608-616.

role

of schedule

in antibi-

otic therapy of the neutropenic patient. Infection 8(Suppl. 1):1980;75-81. 9. Feld R, Valdivieso M, Bodey GP, Rodriguez V: A comparative trial of sisomycin therapy by intermittent versus continuous infusions. Am J Med Sci 1977; 274:179-188. 10. Yap B, Bodey GP: Netilmicin patients with cancer. Arch Intern

in the treatment of infections Med 1979;139:1259-1262.

11. Bigger JW: Treatment of staphylococcal cillin by intermittent sterilization. Lancet

infections 1944;

with

in peni-

ii:497.

Ghisholm GD, Smith CB, Waterworth influencing the distribution of antibacterial fluid: Molecular size and protein binding. 2):S123-S127. 14.

PM, Calnan SS: Factors agents in interstitial Infection 1976;4(Suppl.

Braza M, Brusch J, Bergeron MG, Weinstein L: Penetration antibiotics into fibrin loci in vivo. III. Intermittent vs continuous infusion and the effect of probenecid. I Infect Dis 1974:129:73-78.

SYMPOSIUM

ON

ONCE-DAILY

ORAL

ANTIMICROBIAL

20. lngerman MJ, Pitsakis PG, Rosenberg AF, Levison ME: The importance of pharmacodynamics in determining the dosing interval in therapy for experimental Pseudomonas aeruginosa endocarditis in the rat. I Infect Dis 1986;153:707-714. 21. Vogelman B, Craig WA: Kinetics of antimicrobial effects. J Pe1986:108:835-840.

Bergeron MG, Nguyen BM, Trottier 5, Gauvreau L: Penetration of cefamandole, cephalothin and desacetylcephalothin into fibrin clots. Antimicrob Agents Chemother 1977:12:682-686. 23. Patel G, Chau NP, Pangon B, Fantin B, Vallois JM, Faurisson F, Carbon C: Single daily dosing of antibiotics: Importance of in vitro killing rate, serum half-life and protein binding. Antimicrob Agents Chemot her 1991:35:2085-2090. 24. Patel G, Caillon J, Fautin B, Raza J, Le Gallou F, Lepage JY, Leconte P, Bugnon D, Baron D, Drugeon H: Impact of dosage schedule on the efficacy of gentamicin, tobramcin or amikacin in an experimental model of Serratia marcescens endocarditis. In vitro and in viva correlation. Antimicrob Agents Chemother 22.

of the dosG. J Pharma-

15.

18. Carbon C, Chau NP, Contrepois A, Lamotte-Barillon S: Interstitial diffusion and accumulation of cephalothin according to various modes of intermittent administration to rabbits. J Antimicrob Chemother 1978;4:349-353. 19. Craig WA, Gudmundsson 5: The post-antibiotic effect. P. 515536, in Lorian V (ed): Antibiotics in Laboratory Medicine, 3rd ed. Baltimore: Wiliams & Wilkins, 1991:12:403-431.

diatr

12. Schmidt LH, Walley A: The influence of the dosage regimen on the therapeutic effectiveness of penicillin G in experimental lobar pneumonia. J Pharmacol Exp Ther 1951:103:479-488. 13. Schmidt LH, Walley A, Larson RD: The influence age regimen on the therapeutic activity of penicillin col Exp Ther 1949;96:258-268.

16. Lavoie GY, Bergeron MG: Influence of four modes of administration on penetration of aztreonam. cefuroxime and ampicillin into interstitial fluid and fibrin clots and on in vivo efficacy against Haemophilus influenzae. Antimicrob Agents Chemother 1985:28:404-412. 17. Barza M, Kane A, Baum J: Comparison of the effects of continuous and intermittent systemic administration on the penetration of gentamicin into infected rabbit eyes. J Infect Dis 1983; 147:144148.

of

1991;

THERAPY

25:111-116.

705

What preclinical data are needed to justify once-daily therapy?

Before applying in clinical practice once-daily dosing of antimicrobials, one must take into consideration several factors that may influence the phar...
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