Single-Dose What Has

Antibiotic Therapy: the Past Taught Us? Claude

proper

dosage

due

to the

difficulty

schedule

of antibiotics

of clinical

trials.

Initially,

his symposium

considers the feasibility of once administration of antibiotics through the oral route. This point was stimulated by the occurrence of new compounds belonging to various groups of antimicrobials, exhibiting favorable pharmacokinetic and/or pharmacodynamic properties. For decades, the dosage schedules of antimicrobial agents were designed empirically, based on in vitro data describing a level of activity, basic kinetic properties such as elimination half-life and clinical experience, without in the majority of cases, any objective evaluation of dose response, proper interval between doses, or optimal duration of therapy. No attempt was also made to determine dosage schedules on the basis of the severity of the infectious prodaily

(OD)

-

-

From H#{244}pital claude Bernard, Paris, France. Address for reprints: claude Carb#{243}n, MD, INSERM U.13, H#{244}pital claude Bernard, Avenue de Ia Porte d’Aubervilliers, 75019 Paris, France.

686

#{149} J CIIn Pharmacol

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has

MD

determined empirically, was chosen to allow high sustained levels > MIC in the blood. Antibiotics ( lactams, tetracyclins, macrolides) were given at high doses three to six times daily, whatever their kinetic properties. The data obtained by Eagle3 with ,t3 lactams in animal models of streptococcal and treponemal infections outlined the importance of interval between doses on the in vivo efficacy. They also showed that increasing the dose of penicillin had a positive effect on the bactericidal activity only through the persistence of effective levels (>MIC) at the site of infection. Further illustrations were given through experimental and clinical studies with f lactams or other compounds on different types of infections: LlITls, UTIs, meningitis, and endocard itis. The importance of both dynamic (i.e., pattern of bactericidal effect) and kinetic (elimination half-life) parameters was thus further identified. Information on toxicity with some compounds with a narrow therapeutic index, such as aminoglycosides, indicated that increasing the dose to enhance efficacy had some limitations. This led to numerous studies on the relations between concentration and toxicity, stating that nephroor ototoxicity were not directly related to peak level in serum. Experimental studies showed that OD administration of aminoglycosides was both more efficient and less toxic than the multiple-dose regimen of the same daily amount. Economic considerations progressively justified attempts to both reduce the dose and the work load related to multiple administrations. Development of oral compounds able to be given as initial therapy or as a quick alternative to parenteral administration raised the question of applicability to oral route of OD dosing. High bioavailability is required to ensure efficacy. Oral OD dosing may be discussed in more or less severe infectious processes and in some difficult-to-cure chronic infections.

T

The

Carbon,

generally the dosage

been

cess. A lot of knowledge, which may lead to a more rational approach of the problem of a proper dosing regimen of antibiotics has been accumulated over the years. This article describes the determinants of changes in attitudes and the establishment of the concept of OD dosing.

What

are

the

Basic

Questions?

1.Which is the main determinant of clinical efficacy of an antibiotic: Is it the serum peak level or the duration of an adequate concentration over the MIC in the interval between two doses? 2. Is it possible to improve clinical efficacy and tolerance by modifying the conditions of administration of the drug, i.e., dose, interval between doses and modalities of injection (IV bolus, short infusion, or continuous IV infusion)? 3. Is it necessary, for all kinds of infection, to

SINGLE-DOSE

ANTIBIOTIC

achieve rapidly the maximum concentrations at the infected site? 4. What are the objective bases on which it is possible to predict the optimal in vivo effect? 5. Do the responses to the aforementioned questions apply to any antibiotic, any type of disease, or to any degree of impairment of host defenses? In the practice of the past years, two different types of antimicrobials had to be considered: those with low or absent toxicity which could be given at high doses and frequent intervals and those with a low therapeutic index which may lead to clinical toxicity within the therapeutic range of doses. The former compounds raise economic problems when their use at high doses is restricted to severe and also rare infections. The main question for their use in benign or moderately severe infections is to search for the lowest efficient dose administered at the longest intervals. For the latter drugs, besides their use in selected indications, the problem is in preventing or reducing the risk of toxicity by modifying the dosing regimen. Searching for optimal dosing regimen may thus lead to significant clinical progress in efficacy, tolerance, and money savings.

INITIAL

EXPERIMENTS

WITH

PENICILLIN

Studies in the early 1940s established that the therapeutic effectiveness of the penicillins depended on their administration in such a way that contacts between drug and organisms were constantly maintained. Thus all major schemes of therapy were designed with the objective of continually maintaining the plasma levels at or above levels known to inhibit in vitro growth of the offending agent. In series of experiments performed in white rats that had either a systemic infection after IP injection1 or a lobar pneumonia,2 Schmidt et al. showed that intermittent treatment was efficient, with an optimal interval between doses for a given single dose. The authors established that penicillin levels were below the in vitro effective concentration of penicillin for a portion of the dosage interval. They also showed that duration of treatment may contribute to improve the efficacy whatever the interval between doses. Similar findings were made at the same time by Eagle et al.3 who concluded after a number of experiments in mice and rabbits using infections with Streptococcus pneumoniae, B. Streptococci, or Treponema pailidum that the effective concentration of

SYMPOSIUM

ON ONCE-DAILY

ORAL ANTIMICROBIAL

THERAPY

THERAPY

penicillin at the actual focus of infection was of the same order of magnitude as that which appeared efficient in vitro. They also stated that the duration of the cidal effect of penicillin in vivo was generally approximated by the time for which the serum concentrations remained in excess of two to five times the minimal bactericidal level in vitro. The reasons for which discontinuous therapy with penicillin was effective were discussed by Schmidt.2 A first explanation was that, as indicated by Parker4 and Eagle,5 a period of as much as 8 hours may elapse before organisms previously exposed to penicillin recover and resume normal growth. Also, surviving bacteria may be peculiarly susceptible to phagocytosis. Discontinuous administration of penicillin might have some advantage by allowing regrowth of bacteria given the fact that penicillin was demonstrated as more efficient on multiplying organisms. Finally, high serum levels afforded by intermittent therapy might give rise to high tissue levels. Further studies by Eagle et al.6 with a streptococcal infection in mice demonstrated that cure with aqueous sodium penicillin was effected most rapidly by the continuous provision of maximal effective concentrations of the drug. If the penicillin was given so infrequently that the concentration at the site of infection fell to ineffective levels, the time for cure was correspondingly increased. Massive doses similarly injected than small efficient injections did not increase the efficacy. The same authors clearly stated that these conclusions applied solely to penicillin. With this antibiotic, they showed a maximally effective concentration, varying from strain to strain. Even a ten-thousand fold increase in concentration beyond this value did not further accelerate the cidal activity. In contrast, with streptomycin the bactericidal effect increased continuously with the concentration. So, the most rapidly effective schedule would be one providing the maximum concentration and, for the longest continuous period, consistent with the toxicity of the drug. Conversely, the effect of aureomycin or terramycin appeared so slow that it was suggested that host factors might contribute materially to their therapeutic effect. So, as we can see, all the major aspects of antibiotic dosing were roughly described in the early period of antibiotic use i.e.: differences between drugs according to the modalities of their cidal effect, in vitro and in vivo, importance of what will be called later on the post antibiotic effect, role of host defenses on the response to antibiotic therapy, influence of the severity of the disease on the response to static or cidal agents.

687

CARBON

Because of the results obtained by the various authors and the short serum half-life of penicillin G in humans, different strategies were proposed to administer the drug: continuous infusions, intermittent injections q 4 or 6 h, use of probenecid to block tubular secretion or a gain use of procaine or benzathin salts to provide a sustained delivery of the drug. In the same time, it appeared that in some situations, it was possible to administer the drug at long intervals between doses up to every 12 hours; equivalent results were described in scarlet fever7 or in pneumococcal pneumonia.8 Similarly, it appeared that high doses of penicillin were no more effective than low ones on pneumococcal pneumonia9 or in animal models of endocarditis due to streptococci.1#{176}

EVOLUTION CONCEPTS

OF

PHARMACOKINETIC

Progresses in the kinetic evaluation of antibiotic were important in the interpretation of in vivo results. Among the most important steps, few aspects will be discussed. First, the development of sensitive methods of antibiotic assay helped analyze the behavior of drugs in the body more completely. Thus, with the possibility of detecting low concentrations of penicillins (down to 0.02 tg/mL), Ebert et al.11 described a slow elimination phase for penicillin G, both in mice and in humans, confirming the absence of time post antibiotic effect toward S. pneumoniae and also the possibility of large intervals between doses for the treatment of infections due to susceptible microorganisms. Second, a better knowledge of the factors modulating tissue distribution of antibiotics was taken from various studies using animal models giving access to interstitial fluids. These models and their results have been extensively reviewed or discussed in several general papers.1213’14 Among these factors, two have to be further discussed, i.e., binding to serum proteins and elimination half-life. Serum protein binding appears to be one of the important determinants of drug distribution in the body.15 Only the free unbound molecules can readily pass through capillary pores into tissue fluids. It was anticipated that highly bound molecules would tend to remain within the intravascular compartment. In fact, and this is specially true with f3 lactams which are weak acids bound more or less specifically to albumin, there is a constant equilibrium between bound and free antibiotic allowing a slow elimination through glomerular filtration and a tissue distribution with

688

#{149} J ClIn Pharmacol

1992;32:686-691

late maximum concentrations. The value of these maximum levels depends on the relative affinity of the molecule for tissue versus serum proteins. Elimination half-life, which is the basic factor conditioning the interval between doses of the majority of the drugs used in clinical medicine, appeared as an essential parameter for the compounds with a time-dependent cidal effect. The development, through a better knowledge of the structure/kinetics relationships, of long acting jI lactams, such as cephalosporins, allowed the OD administration of compounds such as ceftriaxone.16 However, the report of failures with OD administration of cefonicid in the therapy of bacterial endocarditis outlined the importance of the half-life of free drug as compared with that of the total compound in the definition of the dose intervals.17’18 The third important development in kinetics of antimicrobials was the critical approach of tissue levels. This point has been reviewed elsewhere.19 Briefly, the classical way of assessing tissue distribution of antimicrobials is to measure the concentration in a tissue homogenate. In fact, for a compound without intracellular penetration, the distribution occurs throughout extracellular water, and determination of the content in a whole homogenate underestimates the true concentration available for the effect toward extracellular bacteria. Also, studies with autoradiography of infected cardiac vegetations2#{176} showed that different patterns of more or less heterogeneous distribution were observed from drug to drug. This explains the difficulty in treating such an infected site and the need for “high local concentrations” of cephalosporins or teicoplanin as stated by assay of vegetations homogenates. In the same way, to be effective against intracellular bacteria, antibiotics must not only reach and preferably be retained in the infected subcellular compartments but also be able to express their activity in situ. This fourth major advance in the knowledge of antibiotic kinetics has been reviewed by Tulkens.21 Both pharmacokinetic and pharmacodynamic aspects of intracellular activity of antibiotics have been investigated through a huge number of studies. Nowadays, a rational analysis of the successive factors influencing activity is possible, i.e., uptake, intracellular disposition, metabolism, and the capability of antibiotics to act against the target bacteria under the physicochemical conditions prevailing at the site of their subcellular localization. Thus significant differences were established between the activity of fluoroquinolones, lincosamides, and macrolides both in vitro, on different models of infected macrophages, and in vivo, for instance, on models of legionella infection.

SINGLE-DOSE

ANTIBIOTIC

Regarding oral administration, efforts has been made to improve bioavailability through increased proximal intestinal absorption of cyclins, /3 lactams, or macrolides. At last, the optimal mode of administration of a given dose of antibiotic to achieve the highest interstitial levels has been investigated on several models reviewed by Barza.12 There seems to be a trend indicating better penetration by intermittent infusion than by continuous infusion. Whether the major determinant is the peak serum level or AUG remains to be established and mainly depends on the model used. AUCs at tissue sites are similar, despite different methods of dosing of the same amount of drug. However, the shape of the curve is different and intermittent or pulse dosing produces higher and earlier extravascular peak levels. The clinical relevance of these observations, however, remains unclear.

EVOLUTION CONCEPTS

OF PHARMACODYNAMIC

A variety of different pharmacodynamic parameters has been further explored since the initial work of the 1940s. They have stimulated a lot of studies both in vitro and in animal models. Part of these data has been reviewed and discussed in a symposium held in Stockholm in 1990.22 These include the rate of killing, the post antibiotic effect, the sub-MIC concentration effect, the paradoxical effect, and the postantibiotic leukocyte enhancement. We know how these parameters vary for different antibiotics and microorganisms and how they may be altered by concentrations, pH, and exposure time. However, the molecular mechanisms of these phenomena remain to be elucidated. Some of these parameters may have importance for the dosing of antibiotics. For drugs that exhibit a concentration-dependent killing, optimal dosage regimens should attempt to maximize drug concentrations. Conversely, for drugs exhibiting a time-dependent effect, drug administration must maximize the duration of exposure. The post-antibiotic effect would allow drugs to be dosed less frequently. Pharmacokinetic/pharmacodynamic interactions were progressively approached through the development of appropriate models tissue fluid distribution, as reviewed by Barz&2 or Lebel,23 thigh infection of normal or neutropenic mice,24 or discriminative models of infection (meningitis, pneumonia, endocarditis, pyelonephritis).12’13 They help draw the general statements that (1) AUG and peak levels are the major parameters of therapeutic efficacy of aminoglycosides; (2) time -

SYMPOSIUM

ON ONCE-DAILY

ORAL ANTIMICROBIAL

THERAPY

THERAPY

above MIC was important for /3 lactams; and (3) quinolones have an intermediate position.25 In an attempt to obtain some criteria that can be used by clinicians in selecting the most appropriate dosing regimen in a given clinical situation, various groups have explored different ways. Ellner26 introduced the concept of inhibitory quotient, which reflects the ratio of concentration that can be achieved at the site of infection to the MIG of the offending agent. Sequential evaluation of the serum bactericidal titer,27 the serum bactericidal rate,28 or the serum AUG of free antibiotic/M1G29 have been proposed. More recently, Garaffo et al.3#{176} proposed for the determination of optimal dosing regimen of amikacm the evaluation of bactericidal activity by correlating an index of surviving bacteria with antibiotic concentrations. This method allowed the determination of the maximal effective and the lowest effective concentrations. From these studies, it can be seen that inclusion of dynamic factor with kinetic optimization, called dual individualization by Schentag et al.,31 may provide further insights in the basic knowledge of in vivo activity of antimicrobials but also have practical incidence on the management of severely infected patient or in the investigation of a new compound.

ECONOMIC

CONSIDERATIONS

Special attention has been progressively paid to reduction in cost of therapies and improvement in the quality of management of patients in the past years. Besides the reduction of undue costs of antibiotic therapy related to unproper choice, unnecessary duration or unadequate doses, the possibility of OD dosing of parenteral agents may be an attractive perspective in terms of reduction of number of injections, workload for nurses, or improvement in quality of care to patients. This has been demonstrated for a long-acting cephalosporin such as ceftriaxone.32 Such properties also offer the possibility of reducing the duration of hospitalization. Therapy may be performed at home with parenteral drugs. Long-acting compounds usable once daily are peculiarly convenient for such indications, as demonstrated by Williams.33 The total cost savings vary from one study to another. However, it must be outlined that cost-containment studies are not sufficient to discriminate all the aspects of the progress obtained. Gost-benefit studies should be used with multiple-outcome measures, peculiarly assessment of quality of life.34

THE EXAMPLE OF AMINOGLYCOSIDES: TID TO OD ADMINISTRATION Initially, 8 hours,

aminoglycosides were administered according to their short elimination

FROM every half-

689

CARBON

life. A major concern on their use was renal and ototoxicity. A great deal of effort has been expended to improve our understanding of their kinetics, so as to ensure therapeutic levels while avoiding toxic concentrations at peak or trough. Despite careful attention to dosage regimens designed to achieve targeted levels in serum, no major changes in the incidence of toxicity, mainly renal, were observed. In contrast, it was clearly demonstrated that continuous infusion of aminoglycosides led to a higher incidence of nephrotoxic effects. The evolution of pharmacodynamic concepts concerning these agents and the rationale for decreased toxicity of the OD regimen have been extensively reviewed and discussed by Gilbert35 and Tulkens.36 The concentration-dependent cidal effect, the long post-antibiotic effect observed toward a large variety of bacteria and also demonstrated in viva, stimulated animal studies to determine the efficacy of the OD regimen. Several animal and human studies led to the conclusion that toxicity was not related to peak concentration but rather to the persistence of elevated trough levels. These observations have been rationalized by experimental studies demonstrating a saturable uptake of aminoglycosides by both the renal cortex and the inner-ear tissue. Similar data were obtained in humans. In different animal models, aminoglycoside antibacterial activity appeared greatest with OD administration than with multiple administration of the same total daily dose. Once exception was the neutropenic animal, in a guinea pig model of Pseudomonas aeruginosa pneumonia,37 in which OD administration of tobramycin alone appeared less effective than the every 4 hours regimen. However, when combined with mezlocillin, the aminoglycoside was equally effective when given OD or every 4 hours. All these basic informations stimulated clinical studies using aminoglycosides in combination with other drugs for short treatments in young adults with normal renal function. Generally, the OD regimen appeared as efficient as the TID one and no significant differences in toxicity were observed between the two regimens. These studies demonstrated that OD administration of aminoglycosides is feasible in humans. However, it has to be stressed that caution must be paid to patients with renal failure, children, and patients treated for long periods. Attention has also to be paid to enterococcal infections for which, at least in an experimental model of endocarditis in rabbits, it was demonstrated that when combined with a same regimen of penicillin, netilmicin was less effective when given OD than when administered TID.38 Similar cautions may apply to severe pseudomonas infec-

690

#{149} J Clin Pharmacol

1992;32:686-691

tions. Thus, peutic ratio bly reaching

the “continuing saga of the toxic/therain the use of aminoglycosides”39 is probathe end of an era.

CONCLUSIONS Significant advances in the approach of OD dosing regimen have been made since a previous symposium on pulse dosing of antimicrobials held in 1981.4041 Once-daily administration of antibiotics appear feasible with parenteral compounds in some circumstances. However, the conditions under which OD is applicable to humans vary from drug to drug. The level of bacterial susceptibility, the type of infection, and the degree of host-defenses alterations have to be taken into account. It can be stressed that the feasibility of OD dosing is predictable from in vitro data and from selected animal studies, which may help define the clinical studies to be performed on selected indications. Such studies devoted to this specific issue may intervene at a more or less early stage of new compounds. Special attention to the analysis of failure is warranted, as well as development of economic analysis of the benefits, advantages, and utility of such practice. Is the concept of OD dosing applicable to oral antibiotics? Is OD administration of an oral antimicrobial possible as a first-line therapy or must it be envisaged only as a second choice after few days of parenteral therapy? Is OD administration applicable to all kinds of oral agents and to all the indications of their spectrum of clinical activity or must it be restricted to community acquired and moderately severe infections? The responses to these different questions will be given through the different articles of this issue of the Journal. Obviously, the development of oral compounds with high bioavailability able to be given OD is a fascinating approach of antibiotic therapy for many reasons reduced costs and work load, improved patient comfort, and reduction of the risks of viral transmission related to parenteral injections in some countries. -

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2. Schmidt LH. Walley A: The influence of the dosage regimen on the therapeutic effectiveness of penicillin Gin experimental lobar pneumonia. J Pharmacol Exp Ther 1951;103:479-488. 3. Eagle H, Fleischman R, Musselman AD: The effective concentrations cocci,

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SINGLE-DOSE

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