Pharmaceutical I pharmacokinetic and other considerations for intravenous to oral stepdown therapy

Parenteral to oral stepdown therapy represents an effective cost containment strategy which can minimize intravenous therapy associated morbidity and may facilitate earlier hospital discharge. Several oral anti-infectives are available to the prescriber and there are as many opportunities to stepdown to the same agent as there are to other drugs of the same class or other classes. Recognition of the pharmacokinetic characteristics of these oral agents is essential lo successful therapy. Good bioavailability may not always be assured. A simple regimen will promote compliance.


J\ NTI-INFECTIVE DRUG EXPEND ITURES IN CANADA ARE
.r-\.second in magnitude only lo cardiovascular drugs.In the acule care hospilal selling, anti-infective drugs typically account for 20% lo 30% of total drug expenditures (1.2). alternatives (Figure 1), iv to po slepdown is being used by many hospitals as a cost containment strategy (1,2) .
Since the acquisition, preparation and administration costs of oral (po) anti-infective formulations are typically 10 lo 40% of lhe cosl of their parenteral (iv) As previously described by Louie (4).health care professionals have practised iv to po stepdown therapy in an 'uncontrolled fashion' since the availability of oral and parenteral antimicrobials.To our knowledge.the first reports describing the potential economic benefits of a formal Canadian program of oral antibiotic step- down promotion were not published until 1990 when we described the preliminary results of a formal stepdown program which was initiated by the antibiotic use subcommittee of the drugs and therapeutics committee in early 1987 (5).Perhaps this refl ects the 'coming of age' of this simple, yet effective, concept.

IV TO PO STEPDOWN SCENARIO
Slepdown from a parenteral to an oral antimicrobial agent usually follows one of four scenarios (1).In scenario 1. stepdown involves the use of the same drug in an oral dosage form which has excellent bioavailabilily.Drugs such as metronidazole, clindamycin and cotrimoxazole can provide concentrations in the blood fo llowing oral administration which are similar to those achieved with the parenteral dosage form.Scenario 2 involves stepdown to the same drug with a reduction in achievable systemic drug concentrations.Drugs such as ampicillin, cloxaci!Iin and e1ythromycin are examples of this situation.

PROPERTIES OF THE IDEAL STEPDOWN AGENT
General properties of the ideal oral st.epdown agenl are summarized in Table 1.The ideal oral antimicrobial stepdown agent should possess properties which result in minimal disruption lo the treat.menlcourse.In other words, the process of slepdown would involve the modification of one treatment parameter only, namely a change in the route of drug administration (Scenario 1).In many instances, conversion lo an oral agenl within lhe same class (eg, cefazolin to cephalexin) or of a different class (eg, cefuroxime lo colrimoxazole) should yield favourable results.Scenario 3 slepdown should be considered if the parenteral drug is not available in an oral dosage form, lhe oral formulation is poorly tolerated or absorbed, or there is another objective clinical rationale for this procedure.We should recognize thal prescribers generally prefer lo continue therapy with the same drug which was producing therapeutic results favourable enough to warrant stepdown lo lhe oral dosage fom1 in lhe first place.
The ideal stepdown agenl should also have recognized activity against the pathogen(s) in question and should be supported by clinical trials demonstrating the utility of thal agent for lhe treatment of lhe infection in question.To facilitate good patient compliance, the drug should be available in several dosage forms (eg, tablets, capsules, solution or suspension) lo ensure stepdown is not limited by an inability lo tolerate solid dosage forms.
The ideal stepdown drug should be completely absorbed with no absorption-related drug interactions (eg, tetracyclines and quinolones with antacids).Pa-Lient tolerance to the oral roule of administralion is a critical determinant of successful therapy.The ideal stepdown agent should have minimal side effects including gastrointestinal complaints.The ideal agent should possess a pharmacological profile which per- Stepdown therapy mits infrequent administration (ie, Jess than U1ree doses daily).Finally.this drug must be relatively inexpensive.If a patient is to be discharged from U1e hospital on an oral anli-infective, the cost of therapy may now be borne directly by that individual.When efficacy and toxicity are considered equivalent, cost must be the determinant of drug choice.Figure 2 provides an illustration of the variability of drug acquisition costs for various oral antibiotic regimens in Canada.Clinicians must be cognizant of these disparities to ensure U1e most cost-effective regimen is prescribed.

ANTI-INFECTIVE AGENTS BY DOSAGE FORM
In Canada there are about as many anti-infective agents available with intravenous and oral dosage formulations as there are agents willi an intravenous formulation only (Table 2).In addition, there are several oral agents available which could be considered as acceptable oral stepdown drugs for parenteral agents of the same or different classes.Hence, many potential iv-po combinations are possible when stepdown is being considered.

BIO AVAILABILITY
When conside1ing switching from a parenteral to an oral agent, we introduce a new pharmacokinetic variable which was not.an issue when U1e intravenous route of administration was being used.Bioavailability generally refers to the fraction of an oral dose which actually reaches the systemic circulation following oral ingestion (6).Drugs can differ in their rate and completeness of absorption from Lhe gastrointestinal tract.Absorption can be influenced by patient factors such as motility of the gastrointestinal tract.. blood flow to the sile of absorption and the presence of various malabsorption syndromes.Drug absorption is also significantly influenced by drug properties.Dissolution of U1e dosage form.drug solubility and potential for a 'firstpass effect' (ie.metabolism of drug by gastroinleslinal or hepatic enzymes) are several factors which affect bioavailability.Coadministration of lhe drug willi food or oilier drug products (both prescription and nonprescription) can also have a significant impact on the actual bioavailability of an anti-infective under 'real life' conditions.

ANTI-INFECTIVE DRUGS GROUPED BY BIO AVAILABILITY
The bioavailability of anti-infectives ranges widely, from as low as 10% lo as high as 95% or greater.Anli-infeclives can be stratified into three groups according to their average unimpeded reported bioavailability in adult patients.
Group 1 oral anti-infectives would include those agents for whom average bioavailability (typically determined by calculating the area under the concentrationlime curve (AUC) for the oral regimen and dividing this value by the AUC for the same dose given parenlerally) exceeds 80% when the drug is administered under conditions in which its absorption from the gastrointestinal tract is unimpeded (eg.not given in lhe presence of food or antacids).This parameter is usually determined in healthy fasting adults under controlled experimental conditions.Figure 3 illustrates some representative group 1 agents.For each drug, a minimum, maximum and average reported bioavai lability is provided.The minimum value represents the estimated bioavailability when the drug is administered in the presence of food or other drug produ ts (eg, antacids) which may interfere with absorption from the gastrointestinal tract.There are at least 12 anli -infectives available in Canada with greater than 80% average unimpeded bioavailability.For several of these agents (eg, cefaclor, metronidazole) bioavailability is quite predictable.For others such as doxycycline and ofloxacin.bioavailability is highly dependent upon lhe conditions of administration.Tetracyclines form insoluble chelates with polyvalent metals including aluminum, calcium.iron.magnesium, zinc and others.Co-administration with food or drug products containing these substances can markedly reduce oral absorption.The inhibitory effect of food and milk on the absorption of doxycycline tends, however.to be Jess than that oft.elracycline (7) .The oral absorption of ofloxacin and other quinolones is also affected by the concomitant administration of divalent cations.The result can be a dramatic decrease in the peak antimicrobial blood levels achieved, as well as a marked reduction in the AUC (8).
Although bioavailability of clindamycin is generally considered very good , Gatti and colleagues (9) have recently reported findings which suggest that.a reevaluation may be wa1Tanted.In a crossover design study involving 16 healthy volunteers and 16 patients with AJDS, these investigators found an average absolute bioavailability (Aucpo/ AUCiv) of only 53%±14% and 75%±20%.respectively.This study is important.for al least two reasons.ll is the first determination of oral clindamycin bioavailabilily using a specific assay (ie, gas-liquid chromatography versus a a crossover Since clindamycin microbiologically active metabolites, previous studies using bioassays would have been unable to distinguish between parent drug and active breakdown products.In addition, lhis study reconfirms lhat disease slates can have an apparent influence on drug disposition.AJDS patients in this study demonstrated a higher bioavailability, higher peak blood concentration, a lower volume of distribution and reduced drug clearance compared with their healthy counterparts.The clinical significance of these findings for clindamycin is yet unknown, but it is critical to recognize that there will be inter-and inlrapatient variability in drug disposition whenever one contemplates iv lo po stepdown therapy. Figure 4 shows six anti-infective agents wilh an average unimpeded bioavailabilily of 51 to 80%.Again.bioavailability is quite predictable for some agents (eg, penicillin V and cloxacillin).while quite variable for others (eg, ciprofloxacin and tetracycline).For these group 2 agents it.is possible to achieve blood concentrations similar to t.hal obtained with the parenteral formulation only if a larger oral dose is administered.
Group 3 oral anti-infectives are shown in Figure 5.For these agents bioavailability is so low that we generally cannot expect to achieve blood concentrations equivalent lo those obtained from the parenteral formulations (when available).
Nevertheless, il is possible to stepdown from iv lo po dosage forms with these agents without adversely effecting treatment course out.come.We recently reported our experience with the implementation of a standardized acyclovir prophylaxis protocol for the prevention of herpes simplex virus (HSY) infection and disease in bone marrow transplant and leukaemic patients (10).Under this protocol, patients received an acyclovir regimen of 125 mg/m 2 iv or 600 mg po every 6 h for approximately 35 days duration.Patients were assessed dally and switched from iv to po therapy if oral tolerance criteria were met.With this protocol, the incidence of parenteral therapy without oral stepdown dropped from 1 7% to 0% of treatment courses.A cost savings of approximately $1112.00 per patient was realized without evidence of any negative impact on treatment course outcome.

SERUM ELIMINATION HALF-LIVES OF SOME COMMON ANTI-INFECTIVE AGENTS
The serum elimination half-life has traditionally played a role in determining the frequency of administration of the anti-infective.In general, the longer the elimination half-life, the longer the recommended interval between doses .Unfortunately, this relationship has not always been carefully considered and we have historically adopted dosing regimens which are not well supported by the pharmacological properties of the drug.For example, we have been prescribing some drugs with extended elimination half-lives (eg, melronidazole, 7 to 8 h) in regimens of three to four doses daily.which is probably more oft.enthan is necessary.Con-versely, there are some short.elimination half-life drugs (eg penicillin, 0.5 h) which we prescribe at 6 h intervals which is equivalent to 12-fold their half-lives.Needless lo say. the optimal regim en for these agents must.take into consideration the p h armacological profile of the drug including the serum elimination half-life, the existence and characteristics of active metabolites, post-antibiotic effects and other patient (eg, immunocompetence) and microbiological fact.ors.
Although the relationship between serum elimination half-life and dosing intervals may be less important for drugs which demonstrate a concentration-dependent kill (eg, aminoglycosides).it appears to be relevant for beta lactam agents.Beta-lactan1s tend to exhibit a time dependent kill and it has been generally accepted that maintaining serum concentrations at or near the minimum inhibitory concentration may be most desirable (11)(12)(13).
Figure 6 illustrates the average serum elimination half-lives for various oral anti-infective agents in healthy adults with normal renal and function.The majority of oral beta-lactams have elimination halflives in the range of 0.5 to 3 h.Quinolones tend to demonstrate elimination half-lives in the 3 to 7 h range, while cotrimoxazole and metronidazole exhibit the longest serum elimination half-Jives of our older oral antimicrobial drugs.Newer macrolides (ie, clarithromycin and azithromycin) exhibit elimination half-lives in the 6 to 12 h range.Azithromycin actually undergoes extensive tissue distribution and the terminal serum elimination half-life is dependent on U1e time interval being examined.When serum concentrations are assessed during the first 24 h following oral administration, the serum elimination half-life ranges from 11 to 14 h.When concentrations are assessed for a longer period of time (eg, 12 days).the serum elimination half-life is approximately five days ( 14).

PHARMACOKINETIC CHARACTERISTICS OF ORAL CEPHALOSPORINS
A comparison of the pharmacokinetic characteristics of oral cephalosporins is shown in Table 3.There are five oral cephalosporins currenUy available in Canada.This includes two first generation agents (cephalexin and cefadroxil).two second generation agents (cefaclor and cefuroxime axetil) and one third generation agent (cefixime).These designat.ionshave been made based upon the relative spectrum of antimicrobial activity of these agents.While the oral absorpt.ion of cephalexin, cefadroxil and cefaclor is very good (group 1 drugs).cefuroxime axetil and cefixime demonstrate generally poor absorption from the gastrointestinal tract (group 3 drugs).Cefuroxime axetil is rapidly hydrolyzed to cefuroxime by nonspecific est.erases in the intestinal mucosa and blood.The absorption of this drug is actually improved by coadministration with food.Cefixime has the longest serum elimination half-life of all available Stepdown therapy Figure 6 ) Serum elimination ha/f-life of various oral antimicrobials oral cephalosporins and can be administered once or twice daily.Food and antacids do not appear to influence the bioavailability of this drug (15).
The newer (and as of yet unavailable) oral cephalosporins possess pharmacokinetic characteristics not loo dissimilar to those already available (16).Cefpodoxime proxeW and cefetamet pivoxil demonstrate absorption problems similar to cefuroxime axetil and ceflxime.None of the never agents provide serum concentrations significantly higher than the older agents and none are in the range of that achievable with parenteral formulation.However, the in vitro act.ivity of these agents against many of our common pathogens is often superior to earlier drugs.The serum elimination half-lives of these newer agents are similar to existing agents.Janknegt and van der Meer (17) recenUy reviewed these agents and identified that the period per 24 h during which the serum concentrat.ionexceeds the minimum inhibitory concentration (M 1 c50 in this case) for various pathogens is longer for newer oral cephalosporins, such as cefpodoxime and cefetamet, than older agents , such as oral or parenteral cefuroxime.Activity against Staphylococcus aureus, however, is limited for these newer agents and clinicians must be cautious if contemplating stepdown from a parenteral second or third generation cephalosporin.Whether the new oral cephalosporins will have a significant clinical advantage over our existing oral stepdown armamen-1.ariumwill need to be confirmed in carefully controlled trials.Perhaps future investigation should not only include the identification of better tolerated agents with improved activity against clinically relevant pathogens, but also investigation into the production of sustained release oral beta-lactam formula.I.ions which can be taken once daily and produce predictable, constant blood concentrations above the MIC of these pathogens.

COMPLIANCE AND TREATMENT REGIMEN COMPLEXITY
Probably one of the most significant determinants of successful oral anti-infective therapy is patient compliance.The best drug in the world is useless if the patient  We should keep this observation in mind when prei v to stepdown, regardless of who (ie, patient or nurse) is responsible for administering the medication.

SUMMARY
Parenteral to oral stepdown therapy represents an effective cosl containment strategy which can minimize intravenous therapy associated morbid ity and may facilitate earlier hospital discharge.Several oral anti-infectives are available lo the prescriber and there are as many opportunities to stepdown lo lhe same agent as there are lo other drugs of lhe same class or other classes.Recognition of lhe pha.rmacokinetic characteristics of these oral agents is essential lo successfu l therapy.Good b ioavailability may not always be assured.A simple regimen will promote compliance.A quote from Plateus (BC 254-184) reads: " ... in everything the middle course is best; al l things in excess bring trouble to men ... ", a ph il osop hy which should probably apply lo iv to po stepdown as well.

Figure 2 )
Figure 2) Examples of oral antibiotic daily costs.*Generic brand available.BC Alpha Pharmaceutical Supplies 1993 Price Boole (generic prices used when available}

TABLE 2 Anti-infective agents by dosage form
iv Intravenous: po Oral; 1 Oral form used for Clostridium difficile-associated diarrhea (not absorbed):2Ampicillin prodrugs

TABLE 3 Pharmacokinetic characteristics of oral cephalosporins ~gent/ dose
Data represents typical adult normal renal function values derived from Smith GH.Drug Intel!Clin Pharmacy 1990.Lode H e t al. Drugs 7994.and others.PPB Plasma protein binding is unable or unwilling to adhere to the prescribed dosing schedu le.Using microprocessors in lhe caps of pill bottles.Cramer and associates ( 18) demonstrated lhal compliance rates were 81 % wilh a twice daily regimen versus 39% with a four times daily schedule.