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ROXITHROMYCIN - ERYTHROMYCIN COMPARISON
PATIENT DATA/BACKGROUND:
Please compare the pharmacokinetics, spectrum of activity, drug
interactions and dosing, between roxithromycin and erythromycin.
RESPONSE:
Roxithromycin is an acid-stable macrolide antibacterial agent
structurally related to erythromycin. Roxithromycin has antibacterial
activity similar to that of erythromycin, but reportedly as superior
pharmacokinetic properties.
COMPARATIVE PHARMACOKINETICS
Roxithromycin is more acid-stable than erythromycin, and achieves
higher serum concentrations at equimolar oral doses. The half-life of
roxithromycin is also longer than that of erythromycin (10 to 12
hours versus 1.5 to 3 hours) (Nilsen, 1987; Puri & Lassman, 1987;
Young et al, 1989).
Following oral administration roxithromycin 150 milligrams, mean
peak plasma levels of 6.6 to 7.9 mcg/mL are achieved in 1 to 3
hours (Nilsen, 1987; Young et al, 1989) with doses of 300
milligrams orally, peak levels have ranged from 9.1 to 10.8 mcg/mL
(Young et al, 1989). In comparison, peak serum levels following
erythromycin stearate 500 milligrams orally have ranged from 0.5 to
2.9 mcg/mL, within 1 to 3 hours (Nilsen 1987; Kees et al, 1988).
The area under the plasma concentration-time curve following
roxithromycin 150 milligrams orally is approximately 8 to 10 times
of that achieved following oral erythromycin base or stearate 500
milligrams, suggesting improved bioavailability and/or a lower
clearance of roxithromycin. Tissue distribution of each drug is
similar, although serum protein binding of erythromycin is lower
than that of roxithromycin. Roxithromycin is bound extensively and
saturably to alpha-1-acid-glycoprotein, and significantly increases
free roxithromycin serum concentrations, which are observed when
roxithromycin total serum concentrations exceed 4 mcg/mL
(increase in free concentration from 4.3% to 13.4% when total
serum levels rise from 3.3 to 8.4 mcg/mL). The binding of
erythromycin to alpha-1-acid-glycoprotein exhibits a similar
saturation phenomena, however the pharmacokinetic and clinical
consequences of this binding are less than that observed
roxithromycin, attributable to the lower degree of serum protein
binding of erythromycin (Nilsen, 1987).
Roxithromycin is not metabolized extensively, is excreted primarily
unchanged, and does not interfere with hepatic microsomal enzyme
systems (Periti & Mazzei, 1987; Delaforge et al, 1988; Puri &
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Lassman, 1987). Following roxithromycin 150 milligrams, 74% of
the dose was accounted for, with fecal excretion, pulmonary
excretion, and urinary excretion being 53%, 13%, and 7%,
respectively (McLean et al, 1988). In contrast, erythromycin
interacts with the cytochrome P-450 enzyme system, which can
result in potential drug interactions (Young et al, 1989). A
considerable portion of an oral dose of erythromycin is eliminated in
the feces; 2% to 5% of an oral dose and 12% to 15% of an
intravenous dose is eliminated in the urine (AMA, 1986).
COMPARATIVE DOSING
Based upon available pharmacokinetic data, roxithromycin 150
milligrams orally twice daily or 300 milligrams once daily should
produce plasma concentrations above the minimum inhibitory
concentrations required for antibacterial activity (Nilsen, 1987; Puri
& Lassman, 1987).
In infants and children, the recommended dose of roxithromycin is
2.5 to 5 milligrams/kilogram orally twice daily (Young et al, 1989).
For erythromycin, the recommended dose in children is 30 to 50
milligrams/kilogram/day, in 4 divided doses (AMA, 1986).
Some evidence exists suggesting that bacteriological cure rates are
inadequate with once-daily dosing (Herron, 1987), and more clinical
trials are required before a once-daily dosing regimen can be
recommended. The recommended dose or erythromycin is 250 to
500 milligrams every 6 hours for the base, estolate, and stearate;
doses of 400 to 800 milligrams 4 times daily are recommended for
the ethyl succinate (AMA, 1986). However, lower doses of
erythromycin have been employed clinically (ie, 500 milligrams
every 12 hours), and comparative clinical trials are required to
determine advantages of the superior pharmacokinetic profile of
roxithromycin over erythromycin in the clinical setting.
Dosing adjustments of roxithromycin are not required in the elderly
or in patients with renal insufficiency (Puri & Lassman, 1987;
Young et al, 1989; Nilsen, 1987). Although some investigators
indicate that dosing adjustments are not required in patients with
hepatic disease, including severe cirrhosis (Puri & Lassman, 1987;
Periti & Mazzei, 1987), others suggest dose reductions to 150
milligrams orally once daily in patients with severe cirrhosis, due to
the 2-fold increase in half-life observed in these patients (Young et
al, 1989). Erythromycin may also be given without dosing
adjustments in the elderly and in patients with renal impairment and
alcoholic liver disease (Nilsen, 1987). However, some sources
suggest that caution should be exercised in patients with impaired
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hepatic function, since erythromycin is excreted primarily by the
liver (AMA, 1986).
COMPARATIVE ANTIBACTERIAL ACTIVITY
The antibacterial spectrum of roxithromycin is similar to that of
erythromycin (Jones et al, 1983; Rolston et al, 1986; Young et al,
1989; Barlam & Neu, 1984). Both agents have similar minimum
inhibitory concentration values for gram-positive organisms,
including staphylococci, Streptococcus pneumoniae, Streptococcus
pyogenes, and Bacillus cereus, and Corynerbacterium spp (Young et
al, 1989; Pechere & Auckenthaler, 1987). Similar activity has also
been observed between the 2 agents against Neisseria gonnorrhoeae,
Neisseria meningitidis, and Branhamella catarrhalis (Young et al,
1989). Both agents are similarly active against anaerobic organisms,
including Bacteroides spp (except Bacteroides fragilis) (Dubreuil,
1987; Young et al, 1989). Isolates of Chlamydia and Mycoplasma
are also susceptible to roxithromycin, with minimum inhibitory
concentration values (MIC-90) being similar to that observed with
erythromycin (Young et al, 1989). Both erythromycin and
roxithromycin are relatively inactive against the Enterobacteriaceae
(Young et al, 1989; Jones et al, 1983). Legionella pneumophila is
susceptible to both erythromycin and roxithromycin (MIC-90, 1
microgram/milliliter) (Young et al, 1989). Some studies suggest
superior in vitro activity of roxithromycin over erythromycin against
Legionella pneumophila (Hara et al, 1987), however, this is of
doubtful clinical relevance. Serum concentrations of roxithromycin
of less than 2 micrograms/milliliters inhibit most susceptible
organisms, and these concentrations are easily maintained following
doses of 150 milligrams orally every 12 hours (serum levels of 2.5
mcg/mL observed after 12 hours with this schedule). Most bacterial
strains resistant to erythromycin are also resistant to roxithromycin
(Young et al, 1989).
COMPARATIVE EFFICACY
In limited clinical trials, roxithromycin has been as effective as
erythromycin in the treatment of upper and lower respiratory tract
infections (Bertrand et al, 1988; Gentry, 1987; Herron, 1987;
Melcher, (1987). Overall, roxithromycin 150 milligrams orally
twice daily for 10 days has been effective in treating lower
respiratory tract infections, eyes, nose, and throat infections,
genitourinary infections, and skin and soft tissue infections,
producing clinical cures in 83% to 100% of patients. Clinical cure
rates of 92% to 100% have been observed in pediatric patients with
a variety of infections employing roxithromycin 2.5 to 5
milligrams/kilogram every 12 hours (Young et al, 1989).
 In 1 single-blind study involving 227 patients, roxithromycin 150
milligrams orally twice daily was comparable to erythromycin ethyl
succinate 400 milligrams orally 4 times daily in treating
streptococcal throat infections (Herron, 1987). A satisfactory
clinical response was observed in 83% and 88% of patients,
respectively. Bacteriological cure was seen in 88% and 92% of
patients treated with roxithromycin and erythromycin, respectively.
In this study, roxithromycin 300 milligrams once daily was also
administered in randomized fashion, resulting in a satisfactory
clinical response in 87% of patients treated; however, the
bacteriological response rate was 84%, which was significantly less
than that with erythromycin.
 COMPARATIVE TOXICITY
 As with erythromycin, the most common adverse effects observed
with roxithromycin include nausea, vomiting, abdominal pain, and
diarrhea, each occurring in approximately 1% of patients treated
(Blanc et al, 1987). The comparative incidence of adverse effects
with erythromycin and roxithromycin is difficult to ascertain with
available data. However, collective results of several studies have
indicated a similar incidence of adverse effects, ranging from 2% to
14% with roxithromycin and 3% to 15% with erythromycin ethyl
succinate (Gentry, 1987). In 1 single-blind study involving 227
patients with throat infections, the incidence of adverse reactions
(primarily gastrointestinal in nature) was less with roxithromycin
150 milligrams orally twice daily as compared to erythromycin ethyl
succinate 400 milligrams orally 4 times daily (Herron, 1987).
Abnormalities in hepatic function tests have been observed in less
than 1% of patients treated (Blanc et al, 1987). No cases of hepatitis
have been observed to date with roxithromycin. Lymphopenia and
eosinophilia have been observed rarely (Young et al, 1989).
 DRUG INTERACTIONS
 Due to the apparent lack of effect of roxithromycin on the
cytochrome P-450 system, this agent is less likely than
erythromycin to produce drug interactions mediated via this enzyme
system (Delaforge et al, 1988). In available studies, roxithromycin
has produced only minimal effects on the pharmacokinetics of
theophylline (Saint-Salvi et al, 1987). In contrast, erythromycin
increased the half-life of theophylline by 10% to 20% in most
patients, as well as reducing theophylline oral clearance by 20% to
50% (Ludden, 1985). Roxithromycin also does not appear to affect
the pharmacokinetics of carbamazepine (Saint-Salvi et al, 1987).
Dosing adjustments of theophylline or carbamazepine do not appear
to be required when given in combination with roxithromycin
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(Surjus et al, 1985; Saint-Salvi et al, 1987). Other reports suggest
that roxithromycin does not interact with warfarin, ranitidine, or
antacids (Young et al, 1989).
CONCLUSION:
Roxithromycin is an acid-stable macrolide antibacterial agent
chemically related to erythromycin. The main advantages of
roxithromycin over erythromycin include a potentially superior
pharmacokinetic profile (higher serum concentrations, longer
elimination half-life) and a lower potential for drug interactions.
However, further clinical trials are required to compare these 2
agents and determine if the pharmacokinetic differences between
these 2 agents are clinically relevant. Although a lower incidence of
adverse reactions has been described with roxithromycin as
compared to erythromycin in 1 clinical trial, more studies are
required to determine if roxithromycin offers any advantage with
regard to adverse effects.
REFERENCES:
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3. Bertrand A, Caubarrere I, Chapman A et al: Multicentre
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emphasis on mycoplasma and Legionella. J Antimicrob Chemother
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9. Herron JM: Roxithromycin in the therapy of Streptococcus
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