Download Oral Absorption of Clarithromycin in Acute Illness

Oral Absorption of Clarithromycin in
Acute Illness and During Convalescence
in Patients With Community-Acquired
Pneumonia*
Elliot Offman, BScPhm; Frances Varin, PhD; Tom Nolan, MD;
Charlie D. Bayliff, PharmD; Anne Marie Bombassaro, PharmD; and
Dave G. McCormack, MD, FCCP
Study objective: To compare the extent of oral clarithromycin absorption in patients during an
illness and in health.
Design: Sequential two-phase prospective study including an acutely ill pneumonia phase (PP)
and a subsequent convalescent phase (CP).
Study population: Patients > 18 years old with radiographically confirmed community-acquired
pneumonia (CAP) who were admitted to the hospital.
Methods: During both study phases, patients received one single 500-mg dose of oral clarithromycin. Serial blood samples were drawn over a 24-h period in order to characterize the plasma
concentration-time curves. Area under the curve from zero to 24 h (AUC0 –24), maximum plasma
concentration (Cmax), and time to maximum concentration (Tmax) were determined for both
clarithromycin and its metabolite, 14-hydroxyclarithromycin, and compared between the two phases.
Results: Twelve patients completed both phases of the study. For clarithromycin, there was a
significant increase AUC0 –24 (47.37 ⴞ 8.51 ␮g/h/mL vs 36.22 ⴞ 6.09 ␮g/h/mL) in favor of the PP.
There were no significant differences detected with respect to Cmax (4.32 ⴞ 0.63 ␮g/mL vs
3.57 ⴞ 0.46 ␮g/mL), or Tmax (3.50 ⴞ 0.50 h vs 2.83 ⴞ 0.59 h) between PP and CP. For 14hydroxyclarithromycin, the AUC0 –24 and Cmax were significantly higher (5.84 ⴞ 1.08 ␮g/h/mL vs
8.84 ⴞ 1.92 ␮g/h/mL; 0.42 ⴞ 0.08 ␮g/mL vs 0.76 ⴞ 0.23 ␮g/mL) in the CP as compared to the PP.
Tmax remained unchanged.
Conclusion: The extent of absorption of oral clarithromycin was not diminished during an acute
illness with CAP.
(CHEST 2000; 117:1090 –1093)
Key words: acute illness; clarithromycin; community-acquired pneumonia; pharmacokinetics
Abbreviations: AUC ⫽ area under the curve; AUC0 –24 ⫽ area under the plasma concentration vs time curve from zero to
24 h; CAP ⫽ community-acquired pneumonia; Cmax ⫽ maximum plasma concentration; CP ⫽ convalescent phase;
PP ⫽ pneumonia phase; Tmax ⫽ time to maximum concentration
rationale for the administration of anA common
tibiotics via the IV route, rather than the oral
route, is the concern that there may be a diminished
ability to absorb medications when the patient is
acutely ill. 1 Usually, patients admitted to the hospital
for the treatment of community-acquired pneumonia (CAP) are initially treated with IV antibiotics and,
once the acute stage of their illness has passed, are
*From the London Health Sciences Centre, London, Ontario,
Canada.
Supported by a grant from Abbott Laboratories, manufacturer of
clarithromycin.
Manuscript received February 4, 1999; revision accepted December 21, 1999.
Correspondence to: Dave G. McCormack, MD, FCCP, London
Health Sciences Centre, 375 South St, London, Ontario, Canada
N6A 4G5; e-mail: [email protected]
then converted to oral antibiotic therapy.2 While
undoubtedly ensuring delivery, the use of IV antibiotics is potentially associated with decreased patient
mobility, increased patient discomfort, increased
length of stay, increased treatment costs, and an
increased risk of catheter-associated infections.2,3
Clarithromycin is a broad-spectrum, oral, macrolide antibiotic that has in vivo antibacterial activity
against many of the pathogens associated with
CAP.4 – 6 According to published guidelines, macrolides are among the drugs used for first-line therapy
for many patients with CAP.5,6 In small, randomized
clinical trials, the combination of oral clarithromycin
and IV cefuroxime has compared favorably to the
combination of IV erythromycin and IV cefuroxime.7,8 The oral clarithromycin combination of-
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Clinical Investigations
fered some advantages with respect to clinical cure,
microbiologic cure, and cost of treatment.8
The objectives of this study were to determine the
impact of acute illness with CAP on the extent of oral
absorption of clarithromycin, and to compare it to
the extent of oral absorption in health.
Material and Methods
This was a two-phase prospective study, whereby hospitalized
patients participated in an acute illness phase termed the pneumonia phase (PP), and a convalescent phase (CP). The PP of this
study included patients ⱖ 18 years old who were enrolled within
36 h of admission to hospital, and had a diagnosis of pneumonia
based on clinical and radiographic findings. Patients were excluded from the study if they were unable to sign informed
consent; had a documented GI malabsorption syndrome; were
pregnant or lactating; had excessive nausea or vomiting; had a
known allergy to clarithromycin or other macrolide antibiotics;
had known hepatic or end-stage renal disease; or had completed
a course of a macrolide antibiotic within 2 weeks prior to
admission. Patients were then asked to return for the second
phase of the study (CP), a minimum of 2 weeks after hospital
discharge for their pneumonia. Using a standard drug interaction
text,9 all medications at enrollment were assessed for the potential to interact with clarithromycin. Medications that could
potentially impede the absorption, or affect the plasma concentration of a single oral dose of clarithromycin were held for the
study period. If it was not feasible to hold these medications,
patients were excluded from the study.
On enrollment to the PP, patients were evaluated for their
severity of illness, using a previously published prediction rule to
identify risk of mortality of patients with CAP.10,11
After obtaining informed consent, patients received one single
oral dose of clarithromycin, 500 mg, in addition to antibiotic
therapy for CAP, prescribed at the discretion of the attending
physician. Antibiotic therapy for CAP did not include a macrolide
antibiotic, and generally consisted of IV cefuroxime, 750 mg q8h.
Patients had no oral intake for approximately 6 h before and 4 h
after the dose. Blood samples were obtained in heparinized tubes
either by direct venipucture, or via a catheter inserted into the
antecubital vein, immediately prior to the dose, and 1, 2, 3, 4, 8,
12, 16, and 24 h after administration of the dose. Plasma was
separated, and stored at ⫺ 20°C until assayed for concentrations
of clarithromycin and its metabolite, 14-hydroxyclarithromycin.
When the patients returned for the CP of the study, a second
single oral dose of clarithromycin, 500 mg, was administered, and
serial blood samples were obtained at the same time points as
previously stated. As with the PP, patients had not received
clarithromycin within 2 weeks prior to the CP.
Plasma samples were assayed using a high-performance liquid
chromatographic technique described elsewhere.12 The lower
limit of detection of this assay is 0.03 ␮g/mL using 0.5 mL of
plasma.12 The calibration curves for the determination of clarithromycin and its metabolite were found to be linear in the
range of 31.25 to 6,000 ng/mL and 7.8 to 1,000 ng/mL, respectively, with consistent slopes and correlation coefficients (r2
ⱖ 0.9927) throughout the validation runs. Inter-day assay variability was ⱕ 6.4%, and intra-day assay variability was ⱕ 7.2% for
all standards evaluated. The mean accuracy was 102%. The mean
recovery was found to be 97% for clarithromycin and 92% for
14-hydroxyclarithromycin.
The study protocol was approved by the University of Western
Ontario Review Board for Health Sciences Research Involving
Human Subjects, London, Ontario, Canada. Written informed
consent was obtained from all patients prior to enrollment.
Data Analysis
The goal of the study was to show that the area under the
plasma concentration vs time curve from zero to 24 h (AUC0 –24)
was not statistically different between the CP and PP.13,14 Assuming an ␣ error of 0.05 at 80% power, eight patients were required
per arm to achieve statistical significance.4,15–18 A difference of
⬍ 30% in plasma concentration of clarithromycin (or metabolite)
was believed to be acceptable, as this generally yields plasma
concentrations above the minimum-inhibitory concentration 90%
(MIC90) for the majority of pathogens typically causing CAP.4,16,17
Plasma concentration-time curves were plotted to assist in
determining AUC0 –24, which was calculated using the linear
trapezoidal rule. Individual maximum plasma concentration
(Cmax) and time to maximum concentration (Tmax) values were
determined by visual inspection of the plasma concentration data.
The primary endpoint of AUC0 –24 (in micrograms per hour per
milliliter) and the secondary endpoints of Cmax (in micrograms
per milliliter) and Tmax (in hours) were compared between the
PP and CP by using a computer statistics program.19 Normality of
the data distribution was assessed using a Kolmogorov-Smirnov
test. For data that passed the normality test, comparison between
the two groups was done using two, one-tailed t tests. By setting
the significance level at 10% for the two-tailed paired t test, the
probability of accepting the null hypothesis of no difference is
reduced, and therefore provides a more stringent means of
providing evidence that the two groups are in fact similar. This
would be analogous to using two, one-tailed t tests at the 5%
level. Data that failed the normality test were compared using the
Wilcoxon signed rank test. As the two-tailed significance level was
set at 10% for this comparison, a value of p ⬍ 0.05 was considered to be significant. Results are reported as mean ⫾SEM.
Results
Eight male and four female patients (mean age,
77 ⫾ 2 years) participated in both phases of the
study, and were included in the analysis. The mean
weight of the subjects was 64 ⫾ 5 kg, and the mean
creatinine clearance was 49 ⫾ 6 mL/min. As previously mentioned, all patients included in the study
were evaluated on admission for severity of illness
using a prediction rule for identifying risk of patients
with CAP.10,11 The 12 patients enrolled in the
present study had a mean ⫾ SEM severity of illness
score of 101.5 ⫾ 6.9, suggesting that they were at
high risk for mortality, and therefore acutely ill. The
mean values of clarithromycin and its metabolite for
AUC0 –24, Cmax, and Tmax of both the PP and CP
are reported in Tables 1, 2. With respect to clarithromycin, the AUC0 –24 was greater in the PP than in
Table 1—Pharmacokinetic Parameters of
Clarithromycin for Patients during PP and CP*
Group
AUC0–24, ␮g/h/
mL
Cmax, ␮g/mL
Tmax, h
PP
CP
p value
47.37 ⫾ 8.51
36.22 ⫾ 6.09
0.075
4.32 ⫾ 0.63
3.57 ⫾ 0.46
0.231
3.50 ⫾ 0.50
2.83 ⫾ 0.59
0.368
*Data are presented as mean ⫾ SEM unless otherwise indicated.
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Table 2—Pharmacokinetic Parameters of 14-OH
Clarithromycin for Patients During PP and CP*
Group
AUC0–24, ␮g/h/mL
Cmax, ␮g/mL
Tmax, h
PP
CP
p value
5.84 ⫾ 1.08
8.84 ⫾ 1.92
0.033
0.42 ⫾ 0.08
0.76 ⫾ 0.23
0.027†
4.83 ⫾ 1.29
3.08 ⫾ 0.51
0.322†
*Data are presented as mean ⫾ SEM unless otherwise indicated.
†Data which was compared by nonparametric statistical test (Wilcoxon signed rank).
the CP (p ⫽ 0.075). There were no differences
detected between the two phases for Cmax and
Tmax. With respect to the metabolite 14-hydroxyclarithromycin, a significant difference in AUC0 –24
and Cmax was detected between the two groups in
favor of the CP. There was, however, no difference
detected between the two phases for Tmax. Figures
1, 2 depict the mean ⫾ SEM plasma concentration
of clarithromycin and its metabolite at each sampling
time vs time for both the PP and CP.
Discussion
This study demonstrates that the extent of clarithromycin absorption is altered in patients who are
acutely ill with CAP when compared to the same
patients following their convalescence. The presence
of active CAP appears to significantly increase the
AUC0 –24 of clarithromycin, when a single oral dose
of clarithromycin is administered. However, active
CAP appears to decrease the AUC0 –24 and Cmax of
the metabolite, 14-hydroxyclarithromycin.
The results of this trial are supported by two other
studies examining the impact of acute illness on the
pharmacokinetic parameters of oral antibiotics.
Figure 1. Plasma concentration of clarithromycin vs time following administration of single oral dose in patients acutely ill
with pneumonia and following convalescence.
Figure 2. Plasma concentration of 14-hydroxyclarithromycin vs
time following administration of single oral dose in patients
acutely ill with pneumonia and following convalescence.
Dean et al20 assessed the absorption of a single
500-mg dose of cephalexin in patients who were
acutely ill, and compared this to the absorption of
patients who were hospitalized but not acutely ill.
Results showed no significant differences between
the two groups of patients in Cmax or Tmax of
cephalexin. There was a slightly delayed urinary
excretion time and an increased half-life in the
acutely ill group; however, this difference did not
reach statistical significance.
Guay et al21 determined the pharmacokinetic parameters after multiple doses of ciprofloxacin in
elderly patients during an acute illness. Thirteen
patients were evaluated for area under the curve
(AUC), peak serum concentration, clearance, terminal half-life, and volume of distribution at the beginning of their illness, and again during their convalescence. There were no significant differences
detected in any of these parameters between the two
phases. There was, however, a trend toward an
increased peak serum concentration in the convalescent phase, and a trend toward an increased AUC in
the acutely ill phase. In our study, there was an
increased AUC0 –24 in the acutely ill phase, which is
similar to what Guay et al21 observed.
Unlike the previously mentioned studies, a significant difference was, in fact, detected between the
two groups with respect to AUC. This, along with a
lower AUC0 –24 of the major metabolite in the PP
compared to the CP may indicate that clearance of
the parent compound may be altered or delayed in
the acute phase of an illness such as pneumonia.
There was a trend to this seen in the earlier described study by Dean et al,20 which is similar to our
observations. Changes in renal clearance are less
likely to be involved given the small proportion of
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Clinical Investigations
clarithromycin that is cleared renally (approximately
30%).4 Davey22 reported that there is a progressive
increase in serum concentrations of clarithromycin
and 14-hydroxyclarithromycin with renal impairment
(defined as a glomerular filtration rate ⬍ 30 mL/
min). As none of our patients had documented renal
disease, changes in renal clearance accounting for
the changes in AUC0 –24 are most unlikely.
Clarithromycin undergoes extensive first-pass hepatic metabolism, and as there may be altered or
slowed blood flow in an acute illness, it may be
accompanied by a decrease in first-pass metabolism
of the parent compound, and a decreased generation
of the metabolite.17 The result, a decrease in the
metabolism of clarithromycin, would be both an
increase in serum level of the parent compound and
a decrease in the serum level of the metabolite. The
implications of a decrease in the generation of the
active metabolite are unknown. However, if it were
simply a delay, an equivalent AUC would be
achieved after repeated dosing.
With respect to this study, an important point to
consider is the effect of concomitant medications on
the pharmacokinetics of clarithromycin. As mentioned, medications that were known to affect gut
motility, or have an effect on the pharmacokinetics of
clarithromycin, were held during the dosing period.
In the convalescent phase, one patient insisted on
smoking cigarettes, of which the effect on clarithromycin is not known.
In this study, there was significant interindividual
variability in the results. Reasons for this can include
a small sample size, but more importantly a large
variability in the concomitant disease states found in
the subjects. As it was difficult to enroll subjects
when their only reason for admission was CAP, there
tended to be a variety of other factors that could not
be controlled for in this particular study. Further
studies may be needed to evaluate the impact of
concomitant illness on the pharmacokinetic parameters of clarithromycin in CAP.
Current guidelines suggest the use of IV antibiotics
for a variable length of time, and the use of a second- or
third-generation cephalosporin in combination with a
macrolide antibiotic.2,5,6 This study suggests that the
bioavailability of oral clarithromycin for patients admitted to hospital for the treatment of CAP is adequate.
Conclusion
The oral absorption of clarithromycin is not impaired in patients who are acutely ill with CAP.
References
1 Jellett LB, Heazelwood VJ. Pharmacokinetics in acute illness.
Med J Aust 1990; 153:534 –541
2 Louie TJ. Intravenous to oral step-down antibiotic therapy:
another cost-effective strategy in an era of shrinking health
care dollars. Can J Infect Dis 1994; 5:45C–50C
3 Pittet D, Tarara D, Wenzel R. Nosocomial bloodstream
infection in critically ill patients: excess length of stay, extra
costs, and attributable mortality. JAMA 1994; 271:1598 –1601
4 Biaxin product monograph. Compendium of pharmaceuticals
and specialties. 34th ed. Ottawa, Ontario: Canadian Pharmacists Association; 1999
5 Niederman MS. Guidelines for the initial management of
adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy. American Thoracic Society Medical Section of the American Lung
Association. Am Rev Respir Dis 1993; 148:1418 –1426
6 Bartlett JG. Community-acquired pneumonia in adults:
guidelines for management. The Infectious Diseases Society
of America. Clin Infect Dis 1998; 26:811– 838
7 Gotfried MH, Killian A, Servi R, et al. Oral clarithromycin
versus intravenous erythromycin for the treatment of community-acquired pneumonia in hospitalized patients. Third
International Conference on the Macrolides, Azalides and
Streptogramins [abstract]. (poster) 1996
8 Skupien D, Margulis A, Kaczander N, et al. Randomized
comparative trial of the safety, efficacy and cost of intravenous
cefuroxime plus erythromycin vs. intravenous cefuroxime plus
oral clarithromycin in the therapy of community-acquired pneumonia. Third International Conference on the Macrolides,
Azalides and Streptogramins [abstract]. (poster) 1996
9 Horn J, Hansten P Drug interactions: analysis and management. Vancouver, WA: Applied Therapeutics, 1997
10 Fine MJ, Auble TE, Yealy SM, et al. A prediction rule to
identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243–250
11 Farr BM. Prognosis and decisions in pneumonia. N Engl
J Med 1997; 336:288 –289
12 Chu SY, Senello LT, Sonders RC. Simultaneous determination of clarithromycin and 14(R)-hydroxyclarithromycin in
plasma and urine using high-performance liquid chromatography with electrochemical detection. J Chromatogr 1991;
571:199 –208
13 Blackwelder WC. “Proving the null hypothesis” in clinical
trials. Control Clin Trials 1982; 3:345–353
14 Ware JH, Antman E. Equivalence trials. N Engl J Med 1997;
337:1159 –1161
15 Young MJ, Bresnitz E, Strom B. Sample size nomograms for
interpreting negative clinical studies. Ann Intern Med 1983;
99:248 –251
16 Nightingale C. The pharmacokinetic profile of clarithromycin. Infect Med 1997; 14(SupplC):8 –16
17 Langtry HD, Brogden R. Clarithromycin: a review of its
efficacy in the treatment of respiratory tract infections in
immunocompetent patients. Drugs 1997; 53:973–1004
18 Chu SY, Wilson D, Guay D, et al. Clarithromycin pharmacokinetics in healthy young and elderly volunteers. J Clin
Pharmacol 1992; 32:1045–1049
19 Glantz SA. Primer of biostatistics. 1992
20 Dean S, Harding L, Wise R, et al. Absorption and excretion
of cephalexin in health and acute illness. Eur J Clin Pharmacol 1979; 16:73–74
21 Guay DR, Awni W, Peterson P, et al. Pharmacokinetics of
ciprofloxacin in acutely ill and convalescent elderly patients.
Am J Med 1987; 82:124 –129
22 Davey PG. The pharmacokinetics of clarithromycin and its
14-OH metabolite. J Hosp Infect 1991; 19(SupplA):29 –37
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