Steady-state plasma and bronchopulmonary characteristics of clarithromycin extended-release tablets in normal healthy adult subjects

Mark H. Gotfried1,2,3, Larry H. Danziger3,4 and Keith A. Rodvold3,4,*

1 Pulmonary Associates and 2 School of Medicine, University of Arizona, Phoenix, AZ; Colleges of 3 Pharmacy and 4 Medicine, University of Illinois, 833 South Wood Street, Chicago, IL 60612, USA

Received 6 January 2003; returned 15 April 2003; revised 19 May 2003; accepted 2 June 2003


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: The steady-state concentrations of clarithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL). Concentrations of the major metabolite, 14-hydroxyclarithromycin, were also determined in plasma and AM.

Materials and methods: Forty-two healthy, non-smoking adult subjects (age: 18–54 years; 19 females, 23 males) received oral clarithromycin extended-release formulation (1000 mg once daily for five consecutive days). Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, 24 or 48 h after the last administered dose of clarithromycin. In addition, three subjects who did not take clarithromycin served as controls and underwent bronchoscopy at 0 h. Drug concentrations in plasma, ELF, and AM were determined by high-performance liquid chromatography.

Results: Clarithromycin was extensively concentrated in ELF [range of mean (±S.D.) concentrations: 6.38 ± 3.92 to 11.50 ± 6.65 mg/L] and AM (127.0 ± 61.5 to 573.8 ± 309.3 mg/L) than simultaneous plasma concentration (0.75 ± 0.31 to 2.22 ± 0.72 mg/L). The ranges of mean (±S.D.) concentrations of 14-hydroxyclarithromycin in plasma and AM were 0.52 ± 0.29 to 0.80 ± 0.31 mg/L and 22.1 ± 13.5 to 49.5 ± 16.2 mg/L, respectively.

Conclusions: Once-daily dosing of extended-release formulation clarithromycin 1000 mg produced significantly (P < 0.05) higher steady-state concentrations of clarithromycin in ELF (2–14 times) and AM (50–700 times) compared to simultaneous plasma concentrations throughout the 24 h period after drug administration. The 14-hydroxy metabolite of clarithromycin achieved significantly (P < 0.05) higher steady-state concentrations in AM (18–180 times) compared with concurrent plasma concentrations.

Keywords: pharmacokinetics, bronchoscopy, epithelial lining fluid, alveolar macrophages


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Clarithromycin is a macrolide antibiotic that has in vitro antimicrobial activity against typical (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) and atypical (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila) pathogens commonly associated with community-acquired lower respiratory tract infections.1 Compared with erythromycin, clarithromycin possesses greater acid stability, improved pharmacokinetic properties, and fewer gastrointestinal side effects.2 The recommended dosage regimen for these types of infections in adult patients is 250 to 500 mg twice daily of the immediate-release oral formulation of clarithromycin.3

An extended-release formulation of clarithromycin has recently become available for once-a-day oral therapy of upper and lower respiratory tract infections.48 The extended-release formulation of clarithromycin results in prolonged absorption of clarithromycin from the gastrointestinal tract after oral administration.9 Compared to an equal total daily dose of immediate-release clarithromycin tablets, the extended-release tablets produce a significantly lower and later steady-state plasma concentration of clarithromycin and its active metabolite, 14-(R)-hydroxy-clarithromycin (14-hydroxyclarithromycin). The systemic exposure (measured by the 24 h area under the concentration–time curve [AUC]) is similar for the two formulations.

No study has evaluated the impact of lower plasma concentrations associated with the extended-release formulation of clarithromycin on the intrapulmonary penetration of this antibiotic into epithelial lining fluid (ELF) and alveolar macrophages (AM). The objective of this study was to measure the steady-state concentrations of clarithromycin and 14-hydroxyclarithromycin in plasma, ELF and AM following the oral administration of extended-release tablets of clarithromycin to healthy, non-smoking adult subjects who underwent bronchoscopy and bronchoalveolar lavage (BAL) at selected sampling times.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study design and subjects

This was a Phase IV, multiple dose, non-fasting, open-label, single-centre study of clarithromycin extended-release formulation (Abbott Laboratories, Abbott Park, IL, USA). Non-smoking, healthy adult male and female subjects 18 years of age or older were considered eligible for this study. The definition used for non-smoking was no history of tobacco smoking within the last 12 months. Female subjects could not be lactating or pregnant. If a woman was of child-bearing potential, the subject must have had a negative pregnancy test and used a recommended method of birth control throughout the course of the study. All subjects were required to be within 10% of their acceptable range of weight according to height and frame tables of the Metropolitan Life Insurance Company.10 Exclusion criteria included evidence of significant organ dysfunction or conditions affecting drug absorption, history of drug or alcohol dependence, known hypersensitivity or intolerance to benzodiazepines, lidocaine, or macrolide agents, and concomitant treatment with drugs which might interact with macrolide agents (e.g. theophylline, carbamazepine, terfenadine). No over-the-counter or prescription medications were permitted during the study. The study was approved by the Institutional Review Boards of the investigators, and written informed consent was obtained from each subject before study entry.

Subjects randomized to clarithromycin extended-release formulation received five oral doses administered as 1000 mg (2 x 500 mg tablets) once daily. Complete physical examinations, medical histories, and laboratory review of serum chemistries and haematology from each enrolled subject were carried out before receiving study medications. Physical examinations and laboratory tests were repeated at the end of the study. Subjects received verbal and written instructions regarding the dosing schedule of their medication and were contacted daily by telephone to monitor compliance and to assess any adverse events.

Bronchoscopy and BAL

One standardized bronchoscopy with BAL was carried out once in each subject at 3, 6, 9, 12, 24 or 48 h after the last morning dose of clarithromycin was administered. For the subjects not receiving clarithromycin, bronchoscopy with BAL was conducted on the first day of the study. Blood pressure, heart rate, respiratory rate and pulse were recorded before, at the end of, and between 30 and 60 min after the bronchoscopy.

Two percent topical lidocaine was applied to the upper airway to prepare subjects for bronchoscopy. If needed, 0.5% lidocaine was used in the lower airway. A fibre-optic bronchoscope (Olympus P-10, Olympus America Inc., Melville, NY, USA) was inserted into a subsegment of the right middle lobe. Four 50 mL aliquots of sterile 0.9% normal saline were instilled into the middle lobe and each specimen was immediately aspirated and placed in ice. The aspirate from the first 50 mL instillation (BAL 1) was collected separately and discarded. The aspirates recovered from the next three instillations were pooled (BAL 2). The volume of BAL 2 was measured and recorded. A 4 mL aliquot was removed, and the sample was sent to the laboratory for cell count and differential. The remaining volume of BAL was immediately centrifuged at 400g for 5 min, and the supernatant and cell pellet were separated. An aliquot of supernatant was removed for determining urea in BAL fluid. All samples were frozen at –70°C until being shipped to the analytical laboratory.

A 20 mL blood sample to determine drug and urea concentrations was obtained just before scheduled bronchoscopy. In addition, a blood sample for determining drug concentrations was obtained before the first dose of clarithromycin. Blood samples were immediately centrifuged at 1000g for 10 min, and plasma was separated and frozen at –70°C. All samples for drug and urea assays were packed on dry ice and sent overnight to the analytical reference laboratory (Department of Pharmacy Research, Hartford Hospital, Hartford, CT, USA).

Sampling preparation procedures

The sample preparation procedures for BAL fluid and macrophage cell suspensions were based on previously described methods of Patel et al.11 For this study, cells were resuspended to a total of 5% of their recovered lavage fluid volume with a phosphate buffer at pH 8.0.

Drug assays

Concentrations of clarithromycin and 14-hydroxyclarithromycin were determined by high-performance liquid chromatography (HPLC) with electrochemical detection by adapting previously established procedures.1114 In brief, the HPLC system consisted of a Waters M580 solvent delivery system (Waters Associates, Milford, MA, USA), WISP 717plus automated sample processor system (Waters Associates, Milford, MA, USA), and a Coulchem II electrochemical detector with analytical cell M5010 and conditioning cell M5020 (Environmental Sciences Associates, Inc., Chelmsford, MA, USA). The mobile phase consisted of acetonitrile–water (37:63 vol/vol) in a 0.05 M phosphate buffer at pH 7.2. Prepared samples were pumped through a C-18 Bondapak column at a flow rate of 0.9 mL/min. The internal standard was erythromycin. The potentials for the two analytical electrodes were set at +600 and +730 mV, and the conditioning cell was set at +1000 mV. Further detailed description of the analytical procedure has been previously reported.11

For this study, the lower limit of detection for clarithromycin was 0.05 mg/L. The respective interassay coefficients of variation for quality control samples at 0.2 and 2.6 mg/L were 4.22% and 5.24% for plasma, 4.88% and 4.18% for BAL fluid, and 2.39% and 2.72% for cell suspension, and respective intraday coefficients of variation for the same quality control samples were 5.46% and 1.26% in plasma, 3.67% and 2.12% in BAL fluid, and 3.78% and 0.89% in cell suspension. For 14-hydroxyclarithromycin, the lower limit of detection was 0.05 mg/L. The respective interassay coefficients of variation for quality control samples at 0.1 and 1.3 mg/L were 4.72% and 4.62% for plasma, and 6.14% and 2.99% for cell suspension, and respective intraday coefficients of variation for the same quality control samples were 4.75% and 1.21% in plasma, and 3.74% and 3.17% in cell suspension. The concentrations of 14-hydroxyclarithromycin in ELF were not determined because of interference by lidocaine in the BAL.

Urea assays

Concentrations of urea in plasma were measured by a COBAS Integra (Roche Diagnostics, NJ, USA) with the COBAS urea/BUN [UREAL] cassette (Roche Diagnostics, NJ, USA). The standard curve was linear (r2 = 0.999) over the range of concentrations of 0.1 to 240 mg/dL. All samples were determined with a single assay run. The intraday coefficients of variation were 2.3% and 0.89% at concentrations of 24.6 and 186 mg/dL, respectively.

Concentrations of urea in BAL fluid were carried out with a commercial assay kit (Urea Nitrogen Procedure No. 640, Sigma Diagnostics, St. Louis, MO, USA) and measured on a Cary 219 spectrophotometer (Varian, Walnut Creek, CA, USA). A modification of the manufacturer’s procedure was made and standard curves were over a range of concentrations from 0.1 to 2.0 mg/dL. Standard curves were linear (r2 = 0.999) and the relative accuracy ranged from 101.6% to 106.7%. The respective inter- and intraday coefficients of variation were 4.2% and 2.1% for the low control sample (0.15 mg/dL) and 6.9% and 2.7% for the high control sample (1.5 mg/dL).

Calculation of ELF volume and antibiotic concentrations in ELF and AM

The apparent volume of ELF (VELF) in BAL fluid was determined with the urea dilution method as previously described by Rennard and colleagues.15 Since the urea concentration in BAL fluid (UreaBAL) could potentially contain urea from blood, the amount of urea in BAL was corrected (UreaCORR) based on the following calculation:

UreaCORR = UreaBAL – (RBCBAL/RBCBlood x VBAL x Ureaplasma)

where RBCBAL is the number of erythrocytes (RBCs) measured in BAL, RBCBlood is the RBC count in blood, VBAL is the volume of aspired BAL fluid, and Ureaplasma is the concentration of urea in plasma.16 The VELF was determined from the following equation:

VELF = VBAL x UreaCORR/Ureaplasma

The concentration of clarithromycin in ELF (ABXELF) was determined as follows:

ABXELF = ABXBAL x VBAL/VELF

where ABXBAL is the measured concentration of drug in BAL fluid.

The concentration of clarithromycin or 14-hydroxyclarithromycin in AM (ABXAM) was determined as follows:

ABXAM = ABXPellet/VAC

where ABXPellet and VAC are the measured concentration of drug and volume of alveolar cells in the cell suspension, respectively. Differential cell count of the BAL fluid was carried out, and the percentage of macrophages and monocytes was determined. As previously reported by Baldwin et al., a mean macrophage cell volume of 2.42 µL/106 cells was used in the calculations for VAC.17

Pharmacokinetic analysis

Area under the concentration–time curve from time 0 to 24 h (AUC0-24) for the three matrices of clarithromycin was determined with the linear trapezoidal method using the computer program, WinNonlin Standard (version 3.1, Pharsight Corporation, Mountain View, CA, USA). The mean concentration values at each sampling time were used to estimate the AUC0-24. The mean concentration at the 24 h sampling time was also used as a time zero value for determining AUC0-24.

The ratios between ELF to plasma, AM to plasma, and AM to ELF were determined from concentration values of each subject. In addition, parent-to-metabolite ratios in plasma and AM were determined for clarithromycin and 14-hydroxyclarithromycin concentrations.

Statistical analysis

All statistical analyses were carried out using PC SAS, Version 6.12 (SAS Institute, Inc., Cary, NC, USA). The linear regression analysis used the method of least-squares estimation. Before comparing the data sets, a test for normality was carried out using Shapiro-Wilks test. If needed, drug concentration values were normalized using a logarithmic transformation. Comparisons between sampling times were carried out using a contrast statement within PROC GLM. Comparison between concentrations within each sampling time were carried out using PROC TTEST. Demographic comparisons between sampling times were carried out using Fisher’s exact test for gender and ANOVA for age, weight and height. A P value less than 0.05 was considered as statistically significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fifty-one subjects signed an informed consent form to take part in this study. Six subjects did not participate because pre-therapy laboratory test values were outside the protocol limits. A total of 45 subjects met inclusion criteria and participated in the study.

The characteristics of the 42 study subjects receiving clarithromycin extended-release tablets for 5 days are reported in Table 1. Clarithromycin and 14-hydroxyclarithromycin plasma concentrations determined before receiving study drug were below the quantitative limit of detection in all 42 study subjects. Subsequently, one subject (from the 24 h sampling time) was withdrawn from the study and the bronchoscopy was not carried out due to a persistent gag reflex and marked anxiety. The three subjects (one female, two males; age range: 25–40 years) serving as the control group and not receiving clarithromycin had similar demographic characteristics as the 42 study subjects receiving clarithromycin.


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Table 1. Characteristics of study subjects in the pharmacokinetic analysis
 
The extended-release tablets of clarithromycin were well tolerated, and no serious drug-related adverse effects were reported. Ten of the subjects receiving clarithromycin reported at least one mild adverse effect. These events included abnormal taste (n = 8), nausea (n = 3), and loose stools (n = 1).

The individual plasma, ELF and AM concentrations of clarithromycin during the 24 h interval following the last dose are shown in Figure 1. The mean (±S.D.) steady-state concentrations of clarithromycin in plasma, ELF and AM are reported in Table 2. The concentrations of clarithromycin in ELF and AM were significantly (P < 0.05) greater than concurrent plasma concentrations during the 24 h interval following the last dose. The highest observed concentrations for all three matrices occurred at the 9 h sampling time. Clarithromycin concentration in plasma and ELF at the 48 h sampling time were below the quantitative limit of detection in the majority of subjects. The AUC0-24 of clarithromycin based on mean concentration values of plasma, ELF and AM were 28.7, 179 and 5734 mg×h/L, respectively. During the 24 h dosing interval, the mean ratios of ELF to plasma clarithromycin concentrations at each sampling time ranged from 4.1:1 to 9.1:1. In comparison, the mean ratios of AM to plasma concentrations of clarithromycin ranged from 169:1 to 258:1.



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Figure 1. Plasma (filled circles), epithelial lining fluid (filled triangles) and alveolar macrophage (filled squares) concentrations of clarithromycin at 3, 6, 9, 12 and 24 h after the administration of the last dose. The y-axis is in log scale.

 

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Table 2. Concentrations of clarithromycin and 14-hydroxyclarithromycin in plasma, ELF or AM
 
The individual plasma and AM concentrations of 14-hydroxyclarithromycin during the 24 h interval following the last dose are shown in Figure 2. The mean (±S.D.) steady-state concentrations in plasma and AM are reported in Table 2. Concentrations of 14-hydroxyclarithromycin in AM at the 48 h sampling time were below the quantitative limit of detection in all subjects. The concentrations of 14-hydroxyclarithromycin in AM were significantly (P < 0.05) greater than concurrent plasma concentrations during the 24 h interval following the last dose. The mean ratios of AM to plasma concentrations of 14-hydroxyclarithromycin during the 24 h dosing interval ranged from 41.6:1 to 83.5:1.



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Figure 2. Plasma (filled circles) and alveolar macrophage (filled squares) concentrations of 14-hydroxyclarithromycin at 3, 6, 9, 12 and 24 h after the administration of the last dose. The y-axis is in log scale.

 
The ratio between clarithromycin and 14-hydroxyclarithromycin in plasma averaged 2.2:1 during the 24 h dosing interval. A higher ratio of 5.9:1 was observed between clarithromycin and metabolite in AM.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our group and others have previously reported the intrapulmonary penetration of clarithromycin and 14-hydroxyclarithromycin following oral administration of 500 mg twice daily of the immediate-release formulation.11,16,18,19 This study is the first report of the intrapulmonary disposition of clarithromycin and its metabolite following multiple doses of 1000 mg once-daily of an extended-release oral formulation of clarithromycin. Our data provide important information on the time course as well as the magnitude of extracellular and intracellular concentrations of clarithromycin in the lung.

The observed plasma concentrations in our study are similar to those recently reported from two multiple-dose pharmacokinetic studies in healthy adult subjects.9 The mean (±S.D.) peak (Cmax) plasma concentrations of clarithromycin in these studies were 2.59 ± 0.71 mg/L (at 7.8 h) and 2.33 ± 0.70 mg/L (at 5.5 h), and are comparable to our 2.22 ± 0.72 mg/L at the 9 h sampling time (Table 2). The reported trough (Cmin) plasma concentrations of 0.76 ± 0.37 and 0.76 ± 0.44 mg/L in the two studies were nearly identical to our 0.75 ± 0.31 mg/L observed at the 24 h sampling time. However, our observed AUC0-24 of 28.7 mg×h/L (based on mean plasma concentrations) was lower than the previously reported two values of 42.1 ± 13.2 and 35.9 ± 12.4 mg×h/L. These differences in AUC0-24 may be explained, in part, by differences in study design where our estimation of AUC0-24 is based on mean concentrations from a limited number sampling times (n = 6) versus the calculation of individual AUC0-24 based on extensive sampling times (n = 13 to 18) in the previously reported two pharmacokinetic studies.

The ELF concentrations of clarithromycin were significantly higher than concurrent plasma concentrations during the 24 h after the administration of the last dose of the extended-release formulation. In contrast to the previous studies with immediate-release formulation of clarithromycin,11,16,18,19 our observed ELF concentrations with the extended-release formulation tended to be lower in magnitude and remain constant throughout the 24 h dosing interval (Figure 1). The mean values of clarithromycin in ELF ranged from 6.38 to 11.5 mg/L, and 76% of the values were greater than 4 mg/L. Similar to plasma concentrations, the highest ELF concentrations were observed at the 9 h sampling time (Table 2). The ratio of ELF to plasma concentration of clarithromycin from individual subjects ranged from 1.8 to 13.7 (mean: 6.4).

The concentration–time profile of clarithromycin in AM was similar to plasma and ELF. The Tmax for AM concentrations occurred at the 9 h sampling time (Table 2) and the range of AM concen trations remained relatively constant over the 24 h dosing interval (Figure 1). However, clarithromycin was significantly more concentrated in AM than in plasma or ELF. The ratio of clarithromycin concentrations between AM to plasma and AM to ELF ranged from 52 to 702 (mean: 213) and 8.1 to 172 (mean: 44), respectively. The average concentration of clarithromycin in AM during the 24 h dosing interval of the extended-release formulation was 303 mg/L (range: 43 to 1087 mg/L). These observed values of AM concentrations are comparable to those reported for the immediate-release formulation of clarithromycin.11,16,18,19

For the extended-release formulation of clarithromycin, the average ratio between clarithromycin and 14-hydroxyclarithromycin in plasma and AM was 2.2:1 and 5.9:1, respectively. These values are similar to our previous report with the immediate-release formulation of clarithromycin, and suggest that the extent of formation of this microbiologically active metabolite is consistent between both products.18 The observed differences in the ratio between clarithromycin and its metabolite in plasma and AM may reflect the more favourable un-ionized state of clarithromycin and intracellular accumulation.

Randomized, double-blind clinical trials have established the clinical efficacy of the extended-release formulation of clarithromycin for the treatment of lower respiratory tract infections such as community-acquired pneumonia and acute exacerbations of chronic bronchitis.58 The pharmacokinetic–pharmacodynamic parameter that best correlates with the efficacy of clarithromycin remains unresolved.20 Based on the pattern of antimicrobial activity (e.g. time-dependent bactericidal activity and minimal to moderate post-antibiotic effect), Craig initially recommended the duration of time (as a percentage [%T]) that unbound plasma drug concentrations remain above the minimum inhibitory concentration (MIC) (%T>MIC) as the most predictive pharmacodynamic parameter to determine the efficacy of clarithromycin.21 However, several recent reports (including one by Craig et al.23) have proposed the ratio of unbound plasma AUC0-24 to MIC (AUC0-24/MIC) as the most predictive parameter that correlates with efficacy for clarithromycin.14,22,23 The substantial differences that we have observed between plasma, ELF and AM concentrations may explain, in part, the apparent difficulty in establishing a parameter predictive of efficacy for clarithromycin and its metabolite, 14-hydroxyclarithromycin. Further studies are needed to determine the clinical significance of high intrapulmonary concentrations, pharmacodynamic parameters and clinical outcomes.

We consider our observations of high intrapulmonary concentrations of clarithromycin in healthy subjects to be a conservative estimate of the magnitude of concentrations that may be observed in patients with infections and/or inflammatory conditions. Several observations suggest that patients are likely to have increased plasma concentrations that would allow greater penetration across the alveolar–capillary barrier and drug accumulation into cells. Offman et al. reported that patients with community-acquired pneumonia have higher plasma AUC0-24 values of clarithromycin during the acute phase of their illness compared to the convalescent period.24 In addition, subjects who are either elderly or with mild to moderate renal impairment are associated with increased plasma concentrations of clarithromycin and 14-hydroxyclarithromycin secondary to longer elimination half-lives of these agents.25,26 Several reports have also documented that subjects who smoke are likely to have increased intracellular lung concentrations of drugs which are highly concentrated in AM compared to non-smokers.27,28 Penetration studies in patients with respiratory tract infections are needed to further define intrapulmonary disposition of clarithromycin and its metabolite.

In summary, the results of this study demonstrate that once-daily doses of 1000 mg of an extended-release oral formulation of clarithromycin provide higher mean steady-state concentrations in ELF and AM compared to concomitant plasma concentrations throughout the 24 h dosing interval. The extended-release clarithromycin tablets tended to produce concentrations in the extracellular and intracellular compartments of lung that remain at a constant magnitude during the 24 h after the administration of the last dose. The impact that such high intrapulmonary concentrations have upon bacteriological and clinical outcomes remains unknown, and warrants further investigation.


    Acknowledgements
 
We greatly appreciate the analytical and technical assistance of Dr David Nicolau and Pamela Tessier, and the statistical assistance of Todd Busman. This work was funded in part by a grant from Abbott Laboratories. This work was presented, in part, at the Infectious Diseases Society of America Annual Meeting, Chicago, IL, October 2002.


    Footnotes
 
* Correspondence address. m/c 886, Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, Room 164, 833 South Wood Street, Chicago, IL 60612, USA. Tel: +1-312-996-3341; Fax: +1-312-413-1797; E-mail: kar{at}uic.edu Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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6 . Anzueto, A., Fisher, C. L., Busman, T. et al. (2001). Comparison of the efficacy of extended-release clarithromycin tablets and amoxicillin/clavulanate tablets in the treatment of acute exacerbation of chronic bronchitis. Clinical Therapeutics 23, 72–86.[CrossRef][ISI][Medline]

7 . Gotfried, M. H., Dattani, D., Riffer, E. et al. (2002). A controlled, double-blind, multicenter study comparing clarithromycin extended-release tablets and levofloxacin tablets in the treatment of community-acquired pneumonia. Clinical Therapeutics 24, 736–51.[CrossRef][ISI][Medline]

8 . Sokol, W. N., Sullivan, J. G., Acampora, M. D. et al. (2002). A prospective, double-blind, multicenter study comparing clarithromycin extended-release with trovafloxacin in patients with community-acquired pneumonia. Clinical Therapeutics 24, 605–15.[CrossRef][ISI][Medline]

9 . Guay, D. R. P., Gustavson, L. E., Devcich, K. J. et al. (2001). Pharmacokinetics and tolerability of extended-release clarithromycin. Clinical Therapeutics 23, 566–77.[CrossRef][ISI][Medline]

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Articles by Rodvold, K. A.
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Articles by Gotfried, M. H.
Articles by Rodvold, K. A.