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Antimicrobial Agents and Chemotherapy, January 2005, p. 336-341, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.336-341.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Single-Dose Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitor, in HIV-Infected Children

Ram Yogev,1* Andrea Kovacs,2 Ellen G. Chadwick,1 James D. Homans,2 Yu Lou,3 and William T. Symonds3

Children's Memorial Hospital, Division of Infectious Diseases, Chicago, Illinois,1 Maternal, Child, and Adolescent Center for Infectious Diseases and Virology, Los Angeles County and University of Southern California Medical Center, University of Southern California Keck School of Medicine, Los Angeles, California,2 Glaxo Wellcome, Inc., Research Triangle Park, North Carolina3

Received 23 April 2004/ Returned for modification 23 June 2004/ Accepted 8 September 2004


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A phase I, open-label, dose-escalating trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of single, oral doses of amprenavir (141W94), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, in 20 HIV-infected children 4 to 12 years of age. The doses of amprenavir evaluated, 5, 10, 15, and 20 mg/kg of body weight, were comparable to those evaluated in adult phase I and II studies. The most common clinical adverse event associated with amprenavir, administered as soft gelatin capsules, was nausea. Amprenavir was rapidly absorbed, with a mean time to maximum concentration (Tmax) occurring 0.95 to 1.58 h after dosing. The area under the concentration-time curve (AUC0->{infty}) was dose proportional, and the mean maximum plasma concentration (Cmax) increased linearly in a less than dose-proportional manner. Amprenavir was eliminated relatively slowly, with a mean terminal-phase half-life (t1/2) of 6.17 to 8.28 h. The t1/2, apparent total clearance, and apparent volume of distribution during the elimination phase were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters of amprenavir. The results of this study suggest that 20 mg of amprenavir/kg administered twice a day should be used in future pediatric studies.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The virologic and clinical manifestations of human immunodeficiency virus (HIV) infection and AIDS in children are different from those in HIV-infected adults. It is believed that these differences exist in part because infants and young children have an immature but evolving immune system, and many organ systems, including those involved in drug metabolism and excretion (e.g., liver and kidney), are still developing (5, 12). Nevertheless, the goal of anti-HIV therapy—maximal suppression of HIV replication—is the same for both the adult and pediatric populations (1, 2).

Although there are numerous considerations in the development and testing of new agents for HIV-infected pediatric patients (e.g., drug effects on growth and neurologic development in the presence of HIV), there remains an urgent need for more antiretroviral therapies for this population. The most recent guidelines for the use of antiretroviral agents for pediatric patients underscore that clinical testing of new potent agents should begin in the pediatric population as soon as pharmacokinetic and safety studies are completed for HIV-infected adults (1). As with adults, more therapeutic options are needed for HIV-infected pediatric patients because of side effects, virologic failure, drug resistance, palatability, dosing schedule, and/or food-drug and drug-drug interactions.

The protease inhibitor amprenavir is an N,N-disubstituted hydroxyethylamino sulfonamide (molecular size, 506 Da) that was originally synthesized by using a structure-based drug design process (7). This agent showed high antiviral activity in a number of cell culture systems in vitro and good oral bioavailability in several animal species (7, 14, 15, and G. R. Painter, M. H. St. Calir, P. Demiranda, S. Ching, R. Dornsife, D. J. Livingston, S. Pazhanisamy, and R. Tung, Program Abstr. 2nd Natl. Conf. Hum. Retrovir. Related Infect., abstr. LB5, 1995). Preliminary results for adults and pediatric patients suggest that amprenavir is well tolerated, has good bioavailability following oral administration, and suppresses viral load, as demonstrated in multiple-dose studies (6, 15, 16, and P.-A. Bart, G. P. Rizzardi, S. Gallant, P. Meylan, W. Spreen, H. McDade, and U. K. Pantaleo, Program Abstr. 12th World AIDS Conf., abstr. 286/12204, 1998).

We report here the safety and pharmacokinetics of four single, escalating doses of amprenavir in HIV-infected children using a soft gelatin capsule formulation. The doses chosen for evaluation in children (5, 10, 15, and 20 mg/kg of body weight) were based on those studied in dose-ranging and safety studies of adults (amprenavir doses of 300 to 1,200 mg) (16). This range provides the flexibility to dose children within the exposure range studied in adults and will allow dose selection for future trials in this population guided by efficacy data from adults.

(Preliminary data from this study were originally reported at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection, Hamburg, Germany, 11 to 15 October 1997.)


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study population. Twenty HIV-infected children (greater than 6 and less than 13 years of age, or less than 6 years old if able to take solid medication) were sequentially enrolled in one of two dose escalation groups. To be included in the trial, subjects had to have a normal electrocardiogram (ECG) and clinical laboratory and urinalysis values of no more than Grade 2 of the Division of AIDS Toxicity Table for Grading Severity of Pediatric Adverse Experiences (13). A parent or guardian of each subject had to give written informed consent to participate in the trial. Subjects were excluded from the trial if they had wasting or failure to thrive, progressive encephalopathy, an active opportunistic infection, or an acute bacterial infection requiring medical intervention at the time of screening. Subjects were also excluded if they had documented malabsorption syndrome, if the screening dipstick analysis revealed ≥1+ blood and protein in their urine, or if they required any medication or drugs (including antiretroviral therapy and/or chemoprophylaxis for Pneumocystis carinii pneumonia) that could not be interrupted for the dosing phase of the study. With the exception of antiretroviral agents, all medications had to be withheld at least 48 h prior to dosing until 24 h postdose; antiretroviral agents had to be discontinued at least 24 h prior to dosing. Consumption of beverages or foods containing alcohol or methyl xanthines, such as tea, chocolate, grapefruit, or grapefruit juice, was prohibited for 48 h prior to dosing and during the day of the study. Children who met all entry criteria underwent a physical examination; had an ECG and urinalysis; and had blood drawn for clinical chemistry, hematology, CD4+/CD8+ T-cell analyses, and HIV serology. All subjects were closely monitored for vital signs, clinical adverse experiences, and/or abnormal laboratory test values throughout the study period, including the follow-up assessment, which was conducted 7 to 10 days after administration of the last dose of amprenavir.

Study design. The four amprenavir dosages evaluated (5, 10, 15, and 20 mg/kg) were selected based on the doses studied in the multiple-dose trials of HIV-infected adults (using 70 kg as an average adult weight). Amprenavir was administered orally as soft gelatin capsules of either 25 or 150 mg. Body weight was determined to the nearest kilogram, and the dose per kilogram was calculated to one decimal place. The first 10 children enrolled were sequentially assigned to receive two single, escalating doses of amprenavir: 5 mg/kg, followed by a wash-out period of at least 7 days before the next (10-mg/kg) dose was administered. A second group of 10 children was sequentially assigned to receive two single, escalating doses: 15 mg/kg, followed by a wash-out period of at least 7 days before the next (20-mg/kg) dose was administered. Amprenavir doses were administered to children in the second dosing group after the first five subjects in the first dosing group completed the 10-mg/kg-dose level. Study participants fasted from 2 h prior to dosing until 1 h postdosing but were allowed water ad libitum. The collection of plasma samples were scheduled to follow the morning dose. The study was conducted at two centers in the United States, and the study protocol was approved by the institutional review boards (IRB) affiliated with each study site.

Safety evaluation. Safety and tolerability were evaluated by physical examination, vital signs, ECG, hematology (complete blood count with differential, mean corpuscular volume, hemoglobin, hematocrit, and platelet count), clinical chemistry (electrolytes, alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, total bilirubin, serum creatinine, glucose, alkaline phosphatase, and serum amylase), urinalysis (dipstick for protein and blood), and clinical adverse experiences. Physical examinations and ECG testing were performed at screening and at follow-up only, unless otherwise warranted. Hematology and clinical chemistry tests and urinalysis were performed for each subject prior to each dose; vital signs were checked, and occurrences of any clinical adverse experiences were recorded during the 24-h postdose period. The follow-up assessment included a comprehensive physical examination, ECG, measurement of weight and vital signs, urinalysis, hematology, clinical chemistry, and clinical adverse event reporting. The Division of AIDS Toxicity Table for Grading Severity of Pediatric Adverse Experiences (13) was used to evaluate clinical adverse events and laboratory values; according to this table, any Grade 3 or 4 toxicity was reported as a serious adverse event.

Blood collection. Serial blood samples were collected to determine the plasma concentration of amprenavir. Blood samples were collected immediately prior to each dose of study drug (predose, or 0 h) and then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h postdose, and the samples were immediately processed. Plasma samples were stored at –20°C until analysis was performed. Amprenavir in human plasma was stable for at least 19 months when stored at –20°C (Glaxo Wellcome, Inc., Research Triangle Park, N.C., unpublished data).

Assay for amprenavir. Plasma concentrations of amprenavir were determined by using a reversed-phase high-performance liquid chromatographic method with fluorescence detection (excitation at 245 nm, emission at 340 nm). At least three serially diluted quality control samples were included at the beginning, middle, and end of each assay run. Amprenavir was extracted from the samples by solid-phase extraction performed with a Waters MilliLab Workstation and an activated Bond-Elut C18 cartridge. Samples were eluted from the cartridge with 100% acetonitrile. After extraction and reconstitution, samples were injected onto a Waters Symmetry C18 liquid chromatography column (3.9 by 150 mm) at 40°C. Samples were eluted off the column using a mobile phase consisting of 45% acetonitrile (in water, 45:55 [vol/vol]) at a constant flow rate of 1.0 ml/min. Analytical standards, calibration standards, and spiked samples were used to validate the study assay. The within-assay bias was <5% and had a precision of 1.8 to 11.3%, while the between-assay bias was <2% and had a precision of 1.8 to 4.7%. The range of detection of amprenavir was 0.01 to 1.0 µg/ml. Samples with concentrations exceeding the upper limit of the assay were diluted and reanalyzed.

Pharmacokinetic analyses. Pharmacokinetic parameters for each subject were calculated from plasma concentrations obtained during each dosing period using model-independent methods. The peak or maximum amprenavir plasma concentration (Cmax) and the time to reach maximum plasma concentration (Tmax) were observed from the data. The apparent terminal elimination rate constant ({lambda}z) was obtained by log-linear regression of the terminal portions of the plasma concentration versus time curves, and the terminal-phase half-life (t1/2) was then calculated as ln(2)/{lambda}z. The area under the plasma concentration-time curve (AUC0->t) from t = 0 to the time of the last quantifiable sample (tlast) was calculated using the linear trapezoidal rule. AUC0->t was extrapolated from tlast to infinity (AUC0->{infty}) by adding Clast/{lambda}z, where Clast is the last quantifiable plasma concentration. The apparent total clearance (CL) was calculated as dose/AUC0->{infty}. The apparent volume of distribution during the elimination phase (Vß) was calculated as (CL)/{lambda}z.

Data analysis. Statistical analysis was performed using SAS version 6.12 (SAS Institute, Cary, N.C.) Summary statistics were performed for AUC0->{infty}, AUC0->t, Cmax, {lambda}z, t1/2, CL, Tmax, and Vß.

Dose proportionality and dose independence for all pharmacokinetic parameters was assessed by using two mixed models (full and reduced). The full model is described by the equation log(Y) = (a + b) · (cohort + c) · [log(dose) + d] · [log(dose)2 + e] · cohort · [log(dose)], and the reduced model is described by the equation log(Y) = (a + c) · log(dose). In both models, Y represents the pharmacokinetic parameter of interest, cohort is a categorical variable equal to 0 for subjects in the 5- and 10-mg/kg treatment groups and equal to 1 for subjects in the 15- and 20-mg/kg treatment groups, and a, b, c, d, and e are the estimated coefficients. Cohorts were defined as subjects receiving amprenavir at either 5 and 10 mg/kg or 15 and 20 mg/kg. In the full model, curvature was estimated by log(dose)2, and cohort was used to estimate an additional intercept and slope from the second dosing group. If the estimated coefficient for b, d, or e was not significantly different from 0 at the P = 0.05 level, the reduced model without the associated term was used to estimate the dose-dependent slope. The coefficients for curvature (d) and cohort slope (e) and intercept (b) were not significantly different from 0 for all parameters examined. The reduced model was used to estimate the dose-dependent slope in all cases. Random effects for between- and within-subject variance were assessed by differences in the intercepts.

Dose proportionality of pharmacokinetic parameters was assessed by using the slope of log(dose) for log-transformed pharmacokinetic parameters and the 90% confidence interval (CI). The inclusion of 1 in the 90% CI estimated for the slope of AUC0->{infty} and Cmax indicated dose proportionality. The inclusion of 0 in the 90% CI estimated for the slope of t1/2, CL, and Vß indicated dose independence.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Subject demographics. Twenty children were enrolled in the study. All but two subjects met the study entry criteria: one had elevated creatinine phosphokinase and the other continued Pneumocystis carinii prophylaxis (with cotrimoxazole, azithromycin, and atavaquone) up to 24 h prior to dosing (instead of 48 h). Both subjects were granted an exemption and continued to participate in the study. No other medications with known or potential interaction with the study drug were taken by any of the participants. All 20 enrolled children (11 males and 9 females; median age, 9 years; range, 4 to 12 years) completed the two single-dosing periods to which they were assigned. With the exception of race, subject demographics were similar for the 10 subjects who received amprenavir doses of 5 and 10 mg/kg and the 10 subjects who received amprenavir doses of 15 and 20 mg/kg (Table 1). Upon entry, five study participants had severe signs and symptoms of HIV infection (Centers for Disease Control and Prevention [CDC] classification C), six subjects were classified with moderate HIV infection (CDC classification B), and the remaining nine subjects had mild HIV infection (CDC classification A) (3).


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  		TABLE 1. Subject demographic and HIV-related data for the single-dose, dose-escalation study

 
Safety and tolerability. No deaths or withdrawals due to clinical adverse events occurred. A total of 32 clinical adverse events were reported for 12 subjects; the majority were of mild or moderate intensity. Three subjects each reported one serious adverse experience, all of which were judged to be unrelated to the study drug: one case each of cervical lymphadenitis, hypoglycemia, and Grade 3 anemia. Of the 32 clinical adverse events reported, 10, occurring in 7 subjects, were judged as possibly related to the study drug. Of these 10 drug-related adverse events, 1 was reported for each of the 5- and 10-mg/kg-amprenavir-dose levels, 6 were reported for the 15-mg/kg-dose level, and 2 were reported for the 20-mg/kg-dose level. The most common drug-related clinical adverse event was nausea, which occurred in three subjects, once each at the 5, 15, and 20-mg/kg levels. Other adverse events reported as possibly attributable to amprenavir were one instance of vomiting (at the 10-mg/kg-dose level); one instance each of gastric pain (15 mg/kg), tiredness (15 mg/kg), common cold (15 mg/kg), and watery stools (20 mg/kg); and two instances of headache (15 mg/kg).

No clinically significant changes in clinical chemistry or hematology values were observed. Subjects with hematology and/or clinical chemistry values that were higher or lower relative to a reference range during one or more dosing periods either had correspondingly high or low values prior to the start of the study or had values that returned to the normal range by the second dose or the follow-up assessment. With one exception, all subjects had normal urinalysis values at each treatment session and at the follow-up assessment. (The exception was a patient with more than a trace of protein in her urine at follow-up.) No drug-related changes were detected by physical examination, vital signs, or ECG in any subject during the course of the study.

Pharmacokinetics. The mean plasma concentrations of amprenavir for each dose level, from 30 min to 24 h postdose, are shown in Fig. 1. The mean plasma concentration for 13 of 20 subjects exhibited a small second peak or shoulder, occurring between 8 to 12 h after dosing. For all dose levels, measurable plasma concentrations were obtained within 30 min after dosing. For the three highest dose levels, plasma concentrations of amprenavir were still quantifiable at 24 h after dosing. For the 5-mg/kg dose, amprenavir levels were quantifiable at 24 h after dosing in 3 of 10 subjects.



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  		FIG. 1. Mean plasma concentration of amprenavir versus time in children after single dosing with 5, 10, 15, and 20 mg/kg. Concentrations at 12 h were uniformly detectable in the 10-, 15-, and 20-mg/kg-dose groups. Concentrations at 24 h were quantifiable in ≥75% of samples in these same groups at 24 h.

 
The estimated values of pharmacokinetic parameters for amprenavir after single, oral dosing for children are presented in Table 2. AUC0->{infty} versus dose was approximately linear and dose proportional for all four doses (Fig. 2). A two-, three-, and fourfold increase in dose from 5 mg/kg resulted in a 1.82-, 2.42-, and 3.85-fold increase in AUC0->{infty}, respectively (Table 2). Cmax increased in a less than dose-proportional manner, such that a two-, three-, and fourfold increase in dose from 5 mg/kg resulted in a 1.73-, 1.82-, and 2.31-fold increase in Cmax, respectively. For all doses, the mean Tmax was reached within 1.6 h after dosing (range, 0.5 to 4.0 h). The mean t1/2 was approximately 7 h (range, 1.25 to 18.15 h). Both CL and Vß were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters.


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  		TABLE 2. Mean (± standard deviation) pharmacokinetic parameters for amprenavir after a single dose in childrena

 


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  		FIG. 2. Log-log regression analysis of AUC versus dose.

 
In the dose proportionality analysis, no significant difference between the two cohorts (those receiving 5 and 10 mg/kg versus those receiving 15 and 20 mg/kg) was found with respect to slope and intercept, nor was there evidence of curvature in any of the parameters using the full model. Dose proportionality of AUC0->{infty} and Cmax for the 5-, 10-, 15-, and 20-mg/kg doses was further demonstrated by using the reduced model to estimate the dose-dependent slope for both cohorts. The estimated slope for AUC0->{infty} was 0.94 with a 90% CI of 0.63 to 1.24, indicating dose proportionality (90% CI includes 1), whereas the estimated slope for Cmax was 0.54 with a 90% CI of 0.33 to 0.82, indicating less than dose proportionality (90% CI does not include 1).


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The doses evaluated in this trial, 5, 10, 15, and 20 mg/kg, were selected based on single-dose safety and pharmacokinetic studies conducted in adults (16) and multiple-dose safety and efficacy studies (6). The initial single-dose study with adults used doses ranging from 150 to 1,200 mg. The first multiple-dose study investigated doses from 300 to 1,200 mg given twice a day (BID). Using 70 kg as an average adult weight, the 1,200-mg adult dose is equivalent to 17.1 mg/kg. Therefore, the maximum dose used in the present single-dose study is within 17% of the dose initially used for adults (16).

There were no acute, life-threatening adverse events related to amprenavir use seen in the pediatric patients (age range, 4 to 12 years). The most common clinical adverse experience related to the study drug was nausea. Other drug-related adverse events were vomiting, gastric pain, tiredness, watery stools, and headache; these occurred with a low frequency (headache was reported twice; the others, once). The safety of single oral doses of amprenavir was further demonstrated by the lack of any apparent effect on clinical chemistry or hematology values, physical examination changes, vital signs, or ECG data. These safety and tolerability findings compare favorably with those of other presently available protease inhibitors (4, 8, 10, and S. Jankelevich, B. Mueller, S. Smith, C. Boss, S. Zwerski, S. Steinberg, L. Wood, S. Zeichner, L. Serchuck, J. Sleasman, R. Nelson, B. Y. Nguyen, C. Shadle, P. Pizzo, and R. Yarchoan, Program Abstr. 5th Conf. Retrovir. Opportun. Infect., abstr. 231, 1998).

The pharmacokinetic findings of this study show that, following oral administration, amprenavir reaches maximum concentration rapidly (within 1.6 h), has adequate bioavailability, and has a relatively long terminal-phase half-life (t1/2) (approximately 7 h). A small second concentration peak, or shoulder, in the plasma concentration-time curve was observed 8 to 12 h after amprenavir administration, suggesting the possibility of secondary absorption or enterohepatic recirculation.

The area under the concentration-dose curve (AUC0->{infty}) was linear, and dose proportionality was confirmed by using full and reduced statistical models. Although the slope of Cmax versus dose curve was also linear according to estimates calculated by the full and reduced models, Cmax increased in a less than proportional manner with increasing doses. This was accompanied by an increase in Tmax with dose. Thus, the rate of absorption, but not the extent, appears to be slower at higher doses, perhaps due to differences in solubility or dissolution. The dose independence of t1/2, CL, and Vß was confirmed by the full and reduced models.

The linear kinetics of AUC0->{infty} and Cmax are consistent with pharmacokinetic data obtained in single-dose studies with adults (16). Mean AUC0->{infty} for adults ranged from 4.03 to 47.14 h · µg/ml for the five doses tested (150, 300, 600, 900, and 1,200 mg), compared to 5.68 to 21.88 h · µg/ml for children. As in the pediatric study, Cmax versus dose was linear but slightly less than dose proportional in the adult studies. Cmax for adults ranged from 2.00 to 9.11 µg/ml, compared to 3.80 to 5.76 µg/ml for children. Tmax was rapid at all doses both in adults (range of mean values, 1.13 to 2.09 h) and in children (range of mean values, 0.91 to 1.58 h). The t1/2 of amprenavir was also comparable in adult and pediatric patients (8 and 7 h, respectively). Dose independence of t1/2, CL, and Vß was observed in the adult studies and the pediatric study, with each of these parameters having relatively stable values across all dose levels.

The relatively long t1/2 of amprenavir in children (~7 h) and the AUC0->{infty} and Cmax, which are comparable to those found in adults, suggest that the 20-mg/kg dose of amprenavir administered twice daily should be investigated in a multiple-dose pediatric study.

The overall pharmacokinetic profile of amprenavir in children compares favorably with that of other protease inhibitors. Amprenavir is absorbed as quickly as or more quickly than the other drugs (within 1.6 h for amprenavir versus 2 to 4 h for ritonavir and nelfinavir [M. Gersten, A. K. Petersen, A. Hendricks, B. Boczany, M. Knowles, B. Derr, Y. Chang, G. Yu, and N. J. Clendeninn, Program Abstr. 6th Eur. Conf. Clin. Aspects Treatment HIV Infect., abstr. 591, 1997], 0.5 to 2 h for indinavir [9, 11, 13], and 1 h for saquinavir [4]) and has a relatively longer t1/2 (~7 h for amprenavir versus ~3 to 5 h for ritonavir and nelfinavir, 0.9 h for indinavir, and 1.6 h for saquinavir). Therefore, a BID dosing of amprenavir seems to be a reasonable start to explore this drug's efficacy in HIV-infected children.

In summary, single-dose administration of amprenavir as a soft gelatin capsule produced side effects that were of mild to moderate intensity in HIV-infected children. The most common side effect was nausea. The pharmacokinetic profile of amprenavir appears to be favorable for use in children due to its rapid absorption, adequate bioavailability, and long t1/2. The results of this study suggest that a 20-mg/kg BID dose of amprenavir should be used in multiple-dose studies evaluating the safety, efficacy, and resistance development of this drug in pediatric patients.


   ACKNOWLEDGMENTS
 
We thank all the patients that participated in this study. We also thank Cindy M. Rawls, Debbie Fonken-Cloutier, Margaret M. Khoury, Pat Gayle, Brian M. Sadler, Gregory E. Chittick, Christina Pilati-Stevens, Belinda F. Ha, and Seth V. Hetherington for their important contributions.


   FOOTNOTES
 
* Corresponding author. Mailing address: Division of Infectious Diseases, Children's Memorial Hospital, 2300 Children's Plaza, Box 155, Chicago, IL 60614. Phone: (773) 880-4757. Fax: (773) 880-3208. E-mail: ryogev{at}childrensmemorial.org. Back


   REFERENCES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Antimicrobial Agents and Chemotherapy, January 2005, p. 336-341, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.336-341.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.




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