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A Prospective, Randomized Trial Examining the Efficacy and Safety of Clarithromycin in Combination with Ethambutol, Rifabutin, or Both for the Treatment of Disseminated Mycobacterium avium Complex Disease in Persons with Acquired Immunodeficiency Syndrome

  1. Constance A. Benson1,
  2. Paige L. Williams2,
  3. Judith S. Currier3,
  4. Fiona Holland2,
  5. Laura F. Mahon5,
  6. Rob Roy MacGregor8,
  7. Clark B. Inderlied4,
  8. Charles Flexner6,
  9. Judith Neidig9,
  10. Richard Chaisson6,
  11. Gerard F. Notario10,
  12. Richard Hafner7, and
  13. AIDS Clinical Trials Group 223 Protocol Teama
  1. 1Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver
  2. 2Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts
  3. 3University of California at Los Angeles CARE Center, Los Angeles
  4. 4University of Southern California Children's Hospital, Los Angeles
  5. 5AIDS Clinical Trials Group Operations Center, Social and Scientific Systems, Silver Spring
  6. 6Johns Hopkins University School of Medicine, Baltimore
  7. 7Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
  8. 8University of Pennsylvania Medical Center, Philadelphia
  9. 9Ohio State University College of Medicine, Columbus
  10. 10Abbott Laboratories, Abbott Park, Illinois
  1. Reprints or correspondence: Dr. Paige L. Williams, Center for Biostatistics in AIDS Research, Harvard School of Public Health, 655 Huntington Ave., Boston, MA 02115 (paige{at}sdac.harvard.edu).

  • ↵Participating sites are listed at the end of the text.

 
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Abstract

This multicenter, randomized, open-label phase 3 clinical trial compared the safety and efficacy of 3 clarithromycin-containing combination regimens for the treatment of disseminated Mycobacterium avium complex (MAC) disease in persons with acquired immunodeficiency syndrome. A total of 160 eligible patients with bacteremic MAC disease were randomized to receive clarithromycin with either ethambutol (C+E), rifabutin (C+R), or both (C+E+R) for 48 weeks. After 12 weeks of treatment, the proportion of subjects with a complete microbiologic response was not statistically significantly different among treatment arms: the proportion was 40% in the C+E group, 42% in the C+R group, and 51% in the C+E+R group (P = .454). The proportion of patients with complete or partial responses who experienced a relapse while receiving C+R (24%) was significantly higher than that of patients receiving C+E+R (6%; P = .027) and marginally higher than that of patients receiving C+E (7%; P = .057). Subjects in the C+E+R group had improved survival, compared with the C+E group (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23–0.83) and the C+R group (HR, 0.49; 95% CI, 0.26–0.92).

Disseminated disease due to Mycobacterium avium complex (MAC) has been among the most common serious opportunistic infections occurring in persons with HIV-1 infection and advanced immunosuppression [1–8]. Since 1995, the incidence of MAC disease has decreased dramatically, to an estimated 1–3 cases/100 patient-years, coincident with widespread use of both MAC prophylaxis and potent antiretroviral therapies [9–13]. However, HIV-infected individuals with advanced immunosuppression who are not receiving or are unable to tolerate antiretroviral regimens continue to develop disseminated MAC disease.

Published recommendations for treating disseminated MAC disease state that at least 2 antimycobacterial drugs active against MAC should be used to reduce the potential that antibiotic resistance will develop [8, 13]. Either clarithromycin or azithromycin is recommended as the first agent; ethambutol is the recommended second drug [8, 13]. For severe cases, some suggest adding rifabutin, ciprofloxacin, amikacin, or another antimycobacterial drug [8, 13]. In previous studies, macrolide-based therapy of disseminated MAC disease has resulted in improvement of symptoms, clearance of mycobacteremia, and prolonged survival, but relapse due to resistant organisms was common [14–23]. Although macrolides are recognized to be the most active of the drugs available for treatment of MAC disease, several important questions remain in defining optimal treatment. Namely, it remains critical to evaluate the contribution of any single additional drug versus ⩾2 drugs to macrolide-containing combination regimens with respect to the rate of relapse, emergence of resistance, and survival. This study was undertaken to compare the contribution of ethambutol, rifabutin, or both when added to clarithromycin for the treatment of disseminated MAC disease in persons with AIDS.

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Methods

Study population and study design. This open-label, phase 3 study compared the safety and efficacy of 3 clarithromycin-containing regimens for the treatment of disseminated MAC disease in AIDS patients. Subjects were recruited from 21 sites of the National Institute of Allergy and Infectious Diseases (NIAID) Adult AIDS Clinical Trials Group. This protocol was approved by the institutional review board at each participating site, and each subject gave written informed consent before enrollment. The human experimentation guidelines of the US Department of Health and Human Services and local institutional review boards were followed at all participating sites.

HIV-infected subjects were eligible if they were at least 13 years old, had a Karnofsky performance score of ⩾30, had stable condition while receiving therapy for any infectious processes other than MAC infection, had received at most 14 days of antimycobacterial therapy within the 30 days before study entry, and had either (1) symptoms of MAC disease and 1 culture of blood or a specimen from a normally sterile body site positive for MAC or acid-fast bacilli or (2) no symptoms but 2 blood cultures obtained at least 24 h apart that were positive for MAC or acid-fast bacilli. Subjects were excluded if they were pregnant or lactating, had active mycobacterial infection caused by microorganisms other than MAC that required treatment, or had life expectancy of <8 weeks. Because of the time required to detect MAC in blood cultures, subjects were enrolled pending baseline culture results. However, those with negative results of baseline culture were considered ineligible, their study participation was discontinued, and they were followed up for survival only.

Subjects were randomized in equal proportions to receive either clarithromycin (500 mg twice daily) and ethambutol (15 mg/kg once daily; C+E), clarithromycin (500 mg twice daily) and rifabutin (450 mg once daily; C+R), or a combination of clarithromycin, ethambutol, and rifabutin in the same dosages (C+E+R). After protease inhibitors (PIs) became available, the protocol was amended to decrease rifabutin dosages to 150 mg/day for subjects receiving indinavir or nelfinavir and to 150 mg every other day for those receiving ritonavir.

Subjects were evaluated for symptoms of MAC disease, adverse events, and adherence to the drug regimens, and a blood sample for culture for MAC was obtained at baseline; at weeks 4, 6, 8, 12, 16, 20, and 24; and then every 8 weeks until week 48. A targeted physical examination was performed at baseline, at weeks 4 and 8, and every 8 weeks thereafter. If a subject developed symptoms of MAC infection between scheduled visits, blood specimens were obtained and cultured. When a patients had treatment failure or a relapse, study treatment was discontinued, and the best available salvage therapy was offered through that patient's primary care provider.

Mycobacterial blood culture and susceptibility testing. Peripheral blood was collected in tubes containing sodium polyanetholium sulfate (Vacutainer; Becton Dickinson) and shipped overnight to a central laboratory (Non-Tuberculous Mycobacteria Reference Laboratory, Children's Hospital, Los Angeles). Blood specimens were cultured for MAC using a radiometric method (Bactec 460TB System; Becton Dickinson Diagnostic Instrument Systems), and bacteremia levels were quantified as described elsewhere [24, 25]. Susceptibility testing for clarithromycin, ethambutol, and rifabutin was performed using radiometric assays in Bactec 12B broth [24–27]. MICs of at least 32, 1, and 16 µg/mL were used to define in vitro resistance to clarithromycin, rifabutin, and ethambutol, respectively.

Study end points. The primary study end points were (1) complete microbiologic response by week 12 and (2) complete microbiologic and clinical response by week 12 (defined as achievement of a complete microbiologic response by week 12 and remaining alive and afebrile through week 12). A complete microbiologic response at any given week was defined as 2 consecutive blood cultures negative for MAC without evidence of relapse. A partial microbiologic response was defined as either a single blood culture negative for MAC without evidence of relapse or 2 consecutive cultures showing decreases in the number of MAC colony-forming units, compared with baseline, with at least 1 decrease of ⩾1 log10 cfu/mL. Treatment failure was defined as the absence of a complete or partial response by a given week or as death, with MAC disease indicated as the primary or contributing cause. Relapse was defined as either a single blood culture positive for MAC with ⩾1 log10 cfu/mL after a complete or partial response or 2 consecutive increases of at least 1 log10 cfu/mL, compared with the week in which a partial response was found. Response was unevaluable in subjects from whom no follow-up samples were obtained for culture through a given week and who did not die as a result of MAC disease; such subjects were considered to have had treatment failure in the intent-to-treat analyses.

Secondary study end points included reduction in the level of MAC bacteremia, the distribution of microbiologic responses (complete, partial, failure, and relapse) at weeks 6–16, relapse, survival, resistance to study drugs, and treatment discontinuation due to drug toxicity.

Statistical analysis. This study was designed to test the primary hypothesis that the 3-drug combination would be 25% more effective than each of the 2-drug combinations with regard to the primary end points. The sample size of 195 evaluable patients provided 80% power for each pairwise comparison, using a 2-sided test at a 5% significance level. The overall accrual target was initially increased to 246 subjects to allow for subjects lacking primary end-point data (due to death, loss to follow-up, or missing cultures) but was later reduced to 204 subjects as a result of high end-point evaluability. The NIAID Therapeutics Data and Safety Monitoring Board conducted 3 interim analyses of efficacy and safety; O'Brien-Fleming stopping boundaries were used as guidelines for interim monitoring. All P values and 95% CIs presented here are unadjusted for interim analyses.

Fisher's exact test was used to compare the proportion of patients with complete response in pairwise comparisons and across treatment arms. Pearson's χ2 tests (for categorical outcomes) and Kruskal-Wallis tests (for continuous outcomes) were used to compare baseline demographic characteristics. Kaplan-Meier curves and associated log-rank tests were used to compare the distributions of time to complete response, time to relapse, time to death, and time to treatment discontinuation. Cox proportional hazard models were used to evaluate risk factors for survival, and logistic regression models were used to assess predictors of complete microbiologic response. Baseline covariates considered were treatment assignment, CD4+ cell count, previous MAC prophylaxis, PI use, MAC bacteremia level, and resistance of isolates to ethambutol or rifabutin.

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Results

Patient Population and Baseline Characteristics

A total of 203 patients were enrolled between December 1994 and February 1998. Thirty-nine subjects had baseline blood cultures that were negative for MAC, and 4 subjects were enrolled but not randomized; these subjects were considered to be ineligible and were excluded from the analysis. Of the 160 eligible subjects, 53 were randomized to receive C+E; 50, C+R; and 57, C+E+R. Patients were followed up through June 1998, with a median follow-up period of 41 weeks.

Demographic and selected clinical characteristics and laboratory findings for randomized subjects are summarized in table 1. The median baseline CD4+ T cell count was 8 cells/µL. Previous MAC prophylaxis was reported for 27% of subjects, and 14% were receiving PIs at study entry. The 3 treatment arms were well balanced with regard to baseline characteristics, with no significant differences for any of these measurements.

Primary Study End Points

The proportion of subjects with a complete microbiologic response at week 12 was 40% (95% CI, 26%–54%) for the C+E group, 42% (95% CI, 28%–57%) for the C+R group, and 51% (95% CI, 37%–64%) for the C+E+R group (table 2). There were no significant differences between the treatment arms, either overall (P = .454) or in pairwise comparisons. The median time to a complete response was 12–13 weeks for each treatment arm, with no significant difference between treatment arms (P = .964; figure 1). The proportion of patients who developed a complete microbiologic response during follow-up was 55% for C+E, 46% for C+R, and 70% for C+E+R (P = .036). In logistic regression models, only a lower baseline level of MAC bacteremia was significantly associated with a complete response at week 12 (relative risk [RR], 6.06; P < .001).

Figure 1
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Figure 1

Time to complete microbiologic response, by treatment arm, among patients with AIDS who were receiving treatment for Mycobacterium avium complex disease. Nos. of patients in each group and median weeks between randomization and complete response are listed at the bottom of the figure. P = .954, by log-rank test. C, clarithromycin; E, ethambutol; R, rifabutin.

The proportion of patients who had complete microbiologic and clinical response by week 12 was 26% (95% CI, 15%–40%) for the C+E arm, 26% (95% CI, 15%–40%) for the C+R arm, and 30% (95% CI, 18%–43%) for the C+E+R arm. There were no differences in these proportions at week 12 overall (P = .903) or in pairwise comparisons (table 2).

Figure 2
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Figure 2

Change from baseline level of bacteremia, by treatment arm, among patients with AIDS who were receiving treatment for Mycobacterium avium complex disease. Bars show 95% CIs. C, clarithromycin; E, ethambutol; R, rifabutin.

Figure 3
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Figure 3

Time to relapse, by treatment arm, among patients with AIDS who had complete or partial responses to treatment for Mycobacterium avium complex disease. Nos. of patients in each group are listed at the bottom of the figure. P = .014, by log-rank test. C, clarithromycin; E, ethambutol; R, rifabutin.

Figure 4
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Figure 4

Time to death, by treatment arm, among patients with AIDS who were receiving treatment for Mycobacterium avium complex disease. Nos. of patients in each group and median weeks between randomization and death are listed at the bottom of the figure. P = .020, by log-rank test. C, clarithromycin; E, ethambutol; R, rifabutin.

Table 1
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Table 1

Selected baseline characteristics and laboratory values for patients with AIDS who received combination clarithromycin therapy for Mycobacterium avium complex (MAC) disease, by treatment arm.

Table 2
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Table 2

Proportions of patients with AIDS with a complete microbiologic response and with a complete clinical response to combination clarithromycin therapy for Mycobacterium avium complex disease, by treatment arm and week of therapy.

Secondary Study End Points

Reduction in MAC bacteremia and distribution of microbiologic responses. The quantity of MAC in blood decreased over time in patients in all 3 treatment arms (figure 2). All 3 arms demonstrated a mean decrease of >1 log10 cfu/mL by week 4 and 2 log10 cfu/mL by week 12. The distribution of microbiologic responses is shown in table 3 for weeks 12 and 16. At week 12 of treatment, 44% of evaluable patients had a complete microbiologic response, 30% had a partial response, 19% had treatment failure, and 1% had experienced relapse. There were no significant differences between treatment arms at any week for these end points.

Table 3
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Table 3

Distribution of microbiologic responses at weeks 12 and 16 of therapy among patients with AIDS receiving combination clarithromycin therapy for Mycobacterium avium complex disease, by treatment arm.

Relapse of MAC disease. Of the 127 patients who experienced a complete or partial response during study follow-up, 15 subsequently experienced relapses. Although the number of relapses was small, there was a significant difference among treatment arms in time to relapse (P = .014; figure 3). The proportion of patients with complete or partial responses who experienced a relapse while receiving C+R (24%) was significantly higher than the proportion for the C+E+R group (6%; P = .027) and marginally higher than the proportion for the C+E group (7%; P = .057).

Survival. A total of 66 (41%) of the 160 eligible subjects died during the study; 25 deaths occurred in the C+E arm, 25 occurred in the C+R arm, and 16 occurred in the C+E+R arm. Progression of HIV-1 infection and MAC disease were the 2 most common causes of death. The median survival times for the C+E group and the C+R group were 35 and 45 weeks, respectively; the median survival time could not be calculated for the C+E+R group, because the estimated survival probability remained >0.50 for the duration of the follow-up period. There was an overall significant difference in time to death (P = .020, by the log-rank test; figure 4), with improved survival for those randomized to receive C+E+R, compared with either C+E (hazard ratio, 0.44; 95% CI, 0.23–0.83; P = .009) or C+R (hazard ratio, 0.49; 95% CI, 0.26–0.92; P = .024). In a multivariate Cox proportional hazards model that was adjusted for PI use and other prognostic factors, treatment with C+E+R was still associated with a significantly decreased risk of death, compared with treatment with C+E (RR, 0.35; P = .002) or C+R (RR, 0.46; P = .026); the association was not statistically significant for any covariate other than treatment.

Resistance of MAC isolates to study drugs. Baseline susceptibility results (available for 156 of the 160 subjects) indicated that only 3 isolates (2%) from samples obtained at baseline were resistant to clarithromycin, whereas 84 (54%) were resistant to ethambutol and 104 (67%) were resistant to rifabutin. The baseline MIC distributions were similar across treatment arms, and there were no significant differences in the proportions of isolates with resistance to clarithromycin, ethambutol, or rifabutin. Most patients (7 of 9) who experienced relapses while receiving C+R had isolates that were resistant to clarithromycin before the relapse, whereas only 1 of 3 patients had resistant isolates in each of the other arms. By the end of follow-up, all but 1 of the 15 patients who had experienced relapses had isolates that were resistant to clarithromycin.

Treatment discontinuation and adverse experiences. There were no significant differences among treatment arms in the time to treatment discontinuation due to toxicity or in the proportion of subjects experiencing such treatment-limiting toxicities (table 4). In addition, there were no differences among treatment arms in the incidence of grade 3 (severe) or 4 (life-threatening) adverse experiences, as defined according to the Division of AIDS Tables for Grading Severity of Adult Adverse Experiences. Gastrointestinal side effects were the most common clinical toxicity, and neutropenia was the most common laboratory toxicity. Confirmed uveitis (any grade) occurred in 8 (5%) of 160 patients. Only 3 cases of uveitis were reported as grade 3 or worse severity, and uveitis resolved in all 8 patients.

Table 4
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Table 4

Proportion of patients with AIDS receiving combination clarithromycin therapy for Mycobacterium avium complex disease who experienced treatment-limiting toxicities or severe adverse effects, by treatment arm.

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Discussion

This study demonstrated no differences in 3 clarithromycin-containing treatment regimens with regard to the primary end point of proportion of patients who achieved a complete microbiologic response or a complete microbiologic and clinical response by week 12 of therapy. All 3 regimens appeared to provide effective treatment; 70%–84% of patients had either complete or partial microbiologic response by week 12. Planned secondary analyses suggested that the 3-drug regimen, C+E+R, had greater overall efficacy. First, patients randomized to receive C+E+R had a lower risk of death than did patients randomized to receive either of the 2-drug regimens. Second, the rate of relapse was lower in the C+E+R group than in the C+R group. Third, the 3-drug regimen group had the highest proportion of patients who attained a complete response at any point during the study.

Several studies have evaluated the safety and efficacy of clarithromycin in combination with other agents for treatment of MAC disease. Only 2 of these have demonstrated a survival benefit of one regimen compared with another. Shafran et al. [19] evaluated 187 patients with AIDS who had MAC bacteremia and were randomized to receive either rifampin, ethambutol, clofazimine, and ciprofloxacin or clarithromycin, ethambutol, and rifabutin. The clarithromycin regimen was more effective in clearing MAC from blood (clearance in 69% vs. 30% of patients) and showed improved survival (median, 8.7 vs. 5.2 months). The microbiologic response and median survival time were similar to those reported for the C+E+R treatment arm of our study. Chaisson et al. [20] reported contrasting results for 89 patients with AIDS who had MAC bacteremia and were randomized to receive either clarithromycin and ethambutol or these drugs plus clofazimine. The clearance of MAC bacteremia, relapse rates, and clinical response were similar between treatment arms, but patients randomized to the 3-drug arm had a higher mortality rate and more treatment-limiting side effects. Our study demonstrated improved survival with the 3-drug regimen of C+E+R, compared with C+E, without greater treatment-limiting toxicity. The clofazimine used in the former study [20] may have contributed to the excess mortality and toxicity observed with the 3-drug regimen.

Finally, Gordin et al. [28] compared the combination of C+E with C+E+R in 198 patients with AIDS who had MAC bacteremia. At week 16, 63% and 61% of patients receiving C+E+R and C+E, respectively, experienced a bacteriologic response to therapy. No differences between treatment arms were reported in clinical improvement or median survival time. No overall differences were noted with regard to development of clarithromycin resistance; however, among patients with bacteriologic responses at week 16, MAC isolates in only 2% of those receiving C+E+R developed clarithromycin resistance, whereas isolates in 14% of those receiving C+E developed resistance. In contrast, the proportions of patients with complete microbiologic response at week 16 in our study were 63% for the C+E+R arm and 47% for the C+E arm. The analysis of the secondary end point of survival in our study indicated that use of C+E+R was associated with improved survival time, compared with treatment with the 2-drug regimens. In addition, our study did not find any difference in resistance or relapse rates between the C+E+R arm and the C+E arm, which suggests that rifabutin provided no additional advantage with regard to prevention or delay of resistance.

Several differences in study design and patient population may have contributed to the differences between the results of our study and those of the study by Gordin et al. [28]. First, in our study, the definition of complete microbiologic response required 2 consecutive blood cultures negative for MAC, whereas in their study, either a single negative culture or a log10 decrease from baseline in bacteremia level was required. Second, patients in our study were followed for a longer period of time, which may have increased our ability to detect survival differences among the treatment arms. Third, a higher rifabutin dose was used in our study, which may have decreased clarithromycin concentrations through the documented interaction between the 2 drugs [29], resulting in a greater likelihood of resistance in the C+E+R arm, despite similar patterns of baseline clarithromycin resistance. However, the higher rifabutin dose may have enhanced the microbiologic activity against MAC and contributed to the greater overall activity of the 3-drug regimen.

Two notable limitations of our study are the failure to fully accrue the originally planned sample size and the use of open-label treatment. Accrual was greatly hampered by the dramatic decrease in the incidence of MAC infection that resulted from the widespread use of MAC prophylaxis and the advent of PI therapy. Although this affected the overall power of the study to detect differences, significant differences in planned secondary analyses were nonetheless observed. The use of open-label therapy could have influenced the results had patients or investigators been more likely to discontinue assigned treatment in one arm than in another, but rates of treatment discontinuation due to voluntary withdrawal, investigator request, and loss to follow-up were similar across treatment arms.

We conclude that, in our study, the combination of clarithromycin with ethambutol and rifabutin was more effective than a 2-drug regimen of clarithromycin with either ethambutol or rifabutin in prolonging survival, and more effective than clarithromycin plus rifabutin in reducing the risk of relapse. Rifabutin, at the dosage used in this study, did not appear to prevent or delay the emergence of resistance but did appear to contribute to the significant improvement in survival in the 3-drug arm. These data suggest that, with appropriate dose adjustment for drug interactions, the 3-drug combination of clarithromycin, ethambutol, and rifabutin may be among the most effective treatments for disseminated MAC disease in HIV-infected individuals.

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Participating Sites in the Aids Clinical Trials Group Protocol 233

Boston Medical Center, Boston, Massachusetts (Donald Craven and Diane Otis); University of California, San Diego (Joanne Santangelo); San Francisco General Hospital, San Francisco, California (Judith Aberg, Carol Arri, and Mark Jacobson); University of Rochester Medical Center, Rochester, New York (Ross Hewitt and Richard Reichman); State University of New York—Buffalo, Buffalo (Paul Stockdill and Chiu-Bin Hsiau); University of Southern California, Los Angeles (Michael Dube, Frances Canchola, and Claire Hughlett); University of Washington, Seattle (Becky Royer and Mary Paradise); University of Minnesota, Minneapolis (Nancy Reed); Beth Israel Medical Center, New York, New York (Donna Mildvan); Montefiore Medical Center, Bronx, New York (Barry Zingman David Stein, Elizabeth Jenny-Avital, and Carol Harris); Washington University, St. Louis, Missouri (Kimberly Gray and Michael Royal); Ohio State University, Columbus (Susan Koletar and Kathy Watson); University of Kentucky, Lexington (Joseph Berger); University of Cincinnati, Cincinnati, Ohio (Richard Greenberg); Indiana University Hospital, Indianapolis (Kristen Todd, Beth Zwickl, Sarah Ryan, and John Black); Cook County Hospital, Chicago, Illinois (Joseph Pulvirenti); University of North Carolina, Chapel Hill (Charles van der Horst, Irene Vangsness, and Barbara Longmire); University of Hawaii, Honolulu (Monica Millard); University of Alabama at Birmingham (Donna Davis and Bob Hill); Emory University, Atlanta, Georgia (Robert Horsburgh and Molly Eaton); University of Colorado Health Sciences Center, Denver (Graham Ray, Steven Johnson, and Michael Grodesky); and Vanderbilt University, Nashville, Tennessee (Judy McKinsey).

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Footnotes

  • Financial support: National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants U01 AI38858 to the Adult AIDS Clinical Trials Group and U01 AI38855 to P.L.W. and F.H. [for statistical support]). Abbott Laboratories supplied clarithromycin and ritonavir, Lederle Laboratories supplied ethambutol, Pharmacia & Upjohn supplied rifabutin, and Merck supplied indinavir to study subjects during the course of this trial.

  • Received February 28, 2003.
  • Accepted June 20, 2003.
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  1. Clin Infect Dis. (2003) 37 (9): 1234-1243. doi: 10.1086/378807
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