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Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

  1. Peter G. Pappas1,
  2. Coleman M. F. Rotstein9,
  3. Robert F. Betts2,
  4. Marcio Nucci10,
  5. Deepak Talwar11,
  6. Jan J. De Waele13,
  7. Jose A. Vazquez3,
  8. Bertrand F. Dupont14,
  9. David L. Horn4,
  10. Luis Ostrosky-Zeichner6,
  11. Annette C. Reboli7,
  12. Byungse Suh5,
  13. Raghunadharao Digumarti12,
  14. Chunzhang Wu8,
  15. Laura L. Kovanda8,
  16. Leah J. Arnold8, and
  17. Donald N. Buell8
  1. 1University of Alabama at Birmingham, Rochester, New York
  2. 2University of Rochester, Rochester, New York
  3. 3Henry Ford Health System, Detroit, Michigan
  4. 4Thomas Jefferson University, Philadelphia, Pennsylvania
  5. 5Temple University, Philadelphia, Pennsylvania
  6. 6University of Texas-Houston, Camden, New Jersey
  7. 7Cooper University Hospital, Camden, New Jersey
  8. 8Astellas Pharma US, Deerfield, Illinois
  9. 9Hamilton Health Sciences, Hamilton, Canada
  10. 10Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil
  11. 11Metro Hospitals and Heart Institute, Uttar Pradesh
  12. 12Nizam Institute of Medical Sciences, Hyderabad, India
  13. 13Ghent University Hospital, Ghent, Belgium
  14. 14Hôpital Necker, Paris, France
  1. Reprints or correspondence: Dr. Peter G. Pappas, Div. of Infectious Diseases, University of Alabama at Birmingham, 1900 University Blvd., THT 229, Birmingham, AL 35294-0006 (pappas{at}uab.edu); Dr. Coleman M. F. Rotstein, McMaster University, 711 Concession St., Mailton, ON L8V 1C3 (crotstei{at}mcmaster.ca).
 
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Abstract

Background. Invasive candidiasis is an important cause of morbidity and mortality among patients with health care–associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis.

Methods. This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy.

Results. A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms.

Conclusions. Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Invasive Candida infections are an important causes of morbidity and mortality among patients with health care–associated infections in developed countries [1,2,3,4,5–6]. The attributable mortality associated with candidemia may be as high as 47% [7, 8], although it is estimated to be 15%–25% for adults and 10%–15% for neonates and children [1, 9, 10]. Moreover, it has been estimated that, in the United States, each episode of candidemia in adults leads to an additional $40,000 in hospitalization costs [11].

Several drugs have received US Food and Drug Administration approval for treatment of invasive candidiasis, including conventional and lipid formulations of amphotericin B, fluconazole, caspofungin, anidulafungin, and voriconazole [12,13–14], and most have been studied in randomized, controlled trials [15,16,17,18,19–20]. In the treatment of candidemia, the echinocandins have demonstrated consistent efficacy and a favorable safety profile [19, 20]. The in vitro antifungal activity, pharmacokinetics, and toxicity profiles are slightly different for each echinocandin [21, 22], but the relevance of this finding is unclear. There are no clinical trials comparing the safety and efficacy of different echinocandins.

Micafungin is an echinocandin with potent in vitro activity against Candida species [23]. A dosage of 150 mg per day is currently approved in the United States for the treatment of esophageal candidiasis, and a dosage of 50 mg per day is approved for the prevention of Candida infection in hematopoietic stem cell transplant recipients. Two recently completed clinical trials further suggest that micafungin is effective for the treatment of invasive candidiasis [24, 25]. This study was designed to compare the safety and efficacy of 2 dosages of micafungin with that of a standard dosage of caspofungin in adults with candidemia or invasive candidiasis.

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Patients and Methods

Study design. This was a randomized, double-blind phase III study stratified by APACHE II score (⩽20 or >20) and region (North America, Europe, Brazil, or India). Patients were randomized in a 1 : 1 : 1 ratio to receive 100 mg of micafungin, 150 mg of micafungin, or caspofungin (70 mg on day 1 and 50 mg thereafter) once daily intravenously. The maintenance dosage of caspofungin was adjusted to 35 mg daily for patients with moderate hepatic insufficiency, defined as a Child-Pugh score of 7–9. There was no dosage adjustment for patients with renal dysfunction. Study medications were administered for 14-28 days or, in patients with chronic disseminated candidiasis or Candida endophthalmitis, for up to 8 weeks; baseline was defined as the day study therapy was initiated. Investigators were encouraged to continue treatment with the study medication for 14 days after clearance of Candida organisms from the bloodstream (if the patient had a Candida-positive culture at baseline) and resolution of symptoms attributable to invasive candidiasis. Patients were permitted to switch to oral fluconazole therapy (400 mg daily) at the investigators' discretion after a minimum of 10 days of blinded intravenous therapy, provided the following criteria were met: the Candida infection at baseline was not due to C. krusei or C. glabrata, neutropenia was not present, the clinical signs and symptoms had improved or resolved, the Candida isolate recovered at baseline was susceptible to fluconazole, and negative results of 2 cultures of blood specimens obtained at least 24 h apart were documented. Clinical signs and symptoms were assessed at baseline, on each day of therapy, at the end of blinded intravenous therapy, at the end of all antifungal therapy (including oral therapy, if applicable), and 2 and 6 weeks after the end of all antifungal therapy. Laboratory tests were performed at baseline, periodically during therapy, at the end of blinded intravenous therapy, and at follow-up visits. Investigator assessment at the end of blinded intravenous therapy was used to determine whether treatment was successful, both clinically and mycologically. A data review panel comprising 5 blinded infectious diseases physicians (B.F.D., D.L.H., L.O.-Z., P.G.P., and A.C.R.) received pertinent data concerning each case. The primary purpose of the panel was to confirm the baseline diagnosis and the investigator's assessment of clinical and mycological outcome and to assess all deaths.

This international study was conducted at 128 sites in 15 countries. The study protocol was approved by the institutional review board at each study site. The study was conducted between August 2004 and April 2006 and complied with the ethical principles of good clinical practice. All patients or their legally authorized representatives provided written informed consent before enrollment.

Study patients. Patients aged ⩾18 years who had a diagnosis of candidemia, defined as at least 1 blood culture positive for Candida organisms, or a diagnosis of noncandidemic invasive candidiasis, defined as a Candida-positive culture of a specimen obtained from a normally sterile site ⩽96 h before day 1 or receipt of the first dose, were eligible for enrollment. In addition, patients were required to have at least 1 of the following characteristics: fever (temperature, ⩾38°C) or hypothermia (temperature, <36°C), hypotension (defined as a systolic blood pressure of <90 mm Hg or a decrease of >30 mm Hg from the measurement at baseline), local signs and symptoms of inflammation, and/or radiologic findings that suggested invasive candidiasis. Antifungal prophylaxis with an azole or systemic amphotericin B was allowed prior to enrollment, independent of dose, duration, and route of administration.

Patients were not eligible for enrollment if they were pregnant or nursing, had hepatic disease with a Child-Pugh score of >9, had a life expectancy of <5 days, and/or had proven or suspected Candida endocarditis, osteomyelitis, or meningitis. Additional exclusion criteria included the presence of any of the following characteristics: current receipt of a cyclosporine, receipt of an echinocandin ⩽1 month before randomization, or receipt of systemic antifungal therapy for the current infection for >48 h (the daily dose could not exceed 1 mg/kg for amphotericin B, 5 mg/kg for lipid amphotericin B, 800 mg for fluconazole, 400 mg for itraconazole, or 12 mg/kg for voriconazole).

Evaluation of efficacy and safety. The primary efficacy end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy and determined by the investigators. Clinical success was defined as a complete response to treatment (i.e., resolution of all attributable signs, symptoms, and abnormal radiographic findings associated with fungal infection) or a partial response to treatment (i.e., improvement of attributable signs, symptoms, and abnormal radiographic findings since baseline). For patients with candidemia, mycological success was defined as eradication if 2 cultures of blood specimens obtained at least 24 h apart had negative results. For patients with noncandidemic invasive candidiasis, mycological success was defined as presumed eradication if the patient had a complete clinical response, including resolution of abnormal radiographic findings present at baseline, but no follow-up culture or biopsy performed. Treatment failure was defined as either progression of disease or no detectable improvement in the patient's condition, independent of culture findings, or as mycological persistence at the end of blinded intravenous therapy. Treatment failure was also recorded for patients for whom clinical or mycological data from the end of blinded intravenous therapy were missing and for patients who died during receipt of blinded intravenous therapy. Emergent fungal infection was defined as invasive infection that developed during the treatment or follow–up periods; etiological agents consisted of Candida species (other than the baseline Candida species) recovered >72 h after enrollment and non-Candida organisms. Recurrent fungal infection was defined as a mycologically confirmed infection with the same baseline Candida species during the follow-up phase or a suspected infection that required additional systemic antifungal therapy after the end of all antifungal therapy in patients previously considered to have successfully responded to treatment. A safety analysis was performed for all patients who received at least 1 dose of study drug and was based on the presence of treatment-emergent adverse events and results of routine laboratory tests.

Statistical analysis. The intent-to-treat (ITT) population was defined as all patients who received at least 1 dose of study drug. The efficacy data are from the modified ITT population, defined as all patients in the ITT population with noncandidemic invasive candidiasis or candidemia documented at baseline and confirmed by the data review panel but without Candida endocarditis, osteomyelitis, or meningitis. A treatment success rate of 73% at the end of blinded intravenous therapy was assumed for all 3 arms on the basis of previously published data [19]. The primary null hypothesis was that the rate of treatment success with either dosage of micafungin was >15% inferior to the rate of treatment success with caspofungin. On the basis of a 2-sided α level of .05, a total of 180 patients per treatment arm were required to determine whether the micafungin regimens were noninferior to the caspofungin regimen, using a 2-sided CI of 95% for the difference in efficacy (not exceeding 15%) and a power of ⩾90%, after adjusting for the problem of multiple comparisons by use of the Hochberg method [26]. The sample size was increased by ∼10% to 595 patients, to ensure that enough patients were eligible for inclusion in the modified ITT population. Differences in the percentage of patients who achieved the primary efficacy end point were calculated for each micafungin group and the caspofungin group, and 2-sided 95% CIs were determined for both differences, adjusting for geographic region and APACHE II score (⩽20 and >20) by use of the Cochran-Mantel-Haenszel weights, as specified by Mehrotra and Railkar [27]. The same method was used to analyze the following rates: treatment success, based on the data review panel's assessment; clinical response; mycological response; and emergent fungal infections. The relapse rates were analyzed similarly but involved an adjustment for the duration of oral fluconazole therapy (⩽2 doses vs. >2 doses).

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Results

Patients. A total of 595 patients were randomized, received at least 1 dose of blinded study drug, and were included in the safety analysis. For the modified ITT population, 17 patients were excluded, because of Candida endocarditis at baseline (for 2 patients) or no documentation of candidemia or noncandidemic invasive Candida infection at baseline (for 15 patients). Baseline demographic characteristics are summarized in table 1. Data on sex, race, geographic region, age, neutropenia status at baseline, other underlying conditions, APACHE II score, and intravascular catheter management were comparable across treatment groups. Most patients (69.6%) had no evidence of a neoplastic condition.

Figure 1
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Figure 1

Kaplan-Meier estimates of time to Candida eradication, based on blood culture results for the micafungin 100 mg, micafungin 200 mg, and caspofungin treatment arms. P = .1892 for micafungin 100 mg vs. caspofungin, and P = .1697 for micafungin 150 mg vs. caspofungin, by the log-rank test.

Figure 2
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Figure 2

Kaplan-Meier estimates of time to death for the micafungin 100 mg, micafungin 200 mg, and caspofungin treatment arms. P = .665 for micafungin 100 mg vs. caspofungin, and P = .194 for micafungin 150 mg vs. caspofungin, by the log-rank test.

Table 1
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Table 1

Demographic and clinical characteristics at baseline and underlying conditions for the modified intent-to-treat population.

The median duration of treatment with blinded study drug and all other antifungal therapy was 14 days for each treatment arm. This finding reflects the relatively small percentage of patients who received protocol-defined oral fluconazole at the end of blinded intravenous therapy, including 20.9% of patients in the micafungin 100 mg arm (median duration of oral fluconazole therapy, 7.5 days), 15.1% in the micafungin 150 mg arm (6.5 days), and 21.2% in the caspofungin arm (4 days).

Fungal infections at baseline. Characteristics of fungal infections and etiological pathogens at baseline are shown in table 2. Candidemia was observed in 492 (85.1%) of 578 patients at baseline. The most commonly isolated non-albicans species of Candida were C. tropicalis (from 16.6% of patients), C. glabrata (16.4%), and C. parapsilosis (15.9%).

Table 2
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Table 2

Prevalence of Candida species at baseline.

Efficacy. A successful outcome at the end of blinded intravenous therapy was achieved by 146 (76.4%) of 191 patients in the micafungin 100 mg group, 142 (71.4%) of 199 in the micafungin 150 mg group, and 136 (72.3%) of 188 in the caspofungin group (table 3). Micafungin 100 mg was slightly more effective (treatment difference, 4.1%; 95% CI, -4.4% to 12.3%) and micafungin 150 mg slightly less effective (treatment difference, -1.0%; 95% CI, -9.3% to 7.8%) than caspofungin, demonstrating that both micafungin regimens were noninferior to the caspofungin regimen (table 4). For patients from each treatment arm who received oral fluconazole, relative success rates were maintained at the end of all antifungal therapy.

Table 3
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Table 3

Treatment success for the modified intent-to-treat population.

Table 4
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Table 4

Rates of treatment efficacy reported by the investigators.

The overall response rates for patients with C. albicans were similar to those for patients with non-albicans Candida species across treatment arms; however, there were small, non–statistically significant differences noted between some non-albicans species of Candida (table 5). For patients with baseline APACHE II scores of ⩽20 and >20, treatment success at the end of blinded intravenous therapy was similar across treatment arms. Similarly, success at the end of blinded intravenous therapy, based on management of intravascular catheters, did not vary significantly between treatment arms. However, in each arm, patients who underwent intravascular catheter removal or replacement more often achieved treatment success, compared with patients who did not undergo catheter removal. In aggregate, 299 (77.9%) of 384 patients whose intravascular catheter was removed or replaced achieved treatment success, compared with 91 (63.2%) of 144 patients whose catheter was not removed or replaced (P = .001).

Table 5
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Table 5

Characteristics of patients for whom treatment was successful.

Persistently positive culture results as a cause of treatment failure were seen more frequently in micafungin 150 mg group (23 patients [11.6%]) and the caspofungin group (18 [9.6%]), compared with the micafungin 100 mg group (11 [5.8%]) (table 6). Collectively, there were 2 emergent and 13 proven relapsed infections, with no difference in rates of these infections observed between treatment arms. Five percent of patients who received caspofungin had a culture-confirmed relapsed infection, compared with 4.5% who received micafungin 100 mg and 2.9% who received micafungin 150 mg (table 6).

Table 6
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Table 6

Characteristics of cases of treatment failure and relapse.

Among the patients who had positive blood culture results at baseline, the median time to having blood cultures negative for Candida species was 2 days for the micafungin 100 mg and caspofungin groups and 3 days for the micafungin 150 mg group. The time to mycological eradication was not significantly different between the caspofungin group and both the micafungin 100 mg group (P = .189, by the log-rank test) and the micafungin 150 mg group (P = .170, by the log-rank test) (figure 1).

The in vitro susceptibility data for micafungin and caspofungin were similar in each treatment arm. The MICs of both agents were generally higher for C. parapsilosis (MICs90, 2.0 µg/mL) than for C. albicans (micafungin MIC, ⩽0.003µg/mL; caspofungin MIC, 0.5 µg/mL), C. glabrata (⩽0.03 µg/mL; 1.0 µg/mL), and C. tropicalis (⩽0.03 µg/mL; 1.0 µg/mL). There were no isolates with MICs of >2 µg/mL for either agent.

Safety. The safety analysis included 595 patients, of whom 44 (22%) of 200 in the micafungin 100 mg group, 46 (22.8%) of 202 in the micafungin 150 mg group, and 46 (23.8%) of 193 in the caspofungin group experienced treatment-related adverse events. The treatment-emergent adverse events that most commonly appeared (i.e., in ⩾2% of patients per treatment arm) included an increased serum alkaline phosphatase level, abnormal results of liver function tests, nausea, constipation, hypokalemia, and rash. The number of adverse events of special interest (hepatic, renal, injection site reactions, histamine and/or allergic-type reactions, infusion-related reactions, and hemolysis) was similar across all groups. Study drug–related adverse events leading to withdrawal from the study were observed in 5 patients (2.5%) who received micafungin 100 mg, 6 (3.0%) who received micafungin 150 mg, and 7 (3.6%) who received caspofungin and included the following: liver function abnormalities (in 6 patients), rash (in 3 patients), and leukopenia, thrombocytopenia, thrombocytosis, hypokalemia, seizures, confusion, renal failure, fever, and malaise (in 1 patient each).

Mortality. A total of 176 (29.6%) of 595 patients who received one of the study drugs died. More patients died in the micafungin 100 mg arm (58 [29%] of 200) and the micafungin 150 mg arm (67 [33.2%] of 202) than in the caspofungin arm (51 [26.4%] of 193). No deaths were related to the study drugs. The log-rank test indicated that there were no significant differences in survival between the caspofungin group and the micafungin 100 mg (P = .665) and 150 mg (P = .194) groups (figure 2).

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Discussion

To our knowledge, the current study is the largest randomized double-blind therapeutic trial among patients with candidemia and other forms of invasive candidiasis, as well as the first trial to compare different echinocandins for both safety and efficacy. With an enrollment of >180 eligible patients per treatment arm and a conservative noninferiority margin of 15%, the conclusions from this study are statistically reliable and confirm that micafungin dosages of 100 mg and 150 mg daily are safe and effective alternatives to a standard dosage of caspofungin for the treatment of candidemia and invasive candidiasis.

The results of this study are consistent with the strong safety and efficacy profile observed in other trials evaluating the echinocandins [19, 20, 24, 25], including a large randomized, double-blind phase III trial comparing micafungin 100 mg daily with liposomal amphotericin B 3 mg/kg daily for the treatment of invasive candidiasis [25]. In the current study, treatment success at the end of blinded intravenous therapy, the end of all antifungal therapy, and 2 and 6 weeks after completion of all antifungal therapy did not differ among the 3 arms. Furthermore, all 3 study regimens were safe and well-tolerated; only 18 (3%) of 595 patients discontinued blinded study therapy because of a study drug–related adverse event, with no discernible differences between treatment arms.

Candida species recovered at baseline from patients in this trial were similar to those observed in several recently completed therapeutic trials for candidemia and were consistent with recent epidemiologic trends [1,2,3,4,5,6–7, 10]. Treatment success in patients infected with C. albicans was consistent with results reported in recent studies [19, 20]. Among patients with infections due to C. glabrata, C. parapsilosis, or C. tropicalis, there were subtle differences in species-specific outcome between each treatment arm, but none of the differences were statistically significant. Overall, there were too few patients infected with some of the less common Candida species, such as C. guilliermondii, C. lusitaniae, and C. krusei, to determine any trends in clinical, mycological, and overall success.

An important observation in this study is the absence of any trend suggesting that the higher dosage of micafungin (150 mg/day) offered any potential advantage over the lower dosage (100 mg/day). Intravascular catheter management, baseline characteristics, Candida species distribution, and duration of therapy were similar in each arm. A possible explanation is a lower than expected rate of success among patients with noncandidemic invasive Candida infections who were in the micafungin 150 mg study arm. Specifically, 14 (47%) of 30 patients in the micafungin 150 mg group experienced treatment failure, compared with only 6 (22%) of 28 patients in the micafungin 100 mg group. A paradoxical effect observed elsewhere in some Candida isolates exposed to higher concentrations of caspofungin, anidulafungin, and micafungin in vitro [28,29–30] is of interest and could possibly explain the lack of any observed benefit in patients who received the higher dosage of micafungin in this study, but it is unknown whether this laboratory-observed phenomenon has any clinical relevance.

Despite the large number of patients enrolled into this clinical trial, there are several limitations to the interpretation of these results. First, there were relatively few patients in each arm with baseline infections due to individual non-albicans Candida species, and it is possible that subtle differences in clinical activity exist between these regimens that are not demonstrated by these data. This shortcoming notwithstanding, this study remains the largest single investigation of the treatment of infections caused by C. parapsilosis, C. glabrata, and C. tropicalis in a prospective clinical trial. Second, there were few patients with neutropenia at baseline, thus making it difficult to draw meaningful conclusions about the efficacy of the echinocandins in such patients. This has been a shortcoming among all randomized therapeutic studies of invasive candidiasis [19,20,24,27], reflecting the difficulty of enrolling such patients in clinical trials [3]. Finally, ∼25% of patients in each arm did not have baseline vascular catheters removed, and this could have adversely influenced success rates.

In conclusion, this is the largest randomized, double-blind trial for the treatment of candidemia and other forms of invasive candidiasis, and it is the first clinical trial to compare echinocandins. The results of this trial indicate that micafungin 100 mg daily is a safe and effective alternative to both micafungin 150 mg daily and a conventional dosage of caspofungin in the treatment of candidemia and other forms of invasive candidiasis.

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Members of the Study Group

Independent data review panel. P. Pappas (University of Alabama at Birmingham), L. Ostrosky-Zeichner (University of Texas–Houston), D. Horn (Thomas Jefferson University), B. Dupont (Hôpital Necker), and A. Reboli (Cooper University Hospital).

Investigators. Study group members from the United States include B. Alexander (Duke University), K. Almoosa (University of Cincinnati), C. L. Anderson (Bay Pines VA Medical Center), E. Anaissie (University of Arkansas), M. Barron (University of Colorado), R. Betts (University of Rochester), D. Bodensteiner (University of Kansas), D. Busch (California Pacific Medical Center), S. Chapman (University of Mississippi), G. Donowitz (University of Virginia), M. Dugan (St. Francis Hospital), M. Epstein (North Shore University Hospital), G. Forrest (University of Maryland), J. Fraiz (Infectious Disease of Indiana), B. Friedman (Doctors Hospital), J. Garcia-Diaz (Ochsner Health System), M. Gareca (LeHigh Valley Hospital), R. Harvey (Iowa Methodist Medical Center), K. High (Wake Forest University), R. Jones (Berks Infectious Disease), G. M. Lyon (Emory University), J. Mangino (Ohio State University), K. Marr (Fred Hutchinson Cancer Center), F. Marty (Brigham and Women's Hospital), T. Moore (Via Christi Regional Medical Center), M. Morris (University of Miami), K. Mullane (University of Chicago), J. Nowakowski (Westchester Medical Center), L. Ostrosky-Zeichner (University of Texas–Houston), P. Pappas (University of Alabama–Birmingham), D. Paterson (University of Pittsburgh Medical Center), T. Patterson (University of Texas–San Antonio), J. Salgado (St. Mary's Medical Center), C. Savor-Price (University of Colorado), M. Schmidt (Fairfax Hospital), M. Schuster (University of Pennsylvania), S. Shoham (Washington Hospital Center), C. Singer (Long Island Jewish Medical Center), P. Sioson (Jackson–Madison County General Hospital), J. Sobel (Wayne State University), B. Suh (Temple University), E. Tobin (Albany Medical College), J. van Burik (University of Minnesota), E. Vance (Baylor University), and J. Vazquez (Henry Ford Health System). Study group members from Canada include E. Bow (Health Science Centre–Winnipeg), G. Evans (Queen's University), D. Ferris (Kelowna General Hospital), G. Garber (The Ottawa Hospital), D. Grimard (Complexe Hospitalier de la Sagamie), D. Kumar (Toronto General Hospital), D. Kunimoto (University of Alberta Hospital), M. Laverdiere (Hopital Maisonneuve), S. McNeil (Queen Elizabeth II Health Sciences Centre), R. Pelletier (University of Quebec), G. Poirier (Hopital Charles le Moyne), C. Rotstein (Hamilton Health Sciences Corp.), and S. Sanche (Royal University Hospital). Study group members in Europe include J. Aguado (Hospital Doce de Octubre), E. Bouza (Hospital Gregorio Maranon), R. Camara (Hospital Universitario La Princesa), J. Cisneros (Hospital Virgen del Rocio), C. Farinas (Hospital Universitario Marques de Valdecilla), J. Fortun (Hospital Ramon y Cajal), M. Gobernado (Hospital La Fe), F. Lerma (Hospital del Mar), J. Mensa (Hospital Clinic i Provincial), M. Montejo (Hospital de Cruces), and I. Ruiz (Hospital Vall d'Hebron), from Spain; R. Beale (St. Thomas' Hospital), M. Bellamy (St. James's University Hospital), S. Binning (Western Infirmary), A. Mallick (Leeds General Infirmary), and M. Palazzo (Hammersmith Hospital), from the United Kingdom); K. Boggian (DIM Infektiologie), and J. Garbino (Geneva Universit Hospitals), from Switzerland; A. Böhme (Medizinische Klinik III), O. Cornely (Klinik I fur Innere Medizin), W. Heinz (Medizinische Poliklinik Wurzburg), M. Karthaus (Klinik fur Innere Medizin), E. Kuse (Klinik fur Viszeral–und Transplantationschirugie), and M. Ruhnke (Med. Klinik und Poliklinik), from Germany; Y. Cohen (Hopital Avicenne), A. Datry (Laboratoire de Parasilologie et Mycologie), B. Gachot (Institut Gustave Roussy), C. Gibert (Hopital Pitie-Salpetriere), R. Herbrecht (Hopital de Hautepierre), J. Marie (Hotel-Dieu), A. Rio (Centre Hospitalier Regional), F. Saliba (Hopital Paul Brousse), and M. Wolff (Hopital Bichat–Claude Bernard), from France; P. Damas (CHU), I. Demeyer (OLV Ziekenhuis Aalst), F. Jacobs (Erasme), H. Spapen (AZ VUB), and J. de Waele (University Hospital) from Belgium; W. Graninger (Allgemeines Krankenhaus der Stadt Wien), from Austria; A. Hellmann (Medical Academy Gdansk) and T. Robak (M. Kopernikus Hospital), from Poland; B. Jaksic (University Hospital Merkur), from Croatia; and M. Rodgers (Academisch Ziekenhuis Groningen), from The Netherlands. Study group members from Brazil include C. Barrios (Hospital Sao Lucas da PUCRS), A. Colombo (Universidade Federal de Sao Paulo), M. Didier (Felicio Rocho), F. Telles Filho (Hospital Clinical da Universidade Federal do Parana), A. Freire (Consultoria em Controle de Infeccao Hospitalar), E. Kallas (Hospital do Servidor Publico Estadual de Sao Paulo–Molestias), S. Lobo (Hospital de Baso de Sao Jose do Rio Preto), C. Lotfi (Hospital do Cancer AC Camargo), M. Neto (Hospital Mater Dei), M. Nucci (Hospital Universitario Clementino Fraga Filho), A. Paste (Santa Casa de Misericordia-Hospital Santa Izabel-Unidade de), D. Sampaio (Universidade Federal da Bahia), C. Starling (Hospital Vera Cruz), and M. Yasuda (Hospital das Clinicas da FMUSP). Study group members from India include P. Adhikari (KMC Hospital), J. Chacko (Manipal Hospital), M. Dinaker (Mediciti Share Medical Centre), V. Kapoor (Sanjay Gandhi Post Graduate Institute of Medical Sciences), D. Raghunadrao (Nizam Institute of Medical Sciences), T. Raja (Apollo Specialty), V. Ramsubramanian (Apollo Hospitals), D. Divatia (Tata Memorial Hospitals), K. Reddy (Care Hospitals), J. Shekon (Dayanand Medical College and Hospital), S. Sudhindran (Amrita Institute of Medical Sciences), D. Talwar (Metro Heart and Hospital), and S. Todi (AMRI Kolkata).

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Acknowledgments

Financial support. Astellas Pharma US.

Manuscript preparation. Astellas provided assistance with the study design, data acquisition, and data analysis. The article was written by P.G.P., with significant contributions by each coauthor.

Potential conflicts of interest. P.G.P. receives grant support and is on the speaker's bureaus of Astellas Pharma US, Merck, Pfizer, Enzon, and Schering-Plough. C.M.F.R. is a consultant for and on the speaker's bureaus of Astellas, Merck-Frosst Canada, and Pfizer and receives grant support from Astellas Pharma US, Merck, and Pfizer. M.N. is a consultant for, is on the speakers' bureaus of, and receives grant support from Pfizer, Merck, and Schering-Plough. D.H. receives research funding from, is a consultant for, and is on the speakers' bureaus of Pfizer and Astellas. L.O.Z. receives grant support from, is on the speaker's bureaus of, and served as a consultant for Astellas, Merck Pfizer, Enzon, and Gilead. AR receives research support from Merck and Pfizer, is on the speakers' bureau of Pfizer, and is a consultant for Astellas. B.D. is on the speakers' bureaus of Astellas, Schering-Plough, Cephalon, Merck, and BioAlliance. J.V. is on speakers bureaus of Pfizer, Schering-Plough, and Enzon; receives research support from Pfizer, Astellas, Merck, Salix, Schering-Plough, Johnson and Johnson, Basilea, Bayer, Peninsula, ACC, GlaxoSmithKline, Roche, BioAlliance, Theravance, Wyeth, and Novartis; and is a consultant for Schering-Plough, Astellas, Pfizer, and Smith & Nephew. C.W., L.J.A., L.L.K., and D.N.B. are employees of Astellas. All other authors: no conflicts.

  • Received March 26, 2007.
  • Accepted June 12, 2007.
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  1. Clin Infect Dis. (2007) 45 (7): 883-893. doi: 10.1086/520980
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