JAC Advance Access originally published online on May 26, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):363-369; doi:10.1093/jac/dkm169
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Caspofungin for the treatment of less common forms of invasive candidiasis
1 Klinik I für Innere Medizin, Klinikum der Universität zu Köln, 50924 Köln, Germany 2 Hosp Sotero del Rio, Av. Concha y Toro 3459, Puenta Alto, Santiago, Chile 3 University Rochester Medical Center, Box 689, Rochester, NY 14642, USA 4 Medical Academy Postgraduate Education, Santiago de Cuba St., 1/28, St Petersburg, Russia 5 Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA 6 Royal Perth Hospital, GPO Box X2213, Perth 6001, Western Australia, Australia 7 Fundacion Valle del Lili, Cra 98 #18-49, Cali, Colombia 8 Merck Research Laboratories, 10 Sentry Parkway, Blue Bell, West Point, PA 19486, USA
* Corresponding author. Tel: +49-221-478-6494; Fax: +49-221-478-3611; E-mail: oliver.cornely{at}ctuc.de or oliver.cornely{at}uni-koeln.de
Received 11 February 2007; returned 21 March 2007; revised 13 April 2007; accepted 20 April 2007
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Abstract |
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Objectives: Caspofungin has demonstrated efficacy in invasive candidiasis. However, in a comparative study, most patients (>83%) had candidaemia. Therefore, we performed a study in patients with non-fungaemic invasive candidiasis.
Patients and methods: Adults with proven non-fungaemic invasive candidiasis or probable chronic disseminated candidiasis (CDC) received caspofungin primary or salvage monotherapy. Most patients received 50 mg daily following a 70 mg loading dose. Patients with endocarditis, osteomyelitis or septic arthritis received caspofungin at 100 mg daily and were allowed dose escalation up to 150 mg. Primary efficacy endpoint was the overall response at end of caspofungin therapy. A favourable overall response required complete resolution of symptoms and either eradication of Candida or radiographic resolution.
Results: All 48 patients enrolled had confirmed infection and received 
1 dose of caspofungin. At study entry, 8% were neutropenic. The mean APACHE II score was 14.3. Most infections were due to Candida albicans (60%) or Candida glabrata (14%). The overall success at end of caspofungin therapy was 81%. Success by site of infection was as follows: peritonitis 77% (10/13), abdominal abscess 89% (8/9), CDC 88% (7/8), osteomyelitis/septic arthritis 100% (4/4), endocarditis 33% (1/3) and multiple sites 75% (6/8). Outcomes were similar across Candida spp. None of the patients had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Overall mortality until 12 week follow-up was 23%.
Conclusions: In deep-seated invasive candidiasis, including peritonitis, abdominal abscesses, CDC and arthritis, caspofungin was effective and safe at regular doses and up to 100 mg daily.
Keywords: Candida peritonitis , abdominal abscess , chronic disseminated candidiasis , arthritis , endophthalmitis
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Introduction |
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The last two decades have demonstrated a significant increase in the incidence of invasive infections due to Candida species.1 In the US, Candida currently represents the fourth most common organism in nosocomial bloodstream infections and the sixth most common nosocomial pathogen.2 The increasing number of invasive surgical procedures and the use of central venous catheters, broad-spectrum antibiotics and parenteral hyperalimentation have contributed to this epidemiological trend.3 The attributable mortality rate in patients with invasive candidiasis (30% to 40%) is three times higher than in controls.4
Polyenes and triazoles are licensed for the treatment of invasive candidiasis. However, infusion-related and renal toxicity limit treatment with amphotericin B deoxycholate and, to a lesser extent, its lipid preparations.5,6 Fluconazole is a cornerstone in the treatment of candidiasis;7,8 but, certain non-albicans species are less susceptible to fluconazole.9 Widespread fluconazole use has also led to the shift from susceptible strains of C. albicans to less-susceptible strains of non-albicans species.10–12 Voriconazole has also been successfully evaluated in non-neutropenic patients with candidaemia, but drug–drug interactions may limit its use.13
Recently, the echinocandins have emerged as a therapeutic alternative for the treatment of invasive candidiasis. Caspofungin is fungicidal against most Candida species,14,15 and a comparative trial confirmed its efficacy in first-line treatment of invasive candidiasis.16 The majority of patients enrolled in this clinical trial were diagnosed with candidaemia. The overall number of patients with non-fungaemic forms of invasive candidiasis was too limited to draw meaningful conclusions. Furthermore, patients with certain difficult-to-treat forms of candidiasis, including endocarditis, osteomyelitis and septic arthritis, were excluded from the prior study.16 Hence, we conducted a multicentre study to further evaluate caspofungin safety and efficacy in patients with non-fungaemic forms of invasive candidiasis.
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Patients and methods |
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Patient population
This open-label, non-comparative, multicentre clinical trial was designed to assess the efficacy and safety of caspofungin as monotherapy against non-fungaemic forms of invasive candidiasis. The protocol was approved by the institutional review boards of all participating centres. Written informed consent was obtained from all enrolled patients.
Inclusion in this study required that adults, 18 years, had proven invasive candidiasis, per criteria established by the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Bacteriology and Mycology Study Group.17 All patients had clinical evidence of Candida infection, either manifested as (i) fever > 37.8°C or clinically significant hypothermia < 36.0°C; or (ii) hypotension (systolic blood pressure < 90 or 30 mmHg decrease from baseline); or (iii) signs of inflammation from a Candida infected site. Patients were required to have 1 positive culture for Candida spp. obtained from an otherwise sterile, non-blood body site within 96 h prior to study entry. Positive cultures obtained through indwelling drains were not sufficient for diagnosis unless the samples were obtained at the time of drain placement. Infections limited to a positive culture from the blood, urine, sputum, bronchoalveolar lavage or catheter tip, or infections limited to the oropharynx, oesophagus or other superficial surfaces, were excluded. Patients were also excluded if prosthetic devices at a suspected infection site were not removed. Patients with chronic disseminated candidiasis (CDC) could be enrolled without microbiological confirmation provided the patient exhibited the appropriate risk factor (e.g. ongoing or recently resolved neutropenia, recent cytotoxic chemotherapy) and either had histopathological evidence of Candida from a sterile tissue sample or an elevated serum alkaline phosphatase and the appropriate radiographic appearance (multiple small, peripheral, target-like abscesses throughout liver and/or spleen) on abdominal imaging. Similarly, patients with Candida endocarditis were also eligible without a positive Candida culture from a valvular infection provided they had still had ‘definitive’ endocarditis, based on the modified Duke criteria.18 In this case, these patients manifested histopathological evidence of Candida within a valvular vegetation, embolized vegetation or intracardiac abscess and persistently positive blood cultures for Candida species.
Exclusion criteria included a history of active hepatitis or cirrhosis, known echinocandin allergy, or concomitant therapy with rifampicin or other systemic antifungal agents. Echinocandin therapy within the 7 days prior to enrolment also prohibited patient participation. Patients who were refractory to or were intolerant of prior antifungal therapy with either a triazole and/or an intravenous amphotericin B formulation for their current episode of invasive candidiasis remained eligible for enrolment. Abnormal laboratory values that disqualified patients from participation were increases in total serum bilirubin or serum transaminases, i.e. ALT or AST 5 times upper-limit of normal range or international normalized ratio > 1.6 in patients not on anticoagulation therapy. All women of childbearing potential had a negative pregnancy test prior to enrolment.
Most patients received a 70 mg loading dose of caspofungin on day 1, followed by 50 mg daily. Patients with endocarditis, meningitis or osteomyelitis/septic arthritis received caspofungin at 100 mg daily without a loading dose. The choice of the 100 mg dose for these infections was predicated on the notion that these sites are associated with poor prognoses and a higher daily dose of caspofungin could enhance the concentrations of drug at the targeted site. Caspofungin was administered over 
1 h as a single daily dose. The caspofungin daily dose could be increased to 100 mg daily or up to 150 mg daily for patients initiating therapy at 100 mg on or after day 5 at the investigator's discretion, if the infection had not demonstrated meaningful clinical and/or microbiological improvement. Dose escalation afforded the investigators a further option against certain difficult-to-treat infections, thereby allowing for patients to continue within the context of the clinical trial in the event that the initial prescribed dose was not immediately effective. Therapy duration was individualized for each patient in accordance with the guidelines set forth by the Infectious Diseases Society of America.19 Treatment duration was adapted to the patient's clinical and microbiological response to study therapy, underlying immune status and the site of Candida infection. A minimum of 10 days of caspofungin was required. Thereafter patients were either continued on caspofungin or switched to oral fluconazole at 400 mg daily for the remainder of the treatment period. The switch to fluconazole was allowed if the following criteria were met: (i) 96 h had elapsed since the last positive culture; (ii) a significant decrease in the signs and symptoms of infection and, where applicable, radiographic improvement of infection had occurred, i.e. only residual findings remained; (iii) the patient was not neutropenic; and (iv) the Candida species was susceptible to fluconazole. Patients with infections caused by Candida krusei or Candida glabrata were maintained on caspofungin. A switch to fluconazole in patients with endocarditis, meningitis or osteomyelitis/septic arthritis could also be considered after at least 21 days of caspofungin.
Patients were evaluated at study entry, daily during caspofungin therapy or oral fluconazole and at 2, 6 and 12 weeks post-treatment. Signs and symptoms of Candida infection (including the most abnormal temperature and blood pressure) were collected daily while on antifungal therapy. Patients with positive cultures from non-blood sites of infection at study entry had follow-up cultures as indicated. In patients in whom an invasive procedure was necessary for documentation of a negative culture, follow-up cultures were not required and infection was presumed as eradicated if there was no evidence of residual infection from symptoms/signs and relevant radiographic studies. Follow-up radiographs from relevant sites of infection were collected at least monthly to assess status of infection. Radiographic imaging was also obtained within 72 h prior to cessation of caspofungin.
The primary efficacy parameter was the overall clinical and microbiological response, as assessed by the investigator. A favourable overall response required resolution of all symptoms and signs of Candida infection and culture-confirmed Candida eradication or presumptive eradication for non-blood sites of infection in the setting of radiographic resolution. Outcomes were considered unfavourable if: (i) the infection was unresponsive or had progressed; (ii) a drug-related adverse event(s) necessitated a change in therapy; or (iii) withdrawal from caspofungin occurred before improvement; or failure could be clearly documented. Evaluations were performed on day 10 of caspofungin therapy, the end of caspofungin therapy and the end of all antifungal therapy, i.e. caspofungin or oral fluconazole. The primary efficacy assessment was predefined as the end of caspofungin therapy.
Patients with a favourable overall response at the end of caspofungin therapy and at the end of all antifungal therapy were also evaluated for relapse of invasive candidiasis. Patients were counted as relapses if there was a recurrence of positive invasive cultures for Candida spp. or if the patient required systemic antifungal therapy for a proven or suspected Candida infection during the 12 week post-therapy follow-up period. Secondary antifungal prophylaxis was allowed for asymptomatic, immuno-compromised patients.
Patients were monitored for clinical adverse events daily and for 14 days following the completion of caspofungin therapy. Laboratory tests were also monitored twice weekly during this same time frame. All adverse events were rated by the investigator as to their severity and the likelihood of their relationship to study therapy.
The design and sample size of this study were not intended to test specific hypotheses with regard to efficacy. For the primary efficacy endpoint, the 95% confidence interval (CI) was calculated as an exact CI based on binomial distribution. Two separate efficacy patient populations were prespecified: a modified intention-to-treat (MITT) population and an evaluable-patients (EP) population. Inclusion in the MITT analysis required that patients have a documented diagnosis of invasive candidiasis and receive 1 dose of caspofungin. For inclusion in the EP population, the patient needed to fulfil the MITT requirement and: (i) not receive any concomitant systemic antifungal therapy while on caspofungin; (ii) not commit any protocol violations that would interfere with the efficacy assessment; (iii) have an appropriate clinical and microbiological end-of-treatment evaluation; and (iv) receive 5 full days of caspofungin. The MITT was the primary efficacy population.
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Results |
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This trial, conducted in the United States, Central/South America, Europe and Australia, enrolled between August 2004 and February 2006. Seventeen investigators contributed to the overall enrolment of 48 patients. All patients satisfied the predefined MITT criteria. Forty-one patients received an initial caspofungin dose of 50 mg daily following a 70 mg loading dose. The remaining seven patients initially received caspofungin at 100 mg daily for treatment of endocarditis (three) or osteomyelitis/septic arthritis (four).
Baseline characteristics, demographics and site of infection
Many patients had multiple factors predisposing them to the development of invasive candidiasis (Table 1). Eleven patients had acute myelogenous leukaemia (19%) or acute lymphoblastic leukaemia (4%) and five patients had a solid organ malignancy. Eight per cent were neutropenic at enrolment.
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The peritoneal cavity was the most common site of infection (27%), followed by intra-abdominal abscess (19%) and CDC (17%) (Table 2). Ten of the 13 patients with peritoneal involvement had developed Candida peritonitis in the setting of bowel perforation or recent surgery. The remaining three patients developed Candida peritonitis in the setting of peritoneal dialysis. The majority had an infection with C. albicans (60%), C. glabrata (14%) or Candida tropicalis (8%). The MIC for caspofungin (based on CSLI method 27A, read as prominent inhibition after 24 h of incubation) ranged from < 0.015 to 0.25 mg/L for all Candida species.
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Reason for enrolment (refractory or intolerant)
Two-thirds (32/48) of patients received caspofungin as primary therapy, including all 7 with endocarditis or osteomyelitis/septic arthritis. The 16 (33%) patients who received caspofungin as salvage therapy were all refractory to prior antifungal therapy. Although the protocol mandated that refractory patients had received 5 days of prior antifungal therapy, 7 (44%) of these 16 patients received > 10 days of prior therapy. The majority (11 patients) were refractory to fluconazole. The remainder were refractory to amphotericin B (two patients), voriconazole (one patient) or multiple antifungals (fluconazole/amphotericin B, two patients). The patients whose infections were refractory to prior fluconazole were predominantly infected with C. albicans, and the susceptibility to fluconazole in these isolates varied (MIC range 0.06–128 mg/L). Only three of these patients had Candida isolates with an MIC of fluconazole > 8 mg/L.
In the MITT population, 39 patients (81%) had a favourable overall response at the end of caspofungin therapy (Table 3). Among the nine patients with an unfavourable response, four had persistently positive Candida cultures (two due to C. albicans and one each due to C. krusei and C. tropicalis) and three patients had an indeterminate efficacy assessment. The remaining two patients with unfavourable responses had persistent signs/symptoms of endocarditis (despite negative follow-up cultures) or developed metastatic Candida lesions while on caspofungin. Among the 42 patients included in the EP population, 37 (88%) demonstrated a favourable overall response at the end of caspofungin therapy.
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Efficacy was also assessed at day 10 of caspofungin and at the end of all antifungal therapy. Seventy-nine per cent (38/48) responded favourably at the end of all antifungal therapy. Sixty-nine per cent (22/32) also had a successful outcome at the day 10 assessment. Approximately one-third were excluded from the day 10 analysis, despite clinical improvement, because microbiological or radiographic data were not available at that point in time. Notably, 12 of the 16 patients excluded from the day 10 analysis had a favourable overall response at the end of caspofungin therapy.
Underlying factors influencing efficacy outcome
Favourable overall responses at the primary efficacy time point were noted across several variables, including APACHE II score, neutropenic status and reason for study entry (Table 4). Successful responses were also noted across many sites of infection. Success rates in patients with intra-abdominal infections were high: peritonitis 77%, abdominal abscess 89% and CDC 88%. All four patients with osteomyelitis/septic arthritis, both patients with endophthalmitis, and one of three patients with endocarditis responded favourably.
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Favourable overall and microbiological responses were also noted among the different Candida species.
As might be expected by the generally low MIC profiles for caspofungin in this study, the outcome was not predicted by the MIC of caspofungin for any Candida pathogen (data not shown).
Eleven patients (23%) died while on caspofungin therapy or during the 12 week post-therapy period. None of the deaths was attributed to caspofungin. In five patients, mortality was directly attributed to the underlying Candida infection. The remaining deaths were the result of other co-morbidities, including multiorgan failure, other infectious complications, e.g. pneumonia and sepsis, and advancing malignancy.
Among the 38 successfully treated patients at the end of all antifungal therapy, 2 experienced a relapse of invasive candidiasis during the 12 week post-therapy period. In both cases, the patients were clinically asymptomatic, but had blood or peritoneal cultures positive for Candida spp. No change in MIC for caspofungin was noted in these isolates relative to baseline. One of the two patients with relapse was treated successfully with a 26 day course of fluconazole. The other patient did not receive additional antifungal therapy as the peritoneal fluid culture was positive for multiple bacterial pathogens and the Candida sp. did not grow until after a 19 day incubation.
Overall, patients received caspofungin for a mean duration of 26.5 days (range 1–108 days). Among the 48 patients, 43 (90%) developed 1 adverse event. Clinical and laboratory adverse events at least possibly related to caspofungin occurred in 19% and 29% of patients, respectively. None of the patients developed a serious drug-related adverse event or was discontinued from caspofungin as a result of a drug-related adverse event. Vomiting was the only drug-related clinical adverse event reported in > 1 patient (2/48, 4%). Drug-related laboratory adverse events reported in > 1 patient included decreased serum potassium (10%), increased alkaline phosphatase (10%), increased AST (6%), increased ALT (4%) and increased bilirubin (4%). However, many of these abnormalities were already present at baseline. Additionally, many of these abnormalities had returned to prestudy levels or were trending downward by the end of caspofungin therapy. Neither of the two patients who received caspofungin with cyclosporin A manifested drug-related elevations in hepatic transaminases.
Sixteen of the 41 patients initially treated with caspofungin at 50 mg daily following the 70 mg loading dose were dose-escalated to 100 mg daily. Dose escalation predominantly occurred in patients with multiple sites of infection (four patients), CDC (four patients) or hepatic abscess (one patient). The remaining seven patients who were dose-escalated failed prior antifungal therapy (four patients) or had high APACHE II scores (three patients). Following dose escalation, 12 (75%) of these 16 patients ultimately had a favourable overall response at the end of caspofungin therapy. None of the 16 patients developed a clinical drug-related adverse event following dose escalation to 100 mg daily.
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Discussion |
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Most clinical trials evaluating the management of invasive candidiasis have either focused exclusively on patients with candidaemia7,8,13,20 or have been limited in their enrolment of other non-fungaemic forms of infection.16 Nevertheless, patients with non-fungaemic invasive candidiasis represent an important cohort. Hence, it is essential to determine whether newer antifungal compounds may have a role in the treatment of these infections.
We report the results of a prospective, multicentre study of caspofungin monotherapy in the treatment of non-fungaemic invasive candidiasis. The entry criteria and outcome evaluations closely mirrored those implemented in other studies for this disease with the exception of the exclusion of patients with bloodstream involvement as the only identifiable source of infection.13,16,20
Caspofungin treatment resulted in a successful outcome in 81% of patients at the end of caspofungin therapy. Favourable responses were consistently high, even for high-risk patients, e.g. patients with neutropenia or high APACHE II scores. Favourable responses were noted across the different Candida species. Finally, caspofungin was also effective in patients who were refractory to prior antifungal therapy. Successful results were noted regardless of the type or duration of prior antifungal therapy.
The response to caspofungin against the different sites of invasive candidiasis was generally consistent. In particular, a high response rate (88%) was noted in patients with CDC. The four patients with osteomyelitis or septic arthritis responded favourably. The activity of caspofungin against CDC and bone infections is supported by other clinical studies21 or individual case reports.22–26
Finally, the study provides additional data on the use of higher than approved doses of caspofungin. Overall, 16 patients were dose-escalated to 100 mg daily. None of these patients developed a serious drug-related adverse event or dose reduction. Although the limited data suggest that caspofungin dose escalation may prove useful in unresponsive invasive candidiasis, the number of patients at higher doses precludes conclusions regarding the practice of dose-escalation.
In summary, caspofungin monotherapy appears to provide an effective, well-tolerated alternative for the treatment of non-fungaemic invasive candidiasis. Although the non-comparative design of the study limits our ability to compare the effectiveness of this agent relative to other antifungal classes, the consistency of the response rates across a variety of patient subgroups and infection sites is encouraging.
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Transparency declarations |
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O. A. C. has received research grants from Astellas, Basilea, Gilead, Merck/MSD, Pfizer, Essex/Schering-Plough and Vicuron; is a consultant to Astellas, Basilea, Gilead, Mölnlycke, Merck/MSD, Nektar, Pfizer, Essex/Schering-Plough and Zeneus/Cephalon; and served at the speakers' bureau of Astellas, Gilead, Merck/MSD and Essex/Schering-Plough.
R. B. has received research grants from Astellas, Cubist, Merck/MSD, Pfizer, Essex/Schering-Plough, Salir, Vivol, Vicuron and Viropharma; and is a consultant to Pfizer.
N. Klimko. served at the speakers' bureau of Merck/MSD and Pfizer.
J. Vazquez has received research grants from Astellas, Basilea, Bayer, Johnson and Johnson, Merck/MSD, Peninsula, Pfizer, Salix and Schering-Plough; is a consultant to Astellas and Pfizer; and served at the speakers' bureau of Pfizer.
G. D. has received research grants from Astellas, Eli Lilly, Merck/MSD and Pfizer; and is a consultant to Eli Lilly and Merck/MSD.
J. Velez has received research grants from Bristol-Myers Squibb, Merck/MSD and Pfizer; is a consultant to Bristol-Myers Squibb, Merck/MSD and Pfizer; and served at the speakers' bureau of Bristol-Myers Squibb, Merck/MSD and Pfizer.
A. W.-D., J. L., A. T., C. S. and N. Kartsonis are all employees of Merck Research Laboratories, a division of Merck and Co., Inc.
M. L.: none to declare.
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Acknowledgements |
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Participating investigators
The following investigators participated in this study: Australia—G. Dobb (Intensive Care Unit—Royal Perth), D. McGechie (Fremantle Hospital); Belgium—F. Jacobs (Hopital Erasme, Brussels); Brazil—A. Colombo (Escola Pau Universidad, Sao Pau); Chile—M. Lasso (Hospital Sotero del Rio, Puenta Alto); Germany—O. A. Cornely (University Clinic, Köln); Guatemala—E. Arathoon (Unaerc Clinic, Guatemala City); Russian Federation—N. Klimko (Medical Academy Hospital, St Petersburg); Spain—J. Cisneros-Herreros (Hospital Virgen del Rocio, Seville); United States—R. Betts (University of Rochester School of Medicine and Dentistry, Rochester, NY), P. Pappas (University of Alabama at Birmingham), A. Reboli (Copper Hospital, Camden, NJ), J. Vazquez (Henry Ford Hospital, Detroit); Turkey—H. Akan (Ankara University, Ankara).
Financial support
Merck Research Laboratories (Merck & Co., Inc.) provided financial support for this study. Statistical and other analyses were done by Merck & Co., Inc.
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References |
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 T. E. Zaoutis, H. S. Jafri, L.-M. Huang, F. Locatelli, A. Barzilai, W. Ebell, W. J. Steinbach, J. Bradley, J. M. Lieberman, C.-C. Hsiao, et al. A Prospective, Multicenter Study of Caspofungin for the Treatment of Documented Candida or Aspergillus Infections in Pediatric Patients Pediatrics, March 1, 2009; 123(3): 877 - 884. [Abstract] [Full Text] [PDF]
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