Candida in the Respiratory Tract Secretions of Critically Ill Patients and The Efficacy of Antifungal Treatment

Ventilator Associated Pneumonia Clinical Trial

— CANTREAT  

Official title:

Candida in the Respiratory Tract Secretions of Critically Ill Patients and The Efficacy of Antifungal Treatment (The CANTREAT Study): A Prospective, Randomized, Double Blind, Placebo Controlled Pilot Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00934934
• Other study ID #: CANTREAT
• Status: Terminated
• Phase: Phase 2
• Start date: April 2010
• Est. completion date: August 2012

Study information

• Verified date: January 2021
• Source: Clinical Evaluation Research Unit at Kingston General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine whether the effect of treating Candida spp. isolated in the respiratory tract secretions of patients with a clinical suspicion of ventilator associated pneumonia (VAP) on clinical outcomes will be feasible and supported by biomarker data obtained.

Description:

Candida spp. is commonly retrieved from microbiologic specimens of ICU patients with suspected VAP. It has been associated with increased systemic inflammation and worse clinical outcomes. This association may be due to the propensity for Candida to colonize those who are sicker, who have increased levels of systemic inflammation and worse clinical outcomes. However, an alternate possibility is that Candida is more than a colonizer and is responsible for the clinical and biochemical features observed. The only way to clarify the pathogenic role of Candida from this patient population is to treat the organism and see if patients improve compared to an untreated group. The purpose of this research program is to conduct such a study to determine if Candida in respiratory tract secretions should be routinely treated in critically ill patients. Since a definitive randomized controlled trial designed to demonstrate a reduction in mortality would be large, require the commitment of large amount of resources including both time and money, the investigators propose to first conduct a small pilot feasibility study. Eligible patients will be randomized to receive antifungal treatment with anidulafungin or placebo. Following enrollment, study treatment (or placebo) will be started as soon as possible. When the Candida or yeast organisms have been speciated and/or a susceptibility profile is known, the study medication will be adjusted based on susceptibility patterns. The investigators propose to treat with antifungal therapy for a total of 14 days. Patients will be followed daily for their entire stay in ICU or till day 28, whichever comes first. For patients discharged from the ICU to the ward, they will be followed until study treatment is complete (i.e. day 14). Mortality will be determined for the ICU stay, hospital stay and at 90 days. The investigators will record admission and discharge dates to ICU, step down units, and to hospital. All patients will have 13 mL of blood/day drawn at baseline, day 3, day 8 and at the end of the treatment period on day 14 (or last day of treatment). The samples will be prepared on site and shipped to a central lab for processing. The investigators will use the blood specimens to measure markers of inflammation (C-reactive protein, Procalcitonin, and Interleukin-6 and others as determined by the investigators), markers of candida presence (b-glucan and other potential future markers) and markers of immune dysfunction (to be determined by investigators).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 61
• Est. completion date: August 2012
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adult patients (>18 years old)

2. In the ICU > 48 hours

3. Mechanically ventilated (>48 hours)

4. Grow a Candida spp. on respiratory tract secretion culture (either by Bronchoalveolar Lavage or Endotracheal Aspirate) taken on or between 48 hours before or after the day of their suspicion of respiratory tract infection.

5. Develop a clinical suspicion of respiratory tract infection while ventilated as

defined by the following criteria (as defined previously in our VAP trial)5:

• The presence of new, worsening or persistent radiographic features suggestive of pneumonia without another obvious cause AND
• The presence of any two of the following:
• Fever > 38C (core temperature)
• Leukocytosis (>11.0 x109/L) or neutropenia (<3.5 x109/L)
• Purulent endotracheal aspirates or change in character of aspirates
• Isolation of pathogenic bacteria from endotracheal aspirates
• Increasing oxygen requirements

Exclusion Criteria:

1. Patients not expected to be in ICU for more than 72 hours (due to imminent death, withdrawal of aggressive care or discharge).

2. Patients with Candida spp. in the blood or another sterile body site.

3. Patients colonized at other non-pulmonary body site(s) with Candida.

4. Already being treated with antifungal drugs (because of documented fungal infection, pre-emptive therapy, or prophylaxis).

5. Allergy to study drugs (Fluconazole or the Echinocandin on formulary at treating institution).

6. Immunocompromised patients (post-organ transplantation, Acquired Immunodeficiency Syndrome [AIDS], neutropenia [<1000 absolute neutrophils], corticosteroids [>20 mgs/day of prednisone or equivalent for more than 6 months]). These patients are excluded since Candida may be more invasive and these patients are much more likely to require systemic antifungal therapy.

7. Patients with fulminant liver failure or end stage liver disease (Child's Class C).

8. Women who are pregnant or lactating.

9. Enrollment in industry sponsored interventional trial (co-enrollment in other academic studies would be allowed with the proviso that there was no potential interaction between the protocols).

10. Prior randomization in this study.

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Ventilator-Associated
• Respiratory Tract Infection
• Respiratory Tract Infections
• Ventilator Associated Pneumonia

Intervention

Other:
• Normal Saline
Normal Saline

Drug:
• anidulafungin
TBA

Locations

Country	Name	City	State
Canada	Hamilton Health Sciences Centre	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston	Ontario
Canada	Hopital du Sacre-Coeur do Montreal	Montreal	Quebec
Canada	Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Ottawa General Hospital	Ottawa	Ontario
Canada	Hopital l'Enfant-Jesus	Quebec

Sponsors (4)

Lead Sponsor	Collaborator
Daren K. Heyland	Pfizer, Queen's University, The Physicians' Services Incorporated Foundation

Country where clinical trial is conducted

Canada, 

References & Publications (31)

Arnold DM, Burns KE, Adhikari NK, Kho ME, Meade MO, Cook DJ; McMaster Critical Care Interest Group. The design and interpretation of pilot trials in clinical research in critical care. Crit Care Med. 2009 Jan;37(1 Suppl):S69-74. doi: 10.1097/CCM.0b013e3181920e33. Review. — View Citation

Azoulay E, Timsit JF, Tafflet M, de Lassence A, Darmon M, Zahar JR, Adrie C, Garrouste-Orgeas M, Cohen Y, Mourvillier B, Schlemmer B; Outcomerea Study Group. Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia. Chest. 2006 Jan;129(1):110-7. — View Citation

Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med. 2006 Dec 21;355(25):2619-30. — View Citation

Canadian Institutes of Health Research. Available at: www.cihr.ca Accessed February 9, 2009.

Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002 Apr 1;165(7):867-903. Review. — View Citation

Christofilopoulou S, Charvalos E, Petrikkos G. Could procalcitonin be a predictive biological marker in systemic fungal infections?. Study of 14 cases. Eur J Intern Med. 2002 Dec;13(8):493-495. — View Citation

Delisle MS, Williamson DR, Perreault MM, Albert M, Jiang X, Heyland DK. The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients. J Crit Care. 2008 Mar;23(1):11-7. doi: 10.1016/j.jcrc.2008.01.005. — View Citation

el-Ebiary M, Torres A, Fàbregas N, de la Bellacasa JP, González J, Ramirez J, del Baño D, Hernández C, Jiménez de Anta MT. Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem histologic study. Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):583-90. — View Citation

Heyland DK, Dodek P, Muscedere J, Day A, Cook D; Canadian Critical Care Trials Group. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008 Mar;36(3):737-44. — View Citation

Heyland et al, WATTCH database. Observational study of the clinical characteristics and biomarker profiles of 569 critically ill patients. Analysis ongoing.

Inoue K, Takano H, Oda T, Yanagisawa R, Tamura H, Ohno N, Adachi Y, Ishibashi K, Yoshikawa T. Candida soluble cell wall beta-D-glucan induces lung inflammation in mice. Int J Immunopathol Pharmacol. 2007 Jul-Sep;20(3):499-508. — View Citation

Magill SS, Swoboda SM, Johnson EA, Merz WG, Pelz RK, Lipsett PA, Hendrix CW. The association between anatomic site of Candida colonization, invasive candidiasis, and mortality in critically ill surgical patients. Diagn Microbiol Infect Dis. 2006 Aug;55(4):293-301. Epub 2006 May 15. Erratum in: Diagn Microbiol Infect Dis. 2007 Mar;57(3):351. — View Citation

Müller V, Viemann D, Schmidt M, Endres N, Ludwig S, Leverkus M, Roth J, Goebeler M. Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. J Immunol. 2007 Dec 15;179(12):8435-45. — View Citation

Muscedere J, Dodek P, Keenan S, Fowler R, Cook D, Heyland D; VAP Guidelines Committee and the Canadian Critical Care Trials Group. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: diagnosis and treatment. J Crit Care. 2008 Mar;23(1):138-47. doi: 10.1016/j.jcrc.2007.12.008. — View Citation

Muscedere J, Dodek P, Keenan S, Fowler R, Cook D, Heyland D; VAP Guidelines Committee and the Canadian Critical Care Trials Group. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: prevention. J Crit Care. 2008 Mar;23(1):126-37. doi: 10.1016/j.jcrc.2007.11.014. — View Citation

Muscedere JG, Martin CM, Heyland DK. The impact of ventilator-associated pneumonia on the Canadian health care system. J Crit Care. 2008 Mar;23(1):5-10. doi: 10.1016/j.jcrc.2007.11.012. Review. — View Citation

Muscedere JG, McColl C, Shorr A, Jiang X, Marshall J, Heyland DK; Canadian Critical Care Trials Group. Determinants of outcome in patients with a clinical suspicion of ventilator-associated pneumonia. J Crit Care. 2008 Mar;23(1):41-9. doi: 10.1016/j.jcrc.2007.12.007. — View Citation

Nseir S, Jozefowicz E, Cavestri B, Sendid B, Di Pompeo C, Dewavrin F, Favory R, Roussel-Delvallez M, Durocher A. Impact of antifungal treatment on Candida-Pseudomonas interaction: a preliminary retrospective case-control study. Intensive Care Med. 2007 Jan;33(1):137-42. Epub 2006 Nov 8. — View Citation

Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, Ketchum PA, Finkelman MA, Rex JH, Ostrosky-Zeichner L. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis. 2004 Jul 15;39(2):199-205. Epub 2004 Jun 28. — View Citation

Presterl E, Lassnigg A, Mueller-Uri P, El-Menyawi I, Graninger W. Cytokines in sepsis due to Candida albicans and in bacterial sepsis. Eur Cytokine Netw. 1999 Sep;10(3):423-30. — View Citation

Reade MC, Angus DC. The clinical research enterprise in critical care: what's right, what's wrong, and what's ahead? Crit Care Med. 2009 Jan;37(1 Suppl):S1-9. doi: 10.1097/CCM.0b013e318192074c. — View Citation

Rello J, Esandi ME, Díaz E, Mariscal D, Gallego M, Vallès J. The role of Candida sp isolated from bronchoscopic samples in nonneutropenic patients. Chest. 1998 Jul;114(1):146-9. — View Citation

Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic consequences of ventilator-associated pneumonia: a systematic review. Crit Care Med. 2005 Oct;33(10):2184-93. Review. — View Citation

Sakurai T, Ohno N, Yadomae T. Effects of fungal beta-glucan and interferon-gamma on the secretory functions of murine alveolar macrophages. J Leukoc Biol. 1996 Jul;60(1):118-24. — View Citation

Senn L, Robinson JO, Schmidt S, Knaup M, Asahi N, Satomura S, Matsuura S, Duvoisin B, Bille J, Calandra T, Marchetti O. 1,3-Beta-D-glucan antigenemia for early diagnosis of invasive fungal infections in neutropenic patients with acute leukemia. Clin Infect Dis. 2008 Mar 15;46(6):878-85. doi: 10.1086/527382. — View Citation

Tschaikowsky K, Hedwig-Geissing M, Schiele A, Bremer F, Schywalsky M, Schüttler J. Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients. Crit Care Med. 2002 May;30(5):1015-23. — View Citation

Van Saene H., Peric M., De La Cal M., Silvestri L.: Pneumonia during Mechanical Ventilation. Anestiologie a Intenzivni Medicina 2004; 15: 89-100.

van Teijlingen E, Hundley V. The importance of pilot studies. Nurs Stand. 2002 Jun 19-25;16(40):33-6. Review. — View Citation

Wheeler RT, Fink GR. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog. 2006 Apr;2(4):e35. Epub 2006 Apr 28. — View Citation

Williamson D., Albert M., Perreault M., Delisle M., Muscedere J., Rotstein C.Jiang X., Day A. ,Heyland D. Effect of Candida spp. in respiratory tract secretions on systemic inflammation. Submitted to SCCM for Feb. 2009

Williamson D., Martin A., Perreault M., Delisle M., Muscedere J., Rotstein C., Jiang X., Heyland D. Impact of pulmonary Candida colonization on systemic inflammation in the critically ill. Manuscript in preparation.

* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Recruitment Rate	Overall recruitment rate per site	32 months
Secondary	Duration of Stay in ICU	Measure of the duration of participant stay in the ICU	28 days
Secondary	Ventilator Free Days	Number of days in ICU free of ventilation	28 days
Secondary	ICU Free Days	Number of days free of ICU	28 days
Secondary	Antibiotic Free Days 28-day Post Randomization	Number of days free of antibiotic use within the first 28 days	28 days
Secondary	Hospital Length of Stay	Measure of the duration of the participant's hospital stay	90 days
Secondary	(SOFA) Post Randomization	Sequential organ failure assessment. 0-24 The higher the number the more severe organ failure	post randomization
Secondary	Sequential Procalcitonin		28 days
Secondary	C-reactive Protein		28 days
Secondary	Interleukin-6		28 days
Secondary	B-glucan Levels		28 days