Candida in the Respiratory Tract Secretions of Critically Ill Patients and the Efficacy of Antifungal Treatment: A prospective, randomized, double blind, placebo controlled pilot study
Background: Candida spp. is commonly retrieved from microbiologic specimens of ICU patients with CS 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 amounts of resources including both time and money, we propose to first conduct a small pilot feasibility study.
Overall Hypothesis: The treatment of critically ill mechanically ventilated patients with a clinical suspicion of Ventilator Associated Pneumonia (VAP) who have Candida spp. isolated from respiratory tract secretions with antifungal therapy will result in improved outcomes and survival.
Study Design: A randomized double blinded pilot study.
Setting: Approximately 5 tertiary care ICUs in Ontario and 5 tertiary care ICUs in Quebec.
Study Population: 120 mechanically ventilated adult patients in the ICU with a clinical suspicion of respiratory tract infection who grow a Candida spp. on respiratory tract secretion culture (either by BAL or ETA) taken + 48 hours from the day of their suspicion of infection.
Study Intervention: Patients will be randomized to receive initial antifungal treatment with anidulafungin or placebo. Following enrolment, study treatment (or placebo) will be started as soon as possible and initial therapy will continue for at least 72 hours to maximize the likelihood that anidulafungin has cleared the blood stream if the patient was candidemic. When the Candida or yeast organisms have been speciated and/or a susceptibility profile is known, if the organism is susceptible to fluconazole, the anidulafungin will be stopped and fluconazole (or placebo) will be started for the duration of therapy. The treating clinician will remain blinded during the study but pharmacy will be unblinded to allow antifungal treatment modifications according to the susceptibility patterns. Pharmacy will also adjust drug dosages based on renal function.
Outcomes: 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). Patients will be followed out to 90 days and mortality will be determined for the ICU stay, hospital stay and at 90 days. We will record admission and discharge dates to ICU, step down units, and to hospital. We 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). We have selected these biomarkers based on our analysis of biomarkers in patients with Candida isolated in respiratory tract samples. These were uniformly elevated in out patients and would be expected to respond to antifungal therapy if Candida was causal for their elevation.
Trial recruitment and Duration: We expect 0.5-1 patients/center/month. With 10 centers participating, we expect patient accrual to take approximately 18-24 months. The pilot study will allow us to validate these estimated recruitment rates and if low, based on the analysis of screening logs, we will be able to determine barriers to recruitment.
Significance: This programme of research represents a significant change in the way mechanically ventilated critically ill patients are managed. The isolation of Candida in respiratory tract secretions has been traditionally felt to not require treatment. Yet our recent observations suggest that patients with Candida present in their respiratory tract have elevated biochemical markers of systemic inflammation and experience considerable excess morbidity and mortality. It is expected that the results of this study will suggest a potential therapeutic benefit to antifungal therapy in this study population. This program of research has the potential to change practice and may improve the survival of critically ill patients.
This study is registered at Clinicaltrials.gov, Identification # NCT00934934.