Early treatment of invasive fungal infections (IFI) may prevent undue mortality in acute on chronic liver failure (ACLF) patients. We aim to study the impact of early empiric treatment (based on clinical suspicion) of IFI as compared to pre-emptive treatment (based on biomarkers and culture positivity) on the outcomes in ACLF patients with suspected IFI in a randomized trial. The ACLF patients with clinically suspected IFI would be randomly allocated to empiric treatment or pre-emptive treatment group and followed up clinically to assess the impact on survival, clinical outcomes and cost-effectiveness and safety of such an approach. The protocol is designed to cut- down unnecessary usage and to curtail the duration of antifungals use in ICUs based on biomarkers/culture-driven stoppage rules. The results will fuel further studies on formal cost-effective analysis and antimicrobial stewardship protocols in ACLF patients.

Research question: Does an early empiric antifungal therapy improve 28-day overall survival as compared to pre-emptive antifungal therapy in critically ill, non-neutropenic adult ACLF patients with suspected IFI?

This study will be a single-center prospective randomized open-label with blinded end-point PROBE assessment and conducted at Liver ICU.

ACLF patients aged 18 to 75 years with all three criteria will be included

1. ICU stay of 48 hours or recent hospitalization
2. Two or more risk factors for IFI 3. Clinical suspicion of IFI

Exclusion criteria A Neutrophil count of less than 500 per mm3 B Recent antifungal treatment in the past 1months C Hepatocellular carcinoma or other active malignancy D Known hypersensitivity or contraindication to Liposomal AmB E HIV positivity or on HAART F Pregnancy or lactation G Moribund patients

Eligible patients will be randomly assigned, in a 1:1 ratio to receive either early empiric systemic antifungal therapy (SAT: based on risk factors and clinical suspicion) or Pre-emptive SAT (based on risk factors, clinical suspicion and radiological/investigation based evidence of fungal infection) in addition to standard medical therapy SMT and followed up for a period of 28-days or transplant or death

Empirical therapy will be Liposomal AmB 3 to 5 mg per kg of body weight per day.

It is preferred because of maximum efficacy, widest spectrum, and safety in liver disease

Pre-emptive therapy with liposomal AmB will be given if the treatment initiation rules are met including fungal biomarkers positivity, Mycological or radiological evidence of IFI

Proven-IFI will be treated as per IDSA or ESCMID guidelines in either group Stoppage rules in both groups will be based on fungal biomarkers and cultures that will be done twice weekly and twice negative bio-markers or fungal cultures at day7 and 10 will be essential to stop treatment

In case of intolerable adverse effects or contraindications to LipoAmB, the patients will undergo treatment as per IDSA guidelines Standard Medical Therapy will be as indicated and will include nutritional support, rifaximin lactulose albumin diuretics proton-pump inhibitors multivitamins and antibiotics

Outcomes will include survival at 28-day, clinical outcomes, cost-effectiveness and safety of two approaches of antifungal therapy

Inclusion Criteria (All three must be present):

1. ICU stay >48 hours or admission in a tertiary care hospital prior to the current admission

2. Two or more risk factors for IFI from amongst the following:-

   1. Mechanically ventilated at least ≥ 48 hours
   2. Treatment with broad-spectrum antibacterial agents for more than 3 days
   3. Arterial or central vein catheter ≥ 2days
   4. Diabetes Mellitus
   5. Total parenteral nutrition ≥ 48 hours
   6. Acute renal failure requiring any form of renal replacement therapy ≥48hours
   7. Pancreatitis related hospitalization > 7days in last 3 months
   8. Steroid use, immunosuppressant use in the preceding 30 days
   9. High disease score as defined as MELD≥20 or APACHE II ≥16
   10. Refractory ascites, norfloxacin prophylaxis
   11. Gastrointestinal tract surgery, abdominal perforation or anastomotic leaks or any invasive procedures or surgeries in the last 7days
   12. Chronic pulmonary diseases including COPD or Tuberculosis
   13. Moderate to severe sarcopenia as defined by The Royal Free Hospital-global assessment (RFH-GA) scale60 (As per Appendix "4" )
   14. Firm diagnosis of H1N1 influenza infection in the last 3 months

3. Clinical suspicion of IFI as defined by any of the following:

   1. Evidence of unresolved sepsis/SIRS(≥ 2/4) despite appropriate broad-spectrum antibiotics beyond 3days

   2. Recrudescence of fever after a period of defervescence of at least 48 hours while still on antibiotics and without other apparent cause

   3. Tracheobronchial ulcer, nodule, plaque or pseudo-membrane

   4. Sino-nasal infection: features of acute sinusitis with at least 1 of acute localized pain, nasal ulcer, eschar, orbital involvement or

   5. Respiratory symptoms:

      • Worsening respiratory insufficiency despite appropriate ventilator support and antibiotics
      • Any 2 of Pleuritic chest pain, pleural rub, dyspnea, hemoptysis

   6. Characteristic skin lesions suspected of fungal infection

   7. Unexplained worsening of encephalopathy after initial improvement

Exclusion Criteria:

1. Neutrophil count of less than 500/mm3

2. Current or recent antifungal treatment in the past 1 months

3. Hepatocellular carcinoma or other active malignancy

4. Known hypersensitivity or contraindication to Liposomal AmB or any other AmB preparation

5. Human immunodeficiency virus seropositivity on rapid card test/ELISA, or currently on combination antiretroviral therapy (cART)

6. Pregnancy as confirmed by urine pregnancy test or lactation

7. Moribund patients as defined as

   1. ≥ 4 organ failure as per CLIF-SOFA score
   2. Signs of brainstem death- absent brainstem reflexes
   3. Expected ICU stay <48 hours

Single-center, prospective randomized, open-labeled with blinded end-point (PROBE) assessment