Improving survival of acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis

Abstract

The mortality of acute-on-chronic liver failure (ACLF) patients complicated with invasive pulmonary aspergillosis (IPA) was extremely high. We aimed to explore prognostic value of the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) lung score and to establish an optimal voriconazole regimen for ACLF patients complicated with IPA. We retrospectively screened hospitalized ACLF patients in our hospital from July 2011 to April 2016, from which 20 probable IPA cases were diagnosed. Along with onsets of IPA, deteriorated diseases severity, especially lung conditions were found in those 20 ACLF patients. It was found that IPA patients with CLIF-SOFA lung score <2 had better 28-day survival than those with lung score >1 (11/13 vs 0/7, p < 0.001). Based on plasma voriconazole concentration measurement, an optimal voriconazole regimen (loading doses: 0.2 g twice daily; maintenance doses, 0.1 g once daily) was established, which resulted in rational trough plasma drug concentrations (1–5 μg/mL), good clinical outcomes (90-day survival rate of 6/8) and no observed adverse events. In conclusion, CLIF-SOFA lung score >1 was able to identify ACLF patients complicated with IPA encountering much higher 28-day mortality. An optimal voriconazole regimen was safe and effective in our ACLF patients complicated with IPA.

Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study

“…A multicentre, retrospective clinical study found that the recommended dose and halved maintenance dose might be inappropriate in patients with Child–Pugh class B and C cirrhosis 38,39 . It has been reported in a retrospective study 40 that oral voriconazole maintenance doses in patients with Child–Pugh class C should be reduced to approximately 1/3 that of patients with normal liver function, while another clinical study for acute‐on‐chronic liver failure (ACLF) patients 4 has proposed that voriconazole concentration can be maintained a reasonable range (1–5 mg/L) with a loading dose of 200 mg twice daily and a maintenance dose of 100 mg once daily of voriconazole dosing regimen. However, both of these studies are retrospective analyses with small sample sizes (6 cases of cirrhosis C grade and 20 cases of chronic acute liver failure, respectively), so the voriconazole dosing regimen for patients with liver dysfunction still needs further verification.…”

“…Infections are common and represent 1 of the most important reasons for progression of liver failure, development of liver‐related complications and mortality in patients with liver dysfunction 1 . Invasive fungal infections can be a life‐threatening complication in patients with liver dysfunction and are associated with a high morbidity and significant mortality 2–5 . Furthermore, long‐term use of broad‐spectrum antibiotics and glucocorticoids, invasive procedures including liver puncture, ascites drainage, indwelling catheters and haemodialysis, and multiple hospitalizations are also associated with an increased risk of invasive fungal infections 6 and are common in patients with liver dysfunction.…”

Pharmacokinetics Modeling and Simulation of Voriconazole Dosing and Safety in Patients with Liver Cirrhosis

“…Finally, we retrospectively collected 120 cirrhotic patients into the analysis. Among these patients, four initial dosage regimens were administered: (1) patients received the recommended dosage regimen based on package insert or a fixed dose of 200 mg twice daily orally or intravenously; (2) patients received the loading dose of 200 mg twice daily on day 1, following by 100 mg twice daily orally or intravenously or a fixed dose of 100 mg twice daily orally or intravenously; (3) patients received loading dose of 200 mg twice daily on day 1, following by 200 mg daily orally or intravenously or a fixed dose of 200 mg daily orally or intravenously; (4) patients received a fixed dose of 100 mg daily orally or intravenously.…”

“…The most appropriate PPK model had to meet the following criteria: (1) the minimal OFV; (2) A reduction in OFV of > 6.83 in the process of forward selection; (3) the diagnostic plots were improved compared to the basic model. (4) the covariate should be physiologically plausible.…”

“…Liver cirrhosis is a late stage of hepatic fibrosis and is a leading cause of death worldwide (1). Due to the immunocompromised state of cirrhotic patients and their requirement for use of steroids and broad-spectrum antimicrobial agents, as well as invasive procedures, invasive fungal disease (IFD) constitutes an important cause of morbidity in patients with liver cirrhosis (2-4). Voriconazole is a triazole antifungal agent with activity against a broad spectrum of clinically significant fungal pathogens, and it is used to treat and prevent IFD in clinical practice (5, 6).…”