Prospective interventional study to evaluate the efficacy and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant recipients

INTRODUCTION: Invasive fungal infections are a life-threatening complication in transplant recipients. The prevalence of fungal infection after orthotopic liver transplantation (OLT) is 5% to 42%. The most common isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to the development of invasive fungal infections, with prevalence >40% and mortality rates of 78% to 100%. The strategy for fungal prophylaxis in this population has not been defined. PATIENTS AND METHODS: Among 100 consecutive OLT followed for 28 months, 21 recipients (15 men, overall mean age of 48.5 years, range 23-65 years) were considered to be high risk for the development of fungal infections when they presented at least one of the following criteria: acute liver failure, assisted ventilation >7 days, retransplantation, relaparotomy, antibiotic therapy >14 days, transfusion requirements >20 red blood cells units, and/or biliary leakage. This group received intravenous liposomal amphotericin B (1 mg/kg/d for 7-10 days). RESULTS: One-year survival in the high-risk group was 80%. Prevalence of invasive fungal infection was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection: an abdominal aspergillosis treated with percutaneous drainage and liposomal amphotericin B (5 mg/kg/d) showed a favorable clinical outcome. The other patient who developed brain aspergillosis died 25 days after OLT. Adverse events related to the drug were hypokalemia (n = 2), back pain (n = 3), and renal dysfunction (n = 2). None of these events required withdrawal of the prophylaxis regimen. CONCLUSION: In our series, prophylaxis with liposomal amphotericin B in high-risk liver graft recipients showed a low rate of severe fungal infections. More studies are needed in order to determine the highest risk population and the best drug dosage.     

Invasive fungal infections in renal transplant recipients

Invasive fungal infections are a significant and often lethal problem in transplant patients. Infections caused by geographically limited endemic fungi are infrequent, and Aspergillus species, Mucorales species, Candida species, and Cryptococcus neoformans are the opportunistic fungi responsible for most such infections. The symptoms of systemic fungal infections are nonspecific, particularly in their early stages. The high rates of mortality and graft loss owing to fungal infections render early diagnosis and treatment imperative in immunosuppressed patients. Current methods for the diagnosis of systemic fungal infections include imaging procedures, endoscopic methods and biopsies, microscopic and culture techniques, antibody and antigen-based serologic testing, and the detection (via polymerase chain reaction) of fungal deoxyribonucleic acid in blood or bronchoalveolar lavage fluid, as well as the careful analysis of signs and symptoms. Antifungal therapy should be initiated early in patients with a suspected fungal infection (even before laboratory findings have confirmed that diagnosis) and should be administered with appropriate adjustment of immunosuppressive regimens. To manage fungal infections in patients with renal failure, optimizing the pharmacokinetics of antifungal drugs to reduce the risk of nephrotoxicity is crucial.     

Epidemiology of invasive fungal infections in lung transplant recipients on long‐term azole antifungal prophylaxis

Lung transplant recipients (LTR) at our institution receive prolonged and mostly lifelong azole antifungal (AF) prophylaxis. The impact of this prophylactic strategy on the epidemiology and outcome of invasive fungal infections (IFI) is unknown. This was a single‐center, retrospective cohort study. We reviewed the medical records of all adult LTR from January 2002 to December 2011. Overall, 16.5% (15 of 91) of patients who underwent lung transplantation during this time period developed IFI. Nineteen IFI episodes were identified (eight proven, 11 probable), 89% (17 of 19) of which developed during AF prophylaxis. LTR with idiopathic pulmonary fibrosis were more likely to develop IFI (HR: 4.29; 95% CI: 1.15–15.91; p = 0.03). A higher hazard of mortality was observed among those who developed IFI, although this was not statistically significant (hazard ratio [HR]: 1.71; 95% confidence interval [CI] [0.58–4.05]; p = 0.27). Aspergillus fumigatus was the most common cause of IFI (45%), with pulmonary parenchyma being the most common site of infection. None of our patients developed disseminated invasive aspergillosis, cryptococcal or endemic fungal infections. IFI continue to occur in LTR, and the eradication of IFI appears to be challenging even with prolonged prophylaxis. Azole resistance is uncommon despite prolonged AF exposure.     

Trends in invasive fungal infections in liver transplant recipients: correlation with evolution in transplantation practices.

BACKGROUND: The incidence of invasive fungal infections, particularly invasive candidiasis, after liver transplantation is strongly influenced by surgical factors and technical complexity of the surgery. We assessed the temporal trends in invasive fungal infections in the context of evolution in liver transplantation practices, technical developments, and other risk factors. METHODS: Demographic and clinical characteristics of the patients, transplantation-related variables, and rates of infection were longitudinally analyzed over the last 10 years in 190 consecutive liver transplant recipients at our institution. Trends for categorical data were evaluated using the Cochran-Armitage trend test and for continuous variables using analysis of variance with linear contrast. RESULTS: A decrease in the length of operation (P=0.03), intraoperative transfusion requirements (P=0.0001), cold ischemic time (P<0.0001), use of roux-en-Y biliary anastomosis (P=0.0015), rate of biopsy proven rejection (P<0.0001), and retransplantation (P=0.056) was documented over the successive years. A significant decline in Child-Pugh score (P=0.02) and in the proportion of patients transplanted as UNOS 2a occurred (P=0.0001). Although the incidence of cytomegalovirus infection remained unchanged, a significant increase in the frequency of primary cytomegalovirus infection (P=0.045), and a decrease in cytomegalovirus disease (P=0.0006) was documented. Over the same time period, a significant decrease in the incidence of invasive candidiasis (P=0.015), and an insignificant increase in the rate of invasive aspergillosis (P=0.20) occurred. CONCLUSION: Notable technical developments in liver transplantation practices and risk profiles of patients have occurred over the decade. These variables may have a role in influencing the evolving trends in invasive fungal infections in liver transplant recipients.     

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients

BACKGROUND: Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients. Aerosolized amphotericin B lipid complex (ABLC) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models, but experience with aerosolized ABLC in humans is lacking. METHODS: We conducted a prospective, noncomparative study designed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients. RESULTS: A total of 381 treatments were administered to 51 patients. Complete spirometry records were available for 335 treatments (69 in intubated patients, 266 in extubated patients). ABLC was subjectively well tolerated in 98% of patients. Pulmonary mechanics worsened by 20% or more posttreatment in less than 5% of all treatments. There were no significant adverse events related to study medication in any patient, and 1-year survival for all enrolled patients was 78%. CONCLUSION: Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients. Additional prospective, randomized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients.     

Prospective screening in liver transplant recipients by panfungal PCR-ELISA for early diagnosis of invasive fungal infections.

Invasive fungal infections after liver transplantation (LT) have resulted in high mortality and potentially fatal complications. This study was undertaken to determine the accuracy of the panfungal polymerase chain reaction enzyme link immunosorbent assay (PCR-ELISA) method in early diagnosis of invasive fungal infections in liver transplant recipients (LTRs). A total of 48 liver recipients (cadaver donors) were followed for fungal infections for a period of at least 6 months. All clinical samples were cultured and a direct microscopic examination was performed. Blood samples were cultured by bedside inoculation onto BACTEC medium. Whole blood specimens were collected prospectively once per week and were evaluated for any invasive fungal infections by panfungal PCR and PCR-ELISA. Among 48 transplant recipients between September 2004 and January 2006 (22 females, 28 males, mean age = 34.4 yr), 40 recipients (83.3%) had Candida colonization in different sites of their body before LT. In proven and probable recipients for panfungal PCR-ELISA, the sensitivity, specificity, and positive and negative predictive values were 83.3%, 91.7%, 76.9%, and 94.3%, respectively. By PCR assay, fungal infections were diagnosed in 10 recipients (20.8%). The mean interval time from transplantation to development of fungal infection was 61.4 days (range, 20-150 days) and time of infection in blood before any clinical signs was 7-70 days with mean of 21.4 days. The etiologic agents were Candida albicans (9 cases) and Aspergillus fumigatus (1 case). Use of PCR-ELISA in LTRs may not only improve the ability of early diagnosis of invasive fungal infections (IFIs) when positive results are obtained, but also would provide more confidence to exclude a diagnosis of IFIs when negative results are obtained.     

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients

BACKGROUND: Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined. METHODS: A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation. RESULTS: Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p=0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p=0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period. CONCLUSIONS: Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.     

Effect of prophylaxis on fungal infection and costs for high-risk liver transplant recipients.

We sought to determine whether the prophylactic use of amphotericin B products (conventional amphotericin B and liposomal amphotericin B) reduces the incidence of fungal infections in high-risk liver transplant recipients, and if so, whether this lowers the cost of care. The study sample comprised 232 adult orthotopic liver transplants performed from 1994 to 2005 at a single center for patients classified as being at high risk for fungal infections. High-risk patients who received transplants with a prophylaxis regimen of amphotericin B (n=58 transplants) were compared with high-risk patients who received no prophylaxis (n=174 transplants). Fungal infections occurred in 3 transplants (5.17%) of those who received amphotericin B and 28 transplants (16.09%) in those without prophylaxis (P=0.0432). Regression models were used to analyze fungal infection and costs for the 232 high-risk transplants. Failure to offer prophylaxis conferred a 4-fold greater risk of fungal infection (P=0.046) compared with those who received amphotericin B. A fungal infection in a high-risk recipient increased mean costs by 46.48%. The indirect effect of prophylaxis (operating through infection reduction) is estimated to reduce overall costs in high-risk patients by 8.73%.     

Preemptive therapy for cytomegalovirus based on real-time measurement of viral load in liver transplant recipients

BackgroundReal-time PCR has emerged as the preferred diagnostic assay for CMV. However, its utility as a preemptive therapy tool for CMV disease and related outcomes in liver transplant recipients has not been fully defined.MethodsPatients comprised 117 consecutive liver transplant recipients who underwent CMV surveillance monitoring using real-time PCR. Preemptive therapy with valganciclovir was employed upon detection of viremia. Baseline viral load was considered high based on log values (median).ResultsCMV viremia developed in 54% (63/117) of the patients, including 77% of R−/D+, 63% of R+/D+, 43% of R+/D−, and 10% of R−/D− patients. Overall, 23% (15/63) of the patients had recurrent viremia; R− serostatus (p = 0.065) but not initial viral load correlated with recurrent viremia (p = 0.80). At 12 months post-transplant, CMV disease occurred in 0.85% (1/117) of the patients (R+/D + recipient). None (0/30) of the R−/D + patients had CMV disease. Patients with CMV viremia treated preemptively did not differ significantly from those who never developed CMV viremia with regards to bacterial or fungal infections, rejection, graft loss, mortality rate, and probability of survival at 12 months (p > 0.05 for all variables). The above outcomes also did not differ for patients with high (> 1.9 logs) vs. low viral load (< 1.9 logs) (p > 0.05 for all outcomes).ConclusionsPreemptive therapy guided by real-time PCR based monitoring led to outcomes in all patients or in those with high viral loads that were comparable to outcomes in patients who never developed viremia or had low viral loads, respectively. Late-onset CMV disease at 12 months was observed in < 1% of all patients.     

Efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients with invasive fungal infections

Background: Fungal infections following solid-organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients.
Methods: Three open-label, second-line treatment studies evaluated ABLC as a treatment for severe, life-threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre-existing renal disease.
Results: The 79 solid-organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n=39); candidiasis (n=20); zygomycosis (n=8); cryptococcosis and histoplasmosis (n=3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis , Dactylaria gallopava , and an unspecified fungal infection (n=1 each). The median duration of ABLC therapy was 28 d (1–178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty-six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n=37) or improved (n=27) serum creatinine at the end of treatment.
Conclusions: ABLC is safe and effective treatment for fungal infections in solid-organ transplant recipients. Its renal-sparing properties are particularly suited for this high-risk population for renal failure.     

肝移植术后真菌感染患者免疫抑制方案的调整

目的 探讨肝移植术后真菌感染患者的免疫抑制方案。方法 我院器官移植中心从2004年1月至2005年12月实施376例成人肝移植，对术前、术中存在真菌感染危险冈素的59例患者采用IL-2（interleukin-2）受体单克隆抗体诱导方案，对术后发生真菌感染的患者在应用有效抗真菌药物的同时，调整其免疫抑制方案。结果 共有36例患者发生真菌感染，发生真菌感染的中位时间为术后19d（4～75d），其中无临床症状仅真菌培养阳性16例，20例患者出现临床感染症状，感染部位以呼吸道（11/20，55%）为主，4例患者死于严重感染。真菌菌株培养多为白色念珠菌（24/41，58.5%）。16例患者减少免疫抑制剂，20例有临床表现的患者停用免疫抑制剂，减药或停药过程中仅1例患者出现排斥反应。结论 真菌感染是肝移植术后的重要并发症，术前或术中存在真菌易感因素患者应采用IL-2受体单克隆抗体诱导方案，术后发生真菌感染的患者在应用有效抗真菌药物同时，应减少或停用免疫抑制药物。     

Correlation between lipid abnormalities and immunosuppressive therapy in renal transplant recipients with stable renal function

Background Hyperlipidemia following successful renal transplantation is a frequent and persistent complication. Several immunosuppressive agents including cyclosporine A (CyA), corticosteroids, and tacrolimus appear to have a significant pathogenetic role. The aim of this study is to investigate the differential effects of different immunosuppressive agents on lipids in renal transplant patients. Methods Two groups of renal transplant recipients, each treated with a different combination of immunosuppressive agents, were studied: Group A (n = 13), cyclosporine A, mycophenolate mofetil (MMF), steroids, and basiliximab; Group B (n = 13), tacrolimus, MMF, steroids, and daclizumab). Plasma lipids [cholesterol (CHOL), low-density lipoprotein (LDL)-CHOL, high-density lipoprotein (HDL)-CHOL, and triglycerides (TG)] were examined before transplantation and 1 and 6 months posttransplantation. Results The patients treated with cyclosporine A-MMF showed a significant increase in mean cholesterol and mean LDL-cholesterol values at the 1-month posttransplantation follow-up compared with pretransplant levels (CHOL: 208.9 ± 47.4 vs. 268.7 ± 42.2 mg/dl, P = 0.004; LDL: 118.4 ± 49.9 vs. 198.7 ± 40.7 mg/dl, P = 0.002; pretransplant vs. 1 month, respectively). At 6 months, LDL-cholesterol levels were significantly elevated compared with pretransplant levels (LDL: 118.4 ± 49.9 vs. 148.3 ± 48.5 mg/dl, P = 0.034), whereas there was no significant change in the cholesterol level during the same period. In cyclosporine A-MMF-treated patients, plasma triglyceride levels were reduced at the 1- and 6-month follow-up (TG: 293.9 ± 59.2 vs. 182.9 ± 48.7 mg/dl, P = 0.03; 293.9 ± 59.2 vs. 178.6 ± 74.2 mg/dl, P = 0.023; pretransplant vs. 1 and 6 months, respectively). Patients receiving combined therapy with tacrolimus-MMF showed no significant changes in LDL-CHOL levels during the trial. Cholesterol levels at 6 months posttransplantation were significantly lower than the pretransplant measurements (CHOL: 182.9 ± 44.4 vs. 162.3 ± 37.2 mg/dl, P = 0.024; pretransplant vs. 6 months ). A significant reduction in triglyceride level was documented at the 1-month follow-up followed by a subsequent decrease within 6 months (TG: 228.5 ± 61.6 vs. 147.6 ± 51.5 mg/dl, P = 0.005; TG: 228.5 ± 61.6 vs. 130.4 ± 54.7 mg/dl, P = 0.011; pretransplant vs. 1 and 6 months, respectively). Conclusions In posttransplant patients with stable renal function cyclosporine therapy is associated with increased cholesterol and LDL-cholesterol levels. Hyperlipidemia is less pronounced in patients given tacrolimus. Tacrolimus appears to an immunosuppressant agent with fewer and less severe adverse effects on lipid metabolism.