Association of fungal infection and increased mortality in liver transplant recipients

BACKGROUND: Invasive fungal infection is associated with increased morbidity and mortality following orthotopic liver transplantation (OLTx). Understanding the risk factors associated with fungal infection may facilitate identification of high-risk patients and guide appropriate initiation of antifungal therapy. OBJECTIVES: The aim of this study was to determine the incidence of fungal infections, identify the most common fungal pathogens, and determine the risk factors associated with fungal infections and mortality in OLTx recipients. METHODS: Medical records from 96 consecutive OLTx in 90 American veterans (88 males, 2 females; mean age 48 years, range 32 to 67) performed from January 1994 to December 1997 were retrospectively reviewed for fungal infection in the first 120 days after transplantation. Infection was defined by positive cultures from either blood, urine (<105 CFU/mL), cerebrospinal or peritoneal fluid, and/or deep tissue specimens. Superficial fungal infection and asymptomatic colonization were excluded from study. All patients received cyclosporine, azathioprine, and prednisone as maintenance immunosuppressive therapy. Fungal prophylaxis consisted of oral clotrimazole (10 mg) troches, five times per day during the study period. RESULTS: Thirty-five patients (38%) had documented infection with one or more fungal pathogens, including Candida albicans (25 of 35; 71%), C torulopsis (7 of 35; 20%), C tropicalis (2 of 35; 6%), non-C albicans (2 of 35; 6%), Aspergillus fumigatus (4 of 35; 11%), and Cryptococcus neoformans (1 of 35; 3%). The crude survival for cases with or without fungal infection was 68% and 87%, respectively (P <0.0001). The median intensive care unit stay and overall duration of hospitalization were significantly longer for patients with fungal infection (P <0.01). The mean time interval from transplantation to the development of fungal infection was 15 days (range 4 to 77) with a mean survival time from fungal infection to death of 21 days (range 3 to 64). Fungal infections occurred significantly more often in patients with renal insufficiency (serum creatinine >2.5 mg/dL), biliary/vascular complications, and retransplantation. CONCLUSIONS: Fungal infections were associated with increased morbidity and mortality following OLTx, with Candida albicans being the most common pathogen. Treatment strategies involving antifungal prophylaxis for high-risk patients and earlier initiation of antifungal therapy in cases of presumed infection are warranted.     

Effects of fluconazole administration in critically ill patients: analysis of bacterial and fungal resistance

HYPOTHESIS: The administration of fluconazole in intensive care unit (ICU) patients leads to the emergence of bacterial and fungal resistance. DESIGN: Retrospective analysis of 2 patient cohorts: (1) critically ill patients treated in surgical, trauma, and medical ICUs between June 1997 and January 1999 who did and did not receive fluconazole; and (2) ICU patients with fungal infections and sensitivity testing results from June 1994 to December 1998. SETTING: University-affiliated tertiary care hospital. PATIENTS: The first cohort included 99 ICU patients with documented microorganism culture(s) who were treated with (n = 50) or without (n = 49) fluconazole; the second cohort included 38 patients with Candida species infection, identification, and antifungal susceptibility testing. RESULTS: Mortality (40% vs 20%; P = .03) and hospital length of stay (33.8 vs 25.6 days; P = .04) were higher in the patients treated with fluconazole compared with patients not treated with fluconazole. The ICU length of stay was also higher in patients treated with fluconazole (23.7 vs 15.1 days; P = .009). An increase in bacterial resistance occurred in patients after fluconazole treatment as opposed to bacterial resistance of patients who were treated for bacterial microorganism(s) without fluconazole (16% vs 4%; P = .049). Comparison of patient populations with Candida species identification before and after December 1997 showed an increase in Candida species resistance to fluconazole (11% vs 36%; P = .16), respectively. Fungal strains were dominated by a combination of Candida albicans and Candida glabrata in both populations (60% [before 1998] vs 82% [after 1998]), with an emergence of Candida non-albicans species tolerant to fluconazole. The amount of fluconazole administered and the number of patients receiving fluconazole treatment in the ICUs has also increased when comparing both periods. CONCLUSIONS: Comparison of critically ill patient populations with and without fluconazole treatment found increased mortality and longer hospital and ICU lengths of stay in the fluconazole-treated group. This group also had higher bacterial pathogen resistance to antibiotics after fluconazole administration compared with bacterial resistance of patients without fluconazole treatment. Our results warrant concern regarding worsening bacterial infections, increased mortality, and an increase in Candida resistance to fluconazole from increased use in ICU patients, with a shift in yeast infection that is more difficult to treat.     

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.     

Fungal brain abscess in transplant recipients: epidemiologic,microbiologic, and clinical features

Fungal brain abscess is an unusual but serious complication associated with solid organ and hematopoietic stem cell transplantation. To examine the epidemiology and clinical features of fungal brain abscess in transplant recipients, we reviewed retrospectively all cases of fungal brain abscess diagnosed during a 3-yr period among 1,620 adult patients who underwent allogeneic or autologous stem cell, liver, heart, lung, or renal transplantation at one institution. Seventeen cases of fungal brain abscess were identified and occurred a median of 140 d post-transplantation. Fungal brain abscess was more common among allogeneic stem cell transplant recipients (p < 0.01). Aspergillus species were most commonly isolated, but unusual, opportunistic molds were also identified. Altered mental status was present in 65% of patients, and multiple brain lesions were commonly seen on imaging studies. Although fungal brain abscess is an uncommon disease in this population, outcome was poor, suggesting that early recognition of this disease might be helpful.     

Coccidioidomycosis in liver transplantation.

Coccidioidomycosis is an endemic fungal infection in the southwestern United States. It causes morbidity and mortality among solid organ transplant recipients who reside in or visit the endemic area or who receive organs from donors infected with the fungus. This paper reviews current literature addressing these infections in liver transplantation programs, including risk factors, clinical manifestations in persons with cirrhosis or who have had a liver transplantation, prophylaxis, treatment, and outcomes.     

Prophylactic fluconazole in liver transplant recipients: A randomized,double-blind,placebo-controlled trial

Background:Among persons who receive solid organ 0842 transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective.Objective:To evaluate the efficacy and safety of prophylactic0842 fluconazole in liver transplant recipients.Design:Randomized, double-blind, placebo-controlled trial. 0842Setting:University-affiliated transplantation center.0842Patients:212 liver transplant recipients who received fluconazole0842 (400 mg/d) or placebo until 10 weeks after transplantation.Measurements:Fungal colonization, proven superficial 0842 or invasive fungal infection, drug-related side effects, and death.Results:Fungal colonization increased in 0842 patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003).Conclusions:Prophylactic 0842 fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

Comparison of fungal and nonfungal infections in a broad-based surgical patient population

BACKGROUND: Our aim was to compare fungal and nonfungal infections among a diverse surgical patient population. METHODS: Data on all hospital-acquired infectious episodes among surgical intensive care unit and ward patients were collected prospectively over six years at a single university hospital. The relationships between fungal and nonfungal infection and over 100 variables were examined using univariate and multiple logistic regression analysis. RESULTS: During the study period, 3,980 infectious episodes were identified; 554 were associated with fungal infection. Multiple logistic regression analysis demonstrated that markers of severity of acute illness (higher APACHE II scores and white blood cell counts, greater transfusion of cellular blood products, mechanical ventilator dependency, and prior infection) predicted fungal infection, whereas markers of chronic illness (comorbidities) did not independently predict either fungal or nonfungal infection. Patients with fungal infection were treated with more antibiotics for longer periods of time, had prolonged lengths of stay, and more often died compared with nonfungal infection patients. A separate multiple logistic regression analysis demonstrated that both fungal infection and the number of fungal sites of infection independently predicted mortality. Of all fungal isolates, only Candida albicans and Aspergillus spp. independently predicted mortality. CONCLUSIONS: Fungal infections differ significantly in character and outcomes from nonfungal infections among surgical patients.     

Fungus Infections After Liver Transplantation

The problem of fungus infections after liver transplantation was studied. In 100 consecutive recipients of orthotopic liver homografts there were 10 and 8 examples, respectively, of localized and disseminated infections caused by Candida species. Candidemia was demonstrated in 8 of these 18 patients. One patient who had a localized Candida infection also had disseminated cryptococcosis. An additional 31 patients were infested in that Candida could be cultured from sites where it is not normally found, such as the blood (8 examples), urine (8), ascitic fluid (8), and wounds (22). This exorbitant incidence of monilial infections and infestations was associated with a high frequency of complications involving the homograft as well as the hosts' gastrointestinal tract during the post-transplantation period. The yeasts found in blood, urine, ascitic fluid and elsewhere were thought to have originated from the gut. Ten of the 100 patients had aspergillosis which was localized in 7 instances and disseminated in 3. The lung was the most frequently affected organ. The fungus infections played a contributory role in the downhill course of our patients but in the event of death more fundamental and more frequent causes of failure were technical complications involving the homografts, difficulties in controlling rejection with reasonable immunosuppressive doses and bacterial sepsis. Suggestions have been made for the better control of fungal infections in liver recipients.     

Fungal complications after Candida preservation fluid contamination in liver transplant recipients

Donor‐derived fungal infections can be associated with severe complications in transplant recipients. Donor‐derived candidiasis has been described in kidney transplant recipients where contamination of the preservation fluid (PF) was a commonly proposed source. In liver transplantation, these fungal infections have been less explored. The aim of this study was therefore to determine the incidence and clinical relevance of Candida contamination of preservation fluid in the context of liver transplantation. A 5‐year (2008–2012) retrospective multicentre study involving six French liver transplantation centers was performed to determine the incidence of Candida PF contamination. Postoperative clinical features, outcomes in recipients, and risk factors for Candida‐related complications of liver transplantation were studied. Candida sp. was isolated from 28 of 2107 preservation fluid samples (1.33%). Candida albicans was the most common yeast (n = 18, 64%). Twenty‐two recipients (78.5%) received antifungal therapy (echinocandins in 68%) for 7–37 days. Eight patients developed yeast‐related complications (28.6%) including hepatic artery aneurysms (n = 6) and Candida peritonitis (n = 2). The 1‐year mortality rate among patients after a yeast‐related complication was 62.5%. The incidence of Candida PF contamination was low, but was associated with dramatic postoperative complications and high mortality. Close radiological follow‐up may enable early recognition of the arterial complications associated with PF contamination by Candida.     

“Triple infections” (fungal,bacterial and viral) in immunosuppressed renal transplant recipients

In a period of 5 years, 8 out of 77 renal transplant patients showed simultaneous fungal, bacterial and viral infections. Candida albicans was found in all cases. The most severe bacterial complications were infections with Klebsiella, Pseudomonas and Staphylococcus aureus. Cytomegalovirus, persistent HBsAg positive hepatitis, herpes zoster, and herpes simplex infections were also found. Seven patients died of bacterial superinfection and miliary tuberculosis. The data presented show that "triple infections" are associated with high mortality and that miliary tuberculosis occurred frequently in immunosuppressed renal transplant recipients.     

Invasive aspergillosis in solid-organ transplantation: report of eight cases and review of the literature

Invasive fungal infections are life-threatening complications in solid-organ transplantation. Although the rate of fungal infections in transplant recipients is lower than that of other infections, the mortality rate is higher. The most frequent fungi isolated from these kinds of infections are Candida spp. and Aspergillus spp. We retrospectively evaluated the clinical and laboratory findings in eight patients who were treated for invasive aspergillosis (IA) at our center. This report describes these cases and discusses the relevant literature.     

Clinical spectrum of fungal infections after orthotopic liver transplantation

During a 50-month period, we identified 91 episodes of fungal infection in 72 liver transplant recipients (23.8%). Candida species accounted for 83.5% of cases. Clinical patterns of fungal infections included disseminated infection (19), peritonitis (17), pneumonitis (15), multiple sites of colonization (13), fungemia (11), and other sites (16). The diagnosis of fungal infection was usually made in the first 2 months (84.7% of cases), at a mean time of 16 days after transplantation. Risk factors for fungal infections included retransplantation, Risk score, intraoperative transfusion requirement, urgent status, Roux limb biliary reconstruction (in adults), steroid dose, bacterial infections and antibiotic therapy, and vascular complications. Fungal infections were successfully treated with amphotericin B in 63 cases (74.1%) but were associated with diminished patient survival (50% vs 83.5%). Fungal infection is a frequent source of early morbidity and can be related to well-defined risk factors, suggesting the need for effective prophylaxis.     

原位肝移植术后真菌感染43例次诊治体会

目的 探讨原位肝移植术后真菌感染的诊断、治疗及预防。方法 回顾总结为175位患者所施行的180次原位肝移植的临床资料，并对可能导致真菌感染的危险因素进行统计学分析。结果 全组29例患者出现43例次真菌感染，感染率为16．6％(29／175)。其中念珠菌占98％(42／43)，曲霉菌2％(1／43)。发病中位时间为术后26d(3～96d)。常见感染部位依次是肺部37％(16／43)，肠管19％(8／43)和血液16％(7／43)。26例患者接受氟康唑治疗，感染严重的8例患者改用脂质体两性霉素B治疗。病死率45％(13／29)，直接与真菌感染有关的病死率为4．0％(7／175)。全胃肠外营养时间较长、抗生素治疗超过3周或出现肝动脉并发症的患者真菌感染的发生率显著增加。结论 真菌感染是影响肝移植生存率的重要原因之一。最常见的感染部位和病原菌分别是肺部和念珠菌。减少各种危险因素将有助于降低真菌感染的发生率。早期诊断和及时治疗是治愈的关键，严重的真菌感染应及时给予两性霉素B或其脂质体治疗。     

Fungal infections in solid organ transplantation: An update on diagnosis and treatment

Invasive fungal infections constitute an important cause of morbidity and mortality in solid organ transplantation recipients. Since solid organ transplantation is an effective therapy for many patients with end-stage organ failure, prevention and treatment of fungal infections are of vital importance. Diagnosis and management of these infections, however, remain difficult due to the variety of clinical symptoms in addition to the lack of accurate diagnostic methods. The use of fungal biomarkers can lead to an increased diagnostic accuracy, resulting in improved clinical outcomes. The evidence for optimal prophylactic approaches remains inconclusive, which results in considerable variation in the administration of prophylaxis. The implementation of a standard protocol for prophylaxis remains difficult as previous treatment regimens, which can alter the distribution of different pathogens, affect the outcome of antifungal susceptibility testing. Furthermore, the increasing use of antifungals also contributes to incremental costs and the risk of development of drug resistance. This review will highlight risk factors, clinical manifestations and timing of fungal infections and will focus predominately on the current evidence for diagnosis and management of fungal infections.     

Fungal Infections After Liver Transplantation: Incidence and Outcome

Background

Fungal infections, although less frequent than bacterial infections, represent a severe comorbidity with an exponential increase in mortality rate in liver transplantation patients. The incidence of invasive fungal infections (IFIs) after solid organ transplantation ranges from 7% to 42%, with Candida spp. and Aspergillus spp. as the most common pathogens. Fungal infections in liver transplant recipients have been associated with poor outcome and mortality rates ranging from 65% to 90% for invasive aspergillosis and 30% to 50% for invasive candidiasis. The results largely depend on early diagnosis and early initiation of specific treatment for IFIs. Therefore, the diagnosis must be prompt, preferably based on microbiological data, both cultures and biomarkers, and/or based on clinical features and known risk factors.

Materials and Methods

This study evaluated the incidence of fungal infections in patients after liver transplantation in our center between January 2003 and December 2012. The retrospective analysis of 215 consecutive liver transplantation patients was undertaken to estimate incidence, risk factors, and clinical courses of IFIs in the first 3 months after liver transplantation.

Results

Candidemia and invasive candidiasis microbiologically proven were found in 26 patients (12%), whereas in 6 patients (2.8%) invasive fungal infections from other non-Candida fungi developed: Aspergillus (4 cases: 2 A fumigatus, 2 A terreus), Fusarium oxysporum (1 case), and Rhodotorula rubra (1 case). Two patients with Aspergillus and the patient with Fusarium died. The patient with Rhodotorula as well as 22 of the patients with candidemia (85%) survived. All of the episodes developed during the first 3 months posttransplantation. All cases have followed a previous polymicrobial bacterial infection (especially in the biliary tract) with large use of combined antibiotic therapies.

Conclusions

The rate of fungal infection was found to increase in parallel with the number of risk factors. Prophylactic strategies can decrease the risk of fungal infections. Early detection and treatment with adequate early empiric therapy is the key to obtaining a better outcome in liver transplantation patients.     

Enteral fluconazole is well absorbed in critically ill surgical patients

BACKGROUND: Enteral fluconazole, a triazole antifungal agent with an excellent oral bioavailability, has not been widely studied in critically ill surgical patients. METHODS: During a randomized placebo-controlled trial of enteral fluconazole (N = 130) versus placebo (N = 130) for the prevention of fungal infections in critically ill surgical patients, trough fluconazole levels were measured after the loading dose and 3 times weekly during intensive care unit stay. Minimum inhibitory concentrations (MICs) for fluconazole were measured on all infecting Candida isolates. RESULTS: Four hundred sixty-seven serum samples were assayed for fluconazole levels in 121 patients. The most common infecting fungal species was Candida albicans, isolated in 14 of 31 infections (45%). Other infecting species were C glabrata, C tropicalis, and C parapsilosis. Mean fluconazole levels were above the highest MIC for C albicans and C parapsilosis in all but 5 patients (4%). Mean fluconazole levels were below the median MIC for C glabrata in 93 of 121 patients (77%). No significant relationship was seen between fluconazole levels and risk for fungal infection. CONCLUSIONS: Serum fluconazole levels are above the MIC of most yeast species found in these patients. These levels may not be above the MIC of C glabrata, the second most common Candida isolate causing infection in this study.     

普通外科病人真菌败血症的临床研究

目的探讨普通外科真菌败血症的发生特点、病原菌的种类及防治策略。方法回顾性分析2001年3月至2005年12月间南京军区南京总医院普通外科收治的94例真菌败血症病人的易感因素、病原学特点及治疗效果。结果易感因素主要为使用广谱抗生素、中心静脉插管、全胃肠外营养、入住重症监护病房。94例病人分离出94例菌株。非白色念珠菌是主要致病真菌。94例经抗真菌治疗者中37例死亡。结论真菌败血症多发生在存在腹腔感染病人。念珠菌属是主要致病真菌，其中以非白色念珠菌为主。对高危病人应重视病原学检查及药物敏感性测定，消除易感因素，及时合理选用抗真菌药物和肠内营养有望进一步改善预后。     

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.     

Prolonged rehospitalizations following renal transplantation: causes, risk factors, and outcomes

BACKGROUND: Although some studies have described rehospitalization after transplantation, few have focused on risk factors and consequences of prolonged hospital stay. Our goal was to determine the causes, risk factors, and outcomes of prolonged rehospitalizations after renal transplantation. PATIENTS AND METHODS: In this retrospective study, 574 randomly selected rehospitalization records of kidney transplant recipients were reviewed from 1994 to 2006. Admissions were divided into group 1, prolonged stay (length of stay >14 days, n=149), and group II, short stay (length of stay 62% of all hospital costs; however, they comprised only 26% of the patients. High-risk kidney transplant recipients for prolonged hospitalizations should be closely observed for infections and graft rejection.