Preemptive prophylaxis with a lipid preparation of amphotericin B for invasive fungal infections in liver transplant recipients requiring renal replacement therapy

BACKGROUND: Posttransplant renal replacement therapy has been shown to be an independently significant risk factor for invasive fungal infections after liver transplantation. We assessed the efficacy of a lipid preparation of amphotericin B as prophylaxis for invasive fungal infections, directed toward liver transplant recipients requiring renal replacement therapy. METHODS: A total of 148 patients transplanted between 1990 and 1997 received no antifungal prophylaxis. Since 1997, 38 patients underwent liver transplantation; antifungal prophylaxis with a lipid preparation of amphotericin B was used in patients requiring renal replacement therapy. RESULTS: Fifteen percent (22 of 148) of the patients transplanted before 1997 required renal replacement therapy. In this cohort, the incidence of invasive fungal infections (36% vs. 7%, P=0.0007) and invasive aspergillosis (14% vs. 2%, P=0.02) was significantly higher in patients who required renal replacement therapy compared with those who did not. Since 1997, 29% (11 of 38) of the patients required renal replacement therapy and received antifungal prophylaxis. Invasive fungal infections occurred in 36% (8 of 22) of the patients who received no prophylaxis (patients before 1997), and 0% (0 of 11, P=0.03) in those who received antifungal prophylaxis (since 1997). Antifungal prophylaxis was independently associated with protection from fungal infection (P=0.017). No reduction in mortality with antifungal prophylaxis was documented. CONCLUSION: Prophylaxis with a lipid preparation of amphotericin B was associated with a significant reduction in invasive fungal infections in high-risk liver transplant recipients, i.e., those requiring renal replacement therapy. However, no beneficial effect on survival could be documented.     

Candida infections in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice provide recommendations for the diagnosis and management of Candida infections in solid organ transplant recipients. Candida infections manifest primarily as candidemia and invasive candidiasis and cause considerable morbidity and mortality. Early diagnosis and initiation of treatment are necessary to reduce mortality. For both candidemia and invasive candidiasis, an echinocandin is recommended for initial therapy. However, early transition to oral therapy is encouraged when patients are stable and the organism is susceptible. Candida prophylaxis should be targeted for high‐risk patients in liver, small bowel, and pancreas transplant recipients. Future research should address which patient groups may benefit most from preventative antifungal therapy strategies.     

Invasive Fungal Infections in Low-Risk Liver Transplant Recipients: A Multi-Center Prospective Observational Study

Prevention of invasive fungal infections (IFIs) in orthotopic liver transplant (OLT) recipients utilizing postoperative systemic antifungal prophylaxis, typically with fluconazole, is justified among those at high risk for IFI. Use of postoperative antifungal prophylaxis for low-risk OLT recipients is widely practiced but not universally accepted nor supported by data. We conducted a prospective observational study among 200 OLT recipients who were at low risk for IFI and did not receive postoperative antifungal prophylaxis. Patients were considered low risk if they had /=units of 40 blood products or return to the operating room for intra-abdominal bleeding; return to the operating room for anastomotic leak or vascular insufficiency; preoperative serum creatinine of >/=2 mg/dL; and perioperative Candida colonization. Patients were followed 100 d post-transplantation for evidence of IFI. Of 193 eligible patients, 7 (4%) developed an IFI. Three (2%) IFIs were due to Candida spp. and potentially preventable by standard fluconazole prophylaxis. Three patients developed invasive aspergillosis; one developed late onset disseminated cryptococcosis. Liver transplant recipients at low risk for IFI can be identified utilizing pre-determined criteria, and post-transplantation antifungal prophylaxis can be routinely withheld in these patients.     

Invasive aspergillosis in the recipients of liver retransplantation.

Retransplantation is a major risk factor for invasive aspergillosis in liver transplant recipients. However, the risk for invasive aspergillosis with time elapsed since retransplantation, clinical characteristics, and outcome of patients who develop this infection after retransplantation of the liver has not been defined. Patients comprised 17 liver retransplant recipients with invasive aspergillosis between 1990 and 2004. Retransplantation was considered early if it was performed within 30 days and late if performed after 30 days of the first or primary transplant. Retransplant recipients comprised 25% of all cases of invasive aspergillosis after liver transplantation. Fifty-three percent of the Aspergillus infections occurred within 30 days, and 76% within 90 days of retransplantation. In all, 53% (9/17) of the patients were late retransplant recipients. Late compared to early retransplant recipients with invasive aspergillosis were more likely to have central nervous system involvement with invasive aspergillosis (56% vs. 0%, P = 0.03). Mortality rate was 100% for late and 63% for early retransplant recipients with Aspergillus infections. In conclusion, time-varying risk for invasive aspergillosis after retransplantation has implications relevant for guiding antifungal prophylaxis. Given a greater risk for disseminated infection and poor outcome in late retransplant recipients with aspergillosis, potent and aggressive antifungal therapy should be considered upfront in these patients.     

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.     

Risk stratification and targeted antifungal prophylaxis for prevention of aspergillosis and other invasive mold infections after liver transplantation.

Antifungal prophylaxis has been proposed for liver transplant recipients at increased risk for invasive mold infection. Risk factors for invasive mold infection after liver transplantation were selected to divide recipients into 3 groups: (1) high risk-transplantation on hemodialysis or delay of hospital discharge beyond day 7 after transplantation because of allograft or renal insufficiency; (2) intermediate risk-retransplantation or transplantation for fulminant hepatic failure; (3) low risk-absence of conditions in groups 1 and 2. During an intervention period (February 1999-April 2001), prophylactic administration of a lipid complex of amphotericin (Abelcet) at 5 mg/kg intravenously every 24 to 48 hours was recommended for high-risk recipients. The frequency of mold infection was compared to that of a preintervention period (February 1998-January 1999) when antifungal prophylaxis was not provided. During the intervention period, invasive mold infection developed in 2 (6%) of 35 high-risk recipients, 0 of 28 intermediate-risk recipients, and 1 (0.5%) of 187 low-risk recipients. Overall, of 58 liver transplant recipients, 3 (5%) developed an invasive mold infection during the preintervention period, compared with 3 (1%) of 250 during the intervention period (P = 0.08). The only death from invasive mold infection occurred during the preintervention period. Rates of pulse corticosteroid treatment of rejection and cytomegalovirus infection were lower during the intervention period. In conclusion, readily identifiable patient characteristics can be used to stratify liver transplant recipients for risk of invasive mold infection. Antifungal prophylaxis given to high-risk recipients may provide cost-effective prevention of these infections.     

Antifungal Management Practices in Liver Transplant Recipients

We sought to determine the approach to antifungal prophylaxis, and diagnostic and therapeutic practices for the management of invasive aspergillosis in liver transplant recipients. Data were collected by an electronic survey questionnaire sent to all active liver transplant programs in North America; 63% (67/106) of the sites completed the survey. Overall, 91% of the sites employed antifungal prophylaxis; 28% used universal prophylaxis and 72% targeted it toward high-risk patients. Fluconazole was the most commonly used agent for universal and targeted prophylaxis. The leading choice for mold-active agents for antifungal prophylaxis was the echinocandins. Combination therapy was used as primary therapy for invasive aspergillosis in 47%, and as salvage in 80%. Thus, a vast majority of the surveyed programs employ antifungal prophylaxis and most use targeted prophylaxis. Consideration of these practices could guide clinical trial design to optimize antifungal prophylaxis in these patients. Our findings also merit investigations to better define the role of diagnostic assays and combination therapeutic strategies for invasive aspergillosis in liver transplant recipients.     

Invasive fungal infections following liver transplantation: Incidence, risk factors, survival, and impact of fluconazole-resistant Candida parapsilosis (2003-2007)

Invasive fungal infections (IFIs) are associated with a high mortality rate for liver transplantation (LT) recipients. To study the incidence of and risk factors for IFIs in LT recipients and the associated mortality rates, we retrospectively reviewed the records of first-time deceased donor LT recipients (January 2003 to December 2007). The incidence of IFIs was 12%. Non-albicans Candida species accounted for 55% of IFIs; 50% of these IFIs were Candida parapsilosis. Only 43% of Candida isolates were fluconazole-susceptible (minimum inhibitory concentration ≤ 8 μ/mL). All C. parapsilosis isolates were fluconazole-resistant, and this coincided with a surge of these isolates during a peak period of LT. Factors associated with IFIs included a creatinine level > 2 mg/mL [hazard ratio (OR) = 2.4, 95% confidence interval (CI) = 1.2-5.0, P = 0.01], a Model for End-Stage Liver Disease score > 25 (OR = 2.4, 95% CI = 1.2-4.9, P = 0.02), pretransplant fungal colonization (OR = 7.0, 95% CI = 3.2-15.3, P < 0.001), and a daily prophylactic fluconazole dosage < 200 mg (OR = 2.8, 95% CI = 1.1-7.4, P = 0.03). According to a multivariate analysis, only pretransplant fungal colonization was associated with IFIs (OR = 7.8, 95% CI = 3.9-16.2, P < 0.001). The 1-year patient survival rates with and without IFIs were 41% and 80%, respectively, and the survival rates with C. parapsilosis, other non-albicans Candida, and Candida albicans IFIs were 28%, 50%, and 75%, respectively. In conclusion, IFIs after LT (especially non-albicans Candida species and fluconazole-resistant C. parapsilosis) were associated with reduced survival. The risk factors highlight the importance of pretransplant risk assessments. The identification of pretransplant fungal colonization may allow for risk modifications before or at the time of LT. Additionally, the number of LT procedures and prophylactic strategies may affect institutional outbreaks of resistant Candida strains. Liver Transpl, 2012. ? 2012 AASLD.     

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.     

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.     

Voriconazole Prophylaxis in Lung Transplant Recipients

Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole ± inhaled amphotericin in patients at high risk (pre- or posttransplant Aspergillus colonization [except Aspergillus niger ]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty-nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A threefold or higher increase in liver enzymes was noted in 37–60% of patients receiving voriconazole prophylaxis as compared to 15–41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.     

Safety of anidulafungin in solid organ transplant recipients

The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we included all consecutive SOT recipients from 14 centers who received anidulafungin for at least 48 hours for the treatment of invasive fungal infections (IFIs) or as prophylaxis. Relevant clinical and analytical information on clinical charts was reviewed. Clinical side effects, liver function tests, and serum creatinine levels were assessed at least weekly. The need for the modification of immunosuppressive drugs was also recorded by the investigators. All patients were followed for at least 1 week after the end of treatment (EOT) or until death. Eighty-six SOT recipients were evaluated (56 transplant recipients, 20 lung transplant recipients, 8 kidney transplant recipients, and 2 heart transplant recipients). Sixty-two patients (72%) received anidulafungin for prophylaxis, and 24 (28%) received anidulafungin for the treatment of IFIs [candidemia/invasive candidiasis (16) or invasive aspergillosis (8)]. At the baseline, only 5% of the patients were neutropenic (<500 neutrophils/mL). There was no need for the modification of immunosuppressive drug doses because of anidulafungin therapy. No patient discontinued anidulafungin because of severe adverse effects. While receiving anidulafungin, 1 patient developed mild liver toxicity, but the liver function normalized without the discontinuation of anidulafungin. At EOT, the median serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels were significantly lower than the baseline levels, even in liver transplant recipients and patients who had higher baseline levels of serum creatinine. In conclusion, these results show that anidulafungin is a well-tolerated drug in SOT recipients.     

A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality,acute cellular rejection,infections, and changes in the liver function tests while on caspofungin

Doria C, Bodzin AS, Vaccino S, Daskalakis C, Krawitz S, Ramirez CB. A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality, acute cellular rejection, infections, and changes in the liver function tests while on caspofungin.
Clin Transplant 2011: 25: 569–575. © 2010 John Wiley & Sons A/S. Abstract: This study is a retrospective analysis of death, adverse events (AE), fungal infections, and hepatic function among recipients of liver transplantation at high risk of fungal infection who received prophylactic treatment with caspofungin. After reviewing data of 105 patients who had received isolated liver transplant between January 2003 and April 2007, we identified and analyzed 82 high‐risk patients. Post‐transplant patients at high risk for fungal infection are commonly defined by the presence of at least one of the following: (i) re‐transplantation; (ii) re‐operation; (iii) renal dysfunction. However, in our practice, patients are also considered at high risk for developing fungal infections if they present with the following: (iv) fever of unknown origin; (v) hypothermia; (vi) positive random culture for fungus at the time of transplant (bile and/or ascites); (vii) sepsis; (viii) use of vasopressors; (ix) re‐intubation, during the first hospitalization after liver transplant; (x) prolonged intubation (>24 h), and (xi) acute respiratory distress syndrome, until negative fungal cultures are obtained. Exact conditional logistic regression was used to compare the risk of death, AEs, and fungal infections between patients who received caspofungin, other antifungal drugs, and no antifungal drugs. Analyses were then performed with SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Patients were between 27 and 72 yr old (mean = 55), with two‐thirds male and three‐quarters Caucasian. Sixteen patients received caspofungin (11 preventively), and 32 received other antifungal (26 preventively). There were no proven fungal infections among the patients who received caspofungin, three infections among patients who received other antifungal (3/26 = 12%), and 14 infections among patients who were not preventively treated (14/45 = 31%). These infection rates were significantly different across the three groups (p = 0.029), with caspofungin and other antifungal preventive treatment comparable (p = 0.540), and both better than no preventive treatment at all (OR = 0.15, p = 0.049, for caspofungin versus no preventive treatment; OR = 0.29, p = 0.085, for other antifungal versus no preventive treatment). Caspofungin appears to be an effective preventive agent against fungal infections when used in recipients of liver transplant designated as high risk for fungal infection. Usage of caspofungin in these patients does not carry an apparent increase in risk of death or acute cellular rejection, although we observed a significantly higher risk of AEs, especially acute renal failure (p = 0.001), in patients who received this agent.     

Factors associated with the development of candidemia and candidemia-related death among liver transplant recipients.

OBJECTIVE: The authors' objective was to identify factors associated with candidemia and candidemia-related death among adult liver transplant recipients. SUMMARY BACKGROUND DATA: Invasive candidiasis is the most common severe fungal infection occurring after liver transplantation and is associated with high morbidity and mortality rates. Although candidemia is not always found during invasive candidiasis, it has been considered as an indicator of invasive candidiasis in immunocompromised patients. METHODS: A time-matched case-control study of 26 patients with candidemia, which was defined as the isolation of Candida from at least one blood culture, and 52 control patients without candidemia was reported. Two control patients were matched with each case patient regarding time of transplantation and duration of follow-up. RESULTS: Between December 1985 and December 1992, candidemia developed in 1.4% of adult liver transplant recipients a median of 25 days after transplantation (range, 2-1690 days). The overall mortality rate among patients with candidemia was 81%, and 71% of these deaths were related to candidemia. Conditional logistic regression analysis was used to identify factors associated with candidemia, which were 1) hyperglycemia treated with insulin up to 2 weeks before candidemia (odds ratio [OR], 16.15; p = 0.002), and 2) exposure to more than three different intravenous antibiotics before development of candidemia (OR, 11.15; p = 0.005). The variables predictive of death related to candidemia were abdominal surgery performed up to 1 week before candidemia (relative risk [RR], 7.25; p = 0.02), high white blood cell count (RR, 1.10; p = 0.01), lower platelet count (RR, 0.99; p = 0.02), and elevated AST with candidemia (RR, 1.001; p = 0.01). CONCLUSIONS: Hyperglycemia that requires insulin and exposure to more than three antibiotics are the factors associated with the development of candidemia in liver transplant recipients. When candidemia develops shortly after abdominal surgery and in patients with elevated AST, high white blood cell count, or low platelet count, it is associated with a high mortality rate.     

Pulmonary infiltrates in liver transplant recipients in the intensive care unit

BACKGROUND: A frequent dilemma is discerning the likelihood of pneumonia and the need for empiric antibiotic therapy in liver transplant recipients with pulmonary infiltrates in the intensive care unit (ICU). METHODS: We performed a prospective, observational study of consecutive liver transplant recipients developing pulmonary infiltrates in the ICU. RESULTS: Of 90 consecutive liver transplant patients in the ICU over a 3-year period, 44% (40) developed pulmonary infiltrates. The etiologies were pneumonia (38%, 15 of 40), pulmonary edema (40%, 16 of 40), atelectasis (10%, 4 of 40), adult respiratory distress syndrome (8%, 3 of 40), contusion (3%, 1 of 40), and unknown (3%, 1 of 40). Pneumonia was due to methicillin-resistant Staphylococcus aureus in 27% (4 of 15), Pseudomonas aeruginosa (27%, 4 of 15), invasive aspergillosis (20%, 3 of 15), and Enterobacter cloacae, Serratia marcescens, Pneumocystis carinii pneumonia, and unknown (7%, 1 of 15) in one each. None of the patients had cytomegalovirus or herpes simplex virus pneumonia. Seventy-five percent of methicillin-resistant Staphylococcus aureus and all Aspergillus pneumonias, but only 14% of the Gram-negative pneumonias, occurred within 30 days of transplantation. Twenty-seven percent of the pneumonias occurred >365 days after transplantation; all of these were in patients with recurrent viral hepatitis C virus or hepatitis B virus, disseminated posttransplant lymphoproliferative disorder, or late rejection. Of patients with pneumonia, 87% were ventilated and 40% had bacteremia. Clinical pulmonary infection score (Pugin score) >6 (73% vs. 6%, P = 0.0001), abnormal temperature (73% versus 28%, P = 0.005), and creatinine level >1.5 mg/dl (80% versus 50%, P = 0.05) were predictors of pneumonia versus other etiologies of pulmonary infiltrates. Overall mortality in patients with pulmonary infiltrates was 28% (11 of 40); pneumonia as etiology (P = 0.06), creatinine level >1.5 mg/dl (P = 0.028), higher blood urea nitrogen (P = 0.017), and worse APACHE neurological score (P = 0.04) were predictors of poor outcome. CONCLUSIONS: Our data have implications not only for identifying pneumonia as a potential cause of pulmonary infiltrates, but for the likely etiology of the pneumonia and thus the selection of empiric antibiotic therapy in critically ill liver transplant recipients. Pugin score >6 in patients with pulmonary infiltrates warrants antimicrobial therapy. Early onset within 30 days after transplantation raises the spectra of aspergillosis.     

Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection?

A vast majority of the transplant recipients are cytomegalovirus (CMV)-seropositive (R+). We sought to assess variables predictive of CMV infection, specifically in R+ liver transplant recipients. Study patients comprised 182 consecutive liver transplant recipients who survived at least 14 days after transplantation. Surveillance testing was used to detect CMV infection. Pre-emptive therapy was employed for the prevention of CMV disease, however, no antiviral prophylaxis was used for CMV infection. CMV infection developed in 32.5% (38 of 117) of R+ patients, 84.6% (33 of 39) of R-/D+, and 3.8% (1 of 26) of R-/D- patients. In R+ patients, Hispanic race (21.6% vs. 7.8%, P = 0.06), donor CMV seropositivity (73.7% vs. 45.6%, P = 0.005), and hepatocellular carcinoma (23.7% vs. 6.3%, P = 0.05) correlated with a higher risk of CMV infection. In a multivariate model, Hispanic race (OR: 3.5, 95% CI: 1.03-11.6, P = 0.045), donor CMV serostatus (OR: 4.0, 95% CI: 1.6-10.2, P = 0.003) and hepatocellular carcinoma (OR: 5.8, 95% CI: 1.6-20.5, P = 0.006) were all significant independent predictors of CMV infection. The aforementioned variables did not portend a higher risk of CMV infection in R-/D+ patients; donor CMV seropositivity overwhelmed all other risk factors in R- patients (P < 0.00001). In conclusion, CMV-seropositive liver transplant recipients at risk for CMV infection can be identified based on readily assessable variables. Preventive strategies may be selectively targeted toward these patients.     

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.     

Randomized controlled trial of oral itraconazole solution versus intravenous/oral fluconazole for prevention of fungal infections in liver transplant recipients

BACKGROUND: Liver transplant recipients at high risk for serious fungal infections frequently receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole, safety with amphotericin B, and the cost of lipid formulations of amphotericin, alternative prophylactic regimens are needed. In this randomized, controlled trial, we compared the efficacy and safety of oral itraconazole solution with intravenous/oral fluconazole for prevention of fungal infections. METHODS: Adult liver transplant recipients were randomized to receive either oral itraconazole solution (200 mg every 12 hr) or intravenous/oral fluconazole (400 mg every 24 hr). Each study drug was started immediately before transplant surgery and continued for 10 weeks after transplantation. Patients were evaluated for fungal colonization, proven invasive or superficial fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization decreased from baseline to week 8 after transplantation in both the itraconazole patients (67% to 25%, P<0.001) and the fluconazole patients (77% to 30%, P<0.001). Proven fungal infection developed in 9 (9%) of 97 itraconazole patients and in 4 (4%) of 91 fluconazole patients (P =0.25). The number of proven invasive fungal infections (seven with itraconazole [7%], three with fluconazole [3%]) and proven superficial fungal infections (two with itraconazole [2%], one with fluconazole [1%]) were also similar in both groups of patients. Organisms causing infection were (four patients), (three patients), and species (two patients) in the itraconazole group and (two patients), (one patient), and species (one patient) in the fluconazole group. Mortality from fungal infection was very low and occurred in only 1 (0.5%) of 188 patients. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea) with itraconazole, both itraconazole and fluconazole were well tolerated and not associated with any hepatotoxicity. Mean trough plasma concentrations of itraconazole were greater than 250 ng/mL throughout the study and were not affected by H -receptor antagonists or antacids. CONCLUSION: Oral itraconazole solution has adequate bioavailability in liver transplant recipients for effective antifungal prophylaxis. Similar to fluconazole, prophylactic oral itraconazole decreases fungal colonization and is associated with a low incidence of serious or fatal fungal infections. Except for gastrointestinal side effects, oral itraconazole solution is well tolerated and has no significant hepatotoxicity.     

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.     

Incidence of fungal infections in a solid organ recipients dedicated intensive care unit

Invasive fungal infections are a significant cause of morbidity and mortality for patients undergoing solid organ transplantation. Our aim was to evaluate the incidence of invasive fungal infections in solid organ recipients within a dedicated intensive care unit (ICU). MATERIALS AND METHODS: From May 2002 to May 2005, 278 patients undergoing solid organ transplantation (105 liver, 142 kidney, 20 lung, 2 combined liver-kidney, 9 combined pancreas-kidney) were admitted to our posttransplant intensive care unit. We retrospectively analyzed data obtained from the ICU stay. Fungal infection was defined by positivity of normally sterile biological samples and by elevated positivity of normally non sterile biological samples. We did not consider superficial fungal infections and asymptomatic colonizations. RESULTS: Forty-six patients (16.5%) developed a fungal infection; at least one mycotic agent was isolated from each patient. Candida albicans was the most common pathogen, isolated from 71 % of infected patients (33 of 46). Infected patients showed a mortality rate of 35%, while that for non infected recipients was 3.5%. Total length of ICU stay was the most significant risk factor among infected patients (30.26 days vs 5.04 days P < .0001). Mean time between transplantation and first positive samples was 6.17 days (SD 8.88). CONCLUSION: Fungal infections in solid organ transplant patients are a major issue because of their associated morbidity and mortality. Candida albicans was the most common pathogen and total length of ICU stay was the most important risk factor.