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.     

Efficiency and Safety of Inhaled Amphotericin B Lipid Complex (Abelcet) in the Prophylaxis of Invasive Fungal Infections Following Lung Transplantation

Background

Invasive fungal infections (IFIs) in patients undergoing lung transplantation (LT) are associated with significant mortality. Previous studies have shown the efficacy of aerosolized amphotericin B deoxycholate and oral fluconazole for antifungal prophylaxis. Evolving data show a potential advantage of prophylaxis with lipid-based formulations of amphotericin B in the prevention of IFIs. We reviewed the incidence of IFIs among patients receiving aerosolized amphotericin B lipid complex (ABLC) in LT.

Methods

We undertook a retrospective review of the results of our antifungal protocol in a cohort of 60 LT patients. We analyzed the efficiency, safety, and tolerability of 50 mg of aerosolized ABLC administered postoperatively for IFI prophylaxis once every 2 days for 2 weeks and then once per week for at least 13 weeks. In addition, these transplanted patients received fluconazole (200 mg/d) during the first 21 days posttransplant. The prophylaxis-related efficiency and safety were quantified for IFIs and adverse events (AEs) for 6 months after study drug initiation.

Results

Prophylaxis was efficient in 59 (98.3%) patients. Only one patient developed a possible IFI, due to Aspergillus fumigatus. Four patients presented nausea and vomiting as an AE, although aerosolized amphotericin B was ongoing.

Conclusions

Nebulized ABLC was effective, safe, and well tolerated for the prophylaxis of aspergillosis in lung transplant patients during the early posttransplant period.     

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.     

Role of Liposomal Amphotericin B Prophylaxis After Liver Transplantation Compared With Fluconazole for High-Risk Patients. Impact on Infections and Mortality Within one Year

Background

Fungal infections are still one of the most important issue in liver transplant patients, contributing considerably to both morbidity and mortality. Few studies have been published comparing antifungal protocols for their impact on liver transplant (OLT) patients. The aim of this study was to evaluate the effects of liposomal amphotericin B compared with fluconazole prophylaxis on morbidity and mortality after liver transplantation.

Methods

We evaluated all 44 patients undergoing OLT from January 2006 to January 2009 who were enrolled and randomized to undergo treatment with Amphotericin B (3 mg/kg/d; group A = 25 patients) or fluconazole (800 mg Loading dose and thereafter 400 mg/d according to renal parameters and immunosuppressant trough levels; group B = 18 patients) for at least 7 to 14 days with 12 months follow-up after liver transplantation. A multivariate analysis assessed factors associated with infections and mortality.

Results

Neither antifungal prophylaxis was associated with a fungal episode; however, group A patients experienced fewer bacterial infectious episodes (Mann-Whitney U test P < .05). Furthermore, no renal impairment was observed in either groups. Nonetheless, patients undergoing fluconazole prophylaxis showed significant increases in immunosuppressive trough levels requiring dose adjustment.

Conclusion

We observed comparable results of fluconazole and liposomal amphotericin B to prevent invasive fungal infections throughout 12 months after surgery. The latter drug was associated with fewer bacterial infections after liver transplantation.     

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%.     

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.     

Antifungal Prophylaxis with Voriconazole or Itraconazole in Lung Transplant Recipients: Hepatotoxicity and Effectiveness

Invasive fungal infections (IFI) are common after lung transplantation and there are limited data for the use of antifungal prophylaxis in these patients. Our aim was to compare the safety and describe the effectiveness of universal prophylaxis with two azole regimens in lung transplant recipients.
This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality.
Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole.     

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.     

Renal effects of amphotericin B lipid complex

A study was conducted to compare the renal effects of amphotericin B lipid complex (ABLC), a lipid formulation of the widely used antifungal medication, with conventional amphotericin B (AmB) in the treatment of serious fungal infections, including invasive candidiasis, cryptococcal meningitis, and aspergillosis. The clinical experience of ABLC includes two types of open-label studies: randomized comparative (ABLC 5 mg/kg/d compared with AmB 0.6 to 1 mg/kg) and emergency use. In the comparative studies, changes in serum creatinine were evaluated three ways: doubling of the baseline value, an increase from < or = 1.5 mg/dL at baseline to > or = 1.5 mg/dL, and an increase from < or = 1.5 mg/dL at baseline to > or = 2.0 mg/dL. More patients in the AmB group reached these end points than in the ABLC group (P < or = 0.007), and the time needed to reach each of these end points was significantly shorter for the AmB group (P < or = 0.02). Increased serum creatinine was reported as an adverse event more frequently by patients receiving AmB than by patients receiving ABLC. In the emergency use study, a steady and statistically significant decrease in serum creatinine was observed among patients who started ABLC treatment with serum creatinine greater than 2.5 mg/dL due to prior AmB treatment. ABLC offers the physician a valuable, less-nephrotoxic alternative to AmB for the treatment of patients with severe, invasive fungal infections.     

A randomized prospective trial of amphotericin B lipid emulsion versus dextrose colloidal solution in critically ill patients.

BACKGROUND: Amphotericin B is the agent of choice for most invasive fungal infections in critically ill patients. It is associated with at least a 50% incidence of nephrotoxicity, despite prophylactic measures such as sodium loading. Newer formulations of amphotericin B are available but are costly and have unknown bioavailability in critically ill patients. Previous trials in neutropenic and critically ill patients have demonstrated that mixing amphotericin B with 20% lipid solution (Intralipid; Clintec Nutrition, Deerfield, III) may decrease nephrotoxicity. METHODS: In this randomized, prospective clinical trial, patients with positive fungal blood cultures, tracheal/sputum cultures or peritoneal cavity cultures were randomized to receive either 0.5 mg/kg per day of amphotericin B dextrose or 1.0 mg/kg per day of amphotericin B lipid emulsion. Duration of therapy was determined by the primary care team. Weekly 24-hour creatinine clearance was measured until 2 weeks after amphotericin B therapy was completed. RESULTS: The two groups were similar based on age, white blood cell count, serum creatinine, and creatinine clearance at the beginning of therapy. The group receiving amphotericin B lipid emulsion had significantly less decrease in creatinine clearance compared with controls, despite receiving significantly more amphotericin B. CONCLUSION: Amphotericin B lipid emulsion can be given at a higher total cumulative dose than amphotericin B dextrose with less nephrotoxicity.     

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。     

Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation.

Immunoprophylaxis using intravenous (IV) hepatitis B immune globulin (HBIG) decreases the recurrence of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). However, IV HBIG is expensive, has significant side effects, and is inconvenient to administer. An alternative approach for prophylaxis using intramuscular (IM) HBIG and oral lamivudine was prospectively evaluated in this study. Ten consecutive patients with cirrhosis with HBV infection who underwent OLT were included in this study. Nine of 10 patients received lamivudine, 150 mg/d, for an average duration of 8.6 months before OLT. Two of 10 patients with detectable HBV DNA at the time of OLT received 10,000 U (45 mL) of IV HBIG daily for 7 consecutive days, followed by 5 mL of IM HBIG weekly for the next 3 weeks, then every 3 weeks. The other 8 patients were HBV DNA negative at OLT and received one dose of IV HBIG (45 mL) during surgery, followed by 5 mL of IM HBIG weekly for 4 weeks, then every 3 weeks. All patients received lamivudine, 150 mg/d, after OLT. During a mean follow-up of 15.6 months, 9 of 10 patients achieved a protective hepatitis B surface antibody (HBsAb) titer greater than 200 IU/L and had no evidence of HBV recurrence. One patient failed to develop an adequate HBsAb titer and developed histological and virological evidence of recurrence. One patient died unrelated to HBV recurrence. Our preliminary data suggest that this combination prophylaxis with IM HBIG and lamivudine is effective and potentially cost saving.     

小肠移植后并发侵袭性真菌感染的治疗

目的 总结小肠移植术后侵袭性真菌感染(IFI)的治疗经验和教训.方法 将1994年至2009年6月间15例小肠移植患者分为3个阶段,1994-1995年的3例患者为第1阶段,2003-2006年的7例患者为第2阶段,2007年以后的5例患者为第3阶段.第1和第2阶段患者围手术期真菌感染的预防方案采用静脉注射氟康唑,IFI的治疗以静脉注射氟康唑为主,在病情危重时静脉注射两性霉素B或两性霉素B脂质体,首次用量为1～5 mg/d(或0.02～0.10 mg·kg~(-1)·d~(-1)),视患者耐受情况每日增加5 mg;第3阶段患者围手术期真菌感染的预防方案采用静脉注射两性霉素B脂质体,治疗IFI时,两性霉素B脂质体首次给药便达到目标治疗剂量,用量高达6 mg·kg~(-1)·d~(-1),并严密监测患者的生命体征,肝肾功能及电解质的变化,根据患者病情的变化和肾功能的状况调整剂量.结果 15例患者中有4例术后发生IFI,发生率为26.7%,其中第1、2和第3阶段患者中分别有1例、2例和1例发生IFI.第1和第2阶段3例发生IFI的患者经治疗无效死于严重IFI,第3阶段1例发生IFI的患者经两性霉素B脂质体治疗44 d后被成功救治.治疗期间,患者尿素氮和血清肌酐水平均显著升高,停药后逐渐下降至正常水平.3个阶段患者总体病死率为75%.结论 小肠移植术后IFI是极其凶险的并发症,病死率极高;两性霉素B脂质体能够成功救治IFI患者,在严密监测肾功能下,大剂量应用两性霉素B脂质体是安全的.     

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.     

A Comparision of Several Formats of Amphotericin B as an Inhaled Antifungal Prophylaxis

Objective

We sought compare the economic cost, ease of preparation and administration, and tolerance of the available alternatives of amphotericin B (AmpB) as an inhaled antifungal prophylaxis for lung transplant patients.

Materials and Methods

Doses administered and cost of the 3 formats: desoxycholate (desoxy; 50-mg vial); lipid complex (lipid; 100 mg/20 mL vial) and liposomal (lipos; 50-mg vial). The regimen for antifungal prophylaxis is as follows: AmpB desoxy (reconstituted and dilute): 5 mg/every 8 hours for 4 months and 5 mg/d in the following months; AmpB lipid (nonreconstituted): 25 mg/d for 7 days, 25 mg over 48 hours for days and 25 mg/wk; AmpB lipos (reconstituted): 24 mg 3 times weekly for 2 months, 24 mg/wk for 6 months and 24 mg every 2 weeks. We polled 8 nurses who prepare these drugs habitually. We also asked a random sample of treated patients regarding tolerance.

Results

Number of doses, vials per year per patient, and final cost for each type were: Desoxy, 609 doses, 72 vials, €607.90; lipid, 63 doses, 15 vials, €1428.15; and lipos, 57 doses, 57 vials, €7720.10. Amp B lipid is considered to be the easiest to use, because it does not have to be reconstituted. The following cases of intolerance were recorded: AmpB desoxy 5 (45); AmpB lipid 1 (67); AmpB lipos 0 (4).

Conclusions

AmpB desoxy is the most economical, but it requires greater care in handling, the highest number of doses, and has the worst tolerance. AmpB lipid has an intermediate price and is the easiest to prepare. AmpB lipos is the most expensive and it requires careful handling.     

Prophylactic Use of Liposomal Amphotericin B in Preventing Fungal Infections Early After Liver Transplantation: A Retrospective,Single-Center Study

In this study the authors evaluated the efficacy of prophylaxis with liposomal amphotericin B (L-AmB) in the incidence of fungal infections (FI) during the first 3 months after liver transplant (LT). The study was retrospective and accessed a 4-year period from 2008 to 2011. All patients who died in the first 48 hours after LT were excluded. Patients were divided by the risk groups for FI: Group 1, high-risk (at least 1 of the following conditions: urgent LT; serum creatinine >2 mg/dL; early acute kidney injury [AKI] after LT; retransplantation; surgical exploration early post-LT; transfused cellular blood components [>40 U]); and Group 2, low-risk patients. Group 1 patients were further separated into those who received antifungal prophylaxis with L-AmB and those who did not. Prophylaxis with L-AmB consisted of intravenous administration of L-AmB, 100 mg daily for 14 days. Four hundred ninety-two patients underwent LT; 31 died in the first 48 hours after LT. From the remaining 461 patients, 104 presented with high-risk factors for FI (Group 1); of these, 66 patients received antifungal prophylaxis and 38 did not. In this group 8 FI were observed, 5 in patients without antifungal prophylaxis (P = .011). Three more FI were identified in Group 2. By logistic regression analysis, the categorical variable high-risk group was independently related to the occurrence of invasive FI (P = .006). We conclude that prophylaxis with L-AmB after LT was effective in reducing the incidence of FI. No influence on mortality was detected.     

Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients

OBJECTIVE: To evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. SUMMARY BACKGROUND DATA: Invasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. METHODS: The authors conducted a prospective, randomized, placebo-controlled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. RESULTS: The primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients "on-therapy" and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. CONCLUSIONS: Enteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.     

Therapy of leishmaniasis in France: consensus on proposed guidelines

Because it relies on potentially toxic, difficult-to-handle, or expensive compounds the therapy of leishmaniasis is still a complex issue in 2010, especially for visceral leishmaniasis in immuno-suppressed subjects, or in patients with cutaneous and mucosal involvement. This induces a wide diversity of observed therapeutic practices, some being sub-optimal. The Société de Pathologie Exotique organised a meeting dedicated to the therapy of leishmaniasis in France that led to the first consensus on therapeutic guidelines. Liposomal amphotericin B is the first-line option for visceral leishmaniasis both in immunocompetent, and immunosuppressed patients (cumulated doses of 20 mg/kg and 30-40 mg/kg, respectively). Secondary prophylaxis with either liposomal amphotericin B, pentamidine or meglumine antimoniate is proposed to patients with heavy immunosuppression until immunity has been restored for at least 6 months. While the efficacy of new topical formulations of paromomycin is being tested, patients with Old World cutaneous leishmaniasis may be left untreated, or be administered a combination of superficial cryotherapy plus intralesional antimony, or even--in complex situations--receive systemic therapy. The efficacy of a short course of pentamidine (L. guyanensis/L. panamensis) and a 20-day schedule of meglumine antimoniate (L. braziliensis) is solidly established. However, in well-defined situations, local therapy of New World cutaneous leishmaniasis is now considered acceptable.     

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.     

原位肝移植术后真菌感染的诊治

目的 探讨原位肝移植术后真菌感染的诊断和治疗。方法 58例肝移植患者术后怀疑真菌感染时，行体液（痰、血、尿、胆汁、引流液等）或导管真菌培养，结合胸腹部CT影像学检查、活组织检查及诊断性治疗结果综合判断，一旦诊断确定，即给予氟康唑治疗，无效者改用伊曲康唑和两性霉素B，同时调整免疫抑制治疗方案。结果 58例患者中，16例术后并发真菌感染21例次（5例患者发生两次以上、不同部位或不同菌株的感染），感染发生率为27．6％（16／58），感染发生在术后4～38d，感染好发部位依次为肺（28．6％）、肠道（19．0％）、泌尿系统（14．3％）、腹腔（14．3％）、切口（9．5％）、血液（4．8％）、胆管（4．8％）及肝脏（4．8％）。在21例次真菌感染中，念珠菌感染占85．7％，曲霉菌感染占14．3％。氟康唑治疗有效者占66．7％，伊曲康唑治疗有效者占14．3％，两性霉素B治疗有效者占14．3％，1例（4．7％）各种抗真菌药物治疗均无效，治疗总有效率为95．2％。结论 肝移植术后真菌感染的发生率较高，依据影像学检查、病原学检查及活组织检查综合判断真菌感染，及时选用氟康唑、伊曲康唑及两性霉素B治疗。