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Competing Interests: Potential conflicts of interest. S. D. reports grants or contracts from the National Institutes of Health (payments to Fred Hutchinson Cancer Center, which support the author's salary). C. M. K. reports a role as chair of the patient-centered outcomes research institute Clinical Trial Advisory Panel. C. E. F. reports grants or contracts from the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases and a role as unpaid ad hoc committee member for the Disease Transmission Advisory Committee (United Network for Organ Sharing). A. P. L. is a consulting and/or site investigator for Merck, GlaxoSmithKline, and Takeda Pharmaceuticals. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.

In a post-hoc analysis of the association of CMV DNAemia with long-term mortality in a randomized trial of CMV preemptive therapy vs. antiviral prophylaxis in D+R- liver transplant recipients, post-intervention CMV DNAemia was associated with increased mortality after adjusting for study arm., Competing Interests: Potential conflicts of interest. A. P. L. is a consulting and/or site investigator for and has received institutional payments from Merck & Co, GlaxoSmithKline, Moderna, and Takeda Pharmaceuticals; has received institutional support via consulting fees from AiCures and Vera Therapeutics; reports consulting fees from Merck & Co, Moderna, AlloVir, and GlaxoSmithKline; and was reimbursed for participation on a data and safety monitoring board for Novartis, Syneos, and NobelPharma. C. E. F. is a consulting and/or site investigator holding grants or contracts unrelated to the study for Moderna and Amplyx Pharmaceuticals, Inc; has received support from National Institutes of Health (NIH); reports honoraria from NIH for serving as a VIDD study section ad hoc member; has received travel reimbursement from NIH; and was an unpaid participant of the United Network for Organ Sharing Disease Transmission Advisory Committee. C. M. K. has received institutional funding support unrelated to this article from the NIH, Patient-Centered Outcomes Research Institute (PCORI), and University of New Mexico; was reimbursed for travel expenses for participation on a clinical trials advisory panel for PCORI; and has received honoraria for leadership positions as chair for the PCORI Clinical Trials Advisory Panel and co-chair for the Membership Committee of the Society for Clinical Trials. S. D. has received institutional support from NIH (National Cancer Institute/National Institute of Allergy and Infectious Disease), University of Washington, Gilead Sciences, Inc, and Merck & Co and employee travel support from the Fred Hutchinson Cancer Center. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET., Methods: We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring., Results: Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).  All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts., Conclusions: In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted., (© 2023 Wiley Periodicals LLC.)

Background: Detailed cytomegalovirus (CMV) kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+/R-) transplant recipients receiving preemptive therapy (PET) have not been fully defined., Methods: The study population consisted of the PET arm of a randomized CMV prevention trial in D+/R- liver transplant recipients. CMV DNA polymerase chain reaction (PCR) assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation)., Results: Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3350 IU/mL; 25.7% (19/74) of the patients had peak levels >10 000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance, and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had a significantly lower rate of recurrent viremia than those without such increase (16/40 [40%] vs 28/39 [71.8%], respectively; P = .004)., Conclusions: A majority of D+/R- recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R-) liver transplant recipients have not been assessed in the context of a randomized trial., Methods: A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R- liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy., Results: PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease)., Conclusions: PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R- liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease-associated costs due to delayed onset postprophylaxis disease in the prophylaxis group., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined., Methods: The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant., Results: HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant., Conclusions: Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection., Competing Interests: D.J.W. has received research support form Merck, Chimerix, Shire, Gilead, and Oxford Immnotech. G.M.L. has received research support from Takeda pharmaceutical company. F.P.S. has received research support from Shire, Ansun, and Novartis. A.P.L. has received research support from Merck and Astellas, and consulting support from Helocyte, Inc, Amplyx, Novartis, and AlloVir. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Whether donor (D+) or recipient (R+) cytomegalovirus (CMV) seropositivity is associated with functional impairment in liver transplant recipients is not known., Methods: Patients included adult liver transplant recipients in the Organ Procurement and Transplantation Network database transplanted over a five-year period from 1 January 2014-31 December 2018. Functional status in the database was assessed using Karnofsky performance scale. A logistic regression model that controlled for potential confounders was used to examine the association of CMV serostatus and functional status. Variables significantly associated with functional status ( p < 0.05) were then used to develop propensity score and propensity score matched analysis was conducted where each patient was compared with a matched-control with the same propensity score., Results: Among 30,267 adult liver transplant recipients, D+ or R+ patients had significantly lower functional status at last follow-up than the D-R- cohort (OR 0.88, 95% CI 0.80-0.96, p = 0.007). In propensity score matched model, D+ or R+ patients had significantly lower functional status than matched-controls ( p = 0.009). D+ or R+ CMV serostatus ( p = 0.018) and low functional level ( p < 0.001) were also independently associated with infections as cause-of-death., Conclusions: D+ or R+ liver transplant recipients had lower functional status and higher risk of deaths due to infections. Future studies are warranted to examine the mechanistic basis of these findings in the setting of transplantation.

Background: The risk factors for development of viremia in high-risk donor cytomegalovirus (CMV)-seropositive and recipient CMV-seronegative (D+R-) transplant recipients are incompletely defined., Methods: The study population comprised patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus prophylaxis using valganciclovir in D+R- liver transplant recipients. Weekly surveillance monitoring for viremia for 100 days was performed using a sensitive CMV-DNA polymerase chain reaction assays. Risk factors for viremia and time to onset (≤4 vs >4 weeks) of viremia were examined using logistic regression models., Results: Viremia developed in 84% (79/94) of recipients and older donor age was the only independent factor associated with viremia (odds ratio, 2.20 for each quartile increase in donor age; 95% confidence interval [CI], 1.07-4.52; P = .031). Recipients who developed early-onset viremia (within 4 weeks) also had significantly older donors than those with later-onset viremia (difference in age 10.1 years; 95% CI, 2-19; P = .03)., Conclusions: Older donor age was an independent predictor of viremia and earlier-onset of viremia in D+R- liver transplant recipients. Future studies should assess the mechanistic links underlying this novel association., Clinical Trial Registration: NCT01552369., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Importance: Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients., Objective: To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease., Design, Setting, and Participants: Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018., Interventions: Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105)., Main Outcomes and Measures: The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia., Results: Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46)., Conclusions and Relevance: Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT01552369.

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The utility of Aspergillus galactomannan (GM) and β-D-glucan (BG) in liver transplant recipients remains uncertain., Methods: As part of a randomized, double-blind trial of antifungal prophylaxis in liver transplant recipients at risk for invasive fungal infections (IFIs), GM and BG were assessed in 199 patients at baseline (enrollment) and weekly thereafter for the duration of study drug. Receiver operating characteristic (ROC) analysis was used to evaluate the accuracy of these for the diagnosis of IFIs., Results: Overall, 46.4% of the patients at baseline had positive GM (index ≥ 0.5) and 89.6% had BG of 80 pg/mL or greater with BG level of 500 pg/mL or greater in 31.8%. Patients with invasive aspergillosis (IA) (3/3) had positive GM at baseline as did 45.5% of those without IA (P = 0.098); the area under the ROC curve for the diagnosis of IA was 0.77 (fair test, ie, good sensitivity but poor specificity). Using BG cutoff of 80 pg/mL or higher, 100% (12/12) of the patients with IFI had positive baseline BG and as did 88.9% (160/180) of those without IFI (P = 0.618); the area under the ROC curve for predicting IFIs was 0.56 (poor test). In multivariate analyses, GM positivity was associated with study site (P = 0.041), and BG positivity with renal replacement therapy (P = 0.05) and study site (P = 0.01). The GM and BG levels declined over time; positivity at subsequent time points was lower in comparison with baseline (P < 0.001)., Conclusions: The GM and BG tests had significant center variability and limited accuracy for the diagnosis of IFIs in high-risk liver transplant recipients.

Background: The outcomes and optimal management of cirrhotic patients who develop cryptococcosis before transplantation are not fully known., Methods: We conducted a multicenter study involving consecutive patients with cirrhosis and cryptococcosis between January 2000 and March 2014. Data collected were generated as standard of care., Results: In all, 112 patients were followed until death or up to 9 years. Disseminated disease and fungemia were present in 76.8% (86/112) and 90-day mortality was 57.1% (64/112). Of the 39 patients listed for transplant, 20.5% (8) underwent liver transplantation, including 2 with active but unrecognized disease before transplantation. Median duration of pretransplant antifungal therapy and posttransplant therapy was 43 days (interquartile range, 8-130 days) and 272 days (interquartile range, 180-630 days), respectively. Transplantation was associated with lower mortality (P = 0.002). None of the transplant recipients developed disease progression during the median follow-up of 3.5 years with a survival rate of 87.5%., Conclusions: Cryptococcosis in patients with cirrhosis has grave prognosis. Our findings suggest that transplantation after recent cryptococcal disease may not be a categorical exclusion and may be cautiously undertaken in liver transplant candidates who are otherwise deemed clinically stable.

Invasive aspergillosis (IA) in liver transplant recipients is associated with grave outcomes. We reviewed 116 individual cases reported in the literature from 1985 to 2013. IA was diagnosed after a median of 25 days after transplantation and involved a single organ in 51% of the cases, whereas in the remaining cases, multiple sites were involved. The most common infecting Aspergillus species were Aspergillus fumigatus (73%), Aspergillus flavus (14%), and Aspergillus terreus (8%). Amphotericin B was the drug most frequently used, and it was followed by voriconazole and itraconazole. Combination regimens were used in 51% of the cases. The overall 1-year cumulative survival probability was 35% [95% confidence interval (CI) = 24.6%-49.6%]. Survival was significantly higher for patients reported from the year 2000 and thereafter (P < 0.001), for those diagnosed with IA more than 30 days after transplantation versus those diagnosed earlier (P = 0.019), and for patients without renal failure (P = 0.020). Additionally, the use of voriconazole was significantly associated with a higher probability of survival (P < 0.001). Cox regression analysis showed that subjects with the involvement of multiple sites had a 2.52 times higher risk of a negative outcome (95% CI = 1.08-5.87) than those with the involvement of a single site. Thus, IA causes life-threatening infections in liver transplant recipients. Predictors associated with poor outcomes may help clinicians to optimize the management of this infection., (© 2014 American Association for the Study of Liver Diseases.)

Background: Limited data exist regarding echinocandins as antifungal prophylaxis in liver transplant recipients., Methods: The efficacy and safety of targeted prophylaxis with micafungin or amphotericin B lipid complex (ABLC) was assessed in a sequential cohort of high-risk patients (posttransplantation dialysis, retransplantation, or reoperation) and compared with those without high risk who did not receive prophylaxis. Outcomes were assessed at 90 days., Results: Micafungin versus ABLC recipients were older (P=0.0065) and more likely to have hepatocellular carcinoma (P=0.025). High-risks, that is, dialysis (55.6% vs. 79.2%), retransplantation (5.6% vs. 12.5%), and reoperation (38.9% vs. 20.8%) did not differ between the two groups. Invasive fungal infections developed in 11.1% (2 of 18) of micafungin recipients, 8.3% (2 of 24) of ABLC recipients, and 3% (7 of 234) of patients without high risks (P=0.12). In nondialyzed patients, ABLC versus micafungin recipients had significantly higher serum creatinine on day 14 (P=0.04). However, renal and hepatic function, rejection, graft loss, and mortality did not differ for the two groups on day 90., Conclusions: Targeted prophylaxis with micafungin or ABLC decreased the risk of mycoses in high-risk recipients compared with that in low-risk recipients. Compared with ABLC, however, micafungin appeared to be associated with lower early-renal dysfunction and no additional risk of hepatic dysfunction.

Background: Whether the use of rifaximin for hepatic encephalopathy during liver transplant candidacy has an impact on post-transplant infections is not known., Methods: We compared the frequency and spectrum of infections within 90 d post-transplant in liver transplant recipients who did and did not receive rifaximin for hepatic encephalopathy during transplant candidacy., Results: Of 110 consecutive liver transplant recipients, 30 (27%) received rifaximin. Rifaximin users were more severely ill based on higher Model for End-Stage Liver Disease (MELD) score (p=0.005). When controlled for MELD (stratified by MELD<30, MELD≥30), the risk of infections was significantly lower in rifaximin vs. no rifaximin recipients (OR=0.269, 95% CI 0.078-0.0.934, p=0.026). Rifaximin use was not associated with a higher risk of multidrug resistant bacterial infections (OR=1.8, 95% CI 0.42-8.35, p=0.40). The probability of post-transplant survival at 90 d did not differ for patients with or without rifaximin use (0.90 for both groups, p=0.56)., Conclusions: Rifaximin appeared to have a protective effect against early post-transplant infections in more severely ill liver transplant recipients. Rifaximin use did not select for multidrug resistant bacteria in these patients., (© 2012 John Wiley & Sons A/S.)

Whether the duration of renal replacement therapy (RRT) after liver transplantation influences the rate and types of bacterial infections is not known. In this study, 47 of 299 consecutive liver transplant recipients (16%) required posttransplant RRT. The incidence of bacterial infections was higher in the RRT group versus the non-RRT group (8.84 versus 1.38 per 1000 patient days, P < 0.001). In the RRT group, 49% of the patients (23/47) required long-term RRT (≥30 days), and 51% (24/47) required short-term RRT (<30 days). Long-term RRT (hazard ratio = 2.27, 95% confidence interval = 1.16-4.47, P = 0.017) was a significant predictor of infections. Bacteremia and intra-abdominal infections were the most common sources of infections, and Enterobacteriaceae and enterococci were the predominant pathogens in both groups. The mortality rate for patients requiring RRT was higher than the rate for patients not requiring RRT (P < 0.001), but the mortality rates of the short-term RRT group and the long-term RRT group did not significantly differ (P = 0.654). In conclusion, although both short-term RRT and long-term RRT confer a higher risk of bacterial infections, only long-term RRT is a statistically significant predictor of these infections., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Impact of model for end-stage liver disease (MELD) scoring system on post-transplant infections and associated risk factors are unknown. Infections <90 d post-transplant were assessed in 277 consecutive liver transplant recipients from 1999 to 2008. "High-risk" factors for infections were pre-defined as MELD score >30, ICU stay >48 h prior to transplant, intraoperative transfusion ≥15 units, retransplantation, post-transplant dialysis, or reoperation. Of the 240 recipients in the MELD era (2002-2008), 48.5% had any high-risk factor. The OR for infection was 1.69, 2.00, 18.00, and 4.50 in recipients with any 1, 2, 3, and ≥4 high-risk factors, respectively (χ(2) for trend, p < 0.001). In logistic regression model, recipient age (OR 1.12, p < 0.05) and any high-risk factor (OR 2.42, p < 0.05) were associated with infections. Compared with 37 pre-MELD recipients, the overall infections and mortality at 12 months did not differ in the two eras. In Cox regression model, recipient age (OR 1.09, p < 0.05) and any high-risk factor (OR 2.42, p < 0.05) remained associated with infections. The overall frequency of infections did not increase in the MELD era. Pre-defined risk factors accurately predicted the risk of infections in these patients., (© 2010 John Wiley & Sons A/S.)

Background: Real-time PCR has emerged as the preferred diagnostic assay for CMV. However, its utility as a preemptive therapy tool for CMV disease and related outcomes in liver transplant recipients has not been fully defined., Methods: Patients comprised 117 consecutive liver transplant recipients who underwent CMV surveillance monitoring using real-time PCR. Preemptive therapy with valganciclovir was employed upon detection of viremia. Baseline viral load was considered high based on log values (median)., Results: CMV viremia developed in 54% (63/117) of the patients, including 77% of R-/D+, 63% of R+/D+, 43% of R+/D-, and 10% of R-/D- patients. Overall, 23% (15/63) of the patients had recurrent viremia; R- serostatus (p=0.065) but not initial viral load correlated with recurrent viremia (p=0.80). At 12 months post-transplant, CMV disease occurred in 0.85% (1/117) of the patients (R+/D+recipient). None (0/30) of the R-/D+patients had CMV disease. Patients with CMV viremia treated preemptively did not differ significantly from those who never developed CMV viremia with regards to bacterial or fungal infections, rejection, graft loss, mortality rate, and probability of survival at 12 months (p>0.05 for all variables). The above outcomes also did not differ for patients with high (>1.9 logs) vs. low viral load (<1.9 logs) (p>0.05 for all outcomes)., Conclusions: Preemptive therapy guided by real-time PCR based monitoring led to outcomes in all patients or in those with high viral loads that were comparable to outcomes in patients who never developed viremia or had low viral loads, respectively. Late-onset CMV disease at 12 months was observed in <1% of all patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The posttransplant outcomes and optimal management of patients with end-stage liver disease who develop cryptococcosis prior to transplantation have not been defined. We discuss these issues in the context of successful liver transplantation and pretransplant cryptococcal disease. Our report suggests that liver transplantation may be cautiously considered under the umbrella of fluconazole therapy in patients with end-stage liver disease and pretransplant cryptococcosis, provided that disease control is achieved with adequate treatment before transplantation., ((c) 2010 AASLD.)

Whether pretransplant nonviral infections influence outcomes after transplantation in liver transplant recipients in the current era is not well defined. One hundred consecutive patients undergoing liver transplantation in 2005-2008 were studied. Demographics, posttransplant clinical events, and mortality were compared between recipients with and without infections within 12 months before transplantation. In all, 32% of the patients (32/100) developed 45 episodes of pretransplant infections, which included spontaneous bacterial peritonitis (35.6%), bloodstream infections (28.9%), cellulitis (13.3%), pneumonia (8.9%), urinary tract infections (6.7%), and other infections (6.7%). Compared with 68 recipients without pretransplant infections, those with infections had a higher Model for End-Stage Liver Disease score and a lower likelihood of transplantation from home and required longer and more frequent hospital care before and after transplantation (P < 0.05). Mortality at 90 (9.4% versus 2.9%) and 180 days (15.6% versus 10.3%) post-transplant did not differ significantly between recipients with and without pretransplant infections (P = not significant). A higher Model for End-Stage Liver Disease score (P < 0.05) and posttransplant infections (P < 0.05 and P < 0.001), but not pretransplant infections, were associated with posttransplant mortality at 90 and 180 days. In conclusion, pretransplant infections that have been adequately treated do not pose a significant risk for poor outcomes, including posttransplant mortality.

Background: Liver transplant recipients requiring dialysis have poor outcomes including higher risk of infection, and allograft rejection. The role of T-helper cell cytokine responses in the pathogenesis of infections in these patients has not been fully defined., Methods: Cases were 11 dialyzed liver transplant recipients. Controls (2 for each case) were patients who were transplanted next to the case but did not require dialysis at any time before or after transplantation. Cytokine responses were assessed in sera collected immediately before transplantation. Data were analyzed for candidate cytokines for pro-inflammatory Th1 (IL-1beta, IL-12p70, and IFN-gamma), and Th17 (IL-12p40, IL-17), and anti-inflammatory Th2 phenotypes (IL-4, IL-5, IL-10, and IL-13)., Results: Cases were more likely to have an increase in any of the Th1 or Th1 and Th17 cytokines than the controls (p=0.016 and p=0.04, respectively). Major infections developed in 27% of the study population; these included 46% of the cases and18%, of the controls (p=0.09). Patients with infections vs. those without these were more likely to have an increase in any of the Th2 cytokines (p=0.005). CMV viremia occurred in 30% of the patients and was significantly associated with Th1 responses even when adjusted for CMV recipient/donor serostatus or any major infection (OR 3.2, 95% CI 0.96-10.73, p=0.05)., Conclusions: Requirement of dialysis was characterized by a state of heightened expression of inflammatory responses. However, patients developing infections preferentially expressed Th2 phenotype that may act as a negative regulator of protective inflammatory responses. An enhanced expression of inflammatory mediators may serve to promote CMV infection in liver transplant recipients.

The propensity of liver transplant recipients to develop more fulminant disease presentation and a higher risk of disseminated disease due to a number of opportunistic infections, including invasive aspergillosis, cryptococcosis, zygomycosis, may be related to iron overload. Abnormalities in iron homeostasis may also be a contributor to severe manifestations due to other pathogens such as cytomegalovirus and Staphylococcus aureus in liver transplant recipients. Iron is essential not only for microbial pathogenesis, but directly impairs pivotal pathogen specific host defenses. Studies to assess iron homeostasis and the mechanisms by which iron overload contributes to the pathogenesis of opportunistic infections in liver transplant recipients are warranted.

Prototheca species are unicellular algae of low virulence that are rarely associated with human infections. We report a liver transplant recipient with disseminated protothecosis and review the literature on this unusual opportunistic infection in transplant recipients. Of 9 cases, including ours, 5 had a localized infection, and 4 had disseminated protothecosis. Seven cases were due to Prototheca wickerhamii, and 2 were due to Prototheca zopfii. Overall mortality in transplant recipients with Prototheca infections was 88% (7/8). All 4 cases of disseminated protothecosis died despite therapy with amphotericin B. Posttransplant protothecosis is a rare but significant infection that is associated with a grave prognosis.

The efficacy of valganciclovir as preemptive therapy for the prevention of cytomegalovirus (CMV) disease and its impact on indirect sequelae of CMV were assessed in recipient-negative/donor-positive (R-/D+) liver transplant recipients. Of 187 consecutive liver transplant recipients at our institution since July 2001, 36 (19.2%) belonged to the R-/D+ group. Surveillance tests for CMV were performed on all patients at weeks 2, 4, 6, 8, 10,12, and 16. In all, 27 patients with asymptomatic viremia received preemptive therapy with valganciclovir. At a total follow-up of 62.8 patient years (median: 19 months, range: 3 months to 5.6 years), no episodes of CMV disease were documented in these patients. The incidence of rejection, retransplantation, and bacterial or fungal infections and the probability of survival did not differ for R-/D+ patients and all non-R-/D+ patients treated preemptively with valganciclovir (P > 0.20 for all variables). Thus, preemptive therapy with valganciclovir in R-/D+ patients was not associated with CMV disease during the period of surveillance monitoring or at anytime thereafter (late-onset CMV disease). The indirect outcomes with the use of valganciclovir in R-/D+ patients were comparable to the outcomes of other subgroups of liver transplant recipients receiving preemptive therapy.

Iron is a critical nutrient source and contributes to staphylococcal pathogenesis. We assessed the role of hepatic explant iron overload as a risk factor for Staphylococcus aureus bacteremia in liver transplant recipients. Seven of 13 cases with S aureus bacteremia (53.8%) had hepatic explant iron concentrations that exceeded normal limits (grade > or = 2). Length of posttransplant intensive care unit stay (P= .013) and hepatocellular carcinoma as underlying liver disease (P = .04), but not hepatic explant iron concentration, correlated with a higher risk of S aureus bacteremia after transplantation. However, noncarriers (patients without S aureus nasal carriage) who developed S aureus bacteremia were more likely to have high hepatic iron content; 4 of 7 (57%) noncarriers with high-grade iron content developed S aureus bacteremia but no noncarriers with low-grade iron content did (P = .07). All noncarriers who became infected had high iron content (grade > or = 2) of the hepatic explant. A readily quantifiable assessment of hepatic iron at the time of transplantation can potentially identify patients without carriage who may be at risk for early S aureus bacteremia.

Background: The extent of use of alternative therapies and the psychosocial variables predictive of their use have not been well defined in liver transplant recipients., Objective: To determine types of alternative therapies used by liver transplant recipients and to assess psychosocial, behavioral, and quality of life variables associated with the use of alternative therapies in these patients., Methods: Assessment of types of alternative therapies used, demographic characteristics, satisfaction with social support, coping styles, sense of personal control (mastery), quality of life, and health beliefs in 32 liver transplant recipients., Results: Overall, 34.4% of the liver transplant recipients used a form of alternative therapy. Herbal products were used by 45% of the alternative therapy users and included milk thistle (silymarin), eclipta, and green beet leaf-all considered "hepatic tonics". Alternative therapy users tended to have greater problem-focused coping skills than nonusers (P = .08). Nineteen percent of the patients incurred annual out-of-pocket expense of at least dollars 100 for alternative therapies. Patients incurring out-of-pocket expenses reported better overall health (P = .02), were more likely to be employed (P = .025), and had higher mastery scores (P = .01)., Conclusions: Use of alternative therapies is common after liver transplantation. Herbal products used by liver transplant recipients are disease specific; that is, they claim to promote liver health.

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., ((c) 2006 AASLD.)

In Candida albicans, calcineurin mediates tolerance to azole antifungal drugs, survival in serum, and virulence. In this study, we examined 24 Candida isolates from liver transplant recipients receiving a calcineurin inhibitor as a component of their immunosuppressive therapy. We were unable to detect a difference in susceptibility to calcineurin inhibitors in combination with fluconazole, serum, or calcium in these isolates.

Background: Methicillin-resistant Staphylococcus aureus has emerged as a leading pathogen in transplant recipients and has become endemic in many institutions where transplantation is performed. The role of active surveillance programs based on the detection of colonization in the prevention of S. aureus infection in liver transplant recipients has not been defined., Methods: A total of 47 consecutive patients who underwent liver transplantation during 1996-1999 were compared with 97 patients who received a liver transplant during 2000-2004 after implementation of an intensive intervention program that included use of surveillance cultures to detect nasal and rectal colonization, use of cohorting and contact isolation precautions, and decolonization with intranasal mupirocin therapy., Results: The rate of new acquisition of S. aureus colonization of nares after transplantation decreased from 45.6% (21 of 46 patients) during the preintervention period to 9.9% (9 of 91 patients) during the postintervention period (P<.001). An increased length of hospital stay (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P<.002) was associated with new carriage acquisition, and transplantation during the postintervention period (odds ratio, 0.21; 95% confidence interval, 0.08-0.51; P<.001) was independently protective against new carriage. The rate of infection due to S. aureus decreased from 40.4% (19 of 47 patients) during the preintervention period to 4.1% (4 of 97 patients) during the postintervention period (P<.001), and the rate of bacteremia decreased from 25.5% (12 of 47 patients) to 4.1% (4 of 97 patients), respectively (P<.001). Overall, S. aureus infections occurred more frequently among patients with new carriage than among patients who were carriers at the time of transplantation (P<.001) or patients who were noncarriers (P<.001)., Conclusions: Use of active surveillance cultures to detect colonization and implementation of targeted infection control interventions proved to be effective in curtailing new acquisition of S. aureus colonization and in decreasing the rate of S. aureus infection that was endemic in our population of liver transplant recipients.

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.

Background: The effect of preemptive therapy on indirect sequelae associated with cytomegalovirus (CMV) in liver-transplant recipients has not been clearly delineated., Methods: Thirteen years of outcome with the use of preemptive therapy were assessed in a cohort of 216 consecutive liver-transplant recipients., Results: The incidence of major infections (31% vs. 44.3%), bacterial infections (31% vs. 39.2%), bacteremia (19% vs. 29.1%), or fungal infections (3.4% vs. 7.6%) did not differ significantly for patients with CMV infection who received preemptive therapy compared with those who never developed CMV infection and did not receive antiviral prophylaxis for CMV (P>0.20 for all variables). The rate of opportunistic infections also did not differ when patients were stratified by primary CMV infection, reactivation infection, or no CMV infection. Recurrent hepatitis C virus (HCV) hepatitis occurred in 55.6% of the patients with CMV treated with preemptive therapy and 49.8% of those without CMV infection (P>0.20). The probability of survival at 6 months, 12 months, 2 years, and 3 years was also comparable for the two groups., Conclusions: Liver-transplant recipients with CMV infection, including high-risk R-/D+ patients, when followed using the preemptive therapy approach had no significant difference in meaningful outcomes such as opportunistic superinfections, HCV recurrence rates, rejection, and survival when compared with the patients in whom CMV infection never developed and who did not receive antiviral prophylaxis for CMV.

Background: The efficacy of valganciclovir used as preemptive therapy for cytomegalovirus (CMV) disease in liver transplant recipients is not known., Methods: Between 1996 and 2004, surveillance testing using CMV antigenemia was performed at weeks 2, 4, 6, 8, 10, 12, and 16 posttransplant. A total of 28.8% (17/59) of the patients from 2001 to 2004 with antigenemia who received valganciclovir as preemptive therapy were compared with 26.2% (21/80) of the patients from 1996 to 2000 who received oral ganciclovir as preemptive therapy., Results: The mean decline in the antigenemia level after initiation of valganciclovir and oral ganciclovir was 80.5% versus 50.7% at 1 week, 99.5% versus 89.4% at 2 weeks, and 100% versus 97.7% at 4 weeks, respectively. A higher proportion of patients who received valganciclovir (64.7%) belonged to the high-risk group (R-/D+) than patients who received oral ganciclovir (33.3%, P=0.10). Recurrent shedding was documented in 47.1% (8/17) of the patients in the valganciclovir group and 28.6% (6/21) of the patients in the oral ganciclovir group (P>0.20). Recurrent shedding correlated significantly with R-/D+ CMV serostatus and baseline CMV antigenemia level, regardless of the study group. No patient in either group developed CMV disease during or after the period of surveillance monitoring. The incidence of opportunistic infections and patient outcome did not differ for the valganciclovir group versus the oral ganciclovir group or patients without CMV infection (P>0.20)., Conclusion: Antigenemia-directed valganciclovir as preemptive therapy seems to be effective for the prevention of CMV disease in liver transplant recipients, including high-risk patients.

During the 1990s, gram-positive bacteria emerged as major pathogens after liver transplantation. We sought to determine whether the pathogens associated with bacteremias in liver transplant recipients have changed. Patients included 233 liver transplant recipients transplanted between 1989 and 2003. The proportion of all infections due to bacteremias increased significantly over time (P <.0001). Of other major infections, a trend toward a decrease in fungal infections (P =.089) and a significant decrease in cytomegalovirus (CMV) disease (P =.0004) were documented. Whereas the proportion of bacteremias due to gram-negatives increased from 25% in the period of 1989-1993 to 51.8% in 1998-03, that of gram-positive bacteria decreased from 75% in the period of 1989-93 to 48.2% in the period of 1998-2003. Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most frequent pathogens in bacteremic patients. The incidence of bacteremias due to MRSA and Pseudomonas aeruginosa has remained unchanged (P <.20); however, that due to enteric gram-negative bacteria, particularly Klebsiella pneumoniae has increased (P =.02). Klebsiella pneumoniae isolates in the current quartile were not clonally related. In conclusion, bacteremias as a proportion of all infections in liver transplant recipients have increased significantly over time, due in part to a decline in infections due to other major pathogens, e.g., fungi, primarily Candida species, and CMV. Gram-negative bacteria have emerged as predominant pathogens in bacteremic liver transplant recipients.

We reviewed the cases of patients with cirrhosis, including liver transplant candidates, at our institution in the last 3 years (n = 5) and those individually described in the literature (n = 28), to assess unique characteristics and outcome of cryptococcosis in these patients. Sixty-four percent (21/33) of the patients had no other recognized immunosuppression. Peritonitis (in 45%, 15/33 of the patients) with modest pleocytosis in the ascitic fluid, was the most common presenting feature. Median time to detection of Cryptococcus in the ascitic fluid cultures was 6 days. Overall mortality rate was 81% (26/32); death was deemed attributable to cryptococcosis in 24/26 patients who died. Evaluation of culture-negative neutrocytic ascites in febrile cirrhotic patients warrants consideration of cryptococcal peritonitis.

Background: This study determines whether the recipient and donor characteristics that influence the cytomegalovirus (CMV) infection rate after liver transplantation have changed., Methods: The recipient and donor characteristics that may affect the rate of CMV infection were assessed in 232 liver transplant recipients at our institution during a 14-year period (1989-2003)., Results: Since 1989, the age of recipients (P=0.0001) and donors (P=0.0001) has increased significantly. Pretransplant CMV seropositivity in recipients has decreased significantly (P=0.0001, 86.4% [1989-1992] to 53.7% [2000-2003]), whereas donor CMV seropositivity has remained unchanged (P>0.20). As a result, there has been a significant increase in the proportion of high-risk (CMV recipient-/donor+) patients (P=0.012); 10.6% of recipients from 1989 to 1992 versus 24.1% of recipients from 2000 to 2003 were CMV recipient-/donor+. The Child-Pugh scores of recipients have remained unchanged over time. However, the proportion of patients undergoing transplantation while being cared for in the intensive care unit has decreased significantly over time (P=0.0002). Despite an increase in the rate of CMV infection (P=0.09), the incidence of CMV disease has decreased significantly (P=0.0004)., Conclusions: The proportion of high-risk patients (CMV recipient-/donor+) has increased significantly over time, attributable largely to a declining rate of CMV seropositivity in recipients before transplantation. These data have implications for guiding prophylactic practices and resource use after liver transplantation.

The utility of galactomannan antigen for diagnosing invasive aspergillosis was evaluated in 154 liver transplant recipients. Sample agreement was 98.5%, and patient specificity was 87%. Galactomannan positivity correlated with mortality, even when controlled for the number of tests performed. Whether galactomannan positivity identifies a subgroup at risk for poor outcome warrants further evaluation.

Background: This study determines whether the spectrum, risk factors, and outcome of invasive candidiasis in liver transplant recipients have changed., Methods: Thirty-five consecutive liver transplant recipients with invasive candidiasis were prospectively studied in a case-controlled, multicenter study. One control was matched with the case for duration of hospitalization and the other for antibiotic use so that risk factors unique in liver transplantation could be elicited., Results: In matched-pair analysis, antibiotic prophylaxis for spontaneous bacterial peritonitis (odds ratio [OR] 8.3, P=0.002), posttransplant dialysis (OR 7.6, P=0.0009), and retransplantation (OR 16.4, P=0.0018) were independently significant predictors of invasive candidiasis. Candida spp. included C. albicans in 65% of patients, C. glabrata in 21%, C. tropicalis in 9%, C. parapsilosis in 3%, and C. guilliermondii in 3%. Patients with C. albicans infections were less likely to have received antifungal prophylaxis than those with non-albicans Candida infections (13.6% vs. 50%, P=0.04). The mortality rate was 36.1% for the cases and 2.8% for the controls (OR 25.0, 95% confidence interval, 6.2-100.5, P=0.0002). Non-albicans Candida infections (P=0.04) and prior antifungal prophylaxis (P=0.05) correlated with poorer outcome in the cases., Conclusions: Our study has identified predictors for Candida infections in the current era that have implications relevant for targeting the prophylaxis toward the high-risk patients. Routine use of antifungal prophylaxis warrants concern given the emergence of non-albicans Candida spp. as significant pathogens after liver transplantation and higher mortality in patients with these infections.

Background: Infections with Staphylococcus aureus are a significant problem in patients in liver transplant units. An association between prior nasal carriage with and subsequent infections has been documented previously in liver transplant recipients and patients with cirrhosis. However, the role of decolonization with mupirocin applied intranasally for the prevention of S. aureus infections in these patients has not been determined., Methods: S. aureus nasal carriage was prospectively sought in 70 consecutive liver transplant candidates. Mupirocin two times per day for 5 days was administered to the carriers. Follow-up nasal cultures to document decolonization were performed 5 days after the final application of mupirocin. The primary endpoint was the development of S. aureus infections., Results: Thirty-one of 70 patients (44%) were found to be nasal carriers and 27 of 31 nasal carriers (87%) were successfully decolonized. However, 12 of 27 patients (37%) successfully decolonized became recolonized with S. aureus, and an additional nine patients who were initially noncarriers became newly colonized with S. aureus during the study period. Despite the use of mupirocin, 16 of 70 patients (23%) developed an infection with S. aureus. No isolate was found to be mupirocin resistant., Conclusion: Elimination of S. aureus nasal carriage by mupirocin did not prevent S. aureus infections in patients in our liver transplant unit.

To discern whether the characteristics and outcome of invasive aspergillosis in liver transplant recipients have evolved during the past decade, 26 patients who underwent transplantation during 1990-1995 (known as "the earlier cohort") were compared with 20 patients who underwent transplantation during 1998-2001 (known as "the later cohort"). Twenty-three percent of the Aspergillus infections in the earlier cohort occurred > or =90 days after transplantation, compared with 55% of such infections in the later cohort (P=.026). The earlier cohort was significantly more likely to have disseminated infection (P=.034) and central nervous system (CNS) involvement (P=.0004) than was the later cohort. The mortality rate was significantly higher for the earlier cohort (92%) than for the later cohort (60%; P=.012). Only disseminated infection (not the year of transplantation) approached statistical significance as an independent predictor of outcome. In the current era, invasive aspergillosis occurs later in the posttransplantation period, is less likely to be associated with CNS infection, and is associated with a lower mortality rate, compared with invasive aspergillosis in the early 1990s.

Background: Optimal timing of initiation of isoniazid chemoprophylaxis in liver transplant recipients who test positive on the tuberculin skin test has not been defined. We sought to determine whether isoniazid prophylaxis administered during liver transplant candidacy was safe and effective for the prevention of posttransplantation tuberculosis., Methods: During a 9-year period, 18 liver transplant candidates with tuberculin skin test greater than 5 mm or recent conversion to positive tuberculin skin test were identified and received isoniazid chemoprophylaxis for 12 months. For each case, a control matched with the patient for underlying liver disease and age (within 5 years of the case) was included. Liver function tests were assessed monthly. The median follow-up was 55 months and ranged up to 107 months for the cases., Results: At baseline, the cases had a total bilirubin of 2.2 mg/dL, alanine aminotransferase of 106 IU/L, prothrombin time of 14.2 sec, and serum albumin of 2.9 gm/dL (mean values). Hepatic function tests did not differ significantly for the cases at 3, 6, 9, and 12 months when compared with those at baseline or between the cases and controls at each of the above time points. Discontinuation of prophylaxis was not required in any of the patients. The outcome (proportion of patients who underwent transplantation or were dead or alive at the last follow-up) and survival time for the cases did not differ significantly from those of the controls (P >0.20)., Conclusion: In liver transplant candidates at risk for infection after transplantation, isoniazid chemoprophylaxis used during candidacy was well tolerated and did not adversely effect hepatic function or outcome as compared with the control patients.

The purpose of this study was to assess the effect of voriconazole on the blood tacrolimus concentration in a liver transplant recipient and to examine the interaction between voriconazole and tacrolimus by using human liver microsomes. Two subjects were enrolled in the clinical study: one received voriconazole, and the other received a placebo. Tacrolimus metabolism was evaluated in human liver microsomes at various concentrations in the absence and presence of various concentrations of voriconazole. Coadministration of voriconazole and tacrolimus resulted in elevated (nearly 10-fold-higher) trough tacrolimus blood concentrations in the liver transplant patient. In the in vitro study, voriconazole at a concentration of 10.4 +/- 4.3 micro g/ml inhibited the metabolism of tacrolimus by 50%. Clinically relevant concentrations of voriconazole inhibited the metabolism of tacrolimus in human liver microsomes. Close monitoring of the blood concentration and adjustment in the dose of tacrolimus are warranted in transplant recipients treated with voriconazole.