'The Year of Living Dangerously': Successful Rhodococcus Equi Therapy in an Immunosuppressed Patient with Minimal Toxicity by One Year of Continuous Intravenous Vancomycin Therapy Combined with Oral Levofloxacin And Rifampicin.

Background: Rhodococcus equi is a Gram-positive microorganism that causes infections, particularly in immunocompromised patients. Treatment duration can be prolonged. While vancomycin is an effective drug in this scenario, its use may lead to renal damage. Studies have shown that continuous vancomycin infusion appears to be a safe strategy in terms of adverse effects compared to bolus administration. Case description: We present the case of a 71-year-old female liver transplant recipient. After being diagnosed with a mediastinal infection caused by Rhodococcus equi with poor response to initial therapy, she required 12 months of continuous intravenous domiciliary infusion of vancomycin combined with oral levofloxacin and rifampicin. There was no drug-related complication throughout the follow-up. Conclusions: The use of continuous vancomycin infusion has emerged as a safer, more efficient, and cost-effective alternative to intermittent administration. We want to emphasise the uniqueness of this case, where despite the unprecedented treatment duration, no adverse effects occurred. LEARNING POINTS: Vancomycin therapy based on continuous infusion represents a safer and cheaper strategy than classic intermittent administration.The use of continuous infusion facilitates the management of complex infections with outpatient antimicrobial therapy.

Comparison of conventional dried blood spots and volumetric absorptive microsampling for tacrolimus and mycophenolic acid determination.

Therapeutic drug monitoring (TDM) of immunosuppressants is essential to avoid either rejection or toxicity after solid organ transplantations. Capillary microsampling approaches are an outstanding alternative to conventional venous sampling for TDM (easy and non-invasive collection, enabling self-sampling, and cost-saving shipment, processing and storage). Volumetric absorptive microsampling (VAMS) has gained importance in the last years, as it was meant to overcome the hematocrit (Hct) related issues commonly associated to DBS analysis. Despite all the benefits, microsampling techniques performance (including a thorough clinical validation) should be set up before their implementation in clinical practice. The aim of this study was to perform a clinical validation for both tacrolimus (TAC) and mycophenolic acid (MPA) in both DBS and Mitra™ VAMS. For the clinical validations, two different requirements were set up: analytical (following EMA and FDA guidelines) and clinical (following the Royal College of Pathologists of Australasia -RCPA- recommendations) acceptance criteria. For DBS, both analytical and clinical acceptance criteria were fulfilled for TAC, with 98.7% and 95% of the paired samples within the preset limits, respectively. For MPA, the analytical criterion was met (70.6% of paired specimens), although only half of the pairs were within the clinical limits. For VAMS, the clinical validation for both TAC and MPA showed good correlations but significant lower concentrations in VAMS compared to the routine matrices. After VAMS concentrations correction, the analytical requirement was fulfilled for both analytes (71.1% for TAC, 75% for MPA), although the more restrictive criteria recommended by the RCPA were not met for any analyte (half of the samples fell within the acceptance area). In addition, no significant Hct impact on the quantification was found in any case. Also, a preliminary home-sampling trial was set up, showing promising results. Moreover, a comparison between VAMS vs. DBS analytical and clinical performances was carried out, including a home-sampling trial, sample quality results and costs. Although the analytical performance for both VAMS and DBS was similar, DBS were superior regarding clinical criteria, sampling quality and cost.

Clinical characteristics, aetiology and mortality/recurrence risk factors of acute cholangitis in patients with and without biliary stent.

OBJECTIVES: Acute cholangitis is one of the most frequent complications in patients carrying biliary stents. The aim of our study is to analyze the demographic and clinical characteristics, as well as the microbiological profile and evolution of patients with acute bacteremic cholangitis, comparing them based upon they were or not biliary stent carriers. METHODS: We performed a retrospective analysis of all consecutive patients over 18 years-old with a stent placement in our center between 2008 and 2017 were included. We compared them with our prospective cohort of patients with a diagnosis of acute bacteremic cholangitis. Primary outcome was 30-day mortality. Secondary outcome was clinical cure at day 7, 14-day mortality and 90-day recurrence. RESULTS: Two hundred and seventy-three patients were analyzed, including 156 in the stent-related (SR) and 117 in the stent not-related (SNR) group, respectively. Stent-related colangitis patients were younger, with more comorbidities and with a greater severity of infection. Escherichia coli and Klebsiella pneumonia were the most frequent isolation. Enterococcus spp. was the third most frequent isolation in SR group but were uncommon in SNR patients; where E. coli was the most prevalent microorganism. Septic shock (HR 3.44, 95% [CI 1.18-8.77]), inadequate empirical treatment (HR 2.65, 95% CI [1.38-.7.98]) and advanced neoplasia (HR 2.41, 95% CI [1.55-6.44]) were independent 30-day mortality risk factors. The 90-day recurrence rate significantly higher in those patients with stent-related cholangitis (29% vs. 13%, p=0.016) and stent replacement was associated with lower recurrence rate (HR 0.38, 95% CI [0.11-0.77]). CONCLUSIONS: Clinical and microbiological profile, as well as outcome of patients with SR and SNR cholangitis were different. In SR group, recurrence rate was high and stent replacement was associated with a lower risk.

Clinical characteristics, aetiology and mortality/recurrence risk factors of acute cholangitis in patients with and without biliary stent.

OBJECTIVES: Acute cholangitis is one of the most frequent complications in patients carrying biliary stents. The aim of our study is to analyze the demographic and clinical characteristics, as well as the microbiological profile and evolution of patients with acute bacteremic cholangitis, comparing them based upon they were or not biliary stent carriers. METHODS: We performed a retrospective analysis of all consecutive patients over 18 years-old with a stent placement in our center between 2008 and 2017 were included. We compared them with our prospective cohort of patients with a diagnosis of acute bacteremic cholangitis. Primary outcome was 30-day mortality. Secondary outcome was clinical cure at day 7, 14-day mortality and 90-day recurrence. RESULTS: Two hundred and seventy-three patients were analyzed, including 156 in the stent-related (SR) and 117 in the stent not-related (SNR) group, respectively. Stent-related colangitis patients were younger, with more comorbidities and with a greater severity of infection. Escherichia coli and Klebsiella pneumonia were the most frequent isolation. Enterococcus spp. was the third most frequent isolation in SR group but were uncommon in SNR patients; where E. coli was the most prevalent microorganism. Septic shock (HR 3.44, 95% [CI 1.18-8.77]), inadequate empirical treatment (HR 2.65, 95% CI [1.38-.7.98]) and advanced neoplasia (HR 2.41, 95% CI [1.55-6.44]) were independent 30-day mortality risk factors. The 90-day recurrence rate significantly higher in those patients with stent-related cholangitis (29% vs. 13%, p=0.016) and stent replacement was associated with lower recurrence rate (HR 0.38, 95% CI [0.11-0.77]). CONCLUSIONS: Clinical and microbiological profile, as well as outcome of patients with SR and SNR cholangitis were different. In SR group, recurrence rate was high and stent replacement was associated with a lower risk.

Volumetric Absorptive Microsampling (VAMS) for assaying immunosuppressants from venous whole blood by LC-MS/MS using a novel atmospheric pressure ionization probe (UniSpray™).

Therapeutic drug monitoring (TDM) of immunosuppressants (IMS) is crucial to prevent rejection or toxicity after solid organ transplantation. Microsampling techniques (sampling <50 µL of blood) can be a good alternative to conventional venous sampling for TDM, due to their numerous advantages, including its easy and low-invasive sampling, enabling self-collection, and cost-saving shipment and storage. Furthermore, volumetric absorptive microsampling (VAMS) enables the collection of precise and accurate blood volumes, overcoming the hematocrit (Hct) effect related to dried blood spots, while offering the same benefits. In this work, an LC-MS/MS method for the determination of the 5 most common IMS (mycophenolic acid -MPA-, tacrolimus -TAC-, sirolimus -SIR-, everolimus -EVE- and cyclosporin A -CsA-) in venous blood collected with Mitra™ VAMS devices was developed and validated, employing a novel LC-MS/MS interface, Unispray™. The method was fully validated including linearity, limits of detection (LOD) and quantification (LLOQ), accuracy, precision, selectivity, carry-over, matrix effect, recovery, impact of Hct on recovery and autosampler and short-/long-term stability, satisfying acceptance criteria in all cases. LLOQs were 0.5 ng/mL for TAC, SIR and EVE, 20 ng/mL for CsA and 75 ng/mL for MPA. No impact of the Hct (range: 0.2 to 0.62 L/L) on recovery was found for any analyte. All compounds were stable in VAMS for at least 8 months at -20 °C. In addition, as part of the VAMS analytical method validation, we performed for the first time a broad statistical study to compare liquid venous blood concentrations from patients under TAC (n = 53) and MPA (n = 20) treatment to those observed when the same specimens were absorbed into VAMS. Our results showed that venous blood VAMS concentrations were correlated to those found in the original liquid venous blood, proving that the VAMS material itself will not bias blood drug concentrations. Therefore, the present method could be applied to evaluate possible correlations between venous blood and capillary blood collected with VAMS.

A multidrug LC-MS/MS method for the determination of five immunosuppressants in oral fluid.

Aim: This study aimed: to develop and validate an LC-MS/MS method for mycophenolic acid, tacrolimus, sirolimus, everolimus and cyclosporin A in oral fluid (OF), as an essential tool to study the usefulness of OF as an alternative matrix for immunossuppressants' therapeutic drug monitoring; and to find the best OF collector for these analytes. Materials & Methods: Chromatographic separation was achieved using an XBridge® Shield RP18 analytical column maintained at 65ºC, using 2 mM ammonium formate and 0.1% formic acid in water (A) and acetonitrile (B) as mobile phase. OF sample was extracted with solid phase extraction after sonication and protein precipitation. Results & Conclusions: Method validation met all the acceptance criteria. LODs were 0.05-1 ng/ml, and LOQs 0.1-5 ng/ml. Silanized tubes offered the best recoveries. The method was successfully applied to 31 OF specimens, describing everolimus detection in OF for the first time. Conclusion: The proposed method is sensitive enough for the detection of OF trough concentrations in patients receiving immunosuppressants when using an appropriate OF collector.

Differences in the incidence and clinical evolution of early neurotoxicity after liver transplantation based on tacrolimus formulation used in the immunosuppressive induction protocol.

INTRODUCTION: Posttransplant early calcineurin inhibitor (CNI)-induced neurotoxicity (ECIIN) was related to high CNI levels, among other factors. Minimizing exposure could modify its incidence or clinical evolution. OBJECTIVE: To compare the incidence, predisposing factors, and clinical evolution of ECIIN after immunosuppressive induction with low-dose tacrolimus-MR (Advagraf) or conventional dose tacrolimus (Prograf). PATIENTS AND METHODS: We matched 71 patients treated with an immunosuppression induction schedule with basiliximab and low doses of Advagraf (cases group) 1:1 by recipient age and indication for liver transplantation (OLT) with patients treated with a conventional tacrolimus regimen (control group). Baseline characteristics, liver and kidney function, operative technical characteristics, kidney function, and C0 tacrolimus levels at several time points after liver OLT were analyzed. RESULTS: There were 31 cases of ECIIN (21%), 14 in the cases group (20%) and 17 in the control group (24%; P < .001). The incidence of ECIIN was higher in alcoholic liver disease (odds ratio [OR], 8.2; 95% CI, 2.3-28.6; P < .001) and past history of encephalopathy (OR, 2.6; 95% CI, 1.16-5.9; P < .02). Among cases, the incidence of ECIIN was higher when encephalopathy signs were present at time of transplantation (36% vs 12%; P < .001). Control of ECIIN required a switch to cyclosporine therapy in all those in the cases group, whereas this was only needed for 9 cases in the control group (47%; P < .001). CONCLUSION: In this study, although the incidence rate of neurotoxicity induced by Advagraf was lower than the induced by Prograf, it did not respond to routine treatment and required a significantly higher rate of switch to cyclosporine for its control.

Late recurrence of hepatocellular carcinoma after liver transplantation: is an active surveillance for recurrence needed?

INTRODUCTION: Liver transplantation (OLT) is considered the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rates, when restrictive selection criteria are applied. Nevertheless, tumor recurrence may occur in 3.5% to 21% of recipients. It usually occurs within 2 years following OLT, having a major negative impact on prognosis. The efficacy of active posttransplantation surveillance for recurrence has not been demonstrated, due to the poor prognosis of recipients with recurrences. AIM: To analyze the clinical, pathological, and prognostic consequences of late recurrence (>5 years after OLT). METHOD: We analyzed the clinical records of 165 HCC patients including 142 males of overall mean age of 58 ± 6.9 years who underwent OLT between July 1994 and August 2011. RESULTS: Overall survival was 84%, 76%, 66.8%, and 57% at 1, 3, 5, and 10 years, respectively. Tumor recurrence, which was observed in 18 (10.9%) recipients, was a major predictive factor for survival: its rates were 72.2%, 53.3%, 26.7%, and 10% at 1, 3, 5, and 10 years, respectively. HCC recurrence was detected in 77.8% of patients within the first 3 years after OLT. Three recipients (100% males, aged 54-60 years) showed late recurrences after 7, 9, and 10 years. In only one case were Milan criteria surpassed after the examination of explanted liver; no vascular invasion was detected in any case. Recurrence sites were peritoneal, intrahepatic, and subcutaneous abdominal wall tissue. In all cases, immunosuppression was switched from a calcineurin-inhibitor to a mammalian target of rapamycin inhibitor. We surgically resected the extrahepatic recurrences. The remaining recipient was treated with transarterial chemoembolization with doxorubicin-eluting beads and sorafenib. Prognosis after diagnosis of recurrence was poor with median a survival of 278 days (range, 114-704). CONCLUSIONS: Global survival, recurrence rate, and pattern of recurrence were similar to previously reported data. Nevertheless, in three patients recurrence was diagnosed >5 years after OLT. Although recurrence was limited and surgically removed in two cases, disease-free survival was poor. Thus, prolonged active surveillance for HCC recurrence beyond 5 years after OLT may be not useful to provide a survival benefit for these patients.

Viral and host factors related with histopathologic activity in patients with chronic hepatitis B and moderate or intermittently elevated alanine aminotransferase levels.

OBJECTIVE: viral and host factors are related with progression of pathological lesion in chronic hepatitis B. We analyzed these factors in patients with moderate or intermittently elevated ALT levels, and its threshold that determinate significant histological activity. PATIENTS AND METHODS: retrospective analyses of viral and host parameters in 89 consecutive chronic hepatitis B patients biopsied because of moderate or intermittently elevated ALT levels [1-2 x ULN (ULN = 39 IU/ml)] and/or DNA-HBV > 2 x 10³ IU/ml in AntiHBe+ patients. It was analyzed age, gender, ALT levels, HBeAg, viral load and genotype. It was considered advanced histological lesion a Knodell Score (KS) > 7 and histological lesion indicating treatment, lobular inflammation ≥2 or fibrosis ≥2 according to Scheuer Classification. RESULTS: KS > 7 and histological lesion indicating treatment was found in 47.8 and 60.7% respectively. It was observed relationship between age, male gender, ALT levels and viral load with histological damage (p < 0.05). Frequency of advanced lesion indicating treatment was upper in patients with ALT levels > ULN (69.1 vs. 47.1%, p = 0.04). There were not significant upper frequencies of advanced lesion when a cut-off of 40 years or DNA-HBV > 2 x 10³ IU/ml viral load or serological status HBeAg was considerate. Histological activity was lesser in genotype D patients than those infected with others genotypes (p < 0.05). CONCLUSION: upper frequency of advanced histological lesion in chronic hepatitis B patients with moderate or intermittently elevated ALT levels make recommended liver biopsy, independent of viral load and serological status HBeAg. Other factors like age, gender or genotype can help to indicate biopsy in individual cases.

Valganciclovir-induced leukopenia in liver transplant recipients: influence of concomitant use of mycophenolate mofetil.

INTRODUCTION: An increased incidence and magnitude of leukopenia during concomitant treatment with valganciclovir (VGC) and mycophenolate mofetil (MMF) has been reported. OBJECTIVE: To evalute the incidence and severity of leukopenia and neutropenia among liver recipients treated with VGC and related factors. PATIENTS AND METHODS: Retrospective analysis of clinical and analytical data related to leukopenia (<3000 leukocytes/mm(3)) and neutropenia (<900 neutrophils/mm(3)) in liver transplant patients who were treated with VGC from 2003 to 2007. We examined the influence of concomitant administration of MMF and development of subsequent infections. RESULTS: Among 209 liver transplants, 40 treatments with VGC were prescribed in 37 patients (17.7%), 12 of which (30%) were associated with MMF. The patients has an average age of 49.7 +/- 12.7, body mass index (BMI) of 27.28 +/- 5.17, and Model for End-stage Liver Disease Score (MELD) 12.45 +/- 7.5. The daily average dose of VGC was 1440 +/- 446.5 mg and MMF, 1454.5 +/- 350.3 mg. We observed a decrease of 30% in initial leukocyte count (5353.7 +/- 2706.6) and 40% in neutrophil count (3600 +/- 2182.1). With no relationship to total dose or BMI-adjusted dose of VGC nor concomitant administration of MMF. The initial leukocyte count was significantly lower (4411 +/- 1930 vs 6206 +/- 3053; P = .03) and underwent a main drop (2344.7 +/- 1974.3 vs 898.1 +/- 2435.6; P = .04) when leukopenia developed. In the induced neutropenia group, previous leukocyte count (3797.1 +/- 1223.9 vs 5683.9 +/- 2829.3; P = .01), MELD (18.7 +/- 8.8 vs 11.1 +/- 6.6; P = .01), and the creatinine pretreatment (1.44 +/- 0.4 vs 1.09 +/- 0.3; P = .01) were significantly different. Subsequent infections induced by the leukopenia were not observed. CONCLUSIONS: In our series, the concomitant use of VGC and MMF was not associated with a greater incidence of leukopenia and/or neutropenia than VGC administration alone. Previous leukocyte count was associated with them. MELD and renal dysfunction are factors related to severe neutropenia. Leukopenia was not associated with a greater incidence of infections.

[The autoimmune hepatitis-primary biliary cirrhosis overlap syndrome: a case report]. / Síndrome overlap hepatitis autoinmune-cirrosis biliar primaria: a propósito de un caso.

The autoimmune hepatitis-primary biliary cirrhosis overlap syndrome is an entity characterized by clinical, analytical, immunological and histological manifestations of both entities. We present the case of a 26-year-old woman with a serious acute hepatitis that fulfills the diagnostic criteria of the overlap syndrome and that showed a satisfactory response to oral corticoid therapy.

[Influence of donor age and recipient gender on survival in transplantation due to hepatocarcinoma]. / Influencia de la edad del donante y del sexo del receptor en la supervivencia de los pacientes trasplantados por hepatocarcinoma.

Hepatocarcinoma (HCC) is one of the most frequent indications for liver transplantation. Survival in patients undergoing transplantation due to HCC is similar to that in patients undergoing this procedure for other indications. However, the current shortage of donors has led to longer waiting lists with a consequent risk of tumor progression. The use of older donors in these patients could increase the donor pool and shorten the time spent on the waiting list. We analyzed the influence of donor age on survival in 78 patients with HCC who underwent transplantation in the Santiago de Compostela Hospital between 1994 and 2003.

Malaria infection through multiorgan donation: an update from Spain.

During the last years, immigration has increased and, consequently, the pool of foreign donors and associated infectious diseases from exotic countries (especially from the tropics) has also increased. Only a few cases of malaria transmitted via different donation sources have been published. In the present report, a Plasmodium vivax transmitted through a multiorgan donation is reported. In conclusion, we discuss the features related with the diagnosis, the treatment, and the special characteristics of a case in which the liver and not any other organ is the reservoir of the plasmodium.