'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.

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.

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.

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.

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.

[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.

[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.

[Liver abnormalities in adult celiac disease. Clinicopathologic characterization and outcome after therapy]. / Alteraciones hepáticas en la enfermedad celíaca del adulto. Caracterización clínico-patológica y evolución.

BACKGROUND AND AIM: The clinical manifestations of adult celiac disease are highly varied and may include liver disease. The present study aimed to characterize liver abnormalities and outcome after a gluten-free diet in patients with celiac disease diagnosed in a hepatology clinic. MATERIAL AND METHOD: The clinical records of patients diagnosed with celiac disease during a 7-year period were reviewed. RESULTS: Of 1916 patients attending a first consultation at the clinic, 10 were finally diagnosed with celiac disease. All patients had been referred for evaluation of persistent elevation of liver enzyme levels. All patients were young (mean age 30 years, range 21-39 years) and there were more women than men (eight women, 80%). Six patients (60%) had additional manifestations attributable to undiagnosed celiac disease, sometimes since childhood. In all patients, elevation of liver enzyme levels was moderate and overall liver function was preserved. Liver biopsy was performed in five patients and all showed chronic periportal infiltrate. Immunohistochemical studies revealed that the infiltrate was mainly composed of CD8-positive T lymphocytes. In all patients, a gluten-free diet was followed by normalization of liver enzyme levels. CONCLUSIONS: Although celiac disease is not highly frequent, it should be considered in the differential diagnosis of patients with persistent abnormalities of liver markers. The most conspicuous histopathological change is periportal T-cell infiltrate. Liver abnormalities in celiac disease are generally mild and improve after a gluten-free diet.

[Epidermiology of alcohol withdrawal syndrome. Mortality and factors of poor prognostic]. / Epidemiología del síndrome de abstinencia alcohólica. Mortalidad y factores de mal pronóstico.

INTRODUCTION: Patients with alcoholism and alcohol withdrawal syndrome (AWS) have a worse prognostic. METHODS: We have performed a retrospective analysis of the hospital discharges in with diagnosis include AWS from 1 of January of 1997 to the 31 of December of 2002. RESULTS: We identified 924 hospital stays with 2.4% of mortality (1.6% in Internal Medicine). Mortality is associated with greater age (57 years +/-15 vs. 49+/- 13, p < 0.005), with the diagnostic of hepatic cirrhosis (6.2 vs. 1.8%, p < 0.005), bacteraemia (10 vs. 1.8%, p < 0.001) and respiratory infection (9.6 vs. 1.8%, p < 0,001), with a lower mortality when AWS was secondary diagnosis (1.2 vs. 4.2%, p < 0.005). In multivariant analysis were associated with more mortality age (OR 1.03), hepatic cirrhosis (OR 3.4), bacteriemia (OR 4.5) and respiratory infection (OR 3.6). CONCLUSION: Alcohol withdrawal syndrome mortality could to benefit from treatment in an Internal Medicine Service.

Circadian variability of blood pressure in liver transplant recipients without antihypertensive therapy.

Hypertension is a frequent cardiovascular risk factor in liver transplant recipients. The usefulness of ambulatory blood pressure monitoring (ABPM) in these patients is unknown. This study was aimed at evaluating the circadian rhythms of blood pressure in liver allograft recipients. In 53 liver transplant patients blood pressure was measured with the Spacelabs device program. No patient received antihypertensive therapy for at least 15 days beforehand. Clinical blood pressure measurement showed 26 patients to be hypertensive. Of these, ABPM verified the diagnosis in 23. Overall, 72% of the patients were hypertensive, and 39.5% showed a nondipper pattern. Diastolic hypertension was more frequent than systolic hypertension. No differences were found in renal function, immunosuppressive therapy, or corticosteroids.

Prolongation of the QTc interval during alcohol withdrawal syndrome.

BACKGROUND: Cardiac arrhythmias might explain cases of sudden death in alcoholics during ethanol abstinence. AIM OF STUDY: To evaluate QT interval (and its outcome) in patients with alcohol withdrawal syndrome. PATIENTS AND METHODS: Sixty-two patients (52 male and 10 female, mean age 43.7 years, range 18-71 years), admitted to the hospital as a result of alcohol abstinence syndrome (tremulousness in 7 cases, agitation in 12 cases, delirium tremens in 11 cases, and seizures in 32) were studied. The QT interval was measured on 12 lead ECGs performed on admission in all cases. QTc was obtained using Bazett's formula. In 27 patients a second ECG was performed during hospital stay. Results. Mean QTc interval on admission was 439 +/- 32 ms (range 350-525 ms); 29 patients (46.8%) showed a prolonged (> 440 ms) QTc interval. No significant differences were observed between patients with normal and high QTc values as regards to age, sex, type of withdrawal syndrome, duration of abstinence, liver function tests, serum electrolytes or blood cell counts. In cases where two ECG recordings could be evaluated (n = 27), the mean QTc interval was significantly shorter in the latter than in the former (417 +/- 26 ms versus 447 +/- 30 ms, respectively, p < 0.001). Eight patients found to have prolonged QTc on admission had a second ECG performed on them after complete recovery from withdrawal symptoms. In all these cases the QTc interval eventually became normal. CONCLUSION: The QTc interval is frequently prolonged during alcohol withdrawal syndrome and tends to become normal over time, along with remission of abstinence symptoms.

[De novo hepatitis B with anti-HBc negative in a liver transplant recipient [corrected]]. / Hepatitis B de novo con anticuerpo frente al HBcAg negativo en un trasplantado hepático.

De novo hepatitis B was diagnosed in a 47-year-old man 15 months after liver transplantation for end-stage alcoholic cirrhosis. Serum antibodies to hepatitis B core antigen (anti-HBc) were negative, and remained undetectable over 20 months of follow-up. The possible causes of negative serum anti-HBc despite of active hepatitis B virus infection are reviewed. Immunosuppression may underlie this phenomenon in similar cases.

[Angiosarcoma of gingival presentation]. / Angiosarcoma de presentación gingival.

We present the case of a woman of 62 years old with changes history in the intestinal habit, weak, thing, anemia, violet injuries in the gums and hemoptysis of small quantity. After the various tests accomplishment of image and biopsy of the injuries gingival and of lymphadenopathy supraclavicular was demonstrated the existence of a angiosarcoma of high degree of malignity. This neoplasm is originated in the cells of vascular endothelium and constitutes 1% of all the sarcomas and solely 4% appear the the oral cavity. These tumors has a high mortality (superior to the 20%) to five years. Once diagnosed its manage must be aggressive in spite of its wrong therapeutic response.

[Late-onset Wilsons disease]. / Enfermedad de Wilson de manifestación tardía.

A 58-year old male with a past history of psychiatric disorders was studied for a persistent serum transaminase increase. Low serum ceruloplasmin level (lower than 3 mg/dL), increased urinary copper excretion, and increased liver tissue copper concentration (1050 mcg/g dry weight) confirmed the diagnosis of Wilsons disease. Slit lamp examination did not show Kayser-Fleischer rings. D-penicilamin therapy was followed by serum transaminase normalization. Similar late-onset cases of Wilsons disease are exceptional, but confirm the clinical heterogeneity of the disease.