Prophylaxis In Immunocompromised Patients Research Articles

Efficacy of Tixagevimab/Cilgavimab as Pre-Exposure Prophylaxis against Infection from SARS-CoV-2 and Severe COVID-19 among Heavily Immunocompromised Patients: A Single-Center, Prospective, Real-World Study.

COVID-19 continues to pose a threat to immunocompromised individuals, even with vaccination. The monoclonal antibodies (mAbs) tixagevimab/cilgavimab (TXG/CIL) provide targeted prophylaxis against SARS-CoV-2 with the benefit of a prolonged half-life. Although approved for COVID-19 prevention, there is limited data on their effectiveness among heavily immunocompromised populations. We conducted a prospective, observational study at Laiko General Hospital, Athens, Greece, from August to December 2022 to investigate the efficacy of TXG/CIL as a form of pre-exposure prophylaxis in immunocompromised patients. Data on breakthrough SARS-CoV-2 infections were collected over a six-month follow-up period. Of the 375 participants (mean age 61.3 ± 14.1 years; 59.7% male), 76 (20.3%) developed breakthrough SARS-CoV-2 infections, with an incidence of 3.81 cases/100 patient months. Hospitalization was required for 21 patients (5.6%), with a median stay of 14 days. Seven deaths were recorded, with only one attributed to COVID-19. Previous infection (OR 0.46, 95% CI 0.26-0.82) and hybrid immunity (OR 0.52, 95% CI 0.29-0.92) can protect against new infection. Solid organ malignancy significantly increased the risk of severe outcomes among those infected (OR 7.4, 95% CI 2.2-24.7, p = 0.001). TXG/CIL provides effective prophylaxis against COVID-19 in immunocompromised patients. Future strategies should focus on developing new mAb combinations to address emerging SARS-CoV-2 variants and protect vulnerable populations.

Impaired neutralizing antibody efficacy of tixagevimab-cilgavimab 150+150mg as pre-exposure prophylaxis against Omicron BA.5. A real-world experience in booster vaccinated immunocompromised patients.

Tixagevimab-cilgavimab has been approved as primary pre-exposure prophylaxis in immunocompromised patients as support or replacement for vaccination, even though the Omicron variant of concern (VOC) was spreading at the time. The aim of our study was to evaluate the post-injection neutralising activity (NT90-Abs titre) against the Omicron BA.5 variant in fully vaccinated immunocompromised patients. NT90-Abs titres against BA.5 and 20A.EU1 as well as anti-spike and anti-receptor-binding domain IgG were evaluated 0, 14, and 30d after tixagevimab-cilgavimab administration. The primary end point was NT90-Abs titres≥80 against BA.5 in ≥ 25% of patients, and the secondary end point was NT90-Abs titres≥1280 against 20A.EU1 in >50% of patients on day 14. At baseline, 35.2%, 37.02%, and 32.5% of booster vaccinated patients exhibited undetectable levels of anti-S and anti-RBD IgG antibodies such as NT90-Abs titres against A20.EU1. Moreover, 35 patients (61.5%) had undetectable NT90-Abs titres against BA.5. On day 14, IgG anti-S and anti-RBD levels were 3880BAU/mL and 776.6AU/mL, respectively. Only 12.5% of patients met a NT90-Abs titres≥80 against BA.5, whereas the median NT90-Abs titre against 20A.EU1 was 1280. NT90-Abs titres against BA.5 were 64-fold lower than those against A20.EU1. Four patients (7.5%) had a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the 3 months after treatment, all with a time gap between the booster vaccination and injection. To date, tixagevimab-cilgavimab cannot be considered a substitute for vaccination but may be a useful supporting therapy if the recommended dose for pre-exposure prophylaxis is doubled.

Anti-spike protein to determine SARS-CoV-2 antibody levels: Is there a specific threshold conferring protection in immunocompromised patients?

Identifying a specific threshold level of SARS-CoV-2 antibodies that confers protection in immunocompromised patients has been very challenging. The aim was to assess the threshold of 264 binding antibody units (BAU)/ml using four different SARS-CoV-2 antibody assays (Abbott, Beckman, Roche, and Siemens) and to establish a new optimal threshold of protection for each of the four antibody assays. This study was performed on data retrieved from 69 individuals, who received at least one dose of the Pfizer/BioNTech BNT162b2 or Moderna COVID-19 vaccine (Spikevax) at the Alphabio Laboratory in Marseille, France (European Hospital, Alphabio-Biogroup). The results were compared to the percent inhibition calculated using a functional surrogate of a standardized virus neutralization test (Genscript). Samples from 69 patients were analyzed. For a reference cutoff of 264 BAU/ml, assays showed moderate to good overall concordance with Genscript: 87% concordance for Abbott, 78% for Beckman, 75% for Roche, and 88% for Siemens. Overall concordance increased consistently after applying new thresholds, i.e., 148 BAU/ml (Abbott), 48 (Beckman), 559 (Roche), and 270 (Siemens). We suggest specific adjusted thresholds (BAU/ml) for the four commercial antibody assays that are used to assess pre-exposure prophylaxis in immunocompromised patients.

Tixagevimab-cilgavimab como tratamiento profiláctico preexposición frente a SARS-CoV-2 en pacientes trasplantados renales

IntroductionIt has been reported that after vaccination with RNAm or viral vectors from SARS-CoV-2 a significant number of solid organ transplant recipients do not develop an effective immune response. In this scenario, the use of tixagevimab-cilgavimab was approved by the European Medicines Agency for COVID-19 prophylaxis in immunocompromised patients in March 2022. We present our experience with a group of kidney transplant recipients who received prophylactic treatment with tixagevimab-cilgavimab. Material and methodsProspective study from a cohort of kidney transplant recipients who had been previously vaccinated with 4 doses and did not achieve a satisfactory immune response to vaccination, presenting antibody titers lower than 260 BAU/mL when measured by ELISA. A total of 55 patients who received a single dose of 150mg of tixagevimab and 150mg of cilgavimab between May and September of 2022 were included in this study. ResultsNo immediate or severe adverse reactions, including worsening of kidney function, were observed after administering the drug or during follow up. All patients who had received the drug 3 months prior presented positive antibody titers (>260 BAU/mL). Seven patients were diagnosed with COVID, and one of those patients had to be admitted to the hospital and died 5 days later from infectious complications and a suspected diagnosis of bacterial coinfection. ConclusionsIn our experience, all kidney transplant recipients reached antibody titers higher than 260 BAU/mL 3 months after receiving prophylactic treatment with tixagevimab-cilgavimab with no severe or irreversible adverse reactions.

Azithromycin and Co-Trimoxazole in Antimicrobial Prophylaxis: Special Emphasis on Primary Immunodeficiencies in Children

Patients with primary immunodeficiency diseases (PID) are prone to infectious, and they often determine the course of the disease. Antimicrobial prophylaxis for patients with PID includes co-trimoxazole, amoxicillin and macrolides. Co-trimoxazole is a widely used antimicrobial agent for pneumocystosis prophylaxis in immunocompromised patients, including patients with primary cellular immunodeficiency. Antiinflammatory effect of azithromycin made it a drug of choice in the management of chronic lung diseases in the patients with primary immunodeficiencies, especially in those with antibody deficiencies. Further randomised controlled studies are needed to define the optimal agent for all types of primary immunodeficiencies, its dose, duration of treatment, benefits and safety of long-term use.A recommendation for the prophylactic use of long-term therapy should consider the balance between benefits and risk of adverse events.
 Bangladesh Journal of Medical Science Vol.20(3) 2021 p.530-538

Rezafungin: A Novel Antifungal for the Treatment of Invasive Candidiasis

Rezafungin is a novel echinocandin with exceptional stability and solubility and a uniquely long half-life allowing for front-loaded drug exposure with once-weekly dosing. Rezafungin has been shown comparable to other echinocandins, with activity against Candida spp. and Aspergillus spp. including subsets of echinocandin-resistant Candida auris and azole-resistant Aspergillus isolates. Available clinical data show robust safety and promising efficacy. Phase III trials will provide data on efficacy of rezafungin for the treatment of candidemia and invasive candidiasis and for the prevention of invasive fungal disease in blood and bone marrow transplant recipients. Rezafungin is a promising new candidate in the antifungal arsenal that opens up clinical possibilities based on its impressive half-life, such as early hospital discharge for stable patients and use as prophylaxis in immunocompromised patients.

Phenotypic testing of patient herpes simplex virus type 1 and 2 isolates for acyclovir resistance by a novel method based on real-time cell analysis

BackgroundAcyclovir (ACV) is the most commonly used drug for herpes simplex virus (HSV) infection therapy. Prolonged antiviral therapy or prophylaxis in immunocompromised patients may promote the development of drug-resistant strains. Due to the high polymorphism in genes involved in drug resistance, phenotypic methods, although work-intensive, are still required to test drug susceptibility. Real-time cell analysis (RTCA) based methods could offer a rapid and less labor-intensive alternative for phenotypic testing of ACV resistance. ObjectiveTo investigate the utility of a new RTCA based assay (RTCAA) to test acyclovir susceptibility of HSV clinical isolates. Study designFour reference strains and 93 clinical isolates (60 HSV-1 and 33 HSV-2) were tested by RTCAA. In the presence of ACV concentrations from 2.2 to 140.8 μM, Vero cells were infected with different virus dilutions. IC50 values were calculated by dose-response curve (DRC) with area-under-curve (AUC) method. The reference strains and 22 clinical isolates were additionally tested by dye-uptake assay, and IC50 values of both methods were compared. ResultsIC50 values from RTCAA and dye-uptake assays were positively correlated (Spearman's rho = 0.897, p < 0.001) and quantitatively agreed (Bland-Altman plot). Based on a cut-off of 4 μM for HSV-1 and 13 μM for HSV-2, 87 isolates were classified as ACV-sensitive and 6 isolates as ACV-resistant. The reference strains showed the expected results of ACV susceptibility. ConclusionRTCAA agrees well with the dye-uptake assay. Compared with other phenotypic methods, RTCAA requires less manipulation, reduces the workload and the turnaround time, and appears to be an objective and reliable method to test ACV susceptibility.

RI-002, an intravenous immunoglobulin containing high titer neutralizing antibody to RSV and other respiratory viruses for use in primary immunodeficiency disease and other immune compromised populations

ABSTRACTIntroduction: Novel immune globulin (IG) products (RI-002, RI-001) have been designed to provide protection against respiratory syncytial virus (RSV) mediated respiratory illness while at the same time meeting the manufacturing requirements established by FDA for antibody supplementation in immunocompromised subjects.Areas covered: This review covers the manufacture and development of both RI-001 and RI-002, including the selection of plasma donors for IG preparation with high-titers of anti-RSV antibody, in vitro, and preclinical data in the cotton rat model S. hispidus, and clinical trials including Phase II and compassionate use studies of RI-001 and a multi-center, pivotal Phase III study of RI-002 in PIDD patients.Expert commentary: The data demonstrate that RI-002 is efficacious in the prevention and treatment of RSV in preclinical normal and immune suppressed animal models and is safe and efficacious in the treatment of patients with various forms of primary immunodeficiency disease (PIDD). This product offers potential advantages over other available IG’s for prophylaxis in immunocompromised patients requiring polyclonal immunoglobulin supplementation because of its unique antibody composition. In addition to its enhanced neutralizing anti-RSV activity and its polyclonal IG composition, there is preclinical data to support the use of RI-002 for humoral protection against other respiratory pathogens.

Determining the Incidence of Pneumocystis Pneumonia in Patients With Autoimmune Blistering Diseases Not Receiving Routine Prophylaxis

Pneumocystis pneumonia (PCP) is a potentially lethal opportunistic infection that primary prophylaxis can help prevent. The risk of prophylactic therapy must be weighed against the incidence of PCP in the patient population. Prophylaxis most frequently involves trimethoprim-sulfamethoxazole, with second-line therapies, including atovaquone, dapsone, and pentamide. The indication for prophylaxis in immunocompromised patients without HIV is less well defined. Previously, an incidence of at least 3.5% has been proposed as a cutoff to justify prophylaxis. To assess the incidence of PCP in patients with autoimmune blistering diseases receiving no routine prophylaxis. This was a retrospective analysis of patient medical records to determine the incidence of PCP infections. The multicenter study was performed at tertiary care centers that provide care for patients with autoimmune blistering disease in Germany, Italy, Singapore, Israel, and the Netherlands. Patients had a confirmed diagnosis of pemphigus vulgaris/foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid/cicatricial pemphigoid, or anti-p200 pemphigoid. To determine the incidence of PCP defined as patients with the International Classification of Diseases, Ninth Revision (ICD-9), code 136.3, for PCP, or free text documentation of PCP occurring based on characteristic radiographic findings with elevated lactate dehydrogenase, or hospitalization for pneumonia with bronchioalveolar lavage demonstrating Pneumocystis jiroveci on confirmatory stains. A total of 801 patients with autoimmune blistering diseases were included in this study; their mean (SD) age was 66.5 (17.6) years, and a total of 465 (58%) were female. Only 1 patient developed PCP, resulting in an incidence rate of 0.1%. This incidence significantly fell below the recommended threshold of 3.5% (0.1% vs 3.5%, χ21 = 27.0; P < .001). This incidence was significantly lower than the previously reported incidence of PCP in all immunosuppressed dermatologic patients (0.1% vs 1.3%; χ21 = 8.2; P = .004). Routine Pneumocystis prophylaxis for patients with autoimmune blistering diseases does not seem to be warranted. Patients with autoimmune blistering disease seem to have a lower risk of PCP than the general population of immunosuppressed dermatology patients. Risks of routine prophylaxis include hyperkalemia, hypoglycemia, photosensitivity, thrombocytopenia, and more rare adverse reactions.

Valacyclovir Maintenance Therapy for a Case of Unilateral Acute Retinal Necrosis during Chemotherapy

Acute retinal necrosis (ARN) is an infectious retinitis caused by varicella zoster virus (VZV), herpes simplex or cytomegalovirus. Without systemic therapy, ARN may progress bilaterally in seventy percent of unilateral patients. A 38-year-old-man was admitted to our hospital with Hodgkin's lymphoma and hemophagocytic lymphohistiocytosis. During the chemotherapy, left facial herpes zoster developed. He received valacyclovir for 14 days. After improvement of the blisters, he continued acyclovir as secondary prophylaxis. Three weeks after the facial zoster, sudden visual loss in the left eye occurred. ARN induced by VZV was diagnosed with ophthalmoscopy and the polymerase chain reaction test of the anterior chamber. Because continuous chemotherapy for Hodgkin's lymphoma was needed, he continued valacyclovir as secondary prophylaxis for 6 months and he accomplished the chemotherapy without contralateral progression. Our case suggested the utility of valacyclovir for secondary prophylaxis. Further experiments would be required to establish secondary prophylaxis in immunocompromised patients.

Antifungal Prophylaxis in Immunocompromised Patients.

Invasive fungal infections (IFIs) represent significant complications in patients with hematological malignancies. Chemoprevention of IFIs may be important in this setting, but most antifungal drugs have demonstrated poor efficacy, particularly in the prevention of invasive aspergillosis.Antifungal prophylaxis in hematological patients is currently regarded as the gold standard in situations with a high risk of infection, such as acute leukemia, myelodysplastic syndromes, and autologous or allogeneic hematopoietic stem cell transplantation. Over the years, various scientific societies have established a series of recommendations for antifungal prophylaxis based on prospective studies performed with different drugs. However, the prescription of each agent must be personalized, adapting its administration to the characteristics of individual patients and taking into account possible interactions with concomitant medication.

Cost Benefit and Cost Effectiveness of Antifungal Prophylaxis in Immunocompromised Patients Treated for Haematological Malignancies

There has been a large increase in the incidence of invasive fungal infections (IFIs) over the past decades, largely because of the increasing size of the population at risk. One of the major risk groups for IFIs are patients with haematological malignancies treated with cytotoxic chemotherapy or undergoing haematopoietic stem cell transplantation. These IFIs are associated with high morbidity and mortality rates. Consequently, as the diagnosis of IFIs is difficult, antifungal prophylaxis is desirable in high-risk patients. Furthermore, as the economic impact of IFIs is also significant, it is important to assess the cost benefit and cost effectiveness of each prophylactic agent in order to aid decisions concerning which prophylactic agent provides the best value for limited healthcare resources. This article systematically reviews the available pharmacoeconomic evidence regarding antifungal prophylaxis in immunocompromised patients treated for haematological malignancies. Furthermore, specific points of interest concerning economic analyses of antifungal prophylaxis are briefly discussed. Considering the available evidence, antifungal prophylaxis in immunocompromised patients treated for haematological malignancies seems to be an intervention with favourable cost-benefit, cost-effectiveness and cost-saving potential. Furthermore, recently introduced antifungal agents seem to be attractive alternatives to fluconazole from a pharmacoeconomic point of view. However, due to wide heterogeneity in patient characteristics, underlying diseases, hospital settings and study methods in the included economic studies, as well as the lack of 'head-to-head' trials, it is difficult to find clear evidence of the economic advantages of a single prophylactic agent. Furthermore, we show that the results of cost-effectiveness analyses are highly dependent on several crucial factors that influence the baseline IFI incidence rates and, therefore, differ per patient population or region.

High prevalence of Dapsone-induced oxidant hemolysis in North American SCT recipients without glucose-6-phosphate-dehydrogenase deficiency

Dapsone (4-4'-diaminodiphenylsulfone) is commonly used for Pneumocystis jirovecii pneumonia (PCP) prophylaxis in immunocompromised patients. Oxidant hemolysis is a known complication of dapsone, but its frequency in adult patients who have undergone a SCT for hematological malignancies is not well established. We studied the presence of oxidant hemolysis, by combining examination of RBC morphology and laboratory data, in 30 patients who underwent a SCT and received dapsone for PCP prophylaxis, and compared this group with 26 patients who underwent a SCT and received trimethoprim-sulfamethoxazole (TMP-SMX) for PCP prophylaxis. All patients had normal glucose-6-phosphate dehydrogenase (G6PDH) enzymatic activity. In SCT patients, dapsone compared with TMP-SMX for PCP prophylaxis was associated with a high incidence of oxidant hemolysis (87 vs 0%, P<0.001), and the morphological evaluation of oxidant hemolysis correlated well with laboratory evidence of hemolysis. Dapsone-induced oxidant hemolysis in SCT patients is 20-fold higher than the reported rate in the population of HIV-infected patients, and thus much higher than the prevalence of G6PDH variants in the general population. In our patients, it manifested clinically as a lower Hb that was not significant enough to result in increased packed RBC transfusions.

Oseltamivir‐resistant 2009 H1N1 influenza pneumonia during therapy in a renal transplant recipient

The emergence of oseltamivir-resistant 2009 H1N1 influenza virus (conferred by the H275Y substitution in NA) during therapy or prophylaxis in immunocompromised patients is a serious concern. The optimal therapy for immunosuppressed patients with oseltamivir-resistant 2009 H1N1 influenza virus is unknown and few options exist. We report a 10-yr-old recipient of kidney transplant who was hospitalized with oseltamivir-resistant 2009 H1N1 influenza pneumonia complicated by severe respiratory failure, ARDS, and renal failure requiring institution of ECMO and CRRT. On presentation, treatment with oseltamivir (second course) and broad-spectrum antibiotics was initiated. Immunosuppressive agents were stopped on hospital day (d) 2. On hospital d 7, given his critical status, immunocompromised state, and difficulty in obtaining intravenous zanamivir, after obtaining ethical approval and parental consent, he was treated with intravenous peramivir (through an Emergency Investigational New Drug Application) for two wk. He tolerated the regimen well and his clinical status improved gradually. Several factors may have contributed to virus clearance and survival including recovery of the immune system, aggressive critical care support, and administration of peramivir. Ongoing surveillance is essential to monitor how oseltamivir-resistant H275Y mutant viruses may evolve in the future.

High Prevalence of Dapsone-Induced Oxidant Hemolysis in North American Stem Cell Transplant Recipients without Glucose-6-Phosphate-Dehydrogenase Deficiency.

Abstract 3314Poster Board III-202 IntroductionDapsone (4-4'-diaminodiphenylsulfone) is commonly used for Pneumocystis jirovecii pneumonia (PCP) prophylaxis in immunocompromised patients. Oxidant hemolysis is a known complication of dapsone, but its frequency in adult patients who have undergone stem cell transplantation (SCT) for hematologic malignancies is not well established. We report a high prevalence of hemolytic anemia associated with dapsone use in SCT patients in the absence of glucose-6-phosphate dehydrogenase (G6PDH) deficiency. Patients and MethodsWe retrospectively analyzed laboratory data from 30 SCT (29 Caucasian and 1 African-American; 15 male and 15 female) patients receiving dapsone (100 mg orally daily) for PCP prophylaxis to determine the frequency of oxidant hemolysis. All patients had undergone allogeneic (n = 27) or autologous SCT (n = 3) for hematological malignancy or aplastic anemia. Peripheral blood (PB) smears were reviewed in a blinded fashion for the presence of morphologic features of oxidant hemolysis (multiple bite cells in each high power field), with PB smears from the same patient group while not on dapsone serving as controls. Additional demographic and laboratory data, including G6PDH enzyme activity screening test, hemoglobin, reticulocyte count, lactate dehydrogenase and bilirubin levels, were collected from chart review. Results29 patients had normal G6PDH activity (results were not available for 1 patient). 38 PB smears were obtained while on dapsone (some patients had more than one bone marrow evaluation). 30 (79%) PB smears from 26 (87%) patients had morphologic evidence of overt oxidant hemolysis. This was significantly higher than in the controls, in which 5/22 (23%) PB smears had morphologic features of oxidant hemolysis (p<0.001, Fisher's exact test). Hemoglobin levels were lower in the dapsone group, compared to the controls (10.0 vs. 12.5 g/dL, p=0.012). Mean LDH (507 IU) and direct bilirubin (1.6 g/dL) were also increased in the patients on dapsone. None of the patients had laboratory signs of hemolysis while not on dapsone. ConclusionsDapsone-induced oxidant hemolysis in SCT patients is 20-fold higher than the reported rate in HIV-infected patients receiving this agent. This high prevalence in patients without G6PDH deficiency suggests the coexistence of other sources of oxidant stress specific to this patient cohort. DisclosuresBredeson:Esai: Honoraria.

Posaconazole as Prophylaxis in Immunocompromised Patients: A Single Center Experience

Efficacy of posaconazole was recently demonstrated in the prevention of invasive fungal infections (IFI) in recipients of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with GVHD and in patients undergoing intensive chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes.Between Jan 2007 and April 2008, 54 patients had received posaconazole prophylaxis (200 mg t.i.d orally) either during induction chemotherapy (33 pts) or because of GVHD (25 pts). Four patients belong to the two subgroups. We analyze these two subgroups separately. IFI were defined as possible/probable/proven according to EORTC/MSG criteria. Prophylaxis with posaconazole was performed to 33 patients undergoing induction chemotherapy (29 AML, 3 MDS, 1 aplastic anemia), (19F/14M), median age 67 years ( range 21 – 81). The median duration of neutropenia (ANC< 500 cells/mm3 ) was 39 days (range10 – 278 days). Median duration of posaconazole prophylaxis was 27 days (range 4 – 203 days), early discontinuation of prophylaxis was observed in 20 patients because of progression to IFI in 5 cases, empirical antifungal therapy for persistent fever (11 cases), mucositis (3 cases) and hepatic toxicity (1 case). Possible or probable IFI was diagnosed in 5/33 (14%) patients (3 possible and 2 probable pulmonary aspergillosis). Five deaths were occurred, only one was related to the IFI, other causes of death were intercurrent disease in 3 patients and one septic choc. Twenty five patients with GVHD treated with intensive immunosuppressive therapy had received posaconazole prophylaxis (13F/12M), median age 52 years (range21– 70), one patient had a prior diagnosis of IFI and was in complete resolution. RIC allo-HSCT was performed to 12 patients,10 sibling donors,14 MUD, one patient received umbilical cord blood transplantation. Acute GVHD grade II to IV and chronic extensive GVHD were reported in 16 and 9 patients respectively. All patients had received high dose corticosteroids (0.5 to 2 mg/Kg/d), the majority of them (21) had two or more immunosuppressive agents. The median duration of posaconazole prophylaxis was 110 days (range 19 days - 10 months), 6 patients are still receiving prophylaxis, 4 premature discontinuations due to hepatic toxicity in one case, progression to IFI in 2 cases and diet because of severe digestive GVHD in one case. Two patients (8%) developed IFI ( 1 possible and 1 probable pulmonary aspergillosis) during prophylaxis period. One patient died from IFI. IFI-unrelated death occurred in 5/25 (20%) patients.Conclusions: We observed 6% (2/33) probable/proven IFI in AML patients undergoing intensive chemotherapy and 4% (1/25) in GVHD patients witch is comparable to the incidence reported in recent studies (Oliver et al., NEJM 2007; 356:348–59/Andrew et al., NEJM 2007; 356:335–47). These results suggest that posaconazole prophylaxis is effective in reducing the incidence of IFI in this high risk population.

Intermittent oral trimethoprim/sulfamethoxazole on two non‐consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation

Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.

Dapsone-Induced Artifactual A1c Reduction in Islet Transplant Recipients

The success of any treatment for type 1 diabetes mellitus, from insulin therapy to islet transplantation, is measured by improved glycemic control with or without insulin independence (1). The most well established measure of this is glycated hemoglobin (A1c), which results from exposure of hemoglobin A to plasma glucose over the lifespan of the red blood cell (RBC). An alternative measure is fructosamine, glycated albumin, which is unaffected by RBC lifespan (2). Chronic immunosuppression is required for recipients of allografts, including islets. Consequently, chronic prophylaxis against Pneumocystis jiroveci pneumonia (PCP/PJP) is also required. Trimethoprim/sulfamethoxazole is the agent of choice due to efficacy and ease of administration, however when not tolerated, dapsone (4,4′-diaminodiphenyl sulfone) is typically the preferred alternative. Dapsone, the parent of the sulfones, was introduced for leprosy treatment more than 60 years ago and has proven therapeutic efficacy in several conditions, more recently PCP/PJP prophylaxis in immunocompromised patients. Effective use of dapsone may be limited by dose-dependent adverse hematological reactions including hemolysis and methemoglobinemia (3, 4), less well described is the reduction in A1c caused by this agent (5–8). Three islet transplant recipients at our center received dapsone for PCP/PJP prophylaxis because of sulfa allergy (n=2) and chronic posttransplant leucopenia (n=1). Duration of treatment was 516±456 days (range 163–1,031 days). All subjects demonstrated a significant decrease in A1c during dapsone therapy (6.3±0.3 vs. 4.5±0.6%, P<0.001, n=18–40) with a return to pre-dapsone levels after cessation of therapy (6.3±0.3 vs. 6.6±0.8%, P=0.15, n=18–40). There was no significant change in fructosamine levels over the same time period (pre 267.3±16.7, during 262.4±25.7, and post 277.6±25.4 uMol/L; P=0.14, n=14–22; Fig. 1). During dapsone treatment, fingerstick glucose (FSG) levels were higher than predicted from A1c levels with negative correlation between A1c and mean FSG (r=−0.29, n=108) and a concomitantly positive correlation between fructosamine and FSG values (r=0.28, n=442). The high-performance liquid chromatography for A1c analysis was unremarkable in these patients.FIGURE 1.: Alteration of A1c and fructosamine (FA) in a single subject (A) and mean levels of A1c (B) and fructosamine (C) in all three subjects before, during and after dapsone treatment.The reason for the observed false reduction in A1c is unknown. A reduction in RBC lifespan and/or hemolysis could cause this. Two of the three subjects demonstrated mild intermittent anemia without reticulocytosis during dapsone therapy; however, this was considered secondary to bone marrow suppression and protocol blood draws rather than hemolysis, although specific testing for hemolysis was not performed. This level of anemia was similar to that seen in the majority of our transplant recipients (1, 9). Alternatively, the oxidative effect of dapsone could affect the rate of hemoglobin glycation through altered reactivity of the amino terminus, with which the glucose molecule interacts, or the rate of Amadori rearrangement of the β-chain after glucose molecule attachment, through altered steric factors (10). Inaccuracy in A1c results in erroneous estimation of mean glucose concentrations. For both subject care and for evaluation of outcomes of beta-cell replacement therapies, an accurate measure of glycemic control is essential. A1c is possibly the most well recognized and most common measure of glycemic control, consequently recognition and/or avoidance of the interaction between dapsone and A1c should be attempted whenever possible. ACKNOWLEDGMENTS We express gratitude to the staff of the Clinical Islet Transplant Program, the Islet Cell Processing Center, the General Clinical Research Center, and the Informatics Core for their continuous support. Tatiana Froud Diabetes Research Institute Department of Surgery University of Miami Miller School of Medicine Miami, FL Raquel N. Faradji Lisa Gorn Diabetes Research Institute Department of Medicine University of Miami Miller School of Medicine Miami, FL Kathy Monroy Charlotte Paz David A. Baidal Gaston Ponte Pablo Cure Raffaella Poggioli Diabetes Research Institute University of Miami Miller School of Medicine Miami, FL Antonello Pileggi Camillo Ricordi Diabetes Research Institute Department of Surgery University of Miami Miller School of Medicine Miami, FL Rodolfo Alejandro Diabetes Research Institute Department of Medicine University of Miami Miller School of Medicine Miami, FL

Pylephlebitis and Pyogenic Liver Abscesses: A Complication of Hemorrhoidal Banding

Hemorrhoidal banding is a well-established and safe outpatient procedure. Septic complications of hemorrhoidal banding are rare but can be fatal. The first case of pylephlebitis (septic portal vein thrombosis) and pyogenic liver abscess following hemorrhoidal banding in a 49-year-old man with diabetes is reported in the present study. Risk factors, management and the role of prophylaxis in immunocompromised patients are discussed. Caution against hemorrhoidal banding in immunosuppressed patients, including patients with diabetes, is warranted.

Association of drug‐serum protein adducts and anti‐drug antibodies in dogs with sulphonamide hypersensitivity: A naturally occurring model of idiosyncratic drug toxicity

Sulphonamide antimicrobials, such as sulphamethoxazole (SMX), provide effective infection prophylaxis in immunocompromised patients, but can lead to drug hypersensitivity (HS) reactions. These reactions also occur in dogs, with a similar time course and clinical presentation as seen in humans. Drug-serum adducts and anti-drug antibodies have been identified in sulphonamide HS humans. The aim of this study was to determine whether similar markers were present in dogs with sulphonamide HS. Thirty-four privately owned sulphonamide HS dogs, 10 sulphonamide-'tolerant' dogs, 18 sulphonamide-naïve dogs, and four dogs experimentally dosed with SMX and the oxidative metabolite SMX-nitroso, were tested for drug-serum adducts by immunoblotting, and anti-drug antibodies by ELISA. Sulphonamide-serum adducts were found in 10/20 HS dogs tested (50%), but in no tolerant dogs. Anti-sulphonamide IgG antibodies were detected in 17/34 HS dogs (50%), but in only one tolerant dog; antibody absorbance values were significantly higher in HS dogs. There was a significant association between the presence of sulphonamide-serum adducts and anti-sulphonamide antibodies (P = 0.009). Anti-drug antibodies were also found in dogs experimentally dosed with SMX-nitroso followed by SMX, but not in a dog dosed with drug vehicle, followed by SMX. Similar humoral markers are present in dogs and humans with sulphonamide HS, supporting the use of dogs as a naturally occurring model for this syndrome in humans. These data suggest the potential use of drug-serum adducts and anti-drug antibodies as markers for sulphonamide HS. Preliminary data indicate that anti-sulphonamide antibodies may be triggered by the SMX-nitroso metabolite, not by the parent drug, in dogs.