Добірка наукової літератури з теми "Drug-sparing regimen"

Background: Antiretroviral therapy (ART) poses challenging drug-drug interactions with immunosuppressant agents in transplant recipients. We aimed to determine the impact of specific antiretroviral regimens in clinical outcomes of HIV+ kidney transplant recipients. Methods: A single-center, retrospective cohort study was conducted at a large academic center. Subjects included 58 HIV- to HIV+ adult, first-time kidney transplant patients. The main intervention was ART regimen used after transplantation. The main outcomes assessed at one- and three-years were: patient survival, death-censored graft survival, and biopsy-proven acute rejection; we also assessed serious infections within the first six months post-transplant. Results: Patient and graft survival at three years were both 90% for the entire cohort. Patients receiving protease inhibitor (PI)-containing regimens had lower patient survival at one and three years than patients receiving PI-sparing regimens: 85% vs. 100% (p=0.06) and 82% vs. 100% (p=0.03), respectively. Patients who received PI-containing regimens had twelve times higher odds of death at 3 years compared to patients who were not exposed to PIs (odds ratio, 12.05; 95% confidence interval, 1.31-1602; p=0.02). Three-year death-censored graft survival was lower in patients receiving PI vs. patients on PI-sparing regimens (82 vs 100%, p=0.03). Patients receiving integrase strand transfer inhibitors-containing regimens had higher 3-year graft survival. There were no differences in the incidence of acute rejection by ART regimen. Individuals receiving PIs had a higher incidence of serious infections compared to those on PI-sparing regimens (39 vs. 8%, p=0.01). Conclusions: PI-containing ART regimens are associated with adverse outcomes in HIV+ kidney transplant recipients.

ABSTRACTStrategies involving new drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug-sensitive or multidrug-resistant (MDR) tuberculosis (TB). We compared the sterilizing activity of the standard first-line antitubercular regimen, rifampin-isoniazid-pyrazinamide (RHZ), with that of the novel regimen PA-824–moxifloxacin–pyrazinamide (PaMZ), which is currently being studied in clinical trials (NCT01498419), in the guinea pig model of chronic TB infection, in which animals develop necrotic granulomas histologically resembling their human counterparts. Guinea pigs were aerosol infected with ∼2 log10bacilli of wild-typeMycobacterium tuberculosisH37Rv, and antibiotic treatment was initiated 6 weeks after infection. Separate groups of animals received RHZ, PaMZ, or single or two-drug components of the latter regimen administered at human-equivalent doses 5 days/week for a total of 8 weeks. Relapse rates were assessed 3 months after discontinuation of treatment to determine the sterilizing activity of each combination regimen. PaMZ given at human-equivalent doses was safe and well tolerated for the entire treatment period and rendered guinea pig lungs culture negative more rapidly than RHZ did. After 1 month of treatment, 80% and 50% of animals in the RHZ and PaMZ groups, respectively, had lung culture-positive relapse. Both combination regimens prevented microbiological relapse when administered for a total of 2 months. Our data support the use of PaMZ as a novel isoniazid- and rifamycin-sparing regimen suitable for treatment of both drug-sensitive TB and MDR-TB.

Background Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear. Methods This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings. Results There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44–64] vs 42 years [IQR 35–50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5–8] vs 5 [IQR 4–6]), more co-medications (median 6 [IQR 4–11] vs 3 [IQR 2–7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). Conclusion The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

Background Primary analysis at 24 weeks showed that switching to rilpivirine plus darunavir/cobicistat was non-inferior to continuing a standard three-drug antiretroviral regimen in virologically suppressed people with HIV. We present efficacy and safety data from the 48-week analysis. Methods PROBE 2 is a randomized, open-label trial. Adults who were on a three-drug therapy and had had <50 HIV-1 RNA copies/mL for at least 6 months were randomly assigned (1:1) to 25 mg rilpivirine plus 800/150 darunavir/cobicistat once daily (early switch group) or to continue their regimen for 24 weeks before switching (late switch group). In the 48-week analysis, the efficacy endpoint was the proportion of participants with <50 copies/mL of HIV-RNA (US Food and Drug Administration snapshot algorithm). The trial is registered with ClinicalTrials.gov , number NCT04064632. Findings 160 participants were recruited and randomized. At week 48, 70 (87.5%) in the early switch group and 76 (94.8%) in the late switch group maintained HIV-RNA <50 copies/mL. Virological failure (≥50 HIV-RNA copies/mL) was not seen in any patient of the early switch group and in 2 subjects in the late switch group none of which had treatment emergent resistance-associated mutation. Adverse events leading to treatment discontinuation occurred in 7 (8.7%) participants in the early switch group and in none in the late switch group. Interpretation The combination of rilpivirine plus darunavir/cobicistat sustained virological suppression, was associated with a low frequency of virological failure, and had a favorable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and integrase inhibitor-sparing alternative to three-drug regimens.

OBJECTIVE: To describe a case of an antipsychotic-sparing effect achieved after the addition of memantine to the regimen of a patient with severe Alzheimer's disease and aggressive behavioral disturbances. CASE SUMMARY: A 78-year-old white man with severe Alzheimer's disease was receiving risperidone 2 mg 3 times daily for persistent aggressive and dangerous behavioral disturbances. Memantine was initiated, and the dose was titrated to 10 mg twice daily. The patient's response included improvement in functional status and resolution of problematic behaviors, allowing repeated reduction of the risperidone dose and ultimate discontinuation. DISCUSSION: Antipsychotics are often employed to treat behavioral disturbances for patients with Alzheimer's disease; however, the adverse effect potential of these agents remains a significant concern. Adjunctive medications that maintain or improve behavioral symptoms yet allow an antipsychotic-sparing effect are attractive. Such experiences have previously been described with other drug classes, but clinical experience is evolving with memantine. For this patient, the effect of this agent on behavioral symptoms and risperidone requirements is one example of such an antipsychotic-sparing effect. CONCLUSIONS: Response to memantine therapy may include behavioral improvements allowing a dose-sparing effect of antipsychotic medication. Changes in psychoactive drug burden may be a valuable surrogate marker of memantine's effects on behavior.

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6–9) versus 5 (4–6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49–156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.

Introduction Tenofovir Disoproxil Fumarate (TDF) is the most widely used Anti-Retroviral Therapy (ART) drug due to its potency, safety profile and World Health Organization (WHO) recommendation. TDF causes proximal tubular renal dysfunction (PTRD) leading to Fanconi syndrome, acute kidney injury and chronic kidney disease. Modest rates (2–4%) of TDF related toxicity based on estimated Glomerular Filtration Rate (GFR) have been described, while TDF-induced PTRD has been reported to be 22%. TDF toxicity is more likely among African patients, it is reversible and TDF may be renal dosed in patients with dysfunction. The objective of this study was to assess proximal tubular renal dysfunction, global renal function, and their determinants among patients on TDF versus TDF-sparing regimen. Methods This was a cross-sectional study among people living with HIV/AIDS (PLWHA) attending the Academic Model Providing Access to Healthcare (AMPATH) program. The primary outcome of interest in this study was PTRD while the secondary outcome of interest was estimated GFR. PTRD was defined as any two of beta-2 microglobulin in urine, metabolic acidosis, normoglycemic glucosuria and fractional excretion of phosphate. Student’s t-test, chi-square and their non-parametric equivalents were used to test for statistical significance. Univariate and multivariate logistic regression analysis was carried out. Results A total of 516 participants were included in the final analysis, 261 on TDF while 255 were on TDF-sparing regimens. The mean (SD) age of all participants was 41.5 (12.6) years with majority being female (60.3%). The proportion of PTRD was 10.0% versus 3.1% in the TDF compared to TDF-sparing group (P<0.001). Mean estimated GFR was 112.8 (21.5) vs 109.7 (21.9) ml/min/1.73mm3 (P = 0.20) for the TDF compared to TDF-sparing group. TDF users were more likely to have PTRD compared to non-TDF users, adjusted Odds Ratio (AOR) 3.0, 95% CI 1.12 to 7.75. Conclusion There was significant PTRD in the TDF compared to TDF-sparing group without significant difference in estimated GFR. The clinical significance of these findings may not be clear in the short term.

Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients. However, problems such as short-term or long-term toxicity and the development of drug resistance could necessitate a change in the therapy regimen. Whereas various HAART options with low pill burden and favourable long-term tolerability profiles are available for naive patients, treatment of experienced patients tends to be more complex and remains a challenge. Treatment with class sparing nucleoside-only regimens could be an option in this context, but the combination of zidovudine (AZT), lamivudine (3TC) and abacavir (ABC) has shown to be inferior in terms of virological efficacy compared with the standard regimen. More promising data were obtained when AZT, 3TC and ABC were intensified with tenofovir (TDF), resulting in a quadruple nucleoside therapy. This regimen has demonstrated comparable potency to a standard regimen with AZT, 3TC and efavirenz in treatment-naive patients. Additionally, it has shown to be an efficient treatment option especially in moderately pretreated patients. This is accredited to the potency of the single components and the antagonistic selection pressure of AZT and TDF. The presence of L210W, or at least two of the mutations 41L, 67N, 70R, 215F/Y or 219Q/E, at or before baseline seems to be a predictor of non-response, whereas the presence of M184V does not impede virological response and might even be advantageous. This review summarizes current data on the combined use of AZT, 3TC, ABC and TDF in regard to virological and immunological outcome as well as genotypic predictors of response.

Combined therapy in cardiology is currently the most recognized method of treatment, especially in patients with hypertension. Approximately in 50 % of patients with hypertension, monotherapy is effective. However to achieve the desired effect in the remaining half of patients, simultaneous administration of two and sometimes three drugs is required. Numerous drugs with a fixed combination of two (and even three) antihypertensive drugs, often used in clinical practice, greatly simplify the dosage regimen of drugs and improve patients’ adherence to treatment. Unfortunately, simultaneous prescription of several drugs increases sharply the probability of inter-drug interaction with the increase in the number of prescribed drugs. The result of drug-drug intereaction may be unpredictable. Therefore, the ability to predict the possible adverse reactions in patients with cardiovascular diseases and to prescribe rationally combined pharmacotherapy is a guarantee of highly efficient and safe treatment.Currently, rational combinations of antihypertensive drugs of different groups make hypertension therapy more comfortable and increases patients’ adherence to treatment. The authors present topical combinations of antihypertensive drugs in one drug: angiotensin converting enzyme inhibitor + diuretic, β-adrenoblocker + diuretic; diuretic + angiotensin receptor antagonist; calcium antagonist + angiotensin receptor antagonist; calcium antagonist + β-adrenoblocker, and others.The article presents an overview of both rational (calcium antagonist + diuretic, β-adrenoblocker + diuretic,) and irrational (angiotensin converting enzyme Inhibitor + potassium-sparing diuretic, angiotensin receptor blocker + potassium-sparing diuretic) combinations of antihypertensive drugs. Combinations of some hypotensive and antianginal drugs with drugs of other groups with a high risk of adverse reactions are presented.

Objectifs : L’objectif principal de ce projet était d’évaluer l’impact d’une série d’interventions, auprès des prescripteurs, et des patients, quant aux dépenses de prescriptions en antirétroviraux (ARV) dans le Service des Maladies Infectieuses et Tropicales (SMIT) de l’Hôpital Bichat, Paris, France. Les objectifs secondaires incluaient la description des combinaisons thérapeutiques utilisées, leur prix, l’évaluation des connaissances, des croyances et représentations des prescripteurs et des personnes vivant avec le VIH (PVVIH) sur le prix des traitements ARV, et de l’acceptabilité de telles interventions. Il s’agissait aussi d’étudier la stabilité de la réponse immuno-virologique pour les PVVIH ayant bénéficié d’un changement thérapeutique pour raison économique, et l’absence d’apparition d’intolérance ou de modification dans la relation soignant-PVVIH. Contexte : En 2014, le contexte de crise économique a amené la Sécurité Sociale à accorder davantage d’attention aux dépenses engendrées par les médicaments intégralement remboursés, dont les ARV. Les ARV génériques apparaissaient sur le marché français, et les recommandations intégrèrent le concept d’optimisation du traitement ARV pour les PVVIH en succès thérapeutique. Cette adaptation avait pour but le confort des prises du traitement ARV et la minimisation des effets secondaires au long cours. Elle introduisait aussi des critères de coût, et ainsi de nouveaux enjeux dans la relation médecin-PVVIH. Problématique : Avec des informations et actions sur la bonne utilisation des ARV, est-il possible de maîtriser l’augmentation des dépenses en ARV sans pour autant avoir un impact négatif sur l’efficacité et la tolérance du traitement ou sur la relation soignant-PVVIH ? Méthodes : Une étude interventionnelle de type avant-après, visant à évaluer les dépenses en ARV avant et après une série d’interventions dans le SMIT de Bichat, et contre témoin, a été développée. L’évaluation d’impact budgétaire et du succès thérapeutique était accompagnée d’une évaluation en psychologie sociale basée sur des focus groups avec des prescripteurs et PVVIH, et des questionnaires administrés auprès des deux populations afin d’étudier leurs perceptions autour des ARV, de leur prix, et du vécu de ces interventions. Résultats : L’étude d’impact budgétaire sur 2014 sur le site de Bichat a évalué le budget en ARV à 48 280 200 €, et mis en évidence des combinaisons ARV pouvant potentiellement être changées vers des combinaisons moins chères, à efficacité et tolérance égales, et adaptées au profil médical des PVVIH. Les régimes à base d’Inhibiteurs de protéases (IP) changés pour des allègements thérapeutiques ou régimes sans IP, a fortiori avec des génériques, étaient les scénarios ayant le plus gros impact en termes de diminution du budget. Les focus groups (organisés en 2015) et les questionnaires (administrés en 2016) ont permis de cerner les thématiques des interventions. Après concertation avec un groupe de PVVIH suivi au SMIT, leurs soignants et des associations d’usagers, deux interventions ont été développées (un guide de décision partagée sur le choix des ARV et leur prix, et un site internet calculant le prix de régimes ARV). Elles ont été mises en place en 2018 dans le service expérimental. Discussion et conclusion : La généralisation des interventions créées et les résultats de la phase pré-interventions ont été discutés au niveau national et à un niveau plus global. Les évaluations post-interventions ont été affectées par la pandémie de la COVID-19. Directement, par la mobilisation des personnes dans la lutte contre COVID-19, et indirectement par la crise sanitaire en découlant, et la résilience des populations. Ce contexte a rendu caduque toute comparaison ou constat. ANRS-GOTA constitue une étude pilote dans un site, son design, les outils et les interventions élaborées et mises en place pourraient être réutilisés pour être évalués à plus grande échelle
Abstract in English:Objectives: The main objective of this project was to evaluate the impact of a series of interventions, addressed to prescribers and patients, on the expenditure on antiretroviral therapies (ART) prescribed in the Department of Infectious and Tropical Diseases (SMIT) of the Bichat Hospital, Paris, France. The secondary objectives included the description of the antiretroviral regimens used, their price, the assessment of the knowledge, beliefs and representations regarding the price of ART, and the acceptability of such interventions, among prescribers and people living with HIV (PWH). At inception, an objective was also to monitor the sustainability of the immuno-virological response for PWH who benefited from an ART switch for economic reasons, and the absence of side effects or of an alteration of the healthcare giver-PWH relationship. Background: In 2014, the economic crisis led the French Health Insurance (Social Security) to pay more attention to the expenses generated by medicines free of charge, which included ART. Generic antiretrovirals came onto the French market, and the guidelines included the concept of ART optimisation for PWH in therapeutic success. This adaptation aimed to increase the comfort of ART intake and to decrease long-term side effects. It also tackled cost criteria, thus, introducing new challenges in the doctor-PWH relationship. Problem: With some information and actions on the proper use of ART, is it possible to curb the increase in ART expenditure without a negative impact on the effectiveness and tolerance of the treatment or on the healthcare giver-PWH relationship? Methods: An interventional before-after study, in order to evaluate the expenditure on ART before and after a series of interventions in the SMIT of Bichat, against control, was developed. The budget impact analysis and therapeutic success evaluation were supplemented with a psychosocial evaluation component based on focus groups with the prescribers and PWH of the SMIT of Bichat, and questionnaires administered to these two populations aiming at studying their perceptions around ART and their price, as well as their experience of these interventions. Results: The 2014 budget impact study at the Bichat site estimated the ARV budget at €48,280,200 and highlighted potential antiretroviral combinations that could be switched to cheaper combinations, with equal efficiency and tolerance, and adapted to the medical profile of PWH. Protease inhibitor (PI) regimens changed to drug-sparing regimen or PI-free regimens, moreover with generic antiretrovirals, were the scenarios with the largest impact in terms of budget reduction. Focus groups (organised in 2015) and questionnaires (administered in 2016) helped identify the themes of the interventions. After consultation of a group of PWH followed up at the SMIT, their healthcare givers and PWH associations, two interventions were developed (a shared-decision making guide on the choice of ART and their price, and a website calculating the price of ART). They were implemented in 2018 in the experimental site. Discussion and conclusion: The generalisability of the interventions developed and of the results of the “pre-interventions assessment” stage was discussed at a national and global level. Subsequently, the post-interventions assessment was affected by the COVID-19 pandemic. Directly, through the mobilisation of people in the fight against COVID-19, and indirectly because of the resulting public health crisis and the resilience of populations. This new context makes any comparison or observation obsolete. ANRS-GOTA was a pilot study in one site, its design, tools and interventions, created and implemented, could however be rolled-out for testing on a larger scale

The goals of treatment in renal vasculitis are to stop vasculitic activity and recover renal function. Subsequent strategies are required to prevent vasculitis returning and to address longer-term co-morbidities caused by tissue damage, drug toxicity, and increased cardiovascular and malignancy risk.Cyclophosphamide and high-dose glucocorticoids remain the standard induction therapy with alternative immunosuppressives, such as azathioprine, to prevent relapse. Plasma exchange improves renal recovery in severe presentations. Refractory disease resulting from a failure of induction or remission maintenance therapy requires alternative agents and rituximab has been particularly effective. Replacement of cyclophosphamide by rituximab for remission induction is supported by recent evidence. Methotrexate is effective in non-renal vasculitis but difficult to use in patients with renal impairment. Mycophenolate mofetil seems to be effective but there is less long-term evidence.Drug toxicity contributes to co-morbidity and mortality and has led to newer regimens with reduced cyclophosphamide exposure. Glucocorticoid toxicity remains a major problem with controversy over the rapidity with which glucocorticoids can be reduced or withdrawn.Disease relapse occurs in about 50% of patients. Early detection is less likely to lead to an adverse affect on outcomes. Rates of cardiovascular disease and malignancy are higher than in control populations but strategies to reduce their risk, apart from cyclophosphamide-sparing regimens, have not been developed. Thromboembolic events occur in 10% and may be linked to the recently identified autoantibodies to plasminogen and tissue plasminogen activator.Renal impairment at diagnosis is a strong predictor of patient survival and renal outcome. Other predictors include patient age, antineutrophil cytoplasmic antibody subtype, disease extent and response to therapy. Chronic kidney disease can stabilize for many years but the risks of end-stage renal disease are increased by acute kidney injury at presentation or renal relapse. Renal transplantation is successful with similar outcomes to other causes of end-stage renal disease.

The goals of treatment in anti-neutrophil cytoplasm antibody (ANCA) vasculitis are to stop vasculitic activity, to prevent vasculitis returning, and to address longer-term comorbidities caused by tissue damage, drug toxicity, and increased cardiovascular and malignancy risk. Cyclophosphamide and high-dose glucocorticoids remain the standard induction therapy with alternative immunosuppressives, such as methotrexate or azathioprine, to prevent relapse. Refractory disease resulting from a failure of induction or remission maintenance therapy requires alternative agents and rituximab has been particularly effective. Replacement of cyclophosphamide by rituximab for remission induction is supported by recent evidence. Additional therapy with intravenous methylprednisolone and plasma exchange is employed in severe presentations with failing vital organ function. Drug toxicity contributes to comorbidity and mortality and has led to newer regimens with reduced cyclophosphamide exposure. Glucocorticoid toxicity remains a major problem, with controversy over the rapidity with which glucocorticoids can be reduced or withdrawn. Disease relapse occurs in 50% and requires early detection at a stage when it will not adversely affect outcomes. Rates of cardiovascular disease and malignancy are higher than in control populations but strategies to reduce their risk, apart from cyclophosphamide-sparing regimens, have not been developed. Thromboembolic events occur in 10% and may be linked to the recently identified autoantibodies to plasminogen and tissue plasminogen activator. Outcomes of vasculitis depend heavily on the level of tissue damage at diagnosis, especially renal dysfunction, but are also influenced by patient age, ANCA subtype, disease extent, and response to therapy. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)is treated along similar principles to granulomatosis with polyangiitis (GPA) and microscopic polyangiitis but the persistence of steroid-dependent asthma in over one-third and differences in pathogenesis has suggested alternative treatment approaches. Chronic morbidity results from tissue damage and is especially common in the upper and lower respiratory tract and kidneys. Tracheobronchial disease is a severe late complication of GPA, while deafness, nasal obstruction, and chronic sinusitis are sequelae of nasal and ear vasculitis. Chronic infection of damaged epithelial surfaces acts as a drive for vasculitic activity and adequate infection control is necessary for stable remission. Chronic kidney disease can stabilize for many years but the risks of endstage renal disease (ESRD) are increased by acute kidney injury at presentation or renal relapse. Renal transplantation is successful, with similar outcomes to other causes of ESRD.

Abstract Solid organ transplantation has become an effective life-sparing modality for thousands of patients with organ failure syndromes. In spite of important advances in surgical technique and immunosuppressive regimens that have made solid organ transplantation a safer procedure today when compared to previous decades, there remain substantial risks of infection and other complications related to the procedure. Among the infectious complications of organ transplantation, none is associated with a greater impact on morbidity and mortality than invasive fungal infections (IFI) (Paya, 1993; Hibberd and Rubin 1994; Hadley and Karchmer, 1995a; Dictar et al, 2000). Fungal infections in organ transplant recipients (OTRs) vary in frequency, etiology, and pathogenesis according to the type of organ transplant procedure. Variations in immunosuppressive regimens, surgical technique, infection control, and exposure history further complicate evaluation of these patients. Moreover, the incidence of IFIs among this group of patients varies considerably from center to center, and an understanding of the overall burden of these infections according to type of organ transplant is lacking. Thus, the clinician is faced with a number of challenges in assessing the OTR with possible IFI. First, there is a lack of sensitive and specific diagnostic assays that might lead to earlier intervention. Second, once a diagnosis of proven or suspected fungal infection is established, therapy is frequently toxic, which may be dose-limiting. Third, significant potential for drug–drug interactions exists between existing antifungal agents and immunosuppressive agents. Fourth, only limited data are available that facilitate early identification of patients who are at the highest risk for IFI within each transplant group. This chapter describes risk factors for developing IFIs among OTRs, reviews the specific fungal pathogens, and discusses an approach to the diagnosis, therapy, and prevention of these potentially devastating infections.

The goals of treatment in anti-neutrophil cytoplasm antibody (ANCA) vasculitis are to stop vasculitic activity, to prevent vasculitis returning, and to address longer-term comorbidities caused by tissue damage, drug toxicity, and increased cardiovascular and malignancy risk. Cyclophosphamide and high-dose glucocorticoids remain the standard induction therapy with alternative immunosuppressives, such as methotrexate or azathioprine, to prevent relapse. Refractory disease resulting from a failure of induction or remission maintenance therapy requires alternative agents and rituximab has been particularly effective. Replacement of cyclophosphamide by rituximab for remission induction is supported by recent evidence. Additional therapy with intravenous methylprednisolone and plasma exchange is employed in severe presentations with failing vital organ function. Drug toxicity contributes to comorbidity and mortality and has led to newer regimens with reduced cyclophosphamide exposure. Glucocorticoid toxicity remains a major problem, with controversy over the rapidity with which glucocorticoids can be reduced or withdrawn. Disease relapse occurs in 50% and requires early detection at a stage when it will not adversely affect outcomes. Rates of cardiovascular disease and malignancy are higher than in control populations but strategies to reduce their risk, apart from cyclophosphamide-sparing regimens, have not been developed. Thromboembolic events occur in 10% and may be linked to the recently identified autoantibodies to plasminogen and tissue plasminogen activator. Outcomes of vasculitis depend heavily on the level of tissue damage at diagnosis, especially renal dysfunction, but are also influenced by patient age, ANCA subtype, disease extent, and response to therapy. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)is treated along similar principles to granulomatosis with polyangiitis (GPA) and microscopic polyangiitis but the persistence of steroid-dependent asthma in over one-third and differences in pathogenesis has suggested alternative treatment approaches. Chronic morbidity results from tissue damage and is especially common in the upper and lower respiratory tract and kidneys. Tracheobronchial disease is a severe late complication of GPA, while deafness, nasal obstruction, and chronic sinusitis are sequelae of nasal and ear vasculitis. Chronic infection of damaged epithelial surfaces acts as a drive for vasculitic activity and adequate infection control is necessary for stable remission. Chronic kidney disease can stabilize for many years but the risks of endstage renal disease (ESRD) are increased by acute kidney injury at presentation or renal relapse. Renal transplantation is successful, with similar outcomes to other causes of ESRD.