Beyond the First Year: Epidemiology and Management of Late-Onset Opportunistic Infections After Kidney Transplantation.

Late opportunistic infections (OI) occurring beyond the first year after kidney transplantation (KT) are poorly described and not targeted by prophylactic strategies. We performed a ten-year retrospective monocentric cohort study describing epidemiology, risk factors and impact of late OI occurring 1 year after KT. We included clinically symptomatic OI requiring treatment besides BK virus nephropathy. Control groups included early OI occurring in the first year after KT, and KT recipients without OI since KT and alive with a functional allograft at 1 year. Among 1066 KT recipients, 185 (19.4%) presented a first episode of OI 21.0 (8.0-45.0) months after KT: 120 late OI (64.9%) and 65 early OI (35.1%). Late OI were mainly viral (N = 83, 69.2%), mostly herpes zoster (HZ) (N = 36, 43.4%). Pneumocystis represented most late fungal infections (N = 12/25, 48%). Compared to early OI, we reported more pneumocystis (p = 0.002) and less invasive aspergillosis (p = 0.01) among late OI. Patients with late OI were significatively younger at KT (54.0 ± 13.3 vs. 60.2 ± 14.3 years, p = 0.05). Patient and allograft survival rates between late OI and control groups were similar. Only age was independently associated with mortality. While late OI were not associated with higher mortality or graft loss, implementing prophylactic strategies might prevent such infections.

COVID-19: Overview of rheumatology fellows.

SARS-COV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.

Levofloxacin based non-rifampicin anti-tuberculous therapy: An effective alternative in renal transplant recipients in resource limited setting.

INTRODUCTION: Rifampicin is one of the most effective components of anti-tuberculous therapy (ATT). Since rifampicin is a hepatic enzyme (CYP3A4) inducer, in a post-renal transplant recipient, the dose of calcineurin inhibitors needs to be up-regulated and frequently monitored. In resource-limited (low- and lower-middle-income countries) setting this is not always feasible. Therefore, we evaluated a non-rifampicin-based ATT using levofloxacin in kidney transplant recipients. METHODS: We retrospectively studied the medical records of renal transplant recipients diagnosed with tuberculosis in our institute between 2014 and 2017. After a brief discussion with patients regarding the nature and course of ATT, those who opted for a non-rifampicin based therapy due to financial constraints were included in the study and followed for a minimum of 6 months period after the completion of ATT. RESULTS: Out of the 550 renal transplant recipients, 67 (12.2%) developed tuberculosis after a median period of 24 (1-228) months following transplantation, of them, 64 patients opted for non-rifampicin-based ATT. The mean age was 37.6 years. Only 25% were given anti-thymocyte globulin based induction, while the majority (56; 87.5%) of them were on tacrolimus-based triple-drug maintenance therapy. Extrapulmonary tuberculosis was noted in 33% of cases, while 12 (18.7%) had disseminated disease. The median duration of treatment was 12 months and the cure rate of 93.7% (n = 60) was achieved at the end of therapy. CONCLUSION: Levofloxacin based ATT appears to be a safe and effective alternative of rifampicin in kidney transplant recipients who cannot afford heightened tacrolimus dosage.

Addressing Antiretroviral Therapy-Associated Drug-Drug Interactions in Patients Requiring Treatment for Opportunistic Infections in Low-Income and Resource-Limited Settings.

An increasing number of human immunodeficiency virus (HIV)-infected patients are achieving virologic suppression on antiretroviral therapy (ART) limiting the use of primary and secondary antimicrobial prophylaxis. However, in low-income and resource-limited settings, half of those infected with HIV are unaware of their diagnosis, and fewer than 50% of patients on ART achieve virologic suppression. Management of comorbidities and opportunistic infections among patients on ART may lead to inevitable drug-drug interactions (DDIs) and even toxicities. Elderly patients, individuals with multiple comorbidities, those receiving complex ART, and patients living in low-income settings experience higher rates of DDIs. Management of these cytochrome P450-mediated, nonmediated, and drug transport system DDIs is critical in HIV-infected patients, particularly those in resource-limited settings with few options for ART. This article critically analyzes and provides recommendations to manage significant DDIs and drug toxicities in HIV-infected patients receiving ART.

Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia.

BACKGROUND: Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. METHODS: We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. RESULTS: Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. CONCLUSIONS: Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.

Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.

BACKGROUND: The declining efficacy of existing antibiotics potentially jeopardises outcomes in patients undergoing medical procedures. We investigated the potential consequences of increases in antibiotic resistance on the ten most common surgical procedures and immunosuppressing cancer chemotherapies that rely on antibiotic prophylaxis in the USA. METHODS: We searched the published scientific literature and identified meta-analyses and reviews of randomised controlled trials or quasi-randomised controlled trials (allocation done on the basis of a pseudo-random sequence-eg, odd/even hospital number or date of birth, alternation) to estimate the efficacy of antibiotic prophylaxis in preventing infections and infection-related deaths after surgical procedures and immunosuppressing cancer chemotherapy. We varied the identified effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions) and estimated the additional number of infections and infection-related deaths per year in the USA for each scenario. We estimated the percentage of pathogens causing infections after these procedures that are resistant to standard prophylactic antibiotics in the USA. FINDINGS: We estimate that between 38·7% and 50·9% of pathogens causing surgical site infections and 26·8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA. A 30% reduction in the efficacy of antibiotic prophylaxis for these procedures would result in 120,000 additional surgical site infections and infections after chemotherapy per year in the USA (ranging from 40,000 for a 10% reduction in efficacy to 280,000 for a 70% reduction in efficacy), and 6300 infection-related deaths (range: 2100 for a 10% reduction in efficacy, to 15,000 for a 70% reduction). We estimated that every year, 13,120 infections (42%) after prostate biopsy are attributable to resistance to fluoroquinolones in the USA. INTERPRETATION: Increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. More data are needed to establish how antibiotic prophylaxis recommendations should be modified in the context of increasing rates of resistance. FUNDING: DRIVE-AB Consortium.

Resource Utilization and Safety of Outpatient Management Following Intensive Induction or Salvage Chemotherapy for Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Nonrandomized Clinical Comparative Analysis.

IMPORTANCE: Adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) typically remain hospitalized after induction or salvage chemotherapy until blood cell count recovery, with resulting prolonged inpatient stays being a primary driver of health care costs. Pilot studies suggest that outpatient management following chemotherapy might be safe and could reduce costs for these patients. OBJECTIVE: To compare safety, resource utilization, infections, and costs between adults discharged early following AML or MDS induction or salvage chemotherapy and inpatient controls. DESIGN: Nonrandomized, phase 2, single-center study conducted at the University of Washington Medical Center. Over a 43-month period (January 1, 2011, through July 31, 2014), 178 adults receiving intensive AML or MDS chemotherapy were enrolled. After completion of chemotherapy, 107 patients met predesignated medical and logistical criteria for early discharge, while 29 met medical criteria only and served as inpatient controls. INTERVENTIONS: Early-discharge patients were released from the hospital at the completion of chemotherapy, and supportive care was provided in the outpatient setting until blood cell count recovery (median, 21 days; range, 2-45 days). Controls received inpatient supportive care (median, 16 days; range, 3-42 days). MAIN OUTCOMES AND MEASURES: We analyzed differences in early mortality, resource utilization including intensive care unit (ICU) days, transfusions per study day, and use of intravenous (IV) antibiotics per study day), numbers of infections, and total and inpatient charges per study day among early-discharge patients vs controls. RESULTS: Four of the 107 early-discharge patients and none of the 29 control patients died within 30 days of enrollment (P=.58). Nine early-discharge patients (8%) but no controls required ICU-level care (P=.20). No differences were noted in the median daily number of transfused red blood cell units (0.27 vs 0.29; P=.55) or number of transfused platelet units (0.26 vs 0.29; P=.31). Early-discharge patients had more positive blood cultures (37 [35%] vs 4 [14%]; P=.04) but required fewer IV antibiotic days per study day (0.48 vs 0.71; P=.01). Overall, daily charges among early-discharge patients were significantly lower than for inpatients (median, $3840 vs $5852; P<.001) despite increased charges per inpatient day when readmitted (median, $7405 vs $5852; P<.001). CONCLUSIONS AND RELEVANCE: Early discharge following intensive AML or MDS chemotherapy can reduce costs and use of IV antibiotics, but attention should be paid to complications that may occur in the outpatient setting.

Yarrowia lipolytica: safety assessment of an oleaginous yeast with a great industrial potential.

Yarrowia lipolytica has been developed as a production host for a large variety of biotechnological applications. Efficacy and safety studies have demonstrated the safe use of Yarrowia-derived products containing significant proportions of Yarrowia biomass (as for DuPont's eicosapentaenoic acid-rich oil) or with the yeast itself as the final product (as for British Petroleum's single-cell protein product). The natural occurrence of the species in food, particularly cheese, other dairy products and meat, is a further argument supporting its safety. The species causes rare opportunistic infections in severely immunocompromised or otherwise seriously ill people with other underlying diseases or conditions. The infections can be treated effectively by the use of regular antifungal drugs, and in some cases even disappeared spontaneously. Based on our assessment, we conclude that Y. lipolytica is a "safe-to-use" organism.

[Economical evaluation of the treatment of invasive aspergillosis in pediatric oncology patients. Santiago. Chile]. / Estudio de costo del tratamiento de la aspergilosis invasora en pacientes oncológicos pediátricos. Santiago. Chile.

INTRODUCTION: Invasive aspergillosis (IA) is a serious opportunistic infection in immunocompromised patients. Transplant recipients and patients with cancer represent the highest risk group. The antifungal treatment involves prolonged hospitalization and high economic resources. OBJECTIVE: to estimate costs represented by IA as an intercurrent complication of oncologic treatment. PATIENTS AND METHOD: Retrospective case-control study. Estimation of the cost of treatment in pediatric oncologic patients with IA in the Hospital Luis Calvo Mackenna during the years 2007-2008 was done. A control for each case of IA paired by sex, age, number of diagnosis and clinical department was selected. RESULTS: There were 13 patients during the observation period. The attributable cost of treatment of aspergillosis was US $23,600 and the cost for each indicator was: hospital days US $16,500; antifungal therapy US $7,000; and serum galactomannan US $100. DISCUSSION: In this study, the cost of treating IA is mainly due to hospitalization and antifungal medications. Three patients acquired IA in spite of staying in a protected environment.

Estudio de costo del tratamiento de la aspergilosis invasora en pacientes oncológicos pediátricos: Santiago. Chile / Economical evaluation of the treatment of invasive aspergillosis in pediatric oncology patients: Santiago. Chile

Introducción: La aspergilosis invasora (AI) es una infección oportunista grave en pacientes inmunocompro- metidos. Pacientes receptores de transplantes y oncológicos representan el grupo de mayor riesgo. El tratamiento antifúngico involucra hospitalización prolongada y altos recursos económicos. Objetivo: Estimar los costos involucrados en el tratamiento de la AI como complicación intercurrente en pacientes con cáncer. Pacientes y Método: Estudio caso-control, retrospectivo. Estima el costo del tratamiento de AI en pacientes pediátricos oncológicos del Hospital Luis Calvo Mackenna durante los años 2007 y 2008. Resultados: Se incluyeron 13 pacientes con AI y sus respectivos 13 controles. El costo atribuible de la hospitalización en aquellos pacientes que cursaron con AI fue de US $23.600. El costo atribuible para cada indicador fue: US $16.500 para días de hospitalización; US $7.000 para medicamentos antifúngicos y US $100 para galactomanano sérico. Discusión: En este estudio, el costo del tratamiento de AI se debe principalmente a la estadía hospitalaria y fármacos antifúngicos. Encontramos tres pacientes que desarrollaron AI estando en ambiente protegido.

Introduction: Invasive aspergillosis (IA) is a serious opportunistic infection in immunocompromised patients. Transplant recipients and patients with cancer represent the highest risk group. The antifungal treatment involves prolonged hospitalization and high economic resources. Objective: to estimate costs represented by IA as an intercurrent complication of oncologic treatment. Patients and Method: Retrospective case-control study. Estimation of the cost of treatment in pediatric oncologic patients with IA in the Hospital Luis Calvo Mackenna during the years 2007-2008 was done. A control for each case of IA paired by sex, age, number of diagnosis and clinical department was selected. Results: There were 13 patients during the observation period. The attributable cost of treatment of aspergillosis was US $ 23,600 and the cost for each indicator was: hospital days US $ 16,500; antifungal therapy US $ 7,000; and serum galactomannan US $ 100. Discussion: In this study, the cost of treating IA is mainly due to hospitalization and antifungal medications. Three patients acquired IA in spite of staying in a protected environment.

Activities of antifungal agents against yeasts and filamentous fungi: assessment according to the methodology of the European Committee on Antimicrobial Susceptibility Testing.

We compared the activities of antifungal agents against a wide range of yeasts and filamentous fungi. The methodology of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for yeasts and spore-forming molds was applied; and a total of 349 clinical isolates of Candida spp., other yeast species, Aspergillus spp., and nondermatophyte non-Aspergillus spp. were investigated. The average geometric mean (GM) of the MICs of the various drugs for Candida spp. were as follows: amphotericin B (AMB), 0.55 microg/ml; liposomal amphotericin B (l-AMB); 0.35 microg/ml; itraconazole (ITC), 0.56 microg/ml; voriconazole (VRC), 0.45 microg/ml; posaconazole (POS), 0.44 microg/ml; and caspofungin (CPF), 0.45 microg/ml. The data indicated that the majority of Candida spp. were susceptible to the traditional and new antifungal drugs. For Aspergillus spp., the average GM MICs of AMB, l-AMB, ITC, VRC, POS, and CPF were 1.49 microg/ml, 1.44 microg/ml, 0.65 microg/ml, 0.34 microg/ml, 0.25 microg/ml, and 0.32 microg/ml, respectively. For the various zygomycetes, the average GM MICs of AMB, l-AMB, ITC, and POS were 1.36 microg/ml, 1.42 microg/ml, 4.37 microg/ml, and 1.65 microg/ml, respectively. Other yeastlike fungi and molds displayed various patterns of susceptibility. In general, the minimal fungicidal concentrations were 1 to 3 dilutions higher than the corresponding MICs. POS, AMB, and l-AMB showed activities against a broader range of fungi than ITC, VRC, and CPF did. Emerging pathogens such as Saccharomyces cerevisiae and Fusarium solani were not killed by any drug. In summary, the EUCAST data showed that the in vitro susceptibilities of yeasts and filamentous fungi are variable, that susceptibility occurs among and within various genera and species, and that susceptibility depends on the antifungal drug tested. AMB, l-AMB, and POS were active against the majority of pathogens, including species that cause rare and difficult-to-treat infections.

Cost-effectiveness analysis of antifungal treatment for patients on chemotherapy.

Invasive fungal infections are fatal complications for patients on chemotherapy, and antifungal prophylactic treatment has been commonly recommended. Because its clinical and economic impact is not well known, we evaluated cost-effectiveness of anti-fungal treatment for patients who were neutropoenic as a result of chemotherapy. We constructed a hypothetical cohort of 40-year-old patients with acute myelogenic leukemia to evaluate years of life survived (YLS), costs (US$), and incremental cost-effectiveness ratio (US$/YLS). The following treatment strategies for fungal infections were compared: (1) prophylactic fluconazole strategy: oral fluconazole administration concurrently with chemotherapy; (2) empirical amphotericin B strategy: empirical intravenous amphotericin B administration at the point where fever is detected; and (3) no prophylaxis strategy: intravenous micafangin administration at the point where fungal infections is diagnosed. Baseline analyses showed that prophylactic fluconazole strategy involved higher costs but also longer YLSs (25,900 US$ and 24.08 YLS). The incremental cost-effectiveness ratio of prophylactic fluconazole strategy was 625 US$/YLS compared to no prophylaxis strategy, and 652 US$/YLS compared to empirical amphotericin B strategy. Baseline result was found to be robust through sensitivity analyses. Our study showed that concurrent administration of oral fluconazole during induction chemotherapy appears to ensure clinical benefits together with acceptable cost-effectiveness.

Brief communication: economic comparison of opportunistic infection management with antiretroviral treatment in people living with HIV/AIDS presenting at an NGO clinic in Bangalore, India.

CONTEXT: Highly active antiretroviral treatment (HAART) usage in India is escalating. With the government of India launching the free HAART rollout as part of the "3 by 5" initiative, many people living with HIV/AIDS (PLHA) have been able to gain access to HAART medications. Currently, the national HAART centers are located in a few district hospitals (in the high- and medium-prevalence states) and have very stringent criteria for enrolling PLHA. Patients who do not fit these criteria or patients who are too ill to undergo the prolonged wait at the government hospitals avail themselves of nongovernment organization (NGO) services in order to take HAART medications. In addition, the government program has not yet started providing second-line HAART (protease inhibitors). Hence, even with the free HAART rollout, NGOs with the expertise to provide HAART continue to look for funding opportunities and other innovative ways of making HAART available to PLHA. Currently, no study from Indian NGOs has compared the direct and indirect costs of solely managing opportunistic infections (OIs) vs HAART. OBJECTIVE: Compare direct medical costs (DMC) and nonmedical costs (NMC) with 2005 values accrued by the NGO and PLHA, respectively, for either HAART or exclusive OI management. STUDY DESIGN: Retrospective case study comparison. SETTING: Low-cost community care and support center--Freedom Foundation (NGO, Bangalore, south India). PATIENTS: Retrospective analysis data on PLHA accessing treatment at Freedom Foundation between January 1, 2003 and January 1, 2005. The HAART arm included case records of PLHA who initiated HAART at the center, had frequent follow-up, and were between 18 and 55 years of age. The OI arm included records of PLHA who were also frequently followed up, who were in the same age range, who had CD4+ cell counts < 200/microliter (mcL) or an AIDS-defining illness, and who were not on HAART (solely for socioeconomic reasons). A total of 50 records were analyzed. Expenditures on medication, hospitalization, diagnostics, and NMC (such as food and travel for a caregiver) were calculated for each group. RESULTS: At 2005 costs, the median DMC plus NMC in the OI group was 21,335 Indian rupees (Rs) (mean Rs 24,277/-) per patient per year (pppy) (US $474). In the HAART group, the median DMC plus NMC was Rs 18,976/- (mean Rs 21,416/-) pppy (US $421). Median DMC plus NMC pppy in the OI arm was Rs 13623.7/- paid by NGO and Rs 1155/- paid by PLHA. Median DMC and NMC pppy in the HAART arm were Rs 1425/- paid by NGO and Rs 17,606/- paid by PLHA. CONCLUSIONS: Good health at no increased expenditure justifies providing PLHA with HAART even in NGO settings.

[Economic evaluation of the treatment of systemic fungal infections in immunocompromised patients: the role of itraconazole]. / Aspetti farmacoeconomici del trattamento delle micosi sistemiche profonde in pazienti immunocompromessi: il ruolo di itraconazolo.

In recent years, the incidence of HIV infection, the intensity of chemotherapy regimens for cancer and the use of bone marrow transplantation have all increased. This results in an increase in the incidence of systemic fungal infections, which are associated high rates of morbidity and mortality in this immunosuppressed population; the incidence is growing: 50% for neutropenic/transplant bone marrow patients and 5-20% for organ transplant. Fluconazole, itraconazole, amphotericin-B and, in the recent years, caspofungin and voriconazole are the most frequently used antifungal agents. However, the newly developed formulations of itraconazole and lipid-associated formulations of amphotericin-B have provide new treatment options for systemic fungal infection and have prompted a number of comparisons of the treatment costs of empirical therapy. The i.v. formulation of itraconazole may be more cost effective than either conventional or liposomial formulations of amphotericin-B when used as empirical therapy for neutropenic patients with persistent fever despite broad spectrum antibiotic therapy, but further studies are required. The lack of studies, national and international, and the small amount of available data on the cost of systemic fungal infections mean that the costs saving from prophylactic and empirical use of antifungals are difficult to estimate.

Economic issues: toward a cost-effective approach to the management of febrile neutropenia in Japan.

The cost of treating neutropenic patients unexplained fever is of significant concern in Japan because of the depressed economy and the aging population. Development of a standardized treatment methodology specifically tailored to the situation in Japan will make the treatment more efficient for health care institutions, will allow for improved monitoring of practices and costs, and will result in better patient care. It is essential, however, that the welfare of the patients be the utmost priority--cost savings is not sufficient in the absence of a significant impact on morbidity and mortality.

Fever and neutropenia in cancer patients: the diagnostic role of cytokines in risk assessment strategies.

Cancer patients treated with chemotherapy are susceptible to bacterial infections. Therefore, all neutropenic cancer patients with fever receive standard therapy consisting of broad-spectrum antibiotics and hospitalization. However, febrile neutropenia in cancer patients is often due to other causes than bacterial infections. Therefore, standard therapy should be re-evaluated and new treatment strategies for patients with variable risk for bacterial infection should be considered. This paper reviews the changing spectrum of microorganisms and resistance of microorganisms to antibiotics in infection during neutropenia and discusses new strategies for the selection of patients with low-risk for bacterial infection using clinical and biochemical parameters such as acute phase proteins and cytokines. These low-risk patients may be treated with alternative therapies such as oral antibiotics, early discharge from the hospital or outpatient treatment.