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.

The Rise of Non-Tuberculosis Mycobacterial Lung Disease.

The incidence and number of deaths from non-tuberculous mycobacterial (NTM) disease have been steadily increasing globally. These lesser known "cousins" of Mycobacterium tuberculosis (TB) were once thought to be harmless environmental saprophytics and only dangerous to individuals with defective lung structure or the immunosuppressed. However, NTM are now commonly infecting seemingly immune competent children and adults at increasing rates through pulmonary infection. This is of concern as the pathology of NTM is difficult to treat. Indeed, NTM have become extremely antibiotic resistant, and now have been found to be internationally dispersed through person-to-person contact. The reasons behind this NTM increase are only beginning to be elucidated. Solutions to the problem are needed given NTM disease is more common in the tropics. Importantly, 40% of the world's population live in the tropics and due to climate change, the Tropics are expanding which will increase NTM infection regions. This review catalogs the global and economic disease burden, at risk populations, treatment options, host-bacterial interaction, immune dynamics, recent developments and research priorities for NTM disease.

Economic and epidemiological impact of different intervention strategies for subclinical and clinical mastitis.

The objective of this study was to evaluate and compare different combinations of intervention strategies for contagious or opportunistic subclinical and clinical intramammary infections (IMI). We simulated two different Danish dairy cattle herds with ten different intervention strategies focusing on cow-specific treatment or culling, including three baseline strategies without subclinical interventions. In one herd, the main causative pathogen of IMI was Staphylococcus (S.) aureus. In the other herd, Streptococcus (St.) agalactiae was the main causative agent. For both herds, we investigated costs and effectiveness of all ten intervention strategies. Intervention strategies consisted of measures against clinical and subclinical IMI, with baselines given by purely clinical intervention strategies. Our results showed that strategies including subclinical interventions were more cost-effective than the respective baseline strategies. Increase in income and reduction of IMI cases came at the cost of increased antibiotic usage and an increased culling rate in relation to IMI. However, there were differences between the herds. In the St. agalactiae herd, the clinical intervention strategy did not seem to have a big impact on income and number of cases. However, intervention strategies which included cow-specific clinical interventions led to a higher income and lower number of cases in the S. aureus herd. The results show that intervention strategies including interventions against contagious or opportunistic clinical and subclinical IMI can be highly cost-effective, but should be herd-specific.

A Markov Analysis of Screening for Late-Onset Cytomegalovirus Disease in Cytomegalovirus High-Risk Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Management strategies are unclear for late-onset cytomegalovirus infection occurring beyond 6 months of antiviral prophylaxis in cytomegalovirus high-risk (cytomegalovirus IgG positive to cytomegalovirus IgG negative) kidney transplant recipients. Hybrid strategies (prophylaxis followed by screening) have been investigated but with inconclusive results. There are clinical and potential cost benefits of preventing cytomegalovirus-related hospitalizations and associated increased risks of patient and graft failure. We used decision analysis to evaluate the utility of postprophylaxis screening for late-onset cytomegalovirus infection. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used the Markov decision analysis model incorporating costs and utilities for various cytomegalovirus clinical states (asymptomatic cytomegalovirus, mild cytomegalovirus infection, and cytomegalovirus infection necessitating hospitalization) to estimate cost-effectiveness of postprophylaxis cytomegalovirus screening strategies. Five strategies were compared: no screening and screening at 1-, 2-, 3-, or 4-week intervals. Progression to severe cytomegalovirus infection was modeled on cytomegalovirus replication kinetics. Incremental cost-effectiveness ratios were calculated as a ratio of cost difference between two strategies to difference in quality-adjusted life-years starting with the low-cost strategy. One-way and probabilistic sensitivity analyses were performed to test model's robustness. RESULTS: There was an incremental gain in quality-adjusted life-years with increasing screening frequency. Incremental cost-effectiveness ratios were $783 per quality-adjusted life-year (every 4 weeks over no screening), $1861 per quality-adjusted life-year (every 3 weeks over every 4 weeks), $10,947 per quality-adjusted life-year (every 2 weeks over every 3 weeks), and $197,086 per quality-adjusted life-year (weekly over every 2 weeks). Findings were sensitive to screening cost, cost of hospitalization, postprophylaxis cytomegalovirus incidence, and graft loss after cytomegalovirus infection. No screening was favored when willingness to pay threshold was <$14,000 per quality-adjusted life-year, whereas screening weekly was favored when willingness to pay threshold was >$185,000 per quality-adjusted life-year. Screening every 2 weeks was the dominant strategy between willingness to pay range of $14,000-$185,000 per quality-adjusted life-year. CONCLUSIONS: In cytomegalovirus high-risk kidney transplant recipients, compared with no screening, screening for postprophylactic cytomegalovirus viremia is associated with gains in quality-adjusted life-years and seems to be cost effective. A strategy of screening every 2 weeks was the most cost-effective strategy across a wide range of willingness to pay thresholds.

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.

[Epidemiology of chronic rhinosinusitis, selected risk factors, comorbidities and economic burden]. / Epidemiologie der chronischen Rhinosinusitis, ausgewählter Risikofaktoren und Komorbiditäten, und ihre ökonomischen Folgen.

Chronic rhinosinusitis (CRS) is a relevant and prevalent medical condition in Germany, Europe and the world. If analysed in detail, the prevalence of CRS shows regional and temporary variety. In this review, currently available data regarding the prevalence of CRS is therefore sorted by country and/or region, time point of data collection and the CRS-definition employed. Risk factors like smoking and gastro-oesophageal reflux are discussed regarding their influence on CRS prevalence. Moreover, co-morbidities of CRS, like asthma, conditions of the cardiovascular system and depression are listed and their influence on CRS is discussed. Furthermore, data on CRS prevalence in special cohorts, like immunocompromised patients, are presented. To estimate the economic burden of CRS, current data e.g. from Germany and the USA are included in this review.

Cost-effectiveness of the introduction of specialized oral care with laser therapy in hematopoietic stem cell transplantation.

Oral mucositis (OM) is one of the side effects of hematopoietic stem cell transplantation (HSCT), resulting in major morbidity. The aim of this study was to determine the cost-effectiveness of the introduction of a specialized oral care program including laser therapy in the care of patients receiving HSCT with regard to morbidity associated with OM. Clinical information was gathered on 167 patients undergoing HSCT and divided according to the presence (n = 91) or absence (n = 76) of laser therapy and oral care. Cost analysis included daily hospital fees, parenteral nutrition (PN) and prescription of opioids. It was observed that the group without laser therapy (group II) showed a higher frequency of severe degrees of OM (relative risk = 16.8, 95% confidence interval -5.8 to 48.9, p < 0.001), with a significant association between this severity and the use of PN (p = 0.001), prescription of opioids (p < 0.001), pain in the oral cavity (p = 0.003) and fever > 37.8°C (p = 0.005). Hospitalization costs in this group were up to 30% higher. The introduction of oral care by a multidisciplinary staff including laser therapy helps reduce morbidity resulting from OM and, consequently, helps minimize hospitalization costs associated with HSCT, even considering therapy costs.

[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.

Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the United States, 2000.

OBJECTIVE: Invasive aspergillosis (IA) is the most common filamentous fungal infection observed in immunocompromised patients. The incidence of invasive aspergillosis has increased significantly in recent decades in parallel with the increasing number and improved survival of immunocompromised patients. IA in adults has been well characterized; however, only a few small studies of IA in children have been reported. Therefore, the objective of this study was to describe the incidence and outcomes of children with IA. METHODS: We performed a retrospective cohort study using the 2000 Kids Inpatient Database, a national database of hospital inpatient stays during 2000. IA was defined as aspergillosis that occurred in a child with malignancy (solid tumor, leukemia, or lymphoma), hematologic/immunologic deficiency, or transplant (bone marrow or solid organ). Discharge weighting was applied to the data to obtain nationally representative estimates of disease. RESULTS: During 2000, there were an estimated 666 pediatric cases of IA among 152,231 immunocompromised children, yielding an annual incidence of 437/100,000 (0.4%) among hospitalized immunocompromised children. Children with malignancy accounted for the majority (74%) of cases of IA. The highest incidence of IA was seen in children who had undergone allogeneic bone marrow transplantation (4.5%) and those with acute myelogenous leukemia (4%). The overall in-hospital mortality of immunocompromised children with IA was 18%. Children with malignancy and IA were at higher risk for death than children with malignancy and without IA. Pediatric patients with IA had a significantly longer median length of hospital stay (16 days) than immunocompromised children without IA (3 days). The median total hospital charges for patients with IA were $49309 compared with immunocompromised children without IA ($9035). CONCLUSIONS: The impact of IA on increases in mortality, length of hospital stay, and the burden of cost in the hospital setting underscores the need for improved means of diagnosis, prevention, and treatment of IA in immunocompromised children.

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.

Costs and consequences of cytomegalovirus disease.

The impact of prophylactic oral ganciclovir therapy on the incidence of cytomegalovirus (CMV) disease, patient and graft survival, and costs in patients receiving kidney and liver transplants is described. CMV disease is a common cause of morbidity and mortality in solid organ transplant recipients unless prophylactic drug therapy is used. Prophylactic oral ganciclovir therapy reduces the incidence of CMV disease in kidney and liver transplant recipients. It is more effective for recipients who are seronegative before the transplant and receive organs from seronegative (D-/R-) donors than in seronegative recipients of organs from seropositive (D+/R-) donors. CMV disease remains a problem in the latter. CMV disease increases the risk of graft failure, which decreases the likelihood of patient survival. The extent of matching of the DR subregion of the human leukocyte antigen complex in the donor and recipient may affect graft survival in patients with CMV disease. Graft failure is costly and should be considered in economic analyses of CMV prophylaxis regimens because of the potential impact of prophylaxis on CMV disease. The use of oral ganciclovir for CMV prophylaxis has reduced the incidence of CMV disease in kidney and liver transplant recipients.

Cytomegalovirus immune globulin after liver transplantation: a cost-effectiveness analysis.

OBJECTIVE: Cytomegalovirus (CMV) immune globulin (CMVIG) has been shown to significantly reduce severe CMV-associated disease complicating orthotopic liver transplant (OLT). We evaluated the economic impact of severe CMV-associated disease and calculated the marginal cost-effectiveness (C/E) of routine prophylaxis with CMVIG after OLT. DESIGN: C/E analysis. SETTING: Four teaching hospitals in Boston. PATIENTS: Patients who underwent OLT from January 1988 through June 1990. MEASUREMENTS: We gathered actual cost data of hospital care for patients enrolled in a clinical trial of CMVIG prophylaxis in OLT. We calculated average outpatient expenses from a separate group of patients undergoing OLT and developed a regression model to estimate costs during the first year post-transplant (R2 = 0.77). Based on this model, we calculated variable costs (in 1999 US dollars) for all patients in the randomized trial. From the published literature we obtained the probability of CMV outcomes and of long-term survival after OLT. We then developed a decision analytical model to determine an incremental C/E ratio, using a Markov simulation to estimate long-term survival and long-term costs. We discounted costs and life-years at 3% and 5% per yr. RESULTS: Based on the efficacy rate of 54% in the controlled trial, we estimate that CMVIG will increase life expectancy by 0.65 discounted years at an additional cost of $11,600, providing a marginal C/E ratio of $17,900/yr life saved. Examining the confidence limits of efficacy, we estimate that CMVIG will have a marginal C/E ratio of $66,200 gained/yr at an efficacy of 11% and $14,000 gained/yr at an efficacy of 83%. CONCLUSION: After OLT, prophylactic CMVIG has an incremental C/E ratio comparable to that of other well-accepted medical therapies and should be used routinely in these patients.

[Varicella vaccine]. / Vaccin de la varicelle.

Varicella vaccine has been extensively studied in Japan, the United States and Canada since 1974. Its efficacy in healthy children is good, on the order of 94%. It also has a good efficacy in immunocompromised children, such as children treated for acute leukemia or malignant tumors. However, the vaccine has to be administrated during a 2-3 week transient suppression of chemotherapy. In the USA, varicella vaccination is recommended for receptive adults who are particularly exposed to varicella, such as health professionals working with immunocompromised patients. Benefits and cost analysis of a generalized varicella vaccination in children has shown that it would be beneficial due to the cost of parents' work leave during the children's illness.