Paediatric bacterial meningitis in the USA: outcomes and healthcare resource utilization of nosocomial versus community-acquired infection.

Introduction. Paediatric bacterial meningitis remains a costly disease, both financially and clinically.Hypothesis/Gap Statement. Previous epidemiological and cost studies of bacterial meningitis (BM) have largely focused on adult populations or single pathogens. There have been few recent, large-scale studies of pediatric BM in the USA.Aim. We examined healthcare resource utilization (HCRU) and associated morbidity and mortality of community-acquired versus nosocomial bacterial infections in children across the USA.Methodology. The IBM MarketScan Research databases were used to identify patients <18 years old admitted to USA hospitals from 2008 to 2015 with a primary diagnosis of BM. Cases were categorized as either community-acquired or nosocomial. HCRU, post-diagnosis neurosurgical procedures, 30-day in-hospital mortality, and complications were compared between groups. Multivariable regression adjusted for sex, age and Gram staining was used to compare costs of nosocomial versus community-acquired infections over time.Results. We identified 1928 cases of paediatric BM without prior head trauma or neurological/systemic complications. Of these, 15.4 % were nosocomial and 84.6 % were community-acquired infections. After diagnostic lumbar puncture (37.1 %), the most common neurosurgical procedure was placement of ventricular catheter (12.6 %). The 30-day complication rates for nosocomial and community-acquired infections were 40.5 and 45.9 %, respectively. The most common complications were hydrocephalus (20.8 %), intracranial abscess (8.8 %) and cerebral oedema (8.1 %). The 30-day in-hospital mortality rates for nosocomial and community-acquired infections were 2.7 and 2.8 %, respectively.Median length of admission was 14.0 days (Q1: 7 days, Q3: 26 days). Median 90-day cost was $40 861 (Q1: $11 988, Q3: $114,499) for the nosocomial group and $56 569 (Q1: $26 127, Q3: $142 780) for the community-acquired group. In multivariable regression, the 90-day post-diagnosis total costs were comparable between groups (cost ratio: 0.89; 95 % CI: 0.70 to 1.13), but at 2 years post-diagnosis, the nosocomial group was associated with 137 % higher costs (CR: 2.37, 95 % CI: 1.51 to 3.70).Conclusion. In multivariable analysis, nosocomial infections were associated with significantly higher long-term costs up to 2 years post-infection. Hydrocephalus, intracranial epidural abscess and cerebral oedema were the most common complications, and lumbar punctures and ventricular catheter placement were the most common neurosurgical procedures. This study represents the first nation-wide, longitudinal comparison of the outcomes and considerable HCRU of nosocomial versus community-acquired paediatric BM, including characterization of complications and procedures contributing to the high costs of these infections.

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

The longitudinal health economic impact of viral encephalitis in the United States.

Introduction. Previous studies of viral encephalitis have focused on acute costs, estimating incidence at 7.3 per 100 000 and total US annual charges at $2 billion in 2010.Aim. We aim to quantify the most updated longitudinal health economic impact of viral encephalitis in the USA from 2008 to 2015.Methodology. Data on patients diagnosed with viral encephalitis were obtained from the Truven Health Analytics MarketScan database. Patients with a primary diagnosis of viral encephalitis, from herpetic viruses and other viral aetiologies (e.g. West Nile fever) were included in the analysis. Data concerning healthcare resource utilization, inpatient mortality, length of stay and accrued healthcare costs were collected for up to 5 years.Results. Among 3985 patients with continuous enrolment for 13 months prior to the encephalitis diagnosis, more non-herpes simplex encephalitis (61.7 %) than herpes simplex encephalitis (HSE; 38.3 %) cases were recorded, with the majority concentrated in the southern USA (29.2 %). One-year inpatient mortality was 6.2 %, which over a 5-year period rose to 8.9 % for HSE and 5.8 % for all other viral encephalitides. HSE resulted in longer cumulative stays in the hospital (11 days vs. 4 days; P=0.0025), and accrued 37 % higher first-year costs, after adjusting for known confounders [P<0.001, cost ratio=1.37, 95 % confidence interval (1.20, 1.57)]. Additionally, HSE was associated with greater 5-year cumulative median charges ($125 338 vs. $82 317, P=0.0015).Conclusion. The health economic impact and long-term morbidity of viral encephalitis in the USA are substantial.

Prevalence, healthcare resource utilization and overall burden of fungal meningitis in the United States.

PURPOSE: Previous epidemiological and cost studies of fungal meningitis have largely focused on single pathogens, leading to a poor understanding of the disease in general. We studied the largest and most diverse group of fungal meningitis patients to date, over the longest follow-up period, to examine the broad impact on resource utilization within the United States. METHODOLOGY: The Truven Health Analytics MarketScan database was used to identify patients with a fungal meningitis diagnosis in the United States between 2000 and 2012. Patients with a primary diagnosis of cryptococcal, Coccidioides, Histoplasma, or Candida meningitis were included in the analysis. Data concerning healthcare resource utilization, prevalence and length of stay were collected for up to 5 years following the original diagnosis. RESULTS: Cryptococcal meningitis was the most prevalent type of fungal meningitis (70.1 % of cases over the duration of the study), followed by coccidioidomycosis (16.4 %), histoplasmosis (6.0 %) and candidiasis (7.6 %). Cryptococcal meningitis and candidiasis patients accrued the largest average charges ($103 236 and $103 803, respectively) and spent the most time in the hospital on average (70.6 and 79 days). Coccidioidomycosis and histoplasmosis patients also accrued substantial charges and time in the hospital ($82 439, 48.1 days; $78 609, 49.8 days, respectively). CONCLUSION: Our study characterizes the largest longitudinal cohort of fungal meningitis in the United States. Importantly, the health economic impact and long-term morbidity from these infections are quantified and reviewed. The healthcare resource utilization of fungal meningitis patients in the United States is substantial.

Efficient, Cost-Effective, High-Throughput, Multilocus Sequencing Typing (MLST) Method, NGMLST, and the Analytical Software Program MLSTEZ.

Multilocus sequence typing (MLST) has become the preferred method for genotyping many biological species. It can be used to identify major phylogenetic clades, molecular groups, or subpopulations of a species, as well as individual strains or clones. However, conventional MLST is costly and time consuming, which limits its power for genotyping large numbers of samples. Here, we describe a new MLST method that uses next-generation sequencing, a multiplexing protocol, and appropriate analytical software to provide accurate, rapid, and economical MLST genotyping of 96 or more isolates in a single assay.

Comparing outcomes of early, late, and non-surgical management of intraspinal abscess.

Intraspinal abscesses (ISAs) are rare lesions that are often neurologically devastating. Current treatment paradigms vary widely including early surgical decompression, drainage, and systemic antibiotics, delayed surgery, and sole medical management. The National Inpatient Sample (NIS) database was queried for cases of ISA from 2003 to 2012. Early and late surgery were defined as occurring before or after 48h of admission. Outcome measures included mortality, incidence of major complications, length of stay (LOS), and inpatient costs. A total of 10,150 patients were included (6281 early surgery, 3167 delayed surgery, 702 medical management). Paralysis, the main comorbidity, was most associated with early surgery (p<0.0001). In multivariate analysis, the rates of postoperative infection and paraplegia were highest with early surgery (p<0.0001), but the incidence of sepsis was higher with delayed surgery (p<0.0001). Early surgery was least associated with in-hospital mortality (p=0.0212), sepsis (p<0.001), and had the shortest LOS (p<0.001). Charges were highest with delayed surgery, and least with medical management (p<0.001). Medical management was associated with lower rates of complications (p<0.001). This is the largest study of patients with ISAs ever performed. Our results suggest that patients with ISAs undergoing surgical management have better outcomes and lower costs when operated on within 48h of admission, emphasizing the importance of accurate and early diagnosis of ISA.

Next generation multilocus sequence typing (NGMLST) and the analytical software program MLSTEZ enable efficient, cost-effective, high-throughput, multilocus sequencing typing.

Multilocus sequence typing (MLST) has become the preferred method for genotyping many biological species, and it is especially useful for analyzing haploid eukaryotes. MLST is rigorous, reproducible, and informative, and MLST genotyping has been shown to identify major phylogenetic clades, molecular groups, or subpopulations of a species, as well as individual strains or clones. MLST molecular types often correlate with important phenotypes. Conventional MLST involves the extraction of genomic DNA and the amplification by PCR of several conserved, unlinked gene sequences from a sample of isolates of the taxon under investigation. In some cases, as few as three loci are sufficient to yield definitive results. The amplicons are sequenced, aligned, and compared by phylogenetic methods to distinguish statistically significant differences among individuals and clades. Although MLST is simpler, faster, and less expensive than whole genome sequencing, it is more costly and time-consuming than less reliable genotyping methods (e.g. amplified fragment length polymorphisms). Here, we describe a new MLST method that uses next-generation sequencing, a multiplexing protocol, and appropriate analytical software to provide accurate, rapid, and economical MLST genotyping of 96 or more isolates in single assay. We demonstrate this methodology by genotyping isolates of the well-characterized, human pathogenic yeast Cryptococcus neoformans.

Mucormycosis Rhinosinusitis at Diagnosis of Acute Lymphoblastic Leukemia: Diagnostics and Management Challenges in a Low-Middle-income Country.

We present the case of an adolescent with mucor rhinosinusitis diagnosed concomitantly with acute lymphoblastic leukemia at a hospital in Tegucigalpa, Honduras. We also discuss the challenges faced in the dual management of hematologic malignancies and invasive fungal disease in a low-middle-income country, such as access to diagnostics, immunosuppressants, imaging, and antifungals. Despite these shortcomings, the patient was successfully treated for both the diseases. Low-middle-income country hospitals can effectively treat invasive fungal diseases by providing adequate diagnostic and support services, which can improve the outcomes of pediatric cancer patients.

Cost of invasive fungal infections in the era of new diagnostics and expanded treatment options.

STUDY OBJECTIVE: To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections. DESIGN: Economic analysis. SETTING: Academic medical center. PATIENTS: A total of 200 patients discharged from the hospital during 2004-2005 with a diagnosis of proven, probable, or possible aspergillosis, cryptococcosis, invasive candidiasis, or zygomycosis (cases). Patients were matched in a 1:1 fashion with patients having similar underlying disease states but no invasive fungal infections (controls). MEASUREMENTS AND MAIN RESULTS: Data on demographic and clinical characteristics were collected from patients' medical records. In addition, information concerning each patient's hospitalization was recorded. Resource utilization data for a patient's entire hospitalization were collected from the hospital's charge databases and converted to costs. These data were compared between the cases and the controls. After adjusting for race-ethnicity, sex, age, and comorbid illnesses, mean total hospital cost for cases was $32,196 more than for controls (p<0.0001). Nonpharmacy costs accounted for the majority (63%) of this difference, and an additional $3996 was attributed to systemic antifungal drugs. The mean length of hospital stay was longer for cases than controls (25.8 vs 18.4 days). CONCLUSION: Treatment of patients with invasive fungal infections was associated with a significantly higher inpatient hospital cost compared with controls. However, due to new diagnostic techniques and effective antifungal therapy, the relative cost of these infections appears to be at least stable compared with the previous decade. These findings can help assess the utility of cost-avoidance strategies such as antifungal prophylaxis and application of appropriate treatment.

Cost-effectiveness of posaconazole versus fluconazole for prevention of invasive fungal infections in U.S. patients with graft-versus-host disease.

PURPOSE: The results of a pharmacoeconomic study of the cost-effectiveness of posaconazole versus fluconazole in preventing invasive fungal infections (IFIs) in patients with graft-versus-host disease (GVHD) are reported. METHODS: The results of a randomized clinical trial suggested that posaconazole may be as effective as fluconazole for the prevention of IFIs in recipients of allogeneic cell transplants who develop severe GVHD and that posaconazole may be superior to fluconazole in reducing IFI-related deaths. Using published data from that trial and data from secondary sources, an economic model was developed to estimate the costs, IFIs avoided, and life-years saved with posaconazole versus fluconazole therapy. The results of the modeled 112-day treatment simulation were extrapolated to a lifetime horizon. RESULTS: In the modeled simulation, posaconazole therapy was associated with a lower probability of IFI development (0.05 versus 0.09), increased discounted life-years (7.87 life-years versus 7.66 life-years), and higher discounted costs per patient ($8,860 versus $5,710 in 2006 U.S. dollars) relative to fluconazole therapy. The estimated incremental cost-effectiveness of posaconazole versus fluconazole for IFI prophylaxis was $85,300 per IFI avoided and $15,300 per life-year saved. A sensitivity analysis indicated a 90% probability that the use of posaconazole for this purpose would be cost-effective at a threshold of $50,000 per life-year saved. CONCLUSION: Posaconazole is in the range of currently accepted criteria for cost- effectiveness relative to fluconazole for the prevention of IFIs among patients with GVHD.

The economic costs to United States hospitals of invasive fungal infections in transplant patients.

BACKGROUND: Patients with a solid organ transplant (SOTs) and hematopoietic stem cell or bone marrow transplants (HSC/BMTs) are at risk of contracting invasive fungal infections (IFIs). Data on the economic burden of IFIs in the United States are sparse. METHODS: We conducted a retrospective matched cohort study using the 2004-2005 Healthcare Cost and Utilization Project Nationwide Inpatient Sample. The IFI cohort included patients with ICD-9-CM codes indicating a transplant procedure and an IFI. Matched controls (transplant recipients without an IFI) were chosen based on age (10 year categories), sex, region, hospital type, year, and transplant type. Mortality, length of stay, and costs were reported overall, by transplant type, and by type of mycosis. RESULTS: Nine thousand eight hundred ninety-six patients underwent SOT, and 4661 underwent HSC/BMT. Of these, 80 (0.8%) SOT and 111 (2.4%) HSC/BMT patients had an IFI. Mean age was 41.8 years (SOT) and 37.8 years (HSC/BMT). Aspergillosis was the most common infection. Patients with an IFI had a 5-fold increase in mortality, an additional 19.2 hospital days, and $55,400 in excess costs compared with patients without an IFI. Excess mortality, length of stay, and costs varied by type of transplant and mycosis. CONCLUSION: The clinical and economic burden of IFIs in transplant recipients may be high.

Mortality, length of hospitalization, and costs associated with invasive fungal infections in high-risk patients.

PURPOSE: The mortality, length of hospitalization, and costs associated with invasive fungal infections (IFIs) in hospitalized patients were studied. METHODS: This retrospective database study used data from the 2004 Healthcare Cost and Utilization Project Nationwide In-patient Sample. Patients were selected for inclusion based on diagnostic codes corresponding to an IFI. A control group was matched to the IFI group based on high-risk conditions (i.e., cancer, infection with human immunodeficiency virus, chronic obstructive pulmonary disease, diabetes mellitus, and solid-organ, hematopoietic stem cell, or bone marrow transplant), age, sex, and hospital region and teaching status. Excess mortality, length of hospital stay, and costs were estimated as the differences between the IFI and control groups. RESULTS: A total of 11,881 patients were identified with a discharge diagnosis of an IFI who could be matched to a control. Frequent infections included candidiasis (40.2%), other mycoses (36.3%), and aspergillosis (16.4%). Patients with IFIs had a significantly higher mortality rate (15% versus 5%), mean +/- S.E. length of stay (18.7 +/- 0.4 days versus 7.3 +/- 0.1 days), and mean +/- S.E. costs ($44,726 +/- $1,255 versus $15,445 +/- $404) (p < 0.001 for all comparisons) than did patients without IFIs. The burden of IFIs varied by high-risk condition (highest for transplant recipients and patients with cancer) and type of infection (highest for candidiasis, zygomycosis, and aspergillosis). CONCLUSION: Examination of a large database showed that, compared with high-risk patients without IFIs, those with IFIs had higher mortality, a longer hospital stay, and higher costs associated with their hospitalization.

Cost-effectiveness of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infections among neutropenic patients in the United States.

OBJECTIVES: Clinical trial data indicate that posaconazole is superior to fluconazole (FLU) or itraconazole (ITRA) in preventing invasive fungal infections (IFIs) among neutropenic patients. Our objective was to assess the cost-effectiveness of posaconazole versus FLU or ITRA for prevention of IFIs among neutropenic patients. METHODS: We used modeling techniques to assess the cost-effectiveness of posaconazole versus FLU or ITRA in the prevention of IFIs among patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) and chemotherapy-induced neutropenia. The probabilities of experiencing an IFI, IFI-related death, and death from other causes over 100 days of follow-up were estimated from clinical trial data. Long-term mortality, drug costs, and IFI treatment costs were obtained from secondary sources. RESULTS: Posaconazole is associated with fewer IFIs per patient (0.05 vs. 0.11) relative to FLU or ITRA over 100 days of follow-up, and lower discounted costs ($3900 vs. $4500) and increased life-years (2.50 vs. 2.43 discounted) over a lifetime horizon. Results from a probabilistic sensitivity analysis indicate that there is a 73% probability that posaconazole is cost saving versus FLU or ITRA and a 96% probability that the incremental cost-effectiveness ratio for posaconazole is at or below $50,000 per life-year saved. CONCLUSIONS: We conclude that posaconazole is very likely to be a cost-effective alternative to FLU or ITRA in the prevention of IFIs among neutropenic patients with AML and MDS, and may result in cost savings.

Antifungal pharmacotherapy for invasive mould infections.

The incidence of invasive mould infections is increasing and is associated with significant morbidity and mortality. Among the most prevalent of these infections are those caused by Aspergillus and Fusarium species. Invasive disease caused by moulds frequently presents as a pulmonary infection, but haematogenous infection can occur. Some moulds cause cutaneous disease through either direct inoculation of the skin or secondary spread to the skin after dissemination from another body site. Early diagnosis can often be difficult and, unfortunately, diagnosis occurs late in the course of illness in many cases. Treatment options have historically been limited by the need for intravenous administration (amphotericin B), significant toxicities (amphotericin B), lack of reliable in vitro activity (e.g., amphotericin B in Fusarium and Scedosporium apiospermum infections) and relative lack of clinical experience with newer agents. The recent approval of voriconazole (Vfend, Pfizer) introduces a treatment option that demonstrates both in vitro and in vivo activity against a variety of moulds. With the recent development of the new echinocandin class of antifungal agents and newer broad-spectrum azole antifungal agents with in vitro mould activity, there is a renewed emphasis on fungal treatment strategies. Antimould therapy presents challenges in adverse effect avoidance and management, drug interactions and pharmacoeconomic considerations. Furthermore, combination therapy is being explored with these various new antifungal agents. The administration of an optimal fungicidal therapy early in the course of the illness and control of the underlying disease are vital to prevent complications and mortality from these tenacious mycoses.