Advances in Rapid Molecular Blood Culture Diagnostics: Healthcare Impact, Laboratory Implications, and Multiplex Technologies.

BACKGROUND: For far too long, the diagnosis of bloodstream infections has relied on time-consuming blood cultures coupled with traditional organism identification and susceptibility testing. Technologies to define the culprit in bloodstream infections have gained sophistication in recent years, notably by application of molecular methods. CONTENT: In this review, we summarize the tests available to clinical laboratories for molecular rapid identification and resistance marker detection in blood culture bottles that have flagged positive. We explore the cost-benefit ratio of such assays, covering aspects that include performance characteristics, effect on patient care, and relevance to antibiotic stewardship initiatives. SUMMARY: Rapid blood culture diagnostics represent an advance in the care of patients with bloodstream infections, particularly those infected with resistant organisms. These diagnostics are relatively easy to implement and appear to have a positive cost-benefit balance, particularly when fully incorporated into a hospital's antimicrobial stewardship program.

Cost-effectiveness analysis of chlorhexidine-alcohol versus povidone iodine-alcohol solution in the prevention of intravascular-catheter-related bloodstream infections in France.

OBJECTIVE: To perform a cost-effectiveness analysis of skin antiseptic solutions (chlorhexidine-alcohol (CHG) versus povidone iodine-alcohol solution (PVI)) for the prevention of intravascular-catheter-related bloodstream infections (CRBSI) in intensive care unit (ICU) in France based on an open-label, multicentre, randomised, controlled trial (CLEAN). DESIGN: A 100-day time semi-markovian model was performed to be fitted to longitudinal individual patient data from CLEAN database. This model includes eight health states and probabilistic sensitivity analyses on cost and effectiveness were performed. Costs of intensive care unit stay are based on a French multicentre study and the cost-effectiveness criterion is the cost per patient with catheter-related bloodstream infection avoided. PATIENTS: 2,349 patients (age≥18 years) were analyzed to compare the 1-time CHG group (CHG-T1, 588 patients), the 4-time CHG group (CHG-T4, 580 patients), the 1-time PVI group (PVI-T1, 587 patients), and the 4-time PVI group (PVI-T4, 594 patients). INTERVENTION: 2% chlorhexidine-70% isopropyl alcohol (chlorhexidine-alcohol) compared to 5% povidone iodine-69% ethanol (povidone iodine-alcohol). RESULTS: The mean cost per alive, discharged or dead patient was of €23,798 (95% confidence interval: €20,584; €34,331), €21,822 (€18,635; €29,701), €24,874 (€21,011; €31,678), and €24,201 (€20,507; €29,136) for CHG-T1, CHG-T4, PVI-T1, and PVI-T4, respectively. The mean number of patients with CRBSI per 1000 patients was of 3.49 (0.42; 12.57), 6.82 (1.86; 17.38), 26.04 (14.64; 42.58), and 23.05 (12.32; 39.09) for CHG-T1, CHG-T4, PVI-T1, and PVI-T4, respectively. In comparison to the 1-time PVI solution, the 1-time CHG solution avoids 22.55 CRBSI /1,000 patients, and saves €1,076 per patient. This saving is not statistically significant at a 0.05 level because of the overlap of 95% confidence intervals for mean costs per patient in each group. Conversely, the difference in effectiveness between the CHG-T1 solution and the PVI-T1 solution is statistically significant. CONCLUSIONS: The CHG-T1 solution is more effective at the same cost than the PVI-T1 solution. CHG-T1, CHG-T4 and PVI-T4 solutions are statistically comparable for cost and effectiveness. This study is based on the data from the RCT from 11 French intensive care units registered with www.clinicaltrials.gov (NCT01629550).

[Clinical features and hospital costs of neonatal sepsis caused by bacteria and fungi: a comparative analysis].

OBJECTIVE: To study the clinical features and hospital costs of neonatal sepsis caused by Gram-positive (G(+)) bacteria, Gram-negative (G(-)) bacteria, and fungi. METHODS: The clinical data of 236 neonates with sepsis were analyzed retrospectively. Among these neonates, 110 had sepsis caused by G(+) bacteria, 68 had sepsis caused by G(-) bacteria, and 58 had sepsis caused by fungi. RESULTS: Full-term infants accounted for 62% and 38%, respectively, in the G(+) bacteria and G(-) bacteria groups, and preterm infants accounted for 86% in the fungi group. The neonates in the fungi group had significantly lower gestational ages and birth weights than those in the G(+) and G(-) bacteria groups (P<0.05). Compared with the G(+) bacteria group, the G(-) bacteria and fungi groups had significantly higher rates of multiple births (P<0.0125). Compared with the G(+) bacteria and fungi groups, the rates of premature rupture of membranes >18 hours, grade III amniotic fluid contamination, and early-onset sepsis in the G(-) bacteria group were significantly higher (P<0.0125). Compared with the G(-) bacteria and fungi groups, the G(+) bacteria group showed significantly higher rates of abnormal body temperature, omphalitis or herpes as the symptom suggesting the onset of such disease (P<0.0125). The fungi group had significantly higher incidence rates of apnea and low platelet count than the G(+) and G(-) bacteria groups (P<0.0125). The comparison of length of hospital stay and total hospital costs between any two groups showed that the fungi group had a significantly longer hospital stay and significantly higher total hospital costs than the G(+) and G(-) bacteria groups (P<0.05). CONCLUSIONS: Sepsis caused by G(+) bacteria mainly occurs in full-term infants, and most cases of sepsis caused by G(-) bacteria belong to the early-onset type. Sepsis caused by fungi is more common in preterm infants and low birth weight infants, and has high incidence rates of apnea and low platelet count, as well as a longer hospital stay and higher hospital costs than sepsis caused by bacteria.

Inpatient costs, mortality and 30-day re-admission in patients with central-line-associated bloodstream infections.

Previous work has suggested that central-line-associated bloodstream infection (CLABSI) is associated with increased costs and risk of mortality; however, no studies have looked at both total and variable costs, and information on outcomes outside of the intensive-care unit (ICU) is sparse. The aim of this study was to determine the excess in-hospital mortality and costs attributable to CLABSI in ICU and non-ICU patients. We conducted a retrospective cohort and cost-of-illness study from the hospital perspective of 398 patients at a tertiary-care academic medical centre from 1 January 2008 to 31 December 2010. All CLABSI patients and a simple random sample drawn from a list of all central lines inserted during the study period were included. Generalized linear models with log link and gamma distribution were used to model costs as a function of CLABSI and important covariates. Costs were adjusted to 2010 US dollars by use of the personal consumption expenditures for medical care index. We used multivariable logistic regression to identify independent predictors of in-hospital mortality. Among both ICU and non-ICU patients, adjusted variable costs for patients with CLABSI were c. $32 000 (2010 US dollars) higher on average than for patients without CLABSI. After we controlled for severity of illness and other healthcare-associated infections, CLABSI was associated with a 2.27-fold (95% CI 1.15-4.46) increased risk of mortality. Other healthcare-associated infections were also significantly associated with greater costs and mortality. Overall, CLABSI was associated with significantly higher adjusted in-hospital mortality and total and variable costs than those for patients without CLABSI.

[Costs associated with nosocomial bacteraemias in a University Hospital]. / Costes asociados a las bacteriemias nosocomiales en un hospital universitario.

OBJECTIVE: To describe the increase in costs due to patients who had any episode of nosocomial bacteraemia (NB) in a University Hospital, compared to the costs of patients with the same illness who did not. METHODS: Descriptive and retrospective study. POPULATION: all hospitalisation episodes between January 2005 and December 2007. We compared the patients who suffered some episode of NB, with the patients who did not. Dependent variable: cost of the hospitalisation episode. Main explanatory variable: presence of nosocomial bacteraemia. A generalized linear model was adjusted, with Gamma distribution and link logarithm function, given the distribution of the costs. RESULTS: There were 640 hospital episodes with NB and 28,459 with no NB. The average incremental cost for the hospitalisations with NB was 14,735.5€, adjusted for the disease. The impact on the costs for the hospital due to patients with NB was 9,430,713€. The most frequent source of infection was the catheter (35.5%), with an average increase in cost of 18,078€. In the multivariable model, the cost of patients with NB and involving a Gram(+) microorganism was 2.1 times more than that of patients without bacteraemia (95% CI; 1.96-2.23), if the microorganism was Gram(-) it was 1.8 times more (95% CI; 1.70-1.93), and for a fungus it was 2.4 time more (95% CI; 1.95-2.89). CONCLUSIONS: This analysis shows the significant impact in the financial costs due to NB, and gives a measure of the cost-benefit of investing in resources to prevent them. Knowing the source cause of the bacteraemia allows priority to be given to these areas and to promote the necessary actions designed to prevent them.

Clinical and economic outcomes of decreased fluconazole susceptibility in patients with Candida glabrata bloodstream infections.

BACKGROUND: The impact of reduced fluconazole susceptibility on clinical and economic outcomes in patients with Candida glabrata bloodstream infections (BSI) is unknown. METHODS: A retrospective cohort study was conducted to evaluate 30-day inpatient mortality and postculture hospital charges in patients with C glabrata BSI with decreased fluconazole susceptibility (minimum inhibitory concentration [MIC] ≥ 16 µg/mL) versus fluconazole-susceptible C glabrata BSI (MIC ≤ 8 µg/mL). These analyses were adjusted for demographics, comorbidities, and time at risk. Secondary analyses limited the C glabrata group with decreased fluconazole susceptibility to MIC ≥ 64 µg/mL. RESULTS: There were 45 (31%) deaths among 144 enrolled patients: 19 deaths (25%) among 76 patients with C glabrata BSI with decreased fluconazole susceptibility and 26 deaths (38%) among 68 patients with fluconazole-susceptible C glabrata BSI. Decreased fluconazole susceptibility was not independently associated with increased 30-day inpatient mortality (adjusted odds ratio, .60; 95% confidence interval (CI): .26-1.35; P = 0.22) or hospital charges (multiplicative change in hospital charges, .93; 95% CI: .60-1.43; P = 0.73). Older age was associated with increased mortality and increased time at risk was associated with increased hospital charges. CONCLUSION: Crude mortality rates remain high in patients with C glabrata BSI. However, decreased fluconazole susceptibility was not associated with increased mortality or hospital charges.

Comparison of costs, length of stay, and mortality associated with Candida glabrata and Candida albicans bloodstream infections.

We compared costs, length of stay, and mortality between adults with Candida albicans and Candida glabrata bloodstream infections. Early evidence of C glabrata, as defined by a positive culture within 2 days of admission, was associated with higher costs ($56,026 vs $32,810; P = .04) and longer hospital stays (19.7 vs 14.5 days; P = .05) compared with early evidence of C albicans. Mortality was similar between the groups.

Excess mortality, length of stay and cost attributable to candidaemia.

BACKGROUND: There were 1967 reports of Candida species isolated from blood specimens in 2007 in the UK (excluding Scotland). Such infections are particularly common in the intensive care unit (ICU). The impact of candidaemia on mortality, length of stay (LOS) and cost in a UK hospital was examined. METHODS: A retrospective analysis of candidaemia episodes and appropriate matched controls was undertaken based on data from the ICU, high dependency units and hospital wards at Wythenshawe Hospital in Manchester. The study covered the period November 2003-February 2007. RESULTS: In total, 48 case-patients of candidaemia and 81 control-patients were identified. The attributable mortality due to candidaemia varied from 21.5% to 34.7%. Candidaemia patients spend on average 5.6 days more in the ICU than matched patients and generate mean additional costs of at least 8252 UK pounds per patient, 16,595 pounds in adults only. CONCLUSION: Candidaemia remains a severe disease associated with high attributable mortality in the UK. In addition, candidaemia leads to additional ICU length of stay and costs. The implication is an attributable cost of at least 16.2 million UK pounds with 683 deaths attributable to candidaemia per year in the UK.

[Pharmacoeconomics of therapy in invasive candidiasis]. / Farmacoeconomía del tratamiento de las candidiasis invasoras.

BACKGROUND: Invasive candidiasis episodes have increased during last years and they have been related with high rates of crude mortality. Invasive candidiasis-related deaths have not diminished significantly with the introduction of antifungals in the past decade. Finantial managers are worried about extra costs from acquisition of new antifungal agents. AIM: This review includes the main studies age-stratified to assess different variables related to the economic burden of invasive candidiasis. METHODS: Systematic review of biomedic databases including Medline, PubMed and EMBASE. RESULTS: The studies show hospital stay as the main variable related with higher impact in the increase of invasive candidiasis costs. Acquisition costs of antifungals have a very low impact in the invasive candidiasis costs. CONCLUSIONS: Pharmacoeconomics applied in candidiasis invasive therapy must avoid assessing acquisition costs of antifungals exclusively, needing to include both direct and indirect costs associated with this fungal infection. The cost of antifungal acquisition represents a low impact in the overall economic burden of this fungal infection. Further pharmacoeconomics evaluations should be performed including similar definitions to decrease the possible bias in results interpretation.

Candida albicans and non-albicans bloodstream infections in adult and pediatric patients: comparison of mortality and costs.

We compared length of stay, inpatient costs, and mortality associated with Candida albicans and non-albicans bloodstream infections in adults and children. Compared with adults, children with Candida bloodstream infections had longer lengths of stay (36.7 vs. 20.7 days; P < 0.001) and higher inpatient costs ($133,871 vs. $56,725; P < 0.001) but lower mortality (28.3% vs. 43.5%; P < 0.001).

Farmacoeconomía del tratamiento de las candidiasis invasoras / Pharmacoeconomics of therapy in invasive candidiasis

Antecedentes: Con los años, los episodios de candidiasis invasora se han incrementado y se han asociado con ratios elevados de mortalidad bruta. Los antifúngicos introducidos durante la pasada década no han producido una disminución significativa de la mortalidad relacionada con esta enfermedad infecciosa. Los costes de adquisición de los antifúngicos suponen una gran preocupación en la gestión de los costes de farmacia. Objetivos: Desarrollar una revisión de los principales estudios efectuados, estratificados por grupos de edad, para evaluar las distintas variables que afectan a la carga económica, así como los costes ocasionados por la candidiasis invasora. Métodos: Búsqueda sistemática de bases de datos Medline, PubMed y EMBASE. Resultados: Los estudios efectuados en pacientes con candidiasis invasora muestran que la estancia hospitalaria es la variable con más impacto en el incremento de los costes relacionados con esta infección fúngica. El coste de adquisición de los antifúngicos representa un porcentaje muy inferior al de otras variables analizadas. Conclusiones: El análisis farmacoeconómico de la candidiasis invasora requiere la inclusión del estudio de los costes directos e indirectos que lleva asociados, y no tan sólo, el de los costes de adquisición de los antifúngicos. Estos últimos representan una pequeña parte del coste total de esta enfermedad. Es preciso efectuar nuevos análisis farmacoeconómicos que unifiquen las definiciones utilizadas en los estudios con el fin de disminuir su impacto en la interpretación de los resultados (AU)

Background: Invasive candidiasis episodes have increased during last years and they have been related with high rates of crude mortality. Invasive candidiasis-related deaths have not diminished significantly with the introduction of antifungals in the past decade. Finantial managers are worried about extra costs from acquisition of new antifungal agents. Aim: This review includes the main studies agestratified to assess different variables related to the economic burden of invasive candidiasis. Methods: Systematic review of biomedic databases including Medline, PubMed and EMBASE. Results: The studies show hospital stay as the main variable related with higher impact in the increase of invasive candidiasis costs. Acquisition costs of antifungals have a very low impact in the invasive candidiasis costs. Conclusions: Pharmacoeconomics applied in candidiasis invasive therapy must avoid assessing acquisition costs of antifungals exclusively, needing to include both direct and indirect costs associated with this fungal infection. The cost of antifungal acquisition represents a low impact in the overall economic burden of this fungal infection. Further pharmacoeconomics evaluations should be performed including similar definitions to decrease the possible bias in results interpretation (AU)

Risk-based fluconazole prophylaxis of Candida bloodstream infection in a medical intensive care unit.

Candida bloodstream infection (CBSI) accounted for 50% of bloodstream infections in our medical intensive care unit (MICU) in 2004. Our objective was to evaluate a risk-based fluconazole prophylaxis program. CBSI incidence, patient demographics, and unit metrics were retrospectively reviewed for 2004. Starting on January 2005, patients meeting pre-specified criteria were placed on risk-based fluconazole prophylaxis and their outcomes, adverse events, and unit metrics were prospectively collected. The inclusion criteria were based on a clinical prediction rule and included an MICU stay greater than 72 h, broad-spectrum antibiotics, and central venous catheter, along with at least two of the following: mechanical ventilation for at least 48 h, any type of dialysis, parenteral nutrition, pancreatitis, systemic steroids, or other systemic immunosuppressive agents. For 2004, the unit had nine CBSI, corresponding to a rate of 3.4 CBSI/1,000 line-days. Four cases were caused by C. albicans, four by C. glabrata, and one by C. tropicalis. The mean +/- standard deviation (SD) APACHE II score for these patients was 25 +/- 9. In 2005, a total of 36 patients (2.6% of all unit admissions) received prophylaxis and the unit had two CBSI, corresponding to a rate of 0.79 CBSI/1,000 line-days. One patient had C. albicans and the other had C. tropicalis. The mean +/- SD APACHE II score for these patients was 21 +/- 8. The mean +/- SD duration of fluconazole prophylaxis was 8 +/- 6 days. Fluconazole was discontinued in two patients due to non-severe adverse events (acute eosinophilia, elevated transaminases). The attributable cost of CBSI in the unit in 2004 was $63,000 per episode. The total cost for the 36 courses of fluconazole was $6,000. When comparing the 2004 CBSI patients and the 2005 prophylaxis patients, we found similar acuity, demographics, and risk factors, with no differences in MICU or hospital mortality or length of stay. Risk-based fluconazole prophylaxis in an MICU with a high incidence of CBSI was safe and cost-effective when applied to a limited number of patients and produced a significant decrease in the incidence of this disease.

Candidemia in the in-patient setting: treatment options and economics.

Candidemia is the most common nosocomial fungal infection in the US. More than one in four adults who acquire candidemia in the hospital setting die prior to discharge. In addition to high case-fatality rates and other adverse clinical outcomes in survivors, candidemia is associated with a substantial economic burden. High costs associated with complex diagnostics and procedures contribute to this burden, as do new pharmacotherapeutic approaches. Despite the high costs of many antifungal agents recommended for the treatment of candidemia, unambiguous clinical evidence to guide treatment selection does not exist. This article reviews the clinical and economic burdens of candidemia, describes candidemia cost drivers and discusses existing pharmacoeconomic data regarding the cost-effectiveness of candidemia rapid identification and treatment approaches.

Excess costs of hospital care associated with neonatal candidemia.

BACKGROUND: Nosocomial bloodstream infections are associated with increased hospital costs in adult and pediatric patients. Candida is an increasingly important nosocomial pathogen within intensive care nurseries. The purpose of this study was to determine the attributable cost of candidemia in neonates. METHODS: This case-control study included all neonates with candidemia receiving care in hospitals in Connecticut and in Baltimore County and the city of Baltimore, MD. We identified 47 cases and 130 control patients. Multivariable linear regression was used to control for state, birth weight and mortality to determine the effect of candidemia on length of stay, cost per day and total hospital costs. RESULTS: Candidemia was associated with a $28,000 increase in total hospital costs in multivariable analysis. This increase in total cost was the result of both an increase in costs per day and length of hospital stay. Other cost-increasing variables included in the analysis were: state of origin (Connecticut), survival and decreasing birth weight. CONCLUSIONS: This represents the first study of the adjusted costs of candidemia in neonates. In addition to high mortality, candidemia was associated with increased hospital costs. This cost analysis could be helpful in determining the financial benefits of preventing candidemia in high risk neonates.

Candidaemia and antifungal therapy in a French University Hospital: rough trends over a decade and possible links.

BACKGROUND: Evidence for an increased prevalence of candidaemia and for high associated mortality in the 1990s led to a number of different recommendations concerning the management of at risk patients as well as an increase in the availability and prescription of new antifungal agents. The aim of this study was to parallel in our hospital candidemia incidence with the nature of prescribed antifungal drugs between 1993 and 2003. METHODS: During this 10-year period we reviewed all cases of candidemia, and collected all the data about annual consumption of prescribed antifungal drugs. RESULTS: Our centralised clinical mycology laboratory isolates and identifies all yeasts grown from blood cultures obtained from a 3300 bed teaching hospital. Between 1993 and 2003, 430 blood yeast isolates were identified. Examination of the trends in isolation revealed a clear decrease in number of yeast isolates recovered between 1995-2000, whereas the number of positive blood cultures in 2003 rose to 1993 levels. The relative prevalence of Candida albicans and C. glabrata was similar in 1993 and 2003 in contrast to the period 1995-2000 where an increased prevalence of C. glabrata was observed. When these quantitative and qualitative data were compared to the amount and type of antifungal agents prescribed during the same period (annual mean defined daily dose: 2662741; annual mean cost: 615,629 euros) a single correlation was found between the decrease in number of yeast isolates, the increased prevalence of C. glabrata and the high level of prescription of fluconazole at prophylactic doses between 1995-2000. CONCLUSION: Between 1993 and 2000, the number of cases of candidemia halved, with an increase of C. glabrata prevalence. These findings were probably linked to the use of Fluconazole prophylaxis. Although it is not possible to make any recommendations from this data the information is nevertheless interesting and may have considerable implications with the introduction of new antifungal drugs.

Cost savings with implementation of PNA FISH testing for identification of Candida albicans in blood cultures.

Antifungal expenditures are substantial for many hospitals. Using caspofungin for the treatment of candidemia accounts for a sizable proportion of the costs. A cost minimization study that used a decision analytic model was done to compare in-hospital diagnosis and treatment costs using the Candida albicans peptide nucleic acid fluorescence in situ hybridization (PNA FISH) test versus the C. albicans screen test for differentiating C. albicans from non-albicans Candida species bloodstream infections. Assuming physician notification of yeast identity concurrent with blood culture positivity, potential savings resulting from use of the C. albicans PNA FISH test compared with the C. albicans screen test averaged $1837 per patient treated, although laboratory costs for doing the C. albicans PNA FISH test ($82.72) exceeded those for the C. albicans screen test ($2.83). Savings were realized through a decrease in antifungal drug costs, particularly caspofungin. Incorporating the C. albicans PNA FISH test as part of the initial identification algorithm for yeasts recovered from blood can result in substantial savings for hospitals.

The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis.

BACKGROUND: Candida species are the fourth most common cause of bloodstream infection and are the leading cause of invasive fungal infection among hospitalized patients in the United States. However, the frequency and outcomes attributable to the infection are uncertain. This retrospective study set out to estimate the incidence of candidemia in hospitalized adults and children in the United States and to determine attributable mortality, length of hospital stay, and hospital charges related to candidemia. METHODS: We used the Nationwide Inpatient Sample 2000 for adult patients and the Kids' Inpatient Database 2000 for pediatric patients. We matched candidemia-exposed and candidemia-unexposed patients by the propensity scores for the probability of candidemia exposure, which were derived from patient characteristics. Attributable outcomes were calculated as the differences in estimates of outcomes between propensity score-matched patients with and without candidemia. RESULTS: In the United States in 2000, candidemia was diagnosed in an estimated 1118 hospital admissions of pediatric patients and 8949 hospital admissions of adult patients, yielding a frequency of 43 cases per 100,000 pediatric admissions (95% confidence interval [CI], 35-52 cases per 100,000 pediatric admissions) and 30 cases per 100,000 adult admissions (95% CI, 26-34 cases per 100,000 adult admissions). In pediatric patients, candidemia was associated with a 10.0% increase in mortality (95% CI, 6.2%-13.8%), a mean 21.1-day increase in length of stay (95% CI, 14.4-27.8 days), and a mean increase in total per-patient hospital charges of 92,266 dollars (95% CI, 65,058 dollars-119,474 dollars). In adult patients, candidemia was associated with a 14.5% increase in mortality (95% CI, 12.1%-16.9%), a mean 10.1-day increase in length of stay (95% CI, 8.9-11.3 days), and a mean increase in hospital charges of 39,331 dollars (95% CI, 33,604 dollars-45,602 dollars). CONCLUSION: The impact of candidemia on excess mortality, increased length of stay, and the burden of cost of hospitalization underscores the need for improved means of prevention and treatment of candidemia in adults and children.