Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring?

We describe caspofungin pharmacokinetics (PK) after the first and fourth doses in 20 critically ill septic patients. Monte Carlo simulation was used to analyze the probability of target attainment (PTA) (AUC/MIC > 865) for Candida spp. Caspofungin concentrations were analyzed by HPLC in plasma and urine. A great variability in PK parameters was observed after both doses. Patients were divided in two groups according to their AUC values (AUC ≤ 75 mg h/L cut-off). In the low-AUC group Cmax, Cmin and AUC were lower, while Vd and Cl were higher than in the high-AUC group (p < 0.05, both at day 1 and 4). The mean 24-h urinary recovery of the drug was 8 ± 6.3% (day1) and 9.8 ± 6.3 (day4). Monte Carlo simulation analysis (0.03-1 mg/L MIC-range) showed that PTA was guaranteed only for MICs ≤ 0.03 mg/L in the low-AUC group, and for MICs ≤ 0.06 mg/L in the high-AUC group. No group had a PTA ≥ 90% for 0.125 mg/L MIC (the epidemiological cut-off). Mortality was higher in low-AUC group (p < 0.01). In our 'real-world' population, no clinical data can predict which patient will have lower, suboptimal caspofungin exposure, therefore we suggest TDM to optimize caspofungin therapy and reduce the risk of selecting resistances (CEAVC, 32366/2015; OSS.15.114, NCT03798600).

Candida auris outbreak: Mortality, interventions and cost of sustaining control.

OBJECTIVE: Candida auris has recently emerged as a global cause of multidrug resistant fungal outbreaks. An outbreak occurred at a tertiary care center in London in 2016. Transmission characteristics, interventions, patient outcomes and cost of resources are described. METHODS: Outbreak interventions included patient isolation, contact screening, single-use equipment, environmental screening and decontamination, staff education, and enhanced surveillance. Risk factors for infection were recorded. Survival probabilities of patients with C. auris and other Candida bloodstream infections (BSI) were calculated. Antifungal susceptibility and epidemiological typing were performed. Actual and opportunity costs of interventions were determined. RESULTS: 34 patients acquired the organism including 8 with BSI. Clinical infection was significantly associated with prolonged hospital stay, haemodialysis and antifungal therapy. Variable susceptibility to amphotericin and the triazoles was seen and isolates clustered with the South Asian strains. No significant difference was detected in the survival probabilities of C. auris BSI compared to other candidemias. Outbreak control cost in excess of £1 million and £58,000/month during the subsequent year. CONCLUSION: C. auris outbreaks can be controlled by a concerted infection control strategy but can be expensive. Transmission maybe prolonged due to patient movements and unidentified transmission mechanisms.

De-escalation from micafungin is a cost-effective alternative to traditional escalation from fluconazole in the treatment of patients with systemic Candida infections.

BACKGROUND: Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified. METHODS: The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article. RESULTS: In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY. CONCLUSIONS: De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.

Morbidity and mortality of bloodstream infections in patients with severe burn injury.

BACKGROUND: Bloodstream infections are common in burn patients. OBJECTIVE: To evaluate the effects of bloodstream infections in patients with severe burn injuries. METHODS: A retrospective, pairwise-matched, risk-adjusted cohort study in a 6-bed burn unit was done. "Exposed" patients with microbiological evidence of bloodstream infections (n = 76) were compared with nonexposed patients (n = 103) matched for burn severity (identical Belgian Outcome in Burn Injury score) and length of hospitalization (≥time-to-event in exposed patients). Main outcome measures were length of hospitalization and mortality. RESULTS: Predominant pathogens were Staphylococcus aureus, enterococci, Pseudomonas aeruginosa, Escherichia coli, coagulase-negative staphylococci, and Candida species. Median patient age was 42 years (interquartile range [IQR], 31-52). Median total burned surface area was 40% (IQR, 25%-50%). Inhalation injury occurred in 54%. Median burn injury score was 4 (IQR, 2-5). Median length of stay before onset of bacteremia was 11 days (IQR, 5.3-19.8). Appropriate antimicrobial therapy was initiated within the first 48 hours in 76%. The exposed group had a higher need for vasopressive/inotropic support (P = .02); need for ventilatory assistance and renal replacement therapy did not differ significantly between groups. Hospital mortality did not differ (P = .30). However, bloodstream infection was associated with longer durations of hospitalization (P < .001) and mechanical ventilation (P < .001). CONCLUSIONS: In this cohort of burn patients, bloodstream infections did not adversely affect survival, but greater durations of ventilator dependency and hospital stay increased costs of care.

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.

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).

Outcomes attributable to neonatal candidiasis.

BACKGROUND: The incidence of candidiasis has increased in neonatal intensive care units, and invasive candidiasis is associated with significant morbidity and mortality. However, few data exist on outcomes directly attributable to neonatal candidiasis. METHODS: We estimated the incidence of systemic candidiasis in hospitalized neonates within the United States and determined the attributable mortality, length of hospital stay, and associated costs. We used the 2003 Kid's Inpatient Database from the Healthcare Cost and Utilization Project. Systemic candidiasis and comorbidities were defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Neonates with uncomplicated births and neonates who died within the first 3 days of life were excluded. We used propensity score methods to balance covariates between the neonates with and neonates without candidiasis. Attributable outcomes were calculated between propensity score-matched neonates with and neonates without candidiasis. Because of the known confounding effect of birth weight, we performed separate propensity score analyses for extremely low birth weight (ELBW) neonates (i.e., neonates weighing < 1000 g). RESULTS: The overall incidence of invasive candidiasis in neonates is 15 cases per 10,000 neonatal admissions (95% confidence interval [CI], 13-16 cases per 10,000 neonatal admissions). ELBW neonates with invasive candidiasis were 2 times more likely to die (odds ratio, 2.2; 95% CI, 1.4-3.5) than propensity-matched ELBW neonates without candidiasis. The propensity score-adjusted mortality rate attributable to candidiasis among ELBW neonates was 11.9%. Candidiasis in ELBW infants was not associated with an increase in length of hospital stay but was associated with a mean increase in total charges of $39,045 (95% CI, $1374-$76,715). Among infants with a birth weight > or = 1000 g, those who had candidiasis did not experience a significant increase in mortality, compared with infants without candidiasis. However, the propensity score-adjusted length of stay and charges attributable to candidiasis among neonates with a birth weight > or = 1000 g were 16 days (95% CI, 8-24 days) and $122,302 (95% CI, $80,457-$164,148), respectively. CONCLUSIONS: Invasive candidiasis is associated with a significantly increased risk of death and excess hospital charges in ELBW neonates and with excess hospital stay and excess hospital charges in neonates with a birth weight > or = 1000 g.

Peptide nucleic acid fluorescence in situ hybridization-based identification of Candida albicans and its impact on mortality and antifungal therapy costs.

The impact of rapid identification of Candida albicans blood isolates by peptide nucleic acid fluorescence in situ hybridization (PNA FISH) on the selection and expenditure of antifungal therapy was evaluated. PNA FISH was 100% sensitive and specific in the rapid identification of 31 out of 72 candidemias as C. albicans and resulted in a significant reduction of caspofungin usage, with an overall cost savings of 1,729 US dollars per patient.

Attributable mortality of candidemia: a systematic review of matched cohort and case-control studies.

A systematic review of matched cohort and case-control studies was performed to examine the mortality attributable to candidemia. The review included studies that compared mortality of patients with candidemia (cases) to that of matched patients without candidemia (controls). Secondary variables examined were the length and cost of hospital stay. Relevant studies were identified using the PubMed database and by examining the references of the initially selected studies. Two independent reviewers performed the literature search, study selection and data extraction from the identified studies. A total of seven studies were included in the review. The patients included those hospitalized in intensive care units (ICU) and hospital wards and those undergoing transplantation. The mortality attributed to candidemia in the reviewed studies ranged from 5 to 71%. For six of the reviewed studies the difference in mortality between cases and controls was statistically significant. Among those who survived, the length of stay and the cost of hospitalization of patients with candidemia were significantly higher than those of controls. Despite the methodological heterogeneity of the reviewed studies, the data from the available matched cohort and case-control studies suggest that candidemia is associated with considerable mortality that is attributed, at least to some degree, to the infection itself and not only to the presence of another comorbidity.

Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants.

OBJECTIVES: To assess whether targeted short-term fluconazole prophylaxis reduces late-onset (>3 days of age) invasive fungal infection (IFI) among very low birth weight infants and extremely low birth weight (ELBW) infants and to assess mortality rates, toxicity, and costs associated with this intervention. METHODS: An observational study of 2 subsequent epochs of inborn infants with birth weight of <1500 g or gestational age of <32 weeks, 1 before (control) and 1 after (fluconazole) initiation of routine targeted fluconazole prophylaxis in March 2003, was performed. Targeted fluconazole (3 mg/kg) prophylaxis was administered to infants for whom a decision was made to administer broad-spectrum antibiotics for >3 days. RESULTS: IFI was observed for 13 (6.3%) of 206 infants in the control epoch and 2 (1.1%) of 178 in the fluconazole epoch, with a common odds ratio of 0.166. Logistic regression analysis taking into account all published factors (except for fungal colonization) showed that the fluconazole epoch was associated significantly with lower IFI rates. We observed no change in late (>3 days) mortality rates (11 of 206 infants in the control epoch vs 8 of 178 infants in the prophylaxis epoch). The mortality rate for ELBW infants with IFI was low (15%) in our study. Fluconazole was administered to 81% of ELBW infants, who received a median of 8 doses, and 41% of larger infants, who received a median of 5 doses. The intervention was cost-effective, and the effective number needed to treat to prevent 1 IFI was 10. CONCLUSIONS: This study suggests that targeted short-course fluconazole prophylaxis in very low birth weight and ELBW infants may be efficacious and cost effective.

Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance.

OBJECTIVE: To determine the mortality, hospital stay, and total hospital charges and cost of hospitalization attributable to candidemia by comparing patients with candidemia with control-patients who have otherwise similar illnesses. Prior studies lack broad patient and hospital representation or cost-related information that accurately reflects current medical practices. DESIGN: Our case-control study included case-patients with candidemia and their cost-related data, ascertained from laboratory-based candidemia surveillance conducted among all residents of Connecticut and Baltimore and Baltimore County, Maryland, during 1998 to 2000. Control-patients were matched on age, hospital type, admission year, discharge diagnoses, and duration of hospitalization prior to candidemia onset. RESULTS: We identified 214 and 529 sets of matched case-patients and control-patients from the two locations, respectively. Mortality attributable to candidemia ranged between 19% and 24%. On multivariable analysis, candidemia was associated with mortality (OR, 5.3 for Connecticut and 8.5 for Baltimore and Baltimore County; P < .05), whereas receiving adequate treatment was protective (OR, 0.5 and 0.4 for the two locations, respectively; P < .05). Candidemia itself did not increase the total hospital charges and cost of hospitalization; when treatment status was accounted for, having received adequate treatment for candidemia significantly increased the total hospital charges and cost of hospitalization ($6,000 to $29,000 and $3,000 to $22,000, respectively) and the length of stay (3 to 13 days). CONCLUSION: Our findings underscore the burden of candidemia, particularly regarding the risk of death, length of hospitalization, and cost associated with treatment.

Burden of hospitalization of patients with Candida and Aspergillus infections in Australia.

OBJECTIVES: This study examined the burden of hospitalization of patients with Aspergillus and Candida infections in Australia from 1995 to 1999. METHODS: Data were extracted from the National Hospital Morbidity Database. A hospitalization with an aspergillosis diagnosis was defined as any discharge with a diagnosis of aspergillosis. A hospitalization with a candidiasis diagnosis was defined as any discharge with a diagnosis of disseminated, invasive, or non-invasive candidiasis. Outcome measures included number of hospitalizations, length of stay (LOS), cost (AUS$), and mortality. RESULTS: 4583 hospitalizations with an aspergillosis diagnosis and 57,758 hospitalizations with a candidiasis diagnosis were identified. These hospitalizations were associated with a total of 813,398 hospital days, AUS$563 million in cost, and 4967 in-hospital deaths during the study period. The mean LOS for a hospitalization with an aspergillosis diagnosis was 12 days, cost AUS$9,334, and was associated with 8% mortality. For disseminated, invasive, and non-invasive candidiasis, the respective mean LOS were 31, 17, and 12 days; costs were AUS$33,274, AUS$12,954, and AUS$7,694; and mortality was 26%, 9%, and 8%. CONCLUSIONS: Hospitalizations with diagnoses for fungal infections were associated with lengthy hospital stays, high costs, and high mortality.

Epidemiology, presentation, management and outcome of candidemia in a tertiary care teaching hospital in the United Arab Emirates, 1995-2001.

Sixty episodes of candidemia among hospitalized patients in the United Arab Emirates (0.77/1000 discharges) in 1995-2001 were identified through case retrieval. All patients had malignancy (65%) or serious non-malignant disease (35%). Candida albicans accounted for 45% of isolates. Non-C. albicans Candida species occurred more frequently than C. albicans in adults (67%), hematologic-malignancy patients (58%), and cases of breakthrough candidemia (83%) and were prevalent overall in 2000-2001 (67-73%). C. tropicalis was identified in 15% of cases, C. glabrata in 5%, C. parapsilosis in 5%, C. inconspicua in 2%, C. famata in 2% and C. lusitaniae in 1%. Delayed diagnosis or treatment was common, as was Karnofsky scale < or = 40%, septic shock, and inadequate dosage or duration of antifungal drug therapy. Crude mortality was 50%, and mortality attributable to candidemia was 30%. Univariate analysis indicated patients were more likely to die (odds ratio for death [95% CI]) if they had been stationed in the intensive care unit (ICU) (4.76 [1.31-17.2]), had a Karnofsky scale < or = 40% (38.76 [4.66-322.47]), or suffered septic shock (9.88 [2.9-33.65]). They were more likely to survive in cases with concomitant bacteremia (0.25 [0.07-0.91]), adequate antifungal dose (0.28 [0.08-0.94]), and removal of central lines (0.26 [0.07-0.95]). The high association of bacteremia with candidemia (70% of cases) is unusual. The apparent survival benefit experienced by patients who had bacteremia (odds ratio for survival on multivariate analysis = 2.40 [0.28-20.17], P < 0.03) is novel.