Use of point-of-care molecular tests reduces hospitalization and oseltamivir administration in children presenting with influenza-like illness.

Influenza is associated with increased morbidity, healthcare costs, hospitalization rates, and mortality in children. Rapid immunochromatography assay (ICA), a test with low sensitivity, is often used as point-of-care (POC) test. Recently, the rapid syndromic molecular test FilmArray has become available. This observational study aims to evaluate whether the use of FilmArray would decrease the use of antivirals and hospitalization rates among children presenting to the emergency room (ER) with influenza-like illness (ILI) symptoms. Nasopharyngeal swabs were prospectively collected from children, aged 0-16 years, presenting with ILI at the ER of a tertiary hospital during the peak endemic period. Patients were allocated to be tested by either FilmArray or ICA. The use of antivirals and hospitalization rates were noted. Logistic regression models were used to investigate the impact of testing methods on decision-making. Overall, 80 children were included (mean age: 5 years). Admissions were more likely to occur if an ICA test was performed (OR, 3.16; 95% CI, 1.01-9.82; p = .046). Oseltamivir administration was more likely among children who had undergone the ICA test (OR, 4.67; 95% CI, 1.06-20.43; p = .041). The implementation of rapid molecular test had no impact on complementary diagnostic testing or antibacterial prescription. The use of FilmArray significantly reduced both hospitalization and oseltamivir administration in children. Further knowledge on the use of POC tests is required to improve current management of children presenting with ILI and decrease associated healthcare costs.

Epidemiological Trends of Fungemia in Greece with a Focus on Candidemia during the Recent Financial Crisis: a 10-Year Survey in a Tertiary Care Academic Hospital and Review of Literature.

Updated information on the epidemiology of candidemia, particularly during severe socioeconomic events, is important for proper management of these infections. A systematic literature review on candidemia in Greece and a retrospective surveillance study were conducted in a tertiary university hospital during the years of the recent financial crisis (2009 to 2018) in order to assess changes in incidence rates, patient characteristics, species distribution, antifungal susceptibilities, and drug consumption. The average annual incidence of 429 candidemic episodes was 2.03/10,000 bed days, with 9.88 in adult intensive care units (ICUs), 1.74 in surgical wards, and 1.81 in internal medicine wards, where a significant increase was observed (1.15, 1.85, and 2.23/10,000 bed days in 2009 to 2011, 2012 to 2014, and 2015 to 2018, respectively; P = 0.004). Candida albicans was the most common species (41%), followed by Candida parapsilosis species complex [SC] (37%), Candida glabrata SC (11%), Candida tropicalis (7%), Candida krusei (1%), and other rare Candida spp. (3%). Mixed infections were found in 20/429 (4.7%) cases, while 33 (7%) cases were due to non-Candida spp. Overall, 44/311 (14%) isolates were resistant/non-wild type (WT) to the nine antifungals tested, with 23/113 (20%) C. parapsilosis SC and 2/34 (6%) C. glabrata SC isolates being resistant to fluconazole (1 panechinocandin and 2 panazole resistant). All isolates were susceptible/WT to amphotericin B and flucytosine. While the overall consumption of antifungals diminished (P = 0.02), with a mean of 17.93 defined daily doses (DDD)/100 bed days, increased micafungin use was correlated with the rise in C. parapsilosis SC (P = 0.04). A significant increase of candidemia in internal medicine wards and of C. parapsilosis SC infections was found during the years of financial crisis. Although resistance rates remain low (<14%), fluconazole-resistant C. parapsilosis SC and multidrug-resistant C. glabrata SC isolates are of major concern.

Exploring colistin pharmacodynamics against Klebsiella pneumoniae: a need to revise current susceptibility breakpoints.

Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens. Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 107 and 104 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill). Results: The fAUC/MIC (R2 = 0.64-0.68) followed by fCmax/MIC (R2 = 0.55-0.63) best described colistin's 24 h log10 cfu/mL reduction for both low and high inocula. Dosing regimens with fCmax/MIC ≥6 were always associated with a bactericidal effect (P = 0.0025). However, at clinically achievable concentrations, usually below fCmax/MIC = 6, an fAUC/MIC ≥25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/day, the PTA for this pharmacodynamic target was 100%, 5%-70% and 0%, for isolates with MICs of ≤0.5, 1 and ≥2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC = 2 mg/L). Conclusions: Characterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended.

Dose optimization of voriconazole/anidulafungin combination against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model and response surface analysis: clinical implications for azole-resistant aspergillosis.

BACKGROUND: Combination therapy of voriconazole with an echinocandin is often employed in order to increase the efficacy of voriconazole monotherapy. METHODS: Four clinical Aspergillus fumigatus isolates with different in vitro susceptibilities to voriconazole (MIC 0.125-2 mg/L) and anidulafungin (MEC 0.008-0.016 mg/L) were tested in an in vitro pharmacokinetic/pharmacodynamic model simulating human serum concentrations of standard dosages of voriconazole and anidulafungin. Fungal growth was assessed using galactomannan production and quantitative PCR. Drug concentrations were determined with bioassays. Pharmacodynamic interactions were assessed using Bliss independence analysis (BI) and Loewe additivity-based canonical mixture response-surface non-linear regression analysis (LA). Probability of target attainment (PTA) was estimated with Monte Carlo analysis for different doses of anidulafungin (25, 50 and 100 mg) and azole resistance rates (5%-25%). RESULTS: Synergy [BI 51% (8%-80%), LA 0.63 (0.38-0.79)] was found at low anidulafungin (fCmax/MEC <10) and voriconazole (fAUC/MIC <10) exposures, whereas antagonism [BI 12% (5%-18%, LA 1.12 (1.04-4.6)] was found at higher drug exposures. The largest increase in PTA was found with 25 mg of anidulafungin and voriconazole MIC distributions with high (>10%) resistance rates. PTAs for isolates with voriconazole MICs of 1, 2 and 4 mg/L was 78%, 12% and 0% with voriconazole monotherapy and 96%-100%, 68%-82% and 9%-20% with combination therapy, respectively. Optimal activity was associated with a voriconazole tCmin/MIC ratio of 1.5 for monotherapy and 0.75 for combination therapy. CONCLUSIONS: The present study indicated that the combination of voriconazole with low-dose anidulafungin may increase the efficacy and reduce the cost and potential toxicity of antifungal therapy, particularly against azole-resistant A. fumigatus isolates and in patients with subtherapeutic serum levels. This hypothesis warrants further in vivo verification.

Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications.

VIM-producing Klebsiella pneumoniae isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The in vitro antibacterial activity of meropenem against one WT and three VIM-producing K. pneumoniae clinical isolates (median MICs 0.031, 8, 16 and 128 mg l- 1) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The in vitro PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The in vitro model was correlated with the in vivo data, with log10CFU/ml reduction of < 1 for the VIM-producing (MIC 16 mg l- 1) and >2 for the WT (MIC 0.031 mg l- 1) isolates, with %f T >MIC 25 and 100%, respectively. The in vitro bactericidal activity for all isolates was associated with 40 % f T>MIC and attained in >90% of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l- 1. For isolates with MICs of 2-8 mg l- 1, prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3-6 g) are required. For isolates with a MIC of 16 mg l- 1 the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing K. pneumoniae isolates.

Optimization of polyene-azole combination therapy against aspergillosis using an in vitro pharmacokinetic-pharmacodynamic model.

Although amphotericin B-azole combination therapy has traditionally been questioned due to potential antagonistic interactions, it is often used successfully to treat refractory invasive aspergillosis. So far, pharmacodynamic (PD) interactions have been assessed with conventional in vitro tests, which do not mimic human serum concentrations and animal models using limited doses. We therefore simulated the human serum concentration profiles of amphotericin B and voriconazole in an in vitro dialysis/diffusion closed pharmacokinetic-pharmacodynamic (PK-PD) model and studied the pharmacodynamic interactions against an azole-resistant and an azole-susceptible Aspergillus fumigatus isolate, using Bliss independence and canonical mixture response surface analyses. Amphotericin B dosing regimens with the drug administered every 24 h (q24h) were combined with voriconazole q12h dosing regimens. In vitro PK-PD combination data were then combined with human PK data by using Monte Carlo analysis. The target attainment rate and the serum concentration/MIC ratio were calculated for isolates with different MICs. Synergy (20 to 31%) was observed at low amphotericin B-high voriconazole exposures, whereas antagonism (-6 to -16%) was found at high amphotericin B-low voriconazole exposures for both isolates. Combination therapy resulted in 17 to 48% higher target attainment rates than those of monotherapy regimens for isolates with voriconazole/amphotericin B MICs of 1 to 4 mg/liter. Optimal activity was found for combination regimens with a 1.1 total minimum concentration of drug in serum (tCmin)/MIC ratio for voriconazole and a 0.5 total maximum concentration of drug in serum (tCmax)/MIC ratio for amphotericin B, whereas the equally effective monotherapy regimens required a voriconazole tCmin/MIC ratio of 1.8 and an amphotericin B tCmax/MIC ratio of 2.8. Amphotericin B-voriconazole combination regimens were more effective than monotherapy regimens. Therapeutic drug monitoring can be employed to optimize antifungal combination therapy with low-dose (≤0.6 mg/kg) amphotericin B-based combination regimens against resistant isolates for minimal toxicity.