Evaluation of a risk assessment model to predict infection with healthcare facility-onset Clostridioides difficile.

PURPOSE: We evaluated a previously published risk model (Novant model) to identify patients at risk for healthcare facility-onset Clostridioides difficile infection (HCFO-CDI) at 2 hospitals within a large health system and compared its predictive value to that of a new model developed based on local findings. METHODS: We conducted a retrospective case-control study including adult patients admitted from July 1, 2016, to July 1, 2018. Patients with HCFO-CDI who received systemic antibiotics were included as cases and were matched 1 to 1 with controls (who received systemic antibiotics without developing HCFO-CDI). We extracted chart data on patient risk factors for CDI, including those identified in prior studies and those included in the Novant model. We applied the Novant model to our patient population to assess the model's utility and generated a local model using logistic regression-based prediction scores. A receiver operating characteristic area under the curve (ROC-AUC) score was determined for each model. RESULTS: We included 362 patients, with 161 controls and 161 cases. The Novant model had a ROC-AUC of 0.62 in our population. Our local model using risk factors identifiable at hospital admission included hospitalization within 90 days of admission (adjusted odds ratio [OR], 3.52; 95% confidence interval [CI], 2.06-6.04), hematologic malignancy (adjusted OR, 12.87; 95% CI, 3.70-44.80), and solid tumor malignancy (adjusted OR, 4.76; 95% CI, 1.27-17.80) as HCFO-CDI predictors and had a ROC-AUC score of 0.74. CONCLUSION: The Novant model evaluating risk factors identifiable at admission poorly predicted HCFO-CDI in our population, while our local model was a fair predictor. These findings highlight the need for institutions to review local risk factors to adjust modeling for their patient population.

Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure.

BACKGROUND: Limited retrospective data suggest prophylactic oral vancomycin may prevent Clostridioides difficile infection (CDI). We sought to evaluate the effectiveness of oral vancomycin for the prevention of healthcare facility-onset CDI (HCFO-CDI) in targeted patients. METHODS: We conducted a randomized, prospective, open-label study at Novant Health Forsyth Medical Center in Winston-Salem, North Carolina, between October 2018 and April 2019. Included patients were randomized 1:1 to either oral vancomycin (dosed at 125 mg once daily while receiving systemic antibiotics and continued for 5 days postcompletion of systemic antibiotics [OVP]) or no prophylaxis. The primary endpoint was incidence of HCFO-CDI. Secondary endpoints included incidence of community-onset healthcare facility-associated CDI (CO-HCFA-CDI), incidence of vancomycin-resistant Enterococci (VRE) colonization after receiving OVP, adverse effects, and cost of OVP. RESULTS: A total of 100 patients were evaluated, 50 patients in each arm. Baseline and hospitalization characteristics were similar, except antibiotic exposure. No events of HCFO-CDI were noted in the OVP group compared with 6 (12%) in the no-prophylaxis group (P = .03). CO-HCFA-CDI was identified in 2 patients who were previously diagnosed with HCFO-CDI. No patients developed new VRE colonization, with only 1 patient reporting mild gastrointestinal side effects to OVP. A total of 600 doses of OVP were given during the study, with each patient receiving an average of 12 doses. Total acquisition cost of OVP was $1302, $26.04 per patient. CONCLUSION: OVP appears to protect against HCFO-CDI during in-patient stay in targeted patients during systemic antibiotic exposure. Further prospective investigation is warranted.

Dopamine Evokes a Trace Amine Receptor-dependent Inward Current that is Regulated by AMP Kinase in Substantia Nigra Dopamine Neurons.

We reported recently that activators of AMP-activated protein kinase (AMPK) slow the rundown of current evoked by the D2 autoreceptor agonist quinpirole in rat substantia nigra compacta (SNC) dopamine neurons. The present study examined the effect of AMPK on current generated by dopamine, which unlike quinpirole, is a substrate for the dopamine transporter (DAT). Using whole-cell patch-clamp, we constructed current-voltage (I-V) plots while superfusing brain slices with dopamine (100 µM) for 25 min. Two minutes after starting superfusion, dopamine evoked a peak current with an average slope conductance of 0.97 nS and an estimated reversal potential (Erev) of -113 mV, which is near that expected for K+. But after 10 min of superfusion, dopamine-evoked currents had shifted to more depolarized values with a slope conductance of 0.64 nS and an Erev of -83 mV. This inward shift in current was completely blocked by the DAT inhibitor GBR12935. However, an AMPK blocking agent (dorsomorphin) permitted the emergence of inward current despite the continued presence of the DAT inhibitor. When D2 autoreceptors were blocked by sulpiride, I-V plots showed that dopamine evoked an inward current with an estimated slope conductance of 0.45 nS with an Erev of -57 mV. Moreover, this inward current was completely blocked by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB. These results suggest that dopamine activates a TAAR1-dependent non-selective cation current that is regulated by AMPK.

AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons.

Dopamine neurons in the substantia nigra zona compacta (SNC) are well known to express D2 receptors. When dopamine is released from somatodendritic sites, activation of D2 autoreceptors suppresses dopamine neuronal activity through activation of G protein-coupled K+ channels. AMP-activated protein kinase (AMPK) is a master enzyme that acts in somatic tissues to suppress energy expenditure and encourage energy production. We hypothesize that AMPK may also conserve energy in central neurons by reducing desensitization of D2 autoreceptors. We used whole-cell patch-clamp recordings to study the effects of AMPK activators and inhibitors on D2 autoreceptor-mediated current in SNC neurons in midbrain slices from rat pups (11-23 days post-natal). Slices were superfused with 100 µM dopamine or 30 µM quinpirole for 25 min, which evoked outward currents that decayed slowly over time. Although the AMPK activators A769662 and ZLN024 significantly slowed rundown of dopamine-evoked current, slowing of quinpirole-evoked current required the presence of a D1-like agonist (SKF38393). Moreover, the D1-like agonist also slowed the rundown of quinpirole-induced current even in the absence of an AMPK activator. Pharmacological antagonist experiments showed that the D1-like agonist effect required activation of either protein kinase A (PKA) or exchange protein directly activated by cAMP 2 (Epac2) pathways. In contrast, the effect of AMPK on rundown of current evoked by quinpirole plus SKF38393 required PKA but not Epac2. We conclude that AMPK slows D2 autoreceptor desensitization by augmenting the effect of D1-like receptors.

Phosphoinositol metabolism affects AMP kinase-dependent K-ATP currents in rat substantia nigra dopamine neurons.

We reported recently that ligand-gated ATP-sensitive K+ (K-ATP) current is potentiated by AMP-activated protein kinase (AMPK) in rat substantia nigra compacta (SNC) dopamine neurons. Because phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) regulates K-ATP current, we explored the hypothesis that changes in PI(4,5)P2 modify the ability of AMPK to augment K-ATP current. To influence PI(4,5)P2 levels, we superfused brain slices with phospholipase C (PLC) activators and inhibitors while recording whole-cell currents in SNC dopamine neurons. Diazoxide, superfused for 5 min every 20 min, evoked K-ATP currents that, on average, increased from 38 pA at first application to 122 pA at the fourth application, a 220% increase. This enhancement of diazoxide-induced current was AMPK dependent because K-ATP current remained at baseline when slices were superfused with either the AMPK inhibitor dorsomorphin or the upstream kinase inhibitor STO-609. The PLC inhibitor U73122 significantly increased diazoxide current over control values, and this increase was blocked by dorsomorphin. Enhancement of diazoxide-induced current was also completely prevented by the PLC activator m-3M3FBS. Agonists at 5-HT2C and group I metabotropic glutamate receptors, both of which activate PLC, also prevented augmentation of diazoxide-induced current. Finally, inhibition of spike discharges by diazoxide was significantly antagonized by m-3M3FBS. These results suggest that PLC activity significantly influences the inhibitory effect of K-ATP channels by altering PI(4,5)P2 content. Results also suggest that modification of K-ATP current by PLC requires AMPK activity.

Development of a risk prediction model for hospital-onset Clostridium difficile infection in patients receiving systemic antibiotics.

BACKGROUND: Clostridium difficile infection (CDI) is recognized as a significant challenge in health care. Identification of high-risk individuals is essential for the development of CDI prevention strategies. The objective of this study was to develop an easily implementable risk prediction model for hospital-onset CDI in patients receiving systemic antimicrobials. METHODS: This retrospective, case-control, multicenter study included adult patients admitted to Novant Health Forsyth Medical Center and Novant Health Presbyterian Medical Center from July 1, 2015, to July 1, 2017, who received systemic antibiotics. Cases were subjects with hospital-onset CDI; controls were subjects without a CDI diagnosis. Cases were matched 1:1 with controls by admitted medical unit type. Variables significantly associated with CDI were incorporated into a multivariate analysis. A logistic regression model was used to formulate a point-based risk prediction model. Positive predictive value, negative predictive value, sensitivity, specificity, and accuracy were determined at various point cutoffs of the model. A receiver operating characteristic-area under the curve was created to assess the discrimination of the model. RESULTS: A total of 200 subjects (100 cases and 100 controls) were included. Most patients were Caucasian and female. Risk factors for CDI identified and incorporated into the model included age ≥70 years (adjusted odds ratio, 1.89; 95% confidence interval 1.05-3.43; P = .0326) and recent hospitalization in the past 90 days (adjusted odds ratio, 3.55; 95% confidence interval 1.90-6.83; P < .0001). Sensitivity and specificity were 76% and 49%, respectively, for scores ≥2 and 20% and 93%, respectively, for a score of 6. Diagnostic performance of various score cutoffs for the model indicated that a score ≥2 was associated with the highest accuracy (63%). The receiver operating characteristic-area under the curve was 0.7. DISCUSSION: We developed a simple-to-implement hospital-onset CDI risk model that included only independent risks that can be obtained immediately on presentation to the health care facility. Despite this, the model had fair discriminatory power. Similar risk factors were found in previously developed models; however, the utility of these models is limited owing to the difficulty of assessing other included risk factors and the inclusion of risk factors that cannot be evaluated until the patient is discharged from the health care facility. CONCLUSIONS: Identification of hospitalized patients who are receiving systemic antibiotics, are ≥70 years old, and were recently admitted to the hospital in the past 90 days may allow for an easily implementable hospital-onset CDI risk prevention strategy.

Evaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms.

BACKGROUND: There remains variability in both practice and evidence related to optimal initial empiric dosing strategies for vancomycin. OBJECTIVE: Our primary objective was to describe the percentage of obese patients receiving vancomycin doses consistent with nomogram recommendations achieving targeted initial steady-state serum vancomycin concentrations. Secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance, to describe the rate of supratherapeutic vancomycin accumulation following an initial therapeutic trough concentration, and to describe the rate of vancomycin-related adverse events. METHODS: This single-center, IRB-approved, retrospective cohort included adult patients ≥ 100 kilograms total body weight with a body mass index (BMI) >30 kilograms/m2 who received a stable nomogram-based vancomycin regimen and had at least one steady-state vancomycin trough concentration. Data collected included vancomycin regimens and concentrations, vancomycin indication, serum creatinine, and vancomycin-related adverse events. Patients were divided into two cohorts by goal trough concentration: 10-15 mcg/mL and 15-20 mcg/mL. RESULTS: Of 325 patients screened, 85 were included. Goal steady-state concentrations were reached in 42/85 (49.4%) of total patients. CONCLUSIONS: Achievement of initial steady-state vancomycin serum concentrations in the present study (approximately 50%) was consistent with the use of published vancomycin dosing nomograms.

Differential actions of AMP kinase on ATP-sensitive K+ currents in ventral tegmental area and substantia nigra zona compacta neurons.

ATP-sensitive K+ (K-ATP) channels play significant roles in regulating the excitability of dopamine neurons in the substantia nigra zona compacta (SNC). We showed previously that K-ATP channel function is up-regulated by AMP-activated protein kinase (AMPK). This study extended these studies to the neurons adjacent to the SNC in the ventral tegmental area (VTA). Using patch pipettes to record whole-cell currents in slices of rat midbrain, we found that the AMPK activator A769662 increased the amplitude of currents evoked by the K-ATP channel opener diazoxide in presumed dopamine-containing VTA neurons. However, current evoked by diazoxide with A769662 was significantly smaller in VTA neurons compared to SNC neurons. Moreover, a significantly lower proportion of VTA neurons responded to diazoxide with outward current. However, A769662 was able to increase the incidence of diazoxide-responsive neurons in the VTA. In contrast, A769662 did not potentiate diazoxide-evoked currents in presumed non-dopamine VTA neurons. These results show that AMPK activation augments K-ATP currents in presumed dopamine neurons in the VTA and SNC, although diazoxide-evoked currents remain less robust in the VTA. We conclude that K-ATP channels may play important physiological roles in VTA and SNC dopamine neurons.

Medication discrepancy rates among Medicaid recipients at hospital discharge.

OBJECTIVES: To compare the rate of discrepancies per patient for medications changed during hospitalization in patients with and without prescription provider comments at hospital discharge. Secondary objectives included comparing 35-day readmission rates, describing the overall medication discrepancy rate stratified by age group and type of discrepancy, collecting average number of medication changes, and reporting percentage change in admission medications at discharge. METHODS: This single-center prospective cohort included NC Medicaid recipients discharged from East Carolina University Family Medicine service from November 1, 2015, to January 31, 2016. Patients were assigned to a group based on presence or absence of provider comments on discharge prescriptions. Outpatient pharmacy claims were compared with the discharge summary to identify medication discrepancies. Medication discrepancy rates between groups were to be compared by means of independent-samples t test. Medication discrepancy rates were compared according to 35-day readmission status, age group, and type of discrepancy by means of independent-samples t tests and analysis of variance. Descriptive statistics were used for other secondary outcomes. RESULTS: Of 118 patients included, only 1 had provider comments. Therefore, a medication discrepancy rate comparison was not performed. Patients had a mean of 4 medication changes made to their regimen and 21.3% change in admission medications. Sixty-one percent of patients had at least 1 medication discrepancy, with an overall rate of 1.19. Patients readmitted within 35 days had a significantly greater medication discrepancy rate than those not readmitted (1.63 vs. 1.05, respectively; P = 0.044). Patients 18-49 years of age had the highest discrepancy rate and those older than 80 years of age the lowest (1.58 and 0.50, respectively). New or changed discharge medication not filled accounted for 69% of discrepancies. CONCLUSION: Although medication discrepancies were common, use of provider comments was rare. Future studies should address more effective ways to communicate pertinent information to community pharmacists and methods to improve adherence in obtaining new medications.

Hepatitis C Virus-Genotype 3: Update on Current and Emergent Therapeutic Interventions.

PURPOSE OF REVIEW: Direct-acting antiviral agents (DAAs) have markedly improved the prognosis of hepatitis C virus (HCV)-genotype 3 (GT3), a highly prevalent infection worldwide. However, in patients with hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), GT3 infection presents a treatment challenge compared with other genotypes. The dependence of the HCV life cycle on host lipid metabolism suggests the possible utility of targeting host cellular factors for combination anti-HCV therapy. We discuss current and emergent DAA regimens for HCV-GT3 treatment. We then summarize recent research findings on the reliance of HCV entry, replication, and virion assembly on host lipid metabolism. RECENT FINDINGS: Current HCV treatment guidelines recommend the use of daclatasvir plus sofosbuvir (DCV/SOF) or sofosbuvir plus velpatasvir (SOF/VEL) for the management of GT3 based upon clinical efficacy [≥88% overall sustained virological response (SVR)] and tolerability. Potential future DAA options, such as SOF/VEL co-formulated with GS-9857, also look promising in treating cirrhotic GT3 patients. However, HCV resistance to DAAs will likely continue to impact the therapeutic efficacy of interferon-free treatment regimens. Disruption of HCV entry by targeting required host cellular receptors shows potential in minimizing HCV resistance and broadening therapeutic options for certain subpopulations of GT3 patients. The use of cholesterol biosynthesis and transport inhibitors may also improve health outcomes for GT3 patients when used synergistically with DAAs. Due to the morbidity and mortality associated with HCV-GT3 infection compared to other genotypes, efforts should be made to address current limitations in the therapeutic prevention and management of HCV-GT3 infection.

Effectiveness of ledipasvir/sofosbuvir in real-world patients with chronic hepatitis C: a collaborative treatment approach.

The effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in routine use in clinical practice for the management of chronic hepatitis C virus (HCV) has not been well described. Data with prior agents suggest that management of HCV using an interprofessional approach in clinical practice is associated with better outcomes. This single-centre, prospective, observational cohort study evaluated patients treated with LDV/SOF for 8, 12 or 24 weeks as part of the standardized interprofessional treatment protocol at Novant Health Infectious Diseases Specialists. Eighty-four patients treated with LDV/SOF were evaluated; of these, 97.5% and 91.7% of patients achieved a sustained virological response (SVR) in the per-protocol analysis and the intention-to-treat analysis, respectively. Two patients were not cured after relapse of HCV. No patients required LDV/SOF discontinuation and all patients completed the appropriate treatment duration. The majority (56%) of patients reported no adverse effects and all adverse effects that were reported were mild. The most commonly reported adverse effects were headache and fatigue. SVR and tolerability rates were similar to those seen in the clinical trials. LDV/SOF was associated with a successful translation from the clinical trial setting to clinical practice. A collaborative treatment approach should be considered in the management of HCV.

Role of isavuconazole in the treatment of invasive fungal infections.

Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug-drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug-drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring.

Focus on JNJ-Q2, a novel fluoroquinolone, for the management of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections.

JNJ-Q2 is a novel, fifth-generation fluoroquinolone that has excellent in vitro and in vivo activity against a variety of Gram-positive and Gram-negative organisms. In vitro studies indicate that JNJ-Q2 has potent activity against pathogens responsible for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), such as Staphylococcus aureus and Streptococcus pneumoniae. JNJ-Q2 also has been shown to have a higher barrier to resistance compared to other agents in the class and it remains highly active against drug-resistant organisms, including methicillin-resistant S. aureus, ciprofloxacin-resistant methicillin-resistant S. aureus, and drug-resistant S. pneumoniae. In two Phase II studies, the efficacy of JNJ-Q2 was comparable to linezolid for ABSSSI and moxifloxacin for CABP. Furthermore, JNJ-Q2 was well tolerated, with adverse event rates similar to or less than other fluoroquinolones. With an expanded spectrum of activity and low potential for resistance, JNJ-Q2 shows promise as an effective treatment option for ABSSSI and CABP. Considering its early stage of development, the definitive role of JNJ-Q2 against these infections and its safety profile will be determined in future Phase III studies.

AMP kinase regulates ligand-gated K-ATP channels in substantia nigra dopamine neurons.

AMP-activated protein kinase (AMPK) is a master enzyme that regulates ATP-sensitive K(+) (K-ATP) channels in pancreatic beta-cells and cardiac myocytes. We used patch pipettes to record currents and potentials to investigate effects of AMPK on K-ATP currents in substantia nigra compacta (SNC) dopamine neurons in slices of rat midbrain. When slices were superfused repeatedly with the K-ATP channel opener diazoxide, we were surprised to find that diazoxide currents gradually increased in magnitude, reaching 300% of the control value 60min after starting whole-cell recording. However, diazoxide current increased significantly more, to 472% of control, when recorded in the presence of the AMPK activator A769662. Moreover, superfusing the slice with the AMPK blocking agent dorsomorphin significantly reduced diazoxide current to 38% of control. Control experiments showed that outward currents evoked by the K-ATP channel opener NN-414 also increased over time, but not currents evoked by the GABAB agonist baclofen. Delaying the application of diazoxide after starting whole-cell recording correlated with augmentation of current. Loose-patch recording showed that diazoxide produced a 34% slowing of spontaneous firing rate that did not intensify with repeated applications of diazoxide. However, superfusion with A769662 significantly augmented the inhibitory effect of diazoxide on firing rate. We conclude that K-ATP channel function is augmented by AMPK, which is activated during the process of making whole-cell recordings. Our results suggest that AMPK and K-ATP interactions may play an important role in regulating dopamine neuronal excitability.

Demographic and infection characteristics of patients with carbapenem-resistant Enterobacteriaceae in a community hospital: Development of a bedside clinical score for risk assessment.

BACKGROUND: The objective of this study was to identify risk factors associated with the presence of carbapenem-resistant Enterobacteriaceae (CRE) infections to develop a clinical prediction model that can be used at patient bedside to identify subjects likely infected with a CRE pathogen. METHODS: This case-control study included patients aged ≥18 years admitted to Novant Health Forsyth Medical Center between January 1, 2012, and December 31, 2013, with CRE infections (cases) or non-CRE infections (controls). Controls were matched to their corresponding resistant case (3:1) based on pathogen, place of likely acquisition, isolate source, year of admission, and level of care. A risk prediction model was developed using variables independently associated with CRE isolation. Sensitivities and specificities were obtained at various point cutoffs, and a determination of the receiver operator characteristic (ROC) area under the curve (AUC) was performed. RESULTS: A total of 164 subjects were included. Independent risk factors for CRE included recent antibiotic therapy, recent immunosuppression, and Charlson Comorbidity Index score ≥4. Adjusted odds ratios were 13.37 (95% confidence interval [CI], 4.16-61.19), 6.69 (95% CI, 1.85-29.65), and 3.30 (95% CI, 1.34-8.40), respectively. Diagnostic performance of various score cutoffs for the model indicated a score ≥5 correlated with the highest accuracy (79%). The ROC AUC was 0.83. CONCLUSION: The risk prediction model displayed good discrimination and was an excellent predictor of CRE infection.

Memantine selectively blocks extrasynaptic NMDA receptors in rat substantia nigra dopamine neurons.

Recent studies suggest that selective block of extrasynaptic N-methyl-d-aspartate (NMDA) receptors might protect against neurodegeneration. We recorded whole-cell currents with patch pipettes to characterize the ability of memantine, a low-affinity NMDA channel blocker, to block synaptic and extrasynaptic NMDA receptors in substantia nigra zona compacta (SNC) dopamine neurons in slices of rat brain. Pharmacologically isolated NMDA receptor-mediated EPSCs were evoked by electrical stimulation, whereas synaptic and extrasynaptic receptors were activated by superfusing the slice with NMDA (10 µM). Memantine was 15-fold more potent for blocking currents evoked by bath-applied NMDA compared to synaptic NMDA receptors. Increased potency for blocking bath-applied NMDA currents was shared by the GluN2C/GluN2D noncompetitive antagonist DQP-1105 but not by the high-affinity channel blocker MK-801. Our data suggest that memantine causes a selective block of extrasynaptic NMDA receptors that are likely to contain GluN2C/2D subunits. Our results justify further investigations on the use of memantine as a neuroprotective agent in Parkinson's disease.

Recent advances in the treatment of life-threatening, invasive fungal infections.

INTRODUCTION: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative. AREAS COVERED: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, ß-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole. EXPERT OPINION: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.

Utility of a clinical risk factor scoring model in predicting infection with extended-spectrum ß-lactamase-producing enterobacteriaceae on hospital admission.

OBJECTIVE: To validate the utility of a previously published scoring model (Italian) to identify patients infected with community-onset extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-EKP) and develop a new model (Duke) based on local epidemiology. METHODS: This case-control study included patients 18 years of age or more admitted to Duke University Hospital between January 1, 2008, and December 31, 2010, with culture-confirmed infection due to an ESBL-EKP (cases). Uninfected controls were matched to cases (3:1). The Italian model was applied to our patient population for validation. The Duke model was developed through logistic-regression-based prediction scores calculated on variables independently associated with ESBL-EKP isolation. Sensitivities and specificities at various point cutoffs were determined, and determination of the area under the receiver operating characteristic curve (ROC AUC) was performed. RESULTS: A total of 123 cases and 375 controls were identified. Adjusted odds ratios and 95% confidence intervals for variables previously identified in the Italian model were as follows: hospitalization (3.20 [1.62-6.55]), transfer (4.31 [2.15-8.78]), urinary catheterization (5.92 [3.09-11.60]), ß-lactam and/or fluoroquinolone therapy (3.76 [2.06-6.95]), age 70 years or more (1.55 [0.79-3.01]), and Charlson Comorbidity Score of 4 or above (1.06 [0.55-2.01]). Sensitivity and specificity were, respectively, more than or equal to 95% and less than or equal to 47% for scores 3 or below and were less than or equal to 50% and more than or equal to 96% for scores 8 or above. The ROC AUC was 0.88. Variables identified in the Duke model were as follows: hospitalization (2.63 [1.32-5.41]), transfer (5.30 [2.67-10.71]), urinary catheterization (6.89 [3.62-13.38]), ß-lactam and/or fluoroquinolone therapy (3.47 [1.91-6.41]), and immunosuppression (2.34 [1.14-4.80]). Sensitivity and specificity were, respectively, more than or equal to 94% and less than or equal to 65% for scores 3 or below and were less than or equal to 58% and more than or equal to 95% for scores 8 or above. The ROC AUC was 0.89. CONCLUSION: While the previously reported model was an excellent predictor of community-onset ESBL-EKP infection, models utilizing factors based on local epidemiology may be associated with improved performance.