Evaluation of dalbavancin alone and in combination with ß-lactam antibiotics against resistant phenotypes of Staphylococcus aureus.

Background: Emergence of reduced susceptibility to vancomycin warrants the development of new antimicrobial agents for the treatment of MRSA. We evaluated the activity of dalbavancin, a novel lipoglycopeptide antibiotic, both alone and combined with ß-lactams, in combination MIC testing and time-kill assays against resistant phenotypes of Staphylococcus aureus. Methods: S. aureus isolates included 50 organisms with varying susceptibility patterns. Dalbavancin was tested alone and in combination with five ß-lactams: cefazolin, cefepime, ceftaroline, ertapenem and oxacillin. MIC values of the antibiotics were determined for all isolates. After initial MIC testing, dalbavancin MICs were determined in the presence of 0.5 × MIC of each ß-lactam to determine the effect of each ß-lactam on dalbavancin MIC. Time-kill assays were performed with dalbavancin and ß-lactams tested at 0.5 × MIC for randomly selected organisms representing each MRSA phenotype. Time-kill curves were generated by plotting mean colony counts (log10 cfu/mL) versus time. Results: Dalbavancin MIC50 was 0.0313 mg/L and MIC90 was 0.0625 mg/L. Dalbavancin MICs decreased by zero to greater than five 2-fold dilutions in combination with each ß-lactam. In time-kill assays, dalbavancin was synergistic with cefazolin, cefepime and ertapenem against all strains and the combination of dalbavancin and ceftaroline was synergistic against all but one. The combination of dalbavancin and oxacillin was synergistic against 5/8 strains. Conclusions: Dalbavancin was active against all MRSA strains tested, including heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus, daptomycin-non-susceptible and linezolid-resistant isolates. The synergy demonstrated against these organisms supports the use of dalbavancin in combination with ß-lactams against resistant phenotypes of S. aureus. Further evaluation is warranted.

Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus: Does Vancomycin Heteroresistance Matter?

Vancomycin remains the mainstay treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections, including pneumonia. There is concern regarding the emergence of vancomycin tolerance, caused by heterogeneous vancomycin-intermediate S. aureus (hVISA), and subsequent vancomycin treatment failure. Pneumonia is associated with high morbidity and mortality, especially with delays in appropriate therapy. This study evaluated the clinical outcomes of patients with hVISA pneumonia compared to those with vancomycin-susceptible S. aureus (VSSA) pneumonia. A retrospective cohort of patients with MRSA pneumonia from 2005 to 2014 was matched at a ratio of 2:1 VSSA to hVISA infections to compare patient characteristics, treatments, and outcomes. hVISA was determined by the 48-h population analysis profile area under the curve. Characteristics between VSSA and hVISA infections were compared by univariate analysis and multivariable logistic regression analysis to determine independent risk factors of inpatient mortality. Eighty-seven patients were included, representing 29 hVISA and 58 VSSA cases of pneumonia. There were no significant differences in demographics or baseline characteristics. Sequential organ failure assessment (SOFA) scores were a median of 7 (interquartile ratio [IQR], 5 to 8) in hVISA patients and 5 (IQR, 3 to 8) in VSSA (P = 0.092) patients. Inpatient mortality was significantly higher in hVISA patients (44.8% versus 24.1%; P = 0.049). Predictors of inpatient mortality upon multivariable regression were SOFA score (adjusted odds ratio [aOR], 1.36; 95% confidence interval [CI], 1.08 to 1.70), Panton-Valentine leukocidin (PVL) positivity (aOR, 6.63; 95% CI, 1.79 to 24.64), and hVISA phenotype (aOR, 3.95; 95% CI, 1.18 to 13.21). Patients with hVISA pneumonia experienced significantly higher inpatient mortality than those with VSSA pneumonia. There is a need to consider the presence of vancomycin heteroresistance in pneumonia caused by MRSA in order to potentially improve clinical outcomes.

Unmet needs in the transition to adulthood: 18- to 30-year-old people with hemophilia.

Young adults with hemophilia face unique challenges during the transition to adulthood, including issues associated with switching from pediatric to adult hematology care, building mature interpersonal relationships, and establishing an independent career with an assurance of medical insurance coverage. A greater understanding of these challenges is essential for developing effective strategies to address the specific needs of this population. These challenges may be differentiated from those of older adults with hemophilia in large part because of more extensive childhood prophylaxis and safer factor products, resulting in fewer joint problems and lower rates of HIV and HCV infections. This analysis of the changing nature and unmet needs of today's young adults entering into adult hemophilia treatment centers, as well as potential strategies for optimally addressing these needs, was developed following roundtable discussions between patients, caregivers, hematologists, and other health care professionals participating in comprehensive care. Challenges identified among young adults with hemophilia include psychosocial issues related to maturity, personal responsibility, and increased independence, as well as concerns regarding when and with whom to share information about one's hemophilia, limited awareness of educational and financial resources, and a low perceived value of regular hematology care. The initiatives proposed herein highlight important opportunities for health care professionals at pediatric and adult hemophilia treatment centers, as well as national organizations, community groups, and career counselors, to address key unmet needs of this patient population.

Controlling the mixed potential of polyelectrolyte-coated platinum electrodes for the potentiometric detection of hydrogen peroxide.

The use of a Pt electrode coated with a layer of Nafion has been described in previous works as an attractive way to perform the potentiometric detection of hydrogen peroxide. Despite of the attractive features of this approach, the nature of the non-Nernstian response of this system was not properly addressed. In this work, using a mixed potential model, the open circuit potential of the Pt electrode is shown to be under kinetic control of the oxygen reduction reaction (ORR). It is proposed that hydrogen peroxide acts as an oxygenated species that blocks free sites on the Pt surface, interfering with the ORR. Therefore, the effect of the polyelectrolyte coating can be understood in terms of the modulation of the factors that affects the kinetics of the ORR, such as an increase of the H+ concentration, minimization of the effect of the spectator species, etc. Because of the complexity and the lack of models that accurately describe systems with practical applications, this work is not intended to provide a mechanistic but rather a phenomenological view on problem. A general framework to understand the factors that affect the potentiometric response is provided. Experimental evidence showing that the use of polyelectrolyte coatings are a powerful way to control the mixed potential open new ways for the development of robust and simple potentiometric sensors.

Role of Vancomycin Minimum Inhibitory Concentrations by Modified Population Analysis Profile Method and Clinical Outcomes in High Inoculum Methicillin-Resistant Staphylococcus aureus Infections.

INTRODUCTION: Vancomycin remains the standard of care for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections. Treatment failures from heteroresistant vancomycin-intermediate subpopulations (hVISA) are challenging to detect. Minimum inhibitory concentrations (MIC) identified by modified population analysis profile (PAP) is an alternative testing method. The aim of this study was to evaluate the role of PAP MIC on vancomycin failures in two high inoculum infections: MRSA infective endocarditis and pneumonia. METHODS: Retrospective, observational study at Detroit Medical Center from 2008 to 2016. Adults ≥ 18 years with ≥ 1 positive MRSA blood culture from IE or pneumonia source and received ≥ 48 h vancomycin were included. The primary outcome was composite failure: MRSA bacteremia ≥ 7 days or 30-day all-cause mortality. RESULTS: A total of 191 patients were included; 47.6% IE and 52.4% pneumonia. About 19% were hVISA isolates, median vancomycin PAP MIC of 3 (2, 3). More than half (54.5%) experienced composite failure with a larger proportion of PAP MIC ≥ 4 mg/L in this group (25 vs. 15%, p = 0.086). Patients with IE experienced prolonged bacteremia whereas patients with pneumonia experienced higher 30-day mortality. On logistic regression analysis, age [adjusted odds ratio (aOR), 1.026; 95% confidence interval (CI), 1.005-1.047; p = 0.014] and APACHE II score (aOR 1.039; 95% CI, 1.004-1.076; p = 0.029) independently predicted composite failure. CONCLUSION: Vancomycin PAP MIC may be a more relevant predictor of patient outcomes in persistent bacteremic MRSA infections (e.g., IE). This susceptibility method is less applicable in other high inoculum infections with shorter bacteremia durations and higher mortality rates (e.g., pneumonia).