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Background Lysins (cell wall hydrolases) targeting gram-negative organisms require engineering to permeabilize the outer membrane and access subjacent peptidoglycan to facilitate killing. In the current study, the potential clinical utility for the engineered lysin CF-370 was examined in vitro and in vivo against gram-negative pathogens important in human infections. Methods Minimum inhibitory concentration (MICs) and bactericidal activity were determined using standard methods. An in vivo proof-of-concept efficacy study was conducted using a rabbit acute pneumonia model caused by Pseudomonas aeruginosa. Results CF-370 exhibited potent antimicrobial activity, with MIC50/90 values (in µg/mL) for: P aeruginosa , 1/2; Acinetobacter baumannii , 1/1; Escherichia coli , 0.25/1; Klebsiella pneumoniae , 2/4; Enterobacter cloacae 1/4; and Stenotrophomonas maltophilia 2/8. CF-370 furthermore demonstrated bactericidal activity, activity in serum, a low propensity for resistance, anti-biofilm activity, and synergy with antibiotics. In the pneumonia model, CF-370 alone decreased bacterial densities in lungs, kidneys, and spleen versus vehicle control, and demonstrated significantly increased efficacy when combined with meropenem (vs either agent alone). Conclusions CF-370 is the first engineered lysin described with potent broad-spectrum in vitro activity against multiple clinically relevant gram-negative pathogens, as well as potent in vivo efficacy in an animal model of severe invasive multisystem infection. [ABSTRACT FROM AUTHOR]

Lysins are bacteriophage-derived enzymes that degrade bacterial peptidoglycans. Lysin CF-301 is being developed to treat Staphylococcus aureus because of its potent, specific, and rapid bacteriolytic effects. It also demonstrates activity on drug-resistant strains, has a low resistance profile, eradicates biofilms, and acts synergistically with antibiotics. CF-301 was bacteriolytic against 250 S. aureus strains tested including 120 methicillin-resistant S. aureus (MRSA) isolates. In time-kill studies with 62 strains, CF-301 reduced S. aureus by 3-log10 within 30 minutes compared to 6-12 hours required by antibiotics. In bacteremia, CF-301 increased survival by reducing blood MRSA 100-fold within 1 hour. Combinations of CF-301 with vancomycin or daptomycin synergized in vitro and increased survival significantly in staphylococcal-induced bacteremia compared to treatment with antibiotics alone (P < .0001). Superiority of CF-301 combinations with antibiotics was confirmed in 26 independent bacteremia studies. Combinations including CF-301 and antibiotics represent an attractive alternative to antibiotic monotherapies currently used to treat S. aureus bacteremia. [ABSTRACT FROM AUTHOR]

The goal of the International Classification of Functioning is to standardize the classification of health and function of children around the world. To facilitate the application of this classification, International Classification of Functioning–based tools like the “Core Sets” are being developed. We conducted an international survey of professional experts to identify the most relevant areas of functioning in children with cerebral palsy. The questionnaire covered each component of the classification. In total, 193 professionals completed the survey (response rate 78%). Overall, 9706 answers were linked to the classification (pediatric version) by 2 professionals. From the experts’ perspective, movement-related areas and social participation are the most relevant areas of functioning. Experts suggest a more comprehensive profile of functioning in particular in areas of personal capacity and social participation. The results of this survey will inform the development of the International Classification of Functioning Core Sets for children with cerebral palsy. [ABSTRACT FROM PUBLISHER]

AIMS: In the context of the development of the International Classification of Functioning, Disability and Health (ICF) Core Sets for children and adolescents with cerebral palsy (CP), we investigated the strengths and limitations in functioning important to children with CP, through either child self-reports or caregiver proxy reports, using components of the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY). METHOD: We conducted semi-structured interviews with 10 children with CP (children self-reporting), 10 caregivers of children self-reporting (10 child-caregiver dyads), and 12 caregivers of children not self-reporting. Mean age 10y 6mo, range 4-16y. A convenience sample was recruited representing Gross Motor Function Classification System (GMFCS) levels I to V. Interviews were audio-taped and the content covered all of the relevant ICF-CY components. The interviews were then transcribed verbatim and coded in N-Vivo 10 using the ICF-CY coding system. RESULTS: We identified 1956 themes that linked to 175 ICF-CY categories. Most of the themes were represented by the ICF-CY components activities and participation and environmental factors. The children interviewed discussed issues related to mobility, self-care, and recreation and leisure, whereas the caregivers focused more on physical limitations and on the environmental factors associated with everyday activities. INTERPRETATION: The children and their caregivers described many of the same areas of functioning but provided unique perspectives. Children talked more frequently about their abilities with CP, whereas the caregivers interviewed talked more about their concern over the limitations and broader issues facing their child. The findings highlight the need to explore the perspectives of both the child and the caregiver when characterizing the functional profile of children with CP. [ABSTRACT FROM AUTHOR]