Ariel - Volume 5 Number 5

Editors Mark Dembert J. D. Kanofsky Entertainment Robert Breckenridge Joe Conti Gary Kaskey Photographer Scot Kastner Overseas Editor Mike Sinason Circulation Jay Amsterdam Humorist Jim McCann Staff Ken Jaffe Bob Sklaroff Janet Welsh Dave Jacoby Phil Nimoityn Frank Chervane

Wound infection in clinical practice : principles of best practice

The International Wound Infection Institute (IWII) is an organisation of volunteer interdisciplinary health professionals dedicated to advancing and improving practice relating to prevention and control of wound infection. This includes acute wounds (surgical, traumatic and burns) and chronic wounds of all types, although principally chronic wounds of venous, arterial, diabetic and pressure aetiologies. Wound infection is a common complication of wounds. It leads to delays in wound healing and increases the risk of loss of limb and life. Implementation of effective strategies to prevent, diagnose and manage, is important in reducing mortality and morbidity rates associated with wound infection. This second edition of Wound Infection in Clinical Practice is an update of the first edition published in 2008 by the World Union of Wound Healing Societies (WUWHS). The original document was authored by leading experts in wound management and endorsed by the WUWHS. The intent of this edition is to provide a practical, updated resource that is easy-to-use and understand. For this edition, the IWII collaborative team has undertaken a comprehensive review of contemporary literature, including systematic reviews and meta-analyses when available. In addition, the team conducted a formal Delphi process to reach consensus on wound infection issues for which scientific research is minimal or lacking. This rigorous process provides an update on the science and expert opinion regarding prevention, diagnosis and control of wound infection. This edition outlines new definitions relevant to wound infection, presents new paradigms and advancements in the management and diagnosis of a wound infection, and highlights controversial areas of discussion

ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIVmac251SIV_{mac}251 Challenge

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVΔnef, increased progressively over time, and was proportional to SIVΔnef replication. Persistent infection with SIVΔnef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against $SIV_{mac}251$ challenge, measures of ADCC activity were higher among the SIVΔnef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVΔnef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVΔnef

ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIV(mac)251 Challenge

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVDeltanef, increased progressively over time, and was proportional to SIVDeltanef replication. Persistent infection with SIVDeltanef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIV(mac)251 challenge, measures of ADCC activity were higher among the SIVDeltanef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVDeltanef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVDeltanef

Clonal expansion of new penicillin-resistant clade of neisseria meningitidis serogroup w clonal complex 11, Australia

In Western Australia, Neisseria meningitidis serogroup W clonal complex 11 became the predominant cause of invasive meningococcal disease in 2016. We used core-genome analysis to show emergence of a penicillin-resistant clade that had the penA_253 allele. This new penicillin-resistant clade might affect treatment regimens for this disease

Rise in carriage of group W meningococci in university students in United Kingdom

MenACWY conjugate vaccination was recently introduced in the UK for adolescents and 24 young adults to reduce disease due to Neisseria meningitidis group W (MenW). We 25 conducted a cross-sectional carriage study in first year university students. Despite 71% 26 MenACWY vaccine coverage, carriage of MenW, but not MenY, rose significantly in 27 students

Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance

Background— Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity. Methods and Results— Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 μmol/L)–induced platelet aggregation of less than 10%, 10% to 29%, and ≥30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r=−0.6, P=0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin. Conclusions— Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy

Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: A new drug-drug interaction

Background— We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Methods and Results— Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34±23, 58±15 (P=0.027), 74±10 (P=0.002), and 89±7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55±12 versus 42±12% platelet aggregation; P=0.002), as did troleandomycin (78±18 versus 45±18% platelet aggregation; P less than 0.0003), whereas rifampin enhanced platelet aggregation inhibition (33±18 versus 56±20% platelet aggregation, P=0.001). Conclusions— CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel