Antibiotic Hypersensitivity Mechanisms.

Antibiotics are commonly prescribed to treat a variety of bacterial infections. As with all medications, hypersensitivity reactions may occur and clinicians should be able to recognize them accurately and recommend appropriate management. Antibiotic related hypersensitivity reactions may be one of four different types: Type I reactions, which are IgE mediated and may lead to anaphylaxis; Type II reactions that are antibody-mediated and may result in thrombocytopenia, neutropenia, or hemolytic anemia; Type III reaction that involves an immune complex formation such as vasculitis; and Type IV reactions that consist of four subtypes and typically include a rash of varying level of severity with or without systemic signs and symptoms. Herein, we describe the mechanisms of different types of allergic reactions to commonly prescribed antibiotics and offer recommendations for management. Further, we briefly refer to antibiotic reactions that mimic hypersensitivity reactions but are not immune mediated, such as pseudoallergies and serum sickness-like reactions.

Shingrix: The New Adjuvanted Recombinant Herpes Zoster Vaccine.

OBJECTIVES: To review the immunogenicity, efficacy, and safety of the herpes zoster subunit vaccine (HZ/su) for use in adult patients for the prevention of shingles. DATA SOURCES: A literature search through PubMed was conducted (June 2008 to October 2017) using the terms shingles vaccine and varicella zoster virus. References from retrieved articles and the prescribing information were also reviewed for any additional material. STUDY SELECTION/DATA EXTRACTION: The literature search was limited to human studies published in English. Randomized controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of HZ/su. Literature on the epidemiology and pathology of herpes zoster virus infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. DATA SYNTHESIS: HZ/su is a new adjuvanted recombinant vaccine approved by the Food and Drug Administration for the prevention of herpes zoster in adults 50 years of age and older. HZ/su significantly reduced the risk of developing herpes zoster by more than 90% as compared with placebo and displayed a comparable adverse effect profile. The most common local adverse events were injection site pain, redness, and swelling, and the most common systemic adverse events were myalgia, fatigue, and headache. The ACIP recommends the routine use of HZ/su as the preferred vaccine for the prevention of herpes zoster in immunocompetent adults 50 years of age and older. CONCLUSIONS: Based on published immunogenicity, efficacy, and safety data, as well as the recent recommendations by the ACIP, HZ/su should be included on both hospital and community pharmacy formularies and recommended to all immunocompetent patients older than 50 years to prevent herpes zoster.

Inhibition of phosphorylated-STAT1 nuclear translocation and antiviral protein expression in human brain vascular adventitial fibroblasts infected with varicella-zoster virus.

In varicella-zoster virus (VZV)-infected primary human brain vascular adventitial fibroblasts (BRAFs), levels of beta interferon (IFN-ß,) STAT1, and STAT2 transcripts as well as STAT1 and STAT2 protein were decreased. IFN-α transcript levels were increased but not secreted IFN-α protein levels. Compared to IFN-α-treated control results, in VZV-infected BRAFs, phosphorylated STAT1 did not translocate to the nucleus, resulting in impaired downstream expression of interferon-inducible antiviral Mx1. Overall, VZV interference with the type I interferon pathway may promote virus persistence in cerebral arteries.

T cells increase before zoster and PD-1 expression increases at the time of zoster in immunosuppressed nonhuman primates latently infected with simian varicella virus.

Like varicella zoster virus in humans, simian varicella virus (SVV) becomes latent in ganglionic neurons along the entire neuraxis and reactivates in immunosuppressed monkeys. Five rhesus macaques were inoculated with SVV; 142 days later (latency), four monkeys were immunosuppressed, and T cells were analyzed for naïve, memory, and effector phenotypes and expression of programmed death receptor-1 (PD-1; T cell exhaustion). All T cell subsets decreased during immunosuppression and except for CD8 effectors, peaked 2 weeks before zoster. Compared to before immunosuppression, PD-1 expression increased at reactivation. Increased T cells before zoster is likely due to virus reactivation.

Does apoptosis play a role in varicella zoster virus latency and reactivation?

Varicella zoster virus (VZV) is an exclusively human highly neurotropic alphaherpesvirus. To date, VZV has been shown to induce apoptosis, primarily through the intrinsic pathway in different cell types, except for neurons in which the virus becomes latent. This review summarizes current studies of varicella-induced apoptosis in non­neuronal cells. Future studies are proposed to determine whether apoptosis is terminated prematurely or even begins in neurons that are non-productively infected with VZV.

In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate.

Effective antibody-drug conjugates (ADC) combine high drug-linker stability in circulation and efficient intratumoral release of drug. Conjugation of monomethyl auristatin E (MMAE) to the anti-CD30 monoclonal antibody (mAb), cAC10, produced a selective and potent ADC against CD30(+) anaplastic large cell lymphoma and Hodgkin's disease models. This ADC, cAC10-valine-citrulline-MMAE, uses a protease-sensitive dipeptide linker designed to release MMAE by lysosomal cathepsin B in target cells but maintain a stable linkage and attenuate drug potency in circulation. To evaluate ADC stability in vivo, we developed methods for measuring drug/mAb ratios at progressive times in plasma from ADC-treated mice and nonhuman primates. Anti-idiotype mAb permitted the capture and quantitation of mAb cAC10, whereas antidrug mAb and MMAE-conjugated horseradish peroxidase reporter provided quantitative detection of conjugated drug following its in vitro release by cathepsin B. These data were validated by an alternative ELISA using anti-idiotype and anti-MMAE mAbs for capture and detection, respectively. Both methods differentiated ADC with variable levels of drug loading and were subsequently applied to stability studies in severe combined immunodeficient mice and cynomolgus monkeys. Evaluation of ADC from mouse circulation showed the linker half-life to be approximately 144 hours (6.0 days), significantly greater than that reported for disulfide- or hydrazone-linked ADCs in mice or human trials. In cynomolgus monkey, the apparent linker half-life was approximately 230 hours (9.6 days), suggesting that the drug-linker will be highly stable in humans. These data represent the longest reported drug-linker half-life to date and provide the basis for the pronounced specificity and antitumor activity of cAC10-valine-citrulline-MMAE.