Objective: Faecal microbiota transplantation (FMT) has proved to be an extremely effective treatment for recurrent Clostridioides difficile infection, and there is interest in its potential application in other gastrointestinal and systemic diseases. However, the recent death and episode of septicaemia following FMT highlights the need for further appraisal and guidelines on donor evaluation, production standards, treatment facilities and acceptable clinical indications. Design: For these consensus statements, a 24-member multidisciplinary working group voted online and then convened in-person, using a modified Delphi approach to formulate and refine a series of recommendations based on best evidence and expert opinion. Invitations to participate were directed to Australian experts, with an international delegate assisting the development. The following issues regarding the use of FMT in clinical practice were addressed: donor selection and screening, clinical indications, requirements of FMT centres and future directions. Evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Results: Consensus was reached on 27 statements to provide guidance on best practice in FMT. These include: (1) minimum standards for donor screening with recommended clinical selection criteria, blood and stool testing; (2) accepted routes of administration; (3) clinical indications; (4) minimum standards for FMT production and requirements for treatment facilities acknowledging distinction between single-site centres (eg, hospital-based) and stool banks; and (5) recommendations on future research and product development. Conclusions: These FMT consensus statements provide comprehensive recommendations around the production and use of FMT in clinical practice with relevance to clinicians, researchers and policy makers.
Multiple factors influence the outcome of fungal infection of the central nervous system (CNS). The host and the pathogen in concert with drug delivery across the blood-brain barrier and drug activity are key factors in outcome. Drug costs can be prohibitively expensive. Drug toxicity with standard antifungal agents such as amphotericin B (infusion rate toxicity) can be reduced using simple techniques such as slower infusion and appropriate saline loading. Continuous infusion can allow relatively large doses of amphotericin B (up to 2 mg/kg/day, remaining below 0.08 mg/kg/hour) to be given with toxicity profiles comparable to expensive lipid formulations of amphotericin B. Dedicated peripherally inserted central catheters can remain in situ for weeks to months and are safe and relatively inexpensive. Correction of metabolic pathology in the case of mucormycosis and resolution of neutropenia are essential to effective treatment of filamentous fungal infections such as Mucor, Aspergillus and Scedosporium. The pharmacology and pharmacokinetics of the current major antifungal agents used to treat fungal infections of the CNS are reviewed. Tables that provide information about achievable CNS drug levels, antifungal susceptibilities and the likelihood of intrinsic drug resistance of significant fungal pathogens have been included to help the clinician with therapy. Treatment recommendations for Cryptococcal and Candida meningitis and for rhinocerebral infection with Mucor and Aspergillus have been included.
Synergy between HIV and malaria is being increasingly recognized. We examined the antimalarial activity of sera from subjects receiving chloroquine, no drugs or HAART. Sera from subjects taking ritonavir-boosted saquinavir or lopinavir significantly inhibited parasite growth (median of 55 and 69% inhibition, respectively). These results indicate that patients on protease inhibitors may be afforded some protection from malaria. The clinical relevance of these observations will require confirmation in controlled studies in malaria-endemic regions.
HIV self-testing (HIVST) introduces opportunities for screening in non-conventional settings, and addresses known testing barriers. This study involved the development and evaluation of a free online HIVST dissemination service hosted by a peer-led, community-based organisation with on-site, peer-facilitated HIV testing, and established referral and support programs for people newly diagnosed with HIV to determine whether this model was feasible and acceptable for engaging MSM, particularly among infrequent and naive HIV-testers, or those living in remote and rural areas. Between December 2016 and April 2018, 927 kits were ordered by 794 individuals, the majority of whom were men who have sex with men (MSM) (62%; 494), having condomless sex (50%; 392), or living outside a major city (38%; 305). Very few (5%; 39) sought the available pre-test peer contact, despite 45% (353) being naive HIV-testers. This study demonstrates that online HIVST dissemination is acceptable and feasible for engaging at-risk suboptimal testers, including those unwilling to test elsewhere (19%; 47/225). With half (50%; 403) unwilling to buy a kit, our study suggests that HIVST will need to be subsidized (cost-neutral to users) to enhance population coverage and access.
A 63-year-old man admitted to hospital for the management of a frontal lobe abscess developed elevated liver enzymes within 48 hours of receiving meropenem. Liver enzymes reached a maximum at 5 days postadministration of meropenem, with alanine aminotransferase 1160 U/L, aspartate aminotransferase 787 U/L, alkaline phosphatase 297 U/L and gamma-glutamyltransferase 252 U/L. Meropenem was ceased and liver function normalised. Meropenem was administered for a second time later in the patient’s admission and again the patient developed rapidly increasing liver enzymes, with a mixed hepatocellular/cholestatic pattern. Other possible causes of liver injury were excluded following extensive investigations, and the patient’s liver enzymes continued to normalise following meropenem discontinuation. The patient was asymptomatic during the admission and was transferred to a rehabilitation facility. This case demonstrates that meropenem can cause severe liver injury and that early recognition of drug-induced liver injury is important.
CD103+ dermal dendritic cells (dDCs) are a recently described DC subset of the skin shown to be the principal migratory DCs capable of efficiently cross‐presenting antigens and activating CD8+ T cells. Harnessing their activity would promote vaccine efficacy, but it has been unclear how this can be achieved. We tested a panel of adjuvants for their ability to affect dDCs. In comparison to the other adjuvants tested, the capacity of cholera toxin (CT) to induce the migration of dDCs was unique. Within 24 h of CT injection, large numbers of highly activated dDCs (including CD103+ dDCs) migrated to the draining lymph nodes and cross‐presented coinjected antigens, potently activating naïve CD8+ T cells. Peptide vaccines adjuvanted with CT induced T‐cell responses uniquely characterized by dynamic cytokine responses including the production of IL‐2, and such vaccines were protective in situations reliant on CD8+ T‐cell responses, including liver‐stage Plasmodium challenge, or tumor challenge. This study is the first to examine the effects of adjuvants on CD103+ dDCs and identifies CT as a prototypical adjuvant for the activation of CD103+ dDCs, opening the way to development of vaccines and adjuvants that specifically target dDCs and generate effective CD8+ T‐cell responses.