Jason A. Trubiano

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014

Antifungal agents may be associated with significant toxicity or drug interactions leading to sub‐therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre‐hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non‐compliance, non‐linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.

Faecal microbiota transplantation for severe Clostridium difficile infection in the intensive care unit.

We describe a case of faecal microbiota transplantation (FMT) used for severe binary toxin-positive Clostridium difficile infection in an intensive care setting. The patient was admitted to the ICU of a tertiary hospital and failed traditional maximal pharmacological management. Adjunctive therapy with FMT given through gastroscopy resulted in resolution of the C. difficile-related symptoms. Although there is a growing experience with FMT for recurrent C. difficile infection, published evidence in severe disease is very limited. In a landscape of increasingly severe C. difficile infection, adjunctive FMT may be considered a useful early treatment option.

Antimicrobial stewardship’s new weapon? A review of antibiotic allergy and pathways to ‘de-labeling’

PURPOSE OF REVIEW The continued emergence of multiresistant pathogens and widespread antimicrobial use has led to a greater emphasis on antimicrobial stewardship programs. Concurrently, an increased awareness of the rising number of antibiotic allergy labels and impact on antimicrobial use has surfaced. The integration of antibiotic allergy de-labeling and antimicrobial stewardship programs may be a pathway worthy of further focus and investigation. RECENT FINDINGS Recent literature has evaluated the efficacy of antibiotic allergy management (historical de-labeling, in-vitro testing, skin prick testing, intradermal testing, and oral challenges) and impact of antibiotic allergy labels on patient outcome. The importance of true and perceived antibiotic allergy cross-reactivity in the setting of β-lactam allergies has been highlighted. The impact of dedicated antibiotic allergy de-labeling clinics, inpatient antibiotic allergy testing, and integrated antimicrobial stewardship programs has been recently appraised. SUMMARY More recent literature supports that appropriate antibiotic allergy in-vitro and in-vivo testing and subsequent antibiotic allergy de-labeling, particularly in regard to β-lactams, can decrease broad-spectrum antibiotic use, costs, patient length of stay, and mortality. Integration of antibiotic allergy management into the decision support systems of inpatient and outpatient antimicrobial stewardship programs represents an important opportunity to further improve measured outcomes from antibiotic utilization.

The prevention and management of infections due to multidrug resistant organisms in haematology patients

Infections due to resistant and multidrug resistant (MDR) organisms in haematology patients and haematopoietic stem cell transplant recipients are an increasingly complex problem of global concern. We outline the burden of illness and epidemiology of resistant organisms such as gram-negative pathogens, vancomycin-resistant Enterococcus faecium (VRE), and Clostridium difficile in haematology cohorts. Intervention strategies aimed at reducing the impact of these organisms are reviewed: infection prevention programmes, screening and fluoroquinolone prophylaxis. The role of newer therapies (e.g. linezolid, daptomycin and tigecycline) for treatment of resistant and MDR organisms in haematology populations is evaluated, in addition to the mobilization of older agents (e.g. colistin, pristinamycin and fosfomycin) and the potential benefit of combination regimens.

Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand.

The incidence of Clostridium difficile infection (CDI) continues to rise, whilst treatment remains problematic due to recurrent, refractory and potentially severe nature of disease. The treatment of C. difficile is a challenge for community and hospital‐based clinicians. With the advent of an expanding therapeutic arsenal against C. difficile since the last published Australasian guidelines, an update on CDI treatment recommendations for Australasian clinicians was required. On behalf of the Australasian Society of Infectious Diseases, we present the updated guidelines for the management of CDI in adults and children.

Travel risk assessment, advice and vaccinations in immunocompromised travellers (HIV, solid organ transplant and haematopoeitic stem cell transplant recipients): a review.

International travellers with immunocompromising conditions such as human immunodeficiency virus (HIV) infection, solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT) are at a significant risk of travel-related illnesses from both communicable and non-communicable diseases, depending on the intensity of underlying immune dysfunction, travel destinations and activities. In addition, the choice of travel vaccinations, timing and protective antibody responses are also highly dependent on the underlying conditions and thus pose significant challenges to the health-care providers who are involved in pre-travel risk assessment. This review article provides a framework of understanding and approach to aforementioned groups of immunocompromised travellers regarding pre-travel risk assessment and management; in particular travel vaccinations, infectious and non-infectious disease risks and provision of condition-specific advice; to reduce travel-related mortality and morbidity.

Disseminated Scedosporium prolificans infection in an ‘extensive metaboliser’: navigating the minefield of drug interactions and pharmacogenomics

We report a case of non‐fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole‐chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported.

Old but not forgotten: Antibiotic allergies in General Medicine (the AGM Study).

Objectives: To determine the nature, prevalence and description accuracy of recorded antibiotic allergy labels (AALs) in a cohort of general medical inpatients, and to assess the feasibility of an oral antibiotic re‐challenge study.

Non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population

This retrospective case series identifies the largest cohort of non‐O1, non‐O139 Vibrio cholerae bacteraemia in an Australian population from 2000 to 2013. We examine the risk factors, epidemiology, clinical presentations and mortality of non‐O1, non‐O139 V. cholerae bacteraemia in Victoria and compare them with published cases in the literature. This case series highlights the pathogenic potential of non‐O1, non‐O139 V. cholerae and identifies possible associations with host (underlying chronic liver disease and malignancy) and environmental factors (contaminated water supply and raw seafood). Clinicians should be aware of the morbidity and mortality associated with invasive non‐O1, non‐O139 V. cholerae infections, particularly in immunocompromised patients.

Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort

OBJECTIVES The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD. METHODS As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured. RESULTS The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%). CONCLUSIONS Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.