The introduction of several new antifungals has significantly expanded both prophylaxis and treatment options for invasive fungal infections (IFIs). Relative to amphotericin B deoxycholate, lipid-based formulations of amphotericin B have significantly reduced the incidence of nephrotoxicity, but at a significant increase in drug acquisition cost. Newer, broad-spectrum triazoles (notably voriconazole and posaconazole) have added significantly to both the prevention and treatment of IFIs, most notably Aspergillus spp. (with voriconazole) and the treatment of some emerging fungal pathogens. Finally, a new class of parenteral antifungals, the echinocandins, is employed most frequently against invasive candidal infections. While the role of these newer agents continues to evolve, this review summarizes the activity, safety and clinical applications of agents most commonly employed in the treatment of IFIs.

Background The Core Elements of Outpatient Antibiotic Stewardship provide a framework to improve antibiotic use, but evidence supporting safety are limited. We report the impact of Core Elements implementation within Veterans Health Administration sites. Methods A quasi-experimental controlled study assessed the effects of an intervention targeting antibiotic prescription for uncomplicated acute respiratory tract infections (ARI). Outcomes included per-visit antibiotic prescribing, treatment appropriateness, potential benefits and complications of reduced antibiotic treatment, and change in ARI diagnoses over a 3-year pre-implementation and 1-year post implementation period. Logistic regression adjusted for covariates [OR (95% CI)] and a difference-in-differences analysis compared outcomes between intervention and control sites. Results From 2014-2019, there were 16,712 and 51,275 patient-visits in 10 intervention and 40 control sites, respectively. Antibiotic prescribing rates pre-post implementation in intervention sites were 59.7% and 41.5%, respectively; in control sites they were 73.5% and 67.2%, respectively [difference-in-differences p<0.001]. The intervention site pre-post implementation odds ratio to receive appropriate therapy increased [1.67 (1.31, 2.14)] which remained unchanged within control sites [1.04 (0.91, 1.19)]. There was no difference in ARI-related return visits post-implementation [(-1.3% vs. -2.0%; difference-in-differences p=0.76] but all-cause hospitalization was lower within intervention sites [(-0.5% vs. -0.2%); difference-in-differences p=0.02]. The odds ratio to diagnose upper respiratory tract infection not otherwise specified compared to other non-ARI diagnosis increased post-implementation for intervention [1.27(1.21,1.34)] but not control [0.97(0.94,1.01)] sites. Conclusions Implementation of the Core Elements was associated with reduced antibiotic prescribing for uncomplicated ARIs and a reduction in hospitalizations. ARI diagnostic coding changes were observed.

Echinocandins have made a significant impact in the treatment of select invasive fungal infections, most notably invasive candidiasis and aspergillosis. However, treatment outcomes for such infections are still less than optimal, prompting an examination of dosing and administration techniques in an attempt to exploit known pharmacodynamic properties and improve outcomes. Echinocandins generally exhibit concentration-dependent, fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp. However, increasing drug concentrations of echinocandins above the organism's MIC may result in a paradoxical increase in fungal growth as demonstrated in some in vitro and in vivo models (known most commonly as the 'Eagle effect'). Therefore, the potential impact of dose escalations on improving the clinical efficacy of echinocandins based on in vitro and animal models are uncertain and are still being evaluated. In addition, such strategies have to consider the potential for increased treatment-related toxicities and costs. To date, published clinical studies (both superiority and non-inferiority) demonstrating the potential for dose-related improvements in treatment outcomes have been limited to mucocutaneous and oesophageal candidiasis. Further research is needed to determine if a role exists for optimizing echinocandin pharmacodynamics in various clinical settings.

Tigecycline is a new glycyclcycline antimicrobial recently approved for use in the USA, Europe and elsewhere. While related to the tetracyclines, tigecycline overcomes many of the mechanisms responsible for resistance to this class. It demonstrates favourable in vitro potency against a variety of aerobic and anaerobic Gram-positive and Gram-negative pathogens, including those frequently demonstrating resistance to multiple classes of antimicrobials. This includes methicillin-resistant Staphylococcus aureus, penicillin-resistant S. pneumoniae, vancomycin-resistant enterococci, Acinetobacter baumannii, beta-lactamase producing strains of Haemophilis influenzae and Moraxella catarrhalis, and extended-spectrum beta-lactamase producing strains of Escherichia coli and Klebsiella pneumoniae. In contrast, minimum inhibitory concentrations for Pseudomonas and Proteus spp. are markedly elevated. Tigecycline is administered parenterally twice daily. Randomised, controlled trials have demonstrated that tigecycline is non-inferior to the comparators for the treatment of complicated skin and skin structure infections, as well as complicated intra-abdominal infections. The most frequent and problematic side effect associated with its administration to date has been nausea and/or vomiting.

This study suggests that DDIs are prevalent among patients treated with DAAs for HCV. A HCV clinical pharmacist can help optimize patient care by identifying DDIs and recommending interventions to providers.