Dustin Wilson

Azole antifungals: 35 years of invasive fungal infection management

Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non–life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects.

Antifungal therapy for invasive fungal diseases in allogeneic stem cell transplant recipients: an update.

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug–drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.

Overview of treatment options for invasive fungal infections

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.

Role of isavuconazole in the treatment of invasive fungal infections.

Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug–drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug–drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring.

Focus on JNJ-Q2, a novel fluoroquinolone, for the management of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections

JNJ-Q2 is a novel, fifth-generation fluoroquinolone that has excellent in vitro and in vivo activity against a variety of Gram-positive and Gram-negative organisms. In vitro studies indicate that JNJ-Q2 has potent activity against pathogens responsible for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), such as Staphylococcus aureus and Streptococcus pneumoniae. JNJ-Q2 also has been shown to have a higher barrier to resistance compared to other agents in the class and it remains highly active against drug-resistant organisms, including methicillin-resistant S. aureus, ciprofloxacin-resistant methicillin-resistant S. aureus, and drug-resistant S. pneumoniae. In two Phase II studies, the efficacy of JNJ-Q2 was comparable to linezolid for ABSSSI and moxifloxacin for CABP. Furthermore, JNJ-Q2 was well tolerated, with adverse event rates similar to or less than other fluoroquinolones. With an expanded spectrum of activity and low potential for resistance, JNJ-Q2 shows promise as an effective treatment option for ABSSSI and CABP. Considering its early stage of development, the definitive role of JNJ-Q2 against these infections and its safety profile will be determined in future Phase III studies.

Emerging Treatment Options for Complicated Skin and Skin Structure Infections: Oritavancin

Oritavancin is a semisynthetic lipoglycopeptide with in vitro activity against a variety of aerobic Gram-positive pathogens (including drug-resistant forms of staphylococci, streptococci, and enterococci) and select anaerobic organisms. Available published clinical efficacy and safety studies in humans to date focus primarily in the treatment of complicated skin and skin structure infections. While oritavancin doses in these studies varied, single daily doses of 200 mg (300 mg in patients >100 kg) for 3–7 days have demonstrated efficacy similar to comparators (such as vancomycin followed by cephalexin). The most frequent adverse events reported to date include gastrointestinal complaints, insomnia, dizziness, itching, and rash. Further safety and efficacy data are needed to better define its potential place in therapy.

Impact of automatic infectious diseases consultation on the management of fungemia at a large academic medical center

Purpose. The impact of automatic infectious diseases (ID) consultation for inpatients with fungemia at a large academic medical center was studied. Methods. In this single‐center, retrospective study, the time to appropriate antifungal therapy before and after implementing a policy requiring automatic ID consultation for the management of fungemia for all patients with an inpatient positive blood culture for fungus was examined. The rates of ID consultation; the likelihood of receiving appropriate antifungal therapy; central venous catheter (CVC) removal rates; performance of ophthalmologic examinations; infection‐related length of stay (LOS); rates of all‐cause inhospital mortality, death, or transfer to an intensive care unit within 7 days of first culture; and inpatient cost of antifungals were also evaluated. Results. A total of 173 unique episodes (94 and 79 in the control and intervention groups, respectively) were included. Candida species were the most frequently cultured organisms, isolated from over 90% of patients in both groups. No differences were observed between the control and intervention groups in time to appropriate therapy, infection‐related LOS, or time to CVC removal. However, patients in the intervention group were more likely than those in the control group to receive appropriate antifungal therapy (p = 0.0392), undergo ophthalmologic examination (p = 0.003), have their CVC removed (p = 0.0038), and receive ID consultation (p = 0.0123). Inpatient antifungal costs were significantly higher in the intervention group (p = 0.0177). Conclusion. While automatic ID consultation for inpatients with fungemia did not affect the time to administration of appropriate therapy, improvement was observed for several process indicators, including rates of appropriate antifungal therapy selection, time to removal of CVCs, and performance of ophthalmologic examinations.