Jarrett R. Amsden

Drug–drug interactions of antifungal agents and implications for patient care

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug–drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug–drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

Effect of High-Dose Vitamin C on the Steady-State Pharmacokinetics of the Protease Inhibitor Indinavir in Healthy Volunteers

Study Objective. To determine whether daily high‐dose vitamin C alters the steady‐state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1.

Successful treatment of West Nile virus infection after approximately 3 weeks into the disease course.

West Nile virus can cause a febrile illness that may progress to meningoencephalitis. The only available treatments are ribavirin (although it has had limited success in humans) and interferon α‐2b. A small pilot study showed that starting treatment with interferon α‐2b on days 1–4 of hospital admission may reduce disease severity and complications. We encountered an 83‐year‐old man with West Nile meningoencephalitis who began taking interferon α‐2b 3 weeks after disease presentation. Although studies and reports indicate that treatment is less likely to provide a favorable response if administered after days 1–6 of the disease course, the patient experienced substantial beneficial effects from this treatment. This is the first case report, to our knowledge, that describes successful treatment with interferon α‐2b after several weeks of West Nile virus infection. Further studies are warranted to more fully understand the value of interferon α‐2b in treating West Nile meningoencephalitis.

Tick‐Borne Bacterial, Rickettsial, Spirochetal, and Protozoal Infectious Diseases in the United States: A Comprehensive Review

Approximately 900 tick species exist worldwide, and they parasitize a variety of mammals, including humans; thus, ticks play a significant role in the transmission of infectious diseases. In the United States, tick‐borne diseases are seasonally and geographically distributed; they typically occur during spring and summer but can occur throughout the year. Tick‐borne diseases are endemic to a variety of geographic regions of the United States, depending on the species of tick commonly found in a specific locale. Specific tick‐borne diseases are difficult to diagnose. Most patients have vague constitutional symptoms and nonspecific laboratory findings. Initially, serologic methods are of little benefit because they lack sensitivity early in the disease course. Therefore, a thorough history and physical examination are necessary for establishing a diagnosis. Antimicrobial regimens for tick‐borne infections are poorly studied but well established. Tetracyclines and rifampin form the cornerstones of therapy for most tick‐borne infections, but these agents may not be suitable for all patient populations. Therefore, no single agent can be chosen empirically to treat all tick‐borne diseases. Because pharmacists are the most accessible health care providers, they are often asked how to treat tick‐borne diseases. Thus, practitioners should be familiar with the ticks that inhabit their locale.

Steady-State Pharmacokinetics of Oral Voriconazole and Its Primary Metabolite, N-Oxide Voriconazole, Pre- and Post-Autologous Peripheral Stem Cell Transplantation

ABSTRACT Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT.

Fungal Biomarkers, Antifungal Susceptibility Testing, and Therapeutic Drug Monitoring—Practical Applications for the Clinician in a Tertiary Care Center

Invasive fungal infections (IFIs) have increased steadily over the past several decades. The incidence of IFIs with reduced antifungal susceptibility or resistance is also on the rise. These IFIs carry significant morbidity and mortality. Among the many reasons for these poor outcomes have been the delays in diagnosis and adequate treatment of these infections. Therefore, considerable research has been directed towards earlier diagnostic strategies using biomarkers, the development and standardization of antifungal susceptible testing (AST), as well as therapeutic drug monitoring (TDM) of antifungal agents. This review will provide a summary overview of these areas and their practical application to clinicians practicing in tertiary care centers.

Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy

ABSTRACT Introduction: Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability. A search of English language original research, and scholarly reviews describing the pharmacogenomics of triazole antifungal agents and their impact on drug efficacy, safety, and tolerability published from 1980 to present was undertaken using PubMed. Expert opinion: Currently studies demonstrating the pharmacogenomic influences on itraconazole, posaconazole and isavuconazole are minimal and limited to their inhibitory effects on CYP3A4 in expressors of CYP3A5 variants. Conversely, there are significant pharmacogenomic considerations for voriconazole because it interacts with several polymorphic CYPs, most notably CYP2C19. Pharmacogenomics of CYP2C9 do not appear to effect fluconazole safety and efficacy. However, genetic polymorphisms may influence its drug interactions but this needs further study.