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.

Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations. Subtherapeutic concentrations of antiretroviral agents have been associated with viral resistance and regimen failure, but the clinical significance of our findings remains to be established.

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.

The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n ‫؍‬ 2) or significant increases in the serum creatinine (Scr) levels (n ‫؍‬ 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 g/ml for the first 7 days and >0.220 g/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 g/ml for at least 7 seven days. Amphotericin B (AMB) exhibits concentration-dependent fungicidal activity against many common opportunistic fungal pathogens (19,20). A dose-fractionation study with a murine disseminated candidiasis model demonstrated that maximization of the maximum drug concentration in plasma (C max )/ MIC ratio optimizes the efficacy of AMB (2). Theoretically, this should enable the intermittent administration of large amounts of AMB, which could make its use by ambulatory patients more practical. However, in practice, maximization of the concentration-dependent activity of AMB deoxycholate is difficult due to its dose-related nephrotoxicity. However, lipid AMB formulations are safer and demonstrate subtle pharmacokinetic differences in disposition from that of AMB deoxycholate, which allows the administration of higher doses. Lipid AMB formulations such as liposomal amphotericin B (L-AMB) should enable clinicians to optimize the pharmacodynamic properties of AMB and facilitate their use by ambulatory patients.Data from studies with neutropenic animals suggest that the administration of a single dose or intermittent doses of L-AMB up to 20 mg/kg of body weight can be employed to prevent or manage infections due to yeasts or molds (1,22). Higher L-AMB doses produce increased intravascular concentrations, which may facilitate its penetration into certain tissues and which may produce reductions in the fungal burdens in those tissues more marked than those achieved with other AMB formulations (17,28). In mice, L-AMB administered at 15 mg/kg thrice weekly produced sufficiently high and sustained kidney and spleen concentrations to provide prophylactic efficacy against systemic challenge with a Candida sp. 3 and 6 weeks posttreatment (30). In a murine model, the administration of a single prophylactic L-AMB dose (1, 5, 10, or 20 mg/kg) 7 to 9 days prior to challenge with Candida albicans or Histoplasma capsulatum produced increased L-AMB kidney and spleen concentrations which correlated with dose-dependent increases in efficacy (14).

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.