Peggy L. Carver

Candida glabrata Fungemia: Experience in a Tertiary Care Center

BACKGROUND During the past decade, Candida glabrata has emerged as an important cause of fungemia. We reviewed demographic data, risk factors, treatment, and outcomes associated with C. glabrata fungemia from 1995-2002 and performed susceptibility testing of isolates. METHODS Data on all episodes of fungemia were prospectively recorded, and the associated isolates were saved. Medical records were reviewed retrospectively. Susceptibility testing was performed for fluconazole, itraconazole, and voriconazole. RESULTS C. glabrata caused 103 (17%) of 609 fungemic episodes during the 8-year period that we studied. Medical records and isolates were available for 94 episodes that occurred in 91 patients. The patients included 42 men and 49 women. The mean age was 51 years. Thirty-four episodes (36%) occurred in patients >60 years old; only 3 episodes occurred in patients <1 year old. The most common predisposing factors were use of broad-spectrum antibiotics (in 86% of episodes), use of central venous catheters (77%), stay in an intensive care unit (48%), renal failure (46%), and receipt of parenteral nutrition (45%). Of the 94 episodes, 83 were treated with antifungal agents. The overall mortality rate at day 30 was 29%. For the 11 episodes that were not treated, the mortality rate was 64% (7 of 11 episodes). Outcome appeared to be unrelated to whether fluconazole or amphotericin B was administered. In vitro, 60% of isolates were resistant to fluconazole, 83% to itraconazole, and 44% to voriconazole. Susceptibility to these azoles did not change over the 8 years of the study. CONCLUSION C. glabrata fungemia was most often seen in older adults and was associated with a mortality rate of 29%. Outcomes appeared to be unrelated to in vitro susceptibility results and to the antifungal agent used.

Antifungal agents in the 1990s. Current status and future developments.

SummarySignificant advances in antifungal therapy have occurred in the last decade. Most of these advances have been tied to the introduction of the triazoles, itraconazole and fluconazole. Itraconazole has proved efficacious for the treatment of subacute to chronic infections with the endemic mycoses and other opportunistic filamentous fungi, including Aspergillus spp. Fluconazole is now routinely used for mucocutaneous and systemic candidiasis, and its use for coccidioidal meningitis has obviated the need for intrathecal amphotericin B in most patients. Large, well controlled trials in AIDS patients with cryptococcal meningitis have shown the benefit of induction therapy with amphotericin B and flucytosine, followed by consolidation and life-long maintenance therapy with fluconazole. Concomitant with the increased use of these well tolerated, effective oral triazole agents has come the emergence of drug resistance in AIDS patients and shifts in the species of yeasts causing infection in hospitalised patients. Amphotericin B remains the drug of choice for many fungal infections, especially those that are life-threatening. Lipid-containing formulations of amphotericin B have recently been approved: these preparations significantly reduce the risk of amphotericin B–induced nephrotoxicity. Several new fungicidal agents are currently in early trials. With the increasing number of available antifungal drugs, future studies will help define the appropriate niche for each and the possible benefit of therapy with combinations of drugs.

HIV Protease Inhibitors: Advances in Therapy and Adverse Reactions, Including Metabolic Complications

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Steady‐state pharmacokinetics of delavirdine in HIV‐positive patients: Effect on erythromycin breath test

The steady‐state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus‐positive patients after escalating oral doses and after repeated oral administrations at the same dose level.

Impact of an Antimicrobial Stewardship Program Comprehensive Care Bundle on Management of Candidemia

To analyze the impact of a comprehensive care bundle directed by an antimicrobial stewardship team (AST) on the management of candidemia.

Antifungal prophylaxis in liver transplant recipients

Although the overall incidence of fungal infections in liver transplant recipients has declined, these infections still contribute significantly to the morbidity and mortality of patients with risk factors for infection. Although antifungal prophylaxis has been widely studied and practiced, no consensus exists on which patients should receive prophylaxis, with which agent, and for what duration. Numerous studies have attempted to ascertain independent risk factors for invasive fungal infections in liver transplant patients, and these data, in addition to clinical trials, identify several patient groups at exceedingly high risk of fungal infection. These include retransplant patients, patients with renal failure requiring hemodialysis or renal replacement therapy, and those requiring reoperations after transplant. Because the majority of infections occur in the first month after transplantation, prophylaxis should be continued for 4‐6 weeks. However, local epidemiology and research should guide decisions regarding choice of agent as well as overall development of interinstitutional guidelines, because the incidence and spectrum of infection may differ dramatically among institutions. Liver Transpl 15:842–858, 2009.

Real-World Experience with Echinocandin MICs against Candida Species in a Multicenter Study of Hospitals That Routinely Perform Susceptibility Testing of Bloodstream Isolates

ABSTRACT Reference broth microdilution methods of Candida echinocandin susceptibility testing are limited by interlaboratory variability in caspofungin MICs. Recently revised Clinical and Laboratory Standards Institute (CLSI) breakpoint MICs for echinocandin nonsusceptibility may not be valid for commercial tests employed in hospital laboratories. Indeed, there are limited echinocandin susceptibility testing data from hospital laboratories. We conducted a multicenter retrospective study of 9 U.S., Australian, and New Zealand hospitals that routinely tested Candida bloodstream isolates for echinocandin susceptibility from 2005 to 2013. Eight hospitals used Sensititre YeastOne assays. The Candida spp. were C. albicans (n = 1,067), C. glabrata (n = 911), C. parapsilosis (n = 476), C. tropicalis (n = 185), C. krusei (n = 104), and others (n = 154). Resistance and intermediate rates were ≤1.4% and ≤3%, respectively, for each echinocandin against C. albicans, C. parapsilosis, and C. tropicalis. Resistance rates among C. glabrata and C. krusei isolates were ≤7.5% and ≤5.6%, respectively. Caspofungin intermediate rates among C. glabrata and C. krusei isolates were 17.8% and 46.5%, respectively, compared to ≤4.3% and ≤4.4% for other echinocandins. Using CLSI breakpoints, 18% and 19% of C. glabrata isolates were anidulafungin susceptible/caspofungin nonsusceptible and micafungin susceptible/caspofungin nonsusceptible, respectively; similar discrepancies were observed for 38% and 39% of C. krusei isolates. If only YeastOne data were considered, interhospital modal MIC variability was low (within 2 doubling dilutions for each agent). In conclusion, YeastOne assays employed in hospitals may reduce the interlaboratory variability in caspofungin MICs against Candida species that are observed between reference laboratories using CLSI broth microdilution methods. The significance of classifying isolates as caspofungin intermediate and anidulafungin/micafungin susceptible will require clarification in future studies.

Update on Echinocandin Antifungals

Echinocandins are semisynthetic lipopeptides that competitively inhibit an essential cell wall component of Candida and aspergillus. They are generally inactive against other fungi. Resistance to these agents is infrequent to date. Echinocandins exhibit low oral bioavailability and are available only as parenteral formulations that are dosed once daily. None of the echinocandins serve as major substrates, inducers, or inhibitors of cytochrome P450 enzymes or the P-glycoprotein transport system; thus they have a low potential for serious drug-drug interactions. In candidemia trials, all echinocandins showed similar rates of success and were as efficacious as fluconazole, amphotericin B, or lipid formulations of amphotericin B. Caspofungin and micafungin have been studied as single-agent therapy in patients with invasive aspergillosis and will likely remain as second-line agents. However, because of their unique mechanism of action, echinocandins are ideally suited for use in combination with polyenes or azoles and are likely to be used increasingly in immunosuppressed hosts despite a current lack of controlled trials demonstrating efficacy. Limited experience suggests that caspofungin and micafungin are safe to use in pediatric patients. Hospital formulary committees are likely to view the three echinocandins as equivalent agents and place the least expensive agent on formulary.

Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients.

AbstractPurpose. To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects. Methods. Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan™ (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC. Results. All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0−∞ decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean Cmax was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was significantly delayed from 1 hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects. Conclusions. Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.

Use of azoles for systemic antifungal therapy.

Publisher Summary The azole antifungal agents have expanded the armamentarium of agents useful in the treatment of systemic fungal infections. Clotrimazole, an early imidazole antifungal, proved was found to rapidly induce its own metabolism after oral or intravenous administration. Its use is now confined to topical therapy. Miconazole is toxic and its availability is only as an intravenous formulation. Ketoconazole, the first oral imidazole, has proved useful for a wide variety of fungal infections. This chapter focuses on the use of these four azole agents that have proved beneficial in treating systemic fungal infections. The imidazole compounds contain a five member azole ring with two nitrogen atoms. The triazoles have a third nitrogen atom added. The triazole ring increases tissue penetration, prolongs half-life, and enhances efficacy of the azoles while decreasing the toxicity when compared with imidazole antifungal agents. Azoles inhibit the biosynthesis of ergosterol, a component of fungal cell membranes, via inhibition of the cytochromes P450-dependent enzyme lanosterol14-α-demethylase.Lanosterol14-α-demethylase is necessary for the conversion of lanosterol to ergosterol. Depletion of ergosterol in the fungal cell membrane results in altered membrane fluidity, thereby reducing the activity of membrane-associated enzymes. This leads to increased permeability and subsequent inhibition of cell growth and replication. The binding efficiency of azole antifungal agents to cytochromes P450 differs, resulting in differences in antifungal activity, toxicity of the agents, and the drug interactions with other cytochrome P45O-metabolized drugs. The chapter details the antifungal activity of the azoles, their pharmacology, clinical use, side effects, and administration. Drug interactions with azole antifungals are of two categories—decreases in azole bioavailability because of chelation or secondary to increases in gastric pH; and interactions with other cytochrome P45O-metabolized drugs. Drug interactions in the second category may result in increases or decreases in the azole antifungal, in the interacting drug, or in both drugs.