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Azole antifungals are first-line options in the prophylaxis and treatment of invasive fungal infections. They are often used for prolonged (weeks to months) periods of time, particularly in patients with hematologic malignancies, or in those who have received a solid organ or hematopoietic stem cell transplant. Long-term use of azoles is associated with hepatotoxicity and hormone-related effects, including gynecomastia, alopecia, decreased libido, oligospermia, azoospermia, impotence, hypokalemia, hyponatremia, and (rarely) adrenal insufficiency. Voriconazole and posaconazole have been associated with peripheral neuropathies, and itraconazole and voriconazole with pancreatitis. In addition, voriconazole has been associated with periostitis, phototoxic reactions, and squamous cell carcinoma. Since many at-risk patients are commonly receiving multiple medications, it can be difficult for care providers to identify antifungal agent causality or contribution to patient symptoms. Knowledge and recognition of adverse events caused by azoles, leading to dose reduction or discontinuation, can generally reverse these adverse events.

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.

Trace elements (TEs) are required by both humans and bacterial pathogens. Although metal ion homeostasis is tightly controlled in humans, growing evidence suggests that pathogens utilize a variety of means designed to circumvent the sequestration of TEs. Colonizing pathogenic microorganisms employ a variety of strategies to sense, acquire, store, and export metal ions in the vertebrate host which include the biosynthesis and utilization of siderophores, and the expression of high-affinity metal-ion transporters. For iron, selenium, and zinc, significant correlations have been shown between TE levels in plasma, serum, or tissues, and the prevention or treatment of a variety of infectious diseases; fewer such data exist for copper, chromium, or manganese. TEs are often employed as antioxidants, and as supplements in patients with TE-deficient states. The role of TE supplementation in humans as antioxidants remains controversial, but has demonstrated significant benefit in the role of selenium for patients with sepsis, and of zinc for the prevention of several infectious diseases.

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. 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. All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0-infinity 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 I 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. 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.

In a randomized crossover trial, gastric acidity and gastric microbial colonization in 19 men infected with human immunodeficiency virus (HIV) (of whom nine had AIDS) were assessed. Gastric acidity was assessed during a baseline period and following pentagastrin or glutamic acid administration. Only two (22.2%)of the nine patients with AIDS and none of the non-AIDS patients were hypochlorhydric, as determined by maximal acid output. However, 60% and 67% of patients in the HIV-infected and AIDS groups, respectively, had persistently elevated gastric pH values during the baseline period. Both pentagastrin and glutamic acid significantly increased gastric acidity. Gastric colonization with Candida albicans and gram-positive mouth flora was common. Overall, this study demonstrates that many HIV-infected patients have elevated gastric pH values that may lead to alteration in drug absorption. The large degree of intrasubject and intersubject variability observed in gastric pH suggests that, unfortunately, one cannot predict which patients will have elevated gastric pH values.

The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug-drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug-drug interactions. This, combined with some evidence of decreasing susceptibility among some strains of Candida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents.