Antimicrobial stewardship and Clostridium difficile-associated diarrhea.

Antimicrobial stewardship programs are essential to health care institutions to promote the appropriate use of antibiotics not only to decrease antimicrobial resistance but to prevent the spread and infection of Clostridium difficile. Clostridium difficile-associated diarrhea is increasing rapidly in the United States and is now considered a major public health problem that poses an immediate threat to the health of patients prescribed antibiotics, more so than antimicrobial resistance. Clostridium difficile-associated disease is the result of collateral damage to the normal bacterial flora of the human body, which is an inevitable consequence of any antibiotic use. Antimicrobial stewardship programs such as audit with feedback and antibiotic restriction are designed to help limit Clostridium difficile infections and other hospital-associated organisms by optimizing antimicrobial selection, dosing, de-escalation, and duration of therapy. These programs also incorporate implementation of hospital-wide guidelines, staff education, enforcement of infection-control policies, and the use of electronic medical records when possible to help control antibiotic use. This article reviews the literature on how antimicrobial stewardship programs impact Clostridium difficile rates and discusses experiences in designing, implementing, monitoring, and follow-through of such programs.

An update and review of antiretroviral therapy.

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barriers to successful antiretroviral treatment, developments to limit treatment barriers, and new drug entities for the treatment of HIV.

Voriconazole.

BACKGROUND: Reports of resistance and intolerance to currently available antifungal agents are increasing. Voriconazole is a broad-spectrum azole antifungal agent structurally derived from fluconazole. It is indicated for the treatment of invasive aspergillosis and serious fungal infections caused by Scedosporium apiospermum and Fusarium species in patients who are unable to tolerate or are refractory to other antifungal therapy. OBJECTIVE: This article reviews the pharmacologic and pharmacokinetic properties and clinical usefulness of voriconazole. METHODS: Relevant information was identified through a search of MEDLINE (1966-December 2002), Iowa Drug Information Service (1966-December 2002), International Pharmaceutical Abstracts (1970-December 2002), and meeting abstracts of the Infectious Diseases Society of America (1996-2002) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996-2002) using the terms voriconazole and UK-109,495. RESULTS: In head-to-head comparative trials, voriconazole appeared to be as efficacious as amphotericin B for the treatment of invasive aspergillosis and the empiric treatment of fungal infections in patients with febrile neutropenia. In clinical studies, it was as efficacious as fluconazole for the treatment of oropharyngeal and esophageal candidiasis. The results of in vitro susceptibility studies and case reports suggested that voriconazole may be useful against fluconazole- and/or itraconazole-resistant strains of Candida. Although voriconazole may be associated with a lower incidence of serious systemic adverse effects compared with amphotericin B (13.4% vs 24.3% in 1 pivotal clinical study; P = NS), major adverse effects associated with voriconazole include visual abnormalities ( approximately 30%), skin reactions ( approximately 20%), and elevations in hepatic enzymes (< or =20%). Voriconazole is available as oral and intravenous formulations. Pharmacokinetically, it has widespread distribution, including penetration into cerebral tissue. However, as 80% of voriconazole is hepatically eliminated, primarily via the cytochrome P450 (CYP) isozymes CYP2C19, CYP3A4, and CYP2C9, voriconazole has a high potential for drug interactions, and dose reduction is recommended in patients with mild to moderate hepatic dysfunction (Child-Pugh class A or B). Oral voriconazole may be preferred in patients with a creatinine clearance <50 mL/min due to the potential accumulation of the solubilizing excipient in the parenteral formulation of voriconazole. CONCLUSIONS: Voriconazole appears to be a useful alternative to conventional antifungal agents in cases of resistance or intolerance to initial therapy. However, dose adjustment is recommended in patients with hepatic dysfunction, as well as in those receiving medications that may interact with voriconazole via hepatic metabolism.

Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is the first nucleotide reverse transcriptase inhibitor approved for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in the United States. Unlike the nucleoside reverse transcriptase inhibitors, which must undergo 3 intracellular phosphorylation steps for activation. nucleotide analogues such as tenofovir require only 2 such steps. This reduction in the phosphorylation requirement has the potential to produce more rapid and complete conversion of the drug to its pharmacologically active metabolite. OBJECTIVE: This article describes the pharmacologic properties and potential clinical usefulness of tenofovir DF. METHODS: Relevant information was identified through searches of MEDLINE (1996-April 2002), Iowa Drug Information Service (1996-April 2002), and International Pharmaceutical Abstracts (1970-April 2002), as well as from meeting abstracts of major HIV/AIDS conferences (1996-2002), using the search terms tenofovir tenofovir disoproxil fumarate, PMPA, bis(POC)PMPA, GS-4331-05, acyclic nucleoside phosphonate, and nucleotide reverse transcriptase inhibitor. Additional information was obtained from material submitted to the US Food and Drug Administration by the manufacturer of tenofovir DF in support of its New Drug Application. RESULTS: In vitro, tenofovir DF has exhibited anti-HIV activity in various HIV-infected cell lines and has produced a synergistic or additive effect against HIV when combined with other antiretroviral agents. In adult humans, tenofovir has a volume of distribution of 0.813 L/kg, is minimally bound to plasma protein (7.2%), has a plasma elimination half-life of 12.0 to 14.4 hours, and is mainly excreted unchanged in urine (70%-80%). Dose adjustment based on sex or body weight does not appear to be necessary, although dose reduction may be necessary in the elderly; there are currently no data on tenofovir DF in renal or hepatic insufficiency. The results of clinical trials suggest the efficacy of tenofovir DF in reducing plasma levels of HIV-1 RNA when used as an add-on to a stable antiretroviral regimen. The most commonly (>3%) reported adverse events in clinical trials have included nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdominal pain, and anorexia. The most commonly (>2%) reported laboratory abnormalities (grade III or IV) included increases in creatine kinase, triglycerides, amylase, aspartate aminotransferase, and alanine aminotransferase, as well as hyperglycemia and glucosuria. Serious adverse events leading to discontinuation of tenofovir DF were infrequent (5%), occurring with an incidence similar to that with placebo (8%). The recommended dosage of tenofovir DF in adults is 300 mg/d PO; pharmacokinetic and efficacy studies in children are ongoing. CONCLUSION: Although additional studies are needed, tenofovir DF appears to be a promising agent for the treatment of HIV infection.