Elizabeth Dodds Ashley

Pharmacology of Systemic Antifungal Agents

Traditionally, many invasive fungal infections were associated with a poor prognosis, because effective therapeutic options were limited. The recent development of new antifungal agents has significantly contributed to the successful treatment of fungal diseases. These drugs offer novel mechanisms of action and expanded spectrums of activity over traditional treatment options. However, with these new agents comes the need for increased awareness of the potential interactions and toxicities associated with these drugs. Therefore, an understanding of the pharmacokinetic and pharmacodynamic properties of the classes of antifungal compounds is vital for the effective management of invasive fungal infections. This review provides a summary of the pharmacologic principles involved in treatment of fungal diseases. The number of agents available to treat invasive fungal infections has increased by 30% since the turn of the millennium. Although that statistic is impressive, it brings the total number of approved systemic antifungal drugs to only 14 [1], with the potential for 1 more product to possibly emerge this year. These recent additions have provided clinicians with a tool previously lacking in the management of these life-threatening infections: therapeutic alternatives. Along with new options, however, comes the need to understand the uniqueness of each agent, including its role in therapy, toxicity profile, and interactions with concomitant medications. To attain the maximum effect from these agents, clinicians should also become familiar with strategies to optimize efficacy through an understanding of pharmacokinetic and pharmacodynamic properties. These characteristics are unique for each class of antifungal drug and even for each member within a class. In many cases, this variability is not subtle and merits careful attention.

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients.

Background. Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined. Methods. A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation. Results. Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p =0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p =0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period. Conclusions. Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.

Antimicrobial Stewardship Programs in Community Hospitals: The Evidence Base and Case Studies

By controlling and changing how antimicrobial agents are selected and administered, antimicrobial stewardship programs (ASPs) aim to prevent or slow the emergence of antimicrobial resistance; optimize the selection, dosing, and duration of antimicrobial therapy; reduce the incidence of drug-related adverse events; and lower rates of morbidity and mortality, length of hospitalization, and costs. There is an abundant and growing body of evidence demonstrating that ASPs change the quantity and quality of antimicrobial prescriptions; however, measuring whether, when, and how ASPs improve patient outcomes and change patterns of antimicrobial resistance--which is the ultimate goals of ASPs--has been difficult, but the totality of evidence indicates that ASPs are capable of achieving these goals. In this article, we review the existing data on ASPs and their effects on patient care and antimicrobial resistance, as well as strategies for establishing ASPs in different types of hospitals.

Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists.

Aerosolized delivery of antimicrobial agents is an attractive option for management of pulmonary infections, as this is an ideal method of providing high local drug concentrations while minimizing systemic exposure. With the paucity of consensus regarding the safety, efficacy, and means with which to use aerosolized antimicrobials, a task force was created by the Society of Infectious Diseases Pharmacists to critically review and evaluate the literature on the use of aerosolized antiinfective agents. This article summarizes key findings and statements for preventing or treating a variety of infectious diseases, including cystic fibrosis, bronchiecstasis, hospital acquired pneumonia, fungal infections, nontuberculosis mycobacterial infection, and Pneumocystis jiroveci pneumonia. Our intention was to provide guidance for clinicians on the use of aerosolized antibiotics through evidence based pharmacotherapy. Further research with well designed clinical trials is necessary to elucidate the optimal dosage and duration of therapy and, of equal importance, to appreciate the true risks associated with the use of aerosolized delivery systems.

Aspergillus fumigatus Empyema, Arthritis, and Calcaneal Osteomyelitis in a Lung Transplant Patient Successfully Treated with Posaconazole

ABSTRACT A 64-year-old male with Aspergillus fumigatus infection that had disseminated from the lung to the ankle and adjacent bone was treated successfully with posaconazole after therapy with itraconazole and amphotericin B lipid complex failed. Marked clinical improvement occurred within 6 weeks of initiation of posaconazole therapy; after 6 months, infection had resolved at all sites. The patient has had no recurrence of infection.

Antifungal pharmacotherapy for invasive mould infections

The incidence of invasive mould infections is increasing and is associated with significant morbidity and mortality. Among the most prevalent of these infections are those caused by Aspergillus and Fusarium species. Invasive disease caused by moulds frequently presents as a pulmonary infection, but haematogenous infection can occur. Some moulds cause cutaneous disease through either direct inoculation of the skin or secondary spread to the skin after dissemination from another body site. Early diagnosis can often be difficult and, unfortunately, diagnosis occurs late in the course of illness in many cases. Treatment options have historically been limited by the need for intravenous administration (amphotericin B), significant toxicities (amphotericin B), lack of reliable in vitro activity (e.g., amphotericin B in Fusarium and Scedosporium apiospermum infections) and relative lack of clinical experience with newer agents. The recent approval of voriconazole (Vfend™, Pfizer) introduces a treatment option that demonstrates both in vitro and in vivo activity against a variety of moulds. With the recent development of the new echinocandin class of antifungal agents and newer broad-spectrum azole antifungal agents with in vitro mould activity, there is a renewed emphasis on fungal treatment strategies. Antimould therapy presents challenges in adverse effect avoidance and management, drug interactions and pharmacoeconomic considerations. Furthermore, combination therapy is being explored with these various new antifungal agents. The administration of an optimal fungicidal therapy early in the course of the illness and control of the underlying disease are vital to prevent complications and mortality from these tenacious mycoses.

Cost of Invasive Fungal Infections in the Era of New Diagnostics and Expanded Treatment Options

To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections.

Pharmacist-managed antimicrobial stewardship program for patients discharged from the emergency department

Positive outcomes of antimicrobial stewardship programs in the inpatient setting are well documented, but the benefits for patients not admitted to the hospital remain less clear. This report describes a retrospective case–control study of patients discharged from the emergency department (ED) with subsequent positive cultures conducted to determine whether integrating antimicrobial stewardship responsibilities into practice of the emergency medicine clinical pharmacist (EPh) decreased times to positive culture follow-up, patient or primary care provider (PCP) notification, and appropriateness of antimicrobial therapy. Pre- and post-implementation groups of an EPh-managed antimicrobial stewardship program were compared. Positive cultures were identified in 177 patients, 104 and 73 in pre- and post-implementation groups, respectively. Median time to culture review in the pre-implementation group was 3 days (range 1-15) and 2 days (range 0-4) in the post-implementation group (P = .0001). There were 74 (71.2%) and 36 (49.3%) positive cultures that required notification in the pre- and post-implementation groups, respectively, and the median time to patient or PCP notification was 3 days (range 1-9) and 2 days (range 0-4) in the 2 groups (P = .01). No difference was seen in the appropriateness of therapy. In conclusion, EPh involvement reduced time to positive culture review and time to patient or PCP notification when indicated.

Recent advances in antifungal pharmacotherapy for invasive fungal infections.

Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone®, Bristol–Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas®, Merck and Co.) and voriconazole (Vfend®, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination antifungal therapy. Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients.

Alternative Therapies for Clostridium difficile Infections

Clostridium difficile infection is a serious condition responsible for significant morbidity and mortality, especially in patients being treated with antimicrobials. Increasing frequency of the infection and hypervirulent C. difficile strains have resulted in more severe disease as well as therapeutic failures with traditional treatment (metronidazole and vancomycin). To review the studies assessing nontraditional therapies for the prevention and treatment of primary or recurrent C. difficile infection, we conducted a literature search of the PubMed‐MEDLINE databases (1984–2010). Of the 98 studies identified, 21 met our inclusion criteria. Five clinical trials and one retrospective medical record review evaluated probiotic or prebiotic formulations for the prevention of C. difficile infection. Only one of these studies, which included Lactobacillus casei and L. bulgaricus in the probiotic formulation, showed efficacy. Ten clinical trials evaluated treatment of an initial episode of C. difficile infection (primary treatment) with the antimicrobials fidaxomicin, fusidic acid, rifampin, teicoplanin, and nitazoxanide, as well as the toxin‐binding polymer, tolevamer. Only nitazoxanide and teicoplanin demonstrated noninferiority when compared with vancomycin or metronidazole. Four prospective studies and one retrospective study evaluated treatment of relapsing C. difficile infection. Prebiotic formulations for the prevention and treatment of recurrent C. difficile infection have not proved to be clinically warranted. Nitazoxanide, teicoplanin, and fidaxomicin may be considered as alternatives to traditional treatment; however, clinical experience is limited with these agents for this indication. Bacteriotherapy with fecal instillation has demonstrated high clinical cure rates in case studies and in a retrospective study; however, to our knowledge, randomized clinical trials are lacking for this therapeutic approach. As C. difficile infection rates continue to increase and hypervirulent strains continue to emerge, it is important for future clinical studies to assess alternative therapies.