Richard H. Drew

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.

Ceftriaxone Once Daily for Four Weeks Compared with Ceftriaxone Plus Gentamicin Once Daily for Two Weeks for Treatment of Endocarditis Due to Penicillin-Susceptible Streptococci

This randomized, multicenter, open-label study compared the efficacy and safety of monotherapy with 2 g of intravenous ceftriaxone once daily for 4 weeks with those of combination therapy with 2 g of intravenous ceftriaxone and 3 mg of intravenous gentamicin/kg once daily for 2 weeks as therapy for endocarditis due to penicillin-susceptible streptococci. Sixty-one patients were enrolled in the study. Clinical cure was observed for 51 evaluable patients both at termination of therapy and at the 3-month follow-up: 25 (96.2%) of 26 monotherapy recipients and 24 (96%) of 25 combination therapy recipients. Of the 23 patients in each treatment group who were microbiologically evaluable, 22 (95.7%) in each group were considered cured. No patient had evidence of relapse. Fourteen patients (27.5%) required cardiac surgery after initiation of treatment, including five monotherapy recipients and nine combination therapy recipients. Adverse effects were minimal in both treatment groups. We conclude that 2 g of ceftriaxone once daily for 4 weeks and 2 g of ceftriaxone in combination with 3 mg of gentamicin/kg once daily for 2 weeks are both effective and safe for the treatment of streptococcal endocarditis.

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients

Background. Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients. Aerosolized amphotericin B lipid complex (ABLC) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models, but experience with aerosolized ABLC in humans is lacking. Methods. We conducted a prospective, noncomparative study designed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients. Results. A total of 381 treatments were administered to 51 patients. Complete spirometry records were available for 335 treatments (69 in intubated patients, 266 in extubated patients). ABLC was subjectively well tolerated in 98% of patients. Pulmonary mechanics worsened by 20% or more posttreatment in less than 5% of all treatments. There were no significant adverse events related to study medication in any patient, and 1-year survival for all enrolled patients was 78%. Conclusion. Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients. Additional prospective, randomized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients.

Emerging options for treatment of invasive, multidrug-resistant Staphylococcus aureus infections.

Limited established treatment options exist for the treatment of serious, invasive infections caused by multidrug‐resistant Staphylococcus aureus, most notably nosocomially acquired methicillin‐resistant S. aureus (MRSA). Although vancomycin represents the gold standard for therapy of such invasive infections, reports of increasing in vitro resistance to vancomycin, combined with reports of clinical failures (with this and other antistaphylococcal agents), underscore the need for alternative therapies. Older agents with favorable in vitro activity available in both oral and intravenous dose forms include trimethoprim‐sulfamethoxazole and clindamycin. Limited clinical data exist to support their routine use as initial therapy in the treatment of invasive disease. However, these and other options (e.g., tetracyclines) are being reexplored in the setting of increasing concern over MRSA acquired in the community setting. Newer treatment options for MRSA include linezolid, quinupristin‐dalfopristin, daptomycin, and tigecycline. With the exception of linezolid, these newer agents require intravenous administration. Combination therapy may be considered in select invasive diseases refractory to standard monotherapies. These diseases include infections such as endocarditis, meningitis, and prosthetic device infections. Additional alternatives to vancomycin are under clinical investigation. Those in later stages of development include oritavancin, dalbavancin, telavancin, and ceftobiprole.

Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam.

To determine whether the addition of piperacillin‐tazobactam leads to an increased incidence of nephrotoxicity in patients receiving vancomycin and to explore potential confounding factors that may increase the risk of vancomycin‐induced nephrotoxicity.

Insights from the Society of Infectious Diseases Pharmacists on Antimicrobial Stewardship Guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America

In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America published a document that addressed the major considerations for the justification, description, and conduct of antimicrobial stewardship programs. Our document is intended to continue the dialogue of these formalized programmatic strategies. We briefly review the guidelines, including the two primary strategies (prospective auditing with feedback, and preauthorization), and the supplemental strategies (education, information technology, transitional therapy, deescalation or streamlining, and dose optimization). Discussions are introduced or furthered in the areas of program goals, barriers and solutions, and outcome measures. Definition and training of infectious diseases pharmacists are presented in detail. We offer keys to future success, which include continued collaboration and expanded use of information technology.

Adverse drug reactions to systemic antifungals : prevention and management

SummarySystemic administration of antifungal agents for invasive mycoses has dramatically increased over the past 10 years in many fields of medicine. The increase has been due both to an increasing immune compromised population and to potent antibacterial agents which allow these fungi to invade tissue. It is apparent that our understanding of the use of both the old and new antifungal agents has significantly increased in the last few years. In this review, we attempt to document our extensive knowledge of the adverse effects of the polyenes, flucytosine, griseofulvin and azoles when given systemically for treatment. Interwoven in this documentation of the adverse reactions to these agents is the attempt to help clinicians potentially avoid some of these adverse effects and if they do occur, to be able to identify and successfully manage them.

Liposomal amphotericin B: clinical experience and perspectives

While amphotericin B deoxycholate (Fungizone®, Apothecon Pharmaceuticals) has been considered by many to be the gold standard for the treatment for numerous invasive fungal infections for over 45 years, toxicities associated with its use often necessitate treatment modification or discontinuation. Lipid-based formulations, including liposomal amphotericin B (AmBisome®, Fujisawa Healthcare, Inc.), were developed to decrease many of these toxicities while retaining broad antifungal spectrum and potency of amphotericin B. In clinical trials, liposomal amphotericin B has demonstrated efficacy comparable to that of amphotericin B deoxycholate while reducing the incidence of treatment-related nephrotoxicity, electrolyte-wasting, and infusion-related reactions. In addition, recent clinical trials have also compared liposomal amphotericin B with other antifungal classes. Acquisition costs of liposomal amphotericin B are substantially higher than those of amphotericin B deoxycholate and other antifungals. While pharmacoeconomic analyses consider outcomes and other treatment-related costs, they have yet to clearly demonstrate the cost-effectiveness of liposomal amphotericin B when compared with amphotericin B deoxycholate or other antifungal agents. This review will focus primarily on recent liposomal amphotericin B experience and attempt to put its use into perspective considering other available antifungal agents.

Is It Time to Abandon the Use of Amphotericin B Bladder Irrigation

In this article, we review the issues surrounding funguria and its management. With this background, the value of bladder irrigation with amphotericin B for the management of funguria is directly examined. Amphotericin B bladder irrigation is used frequently in clinical practice. Although its use is not standardized, there are multiple studies that attempt to show the impact on funguria management. These bladder irrigations have been used either for treatment of funguria or (less commonly) as a diagnostic test in attempts to identify upper urinary tract disease. Despite their widespread therapeutic use and relative safety, it is not clear from our experience and a review of the literature that amphotericin B bladder irrigations have any diagnostic or therapeutic value. The patient may be best served by removal of the urinary catheter, if possible, rather than by instillation of bladder irrigation with amphotericin B.

Recent advances in the epidemiology, prevention, diagnosis, and treatment of fungal pneumonia.

Although pneumonia caused by fungi is not a common occurrence in the general population, disease in an enlarging immunocompromized population is encountered with increasing frequency. Fungal pneumonias are most frequently caused by Aspergillus spp., dimorphic fungi and Cryptococcus neoformans. Recent studies have identified risk factors of thrombocytopenia, environmental events (such as construction or renovation) and immunosuppressive drug therapies as being specific risk factors for invasive fungal disease in select patient populations. Diagnostic strategies to detect circulating antigens and polymerase chain reaction based detection systems have been explored to improve identification prior to the progressive advanced disease. Advances in prophylactic strategies include increased use of aerosolized formulations of amphotericin B, usually in conjunction with new and old systemic antifungal agents. Despite recent published guidelines for treatment of fungal pneumonia based on etiology, mortality remains high in some infections with advanced disease. Caspofungin, a new echinocandin antifungal, has recently been approved by the US Food and Drug Administration for the treatment of invasive Aspergillus infections in patients unresponsive to or unable to receive amphotericin B. A triazole antifungal, voriconazole, has shown promise in phase III clinical trials in patients with refractory fungal infections and is expected to be available in early 2002. Other echinocandin and triazole antifungals are under development in attempts to provide improved effective therapy for fungal pneumonia.