Search

Dustin T Wilson,1,2 V Paul Dimondi,1,3 Steven W Johnson,1,4 Travis M Jones,1 Richard H Drew1,5 1Department of Pharmacy Practice, Campbell University College of Pharmacy & Health Sciences, Buies Creek, NC, USA; 2Department of Pharmacy, Duke University Hospital, Durham, NC, USA; 3Department of Pharmacy, Durham VA Medical Center, Durham, NC, USA; 4Department of Pharmacy, Forsyth Medical Center, Winston-Salem, NC, USA; 5Division of Infectious Diseases, Duke University Hospital, Durham, NC, USA Abstract: Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug–drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug–drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring. Keywords: isavuconazole, azole, antifungal, aspergillosis, Mucormycetes, mucormycosis

Background: Studies examining relationships between patient-related factors and treatment outcome in patients with candidemia are limited and often based on all-cause mortality. Objective: Our purpose was to examine the impact of concurrent renal replacement therapy (RRT) and other pre-specified factors on treatment outcome among adults with candidemia. Methods: This Institutional Review Board (IRB)-approved, single-center, case-cohort study included patients over 18 years of age admitted to Duke University Hospital between Jun 1, 2013 and Jun 1, 2017 with a blood culture positive for Candida spp. Treatment-, patient-, and disease-specific data were collected, and outcome (success/failure) determined 90 days after the index culture. An odds ratio (OR) and 95% confidence interval (95%CI) were calculated for the following during therapy: receipt of RRT, fluconazole monotherapy regimen, intensive care unit (ICU) stay, and neutropenia. Results: Among the 112 encounters (from 110 unique patients) included, treatment failure occurred in 8/112 (7.1%). Demographics were comparable between outcome groups. Among 12 patients receiving concomitant RRT, only 1 patient failed therapy. With regard to treatment failure, no significant differences were observed with RRT (OR, 1.21; 95%CI, 0.14 – 10.75), fluconazole monotherapy regimen (OR, 1.59; 95%CI, 0.3-8.27), ICU stay (OR, 1.43; 95%CI, 0.32-6.29), and neutropenia (0 treatment failures). Conclusions: Treatment failure, receipt of concomitant RRT, and neutropenia were infrequent in patients undergoing treatment for candidemia. In our cohort, exposure to RRT, a fluconazole monotherapy regimen, ICU stay, or neutropenia during treatment did not impact treatment outcome.

Background: There remains variability in both practice and evidence related to optimal initial empiric dosing strategies for vancomycin. Objective: Our primary objective was to describe the percentage of obese patients receiving vancomycin doses consistent with nomogram recommendations achieving targeted initial steady-state serum vancomycin concentrations. Secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance, to describe the rate of supratherapeutic vancomycin accumulation following an initial therapeutic trough concentration, and to describe the rate of vancomycin-related adverse events. Methods: This single-center, IRB-approved, retrospective cohort included adult patients ≥ 100 kilograms total body weight with a body mass index (BMI) >30 kilograms/m2 who received a stable nomogram-based vancomycin regimen and had at least one steady-state vancomycin trough concentration. Data collected included vancomycin regimens and concentrations, vancomycin indication, serum creatinine, and vancomycin-related adverse events. Patients were divided into two cohorts by goal trough concentration: 10-15 mcg/mL and 15-20 mcg/mL. Results: Of 325 patients screened, 85 were included. Goal steady-state concentrations were reached in 42/85 (49.4%) of total patients. Conclusions: Achievement of initial steady-state vancomycin serum concentrations in the present study (approximately 50%) was consistent with the use of published vancomycin dosing nomograms.

With the advent of COVID-19, major media outlets and health organizations have been eager to provide projections on the spread of infectious disease through a population based on different variables. This report outlines two activities for leveraging the global interest in COVID-19 to: 1) encourage students to explore simulations and data presentation, and 2) develop models of complex systems using a block-based coding platform (StarLogo Nova). The activities may be used independently or paired to build upon each other.

Policies that promote conversion of antibiotics from intravenous to oral route administration are considered "low hanging fruit" for hospital antimicrobial stewardship programs. We developed a simple metric based on digestive days of therapy divided by total days of therapy for targeted agents and a method for hospital comparisons. External comparisons may help identify opportunities for improving prospective implementation.

The administration of approved antifungals via unapproved formulations or administration routes (such as aerosol, direct injection, irrigation, topical formulation and antifungal-impregnated orthopedic beads or cement) may be resorted to in an attempt to optimize drug exposure while minimizing toxicities and/or drug interactions associated with conventional (systemic) administrations. Existing data regarding such administrations are mostly restricted to uncontrolled case reports of patients with diseases refractory to conventional therapies. Attribution of efficacy and tolerability is most often problematic. This review updates prior published summaries, reflecting the most recent data and its application by available prevention and treatment guidelines for invasive fungal infections. Of the various dosage forms and antifungals, perhaps none is more widely reported than the application of amphotericin B-containing aerosols for the prevention of invasive mold infections (notably Aspergillus spp.).

Background: Penicillin allergy frequently impacts antibiotic choice. As beta-lactams are superior to vancomycin in treating methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, we examined the effect of reported penicillin allergy on clinical outcomes in patients with MSSA bacteremia., Methods: In this retrospective cohort study of adults with MSSA bacteremia admitted to a large tertiary care hospital, outcomes were examined according to reported penicillin allergy. Primary outcomes included 30-day and 90-day mortality rates. Multivariable regression models were developed to quantify the effect of reported penicillin allergy on mortality while adjusting for potential confounders., Results: From 2010 to 2015, 318 patients with MSSA bacteremia were identified. Reported penicillin allergy had no significant effect on adjusted 30-day mortality (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.29-1.84; P = .51). Patients with reported penicillin allergy were more likely to receive vancomycin (38% vs 11%, P < .01), but a large number received cefazolin regardless of reported allergy (29 of 66, 44%). Mortality rates were highest among nonallergic patients receiving vancomycin (22.6% vs 7.4% for those receiving beta-lactams regardless of reported allergy, P < .01). In multivariable analysis, beta-lactam receipt was most strongly associated with survival (OR, 0.26; 95% CI, 0.12-0.54)., Conclusions: Reported penicillin allergy had no significant effect on 30- or 90-day mortality. Non-penicillin-allergic patients receiving vancomycin for treatment of MSSA bacteremia had the highest mortality rates overall. Receipt of a beta-lactam was the strongest predictor of survival. These results underscore the importance of correct classification of patients with penicillin allergy and appropriate treatment with a beta-lactam when tolerated.

Purpose: The impact of automatic infectious diseases (ID) consultation for inpatients with fungemia at a large academic medical center was studied., Methods: In this single-center, retrospective study, the time to appropriate antifungal therapy before and after implementing a policy requiring automatic ID consultation for the management of fungemia for all patients with an inpatient positive blood culture for fungus was examined. The rates of ID consultation; the likelihood of receiving appropriate antifungal therapy; central venous catheter (CVC) removal rates; performance of ophthalmologic examinations; infection-related length of stay (LOS); rates of all-cause inhospital mortality, death, or transfer to an intensive care unit within 7 days of first culture; and inpatient cost of antifungals were also evaluated., Results: A total of 173 unique episodes (94 and 79 in the control and intervention groups, respectively) were included. Candida species were the most frequently cultured organisms, isolated from over 90% of patients in both groups. No differences were observed between the control and intervention groups in time to appropriate therapy, infection-related LOS, or time to CVC removal. However, patients in the intervention group were more likely than those in the control group to receive appropriate antifungal therapy ( p = 0.0392), undergo ophthalmologic examination ( p = 0.003), have their CVC removed ( p = 0.0038), and receive ID consultation ( p = 0.0123). Inpatient antifungal costs were significantly higher in the intervention group ( p = 0.0177)., Conclusion: While automatic ID consultation for inpatients with fungemia did not affect the time to administration of appropriate therapy, improvement was observed for several process indicators, including rates of appropriate antifungal therapy selection, time to removal of CVCs, and performance of ophthalmologic examinations., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Knowledge of local antimicrobial resistance is critical for management of infectious diseases. Community hospitals' compliance with Clinical and Laboratory Standards Institute (CLSI) guidance for creation of cumulative antibiograms is uncertain. This descriptive cohort study of antibiogram reporting practices included community hospitals enrolled in the Duke Infection Control Outreach Network. Cumulative antibiograms from 2012 were reviewed for criteria on reporting practices and compliance with CLSI guidelines. Microbiology personnel were sent a voluntary, electronic survey on antibiogram preparation practices. Data were compiled using descriptive statistics. Thirty-two of 37 (86%) hospitals provided antibiograms; 26 of 37 (70%) also provided survey responses. Twelve (38%) antibiograms specified methods used for compiling data and exclusion of duplicates. Eight (25%) reported only species with >30 isolates. Of the 24 that did not follow the 30-isolate rule, 3 (13%) included footnotes to indicate impaired statistical validity. Twenty (63%) reported at least 1 pathogen-drug combination not recommended for primary or supplemental testing per CLSI. Thirteen (41%) separately reported methicillin-resistant and -susceptible Staphylococcus aureus. Complete compliance with CLSI guidelines was observed in only 3 (9%) antibiograms. Survey respondents' self-assessment of full or partial compliance with CLSI guidelines was 50% and 15%, respectively; 33% reported uncertainty with CLSI guidelines. Full adherence to CLSI guidelines for hospital antibiograms was uncommon. Uncertainty about CLSI guidelines was common. Alternate strategies, such as regional antibiograms using pooled data and educational outreach efforts, are needed to provide reliable and appropriate susceptibility estimates for community hospitals., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Purpose: Although newer agents (dipeptidyl peptidase [DPP]-4 inhibitors and glucagon-like peptide [GLP]-1 receptor agonists) are available for the treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), the impact of the availability of these agents on the use of second-generation sulfonylureas (SUs) is unknown. This article presents percentages of patients prescribed SUs, using data from the National Ambulatory Medical Care Survey (NAMCS). The associations between SU prescribing and prespecified variables of interest were also explored., Methods: The NAMCS database was queried for visits of patients aged ≥18 years with an International Classification of Diseases, Ninth Revision diagnostic code relevant to T2DM. χ(2) tests were conducted to assess the associations between SU use and year-group (2003-2004, 2007-2008, or 2009-2010) and other variables of interest. A multivariate logistic regression model was constructed to jointly assess the value of these variables in predicting SU use. All analyses were weighted using procedures recommended by the National Center for Health Statistics., Findings: Data from 7042 eligible visits were included, representing an extrapolated national estimate of 280,733,405 patient visits. The percentages of patients who received a prescription for an SU, by study year, were 25.7%, 23.4%, and 23.7% in 2003 to 2004, 2007 to 2008, and 2009 to 2010, respectively (P = 0.57). In the multivariate model, age ≥70 years, male sex, nonwhite race, primary care physician seen, and concurrent DPP-4 inhibitor use were significantly associated with SU use., Implications: No significant decrease in the use of SUs was observed after the introduction of DPP-4 inhibitors and GLP-1 receptor agonists. However, patient-specific factors (eg, select demographic variables, site of care, and concurrent medication use) were associated with SU use., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Background: Invasive infections with Pseudomonas aeruginosa (PA) are associated with significant morbidity and mortality. While risk factors for mortality have been identified, their influence on short-term outcomes impacting treatment selection has not been reported., Objectives: The objective of this study was to evaluate the relationship between select patient- and treatment-related factors and short-term outcomes in patients with PA pneumonia and/or bacteremia., Setting: Large academic medical center in the United States., Methods: This IRB-approved single-center, retrospective case-cohort study included patients >18 years of age with culture-confirmed PA bacteremia and/or pneumonia receiving antimicrobial agent(s) active against PA., Main Outcome Measure: Risk of unfavorable short-term treatment result., Results: The population consisted of 117 patients (40 [34 %] and 77 [66 %] in the unfavorable and not-unfavorable groups, respectively). Baseline characteristics including age (mean of 63 years), gender (55 % male), Charlson score, creatinine clearance, and body mass index were comparable between groups. Piperacillin/tazobactam was the most common monotherapy antibiotic (46 and 33 % in unfavorable and not-unfavorable groups, respectively). Combination therapy primarily consisted of a beta-lactam plus ciprofloxacin in both unfavorable (10 %) and not-unfavorable (20 %) outcome groups. The preliminary regression model indicated that SIRS, direct ICU admission, and vasopressor therapy were associated with an unfavorable outcome. In addition, patients who received more than two active antimicrobials had a reduced risk of an unfavorable outcome. The final regression model revealed that vasopressor therapy (odds ratio [OR] 6.0; 95 % confidence interval [95 % CI] 2.3, 17) was associated with an unfavorable outcome, while receipt of greater than two active antibiotics was associated with a reduced risk of an unfavorable outcome (OR 0.26; 95 % CI 0.07, 0.83)., Conclusions: Treatment with more than two agents with activity against PA was associated with a reduced risk of an unfavorable short-term treatment outcome in patients with bacteremia and/or pneumonia.

Study Objectives: 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., Design: Single-center, retrospective cohort study., Setting: Large, academic, tertiary-care hospital., Patients: One hundred ninety-one adults hospitalized between July 1, 2009, and July 1, 2012, with normal baseline renal function who received a minimum of 48 hours of vancomycin for any indication were included in the analysis. Of these patients, 92 received a minimum of 48 hours of intravenous piperacillin-tazobactam concurrently with vancomycin, with piperacillin-tazobactam being initiated within 48 hours of the initiation of vancomycin (combination group); 99 received vancomycin without piperacillin-tazobactam (vancomycin group)., Measurements and Main Results: A univariate analysis was performed to assess the effect of the following risk factors on the incidence of nephrotoxicity within the first 7 days of vancomycin treatment: concomitant nephrotoxic agents, advanced age, steady-state vancomycin trough concentration of 15 μg/ml or greater, elevated Charlson Comorbidity Index, and a total daily vancomycin dose of 4 g or greater. A multivariate model was constructed to compare the incidence of the primary end point of nephrotoxicity, defined as a minimum 1.5-fold increase in serum creatinine concentration, between groups. Nephrotoxicity developed in 8 (8.1%) of 99 patients in the vancomycin group and in 15 (16.3%) of 92 patients in the combination group (1-sided χ(2) test, p=0.041). In the univariate analysis, only vancomycin trough concentration of 15 μg/ml or greater (odds ratio 3.67) was associated with an increased risk of developing nephrotoxicity. In the multivariate analysis, patients with piperacillin-tazobactam added to vancomycin exhibited an increased incidence of nephrotoxicity, with an odds ratio of 2.48 (1-sided χ(2) test, p=0.032)., Conclusion: We observed an increased incidence of nephrotoxicity in vancomycin-treated patients who received concomitant piperacillin-tazobactam. A steady-state vancomycin trough concentration of 15 μg/ml or greater was also associated with an increased risk of the development of nephrotoxicity. These findings should be confirmed in larger, randomized studies., (© 2014 Pharmacotherapy Publications, Inc.)

In preventing invasive fungal disease (IFD) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), clinical trials demonstrated efficacy of posaconazole over fluconazole and itraconazole. However, effectiveness of posaconazole has not been investigated in the United States in real-world setting outside the environment of controlled clinical trial. We performed a single-center, retrospective cohort study of 130 evaluable patients ≥18 years of age admitted to Duke University Hospital between 2004 and 2010 who received either posaconazole or fluconazole as prophylaxis during first induction or first reinduction chemotherapy for AML or MDS. The primary endpoint was possible, probable, or definite breakthrough IFD. Baseline characteristics were well balanced between groups, except that posaconazole recipients received reinduction chemotherapy and cytarabine more frequently. IFD occurred in 17/65 (27.0%) in the fluconazole group and in 6/65 (9.2%) in the posaconazole group (P = 0.012). Definite/probable IFDs occurred in 7 (10.8%) and 0 patients (0%), respectively (P = 0.0013). In multivariate analysis, fluconazole prophylaxis and duration of neutropenia were predictors of IFD. Mortality was similar between groups. This study demonstrates superior effectiveness of posaconazole over fluconazole as prophylaxis of IFD in AML and MDS patients. Such superiority did not translate to reductions in 100-day all-cause mortality., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative., Areas Covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole., Expert Opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.

Objective: To validate the utility of a previously published scoring model (Italian) to identify patients infected with community-onset extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-EKP) and develop a new model (Duke) based on local epidemiology., Methods: This case-control study included patients 18 years of age or more admitted to Duke University Hospital between January 1, 2008, and December 31, 2010, with culture-confirmed infection due to an ESBL-EKP (cases). Uninfected controls were matched to cases (3:1). The Italian model was applied to our patient population for validation. The Duke model was developed through logistic-regression-based prediction scores calculated on variables independently associated with ESBL-EKP isolation. Sensitivities and specificities at various point cutoffs were determined, and determination of the area under the receiver operating characteristic curve (ROC AUC) was performed., Results: A total of 123 cases and 375 controls were identified. Adjusted odds ratios and 95% confidence intervals for variables previously identified in the Italian model were as follows: hospitalization (3.20 [1.62-6.55]), transfer (4.31 [2.15-8.78]), urinary catheterization (5.92 [3.09-11.60]), β-lactam and/or fluoroquinolone therapy (3.76 [2.06-6.95]), age 70 years or more (1.55 [0.79-3.01]), and Charlson Comorbidity Score of 4 or above (1.06 [0.55-2.01]). Sensitivity and specificity were, respectively, more than or equal to 95% and less than or equal to 47% for scores 3 or below and were less than or equal to 50% and more than or equal to 96% for scores 8 or above. The ROC AUC was 0.88. Variables identified in the Duke model were as follows: hospitalization (2.63 [1.32-5.41]), transfer (5.30 [2.67-10.71]), urinary catheterization (6.89 [3.62-13.38]), β-lactam and/or fluoroquinolone therapy (3.47 [1.91-6.41]), and immunosuppression (2.34 [1.14-4.80]). Sensitivity and specificity were, respectively, more than or equal to 94% and less than or equal to 65% for scores 3 or below and were less than or equal to 58% and more than or equal to 95% for scores 8 or above. The ROC AUC was 0.89., Conclusion: While the previously reported model was an excellent predictor of community-onset ESBL-EKP infection, models utilizing factors based on local epidemiology may be associated with improved performance.

What Is Known and Objective: To the best of our knowledge, there has been no published study designed to identify the most appropriate duration of antibiotic therapy in lower extremity skin and skin structure infections in diabetic patients [aka "diabetic foot infections" (DFI)] post-amputation. However, recent guidelines published by the Infectious Diseases Society of America (IDSA) provide recommendations for treatment duration in these patients. Therefore, our objective is to review the literature evaluating antibiotic treatment in DFI to determine if the IDSA guidelines are reasonable., Comment: Evidence for the use of antibiotics after amputation comes largely from perioperative surgical prophylaxis studies evaluating the rate of infection after amputation. Three such studies were identified; 2 found a 5-day course of antibiotics post-amputation resulted in a reduction of infection rate, while 1 found no additional benefit. Comparative antibiotic studies in DFI also offers evidence for treatment duration, of which, 10 studies were identified. Five included patients who received amputations; however, only 1 reported treatment outcomes in a subset of diabetics requiring amputation. In this study, the authors concluded that antibiotic treatment is likely necessary after amputation., What Is New and Conclusion: Given the general lack of data, we recommend that post-operative treatment duration be individualized, and, until further studies are done, it seems reasonable to adhere to the recommendation provided by the 2012 IDSA DFI guidelines for a 2-5 day course of antibiotic therapy post-operatively when no residual infected tissue remains., (© 2013 Blackwell Publishing Ltd.)

This study aimed to determine the feasibility of using likelihood of inadequate therapy (LIT), a parameter calculated by using pathogen frequency and in vitro susceptibility for determination of appropriate empiric antibiotic therapy for primary bloodstream infections. Our study demonstrates that LIT may reveal differences in traditional antibiograms.

Introduction: Morbidity and mortality associated with invasive fungal infections (IFIs) remains unacceptably high. Such diseases represent a substantial burden to the healthcare system. New options are needed to address antifungal resistance in existing and emerging pathogens and improve treatment outcomes while minimizing drug-related toxicities and interactions. Awareness of new and potential future options is of great value for those healthcare professionals who care for patients with IFIs. Areas covered: A search of PubMed, infectious diseases conference abstracts and reference lists from relevant publications was conducted and relevant information abstracted. This review describes the limitations of existing systemic antifungal therapies (e.g., resistance, drug-drug interactions, drug-related toxicities) and summarizes data regarding several emerging antifungal compounds including (but not limited to) new triazoles (e.g. isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin Z. Agents in clinical trials such as (but not limited to) new triazoles (e.g., isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin are included. New formulations of existing drugs including reformulations of miconazole, posaconazole and amphotericin B are also reviewed. Finally, new or novel administration strategies for existing drugs such as combination antifungal therapy, antifungal dose escalation, adjunctive use of iron chelators and preemptive therapy are discussed. Expert opinion: All present antifungal agents have some deficiencies in antifungal spectra, toxicity, pharmacokinetics and/or drug-drug interactions, making them less than ideal for some fungal infections. Therefore, there remains an urgent need to find safe, effective, rapidly fungicidal, broad-spectrum antifungal agents with excellent pharmacodynamics to effectively eliminate the fungus from the body with short antifungal courses.

The introduction of several new antifungals has significantly expanded both prophylaxis and treatment options for invasive fungal infections (IFIs). Relative to amphotericin B deoxycholate, lipid-based formulations of amphotericin B have significantly reduced the incidence of nephrotoxicity, but at a significant increase in drug acquisition cost. Newer, broad-spectrum triazoles (notably voriconazole and posaconazole) have added significantly to both the prevention and treatment of IFIs, most notably Aspergillus spp. (with voriconazole) and the treatment of some emerging fungal pathogens. Finally, a new class of parenteral antifungals, the echinocandins, is employed most frequently against invasive candidal infections. While the role of these newer agents continues to evolve, this review summarizes the activity, safety and clinical applications of agents most commonly employed in the treatment of IFIs., (© 2011 ISHAM)

Cephalosporins have been widely used over the last few decades (often as first-line antibiotic therapy) for numerous infections, owing primarily to their broad spectrum of microbiologic activity and favorable safety profile. Current Infectious Diseases Society of America guidelines identify a third-generation cephalosporin in combination with a macrolide antibiotic as an option for treatment of hospitalized adult patients with community-acquired pneumonia (CAP) outside the intensive care unit setting. Although ceftriaxone is a frequently used agent for CAP, increasing incidence of multidrug-resistant Streptococcus pneumoniae and concerns regarding poor outcomes associated with ineffective therapy have prompted the search for a well-tolerated treatment alternative that is effective against bacteria that can cause CAP. Ceftaroline fosamil, the prodrug of ceftaroline, is a new extended-spectrum cephalosporin that exhibits time-dependant bactericidal activity against numerous Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. pneumoniae. Notable exceptions include Pseudomonas spp. and Gram-negative organisms that produce extended-spectrum β-lactamases or carbapenemases. Two large Phase III clinical trials (FOCUS 1 and 2) reported that ceftaroline fosamil was well tolerated, with a clinical cure rate of CAP that was noninferior to that with ceftriaxone in nonintensive care unit adult inpatients with moderately severe (Pneumonia Outcomes Research Team score of III or IV) community-acquired pneumonia.

Purpose: Recent in vitro and clinical data addressing outstanding issues regarding the selection, dosing, and monitoring of echinocandins for the treatment of invasive fungal infections (IFIs) are reviewed., Summary: The echinocandins (caspofungin, micafungin, and anidulafungin) are attractive treatment options for the treatment of select IFIs, most notably invasive candidiasis and treatment-refractory invasive aspergillosis. A literature review of English-language articles published between January 2007 and May 2010 was performed using the terms caspofungin, micafungin, anidulafungin, and echinocandin. In vitro, in vivo, and both pediatric and adult clinical studies and case reports were included. The challenges to establish meaningful interpretive criteria for in vitro testing of yeasts continue to persist, as do the establishment of the clinical relevancy of both the reduced in vitro susceptibilities to Candida parapsilosis and the paradoxical growth of Candida species at higher dosages. Despite increasing use of these agents and reports of breakthrough infections, echinocandins have continued to maintain potency against a broad spectrum of Candida and Aspergillus species. Recent in vitro studies also support the excellent activity of echinocandins against Candida biofilms. While recent published studies have better defined dosing in special populations (such as pediatric patients and those with organ dysfunction), attempts to increase efficacy by dosage intensification have been unsuccessful. Several pharmacoeconomic studies have been performed in attempts to justify the high acquisition costs of these drugs. In general, these studies found that echinocandins may be cost-effective for such indications., Conclusion: Available in vitro data, animal studies, and clinical studies do not clearly differentiate agents in the echinocandin class. Clinical data continue to support the use of echinocandins as a safe and well-tolerated treatment option for candidemia and invasive aspergillosis.

The aim of this study was to review the application of antimicrobial stewardship principles to the management of community-acquired pneumonia (CAP). Data from 14 published clinical studies, meta-analyses and practice guidelines regarding the application of antimicrobial stewardship strategies to the management of CAP were identified and analysed. In the context of CAP, application of stewardship strategies (alone or in combination) has been shown to increase physician awareness of guidelines, improve appropriate antimicrobial use and reduce unnecessary antimicrobial prescribing. In addition, application has had a profound favourable impact on patient outcomes, including decreased 30-day mortality and in-hospital mortality rates, reduced length of hospital stay, reduced treatment failure rates and reduced healthcare costs. Antimicrobial stewardship programmes have been demonstrated to successfully increase the level of appropriate antibiotic prescribing, reduce pathogen resistance and improve clinical outcomes in the management of CAP within hospitals. Studies have also shown that adherence to evidence-based guidelines, even at the level of the individual clinician, can have a profound and positive impact on patient outcomes and healthcare costs. Adherence to evidence-based guidelines can have a profound and positive impact on patient outcomes and healthcare costs., (© 2011 Blackwell Publishing Ltd.)

Tigecycline is a member of the glycylcycline class of antimicrobials, which is structurally similar to the tetracycline class. It demonstrates potent in vitro activity against causative pathogens that are most frequently isolated in patients with community-acquired bacterial pneumonia (CABP), including (but not limited to) Streptococcus pneumoniae (both penicillin-sensitive and -resistant strains), Haemophilus influenzae and Moraxella catarrhalis (including β-lactamase-producing strains), Klebsiella pneumoniae, and 'atypical organisms' (namely Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila). Comparative randomized clinical trials to date performed in hospitalized patients receiving tigecycline 100 mg intravenous (IV) × 1 and then 50 mg IV twice daily thereafter have demonstrated efficacy and safety comparable to the comparator agent. Major adverse effects were primarily gastrointestinal in nature. Tigecycline represents a parenteral monotherapy option in hospitalized patients with CABP (especially in patients unable to receive respiratory fluoroquinolones). However, alternate and/or additional therapies should be considered in patients with more severe forms of CABP in light of recent data of increased mortality in patients receiving tigecycline for other types of severe infection.

Echinocandins have made a significant impact in the treatment of select invasive fungal infections, most notably invasive candidiasis and aspergillosis. However, treatment outcomes for such infections are still less than optimal, prompting an examination of dosing and administration techniques in an attempt to exploit known pharmacodynamic properties and improve outcomes. Echinocandins generally exhibit concentration-dependent, fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp. However, increasing drug concentrations of echinocandins above the organism's MIC may result in a paradoxical increase in fungal growth as demonstrated in some in vitro and in vivo models (known most commonly as the 'Eagle effect'). Therefore, the potential impact of dose escalations on improving the clinical efficacy of echinocandins based on in vitro and animal models are uncertain and are still being evaluated. In addition, such strategies have to consider the potential for increased treatment-related toxicities and costs. To date, published clinical studies (both superiority and non-inferiority) demonstrating the potential for dose-related improvements in treatment outcomes have been limited to mucocutaneous and oesophageal candidiasis. Further research is needed to determine if a role exists for optimizing echinocandin pharmacodynamics in various clinical settings.

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug-drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.

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, de-escalation 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.

Recently created guidelines for the development of institutional antimicrobial stewardship programs recommend that a pharmacist with infectious diseases training be included as a core member of the antimicrobial stewardship team. However, training and certification requirements for infectious diseases-trained clinical pharmacists have not been established. Although pharmacists have nurtured their interest in infectious diseases by self-directed learning or on-the-job experiences, this mode of training is not considered feasible or sufficient for reliable training of future clinical specialists in infectious diseases. This document, therefore, is forward looking and provides overarching recommendations for future training and certification of pharmacists practicing, mentoring, and educating in infectious diseases pharmacotherapy, with the recognition that full implementation may take several years. We recommend that future pharmacists wishing to obtain a clinical position as an infectious diseases-trained pharmacist should complete a postgraduate year (PGY) 1 residency and a PGY2 residency in infectious diseases, that practitioners become board-certified pharmacotherapy specialists, that a certification examination in infectious diseases be developed, that practitioners maintain a portfolio of educational experiences to maintain qualifications, that current nonaccredited training programs seek accreditation, and that employers and academicians recognize the desirability of these qualifications in hiring decisions.

Owing to the morbidity and mortality associated with invasive fungal infections, particularly in the immunocompromised host, development of new agents for both prevention and treatment is essential. Posaconazole is a recently approved extended-spectrum triazole available as an oral suspension. It exhibits fungistatic activity against a variety of fungal pathogens. Pharmacokinetic data in special patient populations (such as neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome, allogeneic hematopoietic stem cell transplant recipients, febrile neutropenic patients and pediatric patients) have been published recently. Controlled clinical trials establish posaconazole's safety and efficacy in infections, such as oropharyngeal candidiasis and prophylaxis against invasive fungal infections. Data are also emerging in the treatment of zygomycosis and selected cases of aspergillosis. Posaconazole is well tolerated during short- and long-term use, with the most commonly reported adverse events being mild-to-moderate gastrointestinal disturbances. Data suggest a relationship between posaconazole plasma concentrations and prophylactic efficacy; however, the role of therapeutic drug monitoring has yet to be completely defined. Since posaconazole is available only as an oral formulation, its use may be limited in critically ill patient populations.

Telavancin is a lipoglycopeptide derivative of vancomycin. Similar to vancomycin, it demonstrates activity in vitro against a variety of Gram-positive pathogens, including but not limited to methicillin-resistant Staphylococccus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). Modifications to vancomycin's structure expanded telavancin's spectrum of activity in vitro to include organisms such as glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant S. aureus (VRSA) and vancomycin-resistant enterococci (VRE). However, the clinical implications of this are currently unknown. Similar to other glycopeptides, televancin binds to the D-alanyl-D-alanine (D-Ala-D-Ala) terminus in Gram-positive organisms, resulting in inhibition of bacterial cell wall synthesis. In addition, telavancin causes depolarization of the bacterial cell membrane and increased membrane permeability. The resulting activity in vitro is rapidly bactericidal and concentration dependent, with the ratio of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) as the best predictor of activity in animal models to date. In humans, telavancin exhibits a pharmacokinetic profile that permits once-daily intravenous administration. Doses of 7.5 and 10 mg/kg/day have been studied in clinical trials. The need for dosage adjustments based on age, gender and obesity appear unnecessary. In addition, moderate hepatic impairment does not appreciably alter the pharmacokinetics of the drug. Because telavancin is extensively cleared by the kidneys, dosage adjustments will be required in patients with moderate to severe renal impairment. Published phase II and III clinical trials have shown telavancin to be comparable to standard therapy for the treatment of complicated skin and soft tissue infections. Clinical trials in the treatment of S. aureus bacteremia and hospital-acquired pneumonia are under way. Adverse effects overall appear to be mild and reversible, with taste disturbance, foamy urine, headache, procedural site pain, nausea and vomiting being the most commonly reported. However, renal toxicity was reported more frequently with telavancin than with vancomycin in two phase III clinical trials (3% versus 1%). Prolongation of the corrected QT (QTc) interval has been more common with telavancin than comparator agents, but no clinically significant electrocardiogram (ECG) changes or cardiac abnormalities have been observed to date. Although human pregnancy data is not currently available, animal data revealed limb malformations that were possibly related to telavancin therapy. Therefore, the potential teratogenicity of this agent must be considered in women who are pregnant or may become pregnant., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Background: Antimicrobial stewardship programs (ASPs) promote the appropriate use of antimicrobials by selecting the appropriate dose, duration, and route of administration. The appropriate use of antimicrobials has the potential to improve efficacy, reduce treatment-related costs, minimize drug-related adverse events, and limit the potential for emergence of antimicrobial resistance., Objective: To summarize ASP tactics that can improve the appropriate use of antimicrobials in the hospital setting. Several measures can be used to implement such programs and gain multidisciplinary support while addressing common barriers., Summary: Implementation of an ASP requires a multidisciplinary approach with an infectious diseases physician and a clinical pharmacist with infectious diseases training as its core team members. As identified by recently published guidelines, 2 proactive strategies for promoting antimicrobial stewardship include: (1) formulary restriction and pre-authorization, and (2) prospective audit with intervention and feedback. Other supplemental strategies involve education, guidelines and clinical pathways, antimicrobial order forms, de-escalation of therapy, intravenous-to-oral (IV-to-PO) switch therapy, and dose optimization. Several barriers exist to successful implementation of ASPs. These include obtaining adequate administrative support and compensation for team members. Gaining physician acceptance can also be challenging if there is a perceived loss of autonomy in clinical decision making., Conclusion: ASPs have the potential to reduce antimicrobial resistance, health care costs, and drug-related adverse events while improving clinical outcomes. The efforts and expense required to implement and maintain ASPs are more than justified given their potential benefits to both the hospital and the patient.

The high incidence of invasive aspergillosis (IA) in 'at-risk' patient populations, combined with poor treatment outcomes, necessitates the application of novel prevention and management strategies. Among such strategies is administration of antifungal agents using alternate routes of administration (such as local injections, irrigations, and aerosols). In general, such strategies are used adjunctively to systemic administration of antifungals and/or surgical intervention for treatment-refractory infections. Adequately-controlled clinical trials are lacking with many of these therapies to justify routine use as a primary prophylaxis or treatment strategy. Aerosolized administration of various formulations of amphotericin B has found more widespread acceptance, especially in the prevention of invasive aspergillosis in patients at highest risk. Given the pharmacokinetics, safety and efficacy of newer treatment options, the need for such novel administration for prevention and management of IA will need to be re-evaluated in the future.

Invasive fungal infections (IFIs) are occurring with increasing incidence and are associated with significant morbidity and mortality. Understanding the relationship between the pharmacokinetic and pharmacodynamic properties of antifungals is essential to optimize the potential for favourable clinical and microbiological outcomes while minimizing risks of treatment-related toxicity. Antifungal serum concentrations may aid in the determination of appropriate dosing in select circumstances. The polyene and echinocandin classes of antifungals lack sufficient data to justify serum concentration monitoring in routine clinical practice. In contrast, serum concentration monitoring of flucytosine may help to reduce the risk of treatment-related haematological toxicity. Determination of itraconazole serum concentrations is advised in situations where the drug is used for prolonged periods to treat serious IFIs (such as invasive aspergillosis or histoplasmosis) because of variability in absorption following oral administration (most notable for the capsule formulation). The use of serum concentration monitoring during therapy with the extended-spectrum triazoles (i.e. voriconazole and posaconazole) is still evolving, due primarily to inter-patient variability in drug exposure combined with sparse data regarding relationships with efficacy (posaconazole) and both safety and efficacy (voriconazole).

Tigecycline, a glycylcycline related to the tetracycline class of antibiotics, represents a new option for the treatment of complicated intra-abdominal and complicated skin and skin structure infections. It displays favorable activity in vitro against the most common causative Gram-positive, Gram-negative and anaerobic pathogens. In addition, tigecycline demonstrates activity against drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and organisms (such as Escherichia coli and Klebsiella pneumoniae) producing extended-spectrum beta-lactamases. Tigecycline lacks activity in vitro against Pseudomonas and Proteus spp. In randomized clinical trials, tigecycline administered intravenously twice daily has demonstrated efficacy similar to comparators for a variety of complicated skin and skin structure and complicated intra-abdominal infections. The potential for significant drug interactions with tigecycline appears to be minimal. Dosing adjustment is needed for patients with severe hepatic impairment. The predominant side effect associated with its use to date has been gastrointestinal intolerance (nausea and vomiting).

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.

Tigecycline is a new glycyclcycline antimicrobial recently approved for use in the USA, Europe and elsewhere. While related to the tetracyclines, tigecycline overcomes many of the mechanisms responsible for resistance to this class. It demonstrates favourable in vitro potency against a variety of aerobic and anaerobic Gram-positive and Gram-negative pathogens, including those frequently demonstrating resistance to multiple classes of antimicrobials. This includes methicillin-resistant Staphylococcus aureus, penicillin-resistant S. pneumoniae, vancomycin-resistant enterococci, Acinetobacter baumannii, beta-lactamase producing strains of Haemophilis influenzae and Moraxella catarrhalis, and extended-spectrum beta-lactamase producing strains of Escherichia coli and Klebsiella pneumoniae. In contrast, minimum inhibitory concentrations for Pseudomonas and Proteus spp. are markedly elevated. Tigecycline is administered parenterally twice daily. Randomised, controlled trials have demonstrated that tigecycline is non-inferior to the comparators for the treatment of complicated skin and skin structure infections, as well as complicated intra-abdominal infections. The most frequent and problematic side effect associated with its administration to date has been nausea and/or vomiting.

The echinocandins are a new class of antifungals, developed in response to the need for safe and effective antifungals for the treatment of invasive fungal infections. These agents work by inhibiting 1,3-beta-d-glucan synthase, an enzyme essential for production of cell walls in select fungi. Echinocandins appear to demonstrate favourable activity in vitro against a variety of yeasts (including both Candida albicans and non-albicans Candida) as well as select moulds (including Aspergillus spp.) In general, all echninocandins demonstrate a favourable safety profile and require once-daily parenteral administration. Caspofungin is the first of these agents to be available in the US, and is approved for empirical antifungal therapy in febrile neutropenic patients, candidaemia and select forms of invasive candidiasis, and for management of invasive aspergillosis in patients refractory to or intolerant of other therapies. Micafungin was recently approved by the FDA for treatment of oesophageal candidiasis, and for the prophylaxis of fungal infections in haematopoietic stem cell transplant recipients. Emerging data indicate micafungin may have an important role in the treatment of invasive forms of candidiasis. Anidulafungin is an echinocandin approved in the US for treatment of candidaemia and oesophageal candidiasis. Aminocandin (HMR-3702, IP-960) is an investigational agent, with published experience limited to in vitro studies and animal models of infection.

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.

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.

Administration of antifungals by routes other than that for which the agent was designed or approved have been utilised in attempts to provide directed therapy, reduce adverse effects and improve drug penetration into selected infection sites, such as the central nervous system, lungs and peritoneum. The most widely investigated agent utilising a novel method of drug delivery is amphotericin B. Dose forms for this agent include topicals (aerosol, nasal spray, irrigations, pastes, absorbable sponges, impregnated bone cement and gelatin), oral dosage forms (solutions, suspensions, tablets and so on) and ophthalmic preparations (drops, ointments and injections). Amphotericin B has been administered by routes such as oral, endobronchial, intrathecal, intracisternal, intra-articular, intraperitoneal, ophthalmic and as an antibiotic 'line lock'. Nystatin has been administered as an aerosol, percutaneous paste and bladder washes. Azoles, such as miconazole, fluconazole, ketoconazole and posaconazole, have been administered by novel methods but to a lesser degree. Most of these reports involve miconazole. The dose forms and routes of administration for azoles have included irrigants (bladder, joint), ophthalmic preparations (eye drops, intraocular injections, ointments), impregnated bone cement, endobronchial and intrathecal administration. Finally, both methylene blue (bladder washes) and flucytosine (peritoneal lavage, ophthalmic eye drops) have also been employed. Adequate evaluations of both the safety and efficacy of these therapies are most often hindered by prior or concomitant antifungal therapies, comorbidities and the lack of controlled clinical trials. In addition, the availability of newer treatment options, which demonstrate significant improvement in drug distribution and treatment-related adverse effects make many such novel modes of administration less practical or necessary. In contrast, the inhalation of antifungal aerosols, such as amphotericin B, is rapidly becoming a viable prophylactic option.

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.

To determine the effect of omeprazole on peak serum concentrations (C(max)) of itraconazole oral solution (IOS), we carried out a randomized, open-label, prospective, crossover study. Fifteen healthy, non-pregnant adults received a single dose of IOS 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before either IOS dose 1 or 2. C(max), time to C(max) (T(max)) and AUC(0-8) were determined for itraconazole and its active metabolite, hydroxyitraconazole, for each dose and compared. Omeprazole did not significantly affect the C(max), T(max) or AUC(0-8) of itraconazole or hydroxyitraconazole when administered as IOS.

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.

Background: Antibiotic-resistant Gram-positive pathogens are an increasingly common cause of serious pediatric infections. Although quinupristin/dalfopristin demonstrates favorable activity against resistant Gram-positive pathogens (including many vancomycin-resistant and methicillin-resistant staphylococci), published experience in the pediatric patient population is limited., Methods: We retrospectively analyzed data from the global quinupristin/dalfopristin Emergency-Use Program, which enrolled patients with serious Gram-positive infections who had no further therapy options because of resistance to, failure on or intolerance to standard antibiotic treatments. Our subset included safety and efficacy data from pediatric patients (age <18 years). There were no restrictions on underlying diseases, severity of illness or prior/concomitant antimicrobial use., Results: Between May 1995 and October 1999, 127 pediatric patients with 131 infections were enrolled. Microbiologic confirmation of etiology was available in 124 patients. All patients had 1 or more concomitant conditions, including malignancy and solid organ or bone marrow transplantation. The most frequent causative pathogens were vancomycin-resistant (80%), spp. (7%), methicillin-resistant (6%) and (4%). All but 21 patients received intravenous quinupristin/dalfopristin 7.5 mg/kg every 8 h. The favorable clinical response rate of quinupristin/dalfopristin was 86 of 124 (69%); the favorable microbiologic response rate was 97 of 124 (78%). Eleven patients (8%) had nonvenous adverse events classified as possibly or probably related to quinupristin/dalfopristin., Conclusions: Quinupristin/dalfopristin demonstrated favorable response rates and was reasonably well-tolerated in pediatric patients with serious Gram-positive infections unable to receive alternative therapy. In our opinion quinupristin/dalfopristin is a therapeutic option for the management of such infections.