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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.

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.

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.)

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.)

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.

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.

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.

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.

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).

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.

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.

Amphotericin B, the first commercially significant antifungal drug, has been available for more than 30 years. This polyene macrolide antifungal agent continues to play a major role in the treatment of systemic fungal infections, despite the introduction of newer agents such as the azoles. Given the proved efficacy of amphotericin B--and the increasing number of indications for antifungal agents--an extensive review of this drug is warranted. This paper discusses the clinical uses of amphotericin B, including its application in AIDS-related fungal infections, in neutropenic cancer patients who are persistently febrile, and in infections of the central nervous system, lung, peritoneum, genitourinary system, eye, and skin. The paper also reviews the drug's adverse reactions, with a discussion of administration techniques that may reduce these reactions, and its spectrum of activity, pharmacokinetics, and dosage and administration.

The objectives of this open-labeled, multiple-dose, three-way-crossover trial were to evaluate the safety and tolerance of zidovudine (Retrovir) oral syrup and to assess the bioequivalence of this formulation relative to zidovudine solution and capsule formulations in human immunodeficiency virus-infected patients. Over the 7-day study, 12 adult male subjects received 12 administrations each of the capsule, solution, and syrup formulations every 4 h (six times daily) in a randomized sequence. Frequent blood samples were collected over the 4-h period after dose 12 was administered. Zidovudine concentrations in plasma were determined by a specific and sensitive radioimmunoassay. Results from statistical analyses indicated that all three formulations were bioequivalent with respect to systemic availability (area under the time-concentration curve) and that the syrup was also equivalent to the solution with respect to the maximum peak concentration in serum. The lower relative maximum peak concentration in serum (approximately 81%) and small delays in time to peak concentration (less than 30 min) of the capsule formulation as compared with the liquid formulations are thought to be due to the additional processes of disintegration and dissolution associated with capsule administration. All three preparations were well tolerated during the 7-day study.