Challenges in Preparation of Cumulative Antibiogram Reports for Community Hospitals.

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.

Harvesting the low-hanging fruit? Comparative assessment of intravenous to oral route antimicrobial conversion policy implementation.

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.

Conventional Antifungals for Invasive Infections Delivered by Unconventional Methods; Aerosols, Irrigants, Directed Injections and Impregnated Cement.

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.).

Addressing current medical needs in invasive fungal infection prevention and treatment with new antifungal agents, strategies and formulations.

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.

Overview of treatment options for invasive fungal infections.

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.

Echinocandin pharmacodynamics: review and clinical implications.

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.

Aerosol and other novel administrations for prevention and treatment of invasive aspergillosis.

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.

Antimicrobial stewardship programs: how to start and steer a successful program.

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.

Antifungal therapy for invasive fungal diseases in allogeneic stem cell transplant recipients: an update.

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.

Impact of select risk factors on treatment outcome in adults with candidemia.

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.

Antifungal serum concentration monitoring: an update.

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).

Evaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms.

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.

Influence of Reported Penicillin Allergy on Mortality in MSSA Bacteremia.

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.

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.

Could risk assessment for non-albicans Candida improve empiric treatment for invasive candidiasis?

The changing epidemiology of invasive candidiasis, along with concerns for the emergence of drug resistance, necessitates the identification of patients at increased risk of non-albicans Candida (NAC) to optimize selection of antifungal therapy. The major findings of a study regarding the demographic characteristics, costs, and outcomes of nonneutropenic patients with candidemia due to NAC are discussed. Given available treatment options, such risk assessment is most relevant to initial empiric therapy in stable patients without neutropenia who might be candidates for initial therapy with an azole (eg, fluconazole). The study's investigators reinforce the need for timely antifungal therapy for patients with candidemia.

Impact of automatic infectious diseases consultation on the management of fungemia at a large academic medical center.

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.

Emerging echinocandins for treatment of invasive fungal infections.

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.

Role of isavuconazole in the treatment of invasive fungal infections.

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.

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.