Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia.

BACKGROUND: Candidaemia is associated with poor outcomes including high mortality rates. Controversy remains regarding whether fluconazole or an echinocandin is the optimal choice for initial candidaemia treatment, particularly among high-risk patients such as the immunocompromised or critically ill. OBJECTIVES: To understand optimal initial treatment of candidaemia. METHODS: We conducted a retrospective study of immunocompromised or ICU adult patients with candidaemia from 2010 to 2014. Patients who received ≥3 consecutive days of initial treatment with fluconazole or micafungin were included. The primary outcome was complete response at day 14, defined as clinical improvement and blood culture sterilization. Secondary outcomes included microbiological and clinical success, survival and recurrent candidaemia. RESULTS: A total of 197 patients were included; 76 received fluconazole and 121 received micafungin. There was no difference in complete response between the fluconazole and micafungin groups (ICU: 38% versus 40%, P = 0.87; immunocompromised: 57% versus 59%, P = 0.80). Secondary outcomes including survival were also similar. In multivariable analysis, among ICU patients, Pitt bacteraemia score < 4 (P = 0.002) and time to antifungal (P = 0.037) were associated with meeting the primary outcome; white blood cell count > 11 cells × 103/µL on day 0 (P < 0.001) and Candida isolated from a non-blood site (P = 0.025) were associated with not meeting the primary outcome. Among immunocompromised patients, white blood cells > 11 × 103/µL (P = 0.003) and Candida isolated from a non-blood site (P = 0.026) were associated with not meeting the primary outcome. CONCLUSIONS: These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.

Improving Antibiotic Stewardship for Inpatients with Reported Beta-Lactam Allergies and Limited Access to Penicillin Skin Testing.

BACKGROUND: Penicillin allergy is commonly reported, but true allergy is rare. Inpatients with reported beta-lactam allergy are often treated with alternative antibiotics. Penicillin skin testing (PST) is not universally available for inpatients. METHODS: We designed a four-phase quality improvement project aimed to increase the percentage of inpatients on medical services with reported beta-lactam allergy who safely receive beta-lactam antibiotics at two hospitals with limited access to PST. First, we updated our hospital guideline to allow for cephalosporin graded challenge without antecedent PST. Second, we educated physicians, physician assistants, and nurses about the new guideline and beta-lactam allergy classification and management. Third, we designed a pocket card to reinforce the education. Last, we used antimicrobial stewardship software to screen our daily census to identify opportunities to improve management of patients with reported beta-lactam allergies. RESULTS: We observed a 29.2% increase in the percentage of patients who received beta-lactam antibiotics (excluding carbapenems) among those with reported beta-lactam allergy, from 42.2% (470/1,115) at baseline to 54.5% (379/696), p < 0.001, during the project period. There was a decrease in the use of alternative antibiotics, no change in hospital-onset Clostridioides difficile cases, and no increase in the number of infectious disease or allergy consults. The number of graded challenges increased during the project period, without any anaphylaxis events. CONCLUSION: A multiphase quality improvement project aimed to improve management of beta-lactam allergies and access to graded challenges led to an increase in beta-lactam utilization without an increase in anaphylaxis, even with limited access to PST.

Real-world implementation and impact of a rapid carbapenemase detection test in an area endemic for carbapenem-resistant Enterobacterales.

A retrospective study was conducted to describe the impact of a molecular assay to detect the most common carbapenemase genes in carbapenem-resistant Enterobacterales isolates recovered in culture. Carbapenemases were detected in 69% of isolates, and assay results guided treatment modifications or epidemiologic investigation in 20% and 4% of cases, respectively.

Antimicrobial stewardship perspectives from a New York City hospital during the COVID-19 pandemic: Challenges and opportunities.

PURPOSE: To share challenges and opportunities for antimicrobial stewardship programs based on one center's experience during the early weeks of the coronavirus disease 2019 (COVID-19) pandemic. SUMMARY: In the spring of 2020, New York City quickly became a hotspot for the COVID-19 pandemic in the United States, putting a strain on local healthcare systems. Antimicrobial stewardship programs faced diagnostic and therapeutic uncertainties as well as healthcare resource challenges. With the lack of effective antivirals, antibiotic use in critically ill patients was difficult to avoid. Uncertainty drove antimicrobial use and thus antimicrobial stewardship principles were paramount. The dramatic influx of patients, drug and equipment shortages, and the need for prescribers to practice in alternative roles only compounded the situation. Establishing enhanced communication, education, and inventory control while leveraging the capabilities of the electronic medical record were some of the tools used to optimize existing resources. CONCLUSION: New York City was a unique and challenging environment during the initial peak of the COVID-19 pandemic. Antimicrobial stewardship programs can learn from each other by sharing lessons learned and practice opportunities to better prepare other programs facing COVID-19 case surges.

Implementation of infectious diseases rapid molecular diagnostic tests and antimicrobial stewardship program involvement in acute-care hospitals.

A survey of acute-care hospitals found that rapid molecular diagnostic tests (RMDTs) have been widely adopted. Although many hospitals use their antimicrobial stewardship team and/or guidelines to help clinicians interpret results and optimize treatment, opportunities to more fully achieve the potential benefits of RMDTs remain.

Efficacy of Amphotericin B in Corneal Preservation Media After Extended Frozen Storage.

PURPOSE: To investigate the antimycotic activity of amphotericin B deoxycholate that has been previously frozen for 28 days before supplementation of Optisol-GS. METHODS: Triplicate Optisol-GS samples were inoculated with 10 colony-forming units (CFU) of Candida albicans. Each set of triplicate cultures was supplemented with 2.5 µg/mL of amphotericin B that was either freshly resuspended and never frozen, frozen overnight at -20°C and thawed, or frozen at -20°C for 4 weeks and thawed. The cultures were stored at 4°C, with aliquots taken at 0, 6, 24, and 72 hours for quantification. The efficacy of each preparation of amphotericin B in reducing C. albicans growth was assessed at these time points. RESULTS: Six hours after antifungal supplementation, there was a 1.33 log10 CFU reduction with freshly resuspended amphotericin B, compared with a 1.31 log10 reduction with amphotericin B that was frozen overnight (P = 0.20) and a 1.18 log10 reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). After 72 hours, there was a 2.72 log10 CFU reduction with freshly resuspended amphotericin B, a 2.64 log10 CFU reduction with amphotericin B that was frozen overnight (P = 0.45), and a 2.18 log10 CFU reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). CONCLUSIONS: Previously frozen amphotericin B remains highly effective against C. albicans. Optisol-GS supplemented with 2.5 µg/mL amphotericin B that was frozen for 4 weeks at -20°C resulted in >90% CFU reduction by 6 hours and >99% reduction by 72 hours.

Therapeutic drug monitoring of systemic antifungal agents: a pragmatic approach for adult and pediatric patients.

Introduction: Therapeutic drug monitoring (TDM) has been shown to optimize the management of invasive fungal infections (IFIs), particularly for select antifungal agents with a well-defined exposure-response relationship and an unpredictable pharmacokinetic profile or a narrow therapeutic index. Select triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine fulfill these criteria, while the echinocandins, fluconazole, isavuconazole, and amphotericin B generally do not do so. Given the morbidity and mortality associated with IFIs and the challenges surrounding the use of currently available antifungal agents, TDM plays an important role in therapy.Areas covered: This review seeks to describe the rationale for TDM of antifungal agents, summarize their pharmacokinetic and pharmacodynamic properties, identify treatment goals for efficacy and safety, and provide recommendations for optimal dosing and therapeutic monitoring strategies.Expert opinion: Several new antifungal agents are currently in development, including compounds from existing antifungal classes with enhanced pharmacokinetic or safety profiles as well as agents with novel targets for the treatment of IFIs. Given the predictable pharmacokinetics of these newly developed agents, use of routine TDM is not anticipated. However, expanded knowledge of exposure-response relationships of these compounds may yield a role for TDM to improve outcomes for adult and pediatric patients.

Impact of Hospitalist-Led Interdisciplinary Antimicrobial Stewardship Interventions at an Academic Medical Center.

BACKGROUND: Approximately 20%-50% of antimicrobial use in hospitals is inappropriate. Limited data exist on the effect of frontline provider engagement on antimicrobial stewardship outcomes. METHODS: A three-arm pre-post quality improvement study was conducted on three adult internal medicine teaching services at an urban academic hospital. Data from September through December 2016 were compared to historic data from corresponding months in 2015. Intervention arms were (1) Educational bundle (Ed-only); (2) Educational bundle plus antimicrobial stewardship rounds twice weekly with an infectious disease-trained clinical pharmacist (Ed+IDPharmDx2); and (3) Educational bundle plus internal medicine-trained clinical pharmacist embedded into daily attending rounds (Ed+IMPharmDx5). RESULTS: Total antibiotic use decreased by 16.8% (p < 0.001), 6.8% (p = 0.08), and 33.0% (p < 0.001) on Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Broad-spectrum antibiotic use decreased by 26.2% (p < 0.001), 7.8% (p = 0.09), and 32.4% (p < 0.001) on the Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Duration of inpatient antibiotic therapy decreased from 4 to 3 days on the Ed+IMPharmDx5 team (p = 0.01). Length of stay for patients who received any antibiotic decreased from 9 to 7 days on the Ed-only team (p < 0.001) and from 9 to 6 days on the Ed+IMPharmDx5 team (p < 0.001). There was no significant change in 30-day readmission to the same facility, transfer to ICU, or in-hospital mortality for any team. CONCLUSION: Multidisciplinary, frontline provider-driven approaches to antimicrobial stewardship may contribute to reduced antibiotic use and length of hospital stay.

Dosage-dependent reduction of macular pigment optical density in female breast cancer patients receiving tamoxifen adjuvant therapy.

It is now increasingly common for breast cancer patients to receive adjuvant tamoxifen therapy for a period of up to 10 years. As survival rate increases, managing tamoxifen ocular toxicities is important for patients' quality of life. Macular pigments in photoreceptor cells protect against free radical damage, which can cause macular degeneration. By reducing macular pigment concentration, tamoxifen may increase the risk of macular degeneration. Here, we compared macular pigment optical density (MPOD) and central macular thickness between breast cancer patients on tamoxifen adjuvant therapy (n = 70), and a control group (n = 72). Multiple regression analysis indicated that MPOD decreases with increasing tamoxifen dosage, up to a threshold of about 20 g, after which MPOD plateaus out. Mean MPOD in the treatment group (mean = 0.40) was significantly lower (p-value = 0.02) compared to the control group (mean = 0.47) for the left eye, and for the right eye (treatment mean = 0.39; control mean = 0.48; p-value = 0.009). No significant difference in mean central macular thickness was found between the treatment and the control group (p-values > 0.4). In the control group, MPOD and central macular thickness showed significant correlation (r∼0.30; p-values < 0.01) for both eyes. However, in the treatment group, loss of significant correlation was observed in the left eye (r = 0.21; p-value = 0.08). The present results show that MPOD decreases non-linearly as a function of tamoxifen dosage, and highlight the potential of tamoxifen to reduce macular pigment concentration through an unknown mechanism that does not depend on macular thinning solely.

Knowledge, Attitudes, and Practices Regarding Antimicrobial Use and Stewardship Among Prescribers at Acute-Care Hospitals.

OBJECTIVE To assess antimicrobial prescriber knowledge, attitudes, and practices (KAP) regarding antimicrobial stewardship (AS) and associated barriers to optimal prescribing. DESIGN Cross-sectional survey. SETTING Online survey. PARTICIPANTS A convenience sample of 2,900 US antimicrobial prescribers at 5 acute-care hospitals within a hospital network. INTERVENTION The following characteristics were assessed with an anonymous, online survey in February 2015: attitudes and practices related to antimicrobial resistance, AS programs, and institutional AS resources; antimicrobial prescribing and AS knowledge; and practices and confidence related to antimicrobial prescribing. RESULTS In total, 402 respondents completed the survey. Knowledge gaps were identified through case-based questions. Some respondents sometimes selected overly broad therapy for the susceptibilities given (29%) and some "usually" or "always" preferred using the most broad-spectrum empiric antimicrobials possible (32%). Nearly all (99%) reported reviewing antimicrobial appropriateness at 48-72 hours, but only 55% reported "always" doing so. Furthermore, 45% of respondents felt that they had not received adequate training regarding antimicrobial prescribing. Some respondents lacked confidence selecting empiric therapy using antibiograms (30%), interpreting susceptibility results (24%), de-escalating therapy (18%), and determining duration of therapy (31%). Postprescription review and feedback (PPRF) was the most commonly cited AS intervention (79%) with potential to improve patient care. CONCLUSIONS Barriers to appropriate antimicrobial selection and de-escalation of antimicrobial therapy were identified among front-line prescribers in acute-care hospitals. Prescribers desired more AS-related education and identified PPRF as the most helpful AS intervention to improve patient care. Educational interventions should be preceded by and tailored to local assessment of educational needs. Infect Control Hosp Epidemiol 2018;39:316-322.

The Expanding Role of Antimicrobial Stewardship Programs in Hospitals in the United States: Lessons Learned from a Multisite Qualitative Study.

BACKGROUND: Misuse of antibiotics can lead to the development of antibiotic resistance, which adversely affects morbidity, mortality, length of stay, and cost. To combat the threat of antimicrobial resistance, The Joint Commission and the Centers for Medicare & Medicaid Services have initiated or proposed requirements for hospitals to have antimicrobial stewardship programs (ASPs), but implementation remains challenging. A key-informant interview study was conducted to describe the characteristics and innovative strategies of leading ASPs. METHODS: Semistructured interviews were conducted with 12 program leaders at four ASPs in the United States, chosen by purposive sampling on the basis of national reputation, scholarship, and geography. Questions focused on ASP implementation, program structure, strengths, weaknesses, lessons learned, and future directions. Content analysis was used to identify dominant themes. RESULTS: Three major themes were identified. The first was evolution of ASPs from a top-down structure to a more diffuse approach involving unit-based pharmacists, multidisciplinary staff, and shared responsibility for antimicrobial prescribing under the ASPs' leadership. The second theme was integration of information technology (IT) systems, which enabled real-time interventions to optimize antimicrobial therapy and patient management. The third was barriers to technology integration, including limited resources for data analysis and poor interoperability between software systems. CONCLUSION: The study provides valuable insights on program implementation at a sample of leading ASPs across the United States. These ASPs used expansion of personnel to amplify the ASP's impact and integrated IT resources into daily work flow to improve efficiency. These findings can be used to guide implementation at other hospitals and aid in future policy development.

Clinical outcomes associated with polymyxin B dose in patients with bloodstream infections due to carbapenem-resistant Gram-negative rods.

There is significant variation in the use of polymyxin B (PMB), and optimal dosing has not been defined. The purpose of this retrospective study was to evaluate the relationship between PMB dose and clinical outcomes. We included patients with bloodstream infections (BSIs) due to carbapenem-resistant Gram-negative rods who received ≥48 h of intravenous PMB. The objective was to evaluate the association between PMB dose and 30-day mortality, clinical cure at day 7, and development of acute kidney injury (AKI). A total of 151 BSIs were included. The overall 30-day mortality was 37.8% (54 of 151), and the median PMB dosage was 1.3 mg/kg (of total body weight)/day. Receipt of PMB dosages of <1.3 mg/kg/day was significantly associated with 30-day mortality (46.5% versus 26.3%; P = 0.02), and this association persisted in multivariable analysis (odds ratio [OR] = 1.58; 95% confidence interval [CI] = 1.05 to 1.81; P = 0.04). Eighty-two percent of patients who received PMB dosages of <1.3 mg/kg/day had baseline renal impairment. Clinical cure at day 7 was not significantly different between dosing groups. AKI was more common in patients receiving PMB dosages of ≥250 mg/day (66.7% versus 32.0%; P = 0.03), and this association persisted in multivariable analysis (OR = 4.32; 95% CI = 1.15 to 16.25; P = 0.03). PMB dosages of <1.3 mg/kg/day were administered primarily to patients with renal impairment, and this dosing was independently associated with 30-day mortality. However, dosages of ≥250 mg/day were independently associated with AKI. These data support the use of PMB without dose reduction in the setting of renal impairment.

Refractive outcomes comparison between the Lenstar LS 900® optical biometry and immersion A-scan ultrasound.

To determine the accuracy of intraocular lens (IOL) calculations in eyes undergoing phacoemulsification cataract surgery with IOL implantation using immersion A-scan ultrasound (US) and Lenstar LS 900(®) biometry. In this prospective study, 200 eyes of 200 patients were randomized to undergo either Lenstar LS 900(®) or immersion A-scan US biometry to determine the IOL dioptric power prior to phacoemulsification cataract surgery. Post-operative refractive outcomes of these two groups of patients were compared. The result showed no significant difference between the target spherical equivalent (SE) and the post-operative SE value by the Lenstar LS 900(®) (p value = 0.632) or immersion A-scan US biometry (p value = 0.438) devices. The magnitude of difference between the two biometric devices were not significantly different (p value = 0.868). There was no significant difference in the predicted post-operative refractive outcome between immersion A-scan US biometry and Lenstar LS 900(®). Based on the results, the immersion A-scan US technique is as accurate as Lenstar LS 900(®) in the hands of an experienced operator.

Pharmacodynamic target attainment for various ceftazidime dosing schemes in high-flux hemodialysis.

Ceftazidime is a broad-spectrum cephalosporin with high-level activity against a variety of Gram-negative pathogens, including Pseudomonas aeruginosa. Improved outcomes are associated with cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of >45 to 70% of the dosing interval. Optimal dosing to achieve a 90% probability of target attainment (PTA) in patients receiving high-flux hemodialysis (HFHD) is unknown. We used existing data from six anephric adults receiving hemodialysis to construct a population model with the Pmetrics package for R. From the final model's joint probability density, we simulated the PTA for various ceftazidime dosing regimens, HFHD schedules, and organism MICs. For HFHD every 48 h and 1 g of ceftazidime given posthemodialysis, the PTA exceeds 90% for all isolates with MICs of ≤8 µg/ml, assuming a goal of 70%TMIC. For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%TMIC goal only for organisms with MICs of ≤4 µg/ml, while 2 g is adequate for organisms with MICs of ≤8 µg/ml. A dose of 500 mg once daily, regardless of HFHD schedule, has a 90% PTA for organisms with MICs of ≤16 µg/ml, while 1 g once daily may achieve 100% PTA even for resistant organisms with a MIC of 32 µg/ml. Therefore, to ensure maximal ceftazidime activity, once-daily dosing of 500 mg to 1 g ceftazidime in patients receiving HFHD may be preferable for critically ill patients when MIC data are unavailable and for more resistant organisms with ceftazidime MICs of 16 to 32 µg/ml.

Toxicokinetic and mechanistic basis for the safety and tolerability of liposomal amphotericin B.

INTRODUCTION: Amphotericin B (AmB) was first approved by the US Food and Drug Administration in 1959 with sodium deoxycholate (DAmB, Fungizone®). Extensive toxicities associated with the drug led to the development of lipid formulations of AmB, including liposomal amphotericin B (L-AmB, AmBisome®). Phase I studies as well as comparative Phase III clinical trials indicate that L-AmB is associated with less nephrotoxicity and reduced infusion-related toxicity. There is, however, no recent comprehensive review of the safety and tolerability of L-AmB. AREAS COVERED: This article reviews the safety, tolerability and the mechanisms of the major toxicities associated with L-AmB, including nephrotoxicity, infusion-related reactions (IRRs), anemia and thrombocytopenia, and hepatic abnormalities. The article further discusses the mechanism of action and pharmacokinetics of L-AmB. EXPERT OPINION: L-AmB is a broad-spectrum antifungal agent that has significantly reduced toxicities compared to its predecessor, DAmB.

Demographic characteristics and estimated prevalence of Fontan-associated plastic bronchitis.

Plastic bronchitis (PB) is a poorly understood disease that can complicate any underlying pulmonary disease. However, it appears to most often occur in patients with surgically palliated congenital heart disease, particularly after the Fontan procedure. Few data exist about the prevalence and etiology of PB in this population. In an effort to establish data about prevalence, we conducted a retrospective study of an existing Fontan surgery database (n = 654) comprised of data, including sex, age at date of surgery, alive/dead status, New York Heart Association classification at last follow-up, right-ventricular end-diastolic pressure and pulmonary artery pressure before Fontan surgery, and the presence of a Fontan fenestration. An initial medical record review of 173 patients in the database who were followed at the University of Michigan identified seven patients with PB resulting in an estimated prevalence of 4 %. Subsequently, 14 % of 211 surveyed patients reported that they presently expectorate mucus or fibrin plugs (casts). Demographic and clinical variables did not differ between patients with or without possible PB. Collectively, these findings suggest that Fontan patients presently with PB may range from 4 to 14 %, indicating potential under-diagnosis of the disease. There were no remarkable physical or hemodynamic indicators that differentiated patients with or without possible PB. These data also highlight the need for more elaborate, prospective studies to improve our understanding of PB pathogenesis so that more definitive diagnostic criteria for this devastating disease can be established and its prevalence more accurately determined.

Antimicrobial drug-induced thrombocytopenia: a review of the literature.

The incidence of drug-induced thrombocytopenia (DIT) is not well-defined, but is estimated to occur at a minimum of 10 cases per million per year. This review will focus on the potential DIT associated with specific antibacterial, antifungal, antiviral, and antiparasitic agents. Case reports, cohort studies, and clinical trials were identified using PubMed search terms for each antimicrobial along with the Boolean combiner AND to match with the following outcomes: thrombocytopenia and bleed. Thrombocytopenia was defined as a platelet count of < 100 × 10(9)/L or a decrease in platelet count of at least 50% from baseline. A majority of the data supporting antimicrobial-induced thrombocytopenia consist of case reports and small studies. However, clinicians should be vigilant in monitoring patient platelet counts, as an immune-mediated mechanism is frequently responsible for this hematologic adverse effect and is therefore unpredictable.

Scanning laser edema index: a reliable tool to correlate with diabetic retinopathy and systemic risk factors?

To correlate Heidelberg Retina Tomograph (HRT) derived macular edema (DME) index with severity of diabetic retinopathy and systemic factors. A total of 300 diabetic patients were recruited for the study for each of them a value for the macular edema index was obtained using the HRT II. Patients' age, gender, duration and type of diabetes mellitus, latest HbA1c result and presence or absence of co-morbid factors (hypertension, ischemic heart disease, nephropathy) were recorded together with the stage of diabetic retinopathy. These were correlated with DME. Out of 300 patients, HRT defined macula edema was seen in 68 patients (22.6%). There is a wider and higher range (95% percentile) of macula edema index in the severe non proliferative diabetic retinopathy (NPDR) group. Independent samples t test showed significant difference between the severe NPDR group and no DR group (p<0.001), mild NPDR group (p<0.05) and moderate NPDR group (p<0.05). A higher macula edema index was also found to have a low degree of correlation with more advanced stages of retinopathy (r=0.310; p<0.001). Also nephropathy showed a strong and significant correlation with DME. Hypertension had moderately significant correlation with DME. This study found no correlation between ischemic heart disease and DME. HRT derived scanning laser edema index is a reliable objective tool to evaluate diabetic retinopathy and systemic risk factors.