Antimicrobial Stewardship Techniques for Critically Ill Patients with Pneumonia.

Pneumonia is common in the intensive care unit (ICU), infecting 27% of all critically ill patients. Given the high prevalence of this disease state in the ICU, optimizing antimicrobial therapy while minimizing toxicities is of utmost importance. Inappropriate antimicrobial use can increase the risk of antimicrobial resistance, Clostridiodes difficile infection, allergic reaction, and other complications from antimicrobial use (e.g., QTc prolongation, thrombocytopenia). This review article aims to discuss methods to optimize antimicrobial treatment in patients with pneumonia, including the following: procalcitonin use, utilization of methicillin-resistant Staphylococcus aureus nares testing to determine need for vancomycin therapy, utilization of the Biofire® FilmArray® pneumonia polymerase chain reaction (PCR), and microbiology reporting techniques.

Evaluation of Microbiological Concordance of a Rapid Molecular Diagnostic Pneumonia Panel in a Real-World Population with Pneumonia.

BACKGROUND: The Biofire® FilmArray® Pneumonia Panel (PN Panel) provides a more rapid and sensitive method of respiratory pathogen detection than standard culture. However, it is often unclear how to apply the results clinically, especially in the case of discordant culture results. We evaluated the concordance of bacterial organism and resistance gene identification between the PN Panel and standard culture methods in hospitalized patients with a clinical diagnosis of pneumonia. METHODS: This single-center retrospective observational study of 274 inpatients assessed the positive predictive value (PPV) and described the prevalence of individual bacterial organism and resistance marker targets on the PN Panel. RESULTS: The overall PPV of the PN Panel in identifying bacteria was 70.1%, with individual organism PPV ranging from 50.0% to 90.9%. For resistance gene identification, the PN Panel's PPV ranged from 46.2% for CTX-M to 68.4% for mecA/C and the staphylococcal cassette chromosome mec element right extremity junction (MREJ), although resistance was uncommon. Staphylococcus aureus was the most common bacterial pathogen detected by the PN Panel (38.7%), followed by Pseudomonas aeruginosa (22.3%), and Haemophilus influenzae (12.0%). CONCLUSIONS: The PN Panel detected more bacteria and resistance gene targets than standard culture methods. To optimize the use of this technology for both patient care and antimicrobial stewardship, results should be coupled with clinical assessment and clinician education.

Role of Therapeutic Drug Monitoring in the Treatment of Persistent Mycobacterium abscessus Central Nervous System Infection: A Case Report and Review of the Literature.

A patient presenting with recurrent ventriculoperitoneal shunt infection was found to have Mycobacterium abscessus growing from cerebrospinal fluid (CSF), which remained persistently positive. Therapeutic monitoring of clarithromycin, imipenem, and linezolid in CSF and plasma revealed lower than expected concentrations, prompting alternative therapy and culture clearance on hospital day 42.

Impact of early antimicrobial stewardship intervention in patients with positive blood cultures: results from a randomized comparative study.

BACKGROUND: Antimicrobial stewardship intervention (ASI) appears to be necessary to realize the full benefits of rapid diagnostic technologies in clinical practice. This study aimed to compare clinical outcomes between early ASI paired with matrix-associated laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) compared with MALDI-TOF with standard of care (SOC) reporting in patients with positive blood cultures. METHODS: Adult patients with positive blood cultures and organism speciation via MALDI-TOF admitted between February 2015 and September 2015 were randomized to ASI or SOC in a 1:1 fashion. Patients admitted for at least 48 h following positive culture were included in analyses. ASI was defined as a clinical assessment by a stewardship team member with non-binding treatment recommendations offered to the primary team. The primary outcome was time to definitive therapy. Secondary outcomes included post-culture length of stay (LOS), time to first change in antibiotics, and in-hospital mortality. RESULTS: In total, 149 patients were included in the analyses (76 in the ASI group and 73 in the SOC group). ASI and SOC arms did not differ according to age, sex, comorbidities or severity of illness. Gram-positive organisms were common in both SOC and ASI arms (74.0 vs. 61.8%, P=0.11). Time to definitive therapy was reduced, on average, by 30.3 h in the ASI group (71.6 vs. 41.3 h, P=0.01). Hospital LOS following the first positive blood culture was significantly shorter in the ASI group (8.7 vs. 11.2 days, P=0.049). CONCLUSIONS: ASI combined with MALDI-TOF reduced the time to definitive therapy and time to first change in antibiotics, and was associated with a shorter post-culture LOS.

Defining the Importance of Age-Related Changes in Drug Clearance to Optimizing Aminoglycoside Dosing Regimens for Adult Patients with Cystic Fibrosis.

BACKGROUND AND OBJECTIVE: The number of adults living with cystic fibrosis (CF) has increased and will continue to do so with the approval of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Because systemic aminoglycosides are commonly administered for CF pulmonary exacerbations, we sought to define optimized dosing regimens using a population pharmacokinetic modeling and simulation approach. METHODS: Adult CF patients admitted for pulmonary exacerbation, receiving at least 72 h of systemic gentamicin, tobramycin, or amikacin, with measured concentrations were included. Covariates [e.g., age, weight, creatinine clearance (CRCL)] were screened. Population modeling was completed using Monolix, and simulations were conducted in R. Simulated exposures were calculated using noncompartmental analysis. Once-daily fixed (10 mg/kg) and exposure-matched dosing (i.e., 15, 10, 7.5, 6 mg/kg for ages 20, 30, 40, and 50 years, respectively) strategies were compared. First-24 h exposures were evaluated for each strategy according to the probability of target attainment (PTA) (ratio of peak plasma concentrations relative to the minimum inhibitory concentration [Cmax/MIC] or ratio of the area under the concentration-time curve to MIC [AUC/MIC]) and the probability of toxic exposure (PTE) (trough concentration, Ctrough > 2 mg/l). RESULTS: Forty-eight adult patients (55% female) were included. A one-compartment model best fit the data. Estimates for volume of distribution (V) and clearance (CL) were 22 l and 5.57 l/h, respectively. Weight significantly modified CL and V. Age significantly modified CL and was more influential than CRCL. PTA was > 90% at MICs ≤ 1 mg/l for fixed doses of 10 mg/kg and for exposure-matched doses at MIC ≤ 1 mg/l. Exposure-matched dosing reduced PTE roughly 50% in patients aged 40 and 50 years vs. fixed dosing. CONCLUSIONS: Exposure-matching maintained PTA at MICs ≤ 1 mg/l while reducing toxicity risk in older patients compared to fixed dosing. Confirmatory studies are needed.

Exploring the Relationship between FEV1 Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies.

OBJECTIVE: Systemic aminoglycosides remain a cornerstone of treatment for cystic fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides. METHODS: We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and forced expiratory volume over 1 second (FEV1 ) data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain area under the curve (AUC)0-24 hr , maximum concentration (Cmax0-24 hr ), and minimum concentration (Cmin0-24 hr ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV1 by 30 days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis. RESULTS: The study included 51 patients who contributed 188 FEV1 observations. There were 3.0 ± 1.7 (mean ± SD) aminoglycoside concentrations per patient. The mean AUC0-24 hr , Cmax0-24 hr , and Cmin0-24 hr across all agents and patients were 156 ± 96 mg*hr/L, 29.9 ± 12.7 mg/L, and 0.35 ± 0.66 mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery posttreatment. Of the 51 included patients, 6 (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24 hr nor Cmax0-24 hr was associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 . CONCLUSIONS: Increasing aminoglycoside AUC0-24 hr and Cmax0-24 hr were not associated with FEV1 during PEx treatment. Although individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population.

Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update.

Objective: To summarize current antibiotic dosing recommendations in critically ill patients receiving intermittent hemodialysis (IHD), prolonged intermittent renal replacement therapy (PIRRT), and continuous renal replacement therapy (CRRT), including considerations for individualizing therapy. Data Sources: A literature search of PubMed from January 2008 to May 2019 was performed to identify English-language literature in which dosing recommendations were proposed for antibiotics commonly used in critically ill patients receiving IHD, PIRRT, or CRRT. Study Selection and Data Extraction: All pertinent reviews, selected studies, and references were evaluated to ensure appropriateness for inclusion. Data Synthesis: Updated empirical dosing considerations are proposed for antibiotics in critically ill patients receiving IHD, PIRRT, and CRRT with recommendations for individualizing therapy. Relevance to Patient Care and Clinical Practice: This review defines principles for assessing renal function, identifies RRT system properties affecting drug clearance and drug properties affecting clearance during RRT, outlines pharmacokinetic and pharmacodynamic dosing considerations, reviews pertinent updates in the literature, develops updated empirical dosing recommendations, and highlights important factors for individualizing therapy in critically ill patients. Conclusions: Appropriate antimicrobial selection and dosing are vital to improve clinical outcomes. Dosing recommendations should be applied cautiously with efforts to consider local epidemiology and resistance patterns, antibiotic dosing and infusion strategies, renal replacement modalities, patient-specific considerations, severity of illness, residual renal function, comorbidities, and patient response to therapy. Recommendations provided herein are intended to serve as a guide in developing and revising therapy plans individualized to meet a patient's needs.

Diagnostic stewardship of C. difficile testing: a quasi-experimental antimicrobial stewardship study.

OBJECTIVE: We evaluated whether a diagnostic stewardship initiative consisting of ASP preauthorization paired with education could reduce false-positive hospital-onset (HO) Clostridioides difficile infection (CDI). DESIGN: Single center, quasi-experimental study. SETTING: Tertiary academic medical center in Chicago, Illinois. PATIENTS: Adult inpatients were included in the intervention if they were admitted between October 1, 2016, and April 30, 2018, and were eligible for C. difficile preauthorization review. Patients admitted to the stem cell transplant (SCT) unit were not included in the intervention and were therefore considered a contemporaneous noninterventional control group. INTERVENTION: The intervention consisted of requiring prescriber attestation that diarrhea has met CDI clinical criteria, ASP preauthorization, and verbal clinician feedback. Data were compared 33 months before and 19 months after implementation. Facility-wide HO-CDI incidence rates (IR) per 10,000 patient days (PD) and standardized infection ratios (SIR) were extracted from hospital infection prevention reports. RESULTS: During the entire 52 month period, the mean facility-wide HO-CDI-IR was 7.8 per 10,000 PD and the SIR was 0.9 overall. The mean ± SD HO-CDI-IR (8.5 ± 2.0 vs 6.5 ± 2.3; P < .001) and SIR (0.97 ± 0.23 vs 0.78 ± 0.26; P = .015) decreased from baseline during the intervention. Segmented regression models identified significant decreases in HO-CDI-IR (Pstep = .06; Ptrend = .008) and SIR (Pstep = .1; Ptrend = .017) trends concurrent with decreases in oral vancomycin (Pstep < .001; Ptrend < .001). HO-CDI-IR within a noninterventional control unit did not change (Pstep = .125; Ptrend = .115). CONCLUSIONS: A multidisciplinary, multifaceted intervention leveraging clinician education and feedback reduced the HO-CDI-IR and the SIR in select populations. Institutions may consider interventions like ours to reduce false-positive C. difficile NAAT tests.

Patient perceptions of antibiotic use and resistance at a single university dermatology clinic.

Antibiotic resistance is an important problem that requires continued patient education and important prescribing stewardship. Dermatologists prescribe the most antibiotics per provider in comparison to other specialties and have an important role to play in the campaign of mindful prescribing. Data on the dermatology patients' knowledge and perception regarding antibiotic resistance is lacking and could play a role in providers' continuation of medications. We conducted a single institution survey of 512 dermatology clinic patients to understand patient's knowledge and potential gaps. Overall, our results demonstrated an overall higher level of knowledge than expected, there were still several knowledge gaps identified. Ninety-one percent of respondents were aware of the term 'antibiotic resistance'. However, 65% of participants believed that a short course of antibiotics could not cause resistance. While our patients have awareness of antibiotic resistance, it is imperative to continue to assess patients' knowledge about antibiotic resistance and provide education whenever possible in order to continue to practice antibiotic stewardship.

Implementation of a multifaceted program to sustainably improve appropriate intraoperative antibiotic redosing.

BACKGROUND: National guidelines recommend intraoperative redosing of prophylactic antibiotics at defined intervals to reduce the risk of surgical site infections. Compliance with these guidelines is poor. METHODS: A quality improvement project-including education, progress reports, and automated redosing reminders in the anesthesia electronic health record-was implemented at a large university-affiliated hospital to increase rates of intraoperative antibiotic redosing for surgeries lasting more than 4 hours. A retrospective, observational study was then conducted. The primary outcome was the compliance rate with intraoperative antibiotic redosing criteria for all surgeries lasting more than 4 hours in the pre- and post-project period. The effect of the intervention was assessed by an interrupted time-series Poisson regression model. RESULTS: A total of 13,695 surgical procedures were evaluated. Time-series analysis demonstrated that the project was associated with significant improvement of compliance rates (incidence rate ratio [IRR]: 1.16; P = .002) with no significant change in underlying improvement trend (IRR: 1.00; P = .22). DISCUSSION: Few peer-reviewed manuscripts describe effective methods to ensure appropriate antibiotic redosing during prolonged surgeries. We demonstrated that a multipronged approach was very effective at producing immediate and sustained improvements in guideline compliance. CONCLUSIONS: Implementation of a multifaceted intervention improved rates of guideline-concordant redosing of intraoperative prophylactic antibiotics.

Implementation of a Mobile Clinical Decision Support Application to Augment Local Antimicrobial Stewardship.

BACKGROUND: Medical applications for mobile devices allow clinicians to leverage microbiological data and standardized guidelines to treat patients with infectious diseases. We report the implementation of a mobile clinical decision support (CDS) application to augment local antimicrobial stewardship. METHODS: We detail the implementation of our mobile CDS application over 20 months. Application utilization data were collected and evaluated using descriptive statistics to quantify the impact of our implementation. RESULTS: Project initiation focused on engaging key stakeholders, developing a business case, and selecting a mobile platform. The preimplementation phase included content development, creation of a pathway for content approval within the hospital committee structure, engaging clinical leaders, and formatting the first version of the guide. Implementation involved a media campaign, staff education, and integration within the electronic medical record and hospital mobile devices. The postimplementation phase required ongoing quality improvement, revision of outdated content, and repeated staff education. The evaluation phase included a guide utilization analysis, reporting to hospital leadership, and sustainability and innovation planning. The mobile application was downloaded 3056 times and accessed 9259 times during the study period. The companion web viewer was accessed 8214 times. CONCLUSIONS: Successful implementation of a customizable mobile CDS tool enabled our team to expand beyond microbiological data to clinical diagnosis, treatment, and antimicrobial stewardship, broadening our influence on antimicrobial prescribing and incorporating utilization data to inspire new quality and safety initiatives. Further studies are needed to assess the impact on antimicrobial utilization, infection control measures, and patient care outcomes.

Streamlined Hyperacute Magnetic Resonance Imaging Protocol Identifies Tissue-Type Plasminogen Activator-Eligible Stroke Patients When Clinical Impression Is Stroke Mimic.

BACKGROUND AND PURPOSE: Stroke mimics (SM) challenge the initial assessment of patients presenting with possible acute ischemic stroke (AIS). When SM is considered likely, intravenous tissue-type plasminogen activator (tPA) may be withheld, risking an opportunity to treat AIS. Although computed tomography is routinely used for tPA decision making, magnetic resonance imaging (MRI) may diagnose AIS when SM is favored but not certain. We hypothesized that a hyperacute MRI (hMRI) protocol would identify tPA-eligible AIS patients among those initially favored to have SM. METHODS: A streamlined hMRI protocol was designed based on barriers to rapid patient transport, MRI acquisition, and post-MRI tPA delivery. Neurologists were trained to order hMRI when SM was favored and tPA was being withheld. The use of hMRI for tPA decision making, door-to-needle times, and outcomes were compared before hMRI implementation (pre-hMRI: August 1, 2011 to July 31, 2013) and after (post-hMRI, August 1, 2013, to January 15, 2015). RESULTS: Post hMRI, 57 patients with suspected SM underwent hMRI (median MRI-order-to-start time, 29 minutes), of whom, 11 (19%) were diagnosed with AIS and 7 (12%) received tPA. Pre-hMRI, no tPA-treated patients were screened with hMRI. Post hMRI, 7 of 106 (6.6%) tPA-treated patients underwent hMRI to aid in decision making because of suspected SM (0% versus 6.6%; P=0.001). To ensure standard care was maintained after implementing the hMRI protocol, pre- versus post-hMRI tPA-treated cohorts were compared and did not differ: door-to-needle time (39 versus 37 minutes; P=0.63), symptomatic hemorrhage rate (4.5% versus 1.9%; P=0.32), and favorable discharge location (85% versus 89%; P=0.37). CONCLUSIONS: A streamlined hMRI protocol permitted tPA administration to a small, but significant, subset of AIS patients initially considered to have SM.

Putative role of beta-1,3 glucans in Candida albicans biofilm resistance.

Biofilms are microbial communities, embedded in a polymeric matrix, growing attached to a surface. Nearly all device-associated infections involve growth in the biofilm life style. Biofilm communities have characteristic architecture and distinct phenotypic properties. The most clinically important phenotype involves extraordinary resistance to antimicrobial therapy, making biofilm infections very difficulty to cure without device removal. The current studies examine drug resistance in Candida albicans biofilms. Similar to previous reports, we observed marked fluconazole and amphotericin B resistance in a C. albicans biofilm both in vitro and in vivo. We identified biofilm-associated cell wall architectural changes and increased beta-1,3 glucan content in C. albicans cell walls from a biofilm compared to planktonic organisms. Elevated beta-1,3 glucan levels were also found in the surrounding biofilm milieu and as part of the matrix both from in vitro and in vivo biofilm models. We thus investigated the possible contribution of beta-glucans to antimicrobial resistance in Candida albicans biofilms. Initial studies examined the ability of cell wall and cell supernatant from biofilm and planktonic C. albicans to bind fluconazole. The cell walls from both environmental conditions bound fluconazole; however, four- to fivefold more compound was bound to the biofilm cell walls. Culture supernatant from the biofilm, but not planktonic cells, bound a measurable amount of this antifungal agent. We next investigated the effect of enzymatic modification of beta-1,3 glucans on biofilm cell viability and the susceptibility of biofilm cells to fluconazole and amphotericin B. We observed a dose-dependent killing of in vitro biofilm cells in the presence of three different beta-glucanase preparations. These same concentrations had no impact on planktonic cell viability. beta-1,3 Glucanase markedly enhanced the activity of both fluconazole and amphotericin B. These observations were corroborated with an in vivo biofilm model. Exogenous biofilm matrix and commercial beta-1,3 glucan reduced the activity of fluconazole against planktonic C. albicans in vitro. In sum, the current investigation identified glucan changes associated with C. albicans biofilm cells, demonstrated preferential binding of these biofilm cell components to antifungals, and showed a positive impact of the modification of biofilm beta-1,3 glucans on drug susceptibility. These results provide indirect evidence suggesting a role for glucans in biofilm resistance and present a strong rationale for further molecular dissection of this resistance mechanism to identify new drug targets to treat biofilm infections.