A narrative review on antimicrobial dosing in adult critically ill patients on extracorporeal membrane oxygenation.

The optimal dosing strategy of antimicrobial agents in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) is unknown. We conducted comprehensive review of existing literature on effect of ECMO on pharmacokinetics and pharmacodynamics of antimicrobials, including antibacterials, antifungals, and antivirals that are commonly used in critically ill patients. We aim to provide practical guidance to clinicians on empiric dosing strategy for these patients. Finally, we discuss importance of therapeutic drug monitoring, limitations of current literature, and future research directions.

Impact of Cefepime Susceptible-Dose-Dependent MIC for Enterobacteriaceae on Reporting and Prescribing.

The CLSI cefepime breakpoints were revised to include a susceptible-dose-dependent (SDD) category for Enterobacteriaceae, with the intention that higher cefepime doses be used for these isolates. In this study, 1.6% of Enterobacteriaceae isolates were reported as SDD, with Escherichia coli the most common SDD organism. Cefepime was prescribed in three cases (4.8%); the majority of SDD isolates were treated with a carbapenem. Enterobacteriaceae with cefepime SDD MICs were not commonly treated with cefepime at our institution.

Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension.

While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection.

Evaluation of impact of statin use on development of CPK elevation during daptomycin therapy.

BACKGROUND: Because both daptomycin and statins may increase creatine phosphokinase (CPK) levels, the manufacturer of daptomycin suggests considering holding statins during daptomycin therapy. Published evidence suggests potential detrimental effects of withdrawing statin therapy. OBJECTIVES: The objectives of this study were to determine the impact of concurrent statin therapy on peak CPK values, incidence of CPK elevation in patients receiving daptomycin therapy, and clinical factors associated with increased risk of developing CPK elevation. METHODS: This was a single-center, retrospective cohort study of patients ≥18 years of age who received daptomycin for ≥72 hours and had ≥1 follow-up CPK during a 5-year period. A Kaplan-Meier curve was used to evaluate time to CPK elevation. Cox regression analyses were used to compare the risk of developing elevated CPK between 3 study groups: those receiving daptomycin alone, daptomycin with concurrent statin therapy, and statin therapy held while on daptomycin. RESULTS: 498 patients were included in the study-384 received daptomycin alone, 63 received daptomycin concurrent with statin, and 51 with statin held during daptomycin therapy. Cumulative incidence of CPK elevation was 5.1% and 12% at 7 and 14 days. Those on daptomycin and statin concurrent therapy demonstrated an approximately 2-fold risk of CPK elevation compared with those having their statin therapy held, but the overall group effect was not statistically significant (P = .17). CONCLUSIONS: Our findings suggest that holding statin during daptomycin therapy may not be necessary, but may indicate need for increased frequency of CPK monitoring when these medications are used concurrently.

Rapid multiplex PCR panel for pneumonia in hospitalised patients with suspected pneumonia in the USA: a single-centre, open-label, pragmatic, randomised controlled trial.

BACKGROUND: The clinical utility of rapid multiplex respiratory specimen PCR panels for pneumonia for patients with suspected pneumonia is undefined. We aimed to compare the effect of the BioFire FilmArray pneumonia panel (bioMérieux, Salt Lake City, UT, USA) with standard of care testing on antibiotic use in a real-world hospital setting. METHODS: We conducted a single-centre, open-label, pragmatic, randomised controlled trial at the Mayo Clinic, Rochester, MN, USA. Hospitalised patients (aged ≥18 years) with suspected pneumonia, from whom expectorated or induced sputum, tracheal secretions, or bronchoalveolar lavage fluid respiratory culture samples (one per individual) could be collected during index hospitalisation, were eligible for inclusion. Samples from eligible participants were randomly assigned (1:1) with a computerised tool to undergo testing with either the BioFire FilmArray pneumonia panel, conventional culture, and antimicrobial susceptibility testing (intervention group) or conventional culture and antimicrobial susceptibility testing alone (control group). Antimicrobial stewardship review in both groups involved an assessment and recommendations for antibiotic modifications based on clinical data and the results from the BioFire FilmArray pneumonia panel, conventional culture, or both. The primary outcome was median time to first antibiotic modification (ie, escalation or de-escalation of antibiotics against Gram-negative and Gram-positive bacteria) within 96 h of randomisation, assessed with the Wilcoxon rank-sum test and analysed in a modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT05937126). FINDINGS: Between Sept 15, 2020, and Sept 19, 2022, 1547 patients were screened for eligibility, of whom 1181 (76·3%) were randomly assigned: 582 (49·3%) to the intervention group and 599 (50·7%) to the control group. In total, 1152 participants were included in the modified intention-to-treat analysis, 589 (51·1%) in the control group and 563 (48·9%) in the intervention group. For the modified intention-to-treat population, median time to any first antibiotic modification was 20·4 h (95% CI 18·0-20·4) in the intervention group and 25·8 h (22·0-28·7) in the control group (p=0·076). Median time to any antibiotic escalation was 13·8 h (9·2-19·0) in the intervention group and 24·1 h (19·5-29·6) in the control group (p=0·0022). Median time to escalation of antibiotics against Gram-positive organisms was 10·3 h (6·2-30·9) in the intervention group and 24·6 h (19·5-37·2) in the control group (p=0·044); median time to escalation of antibiotics against Gram-negative organisms was 17·3 h (10·8-23·3) in the intervention group and 27·2 h (21·3-33·9) in the control group (p=0·010). Median time to any antibiotic de-escalation did not differ between groups (p=0·37). Median time to first de-escalation of antibiotics against Gram-positive organisms was 20·7 h (17·8-24·0) in the intervention group and 27·8 h (22·9-33·0) in the control group (p=0·015); median time to first de-escalation of antibiotics against Gram-negative organisms did not differ between groups (p=0·46). INTERPRETATION: Clinical use of the BioFire FilmArray pneumonia panel might lead to faster antibiotic escalations, including for Gram-negative or Gram-positive bacteria, and faster antibiotic de-escalations directed at Gram-positive bacteria. Additional research is needed regarding antimicrobial de-escalation, especially when antibiotics with broad Gram-negative spectrum are being used, by use of rapid diagnostics in patients with lower respiratory tract infection. FUNDING: bioMérieux.

Effect of combined fluoroquinolone and azole use on QT prolongation in hematology patients.

QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.

Evaluation of an initiative to improve prophylactic antimicrobial prescribing in patients on extracorporeal membrane oxygenation (ECMO) through the application of three antimicrobial-spectrum scores.

Antimicrobial spectrum scoring is a method to quantify the spectrum of antimicrobial utilization. Herein, we applied a locally adapted scoring system, with other pre-existing scoring systems, using a data set of prophylactically administered antibiotics following a 2-stage antimicrobial stewardship program (ASP) intervention in a population of patients on extracorporeal membrane oxygenation (ECMO).

Linezolid and serotonergic drug interactions: a retrospective survey.

BACKGROUND: Linezolid is a reversible, nonselective monoamine oxidase inhibitor. There are currently 11 published case reports of serotonin syndrome being associated with linezolid and selective serotonin reuptake inhibitors (SSRIs). Controversy exists regarding whether linezolid and SSRIs can be given concomitantly. The purpose of this study was to report the incidence of serotonin syndrome in patients receiving linezolid and SSRIs. METHODS: This study was a retrospective chart review of inpatients at the Mayo Clinic (Rochester, MN) with concomitant orders or therapy within 14 days for linezolid and an SSRI from 2000 to 2004. The Sternbach criteria and Boyer criteria for diagnosis of serotonin syndrome were used to identify clinical features of serotonin syndrome. RESULTS: Seventy-two patients received linezolid and an SSRI or venlafaxine within 14 days of each other. Fifty-two patients (72%) received concomitant therapy with linezolid and an SSRI or venlafaxine, and 20 patients (28%) did not receive concomitant therapy but received linezolid and an SSRI within a 14-day period. Overall, only 2 patients (3%) had a high probability of serotonin syndrome. In both patients with high probability, symptoms reversed rapidly on discontinuation of serotonergic therapy. The Boyer criteria were much more specific than the Sternbach criteria for identification of serotonin syndrome. CONCLUSIONS: On the basis of our experience, we suggest that, if the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRIs, without a 14-day washout period and with careful monitoring for signs and symptoms of serotonin syndrome. Serotonergic agents should be promptly discontinued if serotonin syndrome is suspected.

Hospital rules-based system: the next generation of medical informatics for patient safety.

PURPOSE: The hospital rules-based system (HRBS) and its subsystems at a major medical center are described. SUMMARY: The HRBS was implemented at the Mayo Clinic to rapidly identify and communicate crucial information to the clinician in order to optimize patient care. The system also enhances workload efficiency and improves documentation and communication. The system is used by the infectious-diseases division, pharmacy services, nutritional support services, infection control, and the nursing department. The six HRBS subsystems are Web-based programs that share a common structural design and integrate computerized information from multiple institutional databases. The integrated data are presented in a user-friendly format that improves the efficiency of data retrieval. Information, such as monitoring notes and intervention information, can be entered for specific patients. The subsystems use rules designed to detect suboptimal therapy or monitoring and identify opportunities for cost savings in a timely manner. CONCLUSION: The HRBS enhances the identification of drug-related problems while optimizing patient care and improving communication and efficiency at a major medical center.

Non-anti-infective effects of antimicrobials and their clinical applications: a review.

Antimicrobial agents are undoubtedly one of the key advances in the history of modern medicine and infectious diseases, improving the clinical outcomes of infection owing to their inhibitory effects on microbial growth. However, many antimicrobial agents also have biological activities stemming from their interactions with host receptors and effects on host inflammatory responses and other human or bacterial cellular biological pathways. These result in clinical uses of antimicrobial drugs that are distinct from their direct bacteriostatic or bactericidal properties. We reviewed the published literature regarding non-anti-infective therapeutic properties and proposed clinical applications of selected antimicrobials, specifically, macrolides, tetracyclines, sulfonamides, and ketoconazole. The clinical applications reviewed were varied, and we focused on uses that were clinically relevant (in terms of importance and burden of disease) and where published evidence exists. Such uses include chronic inflammatory pulmonary and skin disorders, chronic periodontitis, gastrointestinal dysmotility, rheumatoid arthritis, and cancer. Most of these potential therapeutic uses are not Food and Drug Administration approved. Clinicians need to weigh the use of antimicrobial agents for their non-anti-infective benefits, considering potential adverse effects and long-term effect on microbial resistance.

Detecting delayed microbiology results after hospital discharge: improving patient safety through an automated medical informatics tool.

We developed a computerized medical informatics tool to identify patients who had a culture performed on a sterile body site specimen during their hospitalization that subsequently turned positive after hospital dismissal. During a 13-month period, 533 patients had a positive culture identified by our Computer-Based Antimicrobial Monitoring (CBAM) program after hospital dismissal, and 112 (21%) of these culture results necessitated an intervention and communication with the primary health care professional. Thirty-two (29%) of positive cultures were from the blood. Thirty-eight (34%) of the CBAM interventions with available outcome data resulted in initiation of, change in, or prolongation of outpatient antimicrobial therapy. The CBAM program serves an important role in optimizing patient care and communication with the health care professional during the transition from inpatient to outpatient management.

Characterization of bacterial infections in allogeneic hematopoietic stem cell transplant recipients who received prophylactic levofloxacin with either penicillin or doxycycline.

OBJECTIVE: To describe the effect of a combination prophylactic regimen of levofloxacin, a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class, with either penicillin or doxycycline on the changing epidemiology of bacterial infections and antimicrobial resistance patterns of isolated organisms in the allogeneic hematopoietic stem cell transplant (HSCT) patient population. PATIENTS AND METHODS: We conducted a single-center, retrospective cohort study of all allogeneic HSCT recipients from January 1, 2003, through August 31, 2008, who received prophylactic levofloxacin in combination with penicillin (or with doxycycline in penicillin-allergic patients) from allogeneic stem cell infusion until neutrophil engraftment. RESULTS: Of the 258 patients who underwent allogeneic HSCT during the study period, 231 received levofloxacin prophylaxis, 76 (33%) of whom developed an infection within 3 months after transplant. Over time, the ratio of gram-positive to gram-negative (GN) infections decreased from 2.11 in 2004, the first year that GN organisms were isolated, to 1.11 in 2008 (P=.20). Emergence of fluoroquinolone-resistant GN bacteria was observed (P=.02), whereas resistance to extended-spectrum beta-lactams did not change over time. Combined vancomycin-resistant enterococci colonization and infection rates increased during the study period (P=.04). Clostridium difficile colitis was uncommon. CONCLUSION: Levofloxacin with penicillin or doxycycline prophylaxis may contribute to the emergence of resistant GN infections in allogeneic HSCT recipients over time. Our findings provide additional support for the current standard of practice of administering empiric monotherapy with an antipseudomonal beta-lactam if these patients develop fever or are suspected to have an infection.

Effect of telephoned notification of positive Clostridium difficile test results on the time to the ordering of antimicrobial therapy.

The time between electronic-medical-record reporting of a positive result of a test for Clostridium difficile toxin in stool and the ordering of antimicrobial therapy was compared during consecutive periods when results were not telephoned (n = 274) and when results were telephoned (n = 90) to the clinical service. The mean times to the ordering of antimicrobial therapy were 11.9 and 3.6 hours, respectively (P < .001).