The Approach to Altered Mental Status in the Intensive Care Unit.

Altered mental status (AMS) is a syndrome posing substantial burden to patients in the intensive care unit (ICU) in both prevalence and intensity. Unfortunately, ICU patients are often diagnosed merely with syndromic labels, particularly the duo of toxic-metabolic encephalopathy (TME) and delirium. Before applying a nonspecific diagnostic label, every patient with AMS should be evaluated for specific, treatable diseases affecting the central nervous system. This review offers a structured approach to increase the probability of identifying specific causal etiologies of AMS in the critically ill. We provide tips for bedside assessment in the challenging ICU environment and review the role and yield of common neurodiagnostic procedures, including specialized bedside modalities of diagnostic utility in unstable patients. We briefly review two common etiologies of TME (uremic and septic encephalopathies), and then review a selection of high-yield toxicologic, neurologic, and infectious causes of AMS in the ICU, with an emphasis on those that require deliberate consideration as they elude routine screening. The final section lays out an approach to the various etiologies of AMS in the critically ill.

Opportunities Revealed for Antimicrobial Stewardship and Clinical Practice with Implementation of a Rapid Respiratory Multiplex Assay.

Few studies assess the utility of rapid multiplex molecular respiratory panels in adult patients. Previous multiplex PCR assays took hours to days from order time to result. We analyze the clinical impact of switching to a molecular assay with a 3-h test-turnaround-time (TAT). We performed a retrospective review of adult patients who presented to our emergency departments with respiratory symptoms and had a respiratory viral panel (xTAG RVP; RVP) or respiratory pathogen panel (ePlex RP; RPP) within 48 h of presentation. The average TATs for the RVP and RPP were 27.9 and 3.0 h, respectively (P < 0.0001). In RVP-positive and RPP-positive patients, 68.9 and 44.5% of those with normal chest imaging received antibiotics (P = 0.013), while 95.4 and 89.6% of those with abnormal imaging received antibiotics, respectively (P = 0.187). There was no difference in antibiotic duration in RVP-positive and RPP-positive patients with abnormal chest imaging (6.2 and 6.0 days, respectively; P = 0.923) and normal chest imaging (4.5 and 4.3 days, respectively; P = 0.922). Fewer patients were admitted in the RPP-positive compared to the RVP-positive group (76.9 and 88.6%, respectively; P = 0.013), while the proportion of admissions were similar among RPP-negative and RVP-negative patients (85.3 and 87.1%, P = 0.726). Switching to a multiplex respiratory panel with a clinically actionable TAT is associated with reduced hospital admissions and, in admitted adults without focal radiographic findings, reduced antibiotic initiation. Opportunities to further mitigate inappropriate antibiotic use may be realized by combining rapid multiplex PCR with provider education, clinical decision-care algorithms, and active antibiotic stewardship.

Pharmacokinetic considerations in selecting optimal antibiotic therapy for Mycoplasma pneumoniae encephalitis.

Effective antimicrobial therapy depends on several factors including degree of activity against the pathogen, antibiotic resistance, and when relevant, optimal tissue penetration factors. Central nervous system (CNS) infections illustrate these points well. The pharmacokinetic (PK) parameters important in antibiotic blood cerebrospinal fluid barrier (BCB) penetration that is important in meningitis are different and do not predict blood brain barrier (BBB) penetration. Recently, we had a case of Mycoplasma pneumoniae encephalitis (MPE) which prompted a review of the antibiotic PK determinants of BBB penetration which differ markedly from those of BCB penetration important in encephalitis. Using MPE as an illustrative example, this article reviews host and drug factors of therapeutic importance in optimally treating MPE.

The Clinical Utility of Methicillin-Resistant Staphylococcus aureus (MRSA) Nasal Screening to Rule Out MRSA Pneumonia: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implications.

Background: Recent literature has highlighted methicillin-resistant Staphylococcus aureus (MRSA) nasal screening as a possible antimicrobial stewardship program tool for avoiding unnecessary empiric MRSA therapy for pneumonia, yet current guidelines recommend MRSA therapy based on risk factors. The objective of this meta-analysis was to evaluate the diagnostic value of MRSA nasal screening in MRSA pneumonia. Methods: PubMed and EMBASE were searched from inception to November 2016 for English studies evaluating MRSA nasal screening and development of MRSA pneumonia. Data analysis was performed using a bivariate random-effects model to estimate pooled sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Twenty-two studies, comprising 5163 patients, met our inclusion criteria. The pooled sensitivity and specificity of MRSA nares screen for all MRSA pneumonia types were 70.9% and 90.3%, respectively. With a 10% prevalence of potential MRSA pneumonia, the calculated PPV was 44.8%, and the NPV was 96.5%. The pooled sensitivity and specificity for MRSA community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) were 85% and 92.1%, respectively. For CAP and HCAP both the PPV and NPV increased, to 56.8% and 98.1%, respectively. In comparison, for MRSA ventilated-associated pneumonia, the sensitivity, specificity, PPV, and NPV were 40.3%, 93.7%, 35.7%, and 94.8%, respectively. Conclusion: Nares screening for MRSA had a high specificity and NPV for ruling out MRSA pneumonia, particularly in cases of CAP/HCAP. Based on the NPV, MRSA nares screening is a valuable tool for AMS to streamline empiric antibiotic therapy, especially among patients with pneumonia who are not colonized with MRSA.

Implementing an antimicrobial stewardship program in out-patient dialysis units.

PURPOSE OF REVIEW: Rates of multidrug-resistant organisms (MDRO), including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative bacteria, continue to rise among the population of chronic hemodialysis. Antimicrobial exposure is the main risk factor for MDRO emergence and dissemination. Up to 30% of antimicrobial doses administered in out-patient dialysis units may not be indicated. Antimicrobial stewardship programs (ASP) improve antimicrobial prescribing patterns. The purpose of this review is to highlight the key elements and interventions of ASP. RECENT FINDINGS: The Infectious Disease Society of America and the Society of Healthcare Epidemiology of America have provided evidence-based guidelines for the development and implementation of an ASP. Many of their recommendations can be adapted to the out-patient dialysis setting. SUMMARY: Developing and implementing an ASP by following key elements and interventions in the out-patient dialysis setting can lead to reduced mortality, adverse events, costs, and improvement in antimicrobial susceptibility rates.

Corynebacterium minutissimum vascular graft infection: case report and review of 281 cases of prosthetic device-related Corynebacterium infection.

Corynebacterium spp. have proven their pathogenic potential in causing infections, particularly in the setting of immunosuppression and prosthetic devices. We conducted a PubMed literature review of all cases of Corynebacterium prosthetic device infections published in the English language through December 2013. The majority of cases involved peritoneal dialysis and central venous catheters, but prosthetic joints and central nervous system shunts/drains were also involved. The management of these cases in terms of retention or removal of the device was not uniform; however, the overall mortality remained the same among both groups. All of these prosthetic device infections pose potential problems in management when the device cannot be removed safely for the patient, especially with the lack of data on the pathogenicity of Corynebacterium species. However with better identification of species and sensitivities, successful treatment is possible even with retention of the device.

Combination of a Rapid Diagnostic Assay and Antimicrobial Stewardship Intervention for Gram-Negative Bacteremia.

Background: Traditional blood cultures for gram-negative bacteremia can take up to 72 hours or more to return results, prolonging the duration of empiric broad-spectrum intravenous antibiotics. The Accelerate Pheno system provides rapid identification and susceptibilities for blood cultures in gram-negative bacteremia. Current data on its clinical utility are mixed overall, so the system requires further research. Methods: A multicenter, retrospective quasi-experimental study was conducted comparing the Accelerate Pheno rapid diagnostic system with antimicrobial stewardship intervention and traditional blood cultures alone. Results: A total of 264 patients with blood cultures with gram-negative bacteria growth were included in the final analysis (102 pre-intervention, 162 post-intervention). The antimicrobial stewardship team made 364 recommendations in 152/162 (93.8%) patients in the post group. Duration of intravenous therapy was shorter (P < .001) for the post-intervention group (median, 4.0 days) compared with the pre-intervention group (median, 7.5 days). Hospital length of stay was also shorter (P < .001) for the post-intervention group (median, 5.1 days) compared with the pre-intervention group (median, 7.0 days). Readmission rates within 30 days were reduced (P = .042) post-intervention (13.0%) compared with pre-intervention (22.6%). In the post-intervention group, a larger proportion of patients were transitioned to oral therapy at any point (126/162, 77.8%) compared with pre-intervention (62/102, 60.8%; P < .001). Conclusions: These results suggest that the Accelerate Pheno system, with active review and intervention by a multidisciplinary antimicrobial stewardship team, is a useful tool in improving both patient-centric and antimicrobial stewardship outcomes.

The incidence of opportunistic infections in patients with psoriatic arthritis treated with biologic and targeted synthetic agents: A systematic review and meta-analysis.

Background: Biologic (bDMARD) and targeted synthetic (tsDMARD) disease-modifying anti-rheumatic drugs have broadened the treatment options and are increasingly used for patients with psoriatic arthritis (PsA). These agents block different pro-inflammatory cytokines or specific intracellular signaling pathways that promote inflammation and can place patients at risk of serious infections. We aimed to review the incidence of opportunistic infections (OIs) in patients with PsA who were treated with these agents. Methods: We searched PubMed and EMBASE through 14 April 2022 for randomized clinical trials evaluating bDMARD or tsDMARD in the treatment of PsA. Trials were eligible if they compared the effect of a bDMARD or tsDMARD with placebo and provided safety data. We used the Revised Cochrane risk-of-bias tool to assess the risk of bias among trials, and stratified the studies by mechanism of action (MOA) of the agents studied. Results: We included 47 studies in this analysis. A total of 17,197 patients received at least one dose of an agent of interest. The cumulative incidence of OIs by MOA was as follows: 1) JAK inhibitors: 2.72% (95% CI: 1.05%-5.04%), 2) anti-IL-17: 1.18% (95% CI: 0.60%-1.9%), 3) anti-IL-23: 0.24% (95% CI: 0.04%-0.54%), and 4) anti-TNFs: 0.01% (95% CI: 0.00%-0.21%). Based on their MOA, these agents are known to increase the risk of certain serious infections. The cumulative incidence of herpes zoster infection following treatment with JAK inhibitors (JAKi) was 2.53% (95% CI: 1.03%-4.57%) and the cumulative incidence of opportunistic Candida spp. infections following treatment with anti-IL-17, was 0.97% (95% CI: 0.51%-1.56%). Conclusion: The overall incidence of OIs among patients with PsA who were treated with biologic and targeted synthetic agents is low. However, careful monitoring is warranted for specific OIs such as herpes zoster infection following JAKi treatment, mucocutaneous candidiasis following anti-IL-17 treatment, and Mycobacterium tuberculosis infection following anti-TNF treatment.

Enhancing the quality of prescribing practices for older adults discharged from the emergency department in Rhode Island.

BACKGROUND: We sought to examine the effectiveness of the Enhancing the Quality of Prescribing Practices for Older Adults Discharged from the Emergency Department (EQUiPPED) medication safety program in three emergency departments (EDs) within the largest health system in Rhode Island (RI) with funding through a quality incentive payment by a private insurance partner. METHODS: This study utilized a quasi-experimental interrupted time series design to implement EQUiPPED, a three-prong intervention aimed at reducing potentially inappropriate medication (PIM) prescriptions to 5% or less per month. We included clinicians who prescribed medications to older ED patients during the pre-and post-intervention periods from July 2018 to January 2021. We determined the monthly rate of PIM prescribing among older adults discharged from the ED, according to the American Geriatrics Society Beers Criteria, using Poisson regression. RESULTS: 247 ED clinicians (48% attendings [n = 119], 27% residents [n = 67], 25% advanced practice providers [n = 61]) were included in EQUiPPED, of which 92% prescribed a PIM during the study period. In the pre-implementation period (July 2018-July 2019) the average monthly rate of PIM prescribing was 9.30% (95% CI: 8.82%, 9.78%). In the post-implementation period (October 2019-January 2021) the PIM prescribing rate decreased significantly to 8.62% (95% CI: 8.14%, 9.10%, p < 0.01). During pre-implementation, 1325 of the 14,193 prescribed medications were considered inappropriate, while only 1108 of the 13,213 prescribed medications in post-implementation were considered inappropriate. The greatest reduction was observed among antihistamines, skeletal muscle relaxants, and benzodiazepines. CONCLUSIONS: EQUiPPED contributed to a modest improvement in PIM prescribing to older adults among clinicians in these RI EDs even in the midst of the COVID-19 pandemic. The quality incentive funding model demonstrates a successful strategy for implementation and, with greater replication, could shape national policy regarding health care delivery and quality of care for older adults.

Hydroxychloroquine use in hospitalised patients with COVID-19: An observational matched cohort study.

AIM: To assess the efficacy and safety of hydroxychloroquine with or without azithromycin) in hospitalized adult patients with COVID-19. METHODS: We utilized a hospital based prospective data registry. The primary end point was to assess the impact of hydroxychloroquine with or without azithromycin, on outcome, length of hospitalization, and time to clinical improvement. We utilized treatment effects with inverse-probability-weighting and Cox proportional hazards models. All analyses accounted for age, gender, race, severity on admission, days from symptoms onset and chronic comorbidities. RESULTS: 36 patients received hydroxychloroquine and were age- and sex-matched to 72 patients with COVID-19 who received supportive care. Compared to supportive care, the use of HCQ did not shorten the time to clinical improvement (+0.23 days; 95% CI: -1.8-2.3 days) nor did it shorten the duration of hospital stay (+0.91 days; 95% CI: -1.1-2.9 days). Additionally, HCQ did not decrease the risk of COVID-19 in-hospital death (aHR 1.67; 95% CI: 0.29-9.36). Finally, we observed a slight QTc prolongation from a baseline of 444 ± 26 ms to 464 ± 32 ms (mean±SD) among patients receiving hydroxychloroquine with or without azithromycin. CONCLUSION: This study did not yield benefits from hydroxychloroquine use in patients with COVID-19 and monitoring for adverse events is warranted. Nevertheless, the treatment was safely studied under the guidance of an antimicrobial stewardship program.

Lack of Pharmacokinetic Basis of Weight-Based Dosing and Intra-Operative Re-Dosing with Cefazolin Surgical Prophylaxis in Obese Patients: Implications for Antibiotic Stewardship.

Traditionally, there have been uniform antibiotic dosing guidelines for prophylaxis for clean-clean-contaminated surgery in both non-obese and obese adults. All other factors predisposing to surgical site infections (SSIs) being equal, over time, the preferred drug is cefazolin. The usual dose, given immediately pre-procedure, has been 1 g intravenously (IV) in non-penicillin-allergic patients, which has been highly effective, Recently, it has become common practice to use high-dose cefazolin; i.e., 3 g IV, in obese patients. This article reviews the literature on high-dose cefazolin prophylactic regimens in the obese from a pharmacokinetic (PK) point of view. There are no comparative studies to support this approach, which is based largely on the theory "more must be better." Weight-based dosing of cefazolin in the obese is flawed, because it does not take into account PK factors, which are critical in the obese. Cefazolin is a water-soluble (hydrophilic) antibiotic that does not penetrate adipose tissue regardless of IV dose. Importantly, adipose tissue is not a valid target tissue in clean-clean-contaminated SSI prophylaxis, as it does not become infected. Higher doses result in proportionately higher serum/non-adipose tissue concentrations, but adipose tissue concentrations are unaffected. Cefazolin displays time-dependent killing kinetics so that as long as serum/tissue concentrations are above the minimum inhibitory concentration (MIC) of SSI pathogens, there is no enhanced killing with higher concentrations relative to concentration-dependent antibiotics. Taking into account PK principles, a cefazolin 1 g IV bolus results in peak serum concentrations of ∼185 mcg/mL, provides at least six hours of intra-operative protection, aside from any post-antibiotic effects, and eliminates any rationale for intra-operative re-dosing for procedures lasting six hours or less. Some have argued that a cefazolin 3 g IV dose in the obese does not matter, as more must necessarily be better. However, from an antibiotic stewardship program (ASP) perspective, unneeded antibiotics are unnecessary. Moreover, the costs of cefazolin 1 g (IV push) at $0.75 versus 2 g (IV piggyback) at $ 6.83 can be significant in large centers using cefazolin prophylaxis for cardiothoracic, orthopedic, obstetric/gynecology, and bariatric surgery. Excessive antibiotics also expose the patient to potential adverse effects; i.e., Clostridium difficile. There is no dose-dependent or duration of exposure effect on resistance with one or two pre-operative or intra-operative doses. Well-done PK-based studies in obese patients clearly demonstrate the lack of benefit of using a 3-g dose or intra-operative re-dosing and show no incremental increase in adipose tissue concentrations with high doses. From an ASP point of view, antibiotic dosing recommendations should be reviewed and revised on the basis of PK principles that indicate that weight-based dosing has no basis for pre-operative prophylaxis in obese patients.

Brief history of the clinical diagnosis of malaria: from Hippocrates to Osler.

Since antiquity, malaria had a major impact on world history but this brief historical overview focuses on clinical features of malaria from Hippocrates to Osler. In antiquity, physicians tried to differentiate malaria from other acute fevers. The classic descriptions of malaria by Hippocrates in ancient Greece and Celsus in ancient Rome are excerpted here from the original Greek and Latin. Their clear clinical descriptions prove malaria was recognized in antiquity. In the modern era, it remains difficult to clinically differentiate malaria from typhoid fever. Since physicians used the term 'typhomalaria' to describe acute undifferentiated fevers a testimony to their lack of clinical acumen. Osler, the great clinician, by careful observation in clinical features and fever patterns was able to clearly differentiate malaria from typhoid fever as did the ancients.

Antimicrobial Stewardship Programs: Principles and Practice.

Antimicrobial stewardship involves optimizing antibiotic use while using cost-effective interventions to minimize antibiotic resistance and control Clostridium difficile. An effective hospital-wide antimicrobial stewardship program (ASP) should be led by an infectious disease (ID) physician. The ASP team needs full and ongoing financial support for the ASP from the hospital administration. The ID clinician leader should have special expertise in various aspects of antimicrobial therapy, that is, pharmacokinetics, resistance, pharmacoeconomics, and C difficile. The ASP ID team leader and ID-trained clinical pharmacist staff are responsible for customizing ASP interventions to the hospital's unique set of antibiotic use-related concerns.

The Pharmacoeconomic Aspects of Antibiotic Stewardship Programs.

Optimal antimicrobial therapy must take into account the key factors in antibiotic selection, that is, spectrum, tissue penetration, resistance potential, safety profile, and relative cost-effectiveness. The least expensive drug is usually accompanied by other concerns, such as high resistance potential, poor side effect profile, pharmacokinetic properties that limit penetration into target tissue (site of infection), and/or suboptimal activity against the presumed/known pathogen. It is false economy to preferentially select the least expensive antibiotics solely because of its acquisition cost. Therapeutic failure and hidden costs may make an apparently less expensive antibiotic most costly in the end.

Antibiotic Stewardship Program Perspective: Oral Antibiotic Therapy for Common Infectious Diseases.

Traditionally, initial antibiotic therapy was administered intravenously (IV). Over the past 3 decades, there has been increased understanding, appreciation, and application of pharmacokinetic (PK) and pharmacodynamic (PD) principles in antibiotic therapy. The utilization of PK/PD parameters as applied to antimicrobial therapy has led to optimizing dosage regimens as well as increased awareness and experience with oral versus antibiotic therapy. When an oral antibiotic, given at the same dose as its IV formulation, results in the same serum/tissue levels, then oral antibiotics should be used whenever possible. When chosen carefully, oral therapy provides many benefits over IV therapy.

Antibiotic Stewardship: Strategies to Minimize Antibiotic Resistance While Maximizing Antibiotic Effectiveness.

Empiric therapy of the septic patient in the hospital is challenging. Antibiotic stewardship is concerned with optimizing antibiotic use and minimizing resistance. Clinicians should avoid overcovering and overtreating colonizing organisms in respiratory secretions and urinary catheters. Empiric therapy should take into account the prevalence of multidrug-resistant organisms in the hospital setting. The most effective resistance prevention strategies is to preferentially select a low resistance potential antibiotic, which should be administered in the highest possible dose without toxicity for the shortest duration to eliminate the infection.

Multiple recurrent abscesses in a patient with undiagnosed IL-12 deficiency and infection by Burkholderia gladioli.

We report the occurrence of two severe illnesses experienced by one patient over a 19 year period of time. Both illnesses were characterized by severe inflammation and tissue destruction. Signs and symptoms of the first illness were characteristic of lymphogranuloma venereum (LGV). The second illness mimicked scrofula. During the second illness the patient was discovered to have a rare immunodeficiency due to auto-antibodies to Interleukin (IL)-12 and infection by Burkholderia gladioli, a plant pathogen usually harmless in humans. We were able to retrieve biopsies from the first illness to establish that B. gladioli was already present during the original presentation. That first illness lasted 5 year s, but she survived without the correct pathogen ever being identified, and without a diagnosis of immunodeficiency. After a remission of 10 year s, she experienced her second illness. The responses to treatment before and after the correct diagnoses were established provide us with an excellent opportunity to consider and discuss how disease expression reflects complex relationships between host defenses and microbial characteristics.

Prolonged and perplexing fevers in antiquity: malaria and typhoid fever.

Fever of unknown origin is a topic that has enduring interest to physicians. Prolonged fevers of infectious etiology were of particular concern to the ancient physician. This overview of prolonged fevers in antiquity focuses on malaria and typhoid fever as the primary infectious causes. By studying texts from Mesopotamian, Greek, and Roman physicians and observers of disease, it is possible to determine the likely etiology of many of these ancient plagues. The historical import of these diseases should not be overlooked, and it is for this reason that the prolonged fevers of antiquity have profound significance and enduring interest.