Combination Antifungal Therapy for Invasive Mucormycosis in Immunocompromised Hosts: A Single-Center Experience.

Combination antifungal therapy for invasive mucormycosis remains controversial and is inconsistently defined in prior studies. In a cohort of patients with immunocompromised status and invasive mucormycosis, we found no difference in 6-week mortality with up-front or salvage combination therapy as compared with monotherapy.

Sequential Treatment Failure With Aztreonam-Ceftazidime-Avibactam Followed by Cefiderocol Due to Preexisting and Acquired Mechanisms in a New Delhi Metallo-ß-lactamase-Producing Escherichia coli Causing Fatal Bloodstream Infection.

We report a fatal case of New Delhi metallo-ß-lactamase (NDM)-producing Escherichia coli in a bacteremic patient with sequential failure of aztreonam plus ceftazidime-avibactam followed by cefiderocol. Acquired resistance was documented phenotypically and mediated through preexisting and acquired mutations. This case highlights the need to rethink optimal treatment for NDM-producing organisms.

Informing Building Strategies to Reduce Infectious Aerosol Transmission Risk by Integrating DNA Aerosol Tracers with Quantitative Microbial Risk Assessment.

Using aerosol-based tracers to estimate risk of infectious aerosol transmission aids in the design of buildings with adequate protection against aerosol transmissible pathogens, such as SARS-CoV-2 and influenza. We propose a method for scaling a SARS-CoV-2 bulk aerosol quantitative microbial risk assessment (QMRA) model for impulse emissions, coughing or sneezing, with aerosolized synthetic DNA tracer concentration measurements. With point-of-emission ratios describing relationships between tracer and respiratory aerosol emission characteristics (i.e., volume and RNA or DNA concentrations) and accounting for aerosolized pathogen loss of infectivity over time, we scale the inhaled pathogen dose and risk of infection with time-integrated tracer concentrations measured with a filter sampler. This tracer-scaled QMRA model is evaluated through scenario testing, comparing the impact of ventilation, occupancy, masking, and layering interventions on infection risk. We apply the tracer-scaled QMRA model to measurement data from an ambulatory care room to estimate the risk reduction resulting from HEPA air cleaner operation. Using DNA tracer measurements to scale a bulk aerosol QMRA model is a relatively simple method of estimating risk in buildings and can be applied to understand the impact of risk mitigation efforts.

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update.

Drug dosing in obese patients continues to be challenging due to a lack of high-quality evidence to guide dosing recommendations. We first published guidance for antibiotic dosing in obese adults in 2017, in which we critically reviewed articles identified from a broad search strategy to develop dosing recommendations for 35 antimicrobials. In this updated narrative review, we searched Pubmed, Web of Science, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific generic antimicrobial names, obese, pharmacokinetics, and others. We reviewed 393 articles, cross-referenced select cited references, and when applicable, referenced drug databases, package inserts, and clinical trial data to update dosing recommendations for 41 antimicrobials. Most included articles were pharmacokinetic studies, other less frequently included articles were clinical studies (mostly small, retrospective), case reports, and very rarely, guidelines. Pharmacokinetic changes are frequently reported, can be variable, and sometimes conflicting in this population, and do not always translate to a documented difference in clinical outcomes, yet are used to inform dosing strategies. Extended infusions, high doses, and therapeutic drug monitoring remain important strategies to optimize dosing in this population. Additional studies are needed to clinically validate proposed dosing strategies, clarify optimal body size descriptors, dosing weight scalars, and estimation method of renal function in obese patients.

Use of biomarkers to individualize antimicrobial therapy duration: a narrative review.

BACKGROUND: Reducing the overuse of antimicrobials is imperative for the sake of minimizing antimicrobial-associated adverse effects, optimizing resource utilization, and curtailing the rise in multidrug-resistant organisms. Biomarkers reflect the host responses to infection and may assist with minimizing unnecessary antimicrobial usage. OBJECTIVES: To review the literature pertaining to the performance of biomarkers specifically used to guide the duration of antimicrobial therapy (AMT). SOURCES: Randomized controlled trials, observational studies, and meta-analyses assessing biomarker-guided approaches to AMT decision-making and their impact on the duration of therapy were reviewed. CONTENT: Several randomized controlled trials and real-world observational studies have shown that a procalcitonin (PCT)-guided strategy can help clinicians individualize the duration of AMT, particularly among non-critically ill patients hospitalized with suspected respiratory tract infections when using a PCT cut-off value of <0.25 µg/L and critically ill patients with respiratory tract infections or undifferentiated sepsis when using a PCT cut-off value of <0.5 µg/L or ≥80% decline in the peak level. C-reactive protein is a non-specific marker of inflammation that may also assist with an early discontinuation of AMT; however, data are limited. Haematological biomarkers are prone to variance between individuals and are often influenced by medications and non-infectious conditions, making them less reliable for the purposes of AMT decision-making. Novel biomarkers such as multi-protein signatures and host gene expression tests have shown promise as tools to better differentiate between bacterial and non-bacterial infections; clinical studies are needed to determine whether they can be used to help optimize the duration of AMT. IMPLICATIONS: Studies have demonstrated that a PCT-guided strategy, when utilized appropriately, can help guide clinicians to individualize and often reduce the duration of AMT, especially in patients hospitalized with respiratory tract infections and those admitted to the intensive care unit with suspected respiratory tract infections or sepsis. The impact of utilizing other biomarkers is less clear and requires further study.

Coccidioidal Peritonitis: A Review of 17 Cases.

Coccidioidomycosis is the second most common endemic fungal infection in the United States. Prior descriptions of coccidioidal peritonitis include only single cases. We describe 17 new cases previously unreported from healthcare institutions in California. The majority of cases presented with nonspecific abdominal complaints. PubMed and Google Scholar were searched for additional case series and only single case reports and reviews of single cases were found. The diagnosis was confirmed by culture or histopathology and/or serology in each patient. All patients were treated with anti-fungal therapy. This case series demonstrates that coccidioidal peritonitis may be asymptomatic or present with only subtle abdominal symptoms. In a minority of our patients, the diagnosis was established incidentally during surgery. Based on this series, the overall outcome of coccidioidal peritonitis is favorable with long-term triazole treatment. The term cure is not usually used in disseminated coccidioidal disease because of the risk of late relapse.

Plasma Microbial Cell-free DNA Next-generation Sequencing in the Diagnosis and Management of Febrile Neutropenia.

BACKGROUND: Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management. METHODS: This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results. RESULTS: Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases. CLINICAL TRIALS REGISTRATION: NCT02912117. CONCLUSION: KT shows promise in the diagnosis and treatment optimization of FN.

A Review of Infectious Diseases Associated with Religious and Nonreligious Rituals.

Rituals are an integral part of human life but a wide range of rituals (both religious and non-religious), from self-flagellation to blood brotherhood to ritual sprinkling of holy water, have been associated with transmission of infections. These infections include angiostrongyliasis, anthrax, brucellosis, cholera, COVID-19, cutaneous larva migrans, Ebola, hepatitis viruses, herpes simplex virus, HIV, human T-cell leukemia virus (HTLV), kuru, Mycobacterium bovis, Naegleria fowleri meningoencephalitis, orf, rift valley fever, and sporotrichosis. Education and community engagement are important cornerstones in mitigating infectious risks associated with rituals.

Effect of rapid methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction screening on vancomycin use in the intensive care unit.

PURPOSE: To determine the impact of a pharmacist-driven methicillin-resistant Staphylococcus aureus (MRSA) nasal polymerase chain reaction (PCR) screen on vancomycin duration in critically ill patients with suspected pneumonia. METHODS: This was a retrospective, quasi-experimental study at a 613-bed academic medical center with 67 intensive care beds. Adult patients admitted to the intensive care unit (ICU) between 2017 and 2019 for 24 hours or longer and empirically started on intravenous vancomycin for pneumonia were included. The primary intervention was the implementation of a MRSA nasal PCR screen protocol. The primary outcome was duration of empiric vancomycin therapy. Secondary outcomes included the rate of acute kidney injury (AKI), the number of vancomycin levels obtained, the rate of resumption of vancomycin for treatment of pneumonia, ICU length of stay, hospital length of stay, the rate of ICU readmission, and the rate of in-hospital mortality. RESULTS: A total of 418 patients were included in the final analysis. The median vancomycin duration was 2.59 days in the preprotocol group and 1.44 days in the postprotocol group, a reduction of approximately 1.00 day (P < 0.01). There were significantly fewer vancomycin levels measured in the postprotocol group than in the preprotocol group. Secondary outcomes were similar between the 2 groups, except that there was a lower rate of AKI and fewer vancomycin levels obtained in the postprotocol group (despite implementation of area under the curve-based vancomycin dosing) as compared to the preprotocol group. CONCLUSION: The implementation of a pharmacist-driven MRSA nasal PCR screen was associated with a decrease in vancomycin duration and the number of vancomycin levels obtained in critically ill patients with suspected pneumonia.

Reactivation of Chagas Disease in a Patient With an Autoimmune Rheumatic Disease: Case Report and Review of the Literature.

Reactivation of Chagas disease has been described in immunosuppressed patients, but there is a paucity of literature describing reactivation in patients on immunosuppressive therapies for the treatment of autoimmune rheumatic diseases. We describe a case of Chagas disease reactivation in a woman taking azathioprine and prednisone for limited cutaneous systemic sclerosis (lcSSc). Reactivation manifested as indurated and erythematous cutaneous nodules. Sequencing of a skin biopsy specimen confirmed the diagnosis of Chagas disease. She was treated with benznidazole with clinical improvement in the cutaneous lesions. However, her clinical course was complicated and included disseminated CMV disease and subsequent septic shock due to bacteremia. Our case and review of the literature highlight that screening for Chagas disease should be strongly considered for patients who will undergo immunosuppression for treatment of autoimmune disease if epidemiologically indicated.

Bacteremia due to Methicillin-Resistant Staphylococcus aureus: An Update on New Therapeutic Approaches.

Vancomycin and daptomycin are options for the initial treatment of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Treatment options for persistent MRSA bacteremia or bacteremia due to vancomycin-intermediate or vancomycin-resistant strains include daptomycin, ceftaroline, and combination therapies. There is a critical need for high-level evidence from clinical trials to allow optimally informed decisions in the treatment of MRSA bacteremia.

Building antimicrobial stewardship through massive open online courses: a pilot study in Macedonia.

BACKGROUND: The global struggle against antibiotic resistance requires antimicrobial stewardship (AMS). Massive open online courses (MOOCs) offer health professionals unprecedented access to high-quality instructional material on AMS; the question is how apprehensible it is to non-native English speakers. Furthermore, to better understand how education interventions promote change towards rational antibiotic prescribing, leading institutions call for studies integrating behavioural science. Research from lower- and middle-income countries is particularly needed. OBJECTIVES: To measure the knowledge improvement from an AMS MOOC, the influence of language, course satisfaction and subsequent effect on intention to change antibiotic prescribing behaviour. METHODS: Fifty-five physicians from Macedonia completed the MOOC. Pre- and post-course knowledge test scores were compared using a one-sample t-test. The effect of a language barrier was assessed using self-reported English level. Scores were compared with participants' intention to change behaviour in clinical practice. RESULTS: Scores significantly improved from 77.8% to 82.2%. Participants with a higher English level improved most, while the low-level group showed no significant improvement. Physicians reported a high or very high intention to change behaviour. This was independent of knowledge improvements. CONCLUSIONS: First, lower self-reported English proficiency hindered knowledge acquisition from a MOOC platform. AMS programmes should commit to bridge this barrier so as to enable a global spread of education in AMS. Second, factors underlying the physicians' intentions to engage in AMS appear to be more complex than simple knowledge improvements. This suggests that less time-consuming interventions could be as effective.

Oral Fluoroquinolone or Trimethoprim-sulfamethoxazole vs. ß-lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis.

BACKGROUND: Using published data, we sought to compare outcomes in patients transitioned to either oral fluoroquinolones (FQ) or trimethoprim-sulfamethoxazole (TMP-SMX) versus ß-lactams (BL's) after an initial intravenous (IV) course for gram-negative rod (GNR) bacteremia. METHODS: We conducted a systematic review of PubMed and EMBASE and published IDWeek abstracts. We included studies that reported all-cause mortality and/or infection recurrence in patients transitioned to oral FQ/TMP-SMX and BL's. RESULTS: Eight retrospective studies met inclusion criteria with data for 2,289 patients, of whom 65% were transitioned to oral FQ, 7.7% to TMP-SMX, and 27.2% to BL's. Follow up periods ranged from 21 to 90 days. All-cause mortality was not significantly different between patients transitioned to either FQ/TMP-SMX or BL's (OR 1.13; 95%CI, 0.69-1.87). Overall recurrence of infection, either bacteremia or the primary site, occurred more frequently in patients transitioned to oral BL's vs. FQ's (OR 2.05, 95% CI 1.17 to 3.61). Analysis limited to recurrent bacteremia was similarly suggestive although limited by small numbers (OR 2.32, 95% CI 0.99 to 5.44). However, based on known pharmacokinetics/pharmacodynamics, prescribed ß-lactam dosing regimens were frequently suboptimal. CONCLUSIONS: In the step-down IV to oral treatment of GNR bacteremia, we found insufficient data regarding outcomes after oral TMP-SMX; however, selection of a FQ over commonly utilized ß-lactam regimens may reduce chances of infection recurrence. While this may be a class effect, it may simply be the result of inadequate dosing of ß-lactams. Additional investigations are warranted to determine outcomes with TMP-SMX and optimized oral ß-lactam dosing regimens.

Application of pharmacoeconomics to formulary management in a health system setting.

PURPOSE: A novel value-based approach to evaluate costly specialty drugs for formulary addition was developed. SUMMARY: In February 2016, Stanford Health Care launched the specialty drug subcommittee (SDSC), a subcommittee of the pharmacy and therapeutics committee, responsible for the formulary review of specialty pharmaceuticals. A process was developed for value-based review that includes not only consideration of clinical trial data and institutional acquisition costs but also internal patient outcomes and a cost-effectiveness model using internal financial data. A Markov model was developed to assess the value of trabectedin, which was approved for formulary addition in April 2016, relative to the addition of dacarbazine. The economic model and internal patient outcome analysis were presented to the prescribing oncologist and the SDSC for review. Internal data revealed that fewer patients than had been estimated received trabectedin, with outcomes significantly worse than those observed in the clinical trial leading to Food and Drug Administration approval. In the cost-effectiveness model, trabectedin had higher costs and poorer outcomes compared with dacarbazine. Based on the economic model, low utilization, and real-world outcomes, trabectedin was removed from formulary and a restrictive treatment pathway for nonformulary use, developed by the primary prescriber, was implemented. This process has since been applied to 11 more specialty drugs. CONCLUSION: Internal cost-effectiveness models in combination with real-world patient outcomes data can be effective formulary management tools. Engagement and collaboration with the requesting provider are key to developing thoughtful treatment pathways.

Omadacycline: A Novel Tetracycline Derivative With Oral and Intravenous Formulations.

Omadacycline, an aminomethylcycline, is a novel member of the tetracycline class of antibiotics. It has received approval by the US Food and Drug Administration for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections, and is available in both oral and intravenous formulations. It is also being evaluated in clinical trials for the treatment of cystitis and pyelonephritis. The omadacycline molecule was designed to overcome tetracycline resistance and has broad-spectrum activity that includes gram-positive bacteria, gram-negative bacteria, anaerobes, atypicals, and other drug-resistant strains, like methicillin-resistant Staphylococcus aureus, as well as Yersinia pestis and Bacillus anthracis, organisms of biodefense interest. Omadacycline has minimal drug-drug pharmacokinetic interactions and a favorable safety profile, with the most common adverse events being gastrointestinal symptoms.