Lefamulin: A Novel Semisynthetic Pleuromutilin Antibiotic for Community-Acquired Bacterial Pneumonia.
antimicrobial resistance; community-acquired bacterial pneumonia; lefamulin
Community-acquired bacterial pneumonia (CABP) remains a significant cause of morbidity and mortality worldwide. Antimicrobial resistance, including in pathogens that cause CABP, continues to spread at an alarming rate. Because of these factors, the development of new antibiotic classes is urgently needed. Lefamulin, previously known as BC-3781, is a semisynthetic pleuromutilin antibiotic that was approved by the Federal Drug Administration for the treatment of CABP in adults. Available in both oral and intravenous (IV) formulations, lefamulin has potent in vitro activity against both typical and atypical CABP pathogens. The first pleuromutilin to be used systemically in humans, lefamulin has a unique mechanism of action that inhibits protein synthesis by preventing the binding of tRNA for peptide transfer. This review summarizes the available data about lefamulin, including recent evidence from two phase III clinical trials (LEAP 1 and LEAP 2), and discusses its potential role in the treatment of CABP.
Watkins Richard R; File Thomas M
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
2020
2020-03-28
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1093/cid/ciaa336" target="_blank" rel="noreferrer noopener">10.1093/cid/ciaa336</a>
Antibiotics and adverse events: the role of antimicrobial stewardship programs in 'doing no harm'
PURPOSE OF REVIEW: Antimicrobial resistance (AMR) is a global threat worldwide, with deaths associated with AMR infections projected to exceed 10 million per year by the year 2050. The overuse and misuse of antibiotics is the primary driver of this resistance, with up to 50% of antibiotics prescribed in the hospital setting being either unnecessary or inappropriate. Antimicrobial stewardship (AMS) programs (ASPs) can mitigate some of this resistance, with the benefits well recognized; however, if we are to truly advance the state of AMS, the principles and practices should align with patient safety. RECENT FINDINGS: In a recent evaluation, among 1488 adult patients receiving systemic antibiotic therapy, 298 (20%) experienced at least one antibiotic-associated adverse drug event (ADE). Fifty-six (20%) nonclinically indicated antibiotic regimens were associated with an ADE. It is also well recognized that besides ADEs, the inappropriate use of antibiotics is associated the development of multidrug-resistant infections and Clostridium difficile infection. SUMMARY: Currently, there is a significant gap in ASPs correlating initiatives with patient safety goals, including reductions in antibiotic-associated ADEs and multidrug-resistant infections. Therefore, in this article, we provide the rationale for why ASPs are best suited to lead a collaborative effort to prevent antibiotic-associated ADEs and multidrug-resistant infections.
Bauer Karri A; Kullar Ravina; Gilchrist Mark; File Thomas M
Current Opinion In Infectious Diseases
2019
2019-12
Journal Article
<a href="http://doi.org/10.1097/QCO.0000000000000604" target="_blank" rel="noreferrer noopener">10.1097/QCO.0000000000000604</a>
PMID: 31567566
An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic
COMMUNICABLE diseases; community-acquired bacterial pneumonia; COMMUNITY-acquired pneumonia; DENTAL discoloration; omadacycline; PATIENT safety; safety; skin and skin structure infections; SKIN diseases; TEETH abnormalities; TETRACYCLINE; THERAPEUTIC use
Omadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Package insert warnings and precautions for omadacycline include tooth discoloration; enamel hypoplasia; inhibition of bone growth following use in late pregnancy, infancy, or childhood up to 8 years of age; an imbalance in mortality (2%, compared with 1% in moxifloxacin-treated patients) was observed in the phase III study in patients with community-acquired bacterial pneumonia. Omadacycline has no effect on the QT interval, and its affinity for muscarinic M2 receptors resulted in transient heart rate increases following dosing.
Opal Steven; File Thomas M; van der Poll Tom; Tzanis Evan; Chitra Surya; McGovern Paul C
Clinical Infectious Diseases: An Official Publication Of The Infectious Diseases Society Of America
2019
2019-08
<a href="http://doi.org/10.1093/cid/ciz398" target="_blank" rel="noreferrer noopener">10.1093/cid/ciz398</a>
Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa.
treatment; influenza; diagnostic testing; chemoprophylaxis; institutional outbreaks; seasonal
Uyeki Timothy M; Bernstein Henry H; Bradley John S; Englund Janet A; File Thomas M; Fry Alicia M; Gravenstein Stefan; Hayden Frederick G; Harper Scott A; Hirshon Jon Mark; Ison Michael G; Johnston B Lynn; Knight Shandra L; McGeer Allison; Riley Laura E; Wolfe Cameron R; Alexander Paul E; Pavia Andrew T
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
2019
2019-03
<a href="http://doi.org/10.1093/cid/ciy874" target="_blank" rel="noreferrer noopener">10.1093/cid/ciy874</a>
Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa.
treatment; diagnostic testing; chemoprophylaxis; institutional outbreaks; seasonal influenza
These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.
Uyeki Timothy M; Bernstein Henry H; Bradley John S; Englund Janet A; File Thomas M; Fry Alicia M; Gravenstein Stefan; Hayden Frederick G; Harper Scott A; Hirshon Jon Mark; Ison Michael G; Johnston B Lynn; Knight Shandra L; McGeer Allison; Riley Laura E; Wolfe Cameron R; Alexander Paul E; Pavia Andrew T
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
2019
2019-03
<a href="http://doi.org/10.1093/cid/ciy866" target="_blank" rel="noreferrer noopener">10.1093/cid/ciy866</a>
The science of selecting antimicrobials for community-acquired pneumonia (CAP).
Humans; Microbial Sensitivity Tests; Anti-Bacterial Agents/*therapeutic use; Practice Guidelines as Topic; Streptococcus pneumoniae/isolation & purification; Community-Acquired Infections/drug therapy; *Drug Resistance; beta-Lactams/*therapeutic use; Chlamydophila pneumoniae/isolation & purification; Fluoroquinolones/*therapeutic use; Legionnaires' Disease/drug therapy; Macrolides/*therapeutic use; Pneumonia; Bacterial; Drug Therapy; Bacterial/*drug therapy; Combination
BACKGROUND: Among infectious diseases, community-acquired pneumonia (CAP) is the leading cause of death in the United States and is associated with a substantial economic burden to the health care system. Initiating appropriate empiric therapy can be challenging given elevated resistance rates among Streptococcus pneumoniae strains. OBJECTIVE: To present current recommendations for management of CAP with respect to (a) choosing the appropriate site of care, and (b) antimicrobial selection based on bacterial etiology and the prevalence of resistance. SUMMARY: Mortality prediction tools, such as the PORT (Pneumonia Outcomes Research Team) Severity Index, CURB-65 (Confusion, Urea concentration, Respiratory rate, Blood pressure, and age\textgreater65), or CRB-65 (Confusion, Respiratory rate, Blood pressure, and age\textgreater65), can be invaluable in determining which CAP patients require hospitalization. These tools can help reduce overall costs for CAP by limiting hospitalizations of low-risk patients. S. pneumoniae remains the most common causative pathogen for CAP across all disease severities, and elevated rates of resistance to penicillin and macrolides can hinder selection of appropriate antimicrobial therapy. Antimicrobial resistance can impact clinical outcomes, including increasing the risk of treatment failure and breakthrough bacteremia. Current management guidelines recommend monotherapy with a respiratory fluoroquinolone or combination therapy with a beta-lactam and a macrolide (for patients admitted to the general medical ward) or with a beta-lactam and either a respiratory fluoroquinolone or a macrolide (for patients admitted to the intensive care unit [ICU] and who do not have risk factors for methicillin-resistant S. aureus or Pseudomonas). Optimized dosing regimens aim to ensure that pharmacokinetic and pharmacodynamic targets are met to achieve successful clinical outcomes and minimize resistance development. CONCLUSION: Effective management of patients with CAP requires selection of the proper site of care and appropriate empiric antimicrobial. Given the elevated rates of resistance among S. pneumoniae, local resistance patterns must be considered when choosing empiric therapy.
File Thomas M
Journal of managed care pharmacy : JMCP
2009
2009-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.18553/jmcp.2009.15.s2.5" target="_blank" rel="noreferrer noopener">10.18553/jmcp.2009.15.s2.5</a>
Assessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.
Adult; Aged; Anti-Bacterial Agents/*therapeutic use; Bacterial/*drug therapy; Ceftriaxone/*therapeutic use; Cephalosporins/*therapeutic use; Community-Acquired Infections/*drug therapy; Female; Humans; Male; Middle Aged; Pneumonia; Treatment Outcome
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n=562; ceftriaxone, n=554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P=0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).
Lodise Thomas P; Anzueto Antonio R; Weber David J; Shorr Andrew F; Yang Min; Smith Alexander; Zhao Qi; Huang Xingyue; File Thomas M
Antimicrobial agents and chemotherapy
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1128/AAC.03643-14" target="_blank" rel="noreferrer noopener">10.1128/AAC.03643-14</a>
Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials.
Anti-Bacterial Agents/*therapeutic use; Bacterial/*drug therapy; Ceftriaxone/*therapeutic use; Cephalosporins/*therapeutic use; Community-Acquired Infections/*drug therapy; Humans; Pneumonia; Randomized Controlled Trials as Topic
BACKGROUND: We conducted a meta-analysis of clinical trials of adults hospitalized with pneumonia outcomes research team (PORT) risk class 3-4 community-acquired pneumonia (CAP) receiving ceftaroline fosamil versus ceftriaxone. METHODS: Three Phase III trials (clinicaltrials.gov registration numbers NCT00621504, NCT00509106 and NCT01371838) including 1916 hospitalized patients with CAP randomized 1:1 to empirical ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (1-2 g every 24 h) for 5-7 days were included in the meta-analysis. Primary outcome was clinical response at the test-of-cure visit (8-15 days after end of treatment) in the PORT risk class 3-4 modified ITT (MITT) and clinically evaluable (CE) populations. Data were tested for heterogeneity (chi(2) test) and, if not significant, results were pooled and OR and 95% CI constructed. A logistic regression analysis assessed factors impacting cure rate and treatment interactions. RESULTS: Clinical cure rates in each trial consistently favoured ceftaroline fosamil versus ceftriaxone, with no evidence of heterogeneity. In the meta-analysis, ceftaroline fosamil was superior to ceftriaxone in the MITT (OR: 1.66; 95% CI 1.34, 2.06; P \textless 0.001) and CE (OR: 1.65; 95% CI 1.26, 2.16; P \textless 0.001) populations. Results were consistent across various patient- and disease-related factors including patients' age and PORT score. Prior antimicrobial use within 96 h of starting study treatment was associated with diminished differences in cure rates between treatments. CONCLUSIONS: Ceftaroline fosamil was superior to ceftriaxone for empirical treatment of adults hospitalized with CAP. Receipt of prior antimicrobial therapy appeared to diminish the observed treatment effect.
Taboada Maria; Melnick David; Iaconis Joseph P; Sun Fang; Zhong Nan Shan; File Thomas M; Llorens Lily; Friedland H David; Wilson David
The Journal of antimicrobial chemotherapy
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/jac/dkv415" target="_blank" rel="noreferrer noopener">10.1093/jac/dkv415</a>
Community-acquired pneumonia.
*Community-Acquired Infections/diagnosis/drug therapy/microbiology; *Pneumonia; Adult; Anti-Bacterial Agents/pharmacology/therapeutic use; Bacteria/drug effects/isolation & purification; Bacterial; Bacterial/diagnosis/drug therapy/microbiology; Drug Resistance; Female; Humans; Male
This seminar reviews important features and management issues of community-acquired pneumonia (CAP) that are especially relevant to immunocompetent adults in light of new information about cause, clinical course, diagnostic testing, treatment, and prevention. Streptococcus pneumoniae remains the most important pathogen; however, emerging resistance of this organism to antimicrobial agents has affected empirical treatment of CAP. Atypical pathogens have been quite commonly identified in several prospective studies. The clinical significance of these pathogens (with the exception of Legionella spp) is not clear, partly because of the lack of rapid, standardised tests. Diagnostic evaluation of CAP is important for appropriate assessment of severity of illness and for establishment of the causative agent in the disease. Until better rapid diagnostic methods are developed, most patients will be treated empirically. Antimicrobials continue to be the mainstay of treatment, and decisions about specific agents are guided by several considerations that include spectrum of activity, and pharmacokinetic and pharmacodynamic principles. Several factors have been shown to be associated with a beneficial clinical outcome in patients with CAP. These factors include administration of antimicrobials in a timely manner, choice of antibiotic therapy, and the use of a critical pneumonia pathway. The appropriate use of vaccines against pneumococcal disease and influenza should be encouraged. Several guidelines for management of CAP have recently been published, the recommendations of which are reviewed.
File Thomas M
Lancet (London, England)
2003
2003-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/S0140-6736(03)15021-0" target="_blank" rel="noreferrer noopener">10.1016/S0140-6736(03)15021-0</a>
Telithromycin new product overview.
*Anti-Bacterial Agents/adverse effects/chemistry/pharmacokinetics/pharmacology/therapeutic use; *Ketolides/adverse effects/chemistry/pharmacokinetics/pharmacology/therapeutic use; Drug Interactions; Humans
Community-acquired respiratory tract infections (CARTIs), including community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis, contribute substantially to health care costs in the United States. Although many prescriptions for antibiotics are written each year for the treatment of CARTIs, most are prescribed on an empiric basis. Concerns about the increasing prevalence of antimicrobial resistance and the changing pattern of pathogens isolated from subjects with CARTIs have raised questions about the empiric treatment paradigm. When choosing appropriate antimicrobial therapy for CARTIs, physicians must consider not only the spectrum of activity of antibiotics but also the potential risk of resistance. Telithromycin is the first member of the ketolide class, a new family of antimicrobials structurally related to the macrolides, to be approved by the US Food and Drug Administration for the treatment of CARTIs. The spectrum of activity of telithromycin includes common typical and atypical causative pathogens associated with community-acquired respiratory tract infections, including antibiotic-resistant strains of Streptococcus pneumoniae. Clinical trials have shown that telithromycin is as effective as traditionally used antimicrobial agents in the treatment of mild-to-moderate community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis.
File Thomas M
The Journal of allergy and clinical immunology
2005
2005-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.jaci.2004.11.029" target="_blank" rel="noreferrer noopener">10.1016/j.jaci.2004.11.029</a>
Necrotizing Soft Tissue Infections.
Necrotizing soft tissue infections are characterized by necrosis of skin and associated structures. Despite advances in the diagnosis and treatment of these infections, the mortality remains high. There have been increasing reports of necrotizing fasciitis caused by group A Streptococcus over the past decade. Recent information supports the role of superantigens in the pathogenesis of this infection. The approach to management requires expeditious evaluation with early surgery and appropriate antimicrobial agents. Limited data suggest that surgical debridement may be delayed in selected patients until the patient is stable by the use of intravenous immunoglobulin, which can neutralize superantigens.
File Thomas M
Current infectious disease reports
2003
2003-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s11908-003-0021-y" target="_blank" rel="noreferrer noopener">10.1007/s11908-003-0021-y</a>