Antibiotic Update
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IDSA Guideline Review
1 Infectious Diseases Society of America Antimicrobial Resistant Treatment Guidance: Gram- Negative Bacterial Infections A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem- Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR- P. aeruginosa) Guideline Summary by Kendra Suder, PharmD Candidate General Recommendations Considerations for choosing empiric therapy: o Local susceptibility patterns/ antibiogram o Patient’s previous organisms isolated & susceptibility data in the last 6 months o Antibiotic exposure in the last 30 days What if a patient was empirically placed on an antibiotic regimen that is now considered inactive against the organism based on susceptibility data? o If an inactive agent was started empirically for cystitis and patient improves, no change in antibiotic or extension of therapy is necessary o However, for other types of infections, guidelines recommend a change to an active regimen for a full treatment course (dated from the start of active therapy) Extended-Spectrum β-Lactamase-Producing Enterobacterales (ESBL-E) Extended-spectrum β-lactamase o Enzymes that inactivate most penicillins, cephalosporins, and aztreonam o Most commonly produced by Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis (guideline recommendations refer to ESBL-E infections caused by these organisms) o Most common type in the US is the CTX-M, especially CTX-M-15 In institutions that do not perform ESBL testing, a lack of -
Brilacidin First-In-Class Defensin-Mimetic Drug Candidate
Brilacidin First-in-Class Defensin-Mimetic Drug Candidate Mechanism of Action, Pre/Clinical Data and Academic Literature Supporting the Development of Brilacidin as a Potential Novel Coronavirus (COVID-19) Treatment April 20, 2020 Page # I. Brilacidin: Background Information 2 II. Brilacidin: Two Primary Mechanisms of Action 3 Membrane Disruption 4 Immunomodulatory 7 III. Brilacidin: Several Complementary Ways of Targeting COVID-19 10 Antiviral (anti-SARS-CoV-2 activity) 11 Immuno/Anti-Inflammatory 13 Antimicrobial 16 IV. Brilacidin: COVID-19 Clinical Development Pathways 18 Drug 18 Vaccine 20 Next Steps 24 V. Brilacidin: Phase 2 Clinical Trial Data in Other Indications 25 VI. AMPs/Defensins (Mimetics): Antiviral Properties 30 VII. AMPs/Defensins (Mimetics): Anti-Coronavirus Potential 33 VIII. The Broader Context: Characteristics of the COVID-19 Pandemic 36 Innovation Pharmaceuticals 301 Edgewater Place, Ste 100 Wakefield, MA 01880 978.921.4125 [email protected] Innovation Pharmaceuticals: Mechanism of Action, Pre/Clinical Data and Academic Literature Supporting the Development of Brilacidin as a Potential Novel Coronavirus (COVID-19) Treatment (April 20, 2020) Page 1 of 45 I. Brilacidin: Background Information Brilacidin (PMX-30063) is Innovation Pharmaceutical’s lead Host Defense Protein (HDP)/Defensin-Mimetic drug candidate targeting SARS-CoV-2, the virus responsible for COVID-19. Laboratory testing conducted at a U.S.-based Regional Biocontainment Laboratory (RBL) supports Brilacidin’s antiviral activity in directly inhibiting SARS-CoV-2 in cell-based assays. Additional pre-clinical and clinical data support Brilacidin’s therapeutic potential to inhibit the production of IL-6, IL-1, TNF- and other pro-inflammatory cytokines and chemokines (e.g., MCP-1), identified as central drivers in the worsening prognoses of COVID-19 patients. -
Criteria for Use of Dalbavancin for Acute Bacterial Skin/Soft Tissue Infection (Abssti)
Criteria for Use of Dalbavancin for Acute Bacterial Skin/Soft Tissue Infection (abSSTI) 1. Patients meeting any of the following are NOT ELIGIBLE for dalbavancin therapy: a. History of hypersensitivity reaction to lipoglycopeptide antibiotics (vancomycin, televancin, dalbavancin, oritavancin). b. Patients with acute bacterial skin or skin structure infections such as superficial/simple cellulitis/erysipelas, impetiginous lesion, furuncle, or simple abscess that only requires surgical drainage for cure. c. Infection thought to be caused by gram-negative bacteria d. Infection due to an organism suspected or known to be resistant to dalbavancin or vancomycin 2. For outpatient use (i.e. ED) a. Contact infectious disease for authorization: ABX approval pager (see ON-CALL schedule) b. The following clinical criteria must be met: i. Pre-antibiotic blood cultures must be drawn. ii. Clinical condition expected to require ≥ 24 hours of IV antibiotics – must not qualify for oral antibiotic therapy. iii. Presence of cellulitis, major abscess or a wound infection associated with at least 75cm2 of erythema highly suspected or known to be caused by gram-positive bacteria. iv. The size of the infection must be clearly documented and/or outlined prior to leaving the ED, preferably with a photograph. v. Patient to be discharged to home ± home health (not to skilled nursing facility). c. Required follow up must be set up prior to leaving the ED: i. Must document patient contact info for follow up, preferably reliable cell phone number. ii. Must have follow up within 48-72H with Dr. Turnipseed (916-765-0196) or Rominski. 1. Email patient name, MRN, and phone number. -
Current Topics in Medicinal Chemistry, 2017, 17, 576-589
576 Send Orders for Reprints to [email protected] Current Topics in Medicinal Chemistry, 2017, 17, 576-589 REVIEW ARTICLE ISSN: 1568-0266 eISSN: 1873-5294 Impact Factor: Mimics of Host Defense Proteins; Strategies for Translation to Therapeutic 2.9 The international journal for in-depth reviews on Applications Current Topics in Medicinal Chemistry BENTHAM SCIENCE Richard W. Scott*,1 and Gregory N. Tew2 1Fox Chase Chemical Diversity Center, Pennsylvania Biotechnology Center, Doylestown, PA, USA; 2Polymer Science and Engineering, Veterinary and Animal Science, Cell and Molecular Biology, University of Massachusetts, Amherst MA, USA Abstract: New infection treatments are urgently needed to combat the rising threat of multi-drug re- sistant bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins (HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at multiple targets and their repertoire includes disruptive membrane and intracellular activities against numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these novel activities are associated with a low potential for emergence of resistance and little cross- resistance with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candi- A R T I C L E H I S T O R Y dates for new antibiotics; however, their development has been plagued by the many therapeutic limi- tations associated with natural peptidic agents. This review focuses on HDP mimetic approaches Received: May 22, 2015 Revised: October 29, 2015 aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early ef- Accepted: November 30, 2015 forts with β-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but DOI: 10.2174/15680266166661607 demonstrated that antimicrobial activity was modulated by more, complex structural properties. -
Recarbrio, INN-Imipenem / Cilastatin / Relebactam
EMA/572792/2020 EMEA/H/C/004808 Recarbrio (imipenem / cilastatin / relebactam) An overview of Recarbrio and why it is authorised in the EU What is Recarbrio and what is it used for? Recarbrio is an antibiotic for treating adults with the following infections: • lung infections caught in hospital (hospital-acquired pneumonia), including ventilator-associated pneumonia (pneumonia caught while on a ventilator, which is a machine that helps a patient to breathe); • infection that has spread into the blood (bacteraemia) as a likely complication of hospital-acquired pneumonia or ventilator-associated pneumonia; • infections caused by bacteria classed as aerobic Gram-negative bacteria when other treatments might not work. Official guidance on the appropriate use of antibiotics should be considered when using the medicine. Recarbrio contains the active substances imipenem, cilastatin and relebactam. How is Recarbrio used? Recarbrio can only be obtained with a prescription and it should be used only after consulting a doctor with experience of managing infectious diseases. Recarbrio is given by infusion (drip) into a vein over 30 minutes. It is given every 6 hours for 5 to 14 days, depending on the nature of the infection. For more information about using Recarbrio, see the package leaflet or contact your doctor or pharmacist. How does Recarbrio work? One of the active substances in Recarbrio, imipenem, kills bacteria and the other two, cilastatin and relebactam, increase imipenem’s effectiveness in different ways. Imipenem interferes with bacterial proteins that are important for building the bacterial cell wall. This results in defective cell walls that collapse and cause the bacteria to die. -
New Β-Lactamase Inhibitor Combinations: Options for Treatment; Challenges for Testing
MEDICAL/SCIENTIFIC AffAIRS BULLETIN New β-lactamase Inhibitor Combinations: Options for Treatment; Challenges for Testing Background The β-lactam class of antimicrobial agents has played a crucial role in the treatment of infectious diseases since the discovery of penicillin, but β–lactamases (enzymes produced by the bacteria that can hydrolyze the β-lactam core of the antibiotic) have provided an ever expanding threat to their successful use. Over a thousand β-lactamases have been described. They can be divided into classes based on their molecular structure (Classes A, B, C and D) or their function (e.g., penicillinase, oxacillinase, extended-spectrum activity, or carbapenemase activity).1 While the first approach to addressing the problem ofβ -lactamases was to develop β-lactamase stable β-lactam antibiotics, such as extended-spectrum cephalosporins, another strategy that has emerged is to combine existing β-lactam antibiotics with β-lactamase inhibitors. Key β-lactam/β-lactamase inhibitor combinations that have been used widely for over a decade include amoxicillin/clavulanic acid, ampicillin/sulbactam, and pipercillin/tazobactam. The continued use of β-lactams has been threatened by the emergence and spread of extended-spectrum β-lactamases (ESBLs) and more recently by carbapenemases. The global spread of carbapenemase-producing organisms (CPOs) including Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii, limits the use of all β-lactam agents, including extended-spectrum cephalosporins (e.g., cefotaxime, ceftriaxone, and ceftazidime) and the carbapenems (doripenem, ertapenem, imipenem, and meropenem). This has led to international concern and calls to action, including encouraging the development of new antimicrobial agents, enhancing infection prevention, and strengthening surveillance systems. -
AMEG Categorisation of Antibiotics
12 December 2019 EMA/CVMP/CHMP/682198/2017 Committee for Medicinal Products for Veterinary use (CVMP) Committee for Medicinal Products for Human Use (CHMP) Categorisation of antibiotics in the European Union Answer to the request from the European Commission for updating the scientific advice on the impact on public health and animal health of the use of antibiotics in animals Agreed by the Antimicrobial Advice ad hoc Expert Group (AMEG) 29 October 2018 Adopted by the CVMP for release for consultation 24 January 2019 Adopted by the CHMP for release for consultation 31 January 2019 Start of public consultation 5 February 2019 End of consultation (deadline for comments) 30 April 2019 Agreed by the Antimicrobial Advice ad hoc Expert Group (AMEG) 19 November 2019 Adopted by the CVMP 5 December 2019 Adopted by the CHMP 12 December 2019 Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Categorisation of antibiotics in the European Union Table of Contents 1. Summary assessment and recommendations .......................................... 3 2. Introduction ............................................................................................ 7 2.1. Background ........................................................................................................ -
Evaluation of Pharmacodynamic Interactions Between Telavancin
Infect Dis Ther DOI 10.1007/s40121-016-0121-2 ORIGINAL RESEARCH Evaluation of Pharmacodynamic Interactions Between Telavancin and Aztreonam or Piperacillin/ Tazobactam Against Pseudomonas aeruginosa, Escherichia coli and Methicillin-Resistant Staphylococcus aureus Juwon Yim . Jordan R. Smith . Katie E. Barber . Jessica A. Hallesy . Michael J. Rybak Received: May 2, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com ABSTRACT Methods: In vitro one-compartment PK/PD models were run over 96 h simulating TLV Introduction: In clinical trials comparing 10 mg/kg every 48 h, ATM 500 mg every 8 h telavancin (TLV) with vancomycin for and PTZ continuous infusion 13.5 g over 24 h treatment of hospital-acquired pneumonia, alone and in combination against P. aeruginosa, TLV demonstrated lower clinical cure rates E. coli and methicillin-resistant S. aureus than vancomycin in patients who had mixed (MRSA). The efficacy of antimicrobials was gram-positive and -negative infections and were evaluated by plotting time-kill curves and concomitantly treated with either aztreonam calculating the reduction in log10 cfu/ml over (ATM) or piperacillin/tazobactam (PTZ). Here, 96 h. we investigated therapeutic interactions Results: Against both MRSA strains, TLV was between TLV and ATM or PTZ in an in vitro rapidly bactericidal at 4 h and maintained its pharmacokinetic/pharmacodynamic (PK/PD) activity over 96 h with no observed antagonism model under simulated reduced renal function by either ATM or PTZ. PTZ maintained conditions. bacteriostatic and bactericidal activities against Enhanced content To view enhanced content for this E. coli ATCC 25922 and clinical strain R1022 at article go to http://www.medengine.com/Redeem/ 96 h, whereas both strains regrew as soon as 22E4F0603737CC9F. -
Advances in Antibiotic Therapy in the Critically Ill Jean-Louis Vincent1*, Matteo Bassetti2, Bruno François3, George Karam4, Jean Chastre5, Antoni Torres6, Jason A
Vincent et al. Critical Care (2016) 20:133 DOI 10.1186/s13054-016-1285-6 REVIEW Open Access Advances in antibiotic therapy in the critically ill Jean-Louis Vincent1*, Matteo Bassetti2, Bruno François3, George Karam4, Jean Chastre5, Antoni Torres6, Jason A. Roberts7, Fabio S. Taccone1, Jordi Rello8, Thierry Calandra9, Daniel De Backer10, Tobias Welte11 and Massimo Antonelli12 In this review, we briefly highlight the importance of Abstract early infection diagnosis before discussing some of the Infections occur frequently in critically ill patients and key issues related to antibiotic management, including their management can be challenging for various problems associated with timing, duration, and dosing. reasons, including delayed diagnosis, difficulties We also briefly consider ventilator-associated pneumonia identifying causative microorganisms, and the high (VAP), the use of inhaled antibiotics, and new antibiotic prevalence of antibiotic-resistant strains. In this and adjunct strategies for the future. We focus on bacter- review, we briefly discuss the importance of early ial infections and issues associated with multi-drug resist- infection diagnosis, before considering in more detail ance will not be covered. some of the key issues related to antibiotic management in these patients, including controversies surrounding use of combination or monotherapy, duration of therapy, Diagnosis and de-escalation. Antibiotic pharmacodynamics and The diagnosis of infection in critically ill patients and pharmacokinetics, notably volumes of distribution and identification of causative microorganisms and their anti- clearance, can be altered by critical illness and can biotic susceptibilities can be a challenge and yet early, influence dosing regimens. Dosing decisions in different appropriate antibiotic therapy is associated with improved subgroups of patients, e.g., the obese, are also covered. -
Title. 1 in Vitro Activity of the New Β-Lactamase Inhibitors Relebactam
bioRxiv preprint doi: https://doi.org/10.1101/499830; this version posted December 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title. 2 In vitro activity of the new β-lactamase inhibitors relebactam and vaborbactam in combination 3 with β-lactams against Mycobacterium abscessus complex clinical isolates 4 5 Authors and affiliations. Amit Kaushik,a Nicole C. Ammerman,a Jin Lee,a Olumide Martins,a 6 Barry N. Kreiswirth,b Gyanu Lamichhane,a Nicole M. Parrish,c Eric L. Nuermbergera 7 8 aCenter for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, 9 Maryland, USA 10 bPublic Health Research Institute Tuberculosis Center, New Jersey Medical School - Rutgers, 11 The State University of New Jersey, Newark, New Jersey, USA 12 cDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 13 USA 14 15 Key words. β-lactamase inhibitors, β-lactams, relebactam, vaborbactam, carbapenems, 16 cephalosporins, Mycobacterium abscessus 17 18 Running title. Relebactam/vaborbactam with β-lactams vs. M. abscessus Page 1 bioRxiv preprint doi: https://doi.org/10.1101/499830; this version posted December 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 19 Abstract 20 Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is 21 notoriously difficult to treat, in large part due to MABC’s intrinsic resistance to most antibiotics, 22 including β-lactams. -
Prospects for New Antibiotics: a Molecule-Centered Perspective
The Journal of Antibiotics (2014) 67, 7–22 & 2014 Japan Antibiotics Research Association All rights reserved 0021-8820/14 www.nature.com/ja REVIEW ARTICLE Prospects for new antibiotics: a molecule-centered perspective Christopher T Walsh and Timothy A Wencewicz There is a continuous need for iterative cycles of antibiotic discovery and development to deal with the selection of resistant pathogens that emerge as therapeutic application of an antibiotic becomes widespread. A short golden age of antibiotic discovery from nature followed by a subsequent golden half century of medicinal chemistry optimization of existing molecular scaffolds emphasizes the need for new antibiotic molecular frameworks. We bring a molecule-centered perspective to the questions of where will new scaffolds come from, when will chemogenetic approaches yield useful new antibiotics and what existing bacterial targets merit contemporary re-examination. The Journal of Antibiotics (2014) 67, 7–22; doi:10.1038/ja.2013.49; published online 12 June 2013 Keywords: antibiotics; mechanism of action; natural products; resistance A PERSONAL PATHWAY TO ANTIBIOTICS RESEARCH chemical logic and molecular machinery and, in part, with the hope For one of us (CTW), a career-long interest in antibiotics1 was that one might learn to reprogram natural antibiotic assembly lines to spurred by discussions on the mechanism of action of engineer improved molecular variants. D-fluoroalanine2,3 during a seminar visit, as a second year assistant We have subsequently deciphered many of the rules -
Strategies in Stewardship and Why Some Antimicrobials Should Be Protected
Strategies in Stewardship and Why Some Antimicrobials Should Be Protected Matt Crotty, PharmD Clinical Pharmacist – Infectious Diseases Methodist Dallas Medical Center September 7, 2017 Disclosures • Acted as a consultant – Nabriva Therapeutics AG – Theravance Biopharma Objectives • Define antimicrobial stewardship • Discuss current and future strategies for antimicrobial stewardship to promote judicious use of antimicrobials • Describe the reasons for “protecting” antimicrobials Outline • The Problem • Antimicrobial stewardship – Concept – Strategies • Passive • Active • Other (…prevention would be nice) • Reasons antimicrobials are protected • Collaboration Misuse adversely impacts patients – Resistance “…. the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out… In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.” - Sir Alexander Fleming, June 1945 Nature Reviews: Drug Discovery. 2007: 6; 8-12. Antibiotics are misused in hospitals . An estimated 30-50% of antimicrobial use in hospitals is inappropriate . Misused in a variety of ways • Given when not needed • Continued when no longer necessary • Wrong dose/drug for infection • Broad spectrum for susceptible organisms IDSA Statement on ‘Antibiotic Resistance: Promoting Critically Needed Antibiotic Research and Development and Appropriate Use (“Stewardship”) of these Precious Drugs’ -Before the House Committee on Energy and Commerce Subcommittee on Health; June 9, 2010 Antibiotics are misused in hospitals CDC, MMWR. 2014; 63. Misuse adversely impacts patients – Adverse Effects . Perception that there is (almost) no risk and (almost) all benefit to giving an antibiotic . Antibiotics account for nearly 1 in 5 (19.3%) of drug-related adverse events • >140,000 ED visits/year • Admission required for 6.1% of adverse events .