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The Role of Nanobiosensors in Therapeutic Drug Monitoring
Journal of Personalized Medicine Review Personalized Medicine for Antibiotics: The Role of Nanobiosensors in Therapeutic Drug Monitoring Vivian Garzón 1, Rosa-Helena Bustos 2 and Daniel G. Pinacho 2,* 1 PhD Biosciences Program, Universidad de La Sabana, Chía 140013, Colombia; [email protected] 2 Therapeutical Evidence Group, Clinical Pharmacology, Universidad de La Sabana, Chía 140013, Colombia; [email protected] * Correspondence: [email protected]; Tel.: +57-1-8615555 (ext. 23309) Received: 21 August 2020; Accepted: 7 September 2020; Published: 25 September 2020 Abstract: Due to the high bacterial resistance to antibiotics (AB), it has become necessary to adjust the dose aimed at personalized medicine by means of therapeutic drug monitoring (TDM). TDM is a fundamental tool for measuring the concentration of drugs that have a limited or highly toxic dose in different body fluids, such as blood, plasma, serum, and urine, among others. Using different techniques that allow for the pharmacokinetic (PK) and pharmacodynamic (PD) analysis of the drug, TDM can reduce the risks inherent in treatment. Among these techniques, nanotechnology focused on biosensors, which are relevant due to their versatility, sensitivity, specificity, and low cost. They provide results in real time, using an element for biological recognition coupled to a signal transducer. This review describes recent advances in the quantification of AB using biosensors with a focus on TDM as a fundamental aspect of personalized medicine. Keywords: biosensors; therapeutic drug monitoring (TDM), antibiotic; personalized medicine 1. Introduction The discovery of antibiotics (AB) ushered in a new era of progress in controlling bacterial infections in human health, agriculture, and livestock [1] However, the use of AB has been challenged due to the appearance of multi-resistant bacteria (MDR), which have increased significantly in recent years due to AB mismanagement and have become a global public health problem [2]. -
Oxazolidinones for TB
Oxazolidinones for TB: Current Status and Future Prospects 12th International Workshop on Clinical Pharmacology of Tuberculosis Drugs London, UK 10 September 2019 Lawrence Geiter, PhD Disclosures • Currently contract consultant with LegoChem Biosciences, Inc., Daejeon, Korea (LCB01-0371/delpazolid) • Previously employed with Otsuka Pharmaceutical Development and Commercialization, Inc. (delamanid, OPC-167832, LAM assay) What are Oxazolidinones • A family of antimicrobials mostly targeting an early step in protein synthesis • Cycloserine technically oxazolidinone but 2-oxazolidinone different MOA and chemical properties • New generation oxazolidinones bind to both 50S subunit and 30S subunit • Linezolid (Zyvox) and Tedizolid (Sivestro) approved for drug resistant skin infections and community acquired pneumonia Cycloserine • Activity against TB demonstrated in non- clinical and clinical studies • Mitochondrial toxicity >21 days limits use in TB treatment Linezolid Developing Oxazolidinones for TB Compound Generic Brand Sponsor Development Status TB Code- Activity/Trials PNU-100766 Linezolid Zyvox Pfizer Multiple regimen Yes/Yes TR-201 Tedizolid Sivextro Merck Pre-clinical efficacy Yes/No PNU-100480 Sutezolid Pfizer Multiple regimen studies Sequella Yes/Yes (PanACEA) TB Alliance LCB01-0371 Delpazolid LegoChem Bio EBA trial recruitment completed Yes/Yes TBI-223 - Global Alliance SAD trial launched Yes/Yes AZD5847 Posizolid AstraZenica Completed EBA Yes/No RX-1741 Radezolid Melinta IND for vaginal infections ?/No RBX-7644 Ranbezolid Rabbaxy None found ?/No MRX-4/MRX-1 Contezolid MicuRx Skin infections Yes/No U-100592 Eperezolid ? No clinical trials ?/No PK of Oxazolidinones in Development for TB Steady State PK Parameters Parameter Linezolid 600 Delpazolid 800 mg QD2 mg QD3 Cmax (mg/L) 17.8 8.9 Cmin (mg/L) 2.43 0.1 Tmax (h) 0.87 0.5 T1/2 (h) 3.54 1.7 AUC0-24 (µg*h/mL) 84.5 20.1 1 MIC90 (µg/mL) 0.25 0.5 References 1. -
Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications
International Journal of Molecular Sciences Review Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications Daniel Fernández-Villa 1, Maria Rosa Aguilar 1,2 and Luis Rojo 1,2,* 1 Instituto de Ciencia y Tecnología de Polímeros, Consejo Superior de Investigaciones Científicas, CSIC, 28006 Madrid, Spain; [email protected] (D.F.-V.); [email protected] (M.R.A.) 2 Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-915-622-900 Received: 18 September 2019; Accepted: 7 October 2019; Published: 9 October 2019 Abstract: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications. Keywords: folic acid antagonists; antifolates; antibiotics; antibacterials; immunomodulation; sulfonamides; antimalarial 1. -
Infectious Diseases
2013 MEDICINES IN DEVELOPMENT REPORT Infectious Diseases A Report on Diseases Caused by Bacteria, Viruses, Fungi and Parasites PRESENTED BY AMERICA’S BIOPHARMACEUTICAL RESEARCH COMPANIES Biopharmaceutical Research Evolves Against Infectious Diseases with Nearly 400 Medicines and Vaccines in Testing Throughout history, infectious diseases hepatitis C that inhibits the enzyme have taken a devastating toll on the lives essential for viral replication. and well-being of people around the • An anti-malarial drug that has shown Medicines in Development world. Caused when pathogens such activity against Plasmodium falci- For Infectious Diseases as bacteria or viruses enter a body and parum malaria which is resistant to multiply, infectious diseases were the current treatments. Application leading cause of death in the United Submitted States until the 1920s. Today, vaccines • A potential new antibiotic to treat methicillin-resistant Staphylococcus Phase III and infectious disease treatments have proven to be effective treatments in aureus (MRSA). Phase II many cases, but infectious diseases still • A novel treatment that works by Phase I pose a very serious threat to patients. blocking the ability of the smallpox Recently, some infectious pathogens, virus to spread to other cells, thus 226 such as pseudomonas bacteria, have preventing it from causing disease. become resistant to available treatments. Infectious diseases may never be fully Diseases once considered conquered, eradicated. However, new knowledge, such as tuberculosis, have reemerged new technologies, and the continuing as a growing health threat. commitment of America’s biopharma- America’s biopharmaceutical research ceutical research companies can help companies are developing 394 medicines meet the continuing—and ever-changing and vaccines to combat the many threats —threat from infectious diseases. -
An Updated Review of Iclaprim
Open Forum Infectious Diseases REVIEW ARTICLE An Updated Review of Iclaprim: A Potent and Rapidly Bactericidal Antibiotic for the Treatment of Skin and Skin Structure Infections and Nosocomial Pneumonia Caused by Gram-Positive Including Multidrug-Resistant Bacteria David B. Huang,1 Catherine D. Strader,3 James S. MacDonald,3 Mark VanArendonk,2 Richard Peck,4 and Thomas Holland5 1Motif BioSciences, New York, New York; Rutgers New Jersey Medical School, 2Vermeer Pharma, Morristown, New Jersey, 3Synergy Partners R&D Solutions, Chester, New Jersey; 4Hemex, Liestal, Switzerland, 5Duke University Medical Center, Durham, North Carolina New antibiotics are needed because of the increased morbidity and mortality associated with multidrug-resistant bacteria. Iclaprim, a bacterial dihydrofolate reductase inhibitor, not currently approved, is being studied for the treatment of skin infections and noso- comial pneumonia caused by Gram-positve bacteria, including multidrug-resistant bacteria. Iclaprim showed noninferiority at –10% to linezolid in 1 of 2 phase 3 studies for the treatment of complicated skin and skin structure infections with a weight-based dose (0.8 mg/kg) but did not show noninferiority at –10% to linezolid in a second phase 3 study. More recently, iclaprim has shown noninferiority at –10% to vancomycin in 2 phase 3 studies for the treatment of acute bacterial skin and skin structure infections with an optimized fixed dose (80 mg). A phase 3 study for the treatment of hospital-acquired bacterial and ventilator-associated bacterial pneumonia is upcoming. If, as anticipated, iclaprim becomes available for the treatment of skin and skin structure infections, it will serve as an alternative to current antibiotics for treatment of severe infections. -
Computational Antibiotics Book
Andrew V DeLong, Jared C Harris, Brittany S Larcart, Chandler B Massey, Chelsie D Northcutt, Somuayiro N Nwokike, Oscar A Otieno, Harsh M Patel, Mehulkumar P Patel, Pratik Pravin Patel, Eugene I Rowell, Brandon M Rush, Marc-Edwin G Saint-Louis, Amy M Vardeman, Felicia N Woods, Giso Abadi, Thomas J. Manning Computational Antibiotics Valdosta State University is located in South Georgia. Computational Antibiotics Index • Computational Details and Website Access (p. 8) • Acknowledgements (p. 9) • Dedications (p. 11) • Antibiotic Historical Introduction (p. 13) Introduction to Antibiotic groups • Penicillin’s (p. 21) • Carbapenems (p. 22) • Oxazolidines (p. 23) • Rifamycin (p. 24) • Lincosamides (p. 25) • Quinolones (p. 26) • Polypeptides antibiotics (p. 27) • Glycopeptide Antibiotics (p. 28) • Sulfonamides (p. 29) • Lipoglycopeptides (p. 30) • First Generation Cephalosporins (p. 31) • Cephalosporin Third Generation (p. 32) • Fourth-Generation Cephalosporins (p. 33) • Fifth Generation Cephalosporin’s (p. 34) • Tetracycline antibiotics (p. 35) Computational Antibiotics Antibiotics Covered (in alphabetical order) Amikacin (p. 36) Cefempidone (p. 98) Ceftizoxime (p. 159) Amoxicillin (p. 38) Cefepime (p. 100) Ceftobiprole (p. 161) Ampicillin (p. 40) Cefetamet (p. 102) Ceftoxide (p. 163) Arsphenamine (p. 42) Cefetrizole (p. 104) Ceftriaxone (p. 165) Azithromycin (p.44) Cefivitril (p. 106) Cefuracetime (p. 167) Aziocillin (p. 46) Cefixime (p. 108) Cefuroxime (p. 169) Aztreonam (p.48) Cefmatilen ( p. 110) Cefuzonam (p. 171) Bacampicillin (p. 50) Cefmetazole (p. 112) Cefalexin (p. 173) Bacitracin (p. 52) Cefodizime (p. 114) Chloramphenicol (p.175) Balofloxacin (p. 54) Cefonicid (p. 116) Cilastatin (p. 177) Carbenicillin (p. 56) Cefoperazone (p. 118) Ciprofloxacin (p. 179) Cefacetrile (p. 58) Cefoselis (p. 120) Clarithromycin (p. 181) Cefaclor (p. -
Nature Nurtures the Design of New Semi-Synthetic Macrolide Antibiotics
The Journal of Antibiotics (2017) 70, 527–533 OPEN Official journal of the Japan Antibiotics Research Association www.nature.com/ja REVIEW ARTICLE Nature nurtures the design of new semi-synthetic macrolide antibiotics Prabhavathi Fernandes, Evan Martens and David Pereira Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events. -
Potent Late-Stage Antibiotic for Serious and Life-Threatening Bacterial
ADVERTISEMENT FEATURE Motif BioSciences, Inc. www.motifbio.com Potent late-stage antibiotic for serious and life-threatening bacterial infections Motif Bio’s iclaprim shows rapid bactericidal activity and low propensity for induction of resistance and is in late-stage clinical testing for acute bacterial skin and skin structure infections. The need for new antibiotics to combat multidrug- a Control Vanco 8×MIC Iclaprim 2×MIC b resistant infections is increasingly urgent in the hos- 1.00E+101010 Induction of resistance with iclaprim and trimethoprim: Staphylococcus. aureus ATCC 25923 (trimethoprim sensitive).* pital setting, where patients often succumb to serious 1.00E+091090 and life-threatening infections that require immedi- 1.00E+081080 140 1.00E+071070 120 profile ate treatment with the best available antibiotic. 100 1.00E+061060 CFU 80 Motif Bio is a clinical-stage biopharmaceutical com- 1.00E+051050 60 40 MIC (mg/ml) pany developing new antibiotics against serious and 1.00E+0410 40 30 1.00E+0310 20 life-threatening infections caused by multidrug-resis- 20 1.00E+0210 0 tant bacteria. Its lead product candidate, iclaprim, is 00 0 5 10 15 20 25 10 Passage number 1.00E+010 being developed for the treatment of the most com- 0 1 2 3 4 5 6 7 8 9 10 Trimethoprim Iclaprim Rifampin mon and serious bacterial infections, such as acute Time (h) *Similar results were obtained with a trimethoprim-resistant (F98Y) S. aureus. bacterial skin and skin structure infections (ABSSSIs) and hospital-acquired bacterial pneumonia (HABP), Figure 1: Iclaprim bactericidal activity and low resistance profile. -
NEW ANTIBACTERIAL DRUGS Drug Pipeline for Gram-Positive Bacteria
NEW ANTIBACTERIAL DRUGS Drug pipeline for Gram-positive bacteria Françoise Van Bambeke, PharmD, PhD Paul M. Tulkens, MD, PhD Pharmacologie cellulaire et moléculaire Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium http://www.facm.ucl.ac.be Based largely on presentations given at the 24th and 25th European Congress of Clinical Microbiology and Infectious Diseases and the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 1 Disclosures Research grants for work on investigational compounds discussed in this presentation from • Cempra Pharmaceuticals • Cerexa • GSK • Melinta therapeutics • The Medicine Company • MerLion Pharmaceuticals • Theravance • Trius 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 2 Belgium 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 3 Belgium 10 millions inhabitants … 10 Nobel prizes (10/850) • Peace - Institute of International Law, Ghent (1904) - Auguste Beernaert (1909) - Henri Lafontaine (1913) - Father Dominique Pire (1958) • Literature - Maurice Maeterlinck, Ghent (1911) • Medicine - Jules Bordet, Brussels (1919) - Corneille Heymans, Ghent (1938) - Christian de Duve, Louvain (1974) - Albert Claude, Brussels (1974) • Chemistry - Ilya Prigogyne, Brussels (1977) - Physics - François Englert, Brussels (2013) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 4 The Catholic University of Louvain in brief (1 of 4) • originally founded in 1425 in the city of Louvain (in French and English; known as Leuven in Flemish) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 5 The Catholic University of Louvain in brief (2 of 4) • It was one of the major University of the so-called "Low Countries" in the 1500 – 1800 period, with famous scholars and discoverers (Vesalius for anatomy, Erasmus for philosophy, …). -
Determinants of the Species Selectivity of Oxazolidinone Antibiotics Targeting the Large Ribosomal Subunit
DOI 10.1515/hsz-2013-0188 Biol. Chem. 2013; 394(11): 1529–1541 Jagmohan S. Saini, Nadine Homeyer, Simone Fullea and Holger Gohlke* Determinants of the species selectivity of oxazolidinone antibiotics targeting the large ribosomal subunit Abstract: Oxazolidinone antibiotics bind to the highly Introduction conserved peptidyl transferase center in the ribosome. For developing selective antibiotics, a profound under- Ribosomes are complex nanomachines that perform standing of the selectivity determinants is required. We protein synthesis in all living cells. This pivotal role makes have performed for the first time technically challenging the bacterial ribosome a prominent target for antibiotics molecular dynamics simulations in combination with that exert their antimicrobial effect by interfering with molecular mechanics Poisson-Boltzmann surface area protein synthesis (David-Eden et al., 2010). Several crystal (MM-PBSA) free energy calculations of the oxazolidinones structures of ribosomal subunits bound to different classes linezolid and radezolid bound to the large ribosomal sub- of antibiotics have been published over the last decade units of the eubacterium Deinococcus radiodurans and revealing the binding site and binding mode in atomic the archaeon Haloarcula marismortui. A remarkably good detail as well as the structural basis for antibiotic specific- agreement of the computed relative binding free energy ity (Brodersen et al., 2000; Carter et al., 2000; Bottger et al., with selectivity data available from experiment for lin- 2001; Schlunzen et al., 2001; Hansen et al., 2003; Yonath, ezolid is found. On an atomic level, the analyses reveal an 2005a; Ippolito et al., 2008; Wilson et al., 2008; Belousoff intricate interplay of structural, energetic, and dynamic et al., 2011). -
O06. 2 in Vitro Combination Testing and Selection of Resistance to Zoliflodacin Combined with Six Antimicrobials for N. Gonorrhoeae
Abstracts Sex Transm Infect: first published as 10.1136/sextrans-2019-sti.135 on 14 July 2019. Downloaded from O06.2 IN VITRO COMBINATION TESTING AND SELECTION OF resistance is reported. Recent data showed resistance-guided RESISTANCE TO ZOLIFLODACIN COMBINED WITH SIX therapy (RGT) using doxycycline then sitafloxacin for macro- ANTIMICROBIALS FOR N. GONORRHOEAE lide-resistant MG cured 92% of infections and doxycycline-azi- thromycin for macrolide-susceptible MG cured 95%. As 1Sunniva Foerster, 2George Drusano, 3Daniel Golparian, 4Michael Neely, 5Laura Piddock, 5Emilie Alirol, 6Magnus Unemo*. 1WHO Collaborating Centre for Gonorrhoea and other sitafloxacin is not widely available, we undertook a study of STIs, Örebro, Sweden; 2University of Florida, Orlando, USA; 3Örebro University, WHO RGT to evaluate the efficacy of moxifloxacin in RGT to pro- Collaborating Centre for Gonorrhoea and Other STIs, Örebro, Sweden; 4University of vide data that is relevant to international guidelines and to Southern California, Los Angeles, USA; 5Global Antibiotic Research and Development assess the efficacy of this alternative approach in a population Partnership (GARDP), Geneva, Switzerland; 6World Health Organization Collaborating with 15–20% quinolone-resistance (ParC mutations). Centre for Gonorrhoea and Other STIs, Faculty of Medicine of Health, Örebro University, Methods Patients attending Melbourne Sexual Health Centre Department of Laboratory Medicine, Microbiology, Örebro, Sweden between April 2017-June 2018 with urethritis, cervicitis or proctitis were treated with doxycycline (7 days)and recalled if 10.1136/sextrans-2019-sti.135 positive for MG. Macrolide-susceptible cases received azithro- Background Resistance in Neisseria gonorrhoeae to all therapeu- mycin (1g, then 500 mg daily 3 days)and resistant-cases tic antimicrobials for gonorrhoea has emerged. -
Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .