DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 9,347,888 B2 Ghirardi Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 9,347,888 B2 Ghirardi Et Al USOO9347888B2 (12) United States Patent (10) Patent No.: US 9,347,888 B2 Ghirardi et al. (45) Date of Patent: May 24, 2016 (54) DETECTION OF BACTERIA EXHIBITING A Wexler et al., “In Vitro Activities of Faropenem against 579 Strains of RESISTANCE TO CARBAPENEMS Anaerobic Bacteria'. Antimicrobial Agents and Chemotherapy, Nov. 2002, vol. 46, No. 11, pp. 3669-3675.* (75) Inventors: Sandrine Ghirardi, Saint Genis les Naiemi et al., “Extended-spectrum beta-lactamases screening agar Ollieres (FR); John Perry, Newcastle with AmpC inhibition”, Eur J. Clin Microbiol Infect Dis (2009) upon Tyne (GB); Gilles Zambardi, 28:989-990. DOI 10.1007/s10096-009-0714-8. Chezeneuve (FR) Rodel et al., “In vitro activities of faropenem, ertapenem, imipenem and meropenem against Borreliaburgdorferi s.l.. International Jour (73) Assignee: BIOMERIEUX, Marcy L’Etoile (FR) nal of Antimicrobial Agents 30 (2007) 83-86.* Pages etal; “Efflux Pump, the Masked Side of B-Lactam Resistance (*) Notice: Subject to any disclaimer, the term of this in Klebsiella pneumoniae Clinical Isolates.” PLoS ONE: Mar. 2009; patent is extended or adjusted under 35 vol. 4: Issue 3, e4817. U.S.C. 154(b) by 0 days. Samraetal; “Evaluation ofCHROMagar KPC for Rapid Detection of Carbapenem-Resistant Enterobacteriaceae.” Journal of Clinical (21) Appl. No.: 14/001565 Microbiology; Jul. 2008; vol. 46; No. 9: pp. 3110-3111. Nordmann et al; "How to Detect NDM-1 Producers.' Journal of (22) PCT Filed: Mar. 16, 2012 Clinical Microbiology; 2011; Dec. 2010; vol. 49; No. 2: pp. 718-721. Mushtaq et al., “Activity of faropenem against cephalosporin-resis (86). PCT No.: PCT/FR2O12/050556 tant Enterobacteriaceae.” Journal of Antimicrobial Chemotherapy; 2007: vol. 59: pp. 1025-1030. S371 (c)(1), Giske et al., “A Sensitive and specific phenotypic assay for detection (2), (4) Date: Aug. 26, 2013 of metallo-B-lactamases and KPC in Klebsiella pneumoniae with the use of meropenem disks Supplemented with aminophenylboronic (87) PCT Pub. No.: WO2012/131216 acid, dipicolinic acid and cloxacilling” Clinical Microbiology and PCT Pub. Date: Oct. 4, 2012 Infection; Jun. 2010; vol. 17; No. 4; pp. 552-556. Malléa et al; "Inhibitors of antibiotic efflux pump in resistant (65) Prior Publication Data Enterobacter aerogenes strains.” Biochemical and Biophysical Research Communications; 2002; vol. 293; pp. 1370-1373. US 2013/0344522-A1 Dec. 26, 2013 Orenga et al; "Enzymatic Substrates in microbiology,” Journal of Microbiological Methods: 2009; vol. 79: pp. 139-155. (30) Foreign Application Priority Data Panagea et al; “Evaluation of CHROMagarTM KPC for the detection of carbapenemase-producing Enterobacteriaceae in rectal Surveil Mar. 25, 2011 (FR) ...................................... 1152477 lance cultures;” International Journal of Antimicrobial Agents; 2010. May 22, 2012 Search Report issued in International Patent Applica (51) Int. Cl. tion No. PCT FR2012/050556. GOIN 2L/76 (2006.01) Translation of May 22, 2012 Written Opinion issued in International CI2N L/20 (2006.01) Patent Application No. PCT/FR2012/050556. CI2N I5/0 (2006.01) CI2O I/04 (2006.01) * cited by examiner (52) U.S. Cl. CPC ................ G0IN 21/763 (2013.01); C12N 1/20 (2013.01): CI2N 15/01 (2013.01); C12O I/04 Primary Examiner — Suzanne M Noakes (2013.01) (74) Attorney, Agent, or Firm — Oliff PLC (58) Field of Classification Search None (57) ABSTRACT See application file for complete search history. Disclosed is a process for detecting and/or identifying, in a (56) References Cited biological sample, bacteria exhibiting a resistance to carbap enems, including: a) contacting said sample with a reaction FOREIGN PATENT DOCUMENTS medium including at least one chromogenic agent and faro penem and/or doripenem; b) incubating the whole so as to FR 2925 O70 A1 6, 2009 allow the bacteria to grow; and c) detecting the strains exhib WO WO 2010/010O83 A1 1, 2010 iting a resistance to carbapenems. The medium employed in OTHER PUBLICATIONS step a) also contains cloxacillin and/or a combination of clox acillin and PAbetaN. Walsh, F., “Doripenem: A new carbapenem antibiotic a review of comparative antimicrobial and bactericidal activities'. Therapeutics and Clinical Risk Management 2007:3(5) 789-794.* 21 Claims, No Drawings US 9,347,888 B2 1. 2 DETECTION OF BACTERIA EXHIBITINGA context, in particular with the emergence of new resistances RESISTANCE TO CARBAPENEMS such as NDM-1, and permits the screening of all of the resis tance mechanisms due to the production of all known types of The present invention relates to a detection and identifica carbapenemases. tion process Suitable for screening bacteria which are resis In this respect, the present invention relates to a process for tant to carbapenems. detecting and/or identifying, in a biological sample, bacteria The increase in the resistance to beta-lactam antibiotics, exhibiting a resistance to carbapenems, comprising the steps Such as penicillins and cephalosporins, complicates the treat consisting in: ment of infections caused by strains of Gram-negative bacte a) contacting said sample with a reaction medium compris ria. These antibiotics are then replaced by other broad-spec 10 ing at least one chromogenic agent and faropenem and/ trum antimicrobials. Amongst these broad-spectrum or doripenem: antimicrobials, carbapenems have taken an important role, b) incubating the whole so as to allow the bacteria to grow; especially for treating hospitalised patients. Carbapenems act c) detecting the strains exhibiting a resistance to carbapen against the majority of Gram-positive and Gram-negative CS. aerobic bacteria, and on certain anaerobic bacteria. 15 The Applicant has shown that the addition of faropenem However, more and more strains resistant to carbapenems and/or doripenem into a chromogenic medium makes it pos are appearing in hospitalised patients. sible for the majority of carbapenemase-producing bacteria to The bacteria concerned are, non-exhaustively, Escherichia grow, whilst inhibiting a majority of strains which do not coli, Enterobacter cloacae, Enterobacter aerogenes, Citro produce them, such as wild strains, and strains which produce bacter sp., Klebsiella pneumoniae, Klebsiella Oxytoca, extended-spectrum beta-lactamases or high-level cepha Pseudomonas aeruginosa, Providencia rettgeri, Pseudomo losporinases, for example. The tests have made it possible to nas putida, Stenotrophomonas maltophilia, Acinetobacter demonstrate a greater sensitivity and specificity than those of baumanii, Comamonas sp., Aeromonas sp., Morganella mor a chromogenic medium using meropenem. ganii, Enterococcus sp., Proteus mirabilis, Salmonella sen According to a first embodiment, the present invention fienberg, Serratia marcescens, Salmonella typhimurium, etc. 25 corresponds to a process for detecting and/or identifying, in a The reduced susceptibility to carbapenems can be due to: biological sample, bacteria exhibiting a resistance to carbap the expression of a gene which is resistant to beta-lactams: enems, comprising the steps consisting in: (i) hyperproduction of ampC beta-lactamases and/or a) contacting said sample with a culture medium compris (ii) ESBL (extended-spectrum beta-lactamase), ing at least one chromogenic Substrate, and at least faro combined with changes in the permeability of the cell wall 30 penem and/or doripenem: (impermeability resistance) and/or with the active efflux of b) incubating the whole so as to allow the bacteria to grow; the antibiotics (Pages et al., 2009; PloS ONE, 4 (3)); and/or c) detecting the strains exhibiting a resistance to carbapen the existence of enzymes which break down carbapenems, CS. called carbapenemases. According to a preferred embodiment of the invention, the The carbapenemase genes may be present in chromosomes 35 bacteria are NDM-1 bacteria. and/or in plasmids. Due to this presence in the form of plas Preferably, the carbapenem concentrations are between mids, these kinds of enzymatic resistance are capable of 0.05 and 32 mg/L. spreading to a great extent and, consequently, pose a major More preferably, the carbapenem concentrations are risk in epidemiological terms. between 2 and 32 mg/L for faropenem, and between 0.05 and The person skilled in the art has difficulty in easily detect 40 2 mg/L for doripenem. ing and/or identifying the strains of bacteria which are resis Advantageously, the medium employed in step a) also tant to carbapenems. comprises cloxacillin and/or a combination of cloxacillin and A method of characterising by using a chromogenic PAbetaN. These compounds provide an additional level of medium comprising meropenem and/or ertapenem was Sug selection and make it possible to distinguish the imperme gested in Application WO 2010/010083 and implemented in 45 ability resistances and other non-enzymatic resistances from the media CHROMagar R. KPC (Samra et al., 2008; J. Clin. the resistances by production of carbapenemase. Microbiol. 46 (9): 3110-31 11: CHROMagarTM, Paris, Biological sample, is to be understood to be a small part or France) and COLOREXTM KPC (BioMed Diagnostics Inc.). Small isolated quantity of an entity for analysis. This can be a This medium does not permit the detection of all of the clinical sample, human or animal, from a specimen of bio carbapenamase-producing strains, particularly the NDM-1 50 logical liquid, or a food sample, from any type of food or a strains which have appeared recently (Nordmann et al., 2011; sample from the food production or processing environment. J Clin Microbiol. 49(2): 718-721). In the current epidemio
Load more

Recommended publications
  • Dose Amoxicillin/Clavulanate
    1 Clinical trial of the treatment of acute sinusitis with standard-dose vs. high- dose amoxicillin/clavulanate Principal Investigator: Paul Sorum, MD, PhD, Professor of Internal Medicine and Pediatrics Co-Investigators: Andrea Matho, MD, 2nd year Med-Ped resident (the four 2nd-year residents will be responsible for the timely follow-up of enrolled patients) Mary Mulqueen, MD, 2nd year Med-Ped resident Aaron Quidort, MD, 2nd year Med-Ped resident Miyuki Tanino, MD, 2nd year Med-Ped resident Sujata Kane, PA-C (who will be enrolling the most patients) Christine McGovern, MS, PA-C (who will work with the residents to assure the smooth enrollment and complete follow-up of patients) Joseph Wayne, MD, MPH, Associate Professor of Internal Medicine and Pediatrics Gina Garrison, Pharm D, Associate Professor of Pharmacy Practice, Albany College of Pharmacy and Health Sciences (who will prepare the medications) Sub-Investigators The other attending physicians at the AMC Internal Medicine and Pediatrics office (who will be enrolling patients): Rahim Dhanani, MD Elizabeth Higgins, MD Hamish Kerr, MD Deborah Light, MD Jennifer Lindstrom, MD Tricia Pelnik-Fecko, MD Ivelisse Verrico, MD Kathleen Zabinski-Kramer, MD The other Medicine-Pediatrics residents (who will be enrolling patients and making follow-up telephone calls) Brady Bowen, DO Melanie Ecung Deyss, MD Laura El-Hage, MD Sara Khalil, MD Preetha Kurian, MD Daniel Lavelle, MD Manpreet Mann, MD Lyndsay Molinari, MD Uwa Otabor, MD Samuel Park, MD Britta Sundquist, MD Lisa Thaler, DO 2 Others Nursing staff (who will provide the patients with documents relating to the study) Medical students for research experience or work-study (who will help the residents to follow-up telephone calls and who will, if possible, enter data into the Excel data base) (to be set up) Statistical consultant: Michael Mulvihill, DPH, Einstein Medical Center, NYC A.
    [Show full text]
  • Consideration of Antibacterial Medicines As Part Of
    Consideration of antibacterial medicines as part of the revisions to 2019 WHO Model List of Essential Medicines for adults (EML) and Model List of Essential Medicines for children (EMLc) Section 6.2 Antibacterials including Access, Watch and Reserve Lists of antibiotics This summary has been prepared by the Health Technologies and Pharmaceuticals (HTP) programme at the WHO Regional Office for Europe. It is intended to communicate changes to the 2019 WHO Model List of Essential Medicines for adults (EML) and Model List of Essential Medicines for children (EMLc) to national counterparts involved in the evidence-based selection of medicines for inclusion in national essential medicines lists (NEMLs), lists of medicines for inclusion in reimbursement programs, and medicine formularies for use in primary, secondary and tertiary care. This document does not replace the full report of the WHO Expert Committee on Selection and Use of Essential Medicines (see The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2019 (WHO Technical Report Series, No. 1021). Licence: CC BY-NC-SA 3.0 IGO: https://apps.who.int/iris/bitstream/handle/10665/330668/9789241210300-eng.pdf?ua=1) and Corrigenda (March 2020) – TRS1021 (https://www.who.int/medicines/publications/essentialmedicines/TRS1021_corrigenda_March2020. pdf?ua=1). Executive summary of the report: https://apps.who.int/iris/bitstream/handle/10665/325773/WHO- MVP-EMP-IAU-2019.05-eng.pdf?ua=1.
    [Show full text]
  • WO 2010/025328 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 4 March 2010 (04.03.2010) WO 2010/025328 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US2009/055306 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 28 August 2009 (28.08.2009) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/092,497 28 August 2008 (28.08.2008) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): FOR¬ GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, EST LABORATORIES HOLDINGS LIMITED [IE/ ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, —]; 18 Parliament Street, Milner House, Hamilton, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Bermuda HM12 (BM).
    [Show full text]
  • Treatment of Drug-Resistant Tuberculosis an Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R
    AMERICAN THORACIC SOCIETY DOCUMENTS Treatment of Drug-Resistant Tuberculosis An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R. Mase, Giovanni Battista Migliori, Giovanni Sotgiu, Graham H. Bothamley, Jan L. Brozek, Adithya Cattamanchi, J. Peter Cegielski, Lisa Chen, Charles L. Daley, Tracy L. Dalton, Raquel Duarte, Federica Fregonese, C. Robert Horsburgh, Jr., Faiz Ahmad Khan, Fayez Kheir, Zhiyi Lan, Alfred Lardizabal, Michael Lauzardo, Joan M. Mangan, Suzanne M. Marks, Lindsay McKenna, Dick Menzies, Carole D. Mitnick, Diana M. Nilsen, Farah Parvez, Charles A. Peloquin, Ann Raftery, H. Simon Schaaf, Neha S. Shah, Jeffrey R. Starke, John W. Wilson, Jonathan M. Wortham, Terence Chorba, and Barbara Seaworth; on behalf of the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY THE AMERICAN THORACIC SOCIETY, THE EUROPEAN RESPIRATORY SOCIETY, AND THE INFECTIOUS DISEASES SOCIETY OF AMERICA SEPTEMBER 2019, AND WAS CLEARED BY THE U.S. CENTERS FOR DISEASE CONTROL AND PREVENTION SEPTEMBER 2019 Background: The American Thoracic Society, U.S. Centers for was judged to be very low, because the data came Disease Control and Prevention, European Respiratory Society, and from observational studies with significant loss to follow-up Infectious Diseases Society of America jointly sponsored this new and imbalance in background regimens between comparator practice guideline on the treatment of drug-resistant tuberculosis groups. Good practices in the management of MDR-TB are (DR-TB). The document includes recommendations on the described. On the basis of the evidence review, a clinical strategy treatment of multidrug-resistant TB (MDR-TB) as well as tool for building a treatment regimen for MDR-TB is also isoniazid-resistant but rifampin-susceptible TB.
    [Show full text]
  • Comparison of Effectiveness and Safety of Imipenem/Clavulanate- Versus Meropenem/Clavulanate-Containing Regimens in the Treatment of MDR- and XDR-TB
    ORIGINAL ARTICLE TUBERCULOSIS Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB Simon Tiberi1,30, Giovanni Sotgiu2,30, Lia D’Ambrosio3,4,30, Rosella Centis3,30, Marcos Abdo Arbex5,6, Edith Alarcon Arrascue7,8, Jan Willem Alffenaar9, Jose A. Caminero8,10, Mina Gaga11, Gina Gualano12, Alena Skrahina13, Ivan Solovic14, Giorgia Sulis15, Marina Tadolini16, Valentina Alarcon Guizado17, Saverio De Lorenzo18, Aurora Jazmín Roby Arias19, Anna Scardigli8, Onno W. Akkerman20, Alena Aleksa21, Janina Artsukevich21, Vera Auchynka13, Eduardo Henrique Bonini5,6, Félix Antonio Chong Marín19, Lorena Collahuazo López19, Gerard de Vries22, Simone Dore2, Heinke Kunst23, Alberto Matteelli15, Charalampos Moschos11, Fabrizio Palmieri12, Apostolos Papavasileiou11, Marie-Christine Payen24, Andrea Piana2, Antonio Spanevello25,26, Dante Vargas Vasquez27, Pietro Viggiani18, Veronica White28, Alimuddin Zumla29 and Giovanni Battista Migliori3 ABSTRACT No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases. 84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60–428) versus 85 (49–156) days, respectively.
    [Show full text]
  • Ige and Drug Allergy: Antibody Recognition of 'Small' Molecules of Widely Varying Structures and Activities
    Antibodies 2014, 3, 56-91; doi:10.3390/antib3010056 OPEN ACCESS antibodies ISSN 2073-4468 www.mdpi.com/journal/antibodies Review IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities Brian A. Baldo † Molecular Immunology Unit, Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney, and Department of Medicine, University of Sydney, Sydney 2065, Australia; E-Mail: [email protected]; Tel.: +61-2-9880-9757 † Author is retired. Formerly: Head of Molecular Immunology Unit. Received: 19 November 2013; in revised form: 19 December 2013 / Accepted: 18 January 2014 / Published: 22 January 2014 Abstract: The variety of chemically diverse pharmacologically-active compounds administered to patients is large and seemingly forever growing, and, with every new drug released and administered, there is always the potential of an allergic reaction. The most commonly occurring allergic responses to drugs are the type I, or immediate hypersensitivity reactions mediated by IgE antibodies. These reactions may affect a single organ, such as the nasopharynx (allergic rhinitis), eyes (conjunctivitis), mucosa of mouth/throat/tongue (angioedema), bronchopulmonary tissue (asthma), gastrointestinal tract (gastroenteritis) and skin (urticaria, eczema), or multiple organs (anaphylaxis), causing symptoms ranging from minor itching and inflammation to death. It seems that almost every drug is capable of causing an immediate reaction and it is unusual to find a drug that has not provoked an anaphylactic response in at least one patient. These facts alone indicate the extraordinary breadth of recognition of IgE antibodies for drugs ranging from relatively simple structures, for example, aspirin, to complex molecules, such as the macrolide antibiotics composed of a large macrocyclic ring with attached deoxy sugars.
    [Show full text]
  • Novel Drug Targets for Food-Borne Pathogen Campylobacter Jejuni: an Integrated Subtractive Genomics and Comparative Metabolic Pathway Study
    OMICS A Journal of Integrative Biology Volume 19, Volume 7, 2015 Original Article ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2015.0046 Novel Drug Targets for Food-Borne Pathogen Campylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study Kusum Mehla and Jayashree Ramana Abstract Campylobacters are a major global health burden and a cause of food-borne diarrheal illness and economic loss worldwide. In developing countries, Campylobacter infections are frequent in children under age two and may be associated with mortality. In developed countries, they are a common cause of bacterial diarrhea in early adulthood. In the United States, antibiotic resistance against Campylobacter is notably increased from 13% in 1997 to nearly 25% in 2011. Novel drug targets are urgently needed but remain a daunting task to accomplish. We suggest that omics-guided drug discovery is timely and worth considering in this context. The present study employed an integrated subtractive genomics and comparative metabolic pathway analysis approach. We identified 16 unique pathways from Campylobacter when compared against H. sapiens with 326 non-redundant proteins; 115 of these were found to be essential in the Database of Essential Genes. Sixty-six proteins among these were non-homologous to the human proteome. Six membrane proteins, of which four are transporters, have been proposed as potential vaccine candidates. Screening of 66 essential non-homologous proteins against DrugBank resulted in identification of 34 proteins with drug-ability potential, many of which play critical roles in bacterial growth and survival. Out of these, eight proteins had approved drug targets available in DrugBank, the majority serving crucial roles in cell wall synthesis and energy metabolism and therefore having the potential to be utilized as drug targets.
    [Show full text]
  • Emerging Modalities to Combat Resistant Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems
    A 2-Part Series on Emerging Modalities to Combat Resistant Gram-Negative Pathogens in Critically Ill Patients: Part 2: Focus on the Carbapenems Date of Release: August 2007 Expiration Date: August 31, 2008 FACULTY Lena M. Napolitano, MD, PROGRAM OVERVIEW Rising rates of nosocomially acquired multidrug-resistant (MDR) Gram- negative pathogens have drastically narrowed the spectrum of available therapeutic options. FACS, FCCP, FCCM Resistance to antimicrobials is a mounting health concern, both in the United States and world- Professor of Surgery wide. Infections caused by resistant Gram-negative pathogens, such as Pseudomonas aeruginosa Division Chief, Acute Care Surgery and Acinetobacter baumannii, result in higher morbidity, mortality, prolonged hospitalization, and Trauma, Burn, Critical Care, increased costs compared with sensitive strains. Carbapenems possess high potency against a Emergency Surgery broad spectrum of organisms and are regarded as the agents of choice for serious infections with Associate Chair of Surgery for extended-spectrum β-lactamase–producing organisms. However, increased prevalence of pan- Critical Care resistant P. aeruginosa and A. baumannii strains worldwide has limited the utility even of the car- Department of Surgery bapenems. To reduce the likelihood of emergence of resistance, clinical practice guidelines have Director, Surgical Critical Care been developed to direct antimicrobial treatment of nosocomial infections. Initial empiric therapy University of Michigan Health System should offer broad-spectrum coverage of Gram-negative pathogens, and therapy should be tai- Ann Arbor, Michigan lored and de-escalated after positive culture results are obtained. Although the polymyxins have been reintroduced, particularly as a last-line treatment of MDR Gram-negative pathogens, hetero- Robert C.
    [Show full text]
  • Gaps in Knowledge in Therapeutics and Treatment
    Gaps in knowledge in therapeutics and treatment Christopher M Parry Liverpool School of Tropical Medicine and Liverpool Clinical Laboratories, Liverpool, UK School of Tropical Medicine and Global Health, Nagasaki University, Japan Outline Trends in antibiotic resistance Impact of resistance Case finding and treatment as control Antimicrobial combinations Clinical trials Chloramphenicol in typhoid fever ‘…the clinical improvement and complete transformation in a few days can only be appreciated by clinicians who have had previous experience of typhoid fever and have known their own helplessness in the past to affect its protracted course…its great value in saving life and curtailing morbidity in this disease is incontestable’ Edge W. 1950. Typhoid fever treated with chloramphenicol: review of 16 cases. Lancet 255:710-712. Gatifloxacin GatR H58 Azithromycin AZMR Ciprofloxacin NalR R Ofloxacin DCS mutation CIP Ceftriaxone R Cefixime CRO Co-trimoxazole MDR Plasmid Chromosome Ampicillin/Amoxycillin Chloramphenicol CR 1950 1960 1970 1980 1990 2000 2010 2020 Wain et al, Lancet 2016 In the culture-confirmed population, 16 (26%) of 62 patient who received gatifloxacin failed treatment compared with four (7%) of 54 who received ceftriaxone (HR 0.24 (95% CI 0.08-0.73) p=0.01]. Treatment failure was associated with the of S.Typhi exhibiting resistance against fluoroquinolones requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone [HR7.5 (95% CI 1.71-32.80), p =0.01). Alternatives Carbapenems iv Meropenem/Imipenem iv Ertapenem oral Faropenem iv 4th generation cephalosporins iv Tigecycline Oral Mecillinam What are we trying to achieve when we treat a patient with typhoid fever? Individual patient Cure the patient, prevent complications and death Prevent relapse Safe in children and adults Affordable, available, easy adherence Parry.
    [Show full text]
  • Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic
    Pharmacology & Pharmacy, 2012, 3, 201-206 201 http://dx.doi.org/10.4236/pp.2012.32027 Published Online April 2012 (http://www.SciRP.org/journal/pp) Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic Toshihide Saito, Rinako Sawazaki, Kaori Ujiie, Masako Oda, Hiroshi Saitoh* Department of Pharmaceutics, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hok- kaido, Japan. Email: *[email protected] Received January 15th, 2012; revised February 12th, 2012; accepted March 5th, 2012 ABSTRACT Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteris- tics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in sec- retory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-ori- ented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2).
    [Show full text]
  • APPLICATION of STRUCTURE ACTIVITY RELATIONSHIPS of the MYCOBACTERIUM TUBERCULOSIS BETA-LACTAMASE (Blac)
    APPLICATION OF STRUCTURE ACTIVITY RELATIONSHIPS OF THE MYCOBACTERIUM TUBERCULOSIS BETA-LACTAMASE (BlaC) AND THE NEW DELHI METALLO-BETA-LACTAMASE (NDM-1) TO COMBATING BETA- LACTAMASE MEDIATED DRUG RESISTANCE A Dissertation by JOSEPH ANDREW MIRE Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, James C. Sacchettini Co-Chair of Committee, Pingwei Li Committee Members, David O. Peterson David H. Russell Head of Department, Gregory D. Reinhart August 2013 Major Subject: Biochemistry Copyright 2013 Joseph Andrew Mire ABSTRACT β-lactamase enzymes catalyze the irreversible hydrolysis of the four-membered cyclic amide ring characteristic of β-lactam antibiotics rendering them inactive and useless against pathogenic bacteria. Understanding structure activity relationships between β-lactam antibiotics and β-lactamases is important for designing novel β- lactams, β-lactamase inhibitors, and β-lactam-based fluorescent probes for rapid diagnosis of β-lactam antibiotic resistant infections. The first half of this study focuses on the class A β-lactamase BlaC from Mycobacterium tuberculosis (Mtb) and addresses intermolecular interactions between BlaC and substrates, inhibitors, and biosensors that influence their kinetic parameters with BlaC and activities against Mtb. The substrate structure activity relationship explained the molecular basis for differential innate resistance of Mtb to faropenem, biapenem, and tebipenem by showing the interactions between BlaC and the lactams that govern differential acyl-intermediate stability and affinity. The inhibitor structure activity relationship revealed features of the BlaC active site that can be exploited to enhance binding and inhibition of BlaC by benzoxaboroles, and demonstrates their utility as potentiators of β-lactam antibiotic activity against Mtb.
    [Show full text]
  • Reinvigorating the Oral Antibacterial Drug Development Pipeline Slide Deck
    Reinvigorating the Oral Antibacterial Drug Development Pipeline Brookings Institution • Washington, DC Thursday, November 20, 2014 Reinvigorating the Oral Antibacterial Drug Development Pipeline Sumati Nambiar MD MPH Director, Division of Anti-Infective Products CDER/FDA The Brookings Institution November 20, 2014 Need for oral antibacterial drugs • Treat less severe infections in an outpatient setting • Step-down therapy for severe infections after a period of intravenous therapy • Safe and effective oral therapies can minimize hospital stay, use of central lines/PICC lines for IV drug administration and its associated complications • Pediatric population: Need for age appropriate formulations in children 3 Recent approvals • Intravenous formulation only – Doripenem: Complicated urinary tract infections and complicated intra-abdominal infections – Ceftaroline: Acute Bacterial Skin and Skin Structure Infections (ABSSSI), community acquired bacterial pneumonia – Oritavancin and dalbavancin: ABSSSI • Intravenous and oral formulations – Tedizolid: ABSSSI • Oral formulation only – Fidaxomicin: Clostridium difficile diarrhea (CDAD) – Bedaquiline: MDRTB when an effective treatment regimen cannot otherwise be provided 4 Oral antibacterial drugs and GAIN • Qualified Infectious Disease Product (QIDP): 62 QIDP designations granted so far • QIDP designations not limited to antibacterial drugs with intravenous formulation only • Fast track status also given to both oral and intravenous formulations 5 Potential development scenarios • Oral therapy
    [Show full text]