DOCSLIB.ORG

New Antibiotics for Bad Bugs: Where Are We? Matteo Bassetti1,2*, Maria Merelli1, Chiara Temperoni1 and Augusta Astilean1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Antibiotics for Bad Bugs: Where Are We? Matteo Bassetti1,2*, Maria Merelli1, Chiara Temperoni1 and Augusta Astilean1 Bassetti et al. Annals of Clinical Microbiology and Antimicrobials 2013, 12:22 http://www.ann-clinmicrob.com/content/12/1/22 REVIEW Open Access New antibiotics for bad bugs: where are we? Matteo Bassetti1,2*, Maria Merelli1, Chiara Temperoni1 and Augusta Astilean1 Abstract Bacterial resistance to antibiotics is growing up day by day in both community and hospital setting, with a significant impact on the mortality and morbidity rates and the financial burden that is associated. In the last two decades multi drug resistant microorganisms (both hospital- and community-acquired) challenged the scientific groups into developing new antimicrobial compounds that can provide safety in use according to the new regulation, good efficacy patterns, and low resistance profile. In this review we made an evaluation of present data regarding the new classes and the new molecules from already existing classes of antibiotics and the ongoing trends in antimicrobial development. Infectious Diseases Society of America (IDSA) supported a proGram, called “the ′10 × ´20′ initiative”, to develop ten new systemic antibacterial drugs within 2020. The microorganisms mainly involved in the resistance process, so called the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) were the main targets. In the era of antimicrobial resistance the new antimicrobial agents like fifth generation cephalosporins, carbapenems, monobactams, β-lactamases inhibitors, aminoglycosides, quinolones, oxazolidones, glycopeptides, and tetracyclines active against Gram-positive pathogens, like vancomycin-resistant S. aureus (VRSA) and MRSA, penicillin-resistant streptococci, and vancomycin resistant Enterococcus (VRE) but also against highly resistant Gram- negative organisms are more than welcome. Of these compounds some are already approved by official agencies, some are still in study, but the need of new antibiotics still does not cover the increasing prevalence of antibiotic- resistant bacterial infections. Therefore the management of antimicrobial resistance should also include fostering coordinated actions by all stakeholders, creating policy guidance, support for surveillance and technical assistance. Keywords: New antibiotics, Resistance, Bacteria, FDA, EMA Introduction significant impact on mortality, hospital stay and Bacterial resistance to antibiotics is growing up day by associated-costs [3]. day in both community and hospital setting, increasing The microorganisms that are mainly involved in mortality and morbidity [1]. the resistance process are the, so called the ESKAPE Nowadays, the continuous development and the pathogens (Enterococcus faecium, Staphylococcus aureus, spread of bacterial resistances pose some questions Klebsiella pneumoniae, Acinetobacter baumanii, Pseudo- about their future and represent a serious threat for their monas aeruginosa, and enterobacteriaceae) emphasizing clinical utility, leading to an urgent requirement for new their capacity to “escape” from common antibacterial compounds. treatments [4]. Multidrug resistance (MDR) bacteria is defined as However despite this scenario, since 2000 only three non-susceptibility to one or more antimicrobials on new classes of antibiotics have been introduced to the three or more antimicrobial classes, while strains that market for human use and one of those is limited to top- are non-susceptible to all antimicrobials, are classified as ical use (Figure 1) [5]. ‘Innovation gap’ is the expression extreme drug-resistant strains [2]. MDR bacteria have a that has been used to describe the lack of novel struc- tural classes introduced to the antibacterial armamentar- ium since 1962. Numerous agencies and professional societies have * Correspondence: [email protected] tried to draw attention to the lack of new antibiotics, es- 1Infectious Diseases Division, Santa Maria Misercordia Hospital, Udine, Italy 2Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della pecially for MDR Gram-negative pathogens. Since 2004 Misericordia, Piazzale Santa Maria della Misericordia 15, Udine 33100, Italy © 2013 Bassetti et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Bassetti et al. Annals of Clinical Microbiology and Antimicrobials 2013, 12:22 Page 2 of 15 http://www.ann-clinmicrob.com/content/12/1/22 18 Tetracyclines 16 Lipopeptides 14 12 Macrolides/Lincosamides/ Streptogramins 10 Quinolones 8 6 Other 4 Oxazolidinones 2 Number of approved Antibiotics 0 Aminoglycosides Figure 1 Number of approved antibiotics during the last 30 years. repeated calls for reinvigorating pharmaceutical invest- lactams [8]. Ceftaroline has activity against Gram- ments in antibiotic research and development have been positive organisms, including S. pneumoniae, S. aureus, made by the Infectious Diseases Society of America including MRSA and Streptococcus pyogenes,and (IDSA) and several other distinguished societies [6]. Gram-negative species (Haemophilus influenzae and Recently, IDSA supported a proGram, called “the ′10 × Moraxella catarrhalis), including resistant phenotypes ′20′ initiative”, to develop ten new systemic antibacterial [9]. It has been the only Food and Drugs Administra- drugs within 2020 through the discovery of new drug clas- tion (FDA) approved cephalosporin with activity against ses, as well as to find possible new molecules from already hetero-resistant vancomycin-intermidiate S. aureus (hVISA), existing classes of antibiotics [7]. and vancomycin-resistant S. aureus (VRSA) [10]. Clinical In this review the new drugs belonging to both old trials have demonstrated that ceftaroline was non-inferior to and new classes of antibiotics will be analysed and thestandardofcareforthetreatmentofcommunity- discussed (Table 1). acquired pneumonia (CAP) and respectively for skin and soft structure infections (SSTI). [11,12]. Ceftaroline has been Cephalosporins approved by FDA in 2010 and by European Medical Agency The cephalosporin class of antimicrobial agents is known (EMA) in 2012 for the treatment of acute bacterial SSSIs for its broad spectrum of activity, proven efficiency and fa- and CAP. Ceftaroline was reported to have synergy when vorable safety profile, making it the most commonly pre- combined with amikacin, tazobactam, meropenem and scribed class of antimicrobials. There are four recognized aztreonam. Even if several studies have demonstrated low class generations of cephalosporins based on their activity probability of developing resistance to ceftaroline, this ceph- spectrum. Now with ceftaroline-fosamil and ceftobiprole, alosporin seems to induce AmpC beta-lactamases despite a new subclass of antimicrobials, cephalosporins with minimal inhibitory concentration (MIC) values in suscep- anti-methicillin-resistant Staphylococcus aureus (MRSA) tible range and this is the reason why this cephalosporin activity has been introduced. Ceftaroline and ceftobiprole should be avoided against Gram-negative bacteria known to have also been described in the literature as ‘fifth-gener- harbor inducible Amp-C beta-lactamases [13]. ation’ cephalosporin; however, such classification suggests The positive attributes of ceftaroline with respect to a broader Gram-negative profile whereas ceftaroline and antimicrobial stewardship proGrams are: the low poten- ceftobiprole spectrum of activity is truly unique for its ex- tial for resistance development and the favorable safety panded Gram-positive activity beyond all other presently and tolerability profile in clinical trials. Ceftaroline rep- available cephalosporins (i.e. MRSA). resents now an interesting agent for the treatment of Ceftaroline fosamil is a new, bactericidal, parental cSSSIs and CAP; future studies with intramuscular (im) cephalosporin with expanded Gram-positive activity, in- formulation should enroll ceftaroline as a potential alter- cluding vancomycin-resistant S. aureus (VRSA) and native to intravenous (iv) administration in outpatient MRSA. Like other beta-lactam antibiotics it works bind- setting. ing to penicillin-bindings-proteins (PBP) on bacterial cell walls leading to irreversible inhibition of cell-wall syn- thesis. The anti MRSA activity is attributed to its ability Ceftobiprole to bind PBP 2a with high affinity and to inhibit the activ- Ceftobiprole (formerly BAL9141) is the active compo- ity of BPB 2a more efficiently than other available beta- nent of the prodrug BAL5788 (ceftobiprolemedocaril), Bassetti et al. Annals of Clinical Microbiology and Antimicrobials 2013, 12:22 Page 3 of 15 http://www.ann-clinmicrob.com/content/12/1/22 Table 1 New antibiotics approved and/or in development Drug Antibiotic class Spectrum of microbiological activity Main clinical Development phase indication BAL30072 Monocyclic β-lactam MDR P. aeruginosa Acinetobacter including NK I metallo-ß-lactamases and enterobacteriaceae BC-3781 Pleuromutilin Gram-positive, including MRSA cSSSIs II Besifloxacin Quinolone Gram-positive and Gram-negative ophthalmicinfection Approved by FDA Biapenem Cerbpenem Gram-negative and Gram-positive RTI, UTI II CB-182,804 Polimyxin MDR Gram-negative NK I Ceftarolinefosamil Cephalosporin Gram-positive cSSSIs, CAP Approved by FDA and EMA Ceftazidime/ Cephalosporin + MDR P. aeruginosaand
Load more

Recommended publications
  • United States Patent ( 10 ) Patent No.: US 10,561,6759 B2 Griffith Et Al
    US010561675B2 United States Patent ( 10 ) Patent No.: US 10,561,6759 B2 Griffith et al. (45 ) Date of Patent : * Feb . 18 , 2020 (54 ) CYCLIC BORONIC ACID ESTER ( 58 ) Field of Classification Search DERIVATIVES AND THERAPEUTIC USES CPC A61K 31/69 ; A61K 31/396 ; A61K 31/40 ; THEREOF A61K 31/419677 (71 ) Applicant: Rempex Pharmaceuticals , Inc. , (Continued ) Lincolnshire , IL (US ) (56 ) References Cited (72 ) Inventors : David C. Griffith , San Marcos, CA (US ) ; Michael N. Dudley , San Diego , U.S. PATENT DOCUMENTS CA (US ) ; Olga Rodny , Mill Valley , CA 4,194,047 A 3/1980 Christensen et al . ( US ) 4,260,543 A 4/1981 Miller ( 73 ) Assignee : REMPEX PHARMACEUTICALS , ( Continued ) INC . , Lincolnshire , IL (US ) FOREIGN PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this EP 1550657 A1 7/2005 patent is extended or adjusted under 35 JP 2003-229277 A 8/2003 U.S.C. 154 ( b ) by 1129 days. (Continued ) This patent is subject to a terminal dis claimer . OTHER PUBLICATIONS Abdel -Magid et al. , “ Reductive Amination ofAldehydes and Ketones ( 21) Appl. No .: 13 /843,579 with Sodium Triacetoxyborohydride: Studies on Direct and Indirect Reductive Amination Procedures ” , J Org Chem . ( 1996 )61 ( 11 ): 3849 ( 22 ) Filed : Mar. 15 , 2013 3862 . (65 ) Prior Publication Data (Continued ) US 2013/0331355 A1 Dec. 12 , 2013 Primary Examiner — Shengjun Wang Related U.S. Application Data (74 ) Attorney, Agent, or Firm — Wilmer Cutler Pickering (60 ) Provisional application No.61 / 656,452 , filed on Jun . Hale and Dorr LLP 6 , 2012 (57 ) ABSTRACT (51 ) Int. Ci. A61K 31/69 ( 2006.01) Method of treating or ameliorating a bacterial infection A61K 31/00 ( 2006.01 ) comprising administering a composition comprising a cyclic (Continued ) boronic acid ester compound in combination with a car ( 52 ) U.S.
    [Show full text]
  • Acinetobacter Baumannii in a Murine Thigh-Infection Model
    RESEARCH ARTICLE Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model Bing Fan1,2☯, Jie Guan3☯, Xiumei Wang4, Yulong Cong1* 1 Clinical Laboratory of South Building, Chinese People’s Liberation Army General Hospital, Beijing 100853, a11111 China, 2 Clinical Laboratory of the Second Clinical District, the General Hospital of Chinese People’s Armed Police Forces, Beijing 100039, China, 3 Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China, 4 Department of Clinical Laboratory, the General Hospital of Chinese People’s Armed Police Forces, Beijing 100039, China ☯ These authors contributed equally to this work. * [email protected] OPEN ACCESS Citation: Fan B, Guan J, Wang X, Cong Y (2016) Abstract Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Few effective therapeutic options are available for treating severe infections caused by Sulbactam against Extensively Drug-Resistant extensively drug-resistant Acinetobacter baumannii (XDR-AB). Using a murine thigh-infec- Acinetobacter baumannii in a Murine Thigh-Infection tion model, we examined the in vivo efficacy of colistin in combination with meropenem, tige- Model. PLoS ONE 11(6): e0157757. doi:10.1371/ journal.pone.0157757 cycline, fosfomycin, fusidic acid, rifampin, or sulbactam against 12 XDR-AB strains. Colistin, tigecycline, rifampin, and sulbactam monotherapy significantly decreased bacterial Editor: Digby F. Warner, University of Cape Town, SOUTH AFRICA counts in murine thigh infections compared with those observed in control mice receiving no treatment. Colistin was the most effective agent tested, displaying bactericidal activity Received: February 13, 2016 against 91.7% of strains at 48 h post-treatment.
    [Show full text]
  • WO 2018/005606 Al 04 January 2018 (04.01.2018) W !P O PCT
    (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 WO 2018/005606 Al 04 January 2018 (04.01.2018) W !P O PCT (51) International Patent Classification: KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, A61K 38/43 (2006.01) A61K 47/36 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, A61K 38/50 (2006.01) A61K 9/S0 (2006.01) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, A61K 33/44 {2006.01) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (21) International Application Number: PCT/US20 17/039672 (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (22) International Filing Date: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 28 June 2017 (28.06.2017) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (25) Filing Language: English TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (26) Publication Langi English MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (30) Priority Data: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 62/355,599 28 June 2016 (28.06.2016) US KM, ML, MR, NE, SN, TD, TG).
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,680,136 B2 Hirst Et Al
    USOO868O136B2 (12) United States Patent (10) Patent No.: US 8,680,136 B2 Hirst et al. (45) Date of Patent: Mar. 25, 2014 (54) CYCLIC BORONIC ACID ESTER WO WOO3,O70714 8, 2003 DERVATIVES AND THERAPEUTCUSES WO WO 2004/039859 5, 2004 THEREOF WO WO 2005/033090 4/2005 WO WO 2007/095638 8, 2007 WO WO 2009/046098 A1 4, 2009 (75) Inventors: Gavin Hirst, San Diego, CA (US); Raja WO WO 2009/064413 A1 5, 2009 Reddy, San Diego, CA (US); Scott WO WO 2009/064414 A1 5.2009 Hecker, Del Mar, CA (US); Maxim WO WO 2009/140309 A2 11/2009 Totroy San Deigo, CA (US); David C. WO WO 2010/1307082010/075286 A1 11,T 2010 Griffith, San Marcos, CA (US): Olga WO WO 2011/O17125 A1 2/2011 Rodny, Mill Valley, CA (US); Michael N. Dudley, San Diego, CA (US); Serge OTHER PUBLICATIONS Boyer, San Diego, CA (US) Fanetal (2009): STN International HCAPLUS database, Columbus (73) Assignee: Rempex Pharmaceuticals, Inc., San (OH), accession No. 2009: 425839.* Diego, CA (US) Vasil'ev et al (1977): STN International HCAPLUS database, Columbus (OH), accession No. 1977: 72730.* (*) Notice: Subject to any disclaimer, the term of this Allen et al., “Ansel's Pharmaceutical Dosage Forms and Drug Deliv patent is extended or adjusted under 35 ery Systems', 8th Edition (2004). U.S.C. 154(b) by 9 days. Arya et al., “Advances in asymmetric enolate methodology'. Tetra hedron (2000) 56:917-947. (21) Appl. No.: 13/205,112 Biedrzycki et al., “Derivatives of tetrahedral boronic acids”. J. Organomet. Chem.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Quantitative Structure-Pharmacokinetic
    Acta Pharm. 62 (2012) 305–323 Original research paper DOI: 10.2478/v10007-012-0024-z Quantitative structure-pharmacokinetic relationship (QSPkR) analysis of the volume of distribution values of anti-infective agents from J group of the ATC classification in humans BRUNO LOUIS1 In this study, a quantitative structure-pharmacokinetic 2 VIJAY K. AGRAWAL * relationship (QSPkR) model for the volume of distribu- tion (V ) values of 126 anti-infective drugs in humans was 1 Department of Pharmacy, Sultan d developed employing multiple linear regression (MLR), Qaboos University Hospital artificial neural network (ANN) and support vector re- PO Box 38, Al Khod, Muscat 123 gression (SVM) using theoretical molecular structural des- Oman criptors. A correlation-based feature selection (CFS) was 2 QSAR and Computer Chemical employed to select the relevant descriptors for modeling. Laboratories, A.P.S. University The model results show that the main factors governing Rewa-486003, India Vd of anti-infective drugs are 3D molecular representa- tions of atomic van der Waals volumes and Sanderson ele- ctronegativities, number of aliphatic and aromatic amino groups, number of beta-lactam rings and topological 2D shape of the molecule. Model predictivity was evaluated by external validation, using a variety of statistical tests and the SVM model demonstrated better performance compared to other models. The developed models can be used to predict the Vd values of anti-infective drugs. Keywords: QSPkR, QSPR, structure pharmacokinetic rela- Accepted June 12, 2012 tionship, volume of distribution, ANN, SVM, CFS There is a constant need to develop new anti-infective drug molecules because the antibiotics and antiviral drugs always face a threat of resistance development, which may eventually lead to therapeutic failure.
    [Show full text]
  • Antimicrobial Resistance Pattern of Clinical Isolates of Pseudomonas Aeruginosa and Escherichia Coli on Carbapenems
    ORIGINAL ARTICLE AFRICAN JOURNAL OF CLINICAL AND EXPERIMENTAL MICROBIOLOGY ISBN 1595-689X JULY 2018 VOL19 No.3 AJCEM/1822 http://www.ajol.info/journals/ajcem COPYRIGHT 2018 https://dx.doi.org/10.4314/ajcem.v19i3.1 AFR. J. CLN. EXPER. MICROBIOL. 19 (3): 159-164 ANTIMICROBIAL RESISTANCE PATTERN OF CLINICAL ISOLATES OF PSEUDOMONAS AERUGINOSA AND ESCHERICHIA COLI ON CARBAPENEMS Oladipo E.K. 1, 2 , Ajibade O.A. 1, 2* , Adeosun I.J 1, Awoyelu E. H. 2, Akinade S.B. 2, Alabi O.A. 2 and Ayilara O. A. 2,3 1Department of Microbiology, Adeleke University, P.M.B 250, Ede, Osun State, Nigeria; 2Department of Pure and Applied Biology (Microbiology/Virology Unit), Ladoke Akintola University, P.M.B 4000, Ogbomoso, Nigeria; 3Department of Medical Microbiology and Parasitology, Ladoke Akintola University Teaching Hospital , Oshogbo, , Osun State, Nigeria Correspondence: O.A Ajibade. Adeleke University, P.M.B 250 Ede, Osun State E – Mail: [email protected] ABSTRACT Background: Carbapenems are the most effective and important therapeutic options to serious infections caused by Enterobacteriaceae and Pseudomonas aeruginosa isolates. However, Carbepenems resistant isolates of Enterobacteriaceae and Pseudomonas aeroginosa are increasing worldwide. This study, therefore, was carried out to determine the resistance pattern of clinical isolates of Pseudomonas aeruginosa and Escherichia coli to Carbapenems . Methods: Fifty (50) E. coli and forty seven (47) Pseudomonas aeruginosa isolates were studied. Antibiotic Susceptibility test was performed as recommended by the CLSI. The antibiotics used were Ertapenem, Imipenem, Colistin Sulphate, Levofloxacin, and Piperacillin/Tazobactam. Results: Out of 97 clinical isolates subjected to drug susceptibilities test, Pseudomonas aeruginosa showed resistance to Ertapenem (87.2%); followed by Levofloxacin (19.1%), Colistin sulphate (12.8%), Piperacillin/tazobactan (4.3%) and Imipenem (2.1%) while E.coli displayed resistance to Ertapenem (30%), Levofloxacin (20%) and Colistin sulphate (4%).
    [Show full text]
  • Thai Hien Tai Ai Ai Ai Ai Un Tata Monitor
    THAI HIEN TAI AIUS009790495B2 AI AI AI UN TATA MONITOR (12 ) United States Patent ( 10 ) Patent No. : US 9 ,790 ,495 B2 Geller et al. (45 ) Date of Patent: Oct . 17 , 2017 ( 54 ) ANTISENSE ANTIBACTERIAL COMPOUNDS 8 , 299 ,206 B2 10 /2012 Fox et al. AND METHODS 8 , 314 , 072 B2 11/ 2012 Geller et al. 8 ,536 , 147 B2 * 9 / 2013 Weller . A61K 48 / 00 514 /44 A @(71 ) Applicants :Bruce L . Geller, Corvallis , OR (US ) ; 9 , 249 ,243 B2 * 2 /2016 Weller .. .. .. A61K 48 /00 David Greenberg , Coppell , TX (US ) 2004 /0029129 A1 * 2 /2004 Wang ** * * * . .. CO7K 14 / 195 435 /6 . 18 @(72 ) Inventors : Bruce L . Geller, Corvallis , OR (US ) ; 2005 / 0288246 Al 12/ 2005 Iversen et al. David Greenberg, Coppell , TX (US ) 2006 / 0241075 A1 * 10 /2006 McSwiggen . .. .. C12N 15 / 1138 514 /44 A @ 2006 /0270621 A1* 11/ 2006 Christiano .. .. A61K 9 /0014 ( 73 ) Assignees : Oregon State University , Corvallis , 514 /44 R OR (US ) ; Board of Regents , The 2007 / 0049542 A1 3 / 2007 Geller et al. University of Texas System , Austin , 2008 / 0194463 A1 8 / 2008 Weller et al . TX (US ) 2010 / 0016215 A1 1 / 2010 Moulton et al. 2010 / 0234281 A1 9 / 2010 Weller et al. ( * ) Notice: Subject to any disclaimer, the term of this 2010 /0261777 A1 * 10 /2010 Shaw . .. .. .. .. .. C12N 15 / 102 514 /44 R patent is extended or adjusted under 35 2012 /0040460 A1 * 2 /2012 Rigoutsos . .. C12N 15 / 111 U . S . C . 154 (b ) by 0 days . 435 /375 2012 / 0122769 A1 5 / 2012 Iversen (21 ) Appl. No. : 14 /713 , 857 2012 / 0213663 A1 8 /2012 Atieh et al.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Development of Antibiotics for Gram-Negatives: Where Now?
    Therapeutic Perspective Development of antibiotics for Gram-negatives: where now? Clin. Invest. (2011) 1(2), 211–227 The incidence of infections due to multidrug-resistance pathogens, such as Enterobacteriaceae, Pseudomonas aeruginosa or Acinetobacter spp. has been Matteo Bassetti†1, Francesca increasing. The paucity of antimicrobials active against multidrug- resistance Ginocchio1, Daniele Roberto strains are an important challenge. Novel anti-Gram-negative agents from Giacobbe1 & Malgorzata Mikulska1 old antimicrobial classes include b-lactamase inhibitors, cephalosporins, 1Division of Infectious Diseases, San Martino carbapenems, aminoglycosides, polymyxin analogs, tetracycline and mono- Hospital & University of Genoa, bactams. Among them, b-lactamase inhibitors seem the most promis- L.go R.Benzi 10, 16132 Genova, Italy † ing as they might restore the activity of already known b-lactams against Author for correspondence: Tel.: +39 010 555 5132 b­-lactamase-producing strains. New classes of antimicrobials include bis- Fax: +39 010 353 7680 indoles, boron-containing antibacterial protein-synthesis inhibitors, outer E-mail: [email protected] membrane synthesis inhibitors, antimicrobial peptides and antibiotics targeting novel sites of the 50S ribosomal subunit. Although promising, they are still far from being introduced into clinical practice. Therefore, optimizing the use of current antibiotics and infection control policies are mandatory. Keywords: antimicrobial peptides • ESKAPE • extended-spectrum b-lactamases • metallo-b-lactamases • new b-lactamase inhibitors • new cephalosporins Multidrug resistance (MDR) is defined as nonsusceptibility to one or more antimicrobials in three or more antimicrobial classes, while strains nonsusceptible to all antimicrobials, including polymyxins and tigecycline, are classified as extreme drug-resistant strains [1]. MDR Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings and are especially common and problematic in some intensive care units [2].
    [Show full text]
  • Zac4943-2Ch105t.Pdf
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2011, p. 4943–4960 Vol. 55, No. 11 0066-4804/11/$12.00 doi:10.1128/AAC.00296-11 Copyright © 2011, American Society for Microbiology. All Rights Reserved. MINIREVIEW Carbapenems: Past, Present, and Futureᰔ Krisztina M. Papp-Wallace,1,2 Andrea Endimiani,1,2,3 Magdalena A. Taracila,2 and Robert A. Bonomo1,2,4,5* Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 441061; Institute for Infectious Diseases, University of Bern 3010, Bern, Switzerland3; and Departments of Medicine,2 Pharmacology,4 and Molecular Biology and Microbiology,5 Case Western Reserve University, Cleveland, Ohio 44106 In this review, we summarize the current “state of the art” of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as “slow substrates” or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This “value-added feature” of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.
    [Show full text]
  • Quantitative Structure-Pharmacokinetic
    Acta Pharm. 62 (2012) 305–323 Original research paper DOI: 10.2478/v10007-012-0024-z Quantitative structure-pharmacokinetic relationship (QSPkR) analysis of the volume of distribution values of anti-infective agents from J group of the ATC classification in humans BRUNO LOUIS1 In this study, a quantitative structure-pharmacokinetic 2 VIJAY K. AGRAWAL * relationship (QSPkR) model for the volume of distribu- tion (V ) values of 126 anti-infective drugs in humans was 1 Department of Pharmacy, Sultan d developed employing multiple linear regression (MLR), Qaboos University Hospital artificial neural network (ANN) and support vector re- PO Box 38, Al Khod, Muscat 123 gression (SVM) using theoretical molecular structural des- Oman criptors. A correlation-based feature selection (CFS) was 2 QSAR and Computer Chemical employed to select the relevant descriptors for modeling. Laboratories, A.P.S. University The model results show that the main factors governing Rewa-486003, India Vd of anti-infective drugs are 3D molecular representa- tions of atomic van der Waals volumes and Sanderson ele- ctronegativities, number of aliphatic and aromatic amino groups, number of beta-lactam rings and topological 2D shape of the molecule. Model predictivity was evaluated by external validation, using a variety of statistical tests and the SVM model demonstrated better performance compared to other models. The developed models can be used to predict the Vd values of anti-infective drugs. Keywords: QSPkR, QSPR, structure pharmacokinetic rela- Accepted June 12, 2012 tionship, volume of distribution, ANN, SVM, CFS There is a constant need to develop new anti-infective drug molecules because the antibiotics and antiviral drugs always face a threat of resistance development, which may eventually lead to therapeutic failure.
    [Show full text]