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K. Pneumoniae

K. Pneumoniae

Paris Meeng on Emerging Muldrug Resistance

Novel Anbiocs and Novel Developments

Drosos E. Karageorgopoulos

Researcher, Alfa Instute of Biomedical Sciences, Athens, Greece Physician of the Hellenic Center for Diseases Prevenon and© by author Control, Tzaneio General Hospital of Pireaus, Pireaus, Greece

ESCMID Online Lecture LibraryParis, 7-6-2011 Resistance to in S. aureus bacteraemia, England and Wales, 1992‐2005

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Trends in Anmicrobial Resistance in England and Wales, 2004‐2005.ESCMID Online Lecture Library London, Health Protecon Agency 2006 Resistance to ciprofloxacin in E. coli bacteraemia, England and Wales, 1992‐2005

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Trends in Anmicrobial Resistance in England and Wales, 2004‐2005.ESCMID Online Lecture Library London, Health Protecon Agency 2006 New anbacterial agents approved in the US, 1983–2002, per 5‐year period

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ESCMID Spellberg B et al. Clin Infect Dis. 2004;38:1279‐1286Online Lecture Library Discovery of new classes of anbacterial drugs

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ESCMID OnlineSingh MP, Greenstein M. 2000;3:167‐176 Lecture Library Between 2000‐10 only two new classes of anbacterials have been introduced in clinical pracce

• Oxazolidinones (linezolid ) • Lipopepdes ()

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ESCMID Online Lecture Library Number of new classes of anbiocs which have reached the market, and predicons of novel classes of anbiocs which are needed during the next 100 years

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ESCMIDCoates ARM, et al. Br. J. Online LecturePharmacol Library. 2011;163(1):184‐194 Worldwide spread of CTX‐M ESBLs

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ESCMIDCantón R, Coque TM. Curr. Opin. Microbiol. 2006;9(5):466‐475 Online Lecture Library Geographic distribuon of KPC worldwide

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Nordmann P, et al. The Lancet Infecous Diseases. 2009;9(4):228‐236.ESCMID Online Lecture Library Newest anmicrobial agents on the market • Fidaxomicin • Cearoline fosamil •

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ESCMID Online Lecture Library Fidaxomicin

• Recently (27 May 2011) approved by the FDA (Dificid) • Use against C. difficile associated diarrhea • Novel anmicrobial class – Macrocyclic anbioc (18‐membered‐ring) – Inhibits RNA polymerase • Minor effect on disturbing normal gut flora© by author (anaerobic and Gram‐negave aerobic)

Louie TJ, et al. New England Journal of Medicine. 2011;364(5):422‐431 Tannock GW, et al. Microbiology (Reading, Engl.). 2010;156(Pt 11):3354‐3359ESCMID Online Lecture Library Fidaxomicin versus for C. difficile Infecon: Primary and Secondary End Points

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ESCMID Louie TJ, et al. NOnline Lecture. Engl. J. Med. 2011;364(5):422‐431 Library Cearoline fosamil

• An‐MRSA – 5th generaon (?) • Acve against ‐resistant S. pneumoniae

• Spectrum against Gram‐negaves similar to that of ceriaxone – Poor an‐pseudomonal acvity – Hydrolyzed by ESBLs • FDA approved (Telfaro) – Community acquired bacterial pneumonia© by author – Αcute bacterial skin and skin structure infecons

ESCMIDLaudano JB. J. AnmicrobOnline. Chemother Lecture. 2011;66( Librarysuppl 3):iii11 ‐iii18 Vidaillac C, et al . Anmicrob. Agents Chemother. 2009;53(6):2360‐2366 Telavancin • The first lipoglycopepde to be marketed • Inhibits synthesis and disrupts cell membrane permeability and integrity • Acvity against Gram‐posives (MRSA) – Not against VRE with VanA phenotype • FDA approved (Vibav) – Complicated skin and skin structure infecons • Phase III studies for community‐acquired pneumonia completed© by author • Nephrotoxicity is of concern – Potenally higher than standard‐dose vancomycin ESCMIDRubinstein E, et al. Online ClinLecture. Infect. Dis. 2011 Jan 1;52(1):31‐40 Library Pfaller MA, et al. J. Anmicrob. Chemother. 2010 Nov;65(11):2396‐2404 None of the recently approved agents solves the problem of MDR Gram‐negave pathogens • Carbapenemase‐producing Enterobacteriaceae • Acinetobacter baumannii •

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ESCMID Online Lecture Library

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ESCMIDFreire‐Moran, et al. Drug Resist. Online LectureUpdat Library. 2011;14(2):118‐124 Novel anbiocs in clinical development Already available classes Novel classes • New analogs that evade • Novel target/mode of known resistance acon mechanisms • Resistance less likely to develop • Less likely to make it to © by authorthe market – Greatest fear of potenal adverse events

ESCMIDCoates ARM, et al. Br. J. OnlinePharmacol Lecture. 2011;163(1):184‐194 Library Novel anbiocs for systemic use: new analogs from available classes

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ESCMID Online Lecture Library Novel : cefrobiprole medocaril • Similar profile with cearoline • Approved in Canada and Switzerland for complicated skin and so ssue infecons – Sale disconnued • FDA declined approval over concerns of integrity of clinical trial data © by author

ESCMIDEl Solh A. Expert OnlineOpin PharmacotherLecture. 2009;10(10):1675‐1686 Library Novel cephalosporins: CXA‐101

• Acvity against Pseudomonas aeruginosa with various mechanisms of resistance to β‐lactams • AmpC overproducing • Porin loss (OprD) • Overexpression of MexAB‐OprM efflux pumps • Modest acvity against Enterobacteriaceae producing ESBLs or AmpCs – potenates its acvity • Hydrolyzed by carbapenemases© by author • Undergoing phase II clinical trials alone or in combinaon with tazobactam Livermore DM, et al. J. Anmicrob. Chemother. 2010;65(9):1972‐1974 MoyaESCMID B, et al. Anmicrob Online. Agents LectureChemother . 2010;54(3):1213‐1217Library Novel : BAL30376 • Siderophore (BAL19764) – Stability against MBLs – Drug entry using natural microbial mechanisms • Bridged monobactam (BAL29880) – Inhibion of AmpCs • – Inhibion of class A (ESBLs) and some class D β‐lactamases • Acve against P. aeruginosa and Enterobacteriaceae producing MBLs, ESBLs, or AmpCs • Not acve against KPC enzymes© by author • Many P. aeruginosa clinical isolates from cysc fibrosis paents were resistant

Page MGP, et al. Anmicrob. Agents Chemother. 2011; 2011; 55(4):1510‐9 Livermore DM, et al. J. ESCMID OnlineAnmicrob Lecture. Chemother . 2010;65(11):2382‐2395Library Novel monobactams: BAL30072 • Monosulfactam with siderophore side chain • Very good in vitro acvity (beer than other β‐ lactams) against non‐fermenters: – ‐resistant A. baumannii • Mainly OXA‐23 and OXA‐25–producers, but also MBL‐ producers – B. cepacia complex isolates from CF paents – MDR P. aeruginosa, including MBL–producers • Beer acvity than © by author – Low MICs for S. maltophilia

Page MGP, et al. Anmicrob. Agents Chemother. 2010;54(6):2291‐2302 ESCMIDMushtaq S, et al. J. OnlineAnmicrob Lecture. Chemother Library. 2010;65(2):266‐270 Novel monobactams: BAL30072 (II)

• Acvity against Enterobacteriaceae: – Stability against MBLs – Slow hydrolysis by KPC‐2 – Variable hydrolysis by other class A, class C and class D enzymes • Currently in phase I clinical trials

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Page MGP, et al. ESCMIDAnmicrob Online. Agents LectureChemother . 2010;54(6):2291‐2302Library Suscepbility (% strain inhibited per concentraon) of 78 NDM‐1 harboring isolates

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ESCMIDWalsh Online TR, et al. 21 Lecturest ECCMID,.Milan Library, Italy. Poster #P1146 Novel Carbapenem Comments / Approved in Asia for lower respiratory tract infecons, UTIs, betamipron obstetrical/ gynecological and surgical infecons Acve against Enterobacteriaceae, but not P. aeruginosa Approved in Japan Broad acvity against Gram‐negaves (except P. aeruginosa) Acve against penicillin‐resistant S. pneumoniae Acvity against Gram‐negaves similar to Beer acvity than meropenem against MRSA Stable against ESBLs Affected by AmpC enzymes, carbapenemases Acvity against MRSA ME1036 Acvity against Enterobacteriaceae and © by author MRSA pivoxil Acve against Enterobacteriaceae, potenally Acinetobacter (oral) Inacve against P. aeruginosa Sugihara K, et al. Anmicrob. Agents Chemother. 2010;54(12):5298‐5302 Livermore DM, et al. J. ESCMID OnlineAnmicrob Lecture. Chemother. 2009 Aug;64(2):330‐335 Library Basse M, et al. Clin Invest. 2011;1:211‐227 Novel carbapenems (II)

• None represents a significant step forward in the “bale” against MDR Gram‐negaves

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ESCMID Online Lecture Library Novel aminoglycosides

• ACHN‐490 (neoglycoside) • Sisomicin analog

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ESCMID Online Lecture Library

ACHN‐490 structure and AMEs from Gram‐negave and© by author Gram‐posive (underlined) organisms AMEs shown with doed arrows cannot modify ACHN‐490 ESCMIDAggen JB, et al. AnmicrobOnline Agents LectureChemother Library. 2010;54:4636‐42 Novel aminoglycosides: ACHN‐40

• Can be a substrate of efflux pumps, such as MexXY in P. aeruginosa • Acvity diminished by low outer membrane permeability, such as in Proteus spp. • Inacve when 16S‐rRNA methylases are present (such as, ArmA, RmtB, RmtC) © by author

AggenESCMID JB, et al. Anmicrob Online Agents LectureChemother. 2010;54(11):4636‐4642 Library Acvity of ACHN‐490 against 202 randomly selected ICU isolates in Israel

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ESCMID Online LectureKotlovsky, et al. 21st ECCMID.P#1148 Library MIC distribuon of ACHN‐490 against 82 carbapenem‐resistant Enterobacteriaceae

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ESCMIDLivermore DM, et al. J. OnlineAnmicrob Lecture. Chemother Library. 2011;66(1):48‐53 Novel β‐lactamase inhibitors

• β‐Lactam structure • Non–β‐lactam structure – 6‐methylidene‐, – Novel class monobactam analogues, – NXL104 trinems, oxapenems, – ME1071 (maleic acid penicillin‐sulfone derivave) analogues • Acvity against MBLs – MK7655 • Inhibits class A (including © by authorKPC) and C enzymes • Combinaon with ESCMID OnlineBasse Lecture M, et al. Clin Invest. 2011;1:211‐227Library Novel β‐lactam inhibitors with a β‐ lactam structure: penems • 6‐methylidene‐penems – ‐1 – BLI‐498 • Inhibion of class A enzymes – Including KPC • Inhibion of class C enzymes • Inhibion of class D enzymes (OXA‐1)© by author

Weiss WJ, et al. Anmicrob. Agents Chemother. 2004;48(12):4589‐4596 EndimianiESCMID A, et al. Anmicrob Online. Agents LectureChemother . 2010;54(4):1650‐1651Library Novel β‐lactams without a β‐ lactam structure: NXL104 • Inhibits class A, C and D (OXA‐48) β‐lactamases – Including KPC carbapenemases • Acve in Enterobacteriaceae and non‐ fermenters – Not against A. baumannii producing OXA‐type carbapenemases (OXA‐23, ‐40, ‐51 and ‐58) • The combinaon of aztreonam plus NXL104 could be acve against most carbapenem‐hydrolyzing enzymes in Enterobacteriaceae© by author

Stachyra T, et al. J. Anmicrob. Chemother. 2009 Aug;64(2):326‐329 Livermore DM, et al. Anmicrob. Agents Chemother. 2011;55(1):390‐394. ESCMIDMushtaq S, et al. J. OnlineAnmicrob Lecture. Chemother. 2010;65(11):2376‐2381 Library Survival curves for mice treated with ceazidime (CAZ) with and without NXL104 in the murine sepcemia model due to KPC‐producing K. pneumoniae

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EndimianiESCMID A, et al. Antimicrob Online. Agents Lecture Chemother Library. 2011;55(1):82-85 Other novel anbiocs against MDR Gram‐negave pathogens • Novel tetracyclines – TP‐434 (fluorocycline) • Novel – CB‐182804 • Less nephrotoxicity than B in animals © by author

ESCMID OnlineBasse Lecture M, et al. Clin Invest. 2011;1:211‐227Library Novel anbiocs against MDR Gram‐ negaves (novel classes/targets) • bis‐Indole anbiocs – Interact with DNA • Leucyl–t‐RNA synthetase inhibitors – Boron containing anbiocs (GSK2251052, AN3365) • Novel 50S ribosome inhibitors – Idenficaon through crystal structure screening© by author

Basse M, et al. Clin Invest. 2011;1:211‐227 ESCMID OnlineButler MS, Cooper MA. J Lecture LibraryAnbiot . 2011 Novel anbiocs against MDR Gram‐ negaves (novel classes/targets) (II) • LpxC inhibitors (CHIR‐090) – LpxC: deacetylase involved in the biosynthesis of lipid A of LPS – Inacvaon of LpxC in A. baumannii linked to polymyxin resistance

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Mansoor UF, et al. Bioorg. Med. Chem. Le. 2011;21(4):1155‐1161 ESCMIDMoffa JH, et al. OnlineAnmicrob Agents LectureChemother Library. 2011;55(6):3022‐4 Novel anbiocs against MDR Gram‐ negaves (novel classes/targets) (III) • Anmicrobial pepdes – Innate immune system – Small pepdes (6‐100 aminoacids), almost all caonic, amphipathic molecules – Disrupt cell membrane forming pores – Broad spectrum of acvity • Defensin‐mimec (PMX‐30063): acvity against NDM‐1 K. pneumoniae© by author • Mastoparan: acvity against colisn‐resistant A. baumannii Peters BM, et al. PLoS Pathog. 2010;6(10):e1001067 ESCMIDVila‐Farres Online X, et al. Clinical Microbiology and Infecon. 2011 Lecture Library

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ESCMID Online Lecture Library

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ESCMID Online Lecture Library How to react now?

• Re‐evaluaon of available agents – Novel uses for old agents • Opmizaon of our therapeuc approach • Limit further resistance from emerging • Infecon control!

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ESCMID Online Lecture Library Is re‐evaluaon of older agents important? • 80 year‐old woman admied with severe sepsis due to urinary tract infecon – Cr 4.0 mg/dl – Hypotension reversed with fluids • Before 2 weeks, she was hospitalized for 5 days at a coronary care unit of another hospital • KPC K. pneumoniae in urine (and rectal swab) • Suscepble only to colisn, gecycline,© by author gentamicin, and trimethoprim/sulfamethoxazole (!) ESCMID Online Lecture Library

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ESCMID Online Lecture Library Opmal use of carbapenems for carbapenemase‐producing K. pneumoniae

Carbapenem monotherapy Carbapenem MIC, mg/l N Effecveness ≤4 32 69% 8 5 60% >8 7 29%

Lowest mortality for combinaon of a carbapenem plus another acve drug (carbapenem MICs were © by author ≤ 4 mg/L), rather than treatment with other drugs

DaikosESCMID GL, Markogiannakis Online A. Clinical Microbiology and Infecon. 2011 Lecture Library Prolonged infusion of 1 g and 2g against KPC K. pneumoniae infecon in immunocompromised mice

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Bulik CC, ESCMIDNicolau DP. Anmicrob Online. Agents LectureChemother. 2010;54(10):4112‐4115 Library Does dosing maer?

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ESCMID Online Lecture Library Appropriate dosing adjustments for: • Crically ill paents – Paents under connuous renal replacement therapy • Paents whose body size characteriscs deviate from average

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ESCMIDTrotman Online RL, et al. ClinLecture. Infect. Dis. 2005;41(8):1159 ‐1166 Library

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ESCMID Online Lecture Library Would you dose these two gentlemen the same?

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ESCMID Online Lecture Library High dose amikacin for severe sepsis due to pandrug resistant P. aeruginosa

Evoluon of C‐reacve protein and creanine levels in paent 1 and 2 during ICU stay © by author

LayeuxESCMID B, et al. Anmicrob Online. Agents LectureChemother. 2010;54(11):4939‐4941 Library Opmal dosing of colisn

• Retrospecve study of 258 paents who received colisn for microbiologically documented infecons • A. baumannii (65.9%), P. aeruginosa (26.4%), K. pneumoniae (7.0%) • Higher daily dosage of colisn independently associated with survival© by author • Nephrotoxicity in 10%

ESCMIDFalagas ME, et al. Int. J. OnlineAnmicrob Lecture. Agents. 2010;35(2):194‐199 Library

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ESCMID Online Lecture Library

• 41 paents with a colisn‐resistant Gram‐ negave pathogen • K. pneumoniae (33), © A. baumannii by author (6), P. aeruginosa (2)

ESCMID Online Lecture Library Adapve resistance to polymyxins, in P. aeruginosa, associated with acvaon of mexXY and downregulaon of oprD Resistance to aminoglycosides, fluoroquinolones, , and © by author imipenem

Muller C, et al. ESCMIDAnmicrob Online. Agents LectureChemother . 2011;55(3):1211‐1221Library Combinaon therapy

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ESCMID Online Lecture Library

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ESCMID Online Lecture Library Synergy of combinaons against 65 XDR K. pneumoniae clinical isolates (51 carbapenemase‐producers, 14 ESBL‐producers)

Anbioc in combinaon with Isolates exhibing synergy, n fosfomycin (%) Imipenem 49 (75.4) Colisn 19 (29.2) Nelmicin © by author27 (41.5) Tigecycline 18 (27.7)

ESCMID OnlineSamonis Lecture G, et al. 21st ECCMID. Poster #P 1175 Library Thank you for your aenon!

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