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![Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide
variety of penicillins and cephalosporins
Class A -
• penicillinases
• ESBL
• Carbapenemases
Class C –
Amp C enzymes – not inhibited by clavulanic acid
Class D –
Oxacillinases, some are carbapenemases
Class B –
Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by
clavulanic acid](https://image.slidesharecdn.com/emergingantibioticsintheicu-170130124509/75/Emerging-antibiotics-in-the-ICU-19-2048.jpg)
Uploaded byDr.Mahmoud Abbas
Emerging antibiotics in the ICU
This document discusses the increasing problem of antibiotic resistance and potential solutions. It notes the emergence of extensively drug-resistant pathogens and classifications of drug resistance. Potential solutions discussed include developing new antibiotics that target resistant bacteria, rediscovering older antibiotics, and using beta-lactamase inhibitors to enhance existing antibiotics. Several new antibiotics are summarized, including their mechanisms of action, clinical indications, and stages of clinical trials.
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Emerging antibiotics in the ICU
- 1. Emerging Antibiotic in ICU Ahmedelmenshawy MD Alexandria University
- 2. Disclosure • No Conflictof interest
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- 5. Classification of Drugresistance • XDR+ • Polymixin Pan PDR • MDR+ carbapenem Extensive XDR • Cephalosporins • B-lactam/B- lactamases inhibitor • Aminoglycosides • Fluroquinolones Multi MDR At least 3
- 6. ESKAPE pathogens • Enterococcusfaecium ….VRE • Staphylococcus aureus ..MRSA, VISA,VRSA • Klebsiella pneumoniae • Acinetobacter baumanii • Pseudomonas aeruginosa, • Enterobacteriaceae Gram Negative ESBL, carbepamase Gram Positive
- 7. Acientobacter resistance to antibiotics Journalof thoracic disease
- 8. Staphylococcus auresus sensitivity toVancomycin 100 100 90 100 100 100 100 100 100 84 86 88 90 92 94 96 98 100 102 2008 2009 2010 2011 2012 2013 2014 2015 2016 Vancomycin Alexandria Critical Care Department
- 9. Klebsiella pneumonia sensitivityto carbapenem 100 100 100 84.6 71.8 52.1 63 61.5 59 58 45 50 97.4 89.5 62.1 73.6 73 71.1 73 50 86 0 20 40 60 80 100 120 0 20 40 60 80 100 120 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Meropenem Impinem Alexandria Critical Care Department
- 10. Pseudomonas aeruginosa sensitivity tocarbapenems 42 32.5 41.3 47.6 30.6 45 51 53 35 49 38.8 40.8 48.1 24.9 28.5 41 57 31 0 10 20 30 40 50 60 2008 2009 2010 2011 2012 2013 2014 2015 2016 Meropenem Impinem Alexandria Critical Care Department
- 11. Acinetobacter baumanii sensitivity tocarbanems 22.1 17.6 14.1 3.8 8.4 6.5 29 9 8.3 39.6 34.5 16.7 11.8 13.6 22 29 9 6 0 5 10 15 20 25 30 35 40 45 2008 2009 2010 2011 2012 2013 2014 2015 2016 Meropenem Impinem Alexandria Critical Care Department
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- 13. New antibiotic 2009 Infectiousdisease Society of America launched 10x20 initiatives 10 new antibiotics by year 2020 Rediscover old antibiotic Polymoxin B chloramphenicol Pharmacoknitics Increasing dosage Prolonged infusion
- 14. •Ceftobiprole •Ceftaroline, Cephalsporin •Ceftozolane/tazobactam •Ceftazidim/Avibactam B-lactamase inhibitors •doripenem, biapenem,Tomopenem •razupenem, Panipenem TebipenemCarbapenem •telavancin, oritavancin Dalbavancin Glycopeptides •Tedizolid •Radezolid Oxazolidinones •Gatifloxacin Delafloxacin Nemonoxacin •Zabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones: •Eravacycline •Omadacycline Tetracyclines: •Plazomicin Aminoglycosides:
- 15. 5th Cephalosporins 1. Ceftobiprolemedocaril 2. Ceftaroline fosamil
- 16. Ceftobiprole medocaril • Betterthan other cephalosporins aganist: 1. MRSA, VISA, VRSA, macrolide-resistant S. pyogenes • bind to PBP2a, protein conferring ORSA resistance to b-lactam 2. Penicillin-resistant S. pneumoniae • bind PBP2x in. 3. Enterococci (fecalis not feacium) 4. Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime) 5. Pseudomonas species superior to cefepime • Trials: (phase 3) 1. Complicated skin and soft tissue infection “cSSSI“ (MRSA) 2. CAP and HAP (not VAP) Bassetti, M. Springer 2015
- 17. Ceftaroline fosamil • Similarto Ceftobiprole: 1. MRSA, heteroresistant VISA, VRSA (PBP2a inhibition ) 2. No Enterococci 3. less activity against gram-ve (as ceftriaxone) • Not ESBL-producing Enterobacteriaceae, • Not Pseudomonas aeruginosa, • Not Acinetobacter baumanii, • Not Bacteroides fragilis • FDA (2010) and European Medical Agency (EMA) (2012) for 1. SSSIs including MRSA 2. CAP including MDR S pneumonia Bassetti, M. Springer 2015
- 18. B-lactam &B- lactamase inhibitor 1.Tazobactam: Ceftozolane/tazobactam 2. Avibactam: Ceftazidime/avibactam 3. MK-7655
- 19. Target for beta- lactamaseenzymes B- lactamases bacterial enzymes able to hydrolyse a wide variety of penicillins and cephalosporins Class A - • penicillinases • ESBL • Carbapenemases Class C – Amp C enzymes – not inhibited by clavulanic acid Class D – Oxacillinases, some are carbapenemases Class B – Metallo betalactamases [MBL] -inhibited by metal ion chelators inhibited by clavulanic acid
- 20. Ceftozolane/tazobactam • Superior toceftazidime in: 1. Greater gram –ve coverage • Most ESBL producing enterobactracae • Bacteroides spp 2. Unique anti-Psuedomonal • superior to ceftazidime, carbapenem, piperacillin/tazobactam • ability to escape various resistance mechanisms (e.g., PBP mutations, efflux pumps) • Not to carbapemenases or metallo-B-lactamases (MBL) • Trial: (Phase 3) 1. Complicated intrabdominal infections (as meropenem) cIAI 2. Complicated UTI (superior to levofloxacin) “cUTI” 3. Ongoing for HAP/VAP Zhanel,GG. Springer 2013
- 21. New B-lactamases inhibitors •Avibactam • beta-lactamase inhibitor characterized by • high affinity with class A and C and some D B-lactamases • potential to inhibit ESBLs, KPCs, OXA, and AmpC • Combinations 1. with ceftazidime (Phase 3) 2. with ceftaroline (Phase 1) 3. With aztreonam (phase 1) • MK-7655 another novel beta-lactamase inhibitor under investigation • activity against class A and class C carbapenemases • Ongoing phase 2 trials for cIAIs and cUTIs (with imipenem/cilastatin) • BLI-489 inhibit Class A,C,D lactamases (with piperacillin)
- 22. Ceftazidime/avibactam • Active against: 1.ESBL 2. AmpC strains 3. OXA-48, and Klebsiella carbamases (KPC) 4. MDR psuedomonas • not metallo-beta-lactamase, not likely Acinetobacter • Trials: 1. Phase 3 in cIAIs, cUTIs, HAP, and VAP. 2. cIAIs (as to meropenem) in combination with metronidazole Sharma R, Clin Ther 2016
- 23. Carbapenem S aureus MRSAStrep Entero GNR Anaerobe Pseud/Acinet Impinem ++++ - +++ Fecalis +++ ++++ ++ Meropenem ++++ - ++ Fecalis +++ ++++ +++ Doripenem +++ - +++ Fecalis +++ ++++ ++++ Biapenem +++ - +++ - +++ ++++ ++ tomopenem +++ ++ ++++ ++ ++ ++ razupenem +++ ++ ++++ fecium ++ ++ ++ Panpenem ++++ - ++ Fecalis ++++ ++++ +++ Ertapenem +++ - ++++ Fecalis ++++ ++++ - tebipenem +++ - ++++ Fecalis ++++ ++++ - Sulopenem +++ - +++ +++ ++++ - Bassetti, M. Springer 2015
- 24. Clinical indications Carbapenem Clinicalindications Meropenem/impinem HAP, cUTIs, cIAIs, and BSI FDA Doripenem 0.5 G/8 hr pyelonephritis, cUTI, and cIAI, HAP,VAP FDA, EMA doripenem + colisitin colistin-resistant, carbapenemase producing K. pneumoniae (KPC) RCT Tebipenem/pivoxil (oral) Sulopenem (oral) Upper resp tract infection still undergoing trials Jaban 3rd phase Panipenem/betamipron 0.5g/12 hr UTIs, lower RTI, obstetrical/gynaecological, and surgical infections. FDA China, Korea Japan Biapenem 0.3g/12 hr RTIs and UTIs RCT Tomopenem cSSSI and HAP. RCT Razupenem cSSSI RCT Bassetti, M. Springer 2015
- 25. Glycopeptide Dosing Tissue penetration Renal toxicity MRSA VISAVRE MDR S Pne CoNS vancomycin 8-12 h + +++ ++ - - ++ ++ teicoplanin 24 hr ++ - ++ +/- - ++ ++ telavancin 24 hr ++++ ++++ ++++ ++ Van- A +++ +++ oritavancin 1 dose ++++ - ++++ +++ Van- A/B ++++ ++++ dalbavancin q 1W ++++ - ++++ +++ Van- A ++++ ++++ Devasahayam G, Expert Opin Investig Drugs. 2010
- 26. Clinical indications • *Telavancinhas good penetration in the alveolar macrophages, and unlike daptomycin, its activity is not affected by pulmonary surfactant Telavancin cSSSI FDA MRSA HAP and VAP* EMA S. aureus bacteremia 3rd phase trial oritavancin SSSIs due to MSSA, MRSA, Strep & E. faecalis. FDA dalbavancin SSSI, including those caused by MRSA. Catheter- related BSI FDA Phase 2 trial Devasahayam G, Expert Opin Investig Drugs. 2010
- 27. Oxazolidinones Tedizolid • oral andIV • superior than linezolid 1. Staphylococcus spp., 2. Streptococcus spp., 3. Enterococcus spp. 4. Anaerobes • once daily • Better safety profile. • No hematological Side effects • does not inhibit the monoamine oxidase pathway • FDA approved for SSSI Radezolid • higher efficacy than linezolid 1. S. pneumoniae , S. pyogenes. 2. Staphylococci 3. Enterococci 4. GNR: H. influenzae & Moraxella catarrhalis (commonly in CAP) • Phase 2 trial: uncomplicated SSSI, CAP
- 28. Quinolones Gram+ve MRSA Gram-vePsued Acine VRE norfloxacin, ciprofloxacin ofloxacin ++ - ++ +++ - - moxifloxacin ++ - ++ + - gatifloxacin ++ ++ +++ - *Delafloxacin ++++ ++++ +++ + - *Nemonoxacin ++++ ++++ +++ + ++ *Zabofloxacin ++++ ++++ +++ + *Finafloxacin +++ ++++ + *JNJ-Q2 ++++ ++++ +++ - - _ *WCK771 ++++ ++++ ++ - - - ozenoxacin ++++ ++++ ++ - - - besifloxacin +++ ++++ ++ - - ++ *Low potential for development of resistance due to multiple mechanisms of action
- 29. Clinical indications Quinolones RTIs,UTIs, SSSI, and IAIs FDA moxifloxacin gatifloxacin CAP and HAP FDA, EMA Delafloxacin CAP (oral/iv) and HAP SSSI 3rd phase trial Nemonoxacin CAP (oral/iv) 3rd phase trial Zabofloxacin CAP 2nd phase trial Finafloxacin cUTI and acute pyelonephritis 2nd phase trial JNJ-Q2 SSSI CAP 2nd phase trial underway ozenoxacin cSSSI RCT besifloxacin Bacterial conjuctivitis RCT
- 30. Plazomicin • new aminoglycosideagainst both gram-positive and gram negative pathogens 1. In combination • against MRSA and VISA with daptomycin / ceftobiprole • against P. aeruginosa with doripenem/ imipenem/ piperacillin/tazobactam, cefepime 2. cUTI and acute pielonephritis • Phase 2 study (As to levofloxacin) 3. BSI or HAI due to carbapenem-resistant Enterobacteriaceae • Phase 3 clinical trial for (as to colistin) with a tigecycline or meropenem
- 31. Glycylcyclines (new Tetracyclines) Eravacycline •Broad-spectrum gram- positive and gram-negative against 1. MRSA, VRE, 2. Enterobacteriaceae (ESBL or carbapenemases) more than tigecycline 3. Not P. aeruginosa • Phase 3 clinical trials for cIAIs and cUTIs Omadacycline • Active against both gram positive and gram-negative bacteria. 1. MRSA, VRE, S. pneumonia, 2. Enterobacteriaceae & Bacteroides fragilis • Phase 2 study in SSSI
- 32. Other classes • Macrolides: 1.Telithromycin: • FDA approval for chronic bronchitis exacerbation and sinusitis was withdrawn in 2006 2. Cethromycin: • very potent against macrolide-resistant strep and enterococci • More potent against S. aureus,epidermidis, H pylori, M avium, Corynebacterium spp., M. pneumoniae, C trachomatis and pneumoniae, Borrelia burgdorferi, H. influenzae, M. catarrhalis, and Toxoplasma gondii • Phase 2 trial for mild to moderate CAP • Trimethoprim: Iclaprim: • MRSA, VISA, MDR S pneumonia • GNB: Enterobacter, Salmonella, L. pneumophila, H. influenzae, C. pneumoniae • Phase 3 trial for cSSSI
- 33. Other classes • NXL103: •mixture of modified quinupristin/dalfopristin &streptogramin • More effective against gram positive than other antibiotics (MRSA, VRSA, VRE, S pnuemonia, H influenza • Oral formulation • Nitazoxanide : (Nidazode®) • broad spectrum activity against anaerobic bacteria and against anaerobic intestinal parasites • FDA approved for Giardia intestinalis and Cryptosporidium parvum in adults and children • off-label use for Clostridium difficile (equivalent to vancomycin and metronidazole)
- 34. Conclusions Only 7 newantibiotics has been approved by US FDA
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- 37. Take home message •Still limited therapeutic options for • Carbapenemase producing Enterobacteriaceae, • XDR A. baumannii, and P. aeruginosa • No good evidence but may be • ceftozolane/tazobactam, • new carbapenems, • combination of avibactam with B-lactam • New tetracylines • plazomicin in combination • Most of newly developed antibiotic target gram positive which glycopeptides and oxazolidinones are highly efficient against MRSA
- 38. Proper usage ofantibiotics
- 39. Phases of antibioticdevelopment
- 40. Antibiotic Abuse inOur units 2013 57.0% 43.0% Antibiotic Abuse in ICU1 No Yes 60.7 % 39.3 % Antibiotic Abuse in ICU3 Alexandria Critical Care Department
- 41. Types of antibioticabuse 2013 27.5% 4.5% 11.4% 0.6% 3.9% 2.2% 5.1% 70% 11.40% 30% 1.40% 10% 5.70% 12.90% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% No clear indication Early change Usage of same class Usage of 2 b-lactam Prolonged duration Redundant Unlikely coverage… ICU1 ICU3 Alexandria Critical Care Department
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