Newer antibiotics

NEWER ANTIBIOTICS

1. DR.K.KRISHNA LOHITHA DEPT. OF MAXILLOFACIAL SURGERY NEWER ANTIBIOTICS

2. Bacterial resistance to antimicrobials – health and economic problem Chronic resistant infections contributing to increasing health care cost Increase in mortality and morbidity with resistant microoraganisms WHY DO WE NEED NEWER ANTOIMICROBIALS

3. Three classes of drug resistant bacteria are a major cause of concern Methicillin resistant staphylococcous aureus Multi drug resistant and pan drug resistance Extensively drug resistant

4. Three classes of drug resistant bacteria are a major cause of concern Methicillin resistant staphylococcous aureus Multi drug resistant and pan drug resistance Extensively drug resistant

5. Organisms posing great danger have been clubbed together under the term “ESKAPE” E nterococcuus faecium S taphylococcus aureus K lebsiella pneumoniae A ctinobacter baumanii P seudomonas aeuroginosa E nterobacter species as these drugs have the ability to escape the ability of antimicrobial drugs

6. Emergence of bacterial resistance Resurgence and new infectious diseases INNOVATION GAP is the novel expression that has been used to describe the lack of novelstructural classes introduced to the antibacterial armamentarium since 1962

7. 10 BY ‘20 INITIATIVE Announced by the ANTIMICROBIAL AVAILABILITY TASK FORCE of the INFECTIOUS DISEASES SOCIETY of AMERICA in feb 2010 Stating “ our audacious but noble aim is the creation of a sustainable global antibacterial drug Research and Development enterprise with the ower in the short term to develop 10 new, safe and effective antibiotics by 2020

8. CEPHALOSPORINS ceftalozone 2014 superheros of gram - ve bacteria Ceftazidime 2015 Ceftaroline 2010 bacterial infections Ceftabiprole approval awaited BETA LACTUM ANTIBIOTICS Ceftaroline fifth generation cehalosporins Ceftabiprole

9. CEFTAROLINE : Developed from cefozopran (4 th gen) Anti MRSA activity FDA approval in october 2010 Indication: Acute bacterial skin and skin structure infections Community acquired bacterial pneumonia SPECTRUM: MRSA,VISA,VRSA,Gram – ve pathogens,inactive against extended spectrum b lactamase producing bacteria MOA: Acts by binding to PBP 1-4 High affinity for PBP2 in S. aureus for methicillin resistance Dose: 600mg IV 12 th hourly Side effects: nausea, dysgeusia , caramel like taste disturbances, vomiting, diarrhoea and headache

10. CEFTABIPROLE: Awaiting FDA approval, completed clinical trail in 2007 SPECTRM: MRSA, penicillin resistant S.pneumoniae , P.aeruginosa , enterococci MOA: Affinity for PBP2a of MRSA and PBP2x of s. pneumoniae Dose: 1hr IV infusion of 500mg every 12 hrs for gram+ve infection 2hr infusion of 5500mg every 8 hrs for gram – ve Side effects: well tolerated with nausea and dysgeusia

11. CARBAPENEMS IMIPENEM-CILASTIN AZTREONAM DORIPENEM 2007 gram+ve MEROPENAM CNS infections RELEBACTUM phase 3 imipenem resistant inf RAZUPENEM clinical trial

12. IMIPENEM-CILASTIN: INDICATION: Lower resp tract,urinary tract, intra abdominal, bone and joint, skin and skin structure, endocarditis , polymicrobic infections and septicemia SPECTRUM: Broad spectrum of activity against gram + ve cocci and gram- ve bacilli, including P. aeuroginosa and anaerobes Cautions: b lactum safety profile(rash, esinophilia ), nausea, seizures Cilastin possess no antibacterial activity, reduces renal imipenem metabolism. Primarly renally eliminated Drug interaction:possibly ganciclovir

13. DORIPENEM: INDICATIONS: Complicated UTI infections Intra abdominal infections MOA: High binding affinity to PBP 2 AND 3 may enhance its activity against drug resistant P.aeuroginosa SPECTRUM: Unique spectrum of activity Activity against gram+ve cocci like imipenem Against gram – ve cocci like meropenem It is stable to ESBLs by E.coli & klebsiella spc . And to AmpC b lactamase enzymes; but vulnerable to acquired b lactamases like class B metallo b lactamases by someP . Aeuroginosa and carbapenems bysome Enterobacteriacea and actinobacter sps DOSE: 500mg IV 8 th hourly Sideeffects : headache, rash,diarrhoea , phlebitis Stevenjohnson syn,toxic epidermal necrolysis , interstitial pneumonia, seizures

14. MEROPENEM : similar to imipenem Preferred carbapenem for treatment of CNS infections CAUTION: b lactum safety profile, 80% renal elimination Drug interaction:probenecid AZTREONAM: Monobactum antibiotic SPECTRUM: Gram – ve aerobic bacteria , Enterobacteriaceaand P. aeuroginosa Useful in penicillin and cephalosporin allergies as no sensitivity and cross reactivity occurs SIDE EFFECTS: rash, thrombophlebitis , esnophilia , Drug interaction:probenecid

15. VANCOMYIN ORITAVANCIN phase III gram + ve DALBAVANCIN phase III gram + ve TEICOPLANIN in clinical use TELAVANCIN 2009 gram + ve GLYCOPEPTIDES

16. VANCOMYCIN: Acts on MRSA Similar MOA of b lactams Resistance : genetic mutation changing the target protein VRE causes nosocomial infections Emergence of VRSA Parenteral route Adverse effects: rashes, thrombophlebitis,ototoxicity , nephrotoxicity Redman or redneck syndrome: maculopapular rash over head, neck and back with fever and chills

17. TELEVANCIN: Derivative of vancomycin toxic to gram + ve bacteria MOA: inhibits celwall synthesis and also damages cell membrane and increases its permiability Dose: once daily , vibantin : 250/750 mg IV TEICOPLANIN: Actinoplanes teichomyceticus INDICATIONS: osteomylitis and endocarditis dur to MRSA and enterococci DOSE: IM 200-400mg/day Relatively least toxic

18. DAPTOMYCIN : Obtained from streptomyces roseosporus FDA approval in 2003 for SSTIs and 2006 for blood stream infections Indicated for complicated SSTIs alternative to vancomycin MOA: binds to bacterial membrane and cause rapid depolarization leads to inhibition of protein, RNA, DNA SPECTRUM:MRSA, MRS epidemidis ,VRE strains Bactericidal It is synergistic with gentamicin ADVERSE EFFECTS: myopathy Life threatening esinophilic pneumonia LIPOPEPTIDES

19. LINEZOLID clinical use RADEZOLID phase II TOREZOLID phase II SPECTRUM:Gram + ve including MRSA and Stretococcus pneumoniae Mycobacterium tb and nocardia OXAZOLIDINONES

20. LINEZOLID: bacteriostatic INDICATIONS: VRE infections Nosocomial and community acquired pneumonia SSTIs MOA: inhibits protein synthesis on binding to 50s ribosomes Resistance:mutations in the peptidyl transferase center of the r RNA Dose: good oral bioavailability oral/IV 600mg BD ADVERSE EFFECTS: Nausea,diarrhoea , dizziness Prolonged use of >2weeks causes mylespression with thrombocytopenia(reversible), peripheral neuropathy and lactic acidosis Torezolid : 4-16 fold greater potency than linezolid

21. QUINPRISTIN AND DALFOPRISTIN Obtained from streptomyces pristinaespiralis A combination in ratio of 30:70 is bactericidal against gram + ve cocci including MRSA,VISA, VRE MAO:inhibits protein synthesis by binding to 50s ribosomes IND: serious infection wwith VISA, VRE MRSA when vancomycin is not tolerated DOSE: IV, not efffective orally ADVERSE EFFECTS: arthralgia , myalgia,nausea , vomiting, diarrhoea , pain at injection site STREPTOGRAMINS

22. Newer class of macrolides designed particularly for respiratory tract pathogens that have acquired resistance to macrolide antibiotics Ketolides are semi synthetic derivatives of 14 membered macrolide , erythromycin TELITHROMYCIN CETHROMYCIN phase III SOLITHROMYCIN phase III KETOLIDES

23. TELITHROMYCIN : First ketolide to entrer clinical use for the treatment of CAP, chronic bronchitis,acute sinusitis MOA: protein synthesis inhibitor acts by binding to 50s ribosome 10 times higher affinity tp 50s than erythromycin SPECTRUM: S. pneumoniae , macrolide resistant strains( S.pyogenes ) Well tolerated orally400mg tablet Acheives high tissue concentrations in respiratory fluids and tissuues including saliva, alveolar macrohages , epithelial lining fluid, bronchial mucosa Drug is cleared by hepatic metabolism Adverse effects: hepatotoxicity,myaesthenia gravis exacerbation, visual disturbances

24. Newer class of antibiotics that are chemical derivatives of minocycline TIGECYCLINE FDA approval 2005 SPECTRUM:aerobic and anarobic Gram+ve and – ve organisms INDICATIONS: cSSTIs , intra abdominal infections, CAP It is designed to overcome 2 common mechanisms of tetracycline resistance ; Resistance mediated by acquired efflux pumps and by ribosomal protection MOA: inhibition of protein synthesis by binding to 30s ribosomes 20 fold more efficient than tetracycline DOSE: Parenteral use Loading dose: 100mg; maintenance dose: 50mg 12 th hourly Side effects: mild GIT disturbances, diarrhoea , vomiting GLYCYLCYCLINES

25. FINOFLOXACIN phase2 GEMIFLOXACIN,BESIFLOXACIN DELAFLOXACIN phase 3 TROVAFLOXACIN 4 th gen quinolone AVOROFLOXACIN , NEMONAXACIN Newer fluoroquinolones have anti pseudomonal activityand additional anti MRSAactivity The activity of nemonoxacin against gram + ve bacteria(including MRSA and MDR streptococcus pneumoniae ) is better than ciprofloxacin, levofloxacin , moxifloxacin GATIFLOXACIN: It is a fourth generation fluro-quinolone agent. Greater affinity for topoisomerase IV. Active against gram + ve cocci . Oral and intravenous route. Dose – 200 to 400 mg orally or i.v . once daily (+½ shown) Active against – Streptococcus pneumonias. Chlamydia pneumonias. banned due to severe hyperglycemia FLORQUINOLONES

26. GEMIFLOXACIN: Oral quinolones approved in 2003 for treatment of acte bacterial exacerbation of chronic bronchitis , CAP SPECTRUM: enhanced activity on gram + ve bacteria(strep, staph) and atypical pathogens( chlamydia , mycoplasma,legionella ) but less against pseudomonas .poor activity on methicillin resistant strains Anaerobic activity + High affinity for DNA gyrase and topoisomerase IV Good activity aghainst fluorquinolone resistant H.influenza Oral administration Respiratory tract infections BESIFLOXACIN : opthalmic ointment DELAFLOXACIN : Aproved by FDA for adult lts with bacterial skin and skin structure infection caused by susceptible organisms Withdrawn due to risk of hepatotoxicity

27. PLAZOMICIN : phase 3 trail Refered as next gen aminoglycoside MOA: inhibition of protein synthesis SPECTRUM: gram+ve and gram- ve Synergism : Plazomicin+cefepime / imipenem / doripenem / piperacillin tazobactum = P. aeuroginosa Plazomicin + daptomycin / ceftobiprole = MRSA, VISA,VRSA Superiority to colistin for bloodstream infections or nosocomial pneumonia AMINOGLYCOSIDES

28. ERAVACYCLINE phase 3 Tetracycline compound modiffied at c-7 and c-9 positions SPECTRUM: MDR gram+ve,gram – ve,anaerobic infections The drgs activity is not hindered by effluxpmps and ribosomal protection mechanism of drug resistance Being evaluated for oral formulation ffor ease pf IV to oral transition OMADACYCLINE phase 3 SPECTRUM: MRSA, b hemolytic streptococci,penicillin resistant s.pneumonia , H.infleunza , legionella Acute bacterial SSTIs It works against those bacteria that are resistant to other tetracyclines , mrthicillin , vancomycin,erythromycin , ciprofloxacin TETRACYCLINES

29. FIDAXOMICIN First drug in this class of antibiotics wit narrow spectrum of activity MOA: inhibition of bacterial enzzyme DNA polymerase SPECTRUM: active against CDI, limited activity on intestinal flora It is alternative to crrently used treatment regimens of vancomycin and metrinidazole against CDI In phase 3 trail,fidaxomicin 200mg (twice a day) was fond to be non inferior to vancomycin 125mg( 4 times a day) for the treatment of first recurrence of CDI Oral, 200mg twice daily MACROCYCLIC ANTIBIOTICS

30. Polymixin and cilastin Given topically,too toxic to be given systematically Polymixin - Bacills polymyxa Cilastin - Bacillus colistinus MOA:alter permeability of cell membrane The global roblem of advancing antimicrobial resistance led to renewed interest in its use USES: Topically for skin, ear and eye infections Oral colisytin in children for diarrhoea POLYPEPTIDE ANTIBIOTICS

31. Targeting virulence factors Targeting bactericidal functions of bacterial proteins Modulating host response pathways Peptides derived from vertebrates, invertebrates and microorganism NEWER TARGETS FOR NEXT GENERATION OF ANTI MICROBIAL DRUGS

32. 1.targeting virulence factorseg . Inhibition of bacterial adhesion Inhibition of toxin production Inhibition of toxin delivery Inhibition of virulence regulators 2. targeting bactericidal functions of bacterial proteins: Eg . Targeting enzymes like B- ketoacyl - acyl -carrier-protein synthase I/II Required for fattyacid biosynthesis in bacteria DRUGS IN PIPELINE: platensimysin - preclinical trails in an effort to combat MRSA in a mouse model

33. 3. modulating host response pathways : toll like receptor activators and modulators cold potentially have an antimicrobial role byy producing antimicrobial peptides that activates the adaptive immune response to combat the infection 4.antimicrobial peptides derived from vertebrates, invertebrates and microorganisms: Novel potential therapeutic target They act by interfering with metabolism, targeting cytoplasmiccomponents and disrpting cell membranes They may enhance immunity by functioning as immunomodulators Eg : dermaseptin - from dog skin defensin & crustin - crustacean DRUGS in pipeline: omiganan clinical trails pexiganan

34. 5. combination of antibiotics with bioenhancers A bioenhancer is an agent capable of enhancing the bio availability and efficacy of a drug with which it is co administered, without any pharmacological activity of its own at the therapeutic dose Bioenhancers can be used to increase the efficacy of commonly used antibiotics, combining antibiotictetracycline with non antibiotic drug loperamide Cow Urine Distillate(CUD) can act asa potential therapeutic target to enhance activity of antibacterial agents CUD+ rifampicin , increased the activity by about 5-7 times against E.coli and 3-11 timesagainst gram+ve bacteria

35. 6. newer strategies or antibacterial drug delivery 7. engineer a prodrug that gets converted into highly potent drug within a microbe Engineer hybrid antibacterial drugs for high potency against two targets Alternative form of drug delivery methods Herbal derivatives as lead molecles

36. There is a great need for newer antimicrobials becase of increasing microbial resistance Because of increase in cost off development and increasing resistance, only few drugs are in pipeline The post marketal survelliance off the newer drugs in clinical trails is must, asrare adverse effects go un noticed during trails due to selected and limited number of patients Some of the newer agents are effective against resistant strains Programs like antibiotic stewardship can be helpful to combat the resistance Rational use of anytibiotics remains the most important measure CONCLUSIONS

37. Pharmacology and pharmacotherapeutics : R.S.SATOSKAR PADMAJA UDAYKUMAR: pharmacology for dental and allied health sciences GOODMAN AND GILMAN: the pharmacological basics of the therapeutics; 9 th edition Insights into newer antimicrobial agents against gram negative bacteria: neelima taneja and harsimran kaur ; microbiology insights 2016:9 Recent advances in antibacterial drugs; international journal of applied and basic medical research;jan-jun 2013 Mechanism of use of newer antibiotics for gram positive pathogens: http:inffection.thelanet.com vol 5 april 2005 Ten new antibiotics in the pipeline for resistant infections: medscape REFERENCES