Antibiotic Update 2009

1. Antibiotic Update2009 Michael S. Bronze, MD Professor and Chair Department of Medicine, OUHSC

2. Objectives • To briefly review some of the current issues with antibiotics • To discuss several newer agents • To discuss several clinical situations in which newer agents may have an expanding role • I have no conflicts of interest to report!

3. Challenges in Antibiotic Design Drug No. Rx Worldwide World-wide Sales (Rx; 000s) (USD; 000s) Amox/clav 136,000 1,971,927 Cipro 80,217 877,718 Clarithro 74,689 1,495,006 Azithro 66,061 2,002,082 Levo 41,484 1,555,325 Cefuroxime 15,552 343,177 Coates and Hu, Drug RD, 2006

4. Challenges in Antibiotic Design • “Hospital surveys indicate that: • 1:3 patients receive at least one anti-infective during their hospital stay • Nearly 25% of all adverse drug reactions are due to anti-infective drugs” Stein, GE. Clin Infect Dis, 2005

5. Challenges in Antibiotic Design • Despite large sales volumes and dollars, many companies have withdrawn from development of new antibiotics. Reasons include • Not considered profitable enough • Fear of liability and litigation • Growing world-wide antibiotic resistance • MRSA, glycopeptide resistant SA (GISA, GRSA) • ESBL-producing GNR (Klebsiella, E. coli) • Acinetobacter, Pseudomonas • VRE • Coates and Hu, Drug RD, 2006

6. Challenges in Antibiotic Design:Newer Drugs Class Agent Phase Indications Lipopeptide daptomycin marketed cSSSI Oxazolidinone linezolid marketed RTI, cSSSI, VRE,BSI Glycopeptides televancin phase 3 cSSSI, HAP Glycylcycline tigecycline marketed cSSSI, CAP, HAP VRE, UTI Carbapenem doripenem phase 3 HAP, VAP, UTI Cephalosporin ceftibiprole, phase 3 CAP, cSSSI ceftaroline invest cSSSI

7. Ceftobiprole • Novel cephalosporin, bactericidal • Acts thru PBP2A’(2a) • Stable against Class A non-ESBL and inducible Class C β-lactamases, bactericidal • Active against • Gram Positives- MSSA, MRSA, E. faecalis, PSRP, VRE • Gram Negative Rods-comparable to cefepime, ceftaz, pip/tazo (including P. aeruginosa, Acinetobacter baumannii) • Anaerobes- modest coverage • Efficacy in animal models for IE, pneumonia, osteomyelitis • FDA approved for cSSSI Jones ME. Clin Microbiol Infect , 2007 Anderson and Gums, Ann Pharmacother, 2008

8. Ceftobiprole • Phase III Experience • On Going: • Hospital Acquired Pneumonia • Febrile Neutropenia • SA Bacteremia • Adverse Reactions • Nausea, headache, dysgeusia (caramel taste) • ? Potential drug interaction with warfarin • Dosing • cSSSI0 500 mg q 8 hr iv or q 12 hr Anderson and Gums, Ann Pharmacother, 2008

9. Ceftaroline • Broad spectrum cephalosporin, largely bacteriostatic • Works thru PBP 2a---- covers MRSA • Renal excretion • Spectrum • GM Positives: MSSA, MRSA, MDR-SP, Streptococci, E. faecalis • GM Negatives: Enterobacteriaceae, Acinetobacter • Not: E. faecium, Pseudomonas, ESBL + GM negatives • Clinical trial • Not inferior to Vanc/Aztreonam in cSSSI Zhanel et al. Drugs, 69:809, 2009

10. Daptomycin (CUBICIN) • Class- cyclic lipopeptide • Derived from Streptomyces roseosporus • Active against Gram positive bacteria • MSSA, MRSA ( rapidly bactericidal) • VRE, β hemolytic streptococci • Some anaerobes (peptostreptococci, Clostridia) • Approved- • cSSTI (4mg/kg/day IV) • SA bacteremia, CRI (6mg/kg/day iv) Hair and Keam, Drugs, 2007 Steenberger et al, JAC, 2005

11. Daptomycin (Cubicin) • Mechanism of Action- • Causes cell death by binding to cell membrane leading to membrane depolarization, K+ efflux and then impairing K+ dependent macromolecule synthesis • Resistance • Not fully delineated • Not thought due to transferable genetic element • Innate non-susceptibility of US S. aureus strains is ~0.7% • Reduced susceptibility has been observed with VISA/GISA strains

12. Daptomycin (Cubicin) Organism Drug Associated MIC 90 Dapto Vanco Linezolid E. faecalis VSE 1-2 2 2 VRE 1-2 64 1-2 S. aureus MSSA 0.25-1 0.5-1.0 2-4 MRSA 0.25-1 0.5-3 1-4 Hair and Keam, 2007

13. Daptomycin (Cubicin) • Pharmacodynamics • Concentration dependent killing, correlated to the AUC:MIC • Metabolism/elimination • No liver metabolism or by CY P450 • Renal excretion • Drug interactions- no significant reactions • Tolerability • Nausea in 6-10% • Constipation- 6-12% • Headache-6-8% • CPK elevation- 1.4-25% (esp. with 6 mg/kg/d)

14. Daptomycin (Cubicin) % Clinical Success cSSSI Bacteremia (SA) Comparator drug 71.1 60 Daptomycin 71.5 79 Hair and Keam, 2007

15. Daptomycin (Cubicin) Clinical Success in cSSSI Percent Clinical Efficacy Daptomycin Comparator Organism MSSA 86 87 MRSA 75 69 Grp A strep 94 91 Grp B strep 85 76 E. faecalis 73 76 Rybak, MJ. Clin Microbiol Infect, 2006

16. Lipoglycopeptides • Investigational, semi-synthetic vancomycin-like agents • Two major compounds being studied, televancin and dalbavancin • Each are cell wall active via the terminal D-ALA-D-ALA binding site • Bactericidal against gram positives including some anaerobes • Promising alternative to vancomycin Attwood and LaPlante, Am J Health Sys Pharm, 2007

17. Televancin • Spectrum of Activity • Comparable to vancomycin, linezolid and daptomycin • Active against MRSE, VISA, VRSA PRSP, VRE (faecalis and faecium) • Resistance– not well worked out • In-vivo efficacy in animal models: • MRSA bacteremia (including in neutropenia) • SA infective endocarditis • Meningitis (MSSA, PRSP) • Pneumonia (MRSA) Attwood and Laplante, 2007

18. Televancin • Synergy—not fully defined • Tolerability • Nausea, vomiting, metallic taste, headache • Prolonged QTc • Follow serum creatinine, platelet count • Pharmacodynamics • Highly protein bound, bactericidal • 70-80% renal excretion– dose reduce if CrCl <50 • Concentration dependent killing (AUC:MIC) • Recommended dose 10 mg/kg/IV/day • Human data • cSSTI- 7.5 mg/kg/d/IV; comparable to vancomycin

19. Dalbavancin • General • 2nd generation lipoglycopeptide • Teicoplanin analogue but more potent • Very long half life allows q week dosing • Activity • MSSA, MRSA, PRSP (? will cover VRSA, VISA) • Anaerobes, less VRE coverage (not VAN A genotypes) • Pharmacodynamics • Cell wall activity, bactericidal • 1/3 Renal excretion, 2/3 fecal • No dose reductions required for renal or liver disease Billeter et al. Clin Infect Dis, 2008; Scheinfield, Drugs of Today, 2007

20. Dalbavancin • Clinical Efficacy • Catheter related infection • CSSTI • Tolerability • Diarrhea, constipation, fever, headache, nausea • No significant drug interactions • No red man syndrome • Recommended Dosing • 1.0 gm load, then 500 mg q week

21. New Carbapenems • In general, carbapenems characterized by: • β-lactams with broad gm+ and gm- coverage; bactericidal • β-lactamase stable including AmpC and ESBL • 3 potential mechanisms of resistance • Δ bacterial PBP • metalloproteinase release • Δ in membrane porins • Indications • Intraabdominal and pelvic infections • cSSSI, diabetic foot, HAP, CAP, cUTI • Adverse– N, V, D, Sz (imipenem) Zhanel et al. Drugs, 2007

22. New Carbapenems Organism _____Activity Against, MIC 90______ Imip Mero Erta Dori MSSA 0.5 0.12 0.25 0.06 MRSA 32 32 >32 16 Grp B strep 0.016 0.06 0.06 0.016 PRSP 1 1 2 1 E. faecalis 4 16 16 16 E. faecium >8 >16 >16 >16 P. aeruginosa >8 16 >8 8 S. maltophilia> >16 >8 >16 B. fragilis 0.5 1 Zhanel et al, 2007

23. Doripenem • Broad spectrum, parenteral • More limited approved indications than others • cUTIs • Intra-abdominal infections • Spectrum • MSSE, MSSA (no MRSA, no VRE) • Gram negatives including Pseudomonas • Anaerobes • Renal excretion • Usual dose 500 mg q 8 h Hussar DA, J Am Pharm Assoc, 2008 Matthews and Lancaster, Clin Therapeutics, 31:42, 2009

24. Faropenem medoxomil • New oral penem • Bactericidal, cell wall active via PBPs • Renal excretion, short half life • Similar coverage to other penems, weak against MRSA, VRE • FDA approval requested for • Acute bacterial sinusitis • CAP • AECB • Uncomplicated SSSI Getting et al. Ann Pharmacother, 2008

25. Tigecycline • General • 1st glycylcycline • Tetracycline derivative, modified to increase potency • Generally bacteriostatic via protein inhibition • Approved for cSSTI, intra-abdominal infections • Spectrum • MSSA, MRSA, GISA • Streptococci including VRE • Gram negatives including ESBL producing E. coli, Klebsiella • Anaerobes, Mycoplasma, Chlamydia • NO reliable activity against Pseudomonas, Proteus spp. Rose and Rybak, Pharmacotherapy, 2006

26. Tigecycline • Resistance- either due to • Efflux pumps encoded by Tet genes (A-E), or • Ribosomal protection mechanisms encoded by Tet M, Tet O • Pharmacodynamics • 60% protein bound • Bile elimination w/o appreciable hepatic metabolism • No CY P450 induction • No adjustment for renal or mild-moderate hepatic dysfunction (1/2 maintenance dose for severe liver disease) • Tolerability: Nausea in 43% • Dose: 100 mg load then 50 mg q 12 h

27. Tigecycline • Perhaps new use in severe C. difficile infection • Reported on 4 cases refractory to standard treatment • Dosed 50 mg twice daily intravenously • All four responded clinically and became toxin negative Harpers et al. Clin Infect Dis, 2009

28. Antifungal Agents • Invasive fungal infections are a major cause of disease in critically ill and immunocompromised pts • Especially due to Candida sp and Aspergillus sp • Risk Factors for invasive infection include • Neutropenia Pancreatitis HIV • Surgery ChemoRx Age • Steroids Organ Tx Atb use • Diabetes Inv. devices • Frequency of non-albicans Candida sp. resistance to fluconazole ~50% Chapman et al. Trans Amer Clim Assoc., 2008

29. Antifungal Agents Chapman, et al. Tans Amer Clin and Climatol Assn, 2008

30. Antifungal Agents • Characteristics of the Ideal antifungal agent • Broad antifungal activity • Fungicidal • Low frequency of resistance • Available in IV and PO preparations • Ease of administration • Low frequency of adverse events • Minimal drug interactions • Reasonable cost Chapman et al. Trans Am Clin Climatol Assoc. 2008; 119: 197–216

31. Current Antifungal Agents Structure Mechanism of Action Primary Use Ampho B ergosterol inhibition moulds/dimorphic fungi Terbinafine cutaneous infxn Azoles ergosterol inhibition dimorphic fungi, Fluc Candida, Itra Aspergillus Vori Posa Echinocandins inhibit glucan synthesis Candida/ Micafungin Aspergillus Caspofungin Anidulafungin

32. Azole Antifungal Agents • Two major types • Imidazoles– ketoconazole, miconazole • Triazoles- Fluconazole, Itraconazole, Posaconazole, Voraconizole • Major limiting adverse effect- hepatotoxicity • Lots of potential drug interactions • Spectrum C. alb Non-C. alb Crypto Dimorphic Aspergillus mycoses Flu + + + + - Vori + + + + + Posa + + + + + AmB + + + + + Echino + + - +/- + Busse et al. J Okla State Med Assoc, 2007

33. Posaconazole • General • Structural analogue of itraconazole, oral preparation • Developed in the era of increased prevalence of invasive fungal infection • Indications • Prophylaxis against Candida and Aspergillus infections in severely immunocompromised patients • Oropharyngeal candidiasis • Action • Induces loss of cell membrane integrity • Active against • Yeasts- Candida, Blasto, Crypto, Histo, Coccidio, Sporo (less active against C. tropicalis) • Moulds- Aspergillus, Zygomycetes, Chromoblastomycoses Schiller et al, Clin Therapeutics, 2007

34. Posaconazole • Pharmacodynamics • Fecal excretion/ no dose adjustment in renal ds • Will interfere with some CYPs (CYP P3A4) • Requires stomach acid for absorption • Although long t1/2- dosed BID • Adverse Reactions • Nausea, vomiting, abdominal pain • Drug interactions: tacrolimus, cyclosporine

35. Echinocandins • Latest class released • Act via cell wall inhibition via 1, 3 β glucan inhibition • Fungicidal to Candida, Static to Aspergillus • Not active against most moulds, dimorphic fungi or C. neoformans • Approved for oral esophageal candidiasis, salvage therapy for aspergillosis • Hepatotoxic • Poorly bioavailable so only IV

36. New Antibiotic Rx for Resistant Gram Negative Bacteria • There is growing resistance among bacteria to standard antibiotic treatment • Many are multi-drug resistant or produce extended spectrum β-lactamases (ESBLs) • Especially problematic for hospital acquired infections with: • Pseudomonas aeruginosa • Klebsiella spp. • Acinetobacter spp.

37. New Antibiotic Rx for Resistant Gram Negative Bacteria Antibiotic Organisms Covered ESBL Stability Ceftobiprole Pseudo, Acinetobacter Yes Enterobacteriaceae Tigecycline Enterobacteriaceae Yes Doripenem Klebsiella Yes Faropenem Enterobacteriaceae Yes Colistin Acinetobacter, Klebsiella Yes Pseudomonas, S. maltophilia

38. Options for the Rx of Clostridiumdifficile Colitis • Issues • Increased incidence of CDAD over last 10 years • Now leading cause of healthcare associated enteric infxn • Risk of disease usually related to antibiotic exposure but case reports w/o exposure are increasing • Host risks include age, co-morbidities, acid suppression • Recent reports of CDAD outbreaks with a hypervirulent strain (BI/NAP) associated with high mortality • Rising prevalence of poor treatment response and relapse • attributable excess cost ~$2500-3200 Balagopal and Sears, Curr Opin Pharmacol, 2007 Dupont et al. Crr Opin Infect Dis, 21:500, 2008

39. Options for the Rx of Clostridiumdifficile Colitis Antibiotic % Relapse Rate Conclusion Metronidazole 16-50 mainstay, usually 20% relapse Vancomycin 19-37 second agent except in severe CDAD Rifaximin** 20 esp. for Tx failures, prevention of relapse Nitazoxanide 25-35 similar to metro Tolavamer+ 25 similar to vanc, role unclear Ramoplanin# 23 similar to vanc + nonabsorbable anionic polymer which absorbs toxin # bactericidal lipoglycodepsipeptide

40. Treatment of S. aureus • Issues: • SA is common, causes a variety of infections from minor skin to life threatening systemic infections • Highly virulent • Genetic plasticity of the organism has allowed for continued emergence of resistant strains • Penicillin resistant recognized very early after initial use of antibiotics • Methicillin resistance now very prominent in both community and in hospitals (encoded by mec A gene) • Glycopeptide resistance first reported in 1997 (VISA, MIC > 8-16) and later VRSA (MIC ≥32); encode by van A gene

41. Treatment of S. aureusIs Vancomycin Still the Standard? • Clinical studies indicate less optimal outcomes when it is used to treat SA infections • MSSA infective endocarditis • MRSA pneumonia • SA osteomyelitis • Although cidal for SA, it slowly kills SA as compared to β–lactams and daptomycin • Increasing MICs for vanc with many strains have been reported (MIC creep) • In toxin producing MRSA strains, vanc works on cell wall, not toxin production Anstead et al, 2007

42. Treatment of S. aureusIs Vancomycin Still the Standard? • To address these issues, strategies might include: • Higher trough vancomycin concentrations (15-20) • Greater use of tmp/smx, especially with CA-MRSA • Use of newer agents • Linezolid • Daptomycin • Tigecycline • Lipoglycopeptides • Ceftobiprole

43. Tx of Resistant Gram Positive Infections Drug Coverage of Indications MRSA PRSP VRE BSI SSTI HAP Bone Abd Q/D yes yes faecium XX XX Linez yes yes yes XX XX XX XX Dapto yes yes yes XX XX Tig yes yes yes XX XX Vanc yes yes no XX XX XX XX XX Telev yes yes yes yes Lentino et al. Eur J Clin Microbiol Infect Dis, 2008

44. New Drugs for Rx of cSSSIs • Issues • Growing resistance among organisms responsible for cSSTI infections • Antibiotics should cover a wide spectrum of organisms: Community Hospital MRSA yes yes VRE no yes Gram neg. +/- yes Stein G. Curr Infect Dis Rep, 2007

45. New Antibiotics Rx for cSSSIs ATB Spectrum % Success Comp Dapto GPC 75-83 vanc Ertapenem GM neg, GPC 82 pip/tazo Anaerobes Linezolid GPC 88-89 Naf, Vanc Tigecycline GPC, GM neg 87-89 Vanc + Aztreo Dalbavan GPC 96 Vanc Ceftobiprole GPC, GM neg 91 Vanc + Ceftaz Ceftaroline GPC, GM neg 95-97 Vanc + Aztreo Stein, 2007; Zhanel, 2009

46. New Antibiotics for Diabetic Foot Infections • Issues • DFI are a major cause of morbidity in diabetic patients • Occur in nearly 15% of all diabetics • They account for nearly 20% of all hospitalizations for diabetic patients • DM is a major cause of amputation • Microbiology • GPC- MSSA, MRSA, Group B streptococci • GM Neg- Enterobacteriaceae, Pseudomonas • Anaerobes- account for 10-50% of the isolates Omar et al, Int. J. Antimicrobiol Ag, 2007

47. New Antibiotics for Diabetic Foot Infections Agent Spectrum Alternative to MRSA Vanc GM- Anaerobes Resist. Linezolid + + - + vancomycin Daptomycin + + - +/- vancomycin Dalbavancin + - - +/- vancomycin Tigecycline + + + + vanc plus 2nd agent Ceftobiprole + - + +/- vanc plus 2nd agent + except Pseudomonas Omar et al, 2007