Updates in Infec3ous Diseases 2011: Inpa3ent An3bio3c Therapy

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1 Updates in Infec3ous Diseases 2011: Inpa3ent An3bio3c Therapy Conan MacDougall, PharmD, MAS, BCPS Associate Professor of Clinical Pharmacy University of California San Francisco School of Pharmacy Conflict of Interest I declare that I have no relevant financial rela3onships to disclose Lecture Outline & Objec3ves New microbiology: end of ESBLs? Describe the recent changes to the Clinical and Laboratory Standards Ins3tute breakpoints for Enterobacteriaceae and the implica3ons for therapy New clinical trials: ZEPHyR the final word on MRSA HAP? Discuss implica3ons of recent studies on the management of MRSA nosocomial pneumonia. New an3microbials: new cephalosporins: a new genera3on or much ado about nothing? Describe two characteris3cs of cezaroline that differen3ate it from other cephalosporins 1

2 Bactericidal What is the minimum inhibitory concentra3on (MIC)? MBC:MIC ratio 1-4 Bacteriostatic MBC:MIC ratio >4 Tolerant MBC:MIC ratio>32 for cidal drugs a) 0.5 mcg/ml b) 1 mcg/ml c) 2 mcg/ml d) 4 mcg/ml Clin Infect Dis 2004;39:1314 The Suscep3bility Breakpoint The breakpoint is the MIC (in mcg/ml) at or below which an organism is considered susceptible Unique for drug-organism-(infection) combination Example: Ceftriaxone & Haemophilus influenzae: 2 mcg/ml Ceftriaxone & Streptococcus pneumoniae: 1 mcg/ml (non-csf isolates) Ceftriaxone & Streptococcus pneumoniae: 0.5 mcg/ml (CSF isolates) Secng Breakpoints Breakpoints set by organizations (CLSI, FDA) using various approaches 1) MIC distributions in large collections of organisms 2) Response rates in clinical trials 3) Pharmacokinetic/pharmacodynamic simulations 2

3 Secng Breakpoints: MIC Distribu3ons What would you choose as the cutoff for suscep3bility (the breakpoint)? a) 1 mcg/ml b) 2 mcg/ml c) 8 mcg/ml d) 64 mcg/ml Clin Micro Rev 2007;20: Secng Breakpoints: Clinical Outcome Data What would you choose as the cutoff for suscep3bility (the breakpoint)? Suscep3ble Suscep3ble dose- dependent 1.0 Resistant a) mcg/ml b) 0.25 mcg/ml c) 0.5 mcg/ml d) 1 mcg/ml Clin Infect Dis 1997;24: Concentra)on Pharmacokinetic/ Pharmacodynamic Parameters Peak/MIC Aminoglycosides Fluoroquinolones Lipopeptides AUC/MIC Glycopeptides Time > MIC Beta-lactams MIC 0 Time (hours) 3

4 PK/PD Targets Craig WA. Diagn Microbiol Inf Dis 1995;22: Bacteriosta3c effect Time>MIC ~30% Target Time>MIC Sta3c ac3vity 30% Cidal ac3vity 60% Bactericidal effect Time>MIC ~60% Craig WA. Diagn Microbiol Inf Dis 1995;22: Secng Breakpoints: PK/PD Analysis: Monte Carlo Simula3on Technique that integrates: Pharmacokine3c data for a drug from pa3ents AUC, Cmax, Cmin Microbiology data for an organism- drug combo MIC distribu3on Determines likelihood that an pa3ent will achieve a goal PK/PD parameter for a given dose and MIC Likelihood of target aqainment (achieving goal value for Time>MIC, AUC/MIC, or Cmax:MIC) 4

5 What would you choose as the cutoff for suscep3bility (the breakpoint)? a) 1 mcg/ml b) 2 mcg/ml c) 4 mcg/ml d) 8 mcg/ml Andes D. Clin Microbiol Infect 2005;11(S6):10-17 A 67 yo F is transferred to your hospital with a history of a complicated UTI, per report due to an ESBL producer at an outside hospital. The pa3ent is transferred on imipenem. Urine cultures are taken on admission and on day 2 grow the organism with the reported suscep3bili3es on the lez. Follow- up with the outside hospital gives the microbiology report on the right. E. coli Ceftriaxone 8 (R) Pip/tazo 16 (S) Cefepime 4 (S) Meropenem 1 (S) Imipenem 1 (S) E. coli ESBL double-disc diffusion test: + The drug of choice for bacteremia and other serious infections, caused by ESBL producing gram negative rods is a carbapenem (e.g. meropenem). Meropenem 1 (S) Imipenem 1 (S) The team would like to know whether the pa3ent can be transi3oned to piperacillin/tazobactam for narrower- spectrum therapy. What is your opinion? Beta-lactamase Family Tree Beta-lactamase Group Functional Group 1 2 Molecular Class C A Subclass (WT) (DR) 2b 2be 2f Example Enzymes AmpC TEM-1, SHV-1 TEM-3, SHV-2 (ESBLs) KPC-1 PCNs st /2 nd GC rd /4 th GC Penems Inhibition by BLI Organisms CAPES E. coli, Klebsiella Location Chromosomal (plasmid) Plasmid Expression Inducible Constituitive Constituitive 5

6 Extended-spectrum beta-lactamase (ESBL) fever: the beginning Retrospective review 32 patients w/klebsiella bacteremia ESBL+ via confirmatory test Treated with cephalosporin Ceftazidime, cefotaxime, ceftriaxone, cefepime MICs to treating cephalosporin S- or I- Breakpoint 8 mg/l Susceptibility Clinical Failure Intermediate 16 mg/l 4/4(100%) Susceptible 8 mg/l 15/28 (54%) Paterson DL. J Clin Micro 2001;39: Identification of ESBLs ESBL phenotype tests take advantage of skewed MIC distribution & inhibition of ESBLs by BLI Screening test (MIC or disk) Aztreonam, ceftazidime, cefotaxime, ceftriaxone MIC 2mcg/ml (breakpoint 8mcg/ml) Test for ESBL E.coli: ceftriaxone MIC % 5.4% S I R Jones RN. Diagn Micro ID 2008;61: Identification of ESBLs Increased activity of cephalosporin in presence of clavulanate: confirmation of ESBL Keystoning Drieux L. Clin Microbiol Infect 2008;14(S1):

7 ESBLs are magic Paradigm: you cannot trust the results of standard susceptibility tests for beta-lactams (except carbapenems) for ESBL+ If phenotypic ESBL test positive, all penicillins, cephalosporins, aztreonam reported as resistant ESBL+ Reporting AMP PIP P/T CFZ CTX CTZ CFP IMI R R R R R R R (MIC) If negative, susceptibility reported according to MIC AMP=ampicillin; PIP=piperacillin; P/T=piperacillin/tazobactam; CFZ=cefazolin; CTX=ceZriaxone CFP=cefepime; IMI=imipenem; R=report as resistant regardless of MIC; (MIC)=report MIC Are ESBLs magic? What would you choose as the cutoff for suscep3bility (the breakpoint)? a) 1 mg/l Alternative explanation b) 2 mg/l Current susceptibility breakpoints c) 4mg/L are too high for cephalosporins & Enterobacteriaceae d) 8 mg/l ESBLs (or other mechanisms) raise MICs above what true breakpoint should be Andes D. Clin Microbiol Infect 2005;11(S6):10-17 Andes D. Clin Microbiol Infect 2005;11(S6):

8 New Paradigm? 1) ESBLs are not magic Any B-lactamase that reduces susceptibility can cause clinical failure 2) ESBLs lead to failure because they increase the MIC such that PK/PD targets cannot be attained at standard dosages 3) All beta-lactams are not equal in susceptibility to ESBLs Beta-lactams that can achieve PK/PD targets may be useful: cefepime, piperacillin/tazobactam Andes D. Clin Microbiol Infect 2005;11(S6):10-17 Ambrose PG AAC 2003;47:

9 Approved (but not yet generally implemented) CLSI Changes for Enterobactericeae Lower breakpoints regardless of ESBL +/- Specify doses that breakpoints apply to Confirmatory testing not needed except for epidemiology/infection control purposes Drug Old breakpoints New breakpoints S I R S I R Cefazolin* (2g q8h) Cefotaxime (1g q8h) Ceftriaxone (1g q24h) Ceftazidime (1g q8h) Aztreonam (1g q8h) Cefepime (2g q12h) Piperacillin/tazobactam Clinical Laboratory Standards Institute M-100 S Take-homes: No more ESBLs Changes coming to how your lab will be reporting susceptibilities for Enterobacteriaceae Organisms will not identified as ESBLs Implications: Treat according to reported susceptibilities Need to ensure adequate doses used Potential reduction in use of carbapenems Limitations: Lab transition is ongoing, potential for confusion Paucity of in-human clinical data supporting use of non-carbapenem beta-lactams for severe ESBL infections A 27 yo M is admiqed to the surgical ICU azer undergoing extensive surgery following a car accident. Three days later he develops a ven3lator- associated pneumonia and is empirically started on vancomycin 1g IV q12h and cefepime 2g IV q12h. His vancomycin level before the 4 th dose is 10 mg/l. 72 hours azer ini3a3ng therapy, the organism below is isolated from a bronchoalveolar lavage culture. Staphylococcus aureus Vancomycin 1 (S) Daptomycin 0.5 (S) Oxacillin 2 (R) Linezolid 1 (S) The pa3ent has showed modest improvement in his ven3latory status but remains febrile. Do you want to con3nue vancomycin at the current dose, change the dose, or change drugs? 9

10 Point: Vancomycin Is Not Obsolete for the Treatment of Infection Caused by Methicillin- Resistant Staphylococcus aureus Counterpoint: Vancomycin and Staphylococcus aureus An Antibiotic Enters Obsolescence There is an antibiotic called mud That s proving to be quite a dud. Its provenance is jungle Its use is a bungle It just won t get rid of your crud. Mohr et al. Clin Infect Dis 2007;44: ; Deresinski Clin Infect Dis 2007;44: Concentra)on Pharmacokinetic/ Pharmacodynamic Parameters Peak/MIC Aminoglycosides Fluoroquinolones Lipopeptides AUC/MIC Glycopeptides Time > MIC Beta-lactams MIC 0 Time (hours) Moise- Broder P et al. Clin Pharmacokinet 2004;43:

11 What would you choose as the cutoff for suscep3bility (the breakpoint)? a) 0.5 mcg/ml b) 1 mcg/ml c) 2 mcg/ml d) 4 mcg/ml Mohr JF, et al. Clin Infect Dis 2007;44: Vancomycin Dosing and Monitoring Table 1. Steady-State Peak, Trough, AUC, and AUC/MIC Values for Male Patients (40 Years of Age) Treated With Various Vancomycin Dosing Regimens Average a Under a Over a Under/Fast a,b Over/Slow a,b Average a Average a Weight (kg) CrCl (ml/min) Vancomycin 1 g 1.5 g 1 g dosing regimen every 12 h every 12 h every 8 h Peak/Trough (mcg/ml) c 27.6/ / / / / / /18.0 AUC (mcg h/ml) , AUC/MIC if: MIC = 0.5 mcg/ml 822 1, ,778 1,234 1,234 MIC = 1 mcg/ml , MIC = 1.5 mcg/ml MIC = 2 mcg/ml a Average, over, and under refer to the weight of the patient; b Fast and slow refer to the elimination of vancomycin from the body; c Peak/Trough refers to the maximum and minimum vancomycin concentrations at steady state; Pharmacokinetic parameters were derived from reference 2; Vancomycin levels were estimated using reference 31; AUC = total drug area under the concentration-time curve over 24 hours; CrCl = creatinine clearance; MIC = minimum inhibitory concentration. DeRyke et al. Hosp Pharm 2009;44: Linezolid vs Vancomycin: Phase III HAP Trials Rubinstein et al. Clin Infect Dis 2001;32: ; Wunderink et al. Clin Ther 2003;25:

12 Linezolid vs Vancomycin: Phase III HAP Trials: Combined Staph aureus subgroups Wunderink et al. Chest 2003;124: Linezolid vs Vancomycin in the Treatment of Nosocomial Pneumonia Proven Due to Methicillin- Resistant Staphylococcus aureus ZEPHyR Linezolid vs Vancomycin in the Treatment of Nosocomial Pneumonia Proven Due to Methicillin- Resistant Staphylococcus aureus Linezolid 618 >18 yo, HAP/HCAP 1225 randomized Did not receive treatment 597 Inten)on- to- Treat (ITT) No proven MRSA pneumonia Vancomycin Modified Inten)on- to- Treat (mitt) 224 <80% of study drug, protocol viola3on, missed study visit Per- Protocol 183 (mitt) 188 Clinical response at End of Study (EOS) in PP Clinical response at End of Study (EOS) in mitt Clinical response at End of Treatment (EOT) in PP & mitt Microbiologic response at End of Treatment (EOT) in PP & mitt Survival in mitt Pfizer. Data on file. Safety in ITT 12

13 Popula)on/ Analysis ZEPHyR Results Outcome Linezolid Vancomycin P- value/ (95% CI) PP/Sponsor Clinical 57.6% (95/165) 46.6% (81/174) 0.04 PP/Inves3gator Clinical 84% (110/131) 78.9% (105/133) 0.29 ( ) mitt/sponsor Clinical 54.8% (102/186) 44.9% (92/205) ( ) mitt/inves3gator Clinical 82.4% (117/142) 76.1% (118/155) 0.18 ( ) PP/Sponsor Clinical 83.3% (150/180) 69.9% (130/186) (4.9-22) PP/Inves3gator Clinical 93.6% (162/173) 82.9% (145/175) ( ) PP/Sponsor Micro 81.9% (149/182) 60.6% (114/188) ( ) PP/Sponsor Micro 58.1% (97/167) 47.1% (82/174) ( ) mitt/sponsor All- cause mortality 15.7% (94/597) 17.0% (100/587) 0.61 mitt/inves3gator Tx- related SAE 1.1% (7/597) 2.2% (13/587) 0.17 Pfizer. Data on file. ZEPHyR Results Vancomycin dosages adjusted per unblinded study pharmacist s judgment Vancomycin trough concentra)ons: Mean (range) in mcg/ml Day 3 Day 6 Day ( ) 17.1 ( ) 17.1 ( ) Maximum vancomycin trough concentra)on (mcg/ml) >22.2 % of total 41/157 (25.7%) 42/157 (26.7%) 36/157 (22.9%) 38/157 (24.2%) % Success 20/41 (48.8%) 20/42 (47.6%) 17/36 (47.2%) 17/38 (44.7%) Vancomycin MIC in vancomycin arm (mcg/ml) % of total 14/202 (6.9%) 168/202 (83.2%) 18/202 (8.9%) 2 (1.0%) % Success Not reported Pfizer. Data on file. ZEPHyR Results Zephyr- what is the real NNT? NNT with linezolid instead of vancomycin for MRSA pneumonia to prevent one clinical failure (based on primary outcome) NNT= 1 / [0.576 (95/165) (81/174)] 9 But in order to follow the trial design, would need to treat ALL pa3ents with HAP/HCAP ini3ally with linezolid instead of vanco (albeit could be d/c d early in many) NNT= 1 / [0.159 (95/597) (81/587)] 45 Assuming we believe the trial results, is this a cost- effec3ve interven3on? 13

14 Take-homes: ZEPHyR Vancomycin vs linezolid debate for nosocomial pneumonia debate is coming to a hospital near you Implications: Totality of evidence suggests linezolid > vanco (but not >> or >>>) for MRSA pneumonia Limitations Unclear what linezolid advantage is for low vanco MIC, AUC/MIC-targeted vanco dosing Treat all HAP patients empirically with linezolid or target only MRSA pneumonia? A 48 yo F is transferred to your hospital for evalua3on for poten3al below- the- knee amputa3on azer presen3ng to her community hospital with a severe diabe3c foot infec3on. The pa3ent s medica3on profile on discharge includes an an3bio3c you ve never heard of before, cezaroline. You call the pharmacy and they tell you they don t have the drug in stock (it is non- formulary) but that they can borrow some from a nearby hospital if you think it s appropriate. The pa3ent seems to be clinically responding (the co- following ortho team seems to think amputa3on might be avoided). Do you con3nue with this agent or start alterna3ve an3bio3cs (and what would the alterna3ve(s) be?) An3- MRSA Cephalosporins Resistance to beta- lactams in Gram- posi3ves ozen due to produc3on of low- affinity penicillin- binding protein MRSA: PBP2a Drug- resistant Streptococcus pneumoniae: PBP 2x New cephalosporins engineered to bind to low- affinity PBPs: ac3ve vs MRSA & DRSP CeZobiprole Approval denied in US in 2009 due to concerns of data integrity in clinical trials; subsequently withdrawn from the market in Canada (had been approved 2008) CeZaroline Approved in US in late 2010 for cssti and CAP 14

15 Vancomycin: Slow to Kill Median days to clearance of bacteremia MSSA with β-lactam abx MRSA with vancomycin 3-4 days 7-9 days Cantoni et al J Infect Dis 1989;159: ; Korzeniowski Ann Intern Med 1982; Levine Ann Intern Med 1991 CeZaroline: In Vitro Ac3vity Pathogen MIC 90 (mcg/ml) FDA Breakpoint (mcg/ml) Strep pneumoniae (PCN- S) (CAP) Strep pneumoniae (PCN- R) 0.12 MSSA (SSTI) MRSA 1 1 (SSTI) Enterococcus faecalis 8 Enterococcus faecium >16 E. coli (CAP/SSTI) E. coli (ESBL- producing) > (CAP/SSTI) Klebsiella pneumoniae (CAP/SSTI) Klebsiella pneumoniae (ESBL- producing) > (CAP/SSTI) Enterobacter cloacae 32 Pseudomonas aeruginosa 128 Acinetobacter spp >16 Jones et al. J An3microb Chemo 2010;65:S17-31; Jacobs et al, An3micro Agents Chemo 2010;54: FDA briefing document CeZaroline: In Vivo Ac3vity Rabbit endocardi3s model Growth control Linezolid Vancomycin CeZaroline Jacqueline et al. An3micro Agents Chemo 2007;51:

16 CeZaroline: Pharmacology Pharmacokine3cs IV only as prodrug (cezaroline fosamil acetate) Administered as 1- hour infusion every 12 hours Minimal protein binding (10-20%) Renal elimina3on (>80%), t ½ ~2.5 hours Requires adjustment in renal dysfunc3on Drug Interac3ons No clinically significant interac3ons Adverse Effects Similar to other cephalosporins Uncommon: rash, nausea, diarrhea Rare: anaphylaxis, seizures FDA briefing document CeZaroline: Clinical Trials: SSTI Complicated Skin/Skin Structure Infec3ons Hospitaliza3on & IV Abx for 5 days Clinical Cure: Popula)on 2 iden3cal R, DB, AC, NI Phase III trials pooled Ce\aroline 600mg IV q12h Vancomycin 1g IV q12h + Aztreonam 1g IV q12h Difference 559/610 (91.6%) 549/592 (92.7%) - 1.1% ( %) 595/693 (85.9%) 586/685 (85.5%) 0.3 % ( %) mmitt: MRSA 155/179 (86.6%) 124/151 (82.1%) 4.4% ( %) FDA /400 (74.0%) 263/397 (66.2%) 7.8% ( %) CE: clinically evaluable popula3on; MITT; modified inten3on- to- treat popula3on; mmitt: microbiologic modified intent- to- treat popula3on; FDA- MITT: FDA early response MITT popula3on; TOC: test of cure vist Corey et al. Clin Infect Dis 2010;51: ; FDA briefing document CeZaroline: Clinical Trials: CAP Community- acquired Pneumonia CAP w/port Class III- IV, no evidence of atypical respiratory infec3on, minimal prior an3bio3cs 2 similar R, DB, AC, NI Phase III trials pooled Clinical Cure: Popula)on/)ming Ce\aroline 600mg IV q12h Ce\riaxone 1g IV q24h Difference 387/459 (84.3%) 349/449 (77.7%) 6.6% ( %) 479/580 (82.6%) 586/685 (85.5%) 6.0% ( %) mmitt: S. pneumo 59/69 (85.5%) 48/70 (68.6%) 17.0% ( %) FDA /151 (70.2%) 90/153 (58.8%) 7.8% ( %) CE: clinically evaluable popula3on; MITT; modified inten3on- to- treat popula3on; mmitt: microbiologic modified intent- to- treat popula3on; FDA- MITT: FDA early response MITT popula3on; TOC: test of cure vist File et al. Clin Infect Dis 2010;51: ; FDA briefing document 16

17 Take- homes: An3- MRSA Cephalosporins New group of an3- MRSA cephalosporins now available Implica3ons Rapid bactericidal ac3vity of beta- lactams vs MRSA, Strep pneumoniae Poten3al for improved outcomes Single drug vs combina3on empiric therapy Coverage of enteric Gram- nega3ve organisms Limita3ons No coverage of resistant Gram- nega3ves Pseudomonas, Acinetobacter, ESBL E. coli/klebsiella No studies in highest- need areas HAP/VAP, bloodstream infec3ons The End 17