Antibiotic Treatment of GNR MDR Infections. Stan Deresinski

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1 Antibiotic Treatment of GNR MDR Infections Stan Deresinski

2 Kucers: The Use of Antibiotics 1st Edition pages

3 Kucers: The Use of Antibiotics 7 th Edition pages

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5 Carbapenem Susceptibility SHC 2016 % SUSCEPTIBLE K. pneumoniae E. coli E. aerogenes E. cloacae Imipenem Meropenem Ertapenem

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8 Mechanisms of Carbapenem Resistance Carbapenemases e.g., bla KPC, bla NDM, bla VIM, bla OXA-48, and bla IMP Porin alterations decreased OM permeability Efflux upregulation Hyperproduction of ESBLs, AmpC in combination with porin, efflux mutations Altered penicillin-binding proteins

9 Rx CRE pre-2015 Polymyxin B/Colistin Tigecycline Best results: combination of one in vitro active drug with optimally dosed/administered anti-pseudomonal carbapenem. Robilotti, Deresinski F1000Rep 2014; 6:80. Watkins, Deresinski Exp Review Anti Infect Ther 2015; 13:405-7.

10 COLISTIN (POLYMYXIN E)

11 Polymyxins Resistance Mechanisms Polymyxins are polycationic at physiologic ph and depend on binding to negatively charged outer layer of outer bacterial cell membrane Resistance primarily due to post-translational modification of OM LPS reducing net negative charge of phosphate residues (ie, making it more +) Most often: addition of, eg, phosphonoethanolamine to lipid A of LPS core Mutational or acquisition of mcr (plasmid-mediated) In some cases, complete loss of LPS Int J Antimicrob Agents 2017; 49:

12 Colistin (Polymyxin E) Multiple components; may be batchbatch variation Administered as inactive prodrug: Na+ salt of colistin methanesulfonate (CMS; colistemethate) Renal clearance of CMS (converted in urine) more efficient than conversion to parent Conversion is slow (hours to therapeutic) and incomplete (approx. 25%) Significant inter-pt clearance variability Nephrotoxic Uses: UTI, Inhalational Polymyxin B Multiple components Active moiety (as sulfate salt) Mainly non-renal excretion dosage adjustments not required Nephrotoxic Uses: Non-UTI

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14 Colistimethate Slow hydrolysis to active Form 4 hours required to reach peak colistin concentration - But below breakpoint

15 TIGECYCLINE: 9-t-butylglycyclyl minocycline 9-t-butylglycyclyl amido side chain: Enables binding to 30s RNA even in presence of Tet(M) Makes tigecycline a poor substrate for tetracycline-specific efflux pumps

16 Tigecycline Intrinsic Resistance Constitutive overexpression of multidrug efflux pumps (e.g., AcrB) Pseudomonas aeruginosa Proteus spp. Providencia spp. Some Morganella morganii Clin Infect Dis 2006; 43:

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18 Treatment of Bacteremia Due to KPC-Producing K. pneumoniae Combination Rx (n=103) Monotherapy (n=72) Survival with Combination Rx Include a carbapenem (n=31) 80.7% No carbapenem (n=72) 69.4% Daikos et al. AAC 2014; 58:

19 Prospective Randomized Trial Rx of Severe Carbapenem- Resistant Gram Negative Infections (Mostly A. baumanii) 312/406 Acinetobacter baumanii Colistin +/- meropenem Overall, no significant difference between mono- or combo-therapy for clinical failure Acinetobacter also no significant difference between mono- or combo-therapy Lancet ID 2018 Published Online February 15,

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21 MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT MEROPENE Enterobacteriaceae Susc: <1 mcg/ml Inter: 2 Resist: >4 Clin Microbiol Infect. 2011; 17:

22 MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT MEROPENE Enterobacteriaceae Susc: <1 mcg/ml Inter: 2 Resist: >4 Clin Microbiol Infect. 2011; 17:

23 MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT MEROPENE Enterobacteriaceae Susc: <1 mcg/ml Inter: 2 Resist: >4 Clin Microbiol Infect. 2011; 17:

24 MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT Enterobacteriaceae Susc: <1 mcg/ml Inter: 2 Resist: >4 MEROPENE Enterobacteriaceae Susc: <1 mcg/ml Inter: 2 Resist: >4 Clin Microbiol Infect. 2011; 17:

25 Altered Antibody PK in Sepsis J Intens Care Soc

26 Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials Lancet ID 2018; 18:108-20

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28 Avibactam active against: Class A & C (including AmpC, ESBLs, KPC) and some OXA (Class D). Not Class B (MLBs)

29 Ceftazidime Avibactam (CAv) IAI: CAv + metronidazole non-inferior to meropenem 1 cuti: CAv vs. imipenem/cilastatin cuti: (RECAPTURE) CAv non-inferior to doripenem cuti due to ceftazidime non-susceptible isolates: (REPRISE) CAv superior to best available Rx: 70.1% vs 50.4% ( 16.1%; 95% CI 4.8 TO 27.1) HAP/VAP: (REPROVE) 1. Clin Infect Dis 2016; 62:

30 REPROVE: Ceftazidime/Avibactam Non- Inferior to Meropenem in HAP/VAP 808 evaluable patients Micro population: 37% of K. pneumoniae, 30% P. aeruginosa 28% ceftazidime non-susceptible Clinically modified intent-to-treat (ITT) Clinical cure in 245 (68.6%) of 356 CAv recipients & 270 (73.0%) of 370 meropenem (difference 4 2% [95% CI 10 8 to 2 5]) Clinically evaluable population Clinical cure in 199 (77.4%) of 257 CAv and 211 (78.1%) of 270 meropenem recipients (difference 0 7% [95% CI 7 9 to 6 4]) Lancet Infect Dis Dec 15. pii: S (17) doi: /S (17)

31 Ceftazidime/Avibactam Vs. Alternative Therapies for Carbapenem-Resistant K. pneumoniae Bacteremia Retrospective Analysis U. Pittsburgh 30-Day Clinical Success Survival Resolution S&S BC negative <7 d No recurrence 106/109 (97%) KPC Shields et al. Antimicrob. Agents Chemother. 2017;61:e

32 % Susceptible 120 P. aeruginosa SHC P/T Cefepime Aztreonam Mero Tobra Cipro P aeruginosa CF-Mucoid CF-Non-Mucoid P aeruginosa (Total) N = 545 CF-Mucoid N = 130 CF-Non-Mucoid. N = 101

33 Ceftolozane/Tazobactam: A Novel Cephalosporin/β Lactamase Inhibitor Combination Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy Volume 35, Issue 7, pages , 1 JUL 2015 DOI: /phar

34 Antimicrob. Agents Chemother.January 2018 vol. 62 no. 1

35 The Inevitable Emergence of Resistance Ceftazidime/ avibactam - Initial FDA Approval Feb 2015 Rx CRE: 3/10 microbiological failures developed resistance Resistance due to mutations in blakpc3 (but restored carbapenem susceptibility in some isolates). Ceftolozane/tazobactam Initial FDA Approval Dec 2014 Rx MDR PA: 3/21 developed resistance ampc overexpression and structural mutations Clin Infect Dis Dec 15;63(12): ; AAC Mar; 61(3): e AAC 2017 Feb 23;61(3). pii: e doi: /AAC

36 Meropenem/Vaborbactam FDA Approval - August 2017 Vaborbactam: non-bl/bli based on a cyclic boronic acid pharmacophore inhibits Class A and C β-lactamases, including Ambler Class A carbapenemases (eg, KPC) Does not inhibit Class B or D carbapenemases Increased expression of OmpK36 porin elevates MICs Major target KPC-producers

37 Meropenem-Vaborbactam & Enterobacteriaeceae Carrying KPC 991 clinical isolates KPC+, negative for OXA-48 & MBL MIC90: 1 mcg/ml (FDA breakpoint: 4 mcg/ml) Range: < >32 mcg/ml 99.0% (989/991) had MIC <4 mcg/ml

38 TANGO-2: Meropenem/Vaborbactam vs. Best Available Bacteremia, Pneumonia, cuti, IAI Stopped after 72 patients (43 CRE, 20 with bacteremia; 86% KP) by DSMB: risk-benefit analysis of available no longer supported randomization of additional patients to the best available therapy comparator arm Efficacy: Statistically significant differences favored meropenem/vaborbactam for clinical cure at TOC visit & mortality rates were also lower AEs: lower rates of renal events and serum creatinine increases particularly in patients receiving colistin and [sic] aminoglycosides

39 What About Infections with MBL-producing Organisms?

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41 K. Pneumoniae NDM+ ESBL+ J Antimicrob Chemother. 2017;73(2): doi: /jac/dkx393

42 K. pneumoniae with NDM, OXA, CTX-M Rx with Aztreonam + Ceftazidime/Avibactam 10 patients infected with K. pneumoniae ST147 carrying NDM-1, OXA- 48, CTX-M MICs: aztreonam >32, ceftaz/avi >16/4 Clinical success (negative culture at 7 days + survival & no recurrence at 30 days): 6/10 3 deaths (none infection-related), 1 recurrence Journal of Antimicrobial Chemotherapy, dkx496,

43 % Susceptible A. baumanii SHC 2016 N = Amp/Sul Cefepime Meropenem Tobra Amikacin Cipro T/S Ceftazidime/Avibactam 321 Acinetobacter spp. MIC50/90: 16/> % susceptible (based on CLSI, ceftaz) AAC 2014; 58:

44 % Susceptible Achromobacter xylosidans SHC 2016 N = Ceftolozane/tazobactam 11/11 CF isolates resistant; 9/11 P/T resistant AAC 2017; 61:e

45 Some Antibiotics Active Against MDR GNR with Expected/Possible Approval Dates Eravacycline (Tetraphase) Plazomicin (Achaogen) Fosfomycin IV (Zavante) Cefiderocol (Shinogi)

46 Cefiderocol Siderophore cephalosporin Panel (N=315) of carbapenemaseproducing MDR GNR MIC <4 mcg/ml: Enterobacteriaeceae 87.5% P. aeruginosa - 100% A. baumanii - 89% Activity by carbapenemase type: A 91.8% B % D 98.0% IDWeek Abstract 1230

47 Cefiderocol (S )MDR GNR Meropenem Non-Susceptible CRE Acinetobacter baumanii N = 1022 N = 368 AAC 2018 Jan 25;62(2). pii: e doi: /AAC

48 Cefiderocol (S ) MDR GNR MDR Pseudomonas aeruginosa N = 262 Stenotrophomonas maltophilia N = 217 AAC 2018 Jan 25;62(2). pii: e doi: /AAC

49 Cefiderocol Vs. Imipenem/Cilastatin in Acute cuti +/- Pyelonephritis Or Acute Uncomplicated Pyelonephritis APEKS-cUTI Response at Test of Cure in Microbiological Intent-to-Treat Population Cefiderocol N (%) Imipenem/Cil N (%) Adjusted % 95% CI # Pts Clinical + Micro* 183 (72.6%) 65 (54.6%) 28.9% 8.23%, 28.92% Clinical 226 (89.7%) 104 (87.4%) 2.4% -4.66%, 9.44% *Primary endpoint Portsmouth et al. IDWeek Abstract 1869

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51 An Alternative Approach: John Lettsome s Guideline If any sick applies to me, I bleeds, cups, and sweats em If they then should chance to die,

52 An Alternative Approach: John Lettsome s Guideline If any sick applies to me, I bleeds, cups, and sweats em If they then should chance to die, I, John Lettsome