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Antibiotic Treatment of GNR MDR Infections
Stan Deresinski
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Kucers: The Use of Antibiotics1st Edition 1972392 pages
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Kucers: The Use of Antibiotics7th Edition 2017 5338 pages
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Carbapenem SusceptibilitySHC 2016
100 100
93
99100 100 100
99100 100
98
90
84
86
88
90
92
94
96
98
100
102
K. pneumoniae E. coli E. aerogenes E. cloacae
% SUSCEPTIBLE
Imipenem Meropenem Ertapenem
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Mechanisms of Carbapenem Resistance
• Carbapenemases• e.g., blaKPC, blaNDM, blaVIM, blaOXA-48, and blaIMP
• Porin alterations – decreased OM permeability
• Efflux upregulation
• Hyperproduction of ESBLs, AmpC – in combination with porin, efflux mutations
• Altered penicillin-binding proteins
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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.
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COLISTIN (POLYMYXIN E)
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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; 49:526-35.
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Colistin (Polymyxin E)
• Multiple components; may be batch-batch 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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Colistimethate
Slow hydrolysis to activeForm
4 hours required to reach peak colistin concentration- But below breakpoint
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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
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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; 43:518-24.
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Treatment of Bacteremia Due toKPC-Producing K. pneumoniae
Combination Rx (n=103)
Monotherapy (n=72)
Daikos et al. AAC 2014; 58:2322-8.
Survival with Combination RxInclude a carbapenem (n=31)
80.7%No carbapenem (n=72)
69.4%
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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, 2018http://dx.doi.org/10.1016/S1473-3099(18)30099-9
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MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
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MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
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MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
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MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
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Altered Antibody PK in Sepsis
J Intens Care Soc http://journals.sagepub.com/doi/full/10.1177/1751143714564816
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Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials
Lancet ID2018; 18:108-20
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Avibactam active against: • Class A & C (including AmpC, ESBLs, KPC) and some OXA (Class D).• Not Class B (MLBs)
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Ceftazidime– Avibactam (CAv)• IAI: CAv + metronidazole non-inferior to meropenem1
• cUTI: CAv vs. imipenem/cilastatin
• cUTI: (RECAPTURE) CAv non-inferior to doripenem
• cUTI due to ceftazidime non-susceptible isolates: (REPRISE) CAvsuperior 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; 62:1380-9.
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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. 2017 Dec 15. pii: S1473-3099(17)30747-8. doi: 10.1016/S1473-3099(17)30747-8
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Ceftazidime/Avibactam Vs. Alternative Therapies for
Carbapenem-Resistant K. pneumoniae Bacteremia
Retrospective Analysis – U. Pittsburgh
Shields et al. Antimicrob. Agents Chemother. 2017;61:e00883-17
30-Day ClinicalSuccess
• Survival
• Resolution S&S• BC negative <7 d• No recurrence
106/109 (97%)KPC
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91 89
79
9097
8684 83 82 81
93
60
78
6367
7278
54
0
20
40
60
80
100
120
P/T Cefepime Aztreonam Mero Tobra Cipro
% S
usc
epti
ble
P. aeruginosa SHC 2016
P aeruginosa CF-Mucoid CF-Non-Mucoid
P aeruginosa (Total) N = 545CF-Mucoid N = 130CF-Non-Mucoid. N = 101
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Ceftolozane/Tazobactam: A Novel Cephalosporin/β‐Lactamase Inhibitor Combination
Pharmacotherapy: The Journal of Human Pharmacology and Drug TherapyVolume 35, Issue 7, pages 701-715, 1 JUL 2015 DOI: 10.1002/phar.1609http://onlinelibrary.wiley.com/doi/10.1002/phar.1609/full#phar1609-fig-0001
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Antimicrob. Agents Chemother.January 2018 vol. 62 no. 1
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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. 2016 Dec 15;63(12):1615-1618; AAC. 2017 Mar; 61(3): e02097-16.• AAC 2017 Feb 23;61(3). pii: e02097-16. doi: 10.1128/AAC.02097-16..
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Meropenem/VaborbactamFDA 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
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Meropenem-Vaborbactam & Enterobacteriaeceae Carrying KPC
• 991 clinical isolates KPC+, negative for OXA-48 & MBL
• MIC90: 1 mcg/ml (FDA breakpoint: 4 mcg/ml)
• Range: <0.03 - >32 mcg/ml
• 99.0% (989/991) had MIC <4 mcg/ml
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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”
http://www.themedicinescompany.com/investors/news/medicines-company-announces-tango-2-trial-meropenem-vaborbactam-formerly-carbavance
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What About Infections with MBL-producing Organisms?
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J Antimicrob Chemother. 2017;73(2):542-544. doi:10.1093/jac/dkx393
K. Pneumoniae
NDM+ESBL+
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K. pneumoniae with NDM, OXA, CTX-MRx 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, https://doi-org.laneproxy.stanford.edu/10.1093/jac/dkx496
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56
31
50
43
50
19
31
0
10
20
30
40
50
60
Amp/Sul Cefepime Meropenem Tobra Amikacin Cipro T/S
% S
usc
epti
ble
A. baumanii SHC 2016 N = 16
Ceftazidime/Avibactam321 Acinetobacter spp.
MIC50/90: 16/>3231.2 % susceptible (based on CLSI, ceftaz)
AAC 2014; 58:1684-92.
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87
13
0
50
0
9
21
83
0
10
20
30
40
50
60
70
80
90
100
% S
usc
epti
ble
Achromobacter xylosidans SHC 2016
N = 23
Ceftolozane/tazobactam11/11 CF isolates resistant; 9/11 P/T resistant
AAC 2017; 61:e02688-16
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Some Antibiotics Active Against MDR GNR with Expected/Possible 2018-2019 Approval Dates
• Eravacycline (Tetraphase)
• Plazomicin (Achaogen)
• Fosfomycin IV (Zavante)
• Cefiderocol (Shinogi)
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Cefiderocol
• Siderophore cephalosporin
• Panel (N=315) of carbapenemase-producing MDR GNR – MIC <4 mcg/ml:• Enterobacteriaeceae – 87.5%
• P. aeruginosa - 100%
• A. baumanii - 89%
• Activity by carbapenemase type:• A – 91.8% B - 74.8% D – 98.0%
IDWeek 2017. Abstract 1230
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Cefiderocol (S-649266)MDR GNR 2014-2016
Meropenem Non-Susceptible CRE Acinetobacter baumaniiN = 1022 N = 368
AAC 2018 Jan 25;62(2). pii: e01968-17. doi: 10.1128/AAC.01968-17.
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Stenotrophomonas maltophiliaN = 217
MDR Pseudomonas aeruginosaN = 262
AAC 2018 Jan 25;62(2). pii: e01968-17. doi: 10.1128/AAC.01968-17.
Cefiderocol (S-649266)MDR GNR 2014-2016
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Cefiderocol Vs. Imipenem/Cilastatin in Acute cUTI +/-Pyelonephritis Or Acute Uncomplicated Pyelonephritis
APEKS-cUTI
Portsmouth et al. IDWeek 2017. Abstract 1869
Cefiderocol N (%) Imipenem/Cil N (%) Adjusted ∆ % 95% CI
# Pts 252 119
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%
Response at Test of Cure in Microbiological Intent-to-Treat Population
*Primary endpoint
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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,
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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