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Antibiotic Treatment of GNR MDR Infections
Stan Deresinski
Kucers: The Use of Antibiotics1st Edition 1972392 pages
Kucers: The Use of Antibiotics7th Edition 2017 5338 pages
Carbapenem SusceptibilitySHC 2016
100 100
93
99100 100 100
99100 100
98
90
84
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102
K. pneumoniae E. coli E. aerogenes E. cloacae
% SUSCEPTIBLE
Imipenem Meropenem Ertapenem
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
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.
COLISTIN (POLYMYXIN E)
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.
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
Colistimethate
Slow hydrolysis to activeForm
4 hours required to reach peak colistin concentration- But below breakpoint
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
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.
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%
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
MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
MEROPENE
Clin Microbiol Infect. 2011; 17:1135-41.
MEROPENEM PHARMACODYNAMIC TARGET ATTAINMENT
Enterobacteriaceae
Susc: <1 mcg/mlInter: 2Resist: >4
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
Altered Antibody PK in Sepsis
J Intens Care Soc http://journals.sagepub.com/doi/full/10.1177/1751143714564816
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
Avibactam active against: • Class A & C (including AmpC, ESBLs, KPC) and some OXA (Class D).• Not Class B (MLBs)
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.
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
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
91 89
79
9097
8684 83 82 81
93
60
78
6367
7278
54
0
20
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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
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
Antimicrob. Agents Chemother.January 2018 vol. 62 no. 1
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..
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
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
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
What About Infections with MBL-producing Organisms?
J Antimicrob Chemother. 2017;73(2):542-544. doi:10.1093/jac/dkx393
K. Pneumoniae
NDM+ESBL+
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
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.
87
13
0
50
0
9
21
83
0
10
20
30
40
50
60
70
80
90
100
% S
usc
epti
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Achromobacter xylosidans SHC 2016
N = 23
Ceftolozane/tazobactam11/11 CF isolates resistant; 9/11 P/T resistant
AAC 2017; 61:e02688-16
Some Antibiotics Active Against MDR GNR with Expected/Possible 2018-2019 Approval Dates
• Eravacycline (Tetraphase)
• Plazomicin (Achaogen)
• Fosfomycin IV (Zavante)
• Cefiderocol (Shinogi)
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
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.
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
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
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,
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
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