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

86

88

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92

94

96

98

100

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

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9097

8684 83 82 81

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6367

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0

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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

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Amp/Sul Cefepime Meropenem Tobra Amikacin Cipro T/S

% S

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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

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50

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9

21

83

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% 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