Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient...

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©2015 MFMER | slide-1 Breaking the Ring β-Lactamases and the Great Arms Race Bryce M Kayhart, PharmD, BCPS PGY2 Pharmacotherapy Resident Mayo Clinic - Rochester

Transcript of Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient...

Page 1: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

©2015 MFMER | slide-1

Breaking the Ringβ-Lactamases and the Great Arms Race

Bryce M Kayhart, PharmD, BCPSPGY2 Pharmacotherapy ResidentMayo Clinic - Rochester

Page 2: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Disclosures• I have no relevant financial relationships to

disclose

Page 3: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Objectives• Discuss the evolving epidemiology of multi-drug

resistant gram negative organisms.

• Review pertinent differences between several classes of beta lactamases.

• Review new agents available for the treatment of multi-drug resistant gram negative organisms.

• Discuss the pharmacologic management of patients infected with carbapenemase-producing bacteria.

Page 4: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Beta LactamasesPenicillin

Cephalosporin

Carbapenem Monobactam

Page 5: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Beta Lactamases• Ancient enzymes that have evolved in bacteria

over the last 2 billion years• Structurally similar to penicillin binding proteins

PBP

β-Lactamase

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A Growing Threat

0

10

20

30

40

50

Motor VehicleAccident

Firearms Falls MDR Infection

Annual Deaths in the United States in Thousands

Antibiotic Resistance Threats in the United States – 2013 Threat Report. CDC. 2013National Health Interview Survey. CDC. 2014

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Beta Lactamase Classification

Ambler Class A B C DOther Names Serine β-

LactamasesMetallo-β-

Lactamases Cephalosporinases Oxacillinases

Examples

TEMSHV

CTX-MKPC

VIMIMPNDM

Amp-CCMY OXA-48

Encoding Location Plasmid Plasmid Chromosome Plasmid

Hydrolyze Carbapenems? Some Yes No Yes

Vasoo, et al. Mayo Clinic Proceedings. 2015

Page 8: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Beta Lactamases – TEM-1, TEM-2• “Broad spectrum”

• Penicillins, 1st generation cephalosporins• Very common in the United States• Responsible for ampicillin and cefazolin

resistance in most Enterobacteriaceae, as well as H. influenzae.

• Reliably inhibited by clavulanic acid, sulbactam, and tazobactam

• Cannot hydrolyze 3rd/4th generation cephalosporins

Tristram S, et al. Clin Microbiol Rev. 2007Bush K, et al. Antimicrob Agents Chemother. 2010

Page 9: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Beta Lactamases – TEM-3, CTX-M• “Extended spectrum”

• Penicillins, aztreonam, oxyimino beta lactams

• Increasingly common in the United States• Variable susceptibility to beta lactamase inhibitors

Bush K, et al. Antimicrob Agents Chemother. 2010

Ceftriaxone Cefepime Ceftaroline

Page 10: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Case #1TJ, a 68 year old male, is admitted to the general ward with community acquired pneumonia.

PMHx: T2DM, hypertension, COPD

A sputum gram stain reveals gram negative rods and the next day, the lab reports the following:

Sample: induced sputum April 5, 2016

4+ Haemophilus influenzae*

* Beta-lactamase positive (susceptibilities in progress)

Page 11: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Case #1Which of the follow agents are expected to remain active against TJ’s H. influenzae isolate?

1. Cefazolin2. Ampicillin3. Ampicillin/Sulbactam4. Ceftriaxone5. 3 & 4

Page 12: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Beta Lactamases – Amp-C• Produced by Serratia, Enterobacter, and

Citrobacter • Most commonly encoded on the bacterial

chromosome (rather than plasmid)• Not constitutively expressed

• Production is induced by exposure to certain beta lactams:

• Strong inducers: ampicillin, cefazolin, cephalothin• Weak inducers: Ceftriaxone, ceftazidime, cefepime,

piperacillin, aztreonam, beta-lactamase inhibitors

Jacoby GA, Clin Microbiol Rev. 2009

Page 13: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Case #2ST is a 21 year old female with fistulizing Crohn’sdisease admitted to the SICU with septic shock secondary to an intestinal perforation. - Blood cultures are drawn and antibiotics initiated

• Vancomycin, piperacillin/tazobactam, caspofungin- Ex-lap with closure performed in the OR- Blood cultures are reported positive with 6/6 bottles growing Gram negative rods

Page 14: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Case #2Enterobacter aerogenesAmpicillin >16 R Amp/Sulb >16/8 R Ciprofloxacin >2 RCeftriaxone 1 S Ceftazidime 2 S Pip/Taz < 16/4 SCefepime ≤ 2 S Meropenem ≤ 1 S Levofloxacin >4 RGentamicin 4 S Tobramycin 2 S Amikacin 4 STMP/SMX > 2/38 R Aztreonam 2 S Minocycline 1 S

• Vancomycin and levofloxacin are discontinued and piperacillin/tazobactam is continued as definitive therapy.

• Three days later, ST remains febrile, hypotensive, and bacteremic.

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Case #2Which of the following most likely explains ST’s clinical failure?

1. Non-optimized pharmacokinetics/dynamics2. Lack of source control3. Inducible beta lactamases4. Piperacillin allergy

Page 16: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Case #2

Enterobacter aerogenesAmpicillin >16 R Amp/Sulb >16/8 R Ciprofloxacin >2 RCeftriaxone >32 R Ceftazidime >16 R Pip/Taz > 64/16 RCefepime 2 S Meropenem 1 S Levofloxacin >4 RGentamicin 4 S Tobramycin 2 S Amikacin 4 STMP/SMX > 2/38 R Aztreonam > 16 R Minocycline 1 S

Your team asks the lab to re-run antimicrobial susceptibilities on a new blood culture:

How should ST’s treatment be modified?

Page 17: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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The Use of Cefepime for Treating AmpC Beta-Lactamase-Producing

Enterobacteriaceae

Pranita D. Tamma, Sonta C. T. Girdwood, Ravindra Gopaul, Tsigereda Tekle, Ava A. Roberts, Anthony D. Harris, Sara E. Cosgrove, Karen C. Carroll

Tamma PD, Clin Infect Dis. 2013

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Tamma PD, Clin Infect Dis. 2013

399 Patients w/ cultures growing Enterobacter,

Serratia, or Citrobacter.

96 (24%) isolates tested positive for AmpC

Enterobacter: 38%Serratia: 15%Citrobacter: 1%

78 (81%) met eligibility for inclusion

46 prescribed cefepime(1-2 g q8h)

32 prescribed meropenem(1-2 g q8h)

More likely to have:• History of MDR organisms• Comorbidities• Compromised immunity

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31.234.3

0

10

20

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40

50

30 Day Mortality

CefepimeMeropenem Tamma PD, Clin Infect Dis. 2013

12.614.6

0

10

20

Length of Stay (days)

P = 0.63P = 0.99

Tamma, et al.

% o

f Pat

ient

s

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Tamma, et al.• Mortality was best predicted by ICU stay, need

for mechanical ventilation, and vasopressor use, but not antibiotic selection.

• One possible case of emergence of cefepimeresistance occurred

• > 93% of patients had adequate source control

Tamma PD, Clin Infect Dis. 2013

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Amp-C Take-Home Points• Amp-C producing bacteria can “trick” the

clinician into prescribing inappropriate therapy.• Enterobacter spp. are most likely to produce

Amp-C beta lactamases. Amp-C production by Citrobacter is rare.

• Cefepime is a reasonable alternative to carbapenems, but the MIC matters.

• Beware of the “inoculum effect.”

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Cefepime MIC and Amp-C

20.8

36.5

50

25.8

10.7

53.8

100

22.2

0

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100

≤ 2 4 8 Carbapenem

EmpiricalDefinitive

Cefepime TherapyCefepime MIC (mcg/mL)

Enterobacter cloacae BSI 30-Day Mortality

% o

f pat

ient

s

Lee NY, et al. Antimicrob Agents Chemother. 2015

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Amp-C and the Inoculum EffectAmp-C-Producing Klebsiella pneumoniae (n = 28)

Inoculum Size 105 cfu/mL 107 cfu/mL

Range 50% 90% Range 50% 90%Ceftriaxone 8- >256 >256 >256 >256 >256 >256

Cefepime ≤ 0.25 – 16 1 4 16 - >256 256 256

Imipenem ≤ 0.25 – 1 0.25 0.5 0.5 – 8 4 8

Kang CI, J Antimicrob Chemother. 2004

• Use a carbapenem when you have suboptimal source control.

• Use a carbapenem if the cefepime MIC is > 2.

Bottom Line

Page 24: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Beta Lactamase Classification

Ambler Class A B C DOther Names Serine β-

LactamasesMetallo-β-

Lactamases Cephalosporinases Oxacillinases

Examples

TEMSHV

CTX-MKPC

VIMIMPNDM

Amp-CCMY OXA-48

Encoding Location Plasmid Plasmid Chromosome Plasmid

Hydrolyze Carbapenems? Some Yes No Yes

Vasoo, et al. Mayo Clinic Proceedings. 2015

Page 25: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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A Growing Threat

Page 26: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

Carbapenemases Around the Globe

NDM-1

OXA-48

KPC

Vasoo, et al. Mayo Clinic Proceedings. 2015

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A Growing Threat – CRE in Feb. 2016

✓✓

✓✓

✓✓

✓✓

CDC. 2015

Page 28: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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CRE – Treatment Options • Carbapenems• Polymyxins

• Colistin and polymyxin B

• Tetracyclines• Tigecycline

• Aminoglycosides• Fosfomycin• Avibactam

Page 29: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Carbapenems

• Enterobacteriaceae is considered “resistant” to meropenem when the MIC is ≥ 4 mcg/mL

• Time above MIC of 40% (40% T>MIC) is achievable with high doses and extended infusions

Rennie RP, et al. Can J Infect Dis Med Microbiol. 2014Nicolau DP, Clin Infect Dis. 2008

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Carbapenems – The MIC Matters

Rennie RP, et al. Can J Infect Dis Med Microbiol. 2014Nicolau DP, Clin Infect Dis. 2008

Roberts JA, et al. Journal of Antimicrobial Chemotherapy. 2009

0

20

40

60

80

100

0.25 0.5 1 2 4 8 16

1 g q8h1 g q8h (extended)2 g q8h (extended)

Meropenem MIC(mcg/mL)

Pro

babi

lity

of ≥

40%

T>M

IC (%

)

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Carbapenems - Synergy

• Dual carbapenem treatment has been described• Ertapenem + meropenem• Ertapenem + doripenem

• Both combinations are synergistic in vitro• Several reports of synergy in truly carbapenem resistant

organisms

• Limited to case reports• Largest case series published to date reports 39% overall

success rate, and 79% microbiological success rate

Ceccarelli G, et al. J Antimicrob Chemother. 2013Cprek JB, et al. Antimicrob Agents Chemother. 2016

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Polymyxins• Utility is limited by significant nephro- and

neurotoxicity.• Serratia, Proteus, and Providencia are

intrinsically resistant.• Often the sole “sensitive” antimicrobial on the

panel.

Lee GC, et al. Annals of Clinical Microbiology and Antimicrobials. 2012Landham D, et al. Clin Microbiol Rev. 2008

Polymyxin monotherapy will fail.

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Fosfomycin• In general, treatment should be limited to lower

urinary tract infections• A single case report describes clearance of

KPC bacteremia after high dose oral therapy with fosfomycin, in addition to doxycycline and meropenem

• 9 grams orally every 8 hours

Kyle JM, et al. Annals of Pharmacotherapy. 2015

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Avibactam

Clavulanic Acid Sulbactam Tazobactam

Avibactam

Sharma R, et al. Clinical Therapeutics. 2016

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Avibactam

• Non-beta lactam beta lactamase inhibitor with activity against Ambler Class A, C, and D enzymes.

• Including KPC• No activity against metallo-beta lactamases

• FDA approval in combination with ceftazidime for complicated intraabdominal infections and complicated urinary tract infections

• CRE poorly represented in phase 3 studies

Ceccarelli G, et al. J Antimicrob Chemother. 2013Cprek JB, et al. Antimicrob Agents Chemother. 2016

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Avibactam

Vasoo S, et al. Antimicrob Agents Chemother. 2015

% of KPC Isolates Inhibited (n = 108)

Antibiotic Concentration (mcg/mL)

0.5 1 2 4 8 16

Ceftazidime - - - - 4% 7%

Ceftazidime + Avibactam 38% 79% 92% 97% 100% -

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Case• You receive a call from a frantic provider who

exclaims over the phone, “I have a patient growing Klebsiella that’s resistant to everything!” What should I do?

You look up the patient’s medical record and find the following culture:

Page 38: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Case

Klebsiella pneumoniae BLOOD (aerobic)Ampicillin >16 R Amp/Sulb >16/8 R Ciprofloxacin >2 RCeftriaxone >32 R Ceftazidime >16 R Pip/Taz > 64/16 RCefepime >16 R Meropenem 4 R Levofloxacin >4 RGentamicin >32 R Tobramycin >16 R Amikacin >32 RTMP/SMX > 2/38 R Aztreonam > 16 R Minocycline >4 RTigecycline 2 S Fosfomycin >128 R Colistin 2 S

• The provider explains that this patient has recurrent episodes of urosepsis due to a chronic indwelling urinary catheter and “each subsequent infection is more resistant.”

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Case• Which of the following statements is true?

1. This organism produces a carbapenaseand meropenem should be avoided.

2. Tigecycline + polymyxin B is a viable treatment option.

3. Extended infusion meropenem + colistin is a viable treatment option.

4. Colistin monotherapy is a viable treatment option.

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Case• Suppose the meropenem MIC > 16. Which of

the following would be reasonable salvage options?

1. Initiate treatment with ceftazidime/avibactam

2. Attempt dual carbapenem treatment3. Extended infusion meropenem + colistin4. 1 & 2

Page 41: Breaking the Ring - Mayo Clinic PGR (2).pdf · ©2015 MFMER | slide-5 Beta Lactamases • Ancient enzymes that have evolved in bacteria over the last 2 billion years • Structurally

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Summary• Not all beta lactamases require “big gun

antibiotics.”• Beware of AmpC production in Enterobacter.

• Have a low threshold to redo susceptibilities in a patient failing therapy.

• Carbapenemases are becoming increasingly common.

• Creativity is needed to treat patients with carbapenemase-producing bacteria.

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Questions & Discussion