id board review: antimicrobial resistance paul pottinger, md, dtm&h director, uwmc antimicrobial...

ID Board Review:ID Board Review:Antimicrobial ResistanceAntimicrobial Resistance

Paul Pottinger, MD, DTM&HPaul Pottinger, MD, DTM&HDirector, UWMC Antimicrobial Stewardship Director, UWMC Antimicrobial Stewardship

ProgramProgram

July 8July 8, 2011, 2011

• Review mechanisms of abx resistance Review mechanisms of abx resistance among gram-positive & gram-negative among gram-positive & gram-negative bacteria.bacteria.

• Best guess as to Boards content.Best guess as to Boards content.

• Suggested approaches for real-life Suggested approaches for real-life clinical ID. clinical ID.

ObjectivesObjectives

• Handful of flat-out resistance Handful of flat-out resistance questions (e.g. questions (e.g. ““The mechanism of The mechanism of vancomycin resistance in VRSA is…vancomycin resistance in VRSA is…””) )

• Likely clinical stem: pt with proven Likely clinical stem: pt with proven bacterial infection is failing therapy, bacterial infection is failing therapy, and you need to decide why... and you need to decide why... And And what to do next.what to do next.

• Probably not much related to abx Probably not much related to abx stewardship stewardship

What will be on the Boards?What will be on the Boards?

Which of the following resistance patterns is Which of the following resistance patterns is accurate for MRSA (ORSA)?accurate for MRSA (ORSA)?

DrugDrug AA BB CC DD EE

PenicillinPenicillin RR RR RR RR RR

Amp-SulbactamAmp-Sulbactam SS RR RR RR RR

CephalothinCephalothin SS RR RR RR RR

CeftazidimeCeftazidime SS SS SS RR RR

ImipenemImipenem SS SS RR RR RR

VancomycinVancomycin SS SS SS SS RR

2007 Virginia Board Review Course

MRSA in 2007:94,000 severely ill19,000 die

1999CDC: 4 healthy kidsdie of CA-MRSA

1981Community-AcquiredMRSA Reported1974

MRSA: 2% of USnosocomialstaph infections

1968MRSA found inBoston Hospitals

1961Methicillin-resistantS.aureus (MRSA)Described in Europe

1950’sS.Aureus shows PCN-resistance

1942Penicillin CuresS.aureus wound

1928Penicillin Discovered(on S.aureus plate)

1959Methicillin Introducedto kill PRSA

Charles DarwinCharles Darwin(1809-1882)(1809-1882)

Told you soTold you so1997MRSA: 50% USnosocomial staph infxns

http://www.lg1.ch/cpg/thumbnails.phphttp://www.lg1.ch/cpg/thumbnails.php

““MRSAMRSA”” a misnomer… a misnomer…but clinical significance is clear:but clinical significance is clear:First-Line First-Line ββ–lactams won–lactams won’’t work!t work!

Therapy may requireTherapy may require:: Expensive and Toxic AbxExpensive and Toxic Abx IV administrationIV administration Longer Courses of TherapyLonger Courses of Therapy

MRSAMRSA MRSA: Resistant to all beta-MRSA: Resistant to all beta-

lactams, monobactams, lactams, monobactams, carbapenemscarbapenems

MOR:MOR:Target Modification: MecA gene encodes Target Modification: MecA gene encodes

altered PCN-binding protein PBP2Aaltered PCN-binding protein PBP2ADx by KB-diffusion (Fox best inducer!), Dx by KB-diffusion (Fox best inducer!),

robotic microtiter, PBP2A latex robotic microtiter, PBP2A latex agglutination, or MecA PCRagglutination, or MecA PCR

Other resistance genes common!Other resistance genes common!

CaseCase• A 20 y/o woman with painful, red rash on A 20 y/o woman with painful, red rash on

buttock for last 4 daysbuttock for last 4 days• Recently joined college rowing teamRecently joined college rowing team

• Clindamycin is started pending susceptibility Clindamycin is started pending susceptibility results.results.

S.aureusS.aureus

DrugDrug InterpretationInterpretation

OxacillinOxacillin RESISTANTRESISTANT

ErythromycinErythromycin RESISTANTRESISTANT

ClindamycinClindamycin SUSCEPTIBLESUSCEPTIBLE

RifampinRifampin SUSCEPTIBLESUSCEPTIBLE

TMP/SMXTMP/SMX SUSCEPTIBLESUSCEPTIBLE

VancomycinVancomycin SUSCEPTIBLESUSCEPTIBLE

A)A) Check on the patient and request a D test Check on the patient and request a D test to rule out inducible resistanceto rule out inducible resistance

B)B) Continue clinda. No further testing.Continue clinda. No further testing.C)C) Change to Trimethoprim / Sulfa Change to Trimethoprim / Sulfa D)D) Add rifampinAdd rifampinE)E) Change to linezolidChange to linezolid

• Clindamycin is started pending susceptibility Clindamycin is started pending susceptibility results.results.

S.aureusS.aureus

DrugDrug InterpretationInterpretation

OxacillinOxacillin RESISTANTRESISTANT

ErythromycinErythromycin RESISTANTRESISTANT


RifampinRifampin SUSCEPTIBLESUSCEPTIBLE



A)A) Check on the patient and request a D test Check on the patient and request a D test to rule out inducible resistanceto rule out inducible resistance

B)B) Continue clinda. No further testing.Continue clinda. No further testing.C)C) Change to Trimethoprim / Sulfa Change to Trimethoprim / Sulfa D)D) Add rifampinAdd rifampinE)E) Change to linezolidChange to linezolid

MRSAMRSA Clinda ResistanceClinda Resistance

MOR:MOR:Target Modification: erm gene encodes Target Modification: erm gene encodes

methylated 50S ribosome subunit, methylated 50S ribosome subunit, inactivating erythro and clinda.inactivating erythro and clinda.

Constitutive or Inducible.Constitutive or Inducible.Erythro a more potent inducer than clinda Erythro a more potent inducer than clinda

in vitro.in vitro.

MRSAMRSA Clinda ResistanceClinda Resistance

Detection:Detection:Put clinda disk next to erythro, look for Put clinda disk next to erythro, look for ““D-D-

zone.zone.””

Clinical Significance:Clinical Significance:Uncertain, but Rx failures reported with Uncertain, but Rx failures reported with

clinda… for boards & your practice, take D-clinda… for boards & your practice, take D-zone seriously, and consider changing zone seriously, and consider changing therapy if this is detected.therapy if this is detected.

MRSA: MRSA: Two FlavorsTwo Flavors

Spectrum of DiseaseSpectrum of Disease

CA-MRSACA-MRSA HA-MRSAHA-MRSA

MRSA: MRSA: Two FlavorsTwo Flavors

MRSA typeMRSA type CommunityCommunity HospitalHospital

Chromosomal Cassette

IV II

Toxins Produced

Numerous Few

PVL Toxin Common Rare

Common Infections

Skin & Soft Tissue

Lung & Blood

Abx Resistance Less Resistant More Resistant

MRSA Susceptibilities: Seattle 2009MRSA Susceptibilities: Seattle 2009

Clindamycin*Clindamycin*

LevofloxacinLevofloxacin

DoxycyclineDoxycycline

TMP/SMXTMP/SMX

VancomycinVancomycin

LinezolidLinezolid

DaptomycinDaptomycin

HarborviewHarborview UWMCUWMC

63%63% 41% 41%

20%20% 12% 12%

94%94% 94% 94%

95%95% 95% 95%

100%100% 100% 100%

100%100% 100%100%

100%100% 100%100%

*D-zone test should be done to look for inducible resistance to *D-zone test should be done to look for inducible resistance to clindamycin: 7% at HMC and 12% at UWMCclindamycin: 7% at HMC and 12% at UWMC

• A PCP calls MEDCON wanting to know A PCP calls MEDCON wanting to know how to interpret a sensi pattern.how to interpret a sensi pattern.

• Otherwise healthy young man with infected Otherwise healthy young man with infected wound of his ankle… already on empiric wound of his ankle… already on empiric cephalexin… no major change in wound cephalexin… no major change in wound appearance since cx drawn 48 hours ago.appearance since cx drawn 48 hours ago.

CaseCase

S.AureusS.Aureus

Beta-Lactamase PositiveBeta-Lactamase PositiveDrugDrug InterpretationInterpretation

PenicillinPenicillin RESISTANTRESISTANT

OxacillinOxacillin SUSCEPTIBLESUSCEPTIBLE


LinezolidLinezolid SUSCEPTIBLESUSCEPTIBLE

LevofloxacinLevofloxacin SUSCEPTIBLESUSCEPTIBLE



A)A) This is MRSA, change to TMP/SMX.This is MRSA, change to TMP/SMX.B)B) This is MRSA, change to IV Vanco.This is MRSA, change to IV Vanco.C)C) This is MSSA, continue cephalexin.This is MSSA, continue cephalexin.D)D) Something is wrong with your lab….Something is wrong with your lab….

A)A) This is MRSA, change to TMP/SMX.This is MRSA, change to TMP/SMX.B)B) This is MRSA, change to IV Vanco.This is MRSA, change to IV Vanco.C)C) This is MSSA, continue cephalexin.This is MSSA, continue cephalexin.D)D) Something is wrong with your lab….Something is wrong with your lab….

MSSA: Beta LactamasesMSSA: Beta Lactamases

• Original form of PCN resistance: PRSA.Original form of PCN resistance: PRSA.

• Still the rule (~5% of MSSA has no Still the rule (~5% of MSSA has no beta-lactamase activity, thus is PSSA).beta-lactamase activity, thus is PSSA).

• For most situations, what you see is For most situations, what you see is what you get for MSSA sensitivities.what you get for MSSA sensitivities.

MSSA: Beta LactamasesMSSA: Beta Lactamases

• Caveat: Caveat: Not all beta-lactamases are the Not all beta-lactamases are the same!same!

• Type A beta-lactamase may hydrolyze Type A beta-lactamase may hydrolyze cefazolin specifically at cefazolin specifically at high inocula high inocula (eg: IE)… this is the (eg: IE)… this is the ““inoculum effectinoculum effect””

• If pt with MSSA IE fails cefazolin, If pt with MSSA IE fails cefazolin, recognize inoculum effect and recognize inoculum effect and recommend change to naf or ox.recommend change to naf or ox.

Nannini et al, CID 2009

CaseCase• A 70 y/o woman with dementia & DM-A 70 y/o woman with dementia & DM-

nephropathy admitted from SNF for sepsis.nephropathy admitted from SNF for sepsis.• Long h/o foot ulcers with VRE & MRSA.Long h/o foot ulcers with VRE & MRSA.• Urine grows MRSA → Vanco begun.Urine grows MRSA → Vanco begun.• Remains febrile after 6 days.Remains febrile after 6 days.A)A) No Big DealNo Big Deal

B)B) Target Vanco trough 15-20 mcg/mLTarget Vanco trough 15-20 mcg/mLC)C) Consider DaptomycinConsider DaptomycinD)D) Consider LinezolidConsider LinezolidE)E) Wish I had dedicated my career to Wish I had dedicated my career to

combating antimicrobial resistance….combating antimicrobial resistance….

> 100K > 100K S.aureusS.aureus

DrugDrug MICMIC InterpretationInterpretation

OxacillinOxacillin 44 RESISTANTRESISTANT

ChloramphenicolChloramphenicol 44 SUSCEPTIBLESUSCEPTIBLE

LinezolidLinezolid 22 SUSCEPTIBLESUSCEPTIBLE

RifampinRifampin 11 SUSCEPTIBLESUSCEPTIBLE

TMP/SMXTMP/SMX 2/382/38 SUSCEPTIBLESUSCEPTIBLE

VancomycinVancomycin 44 SUSCEPTIBLESUSCEPTIBLE

MRSA: Vancomycin MIC Creep?MRSA: Vancomycin MIC Creep?

• Not all VSSA created alike.Not all VSSA created alike.

• Published reports of rising vanco MICPublished reports of rising vanco MIC’’s s in last 5 years.in last 5 years.

• Presumed MOR: increased cell wall Presumed MOR: increased cell wall thickness.thickness.

• Retrospective case series: higher MICRetrospective case series: higher MIC’’s s associated with higher liklihood of associated with higher liklihood of clinical failure on vanco (Soriano et al, clinical failure on vanco (Soriano et al, CID 2008).CID 2008).

MRSA: Vancomycin MIC Creep?MRSA: Vancomycin MIC Creep?

• MIC ≤ 2 still considered susceptible MIC ≤ 2 still considered susceptible (VSSA)… Concern: clinical failures with (VSSA)… Concern: clinical failures with vanco, and theoretically with dapto.vanco, and theoretically with dapto.

• Recommend you check vanco MIC Recommend you check vanco MIC when pt fails to clear bacteremia or when pt fails to clear bacteremia or clinically improve after 7 days of clinically improve after 7 days of therapy.therapy.

• ““ConsiderConsider”” switch to alternative agent if switch to alternative agent if MIC = 2, MIC = 2, andand if pt is failing vanco. if pt is failing vanco.

CaseCase• A 70 y/o woman with dementia & DM-A 70 y/o woman with dementia & DM-

nephropathy admitted from SNF for sepsis.nephropathy admitted from SNF for sepsis.• Long h/o foot ulcers with VRE & MRSA.Long h/o foot ulcers with VRE & MRSA.• Urine grows MRSA → Vanco begun.Urine grows MRSA → Vanco begun.• Remains febrile after 6 days.Remains febrile after 6 days.> 100K > 100K S.aureusS.aureus

DrugDrug MICMIC InterpretationInterpretation

OxacillinOxacillin 44 RESISTANTRESISTANT

ChloramphenicolChloramphenicol 44 SUSCEPTIBLESUSCEPTIBLE

LinezolidLinezolid 22 SUSCEPTIBLESUSCEPTIBLE

RifampinRifampin 11 SUSCEPTIBLESUSCEPTIBLE

TMP/SMXTMP/SMX 2/382/38 SUSCEPTIBLESUSCEPTIBLE

VancomycinVancomycin 44 SUSCEPTIBLESUSCEPTIBLE

Case: VISA / VRSA?Case: VISA / VRSA?

VISA: MIC 4 – 8 mcg/mLVISA: MIC 4 – 8 mcg/mL

• Increasing # of case reports: MSSA & MRSAIncreasing # of case reports: MSSA & MRSA• MOR: MOR: Increased Target DensityIncreased Target Density

Prolonged Vanco Prolonged Vanco exposureexposure

Prolonged Vanco Prolonged Vanco exposureexposure

Selection of Thicker Cell Selection of Thicker Cell WallsWalls

Selection of Thicker Cell Selection of Thicker Cell WallsWalls

Vanco exposure Vanco exposure to to

D-Ala-D-Ala D-Ala-D-Ala residuesresidues

Vanco exposure Vanco exposure to to

D-Ala-D-Ala D-Ala-D-Ala residuesresidues

IDSA may stillIDSA may stillcall this call this ““GISAGISA””IDSA may stillIDSA may stillcall this call this ““GISAGISA””

New ResistantNew Resistant Bacteria Bacteria

Selective Pressure Selective Pressure Upregulation of Upregulation of resistance factors or novel mutations.resistance factors or novel mutations.

XXXX

Susceptible BacteriaSusceptible Bacteria

Emergence of Antimicrobial Emergence of Antimicrobial ResistanceResistance

CDCCDC

Told you soTold you so

Case: VISA?Case: VISA?

VISA: MIC 4 – 8 mcg/mLVISA: MIC 4 – 8 mcg/mL

Clinical SignificanceClinical SignificanceTreatment failures reported with standard-Treatment failures reported with standard-

dose vancomycindose vancomycinIn theory, can overwhelm resistance In theory, can overwhelm resistance

mechanism by pushing dose to mechanism by pushing dose to ““saturatesaturate”” thicker wall… but not recommended thicker wall… but not recommended (higher toxicity, risk of failure, alternatives (higher toxicity, risk of failure, alternatives available)available)


hVISA: MIC 4 – 8 mcg/mLhVISA: MIC 4 – 8 mcg/mL

Heteroresistant VISAHeteroresistant VISAMOR: MOR: Mixed population of thickened cell Mixed population of thickened cell

wall bugswall bugshVISA well described, but of unclear hVISA well described, but of unclear

clinical significanceclinical significanceReports of vanco treatment failure Reports of vanco treatment failure

reported… but detection bias is almost reported… but detection bias is almost certainly taking placecertainly taking place



Detection IssuesDetection IssuesStandard disk diffusion (zone ≤15 mm) and Standard disk diffusion (zone ≤15 mm) and

automated systems (Vitek) will automated systems (Vitek) will missmiss hVISA hVISASuspect hVISA if pt persistently culture + Suspect hVISA if pt persistently culture +

after 7 days on vancoafter 7 days on vancoConsider 0.5 McFarland starting culture for Consider 0.5 McFarland starting culture for

E-testE-testConsider sending isolate to state labConsider sending isolate to state lab

No CLSI-approvedNo CLSI-approveddetection methodsdetection methods

for hVISA!for hVISA!



Robin Howe (ICAAC 2007)Robin Howe (ICAAC 2007)

Reasonable balance of sensitivity & Reasonable balance of sensitivity & specificity: plate on MHA with teicoplanin at specificity: plate on MHA with teicoplanin at 4 mcg/ml x 48 hours to pick up most VISA 4 mcg/ml x 48 hours to pick up most VISA & hVISA.& hVISA.

Consider sending isolate to state lab if any Consider sending isolate to state lab if any question of hVISA!question of hVISA!

Unlikely to appear on boardsUnlikely to appear on boards..

VRSAVRSA

MecAMecAVanAVanA

VREVRE MRSAMRSA

integrationintegration

11th US case reported 5/6/10!

Armageddon: Armageddon: VRSAVRSA

VRSA: MIC VRSA: MIC 16 mcg/mL 16 mcg/mL

• Few case reports… Under-detected?Few case reports… Under-detected?

• MOR:MOR:Altered target.Altered target.

VRE implicated as source of VanA gene VRE implicated as source of VanA gene encoding altered cell wall (D-encoding altered cell wall (D-ala-D-ala → ala-D-ala → D-ala-D-lacD-ala-D-lac))

• Treatment Option: Linezolid first-lineTreatment Option: Linezolid first-line

Case: VISA / VRSA?Case: VISA / VRSA?

DIAGNOSISDIAGNOSIS

• Robots have missed VISA & VRSA!!Robots have missed VISA & VRSA!!

• CDC: Vanco plate (6mg/mL) should CDC: Vanco plate (6mg/mL) should accompany all accompany all S.aureusS.aureus isolates… but this isolates… but this alone is alone is not enoughnot enough..

• Formal rule-outFormal rule-outnotnot done routinely. done routinely.

LINEZOLIDLINEZOLID

VANCOMYCINVANCOMYCIN

FYI only… NOT on boards!

Case: VISA / VRSACase: VISA / VRSANewer Treatment OptionsNewer Treatment Options

LinezolidLinezolid DaptomycinDaptomycin TigecyclineTigecycline•OxazolidinoneOxazolidinone•Inhibits RibosomesInhibits Ribosomes•> 95% Sensitive> 95% Sensitive•PO & IV: 600 mg PO & IV: 600 mg Q12 HQ12 H•Good vol. of Good vol. of distributiondistribution• ~30% ~30% plts after plts after 10-14 days… 10-14 days… •$$$$$$

•LipopeptideLipopeptide•Depolarizes Depolarizes membranemembrane•> 95% Sensitive> 95% Sensitive•IV only: IV only: 4mg/kg/day4mg/kg/day•Will not cover PNAWill not cover PNA•Renal toxicity & Renal toxicity & Myositis…Myositis…•$$$$$$

•GlycylglycineGlycylglycine•Inhibits RibosomesInhibits Ribosomes•~90% Sensitive~90% Sensitive•IV only: 50mg IV only: 50mg Q12HQ12H•Good distributionGood distribution•No renal toxicityNo renal toxicity•30% severe 30% severe nauseanausea•$$$$$$

Watch out for Watch out for Serotonin Syndrome!Serotonin Syndrome!



•LipopeptideLipopeptide•Depolarizes Depolarizes membranemembrane•> 95% Sensitive> 95% Sensitive•IV only: 4-6 mg/kg/ IV only: 4-6 mg/kg/ dayday•Will not cover PNAWill not cover PNA•Renal toxicity & Renal toxicity & Myositis…Myositis…•$$$$$$

•GlycylglycineGlycylglycine•Inhibits RibosomesInhibits Ribosomes•~90% Sensitive~90% Sensitive•IV only: 50mg IV only: 50mg Q12HQ12H•Good distributionGood distribution•No renal toxicityNo renal toxicity•30% severe 30% severe nauseanausea•$$$$$$

• Massive, Cyclic LipopeptideMassive, Cyclic Lipopeptide

• Excellent MICExcellent MIC’’s vs. MRSA, but…s vs. MRSA, but…• Dissolves in Alveolar Surfactant!Dissolves in Alveolar Surfactant!• Failure risk in thick-walled VISA!Failure risk in thick-walled VISA!

VISA / VRSA Rx OptionsVISA / VRSA Rx Options




•GlycylglycineGlycylglycine•Inhibits RibosomesInhibits Ribosomes•~90% Sensitive~90% Sensitive•IV only: 50mg IV only: 50mg Q12HQ12H•Poor staying power Poor staying power in blood!in blood!•No renal toxicityNo renal toxicity•30% severe 30% severe nauseanausea•$$$$$$




•GlycylglycineGlycylglycine•Inhibits RibosomesInhibits Ribosomes•~90% Sensitive~90% Sensitive•IV only: 50mg IV only: 50mg Q12HQ12H•Poor staying power Poor staying power in blood!in blood!•No renal toxicityNo renal toxicity•30% severe 30% severe nauseanausea•$$$$$$

Approved in 2011… Approved in 2011… Ceftaroline!Ceftaroline!

PRSP: WhatPRSP: What’’s New?s New?Odds of PCN Resistance in Odds of PCN Resistance in S.pneumoniaeS.pneumoniae as Function of PCN as Function of PCN

ConsumptionConsumption

MIC Breakpoints for S.pneumoniae MIC Breakpoints for S.pneumoniae isolated from blood in pts with isolated from blood in pts with pneumoniapneumonia (mcg/mL) (mcg/mL)

Susceptible Intermediate Resistant

Updated 4/08

≤ 2 4 ≥ 8

Previous ≤ 0.06 0.12-1 ≥ 2

• A 68 y/o woman with type-2 DM & HTN A 68 y/o woman with type-2 DM & HTN recently Rxrecently Rx’’d for CAP with cefotaxime.d for CAP with cefotaxime.

• Now admitted for major CVA. Now admitted for major CVA. • Febrile → BCx & foley cath urine grew Febrile → BCx & foley cath urine grew

K.pneumoniae → Ceftazidime started.K.pneumoniae → Ceftazidime started.• Two days later: Fever breaks, but she Two days later: Fever breaks, but she

becomes less responsive….becomes less responsive….

A)A) Switch to Levo or CiproSwitch to Levo or CiproB)B) Switch to CeftriaxoneSwitch to CeftriaxoneC)C) Switch to CefepimeSwitch to CefepimeD)D) Switch to MeropenemSwitch to MeropenemE)E) EverythingEverything’’s groovy, make no changes groovy, make no change

A)A) Switch to Levo or CiproSwitch to Levo or CiproB)B) Switch to CeftriaxoneSwitch to CeftriaxoneC)C) Switch to CefepimeSwitch to CefepimeD)D) Switch to MeropenemSwitch to MeropenemE)E) EverythingEverything’’s groovy, make no changes groovy, make no change

CaseCase

Emerging Resistance: ESBLEmerging Resistance: ESBL

Extended Spectrum ß-LactamasesExtended Spectrum ß-Lactamases• Mutant TEM-1, SHV-1, CTX-M, or OXA Mutant TEM-1, SHV-1, CTX-M, or OXA

ß-lactamaseß-lactamase

• MOR: MOR: Drug Inactivation (Enzymes hydrolyze Drug Inactivation (Enzymes hydrolyze all ß-lactams, not inhibited by BLIall ß-lactams, not inhibited by BLI’’s)s)

• Usually in Usually in KlebsiellaKlebsiella spp. and spp. and E.coli… but E.coli… but plasmid-encoded!plasmid-encoded!

• Consider in all nosocomial infections with Consider in all nosocomial infections with these organisms these organisms Risk Factor = Previous ß-lactam useRisk Factor = Previous ß-lactam use

ESBLESBL• Worry if resistance Worry if resistance ““skips a generationskips a generation””

• Confirm with Confirm with 3-fold decrease in MIC with 3-fold decrease in MIC with ßß–lacatmase inhibitor–lacatmase inhibitor

• Rx of choice:Rx of choice: CarbapenemCarbapenem

• Variable success:Variable success: FQFQ AminoglycosideAminoglycoside Cefoxitin (we do NOT report as sensitive)Cefoxitin (we do NOT report as sensitive)

New ResistantNew Resistant Bacteria Bacteria

Susceptible BacteriaSusceptible Bacteria

ResistantResistant Bacteria Bacteria

Resistance Gene TransferResistance Gene Transfer

Emergence of Antimicrobial Emergence of Antimicrobial ResistanceResistance

CDCCDC

MOAMOA ESBLESBLLocation Plasmid

Bugs E.coli, Klebsiella

1 gen Ceph R

2 gen Ceph S

3 gen Ceph R

4 gen Ceph R / S

Cefotax + Clav

S

Carbapenem S

GNR Resistance Detection Summary

• A 58 y/o man with A 58 y/o man with Serratia marcescens Serratia marcescens hardware-associated osteomyelitis of the hardware-associated osteomyelitis of the tibia.tibia.

• Treated for last 4 weeks with IV ampicillin / Treated for last 4 weeks with IV ampicillin / sulbactam, doing well. sulbactam, doing well.

• Unexpected fever develops → BCx grows Unexpected fever develops → BCx grows Serratia.Serratia.

A)A) Switch to Levo or CiproSwitch to Levo or CiproB)B) Switch to CeftriaxoneSwitch to CeftriaxoneC)C) Switch to CefepimeSwitch to CefepimeD)D) Switch to MeropenemSwitch to MeropenemE)E) I should have talked to the Micro Lab!I should have talked to the Micro Lab!

A)A) Switch to Levo or CiproSwitch to Levo or CiproB)B) Switch to CeftriaxoneSwitch to CeftriaxoneC)C) Switch to CefepimeSwitch to CefepimeD)D) Switch to MeropenemSwitch to MeropenemE)E) I should have talked to the Micro Lab!I should have talked to the Micro Lab!

CaseCase

S.marcescensS.marcescens

DrugDrug PriorPrior TodayToday

CiproCipro RR RR

AmpAmp RR RR

Amp / SulbactamAmp / Sulbactam SS RR

CefazolinCefazolin RR RR

CefotixinCefotixin SS RR

CeftriaxoneCeftriaxone SS RR

CefepimeCefepime SS SS

MeropenemMeropenem SS SS

Paul Pottinger, MD

AmpC: WhatAmpC: What’’s in a Name?s in a Name?

SerratiaSerratia

Pseudomonas, ProvidenciaPseudomonas, Providencia

Indole + Proteus (vulgaris)Indole + Proteus (vulgaris)

CitrobacterCitrobacter

EnterobacterEnterobacter

MorganellaMorganella

SS

PP

II

CC

EE

MM

Emerging Resistance: AmpCEmerging Resistance: AmpC

AmpC ß-LactamasesAmpC ß-Lactamases• Enzymes hydrolyze penicillins & Gen 1-3 Enzymes hydrolyze penicillins & Gen 1-3

cephalosporinscephalosporins

• Chromosome of Chromosome of ““SPICEMSPICEM”” organisms, but organisms, but often not expressed until drug pressure often not expressed until drug pressure appliedapplied

• Can be transferred on plasmids alsoCan be transferred on plasmids also

• Consider in all infections with SPICEM bugs Consider in all infections with SPICEM bugs when initial improvement fails (when initial improvement fails (““induction of induction of AmpCAmpC””))

MOAMOA AmpCAmpC ESBLESBLLocation Chromosome Plasmid

Bugs “SPICEM” E.coli, Klebsiella

1 gen Ceph R R

2 gen Ceph R S

3 gen Ceph R R

4 gen Ceph S R / S

Cefotax + Clav

R S

Carbapenem S S

GNR Resistance Detection SummaryGNR Resistance Detection Summary

• A 75 y/o woman is admitted with massive A 75 y/o woman is admitted with massive myocardial infarction.myocardial infarction.

• After five days on the ventilator, she After five days on the ventilator, she develops hypoxemia, fever, leukocytosis, develops hypoxemia, fever, leukocytosis, and infiltrates. She is treated empirically for and infiltrates. She is treated empirically for VAP using meropenem.VAP using meropenem.

• Sputum gram stain shows 3+ GNRSputum gram stain shows 3+ GNR’’s.s.• Clinical illness worsens on therapy….Clinical illness worsens on therapy….

A)A) Switch to Levo or CiproSwitch to Levo or CiproB)B) Switch to CeftriaxoneSwitch to CeftriaxoneC)C) Switch to CefepimeSwitch to CefepimeD)D) Switch to ImipenemSwitch to ImipenemE)E) Switch to tobramycinSwitch to tobramycin

A)A) Switch to Levo or CiproSwitch to Levo or CiproB)B) Switch to CeftriaxoneSwitch to CeftriaxoneC)C) Switch to CefepimeSwitch to CefepimeD)D) Switch to ImipenemSwitch to ImipenemE)E) Switch to tobramycinSwitch to tobramycin

CaseCase

Emerging Resistance: KPCEmerging Resistance: KPC

KPC CarbapenemasesKPC Carbapenemases• Enzymes hydrolyze carbapenemsEnzymes hydrolyze carbapenems

• All Carbapenems susceptibleAll Carbapenems susceptible

• Klebsiella pneumoniae Klebsiella pneumoniae strongest strongest association… also seen in association… also seen in enterobacteriaciae & P.aeruginosaenterobacteriaciae & P.aeruginosa

• Can be transferred on plasmidsCan be transferred on plasmids

• Consider in all infections with Consider in all infections with K.pneumoniaeK.pneumoniae or other enterobacteriaciae which fail to or other enterobacteriaciae which fail to improve on carbapenem therapyimprove on carbapenem therapy


Detection PitfallsDetection Pitfalls• Imipenem, Meropenem, Doripenem may Imipenem, Meropenem, Doripenem may

appear susceptible on standard sensi panel appear susceptible on standard sensi panel (MIC(MIC’’s relatively low)s relatively low)

Ertapenem has highest MICs, so rule out KPC Ertapenem has highest MICs, so rule out KPC with erta E-test.with erta E-test.


Treatment OptionsTreatment Options• Beta-lactams are generally ineffectiveBeta-lactams are generally ineffective

• Plasmids often contain resistance Plasmids often contain resistance determinants for numerous other drugsdeterminants for numerous other drugs

• Tigecycline has been used successfullyTigecycline has been used successfully• Test aminoglycosides, FQTest aminoglycosides, FQ’’s, tetracyclines, s, tetracyclines,

glycylglycines, TMP/SMX, colistin… and pray.glycylglycines, TMP/SMX, colistin… and pray.

MOAMOA AmpCAmpC ESBLESBL KPCKPCLocation Chromosome Plasmid Plasmid

Bugs “SPICEM” E.coli, Klebsiella Klebsiella, enterobacteriaceae

1 gen Ceph R R R

2 gen Ceph R S R / S

3 gen Ceph R R R

4 gen Ceph S R / S R

Cefotax + Clav

R S R

Carbapenem S S R

GNR Resistance Detection Summary

““DonDon’’t forget to take a handful of ourt forget to take a handful of ourcomplimentary antibiotics on your way out.complimentary antibiotics on your way out.””

Resistance Update: Resistance Update: MRSAMRSA

Incidence:Incidence: Huge burden in hospitals and Huge burden in hospitals and outpatient clinics, and sure to rise!outpatient clinics, and sure to rise!

Vanco MIC Creep:Vanco MIC Creep: 2 mcg/mL not 2 mcg/mL not uncommon… and may lead to clinical uncommon… and may lead to clinical failurefailure

Treatment Options:Treatment Options: Vancomycin and TMP/SMX first line or Vancomycin and TMP/SMX first line or

SSTI! SSTI! Linezolid vs ceftaroline alternativesLinezolid vs ceftaroline alternatives Daptomycin (not in pneumonia)Daptomycin (not in pneumonia)

Resistance Update: Resistance Update: VISA / VRSAVISA / VRSA

VISA:VISA: Vanco MIC 4-8 mcg/mL Vanco MIC 4-8 mcg/mL

hVISA:hVISA: Same MIC Same MIC’’s, but harder to detects, but harder to detect

VRSA:VRSA: Vanco MIC ≥ 16 mcg/mL Vanco MIC ≥ 16 mcg/mL

Incidence:Incidence: Likely to rise... Beware vanco Likely to rise... Beware vanco failures!failures!

Detection:Detection: CDC algorithm CDC algorithm

Treatment Options:Treatment Options: LinezolidLinezolid Daptomycin (not in pneumonia)Daptomycin (not in pneumonia)

Resistance Update: Resistance Update: PRSPPRSP

• Apparent disconnect between Apparent disconnect between ““resistanresistantt”” and treatment failures in and treatment failures in pneumococcal pneumoniapneumococcal pneumonia

• IDSA Lobby At Work: New breakpoints IDSA Lobby At Work: New breakpoints for pneumonia allow PCN use at higher for pneumonia allow PCN use at higher MICsMICs

• No change to more stringent MICs for No change to more stringent MICs for meningitismeningitis

Resistance Update: ESBLResistance Update: ESBL

Extended-Spectrum Extended-Spectrum ßß-Lactamases-Lactamases

• Mechanism:Mechanism: Eats PCN Eats PCN’’s & Cephalosporinss & Cephalosporins

• Location:Location: PlasmidPlasmid

• Risk:Risk: Recent cephalosporin use followed by Recent cephalosporin use followed by Klebsiella or E.coli infectionKlebsiella or E.coli infection

• Detection:Detection: E-test with 3E-test with 3rdrd Gen Ceph +/- BLI Gen Ceph +/- BLI

• Empiric Rx:Empiric Rx: Carbapenem (and await lab Carbapenem (and await lab confirmation)confirmation)

Resistance Update: AmpCResistance Update: AmpC

AmpC AmpC ßß-Lactamases-Lactamases

• Mechanism:Mechanism: Eats PCN Eats PCN’’s & 1s & 1stst-3-3rdrd Gen Cephs Gen Cephs

• Location:Location: Chromosome (SPICEM) or plasmidChromosome (SPICEM) or plasmid

• Risk:Risk: Prolonged treatment with Prolonged treatment with ßß-Lactam -Lactam may induce resistance & cause failuremay induce resistance & cause failure

• Detection:Detection: Sensitive only to 4Sensitive only to 4thth Gen Ceph Gen Ceph

• Empiric Rx:Empiric Rx: 44thth Gen Ceph or Carbapenem Gen Ceph or Carbapenem

Resistance Update: KPCResistance Update: KPC

KPC CarbapenemasesKPC Carbapenemases

• Mechanism:Mechanism: Eats all beta lactams & Eats all beta lactams & carbapenemscarbapenems

• Location:Location: PlasmidPlasmid

• Risk:Risk: Klebsiella or enterobacteriaciae Klebsiella or enterobacteriaciae infectioninfection

• Detection:Detection: E-test with ertapenemE-test with ertapenem

• Empiric Rx:Empiric Rx: Combination with Combination with aminoglycoside (and await lab confirmation)aminoglycoside (and await lab confirmation)

Antibiotics Update:Antibiotics Update:What We DidnWhat We Didn’’t Covert Cover

• AntifungalsAntifungals

• AntiretroviralsAntiretrovirals

• AntiparasiticsAntiparasitics

[email protected]@uw.edu

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