Overcoming the PosESBLities of Enterobacteriaceae Resistance the PosESB… · Overcoming the...

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Overcoming the PosESBLities of Enterobacteriaceae Resistance Review of current treatment options

Jamie Reed, PharmD

Pharmacy Grand RoundsAugust 28, 2018

Rochester, MN


Disclosure• No financial relationship(s) pertinent to this session• Off-label use of the following medications will be

discussed during this presentation, including:• Meropenem• Ertapenem• Cefepime• Piperacillin/Tazobactam• Tigecycline• Nitrofurantoin

• Fosfomycin• Levofloxacin• Ciprofloxacin• Ceftolozane/Tazobactam• Ceftazidime/Avibactam


Objectives• Describe the resistance mechanism of

extended-spectrum β-lactamase (ESBL) producing enterobacteriaceae

• Discuss evidence based treatment options for ESBL infections

• Review the role of carbapenem sparing regimens for the treatment of ESBL infections


What is an Extended Spectrum β-Lactamase (ESBL)? • Plasmid mediated enzyme produced by

Enterobacteriaceae causing resistance, including:• Klebsiella spp. • Escherichia coli• Proteus spp.

• Resistance developed towards:• Penicillins• 1st, 2nd and 3rd generation cephalosporins• Monobactams

Ghafourian S et al. Curr Issues Mol Biol. 2015. 17:11-22.


Mechanism of ESBL Resistance

Ghafourian S et al. Curr Issues Mol Biol. 2015. 17:11-22.

NHO

NHO

NHO

NHO OH


Types of Extended Spectrum β-Lactamases

Ghafourian S et al. Curr Issues Mol Biol. 2015; 17:11-22.Bradford P. Clin Microbiol Rev. 2001; 14(4):933-951.

SHVTEM

SHV CTX-M OXATEM


Prevalence of ESBLs

Thaden et al. Infect Control Hosp Epidemiol. 2016; 37(1): 49-54.Ben-Ami et al. CID. 2006;42: 925-934

• In 2013 the CDC reported approximately• 26,000 ESBL infections • 1,700 deaths due to ESBL

• ESBL infection threat level is SERIOUS

ESBL-EC: 10.5 cases per 100,000 patient days

ESBL-KP: 5.3 cases per 100,000 patient days


Question 1What is the mechanism of ESBL resistance to penicillins, cephalosporins, and monobactams?

A. Methylation of the β-lactam ringB. Hydrolysis of the β-lactam ringC. Efflux transport out of the cellD. Modified penicillin binding proteins


Treatment Considerations for ESBL Infections

Effective treatment of ESBL infection

Minimize risk of further resistance

Source Severity Microbiology Drug Properties

Tamma et al. Clin Infect Dis. 2017; 64:972-980.


Treatment Options for ESBL Infections• Carbapenems• β-lactams/β-lactamase inhibitors (βL-βLIs) • Cefepime, cephamycins• Fluoroquinolones• Fosfomycin• Nitrofurantoin• Tigecycline


Generally drug of choice, especially in severe disease/high inoculum infections


ESBL Microbiological Result Example


β-Lactams/β-Lactamase Inhibitors (βL-βLIs)Piperacillin/Tazobactam, Ampicillin/Sulbactam, Amoxicillin/Clavulanate


βL-βLIs Debate for Treatment Efficacy • βLIs prevent hydrolysis of β-lactam ring

• Tazobactam• Sulbactam• Clavulanate

• Concern for inoculum effect with older βL-βLIs • Evidence for piperacillin/tazobactam in urinary or

biliary sourced infections, conflicting evidence for blood stream infections

Thomson et al. Antimicrob Agents Chemother. 2001; 45(12): 3548-3554Tamma et al. Clin Infect Dis. 2017; 64:972-980.


Tamma et al. PTZ vs Carbapenems for empiric ESBL bacteremia

Tamma et al. Clin Infect Dis. 2015; 60:1319- 1325

• Retrospective chart review• January 2007 to April 2014

• 331 adult patients with ESBL-E bacteremia treated empirically with:• Piperacillin/tazobactam (PTZ) (n=103)• Carbapenem (n=110)

• Primary outcome: mortality within 14 days from first day of detectable bacteremia


Tamma et al Results of PTZ for ESBL Infections

• Adjusted death risk is 1.92 times higher with PTZ vs carbapenems


Bacteremia Source Incidence

Catheter-related 46%

Urinary 21%

Intra-abdominal 17%

Pneumonia 9%

Biliary 9%


Tamma et al Conclusion• Increased mortality with PTZ vs carbapenem for

treatment of ESBL blood stream infections• Catheter related, urinary, pneumonia, intra-

abdominal, biliary infections• Carbapenems recommended first line therapy

in severe disease



Gutierrez-Gutierrez et al. βL-βLIs vs Carbapenems for ESBL Bacteremia

Gutierrez-Gutieerrez et al. Antimicrob Agents Chemother. 2016; 60:4159-69.

• Retrospective international study• January 2004-December 2013

• Adult patients with monomicrobial ESBL-E bacteremia • Cohorts: empiric (n=365) vs definitive therapy (n=601)

• Primary outcome: clinical response at day 14 and 30 day mortality


Gutierrez-Gutierrez et al. Mortality of βL-βLIs for ESBL Bacteremia Infections



Urinary 45%

Biliary 12%

Other 43%

βL-βLIs EmpiricIncidence

Definitive Incidence

Piperacillin/Tazobactam 72% 65%

Ampicillin/Sulbactam 27% 35%

Amoxicillin/Clavulanate 1% 0%


Gutierrez-Gutierrez et al. Conclusion• Similar mortality rates for βL-βLIs vs carbapenems in

blood stream infections due to ESBL-E

• βL-βLIs could be considered an alternative option for complicated ESBL infections related to:

• Urinary or biliary sources



Studies Comparing βL-βLI vs CarbapenemsAuthor Organism Bacteremia

SourceTherapy Outcomes (βL-βLI

vs Carbapenem)

Tamma et al K pneumoniae (68%)E coli (31%)P mirabilis (1%)

Catheter, urinary, intra-abdominal, biliary, pneumonia

PTZ (n=103) Mortality at 14 days: 17% vs 8% (p<0.05)

Mortality at 30 days: 26% vs 11% (p<0.01)

Carbapenem (n=110)

Gutierrez-Gutierrez et al

E coli (73%)K pneumoniae (19%)

Urinary or biliary βL-βLIEmpiric (n=170)Definitive (n=92)

Mortality at 30 day (empiric): 18% vs 20% (p=0.6)

Mortality at 30 days (definitive): 10 % vs 14% (p=0.28)

Carbapenem Empiric(n=195)Definitive(n=509)

Tamma et al. Clin Infect Dis. 2017; 64:972-80.Ofer-Friedman et al. Infect Control Hosp Epidemiol. 2015; 36:981-5. Tamma et al. Clin Infect Dis. 2015; 60:1319-25. Gutierrez-Gutieerrez et al. Antimicrob Agents Chemother. 2016; 60:4159-69.


Summary of Piperacillin-Tazobactam for ESBL Treatment• Recommended use in:

• Lower severity disease• Urinary or biliary sources• Lower inoculum infections

• Caution for use in severe disease due to “inoculum effect”

• Increased mortality shown in most studies with severe disease



Cefepime


Cefepime• In vitro activity, inconsistent in vivo activity• Increased mortality in treatment of ESBLs• 2014 CLSI guidelines updated MICs:

Susceptible MIC Susceptible-dose dependent MIC

Resistant MIC

≤ 2 mcg/mL 4-8 mcg/mL ≥ 16 mcg/mL


Lee et al. Cefepime vs Carbapenems

• Retrospective, multicenter study• May 2002-August 2007

• 472 patients included with monomicrobial ESBL-E bacteremia• Cohorts: empiric (n=112) vs definitive therapy (n=178)

• Primary outcome: 30 day crude mortality

Lee et al. Clin Infect Dis. 2013; 56: 488-95.


Mortality Rates of Cefepime for ESBL Infections based on MIC


0

50

71.4

10

62.5

85.7

30

68.8

85.7

0

10

20

30

40

50

60

70

80

90

≤1 2-8 ≥16

Mor

talit

y (%

)

Cefepime MIC level (mcg/mL)

Sepsis-related

30-day

Crude


Lee et al Results of Cefepime vs Carbapenems



Pneumonia 24%


Urosepsis 18%

Skin and soft tissue 15%

Intra-abdominal 6%

Empiric Cohort Outcome

Cefepime vs Carbapenems

P value

Sepsis-related mortality 47% vs 12% 0.002

30-day mortality 59% vs 18% 0.001

Crude mortality 65% vs 39% 0.07

Cefepime - - -Carbapenem –


Summary of Cefepime for ESBL Treatment• Increased mortality compared to carbapenems• Considered use in:

• Non-severe infections• Low inoculum infections• Susceptible MIC ≤ 2 mcg/mL• Maximum dosing with MIC 4-8



FluoroquinolonesCiprofloxacin, Levofloxacin, Moxifloxacin


Lo et al Fluoroquinolones vs Carbapenems in ESBL Bacteremia

• Retrospective, multicenter study in Taiwan and South Korea

• 2008-2010

• 398 patients included with ESBL-E coli or ESBL-K pneumoniae bacteremia• Fluoroquinolone (n=24) vs Carbapenems (n=275)

• Primary outcome: 30 day mortality

L0KZ9H

Lo et al. J Microb Immuno Infect. 2017; 50:355-361.


Lo et al. Fluoroquinolone Results

Fluoroquinolone Susceptibility

Levofloxacin 34.7%

Ciprofloxacin 28.9%

FQ Bacteremia Source Incidence

Urosepsis 29%

Pneumonia 25%


Primary 13%

Intra-abdominal 8%

Skin and soft tissue 4%



Fluoroquinolone Summary• Fluoroquinolones based on susceptibility, may

be considered an alternative to carbapenems • Mayo’s antibiogram susceptibility

• E coli ~70%• Klebsiella spp ~90%

• Additional resistance mechanisms can be developed towards fluoroquinolones



Additional Treatment Options• Nitrofurantoin• Fosfomycin• Tigecycline• Ceftolozane-Tazobactam• Ceftazidime-Avibactam

Consider for lower urinary tract infections

• Very expensive• Not superior to

carbapenems• Restricted medications

Increased mortality warnings


Question 2Which of the following antibiotics is associated with the greatest rate of survival for the treatment of an ESBL infection?

A. FosfomycinB. CefepimeC. Piperacillin-TazobactamD. Meropenem


Concern for Carbapenem Resistance• Carbapenem Resistant Enterobacteriaceae

(CRE) are an URGENT threat• 9,000 infections per year• 600 deaths per year

• Retrospective study at 22 centers in 4 countries:

Alexander et al. Open Forum Infect Dis. 2017;1-10.

Average ICU LOS:

8 days

Average LOS: 14

days

28-day mortality:

28.1%

No clinical cure:

39.8%


Carbapenem Sparing Regimens (CSR)• CSR should be utilized in select cases to

prevent the further development of CRE• Treatment considerations should direct therapy:

Palacios-Baena et al. CID. 2017; 65: 1615-1623Tamma et al. CID. 2017; 65: 972-980Gutierrez-Gutierrez et al. Lancet Infect Dis. 2017; 17:726-734.

Urinary or Biliary Source

Low Severity

Microbiology(MICs)

Drug Properties (PK/PD)


Question 3A carbapenem sparing regimen could be recommended in the which of the following patients with a documented ESBL infection?

A. Ventilator associated pneumoniaB. Urinary tract infectionC. Asymptomatic bacteriuriaD. Bacterial Meningitis


Summary• ESBL resistance is caused by an enzyme that

hydrolyzes the beta-lactam to inactivate the drug• Carbapenems are first-line therapy for

documented ESBL infections• Alternative therapy considerations include source,

severity, microbiology, and drug properties• Carbapenem sparing regimens should be

considered when possible to reduce risk of CRE


Questions & Discussion


Overcoming the PosESBLities of Enterobacteriaceae Resistance Review of current treatment options

Jamie Reed, PharmD

Pharmacy Grand RoundsAugust 28, 2018

Rochester, MN

Overcoming the PosESBLities of Enterobacteriaceae Resistance the PosESB… · Overcoming the...

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