January 27 th , 2017 Nathalie Quach PGY-1 Resident Valley Baptist - - PowerPoint PPT Presentation

January 27th, 2017 Nathalie Quach PGY-1 Resident Valley Baptist Medical Center - Brownsville

Outline

• Objectives
• Extended-spectrum beta-

lactamases

▫ Epidemiology ▫ Risk factors ▫ Mechanism of resistance ▫ Types of ESBL

• “Inoculum Effect”
• Treatment options
• Overuse of carbapenems
• Literature Review

▫ Piperacillin-tazobactam ▫ Cefepime ▫ Fosfomycin ▫ Nitrofurantoin ▫ Trimethoprin-sulfamethoxazole

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Abbreviations

• AG - aminoglycoside
• APN – acute pyelonephritis
• BLI – beta-lactamase inhibitor
• BLBLI – beta-lactam/ beta-lactamase

inhibitor

• BP – blood pressure
• CDC – Center for Disease Control
• CEF - cefepime
• CLSI – Clinical and Laboratory Standards

Institute

• CRE – carbapenemase-resistant

Enterobacteriaceae

• ESBL – extended-spectrum beta-

lactamase

• EUCAST – European Committee on

Antimicrobial Susceptibility Testing

• FOS - fosfomycin
• FQ - fluoroquinolone
• HR – heart rate
• IABD – intra-abdominal
• ICU – intensive care unit
• MBL – metallo-beta-lactamase
• MDR – multi-drug resistant
• MIC – minimum inhibitory

concentration

• MOA – mechanism of action
• NFT - nitrofurantoin
• PK - pharmacokinetic
• PTZ – piperacillin-tazobactam
• RR – respiratory rate
• TMP-SMX – trimethoprim-

sulfamethoxazole

• UTI – urinary tract infection
• VBMC – Valley Baptist Medical Center

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Objectives

• Identify risk factors for extended-spectrum beta-

lactamases (ESBL) infections

• Describe the “inoculum effect”
• Explain the implications of the overuse of

carbapenems

• Evaluate the primary literature regarding the use of

non-carbapenems for ESBL infections

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Patient Case

• MM is a 63 y.o. female who came

into the ED with a temperature

• f 101.2°F, HR 112, RR 24, BP

109/76, and complaints of chills and flank pain for the past two days.

• Zosyn was started empirically.

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Patient Case

• Urine culture came back positive

for ESBL E. coli

• What is the best antimicrobial

therapy for this patient?

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Introduction

• Increasing prevalence of ESBL-producing

Enterobacteriaceae

• ESBL infections are associated with high mortality
• Carbapenems have been the drug of choice for ESBL

infections

• Increasing selection pressure for carbapenem-

resistant organisms

• Emerging evidence that non-carbapenems may be an

effective alternative antibiotic for ESBL infections

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What are ESBLs?

• A subset of beta-

lactamases that hydrolyzes penicillins, cephalosporins, and monobactams while cephamycins and carbapenems remain stable

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http://image.slidesharecdn.com/21oct-copy-150118071331-conversion-gate02/95/beta-lactam-antibiotics-21- 638.jpg?cb=1421586958

Epidemiology

VBMC 2015 CDC 2011-2014 ESBL E. coli 25% 13.4% ESBL Klebsiella spp. 18% 20% ESBL Enterobacter spp.*

• 28.5%

Carbapenem-resistant Enterobacteriaceae (CRE)*

• 3.5%

Centers for Disease Control and Prevention. Antibiotic Resistance Patient Safety Atlas – Antibiotic Resistance HAI Data.

*Data not available 9

Risk Factors

Severity of illness

Length of hospital stay Length of ICU stay Prior administration of any antibiotic Ventilatory assistance Hemodialysis

Procedural/ Instrumentation

Presence of central venous or arterial catheters Presence of a gastrostomy or jejunostomy tube Emergency abdominal surgery Presence of a urinary catheter

Prior residence in a long-term care facility

Nursing home Assisted living facility

Clin Infect Dis. 2015;60(9):1319-25.

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ESBLs – Mechanism of resistance

Beta-lactamases ESBL

• Penicillins
• 1st gen cephalosporins
• 2nd gen cephalosporins
• Penicillins
• 1st gen cephalosporins
• 2nd gen cephalosporins
• 3rd gen cephalosporins
• Monobactam

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http://pharmafactz.com/medicinal-chemistry-of-beta-lactam-antibiotics/

Types of ESBL

Enzyme Number of enzymes Mechanism Organisms TEM 100 Amino acid substitution E.coli, K.pneumoniae, Enterobacteriaceae, P. aeruginosa SHV >100 Amino acid substitution Enterobacteriacea, P. aeruginosa, Acinetobacter spp. CTX 128 Chromosomal mediated Enterobacteriaceae

Clin Microbiol Infect. 2014;20(11):O831-9.

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The “Inoculum Effect”

• A significant increase in the MIC of an antibiotic

when the number of organisms inoculated is increased

• Example:

Ann Clin Microbiol Antimicrob. 2014;13:45.

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Treatment Options

Inpatient Outpatient

• Carbapenems – drug of choice
• Possible alternatives:

▫ 4th gen cephalosporin ▫ Piperacillin-tazobactam

• Carbapenem (ertapenem) – drug
• f choice
• Possible alternatives:

▫ Fosfomycin ▫ Nitrofurantoin ▫ Trimethoprim- sulfamethoxazole

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Why not just use carbapenems?

• Selective pressure for multidrug resistant organisms

(i.e. CRE)

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Piperacillin-tazobactam (PTZ)

• Bactericidal
• PK: time-dependent (Time > MIC)
• MOA: inhibits cell wall synthesis
• Spectrum of coverage: gram-positive and gram-

negative aerobic and anaerobic organisms

• Dosage: 3.375 – 4.5 g IV Q6H or Q8H
• Dose adjustment required for renal impairment
• Adverse effects: pruritus, diarrhea, nausea,

headache

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Cefepime (CEF)

• Bactericidal
• PK: time-dependent (Time > MIC)
• MOA: inhibits cell wall synthesis
• Spectrum of coverage: gram-positive and gram-

negative aerobic organisms

• Dosage: 1 – 2 g IV every 8 – 12 hours
• Dose adjustment required for renal impairment
• Adverse effects: rash, diarrhea

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Fosfomycin

• Bactericidal
• MOA: inhibits UDP-N-acetylglucosamine enolpyruvyl

transferase (MurA), an enzyme that catalyzes the first step in bacterial cell-wall synthesis

• Spectrum of coverage: gram-negative and gram-

positive aerobic bacteria

• Dosage: 3 g orally x 1 dose
• Adverse effects: diarrhea, nausea, backache,

headache, pharyngitis

• ONLY indicated in uncomplicated UTIs

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Nitrofurantoin (NFT)

• Bactericidal
• PK: concentration-dependent
• MOA: interferes with several bacterial enzyme

systems

• Spectrum of coverage: gram-positive (S. aureus, E.

faecalis) and gram-negative (E.coli) organisms

• Dosage: 100 mg twice a day
• Contraindication: CrCl < 60 mL/min
• Adverse effects: nausea and vomiting, loss of

appetite

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TMP-SMX

• Bactericidal
• MOA: blocking bacterial synthesis of dihydrofolic

acid

• Spectrum of coverage: aerobic gram-positive

(S.pneumo) and gram-negative

• Dosage: 2 DS tablet Q12H
• Renal adjustment required
• Adverse Effects: rash, urticaria, nause, vomiting

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Question: Can non-carbapenems be used to treat ESBL infections?

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Study Population Intervention Outcomes Ng et al, 2016  Bacteremia dues to ESBL Enterobacteriaceae  50-70% urinary source of infection  PTZ (PTZ 4.5g q6h or q8h)  Carbapenem (meropenem 1g q8h, imipenem 500mg q6h, ertapenem 1g q24h)  No difference in 30- day mortality (7.4% PTZ vs 29.8% carbapenem, p=0.89) Tamma et al, 2015  ESBL bacteremia  Average age 48 years  PTZ (PTZ 3.375g q6h

• r 4.5g q6h)

 Carbapenem (meropenem 1-2g q8h, imipenem 500mg q6h, ertapenem 1g q24h)  No difference in 14- day mortality (17% PTZ vs 8% carbapenem) 23

PLoS ONE. 2016;11(4):e0153696. Clin Infect Dis. 2015;60(9):1319-25.

Study Population Intervention Outcomes Goethaert et al, 2006  Infections due to ESBL- producing Enterobacter aerogenes  CEF 2g q8h  Carbapenem (meropenem 1g q8h, imipenem 500mg q6h)  No difference in 30- day mortality (33% CEF vs 26% carbapenem, p=0.44) Wang et al, 2016  ESBL bacteremia with isolates susceptible to cefepime  39% immunocompromised  CEF 1-2g q8h  Carbapenem (meropenem 1g q8h, imipenem 500mg q6h, ertapenem 1g q24h)  No difference in 14- day mortality (41% CEF vs 20% carbapenem) 24

Clin Microbiol Infect. 2006;12(1):56-62. Open Forum Infect Dis. 2016;3(3):ofw132.

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Park et al, 2014 OBJECTIVE

• To evaluate the efficacy of non-carbapenem antibiotics for acute

pyelonephritis (APN) due to ESBL-producing E. coli METHODS

• n = 152 (carbapenems = 85; non-carbapenems = 67)
• Interventions:
• Carbapenems (meropenem, imipenem)
• Non-carbapenems (FQ, AG, BLBLIs, TMP-SMX)
• Study design: retrospective
• Inclusion criteria: diagnosis of APN due to ESBL-producing E. coli
• Exclusion criteria: pregnant or if the treatments were incomplete (< 5

days of antibiotic therapy) OUTCOMES

• Microbiological and clinical failure
• Mortality

26

J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 PATIENT POPULATION

• Average age 66 years in carbapenem group vs 37 years in the non-

carbapenem group (p < 0.001)

• Sicker population in the carbapenem group vs non-carbapenem group

RESULTS 27

Outcome Carbapenems Non-carbapenems P value Microbiological failure, n (%) 16 (19.3) 4 (6) 0.986 Clinical failure, n (%) 13 (15.3) 2 (2.99) 0.949 Duration of definitive therapy, days 12 8 < 0.001

J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 RESULTS

• Microbiological failure (p=0.986)

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J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 RESULTS

• Clinical failure (p=0.949)

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J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 DISCUSSION Strengths Limitations

• Selection of primary and

secondary outcome

• Follow-up period of 30 days
• Only ESBL E. coli infections
• Study population was

heterogeneous

• No 4th gen cephalosporins

included

• Single-centre study

CONCLUSION Author’s conclusion Presenter’s conclusion

• Non-carbapenems are as

effective as carbapenems

• Non-carbapenems may possibly

be used for the treatment of APN caused by ESBL-producing E. coli in relatively healthy and younger individuals 30

J Antimicrob Chemother. 2014;69(10):2848-56.

Asakura et al, 2014 OBJECTIVE

• To investigate the efficacy of empirical therapy with non-carbapenems on

UTIs with ESBL-producing Enterobacteriaceae METHODS

• n = 90
• Interventions:
• Carbapanems (imipenem, meropenem)
• Non-carbapenems (AG, aztreonam, cephalosporins, FQ,

minocycline, PTZ, TMP-SMX)

• Study design: retrospective
• Inclusion criteria: first episode of the UTI in patients aged ≥ 18 years,

complicated and uncomplicated UTIs

• Exclusion criteria: patients complicated with another infection, cystitis

OUTCOMES

• Duration of antimicrobial therapy
• 14-day mortality
• Infection-related mortality
• Clinical cure

31

Int J Infect Dis. 2014;29:91-5.

Asakura et al, 2014 PATIENT POPULATION

• Mean age 74 years
• 51% women
• 33.3% susceptible antimicrobial therapy
• 66.7% non-susceptible antimicrobial therapy
• 12 carbapenems
• 14 non-carbapenems
• 30/34 patients who received and continued on non-susceptible

therapy showed substantial improvement RESULTS 32

Outcome Susceptible group (n=30) Non-susceptible group (n=60) p-value Duration of antimicrobial therapy, days 11.7 (6.3%) 12.2 (4.4%) 0.426 14-day mortality 5 (16.7%) 5 (8.3%) 0.292 Infection-related mortality 4 (13.3%) 4 (6.7%) 0.433 Clinical cure 25 (83.3%) 53 (88.3%) 0.525

Int J Infect Dis. 2014;29:91-5.

Asakura et al, 2014 RESULTS

• Independent risk factor for 14-day mortality was the use of

immunosuppressive

• Antimicrobial susceptibility of urine isolates of ESBL-producing

Enterobacteriaceae:

Antibiotic Escherichia coli (n=51) Proteus mirabilis (n=27) Klebsiella pneumoniae (n=12) Cefepime 2 (3.9%) 0 (0%) 1 (8.3%) Piperacillin- tazobactam 44 (86.3%) 27 (100%) 6 (50%)

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Int J Infect Dis. 2014;29:91-5.

Asakura et al, 2014 DISCUSSION Strengths Limitations

• Susceptibility results included
• Retrospective review
• Underpowered
• Not applicable to critically ill

patients CONCLUSION Author’s conclusion Presenter’s conclusion

• The efficacy of non-susceptible

empirical therapy with non- carbapenems is comparable to that of susceptible therapy

• Non-carbapenems may be used in

the management of UTIs with ESBL-producing E. coli if patient is not immunosuppressed 34

Int J Infect Dis. 2014;29:91-5.

Fosfomycin – Susceptibility Data

• Susceptibility: 90-95% of Enterobacteriaceae
• ~ 80-88% of ESBL E.coli and ESBL K.pneumoniae are

susceptible to fosfomycin

• Low level of resistance (5%)

Antibiotic Overall sensitivity ESBL

• E. coli

ESBL Klebsiella TMP-SMX 34.4% 36.9% 25% FOS 87.7% 94.9% 61.7% NFT 77.4% 93.2% 19.6%

Int Urol Nephrol. 2015;47(7):1059-66.

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Fosfomycin – Efficacy Data

Study Type of infection Patient characteristic Causative pathogens Antibiotic regimen Treatment outcome Rodriguez- Bano et al, 2008 Community

• acquired

cystitis Outpatient ESBL E.coli Fosfomycin- trometamol 3 g x 1

• Cure (26 of 28;

93%) Pullucku et al, 2007 Lower UTIs Inpatient/ Outpatient ESBL E.coli Fosfomycin- trometamol 3 g x 3

• Clinical success

(49 of 52; 94.2%)

• Microbiological

success (41 of 52; 78.8%)

• Microbiological

relapse at 28 days post-treatment (0

• f 28; 0%)

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Arch Intern Med. 2008;168(17):1897-902. Int J Antimicrob Agents. 2007;29(1):62-5.

NFT – Susceptibility Data

• ~ 88% of ESBL E.coli are susceptible to NFT
• Susceptibility to ESBL Klebsiella is significantly

decreased

• Low level of resistance (1.9 – 7.7%)

Antibiotic Overall sensitivity ESBL

• E. coli

ESBL Klebsiella TMP-SMX 34.4% 36.9% 25% FOS 87.7% 94.9% 61.7% NFT 77.4% 93.2% 19.6%

Int Urol Nephrol. 2015;47(7):1059-66.

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NFT – Efficacy Data

Study Type of infection Patient characteristic Causative pathogens Antibiotic regimen Treatment outcome Tasbakan et al, 2012 Lower UTIs Inpatient/ Outpatient ESBL E.coli NFT 50 mg Q6H x 14 days

• Clinical success

(52 out of 75; 69%)

• Microbiological

success (51 out

• f 75; 68%)
• Re-infection (2
• ut of 31; 6.5%)
• Relapse rate (1
• ut of 31; 3.2%)

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Int J Antimicrob Agents. 2012;40(6):554-6.

TMP-SMX – Susceptibility Data

Antibiotic Overall sensitivity ESBL

• E. coli

ESBL Klebsiella TMP-SMX 34.4% 36.9% 25% FOS 87.7% 94.9% 61.7% Nitrofurantoin 77.4% 93.2% 19.6%

• Resistance rate of > 70%
• Highest resistance rate to ESBL Enterobacteriaceae

Int Urol Nephrol. 2015;47(7):1059-66.

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Patient Case

• Susceptibility report reveals that

ESBL E. coli isolate is:

▫ Sensitive to piperacillin-tazobactam with an MIC ≤ 16

• Patient is clinically improving (fever

has resolved, HR stabilized,…)

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Patient Case

• What should we do?

 Switch to a carbapenem  Continue Zosyn

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Pros and Cons

Pros Cons

• Emerging data supports the

safety and efficacy of BLBLIs

• ESBL producers are frequently

susceptible in vitro to PTZ

• Carbapenems are truly reserved

for situations in which no other drugs are available

• Decreased selection pressure for

CRE

• Carbapenems remain stable to

ESBLs and are recommended as first-line therapy for serious infections

• An inoculum effect might limit

efficacy of BLBLIs

• Increasing resistance to BLBLIs in

ESBL producers limits efficacy in empirical therapy

• No head-to-head randomized

trials to assess BLBLIs in comparison with carbapenems

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Summary

Antibiotic ESBL: Non-urinary source ESBL: Urinary source Carbapenems

 

CEF





PTZ





FOS



*

NFT



*

TMP-SMX





* Lower UTIs 44

Key Takeaways

• Always consider:

▫ Patient’s history ▫ Severity of infection ▫ Site of infection ▫ Clinical status of the patient ▫ What is the causative microorganism? ▫ In-vitro susceptibility (MIC)

• Avoid use in:

▫ Patients with immunosuppression ▫ Patients with a non-urinary source of infection

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Key Takeaways

• PTZ may be an appropriate alternative to

carbapenems for the treatment of ESBL UTIs

• FOS may be used for complicated and uncomplicated

lower UTIs

▫ Uncomplicated: 3 g x 1 dose ▫ Complicated: 3 g x 3 doses

• NFT may be used for lower UTIs due to ESBL E. coli

but not ESBL K. pneumoniae

• CEF and TMP-SMX should not be used in the empiric

treatment of ESBL infections

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