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

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

Outline • Objectives • Overuse of carbapenems • Extended-spectrum beta- • Literature Review lactamases ▫ Piperacillin-tazobactam ▫ Epidemiology ▫ Cefepime ▫ Risk factors ▫ Fosfomycin ▫ Mechanism of resistance ▫ Nitrofurantoin ▫ Types of ESBL ▫ Trimethoprin-sulfamethoxazole • “Inoculum Effect” • Treatment options 2

Abbreviations • AG - aminoglycoside • FQ - fluoroquinolone • APN – acute pyelonephritis • HR – heart rate • BLI – beta-lactamase inhibitor • IABD – intra-abdominal • BLBLI – beta-lactam/ beta-lactamase • ICU – intensive care unit inhibitor • MBL – metallo-beta-lactamase • BP – blood pressure • MDR – multi-drug resistant • CDC – Center for Disease Control • MIC – minimum inhibitory • CEF - cefepime concentration • CLSI – Clinical and Laboratory Standards • MOA – mechanism of action Institute • NFT - nitrofurantoin • CRE – carbapenemase-resistant • PK - pharmacokinetic Enterobacteriaceae • PTZ – piperacillin-tazobactam • ESBL – extended-spectrum beta- • RR – respiratory rate lactamase • TMP-SMX – trimethoprim- • EUCAST – European Committee on sulfamethoxazole Antimicrobial Susceptibility Testing • UTI – urinary tract infection • FOS - fosfomycin • VBMC – Valley Baptist Medical Center 3

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 4

Patient Case • MM is a 63 y.o. female who came into the ED with a temperature of 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. 5

Patient Case • Urine culture came back positive for ESBL E. coli • What is the best antimicrobial therapy for this patient? 6

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 7

What are ESBLs? • A subset of beta- lactamases that hydrolyzes penicillins, cephalosporins, and monobactams while cephamycins and carbapenems remain stable http://image.slidesharecdn.com/21oct-copy-150118071331-conversion-gate02/95/beta-lactam-antibiotics-21- 8 638.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 - 3.5% Enterobacteriaceae (CRE)* *Data not available Centers for Disease Control and Prevention. Antibiotic Resistance Patient Safety Atlas – Antibiotic Resistance 9 HAI Data.

Risk Factors Prior residence in a Procedural/ Severity of illness long-term care Instrumentation facility Presence of central venous or Length of hospital stay arterial catheters Nursing home Length of ICU stay Presence of a gastrostomy or jejunostomy tube Prior administration of any antibiotic Emergency abdominal surgery Ventilatory assistance Assisted living facility Presence of a urinary Hemodialysis catheter Clin Infect Dis. 2015;60(9):1319-25. 10

ESBLs – Mechanism of resistance Beta-lactamases ESBL • Penicillins • Penicillins • 1 st gen cephalosporins • 1 st gen cephalosporins • 2 nd gen cephalosporins • 2 nd gen cephalosporins • 3 rd gen cephalosporins • Monobactam 11 http://pharmafactz.com/medicinal-chemistry-of-beta-lactam-antibiotics/

Types of ESBL Enzyme Number of Mechanism Organisms enzymes TEM 100 Amino acid E.coli, K.pneumoniae, substitution Enterobacteriaceae, P. aeruginosa SHV >100 Amino acid Enterobacteriacea, P. substitution aeruginosa, Acinetobacter spp. CTX 128 Chromosomal Enterobacteriaceae mediated Clin Microbiol Infect. 2014;20(11):O831-9. 12

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. 13

Treatment Options Inpatient Outpatient • Carbapenems – drug of choice • Carbapenem (ertapenem) – drug • Possible alternatives: of choice • Possible alternatives: ▫ 4 th gen cephalosporin ▫ Fosfomycin ▫ Piperacillin-tazobactam ▫ Nitrofurantoin ▫ Trimethoprim- sulfamethoxazole 14

Why not just use carbapenems? • Selective pressure for multidrug resistant organisms (i.e. CRE) 15

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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 17

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 18

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 19

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 20

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 21

Question: Can non-carbapenems be used to treat ESBL infections? 22

Study Population Intervention Outcomes  PTZ (PTZ 4.5g q6h or  Bacteremia dues to  q8h) No difference in 30- ESBL  Carbapenem day mortality (7.4% Ng et al, Enterobacteriaceae (meropenem 1g q8h, PTZ vs 29.8%  2016 50-70% urinary imipenem 500mg carbapenem, source of infection q6h, ertapenem 1g p=0.89) q24h)  PTZ (PTZ 3.375g q6h or 4.5g q6h)  No difference in 14-   ESBL bacteremia Carbapenem Tamma et day mortality (17%  Average age 48 years (meropenem 1-2g al, 2015 PTZ vs 8% q8h, imipenem carbapenem) 500mg q6h, ertapenem 1g q24h) PLoS ONE. 2016;11(4):e0153696. 23 Clin Infect Dis. 2015;60(9):1319-25.

Study Population Intervention Outcomes    Infections due to ESBL- CEF 2g q8h No difference in 30-  producing Carbapenem day mortality (33% Goethaert Enterobacter (meropenem 1g CEF vs 26% et al, 2006 aerogenes q8h, imipenem carbapenem, 500mg q6h) p=0.44)   ESBL bacteremia with CEF 1-2g q8h   isolates susceptible to Carbapenem No difference in 14- Wang et al, cefepime (meropenem 1g day mortality (41%  2016 39% q8h, imipenem CEF vs 20% immunocompromised 500mg q6h, carbapenem) ertapenem 1g q24h) Clin Microbiol Infect. 2006;12(1):56-62. 24 Open Forum Infect Dis. 2016;3(3):ofw132.

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Park et al, 2014 • To evaluate the efficacy of non-carbapenem antibiotics for acute OBJECTIVE pyelonephritis (APN) due to ESBL-producing E. coli • n = 152 (carbapenems = 85; non-carbapenems = 67) • Interventions: • Carbapenems (meropenem, imipenem) • Non-carbapenems (FQ, AG, BLBLIs, TMP-SMX) METHODS • 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) • Microbiological and clinical failure OUTCOMES • Mortality 26 J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 • Average age 66 years in carbapenem group vs 37 years in the non- PATIENT carbapenem group (p < 0.001) POPULATION • Sicker population in the carbapenem group vs non-carbapenem group Outcome Carbapenems Non-carbapenems P value Microbiological 16 (19.3) 4 (6) 0.986 failure, n (%) RESULTS Clinical failure, n (%) 13 (15.3) 2 (2.99) 0.949 Duration of definitive 12 8 < 0.001 therapy, days 27 J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 • Microbiological failure (p=0.986) RESULTS 28 J Antimicrob Chemother. 2014;69(10):2848-56.

Park et al, 2014 • Clinical failure (p=0.949) RESULTS 29 J Antimicrob Chemother. 2014;69(10):2848-56.