Overcoming the PosESBLities of Enterobacteriaceae Resistance Review of current treatment options Jamie Reed, PharmD Pharmacy Grand Rounds August 28, 2018 Rochester, MN 2018 MFMER slide-1
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 2018 MFMER slide-2
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 2018 MFMER slide-3
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 1 st, 2 nd and 3 rd generation cephalosporins Monobactams Ghafourian S et al. Curr Issues Mol Biol. 2015. 17:11-22. 2018 MFMER slide-4
Mechanism of ESBL Resistance O NH O NH O NH O NH OH Ghafourian S et al. Curr Issues Mol Biol. 2015. 17:11-22. 2018 MFMER slide-5
Types of Extended Spectrum β-lactamases TEM SHV TEM SHV CTX-M OXA Ghafourian S et al. Curr Issues Mol Biol. 2015; 17:11-22. Bradford P. Clin Microbiol Rev. 2001; 14(4):933-951. 2018 MFMER slide-6
Prevalence of ESBLs 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 Thaden et al. Infect Control Hosp Epidemiol. 2016; 37(1): 49-54. Ben-Ami et al. CID. 2006;42: 925-934 2018 MFMER slide-7
Question 1 What is the mechanism of ESBL resistance to penicillins, cephalosporins, and monobactams? A. Methylation of the β-lactam ring B. Hydrolysis of the β-lactam ring C. Efflux transport out of the cell D. Modified penicillin binding proteins 2018 MFMER slide-8
Question 1 What is the mechanism of ESBL resistance to penicillins, cephalosporins, and monobactams? A. Methylation of the β-lactam ring B. Hydrolysis of the β-lactam ring C. Efflux transport out of the cell D. Modified penicillin binding proteins 2018 MFMER slide-9
Treatment Considerations for ESBL Infections Source Severity Microbiology Drug Properties Effective treatment of ESBL infection Minimize risk of further resistance Tamma et al. Clin Infect Dis. 2017; 64:972-980. 2018 MFMER slide-10
Treatment Options for ESBL Infections Carbapenems β-lactams/β-lactamase inhibitors (βl-βlis) Generally drug of choice, especially in severe disease/high inoculum infections Cefepime, cephamycins Fluoroquinolones Fosfomycin Nitrofurantoin Tigecycline Tamma et al. Clin Infect Dis. 2017; 64:972-980. 2018 MFMER slide-11
ESBL Microbiological Result Example 2018 MFMER slide-12
β-lactams/β-lactamase Inhibitors (βl-βlis) Piperacillin/Tazobactam, Ampicillin/Sulbactam, Amoxicillin/Clavulanate 2018 MFMER slide-13
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): 3548-3554 Tamma et al. Clin Infect Dis. 2017; 64:972-980. 2018 MFMER slide-14
Tamma et al. PTZ vs Carbapenems for empiric ESBL bacteremia 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. Clin Infect Dis. 2015; 60:1319-1325 2018 MFMER slide-15
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. Clin Infect Dis. 2015; 60:1319-1325 2018 MFMER slide-16
Tamma et al Conclusion Increased mortality with PTZ vs carbapenem for treatment of ESBL blood stream infections Catheter related, urinary, pneumonia, intraabdominal, biliary infections Carbapenems recommended first line therapy in severe disease Tamma et al. Clin Infect Dis. 2015; 60:1319-1325 2018 MFMER slide-17
Gutierrez-Gutierrez et al. βl-βlis vs Carbapenems for ESBL Bacteremia 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-Gutieerrez et al. Antimicrob Agents Chemother. 2016; 60:4159-69. 2018 MFMER slide-18
Gutierrez-Gutierrez et al. Mortality of βlβlis for ESBL Bacteremia Infections βl-βlis Empiric Incidence Definitive Incidence Piperacillin/Tazobactam 72% 65% Ampicillin/Sulbactam 27% 35% Amoxicillin/Clavulanate 1% 0% Bacteremia Source Incidence Urinary 45% Biliary 12% Other 43% Gutierrez-Gutieerrez et al. Antimicrob Agents Chemother. 2016; 60:4159-69. 2018 MFMER slide-19
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 Gutierrez-Gutieerrez et al. Antimicrob Agents Chemother. 2016; 60:4159-69. 2018 MFMER slide-20
Studies Comparing βl-βli vs Carbapenems Author Organism Bacteremia Source Therapy 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) Carbapenem (n=110) Mortality at 14 days: 17% vs 8% (p<0.05) Mortality at 30 days: 26% vs 11% (p<0.01) Gutierrez- Gutierrez et al E coli (73%) K pneumoniae (19%) Urinary or biliary βl-βli Empiric (n=170) Definitive (n=92) Mortality at 30 day (empiric): 18% vs 20% (p=0.6) Carbapenem Empiric(n=195) Definitive(n=509) Mortality at 30 days (definitive): 10 % vs 14% (p=0.28) 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. 2018 MFMER slide-21
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 Tamma et al. Clin Infect Dis. 2017; 64:972-80. 2018 MFMER slide-22
Cefepime 2018 MFMER slide-23
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 2018 MFMER slide-24
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. 2018 MFMER slide-25
Mortality Rates of Cefepime for ESBL Infections based on MIC 90 85.7 85.7 80 70 62.5 68.8 71.4 60 Mortality (%) 50 40 30 30 50 Sepsis-related 30-day Crude 20 10 0 0 10 1 2-8 16 Cefepime MIC level (mcg/ml) Lee et al. Clin Infect Dis. 2013; 56: 488-95. 2018 MFMER slide-26
Lee et al Results of Cefepime vs Carbapenems Bacteremia Source Incidence Pneumonia 24% Catheter-related 18% Urosepsis 18% Skin and soft tissue 15% Intra-abdominal 6% Cefepime - - - Carbapenem 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 Lee et al. Clin Infect Dis. 2013; 56: 488-95. 2018 MFMER slide-27
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 Lee et al. Clin Infect Dis. 2013; 56: 488-95. 2018 MFMER slide-28
Fluoroquinolones Ciprofloxacin, Levofloxacin, Moxifloxacin 2018 MFMER slide-29
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 L0KZ9H Fluoroquinolone (n=24) vs Carbapenems (n=275) Primary outcome: 30 day mortality Lo et al. J Microb Immuno Infect. 2017; 50:355-361. 2018 MFMER slide-30
Lo et al. Fluoroquinolone Results FQ Bacteremia Source Incidence Urosepsis 29% Pneumonia 25% Catheter-related 21% Primary 13% Intra-abdominal 8% Skin and soft tissue 4% Fluoroquinolone Susceptibility Levofloxacin 34.7% Ciprofloxacin 28.9% Lo et al. J Microb Immuno Infect. 2017; 50:355-361. 2018 MFMER slide-31
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 Lo et al. J Microb Immuno Infect. 2017; 50:355-361. 2018 MFMER slide-32
Additional Treatment Options Nitrofurantoin Fosfomycin Tigecycline Ceftolozane-Tazobactam Ceftazidime-Avibactam Consider for lower urinary tract infections Increased mortality warnings Very expensive Not superior to carbapenems Restricted medications 2018 MFMER slide-33
Question 2 Which of the following antibiotics is associated with the greatest rate of survival for the treatment of an ESBL infection? A. Fosfomycin B. Cefepime C. Piperacillin-Tazobactam D. Meropenem 2018 MFMER slide-34
Question 2 Which of the following antibiotics is associated with the greatest rate of survival for the treatment of an ESBL infection? A. Fosfomycin B. Cefepime C. Piperacillin-Tazobactam D. Meropenem 2018 MFMER slide-35
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: Average ICU LOS: 8 days Average LOS: 14 days 28-day mortality: 28.1% No clinical cure: 39.8% Alexander et al. Open Forum Infect Dis. 2017;1-10. 2018 MFMER slide-36
Carbapenem Sparing Regimens (CSR) CSR should be utilized in select cases to prevent the further development of CRE Treatment considerations should direct therapy: Urinary or Biliary Source Microbiology (MICs) Low Severity Drug Properties (PK/PD) Palacios-Baena et al. CID. 2017; 65: 1615-1623 Tamma et al. CID. 2017; 65: 972-980 Gutierrez-Gutierrez et al. Lancet Infect Dis. 2017; 17:726-734. 2018 MFMER slide-37
Question 3 A carbapenem sparing regimen could be recommended in the which of the following patients with a documented ESBL infection? A. Ventilator associated pneumonia B. Urinary tract infection C. Asymptomatic bacteriuria D. Bacterial Meningitis 2018 MFMER slide-38
Question 3 A carbapenem sparing regimen could be recommended in the which of the following patients with a documented ESBL infection? A. Ventilator associated pneumonia B. Urinary tract infection C. Asymptomatic bacteriuria D. Bacterial Meningitis 2018 MFMER slide-39
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 2018 MFMER slide-40
Questions & Discussion 2018 MFMER slide-41
Overcoming the PosESBLities of Enterobacteriaceae Resistance Review of current treatment options Jamie Reed, PharmD Pharmacy Grand Rounds August 28, 2018 Rochester, MN 2018 MFMER slide-42