Are There Non-Carbapenem β-lactam Options for Treating ESBL Infections?

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1 CIDEIM Are There Non-Carbapenem β-lactam Options for Treating ESBL Infections? Pranita D. Tamma, M.D., M.H.S. Assistant Professor, Pediatrics Director, Pediatric Antimicrobial Stewardship Program

2 CIDEIM Disclosures I have received funding support from the following nonfederal organizations in the past 12 months: Merck Pfizer

3 CIDEIM Objectives Discuss the role of carbapenems in the treatment of ESBL-producing infections Discuss the role of the following agents in treating ESBL-producing infections Cephamycins Cefepime Piperacillin/Tazobactam Newer β-lactam/β-lactamase inhibitors

4 Paterson, et al. Antimicrob Agents Chemother 2003;47:3554. Villegas, et al. PLOS One 2016; CIDEIM11:e Bush. Antimicrob Agents Chemother 2015; 59:3606. ESBLs Since their description in the 1980s, ESBL producing organisms have become recognized as a global threat They have been detected worldwide in several gramnegative organisms, but are most prevalent among E. coli and Klebsiella spp. These enzymes have undergone substantial biochemical alterations resulting in the ability to more efficiently hydrolyze β-lactam antibiotics

5 CIDEIM Role of Carbapenems Carbapenems are considered the traditional gold standard agents against ESBL infections, even when in vitro activity to other β-lactams is demonstrated Carbapenems are stable to ESBL hydrolytic activity and numerous publications demonstrate their efficacy Carbapenem overutilization stimulates resistance pathways including porin mutations and the selection of carbapenemases Whenever possible, efforts should be made to limit the use of carbapenems

6 CIDEIM Anticipated in vitro Susceptibility Pattern for Klebsiella pneumoniae Drug Wild AmpC ESBL KPC NDM OXA-48-like type Ampicillin R 1 R R R R R Piperacillintazobactam S S/R S/R R R R Cefoxitin S R S R R R Ceftriaxone S R R R R S/R Cefepime S S S/R R R S/R Aztreonam S R R R S R Ertapenem S S S S/R S/R S/R Meropenem S S S S/R S/R S/R 1 The majority of K. pneumoniae isolates are resistant to ampicillin due to production of narrow-spectrum TEM of SHV β-lactamases

7 Are There Scenarios Where Non-Carbapenem β-lactams Can Be Considered for ESBL Infections? CIDEIM What if non-carbapenem β- lactam MICs are low? What if high-dose, frequent interval βl-βlis or cefepime is administered? What if extended-infusion noncarbapenem β-lactams are administered? If carbapenem antibiotics are administered when the bacterial burden is highest, can therapy be transitioned to a noncarbapenem after a short period of time? If a βl-βli is administered, does the type of βli matter? Tazobactam vs. sulbactam vs. clavulanic acid vs. avibactam Does it matter if the resistance mechanism is a bla TEM-type, bla CTX- M-type versus a bla SHV-type? Does the genus and species of the ESBL-producer matter? Does the source of infection and if source control measures were taken matter? Should the severity of illness determine if a carbapenem or non-carbapenem is administered?

8 CIDEIM Cephamycins

9 Jacoby, et al. Antimicrob Agents Chemother 1990;34: Paterson & Bonomo, Clin Microbiol CIDEIMRev 2005;18:657. Cephamycins Consistent in vitro activity against ESBL-producing Enterobacteriaceae Early concerns of development of cephamycin or carbapenem resistance during cephamycin therapy because of acquisition of outer membrane protein mutations and/or plasmids encoding AmpC β-lactamases during cephamycin exposure Some in vitro data Isolated clinical cases available Unclear how frequently such mutations and gene acquisitions occur and what the predisposing host and environmental factors are Very limited clinical data to support this theory A number of cephamycins are currently available Cefoxitin, cefotetan, cefmetazole, flomoxef, moxalactam

10 Study Bacteria Sources ICU Outcomes Lee 2006 n=27 Doi 2013 n=22 Yang 2012 n=57 Pilmis 2014 n=39 Matsu mura 2015 CIDEIM K. pneumoniae (100%) E. coli (95%), K. pneumoniae (5%) K. pneumoniae (100%) E. coli (32%), K. pneumoniae (32%), E. cloacae (36%) Site: Blood (100%) Sources: Pneumonia (56%), IAI (19%), urine (11%), SSTI 4%) ~50% Mortality at 14 days: 29% cephamycins vs. 25% carbapenems (ns) Site: Urine (100%) <10% Clinical cure at 4 weeks: 90% cephamycins vs. 100% carbapenems (ns) Site: Bloodstream (100%) Source: Fistula, graft, catheter (100%) Site: Urine (75%), bloodstream (25%) E. coli (100%) Site: Bloodstream (100%) Source: Urine (58%), IAI (42%) ~50% Mortality at 14 days: 55% cephamycins vs 39% carbapenems (p<0.05) <10% Clinical or microbiological relapse at 30 days: 13% cephamycins vs. 23% carbapenems (ns) ~50% Mortality at 30 days: 5% cephamycins vs. 9% carbapenems (ns)

11 Given the limited data on non-urinary sources and severe infections, use of cephamycins for severe ESBL infections should be avoided until more data are available Optimal administration strategy not defined CIDEIM My Thoughts on Cephamycins for the Treatment of ESBL Infections Unclear if similar outcomes between carbapenem and cephamycin groups are because of similar activity against ESBLs or inability to detect a difference if one exists because of small sample sizes & confounding by indication Cephamycins may be useful agents in the treatment of nonsevere ESBL-producing infections from urinary sources Recommended for the treatment of UTIs caused by ESBLproducing E. coli in the 2014 French guidelines

12 CIDEIM Cefepime

13 CIDEIM Cefepime Enhanced stability compared with earlier cephalosporin generations against degradation by β-lactamases The current EUCAST and CLSI susceptibility breakpoints for cefepime are 1 mcg/ml and 8 mcg/ml (accounting for drug dosing), respectively The CLSI cefepime breakpoint may leave a substantial number of ESBLs in the susceptible range hidden resistance A growing body of evidence is challenging the assumption that cefepime is efficacious for the treatment of ESBL producers As a large proportion of microbiology laboratories don t perform confirmatory ESBL testing, there is concern that critically-ill patients may receive cefepime based on misleading in vitro susceptibility reports

14 Cefepime: Inoculum Effect Inoculum effect: Drug MICs increase dramatically in the presence of an increased bacterial load despite apparent initial susceptibility Has been observed in both in vitro and animal studies with cefepime Both low and high inoculum non-esbl infections look like top figure for cefepime, PTZ, and meropenem Contribution of this effect towards treatment failures not clear Low inoculum ESBL High inoculum ESBL CIDEIM Thomson, et al. Antimicrob Agents Chemother 2001;45:3548. Bedenic, et al. Clin Microbiol Infec 2011; 7:626. Szabo, et al. Antimicrob Agents Chemother 2001;45:1287. Rice, et al. Antimicrob Agents Chemother 1991;35:1243. Thauvin-Eliopoulos, et al. Antimicrob Agents Chemother 1997; 41:1053. Jett, et al. Antimicrob Agents Chemother 1995; 39:1187. Burgess, et al. Diag Microbiol Infect Dis 2004; 49:41.

15 Nicasio, et al. Antimicrob Agents Chemother 2009; 53:1476. Andes, et al. Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract A-1099, Wang, et al. Open Forum Infect Dis 2016;3:ofw132. CIDEIM Cefepime: Failure to Meet PK-PD Targets Wide range of dosing regimens for cefepime, may dramatically alter exposure and outcomes associated with treatment Cefepime MICs for ESBLproducers are often increased compared to non- ESBL producers Relative contribution of ESBL production and organism MIC in determining cefepime activity remains controversial Failures also seen with low MICs

16 Study Bacteria Sources ICU Outcomes Zanetti 2003* n=23 Goethaert 2006* n=44 Chopra 2012 n=42 Lee 2013 n=178 Wang 2015* n=68 CIDEIM K. pneumoniae (96%), E. aerogenes (4%) E. aerogenes (100%) K. pneumoniae (100%) E. cloacae (55%), E. coli (24%), K. pneumoniae (21%) E. coli (34%), Klebsiella spp. (62%), P. mirabilis (3%) *Majority received cefepime 2g q8h Site: Pneumonia (100%) 100% Clinical response: 69% cefepime versus 100% carbapenems (p<0.05) Sites: Pneumonia (64%), bloodstream (16%), urine (5%), IAI (14%) 100% Mortality at 30 days: 33% vs. 26% (ns) Site: Bloodstream (100%) 41% In hospital mortality: 33% cefepime vs. 36% carbapenems (ns) Site: Bloodstream (100%) Sources: Pneumonia (24%), catheter (21%), IAI (16%), SSTI (6%), urine (22%) Site: Bloodstream (100%) Sources: catheter (44%), urine (31%), biliary, pneumonia 15%), IAI (13%), SSTI (3%) >70% Mortality at 30 days: 59% cefepime vs. 17% carbapenems (p<0.001) 30% Mortality at 14 days: 41% cefepime vs. 20% carbapenems (p=0.08)

17 CIDEIM My Thoughts on Cefepime for the Treatment of ESBL Infections Cefepime may be reasonable for non-severe infections where the agent can achieve high concentrations to ensure pharmacodynamic targets are met MICs of 2 mcg/ml or urinary sources of infection Would recommend every 8 hour dosing Use of continuous infusion cefepime needs to be explored for higher cefepime MICs

18 CIDEIM Piperacillin-Tazobactam

19 Thomson, et al. Antimicrob Agents Chemother 2001;45:3584. Lopez-Cerero, et al. Clin Microbiol Infect 2010; 16:132. Rice, et al. Antimicrob Agents Chemother 1994; 38:2663. Thauven-Eliopolous, et al. Antimicrob Agents Chemother 1997; 41:1053. Zimhony, et al. Antimicrob Agents Chemother 2006; 50:3179. CIDEIM Piperacillin-Tazobactam Although ESBLs are generally inhibited by PTZ, some organisms produce several ESBLs simultaneously along with AmpCs, providing a complex background that may reduce its effectiveness In vitro, animal data, and case reports suggest efficacy of PTZ reduced when a high inoculum of bacteria is present

20 Study Bacteria Sources ICU Outcomes Kang 2012 n=114 Rodriguez- Baño 2012 n=174 Harris 2015 n=47 Ofer- Friedman 2015 n=79 Tamma 2015 n=213 Gutierrez- Gutierrez 2016 n=601 CIDEIM E. coli (68%), K. pneumoniae (32%) Site: Bloodstream (100%) Sources: Not described E. coli (100%) Source: Urinary or bililary (70%) E. coli (86%) K. pneumoniae (14%) E. coli (53%), K. pneumoniae (28%), P. mirabilis (19%) K. pneumoniae (68%), E. coli, (31%) E. coli (73%), K. pneumoniae (19%) Sources: Urinary (47%), biliary (13%) Sources: Pneumonia (34%), SSTI (28%), biliary (17%), IAI (9%) Sources: Catheter (46%), urine (21%), IAI (17%) biliary (9%), pneumonia (9%) Sources: Urinary (45%), biliary (12%), other (43%) ~40% Mortality at 30 days: 22% vs. 27% (ns) 13% Mortality at 30 days: 9% vs. 17% (ns) 12% Mortality at 30 days: 8% vs. 17% (ns) >50% Mortality at 30 days: 60% vs. 34% (p=0.10) Mortality at 90 days: 80% vs. 48% (p=0.03) 34% Mortality at 30 days: 26% vs. 11% (p<0.01) 11% Mortality at 30 days: 10% vs. 14% (ns)

21 Organisms included Source of bacteremia ICU admission Median PTZ MIC PTZ dosage CIDEIM Why Studies the in favor Conflicting of PTZ Results? (Rodriguez-Baño, Guittierez- Guittierez, Ng) Studies against PTZ (Ofer-Friedman & Tamma) 100% E. coli 53% E. coli 73% E. coli 31% E. coli 67% E. coli -- 30% high inoculum 83% high inoculum 43% high inoculum 70% high inoculum 18% high inoculum 13% >50% 11% 34% 9% -- 2 mcg/ml 8 mcg/ml Not provided 8 mcg/ml Not provided grams q6h Not provided 4.5 grams q6h 40% received 4.5 grams q6h 4.5 grams q6h --

22 Harris, et al. Trials 2015; 16:24. CIDEIM Meropenem vs. PTZ for Definitive Treatment of Bloodstream Infections Due to Ceftriaxone Non- Susceptible E. coli and Klebsiella spp. (MERINO trial) Objective To determine if PTZ results in equivalent outcomes as meropenem for ceftriaxone non-susceptible bacteremia Methods - Multicenter, randomized, open-label, non-inferiority trial - Meropenem (1 g q8h) vs. PTZ (4.5 g q6h) - Target enrollment is 454 patients - Estimated study completion date: December Clinicaltrials.gov: NCT

23 CIDEIM My Thoughts on βl-βli for the Treatment of ESBL Infections Existing evidence indicates for low-moderate severity infections, urinary/biliary sources, or piperacillin MICs 4 mcg/ml, PTZ works as well as carbapenems Consider 4.5 gram every 6 hour PTZ dosing Or, 4.5 grams every 8 hours as extended infusion For severely-ill patients (particularly if PTZ MICs >4 mcg/ml, non-urinary/biliary sources, or K. pneumoniae infections), may be reasonable to initially start with carbapenems

24 CIDEIM Ceftolozane-Tazobactam

25 Zhanel, et al. Drugs 2014;74:31. Craig, et al. Antimicrobial agents and chemotherapy 2013;57:1577. CIDEIM Ceftolozane-Tazobactam: FDA Approved December 2014 FDA approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections for patients 18 years of age and older Ceftolozane demonstrates good activity against Enterobacteriaceae Similar to other oxymino-cephalosporins, its activity is limited against ESBLs Tazobactam is a potent, irreversible inhibitor of most ESBLs

26 Sader, et al. J of Antimicrob Chemo 2014;69:2713. Farrell, et al. Int J of Antimicrob Agents 2014;43:533. Sader, et al. Journ of infection 2014;69:266. Farrell, et al. Antimicrobial Ag Chemo 2013;57:6305.Walkty, et al. Antimicrobial agents and chemotherapy 2013;57:5707. CIDEIM Ceftolozane-Tazobactam: FDA Approved December 2014 Activity against ESBL E. coli is greater than against ESBL K. pneumoniae MIC 50/90 of this agent for ESBL-producing E. coli and K. pneumoniae are 0.5/4 and 4/>32 mcg/ml, respectively bla CTX-M genes predominate in E. coli, whereas often a preponderance of bla TEM/SHV in K. pneumoniae, with variations in local epidemiology Compared to meropenem for ciai in Phase 2&3 studies Total of 54 patients with ESBL-producing Enterobacteriaceae No differences in outcomes, but neither study was designed to evaluate this question

27 CIDEIM My Thoughts on Ceftolozane- Tazobactam for the Treatment of ESBL Infections Further clinical reports evaluating its efficacy for ESBL infections are needed Since the same βli (i.e., tazobactam) is used in piperacillin/tazobactam, it likely has similar activity to this agent for ESBL-producing infections Significant expense of utilizing this new cephalosporin/βli agent is a limiting factor if alternative, generic options are available

28 CIDEIM Ceftazidime-Avibactam

29 DrugsAdvisoryCommittee/UCM pdf. CIDEIM Ceftazidime-Avibactam FDA Approved February 2015 Ceftazidime-avibactam has excellent in vitro activity against ESBL-producing Enterobacteriaceae In vitro results more favorable than ceftolozane-tazobactam MIC 50/90 of this agent for ESBL-producing E. coli and K. pneumoniae are 0.12/0.25 and 0.5/1 mcg/ml, respectively Phase 2 & 3 clinical data indicate it is effective and well-tolerated for complicated urinary tract infections and intra-abdominal infections Did not specifically include confirmed ESBL isolates

30 CIDEIM Summarizing My Thoughts For mild-moderate infections, particularly those from urinary sources or with low MICs, non-carbapenems can be considered with PTZ having the most favorable data available For severe, invasive infections, carbapenems are still first-line options but de-escalation to non-carbapenem β-lactams can be considered when a response is observed