Who needs Antibiotic Stewardship? Read the New WHO (World Health Organization) report

Transcription

1 NEWSLETTER What s inside this fall issue? New reports Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria A Policy Roadmap to Reduce Use of Medically Important Antibiotics in Livestock Antibiotic Awareness Week Tuition waivers available CE Article Who needs Antibiotic Stewardship? Read the New WHO (World Health Organization) report Now is the time for antibiotic stewardship. The Sept 2017 WHO report has received a lot of press and the message is not good. WHO reviewed the publically available information on the current clinical development pipeline of antibacterial agents. The review shows that the current clinical pipeline is still insufficient to mitigate the threat of antimicrobial resistance. Most of the agents in the pipeline are modifications of existing antibiotic classes. They are only short-term solutions as they usually cannot overcome multiple existing resistance mechanisms and do not control the growing number of panresistant pathogens. Among the 33 antibiotics that are being developed for priority pathogens, only eight belong to five distinct new antibiotic classes. The situation is especially dire for Gram-negative bacterial infections. While recent entries in the clinical pipeline show an increased focus on Gram-negative bacteria, almost all of the agents are modifications of existing antibiotic classes. There are a few sentences in the report that every antibiotic stewardship team member should share with their CEO. The report states, New antibiotics alone will not be sufficient to mitigate the threat of antimicrobial resistance. Their development should go hand in hand with infection prevention and control activities and fostering of appropriate use of existing and future antibiotics through stewardship measures. The 2018 planning committee is busy lining up an agenda with expert speakers to address many of these complex topics in antibiotic stewardship. is THE only interprofessional, multiday, international conference dedicated to Antimicrobial Stewardship. Plan to attend May9-12, 2018 Orlando, Florida

2 NEWSLETTER The Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria s (PACCARB) Sept 2017 Report A panel of experts in human and veterinary medicine charged with advising the US government on antibiotic resistance has come up with a set of recommendations to boost development of vaccines, diagnostics, and new therapies that could reduce the spread of antimicrobial resistance (AMR) in humans and animals. The report, which was divided into sections on human and animal health, takes a One Health approach to the AMR problem, acknowledging that solutions must address the spread of drug-resistant bacteria in human, animals, and the environment. In the section addressing human health two issues are addressed; rapid diagnostic tests and the need for experts to conduct research. Both of these issues are roles for ASP. Diagnostics inform appropriate antibiotic prescribing and can reduce hospital lengths of stay, prevent hospital admissions, reduce antibiotic use, and benefit society by curtailing AMR. However, there are important clinical needs in inpatient and outpatient settings for which adequate diagnostic tests do not exist or use of existing diagnostics is limited. Many of the RDT companies display at allowing our attendees to talk one on one with product representatives. Of interest to ASP, the report addresses (see Issue 4 below) how ASP needs to collaborate with RDT companies. To read the full report click on the link Issue Statement 4: Collaboration between diagnostics companies and other stakeholders is limited and inconsistent. Development of a rapid diagnostic test requires substantial investment for companies. There is variability in how and when companies reach out to diagnostics and clinical experts for input. Increasing the interactions between diagnostics companies, clinicians, and clinical laboratorians

3 NEWSLETTER prior to or early in the test design phase could help ensure optimal test development to meet clinical needs and increase the likelihood of adoption of the test into clinical practice. Combating Antibiotic Resistance A Policy Roadmap to Reduce Use of Medically Important Antibiotics in Livestock The antibiotic resistance crisis cannot be resolved by only addressing antibiotic use in people. The CDC states 70% of antibiotics in the US are given to animals. board member Jason Newland MD provided his expert advice in this new report. Did you know in ,389,200 pounds of medically important antibiotic active ingredients were sold for use in foodproducing animals? Colistin-resistant bacteria, enriched by overuse of the drug in pig production outside of the US is spreading around the world. Dr. Newland provides practical ASP tips in the report. 1. Does your hospital serve antibiotic free meat? If not, why not? 2. Invite a dietician to your ASP meeting. To read this compelling report click on the link

4 NEWSLETTER World Antibiotic Awareness Week, November 2017 World antibiotic awareness week is the perfect opportunity for ASP members to highlight their activities to combat antibiotic resistance and increase awareness of antibiotic resistance. the WHO and CDC website have helpful tips on how to conduct several activities in addition to free handouts that can be downloaded and printed. If you need ideas go to the CDC or WHO link. The screenshot shows you how many resources they have made available. Take time to plan for this important public health initiative to help preserve antibiotics.

5 NEWSLETTER Take photos of your team participating in an activity during Antibiotic Awareness Week and they will be featured in the next newsletter. Send a short description of the ASP activity with a photo to Debbie.goff@osumc.edu ASP Basic or Advanced Registration Waivers Remember to check the website ( for registration waivers for either the basic or advanced ASP training for members who practice in a healthcare setting. These are awarded on a first-serve basis and available depending on current funding.

6 NEWSLETTER NEWSLETTER CONTINUING EDUCATION ARTICLE The self-assessment quiz which can be found at the end of this article can be completed for 1 CEU of Continuing Pharmacy Education credit. The quiz may be completed online at ( at no cost for members. Non-members should print and mail the completed quiz, along with a $15.00 check made payable to to:,, Mt. Pleasant, SC Your CE credit will be reported on CPE monitor within 4 weeks of receipt. ACPE UAN# H01-P Knowledge-based activity. Target audience: pharmacists and other healthcare providers (expires 11/17/18) is accredited by the Accreditation Council for Pharmacy Education as the provider of continuing pharmacy education. Carbapenem-Resistant Enterobacteriaceae (CRE): New Treatment Options against Klebsiella pneumoniae carbapenemase (KPC) Josephine L. Tan, PharmD Candidate,, Sarah C.J. Jorgensen, PharmD,, and Michael J. Rybak, PharmD, MPH, PhD Disclosures: Ms Tan and Dr. Jorgensen have no conflicts of interest to disclose related to this learning activity. Dr. Rybak serves as a consultant and member of an advisory board, is a member of a speakers bureau and, in some cases, has research grants with Achaogen, Allergan, Bayer, Merck, The Medicines Company and Theravance. Learning Objectives: At the end of this activity, learners will be able to: 1. Review the epidemiology of CRE, including incidence and mortality. 2. Describe carbapenemases as the main mechanism of resistance employed by CRE. 3. List the advantages and disadvantages of historical treatment options used for CRE. 4. Discuss the mechanisms, preliminary data and potential therapeutic niches for recently approved and novel pipeline agents in development against CRE. Overview One of the biggest challenges facing the infectious disease community today is the emergence of multidrug resistant (MDR) Gram-negative bacteria. The increasing prevalence among Enterobacteriaceae of β-lactamases capable of hydrolyzing carbapenems is of critical concern because these antibiotics have traditionally served as our last line of defense against MDR pathogens. As of August 2017, carbapenem-resistant Enterobacteriaceae (CRE) have been reported in every state but Idaho. 1 CRE are particularly prevalent in long-term acute-care hospitals where approximately 18% of patients experience one or more CRE infections. 2 Their spread also varies by geographic location, with

7 NEWSLETTER regional statistics placing carbapenem-resistant Klebsiella pneumoniae estimates at about 60% in India and Greece. 3 Due in part to the dearth of available treatment options, CRE mortality rates of up to 50% have been reported and are typically two-fold higher than corresponding rates for infections caused by carbapenem-susceptible Enterobacteriaceae. 1,4 This is a concerning trend, especially since the factors that contribute to multidrug resistance, such as inappropriate use of carbapenems, as well as lack of antimicrobial stewardship and appropriate infection control, are still problematic in many healthcare institutions today. 5 Background on Carbapenems and Resistance Carbapenems exert their bactericidal effect through irreversibly binding to the Ser403 residue in the active site of penicillin-binding proteins (PBPs), resulting in inhibition of the transpeptidation step of bacterial cell wall synthesis. 6 Carbapenem resistance among Enterobacteriaceae is largely driven by the production of carbapenemases which cleave the β-lactam ring resulting in antibiotic inactivation. Resistance can also arise through a combination of non-carbapenemase mechanisms: permeability defects (outer membrane porin inactivation or reduced porin expression), increased drug efflux and expression of other class A or C β-lactamases such as extended-spectrum β-lactamases (ESBLs) and AmpC enzymes. 7 Ertapenem appears to be the most affected by non-carbapenemase resistance mechanisms in CRE. 8 In a study conducted by Tamma et al, the 14-day mortality in patients with CRE bacteremia was reported to be 4 times greater in those with carbapenemase-producing CRE compared with non-carbapenemase-producing CRE. This is concerning because carbapenems and non-β-lactam agents are less likely to be effective against carbapenemase-producing CRE. 8 β-lactamases are divided into 4 classes (A, B, C and D) according to the Ambler system based on their amino acid sequence. Class A enzymes include the serine β-lactamases, class B the metallo-βlactamases (MBLs), class C the AmpC β-lactamases and class D the oxacillinases. 6 Carbapenemases belong to the Ambler classes A, B and D. The most notable member of Class A enzymes in regards to carbapenem resistance is the K. pneumoniae carbapenemase (KPC), encoded by the bla KPC gene. 9 It is the most common carbapenemase in Enterobacteriaceae in the United States and is mainly distinguished by 11 variants (KPC-2 through -12), though variants 2 and 3 are the most clinically relevant. 6,10 Bla KPC is carried on transferrable plasmids with the potential for rapid inter- and intra- species spread which poses significant challenges for infection control. In addition, bla KPC is often accompanied by genes encoding resistance to non-β-lactam antibiotics severely limiting treatment options. KPC was first identified in 1996 and was mainly confined to this country until Within the past decade, KPC has been reported in other parts of the world, such as in France, China and Israel. 2,11 The Class B enzymes are metallo-β-lactamases, which rely on a zinc cofactor. Members of this class include VIM, IMP and NDM. B The widespread prevalence of NDM is troubling; since its introduction in 2009, it has spread from the Indian subcontinent and Middle East to cause outbreaks in other parts of the world, though it remains rare in the United States. 9 The MBLs are susceptible to aztreonam in the absence of additional β-lactamases, but they are not susceptible to the currently available β-lactamase inhibitors. 7

8 NEWSLETTER Class D β-lactamases, of which OXA-48 is an example, are more commonly referred to as oxacillinases due to their preferential hydrolysis of oxacillin over penicillin. Like class A carbapenemases, the OXA enzymes utilize an active site serine residue. 12 They are susceptible to ceftazidime and exhibit low-level hydrolysis of cefotaxime. Of note, detection by phenotypic testing is difficult because isolates often coproduce non-carbapenemase β-lactamases. The only commercially available β-lactamase inhibitor that is active against these class D enzymes is avibactam. 13 Table 1. Susceptibility profiles of selected β-lactam antibiotics to carbapenemases. Adapted from Nordmann et al. 14 AMC TZP CZA 12 IPM ETP MEM MVB 15 ATM KPC S/I R S S/I/R I/R S/I/R S R IMP/VIM/NDM R I/R R S/I/R I/R S/I/R R S OXA-48/-181 R S/I/R S/I/R S/I S/I S/I R S AMC: amoxicillin-clavulanate; TZP: piperacillin-tazobactam; CZA: ceftazidime-avibactam; IPM: imipenem; ETP: ertapenem; MEM: meropenem; MVB: meropenem-vaborbactam; ATM: aztreonam Current Treatment Options Older Agents (Historical Treatment Options) Due to the multidrug resistant nature of CRE, there remain only a few antimicrobial options with activity against the pathogens. These historically included tigecycline, polymyxins, fosfomycin and aminoglycosides. 9 In a review of 20 clinical studies pertaining to CRE treatment, mortality rates were lower in patients treated with combination therapy using these agents compared to those who received monotherapy (27.4% vs. 38.7%; p < 0.001, respectively). 16 Aminoglycosides demonstrated the most efficacious results as monotherapy according to the data that was available, however, this was mainly in the setting of urinary tract infection. The potential role that synergy with aminoglycosides might play in treating CRE is still to be explored. Fosfomycin demonstrates in vitro activity against KPC-CRE, however only the oral formulation is currently available in the U.S. which is used exclusively for lower urinary tract infections. The parenteral formulation has been successfully incorporated in combination regimens in other parts of the world and should be available shortly in the U.S. Colistin and polymyxin B show potent in vitro activity against CRE, however, their adverse effects disfavor them from widespread use. Lastly, tigecycline mainly has bacteriostatic activity against CRE, with equally problematic pharmacokinetic properties, such as high tissue distribution and low serum concentrations. In summary, though combination therapy might be more desirable than monotherapy for treating CRE, further studies are needed to elucidate a clear treatment pathway. 9 Additional information regarding the advantages and disadvantages of each agent are detailed in Table 2, adapted from Morill et al. and Thaden et al.

9 NEWSLETTER Table 2. Overview of Historical Treatment Options 13,15 Agents / Class Advantages Disadvantages Further Comments Fosfomycin Phosphonic Acid Derivative Tigecycline Glycylcycline Colistin Polymyxin B Polymyxin Gentamicin Amikacin Aminoglycosides High urine concentrations Bactericidal via inhibiting early bacterial cell wall synthesis Generally well-tolerated Has activity against some Class A, B and D β- lactamases Generally well-tolerated Limited data for use in CRE infections Development of resistance during treatment avoid monotherapy Prolonged course for cuti poorly tolerated due to GI adverse effects 17 Resistance is increasing Limited data and higher mortality for monotherapy Black Box Warning for increased mortality Pharmacokinetics GI tolerability Potent activity against CRE Ideal dosages in renal dysfunction and critical illness largely unknown Neurotoxicity, nephrotoxicity Development of resistance during treatment Variability in MIC results depending on method used and no gold standard method established 18 Most efficacious monotherapy when compared to other antibacterials (for UTI) Nephrotoxicity Ototoxicity Pharmacokinetic considerations for certain infections like pneumonia Intravenous fosfomycin not available in United States but has been shown to have good penetration into tissues and the central nervous system; coming soon Oral fosfomycin approved by FDA for urinary tract infections Increased efficacy when used in combination (either carbapanems, gentamicin or colistin) Increased efficacy in combination for serious infections Limited data on use Likely increased efficacy in combination CRE: carbapenem-resistant Enterobacteriaceae; cuti: complicated urinary tract infection; GI: gastrointestinal; MIC: minimum inhibitor concentration; FDA = U.S. Food and Drug Administration Ceftazidime-Avibactam (CAZ-AVI) Another agent with activity against CRE is ceftazidime-avibactam (CAZ-AVI), a cephalosporin / β- lactamase inhibitor combination, which was approved by the Food and Drug Administration (FDA) in Ceftazidime is a third-generation anti-pseudomonal cephalosporin that inhibits cell wall synthesis in Gram-negative bacteria by binding primarily to PBP-3. In many areas, less than 75% of nosocomial isolates are susceptible to ceftazidime monotherapy. 12 Avibactam is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor (BLI) that inhibits Ambler class A, C and some class D β-lactamases. 12 It is a partially reversible inhibitor of β-lactamases via covalent acylation of a serine residue in the active site of the β-lactamase. Avibactam therefore restores activity of ceftazidime against ESBL, AmpC, and KPC enzymes. 10 It additionally demonstrates minimal

10 NEWSLETTER activity against most OXA enzymes with the exception of OXA-48-like enzymes. It is not active against Ambler class B metallo-β-lactamases, which lack the necessary active site serine residue. There have been rare instances of CAZ-AVI resistance reported in the literature. The prevailing mechanism as elucidated by Shields et al. demonstrates that point mutations in the omega loop of KPC cause increased hydrolysis of ceftazidime and consequent CAZ-AVI resistance. The phenotype associated with many of these variants is notable for restoration of meropenem susceptibility and decreased MICs to other β-lactams. However, increased meropenem MICs have re-emerged after prolonged passage at sub-inhibitory concentrations, suggesting that the potential therapeutic role of meropenem is still uncertain. 20 CAZ-AVI resistance has additionally been documented in isolates with various combinations of decreased permeability, increased efflux and increased bla KPC expression. 21,22 CAZ-AVI has received FDA approval for complicated intra-abdominal infections (ciai) in combination with metronidazole, and for complicated urinary tract infections (cuti) based on Phase 3 trials demonstrating similar efficacy and safety outcomes against comparators meropenem and doripenem, respectively. There were only six meropenem-nonsusceptible Enterobacteriaceae isolates recovered in the ciai registry trials. Clinical trial data suggest that CAZ-AVI is well-tolerated with a safety profile similar to that of ceftazidime alone, although definitive conclusions are limited by the relatively small number of patients exposed. CAZ-AVI requires a dose adjustment to 1.25 g every 8 hours in patients with a creatinine clearance (CrCl) ml/min; 0.94 g every 12 hours for CrCl ml/min; 0.94 g every 24 hours for CrCl 6 15 ml/min; and 0.94 g every 48 hours for CrCl 5 ml/min. A sub-group analysis of patients with moderate renal impairment (CrCl ml/min) enrolled in Phase 3 ciai trials showed decreased clinical cure in both the CAZ-AVI/ metronidazole and meropenem arms, however the decrease was more pronounced in the CAZ-AVI arm leading to warnings in the FDA labeling. 19,23 Preliminary results evaluating CAZ-AVI compared to meropenem in nosocomial and ventilator-associated pneumonia (REPROVE Study) have also been reported. Results suggest that CAZ-AVI is non-inferior to meropenem for the primary endpoint of all-cause mortality at day 28 (treatment difference 1.5, 95% CI -2.4 to 5.3). Efficacy was similar in terms of renal status and type of infection. 24 Early clinical experiences with CAZ-AVI have recently been reported. Shields et al. describe a retrospective analysis of 37 patients with CRE who were treated with CAZ-AVI. Clinical success and survival rates at 30 days were reported to be 59% and 76%, respectively. Of note, resistance to CAZ-AVI developed in 8% of cases (30% of treatment failures) within 10 to 19 days of treatment initiation. 25 King et al. conducted an additional retrospective chart review of 60 patients who had received CAZ-AVI for CRE infections. In-hospital mortality and clinical success rates were reported to be 32% and 65%, respectively. As expected, mortality was higher for those requiring vasopressors or mechanical ventilation, were treated in the intensive care unit, or who required renal dose adjustment. There were no differences in mortality or clinical success for those who received concomitant antibiotic therapy versus CAZ-AVI monotherapy. 26 Most recently, Shields et al. retrospectively compared CAZ-AVI to regimens that included combinations of carbapenems, aminoglycosides, and colistin, among others, for the treatment of carbapenem-resistant K. pneumoniae bacteremia. CAZ-AVI was associated with higher rates of clinical

11 NEWSLETTER success (P = 0.006) and survival (P = 0.01). Notably, baseline characteristics in terms of illness severity and strain type did not vary significantly between groups. 27 In summary, CAZ-AVI demonstrates potent in vitro activity against CRE producing Ambler class A, C, and D β-lactamases. Its safety profile thus far compares favorably with more toxic historical alternatives. However, efficacy outcomes in retrospective series have been variable and certain patient populations, such as those with renal impairment, appear to be at increased risk for treatment failure. The early development of on-therapy resistance underscores the need for additional novel agents with activity against CRE. Meropenem-Vaborbactam (MVB, formerly RPX7009) Vaborbactam is a BLI used in combination with meropenem to restore meropenem activity. 28 It is the first boronic acid inhibitor that is active against class A and C β-lactamases, and was specifically designed to target KPC. 15 Vaborbactam forms a reversible dative bond by utilizing a serine residue in the active site of B-lactamases. It is stable to hydrolysis by the β-lactamase. 29 Vaborbactam s activity against CRE was demonstrated in an in vitro study of 315 serine carbapenemase-producing Enterobacteriaceae isolates. Meropenem alone, at concentrations 2 mg/l, was active against approximately 7% of these isolates. The addition of vaborbactam (³ 8 mg/l) restored activity against 96.5% of isolates. 28 The activity of MVB was additionally studied in multi-drug resistant E. coli, K. pneumoniae, and Enterobacter spp. The combination was active against 98.5% of 133 KPC-producing strains, with the exception of KPC K. pneumoniae that had decreased expression of outer-membrane porin genes ompk35 and ompk36. It should also be noted that vaborbactam does not expand the activity of meropenem against resistant strains of Acinetobacter baumannii or Pseudomonas aeruginosa. 30 The FDA approved MVB in August 2017 for the treatment of cuti including pyelonephritis caused by E. coli, K. pneumoniae, and E. cloacae, based on the TANGO-1 trial demonstrating marginally superior efficacy and similar safety outcomes against piperacillin-tazobactam (TZP). The primary endpoint was overall success, defined as clinical cure and microbiological eradication at the end of IV therapy (EOIVT) in the microbiologic modified intent-to-treat (m-mitt) population. Out of a total 361 patients in the m-mitt population, overall success was seen in 98.4% versus 94.3% of the MVB versus TZP arms, respectively (treatment difference 4.1%, 95% CI 0.3% to 8.8%). 31,32 Only a small number of patients were infected with CRE (n=5) and thus the added benefit of vaborbactam to meropenem could not be assessed in this study. 33,34 This was likely reflective of the study s inclusion/exclusion criteria; patients that are more likely to harbor a resistant pathogen (immunocompromised, high burden comorbidity, multi-organ dysfunction) were either excluded or under-represented. The Phase 3 trial, TANGO-2, was designed to address these limitations. This was a 60-site, 2:1 randomized trial investigating the efficacy and safety of MVB against best available therapy (BAT) in the treatment of suspected CRE infections. 29 The trial was stopped early following a recommendation by the TANGO-2 data and safety monitoring board based on positive results from an interim analysis. 35 Of the 43 patients with confirmed CRE infection, the primary endpoint of clinical cure at test of cure (TOC) was

12 NEWSLETTER observed in 57.1% vs. 26.7% for the MVB and BAT arms, respectively (treatment different 30.5%, 95% CI 1.6% to 59.4%). Efficacy was similar stratified by infection source and immunocompromised status It should be noted that the TANGO-2 trial expanded its eligibility criteria to include populations that were previously excluded in the TANGO-1 trial (immunocompromised, severe sepsis, renal impairment). 39 Additionally, the use of BAT instead of a specific active comparator also appropriately reflected the lack of a current treatment standard against CRE. In addition to the TANGO- 1 and 2 trials, MVB will be compared to TZP in patients with hospital- and ventilator-acquired pneumonia in TANGO-3, a Phase 3B, multicenter, double-blind randomized controlled trial (NCT ) that is not yet open for recruitment. 40 New Agents in Development Imipenem/Cilastatin with Relebactam (IMI-REL) In addition to CAZ-AVI and MVB, imipenem/cilastatin-relebactam (IMI-REL) is another β-lactam/ β- lactamase inhibitor combination in late stage clinical development. 10 Relebactam (previously known as MK-7655) is a BLI with potent activity against class A (KPC) and class C β-lactamases, but lacks activity against MBLs. 41 Like avibactam, it is a non-β-lactam diazabicyclooctane BLI, however, it contains an additional piperidine ring and lacks activity against class D oxacillinases. 42 Though relebactam is active against imipenem-resistant Enterobacteriaceae and P. aeruginosa, it is not active against A. baumannii. 29 Per the results of two dose-ranging Phase 2 trials conducted in patients with ciai and cuti, IMI-REL at doses of 125 mg and 250 mg relebactam were non-inferior to imipenem/cilastatin plus placebo. Less than 15% of isolates in these studies were resistant to imipenem alone, limiting assessment of IMI-REL s efficacy among its target population (i.e. those with CRE infections). 41,43 Haider et al. further investigated the therapeutic niches for CAZ-AVI and IMI-REL in their study of 100 mostly North American isolates, 97% of which were confirmed as carbapenemase-producing. CAZ-AVI resistance was independently associated with the presence of the variant KPC-3 strain described earlier, which results in increased ceftazidime hydrolysis. IMI-REL maintained activity against most of these isolates but showed decreased activity against isolates with ompk36 mutations. CAZ-AVI activity was also attenuated against isolates with ompk36 mutations but to a lesser extent. 42 Only CAZ-AVI demonstrated activity against isolates producing OXA-48-like enzymes. Although further clinical experience is much needed, these observations suggest IMI-REL may be a therapeutic option in patients infected with variant KPC strains resistant to CAZ-AVI. CAZ-AVI, in turn, would be preferred when OXA-48-like enzymes are confirmed or suspected. Eravacycline Eravacycline is a tetracycline-derivative (fluorocycline) that, like other tetracyclines, binds to the bacterial 30s ribosomal subunit inhibiting chain elongation. 9 It is active in the presence of tetracycline-specific resistance mechanisms (drug efflux, ribosomal protection) and has activity against MDR Enterobacteriaceae including KPC-producing strains. 44

13 NEWSLETTER In one study, Zhang et al. determined the in vitro activity of eravacycline and comparators (tigecycline, tetracycline, amikacin, levofloxacin) against CRE isolates (87.3% K. pneumoniae). Of the 110 isolates, most produced a KPC while three isolates produced a SME-1 carbapenemase. Eravacycline and tigecycline were the most active agents demonstrating low cumulative MICs. 45 The efficacy and safety of eravacycline was compared to ertapenem in a Phase 3, randomized, double-blind multicenter study conducted by Solomkin et al. in over 500 patients with ciai. Eravacycline demonstrated an 86.8% clinical cure rate compared to the 87.6% with ertapenem, thus meeting non-inferiority criteria (difference in clinical cure rate -0.80%, 95% CI -7.1% to 5.5%). There were only six confirmed carbapenem-resistant isolates (eravacycline 1, ertapenem 5). 44 An additional Phase 3 trial (IGNITE3, NCT ), comparing eravacycline to ertapenem for cuti is currently recruiting. 46 Furthermore, eravacycline is being investigated in patients with end stage renal disease and impaired hepatic function. These studies have been completed and publication of results are greatly anticipated. Plazomicin Plazomicin is a new sisomicin-derived aminoglycoside that binds to bacterial 30S ribosomal subunits to disrupt protein synthesis. It differs from the current aminoglycosides in that it is generally not affected by aminoglycoside-modifying enzymes. 9,47 Plazomicin has activity against most KPC-producing strains but lacks activity against NDMs. 13 Galani et al. examined plazomicin activity in 300 MDR isolates of K. pneumoniae (80.3%), E. coli (11%), and Enterobacter spp. (8.7%), all from four hospitals in Athens, Greece. The MIC 90 of plazomicin against all organisms was 2 mg/l, which compared favorably to gentamicin (MIC 90 > 8 mg/l) and amikacin (MIC 90 > 32 mg/l) 47 Plazomicin given at a dose of 15 mg/kg daily exhibited a C max of mg/l. The C max values were mg/l and mg/l for amikacin 15 mg/kg daily and gentamicin 7 mg/kg daily, respectively. 48 Overall, plazomicin demonstrated a favorable pharmacokinetic profile when compared to alternative agents in the aminoglycoside drug class. There are several studies for which plazomicin efficacy and safety results are pending. It is being compared to levofloxacin in a Phase 2 trial (NCT ) and to meropenem in a Phase 3 trial (EPIC, NCT ) for cuti including acute pyelonephritis. 49,50 Additionally, preliminary results of a Phase 3 trial comparing plazomicin to colistin for CRE infections (CARE study) were recently reported; plazomicin was associated with a favorable efficacy and safety profile (>80% reduction in all-cause mortality at day 28, lower incidence and magnitude of serum creatinine elevations). 51 Cefiderocol Cefiderocol is a novel siderophore cephalosporin with a catechol moiety conferring in vitro activity against CRE without the use of a β-lactamase inhibitor. Its cephalosporin moiety binds primarily to PBP-3, while its 3-position catechol complexes with ferric iron thus allowing cefiderocol to utilize the bacterial iron transport system to cross the outer membrane. Once in the periplasmic space, cefiderocol is able to inhibit bacterial cell wall synthesis. 10,52 This has been referred to as the Trojan Horse mechanism, and uniquely details how cefiderocol might be able to evade bacterial resistance due to membrane impermeability seen with the novel BL/BLI combinations.

14 NEWSLETTER Cefiderocol activity against over 9000 Gram-negative clinical isolates from North America and Europe was recently reported. The MIC 90 of cefiderocol against North American meropenem-susceptible Enterobacteriaceae isolates was 0.5 mg/l, and 1 mg/l in meropenem non-susceptible isolates. CAZ-AVI on the other hand, showed an MIC 90 value of 4 mg/l against meropenem non-susceptible North American isolates. MICs of 4 mg/l or less for cefiderocol were seen with 99.9% of all Enterobacteriaceae isolates and in 97.0% of all meropenem non-susceptible isolates. 52 Additionally, against organisms with MICs of 4 mg/l or less, cefiderocol dosed at 2 g every 8 hours over a 3-hour infusion achieves a 90% or greater probability of target attainment for 75% free time above MIC in those with normal renal function. 53 Despite this preliminary in vitro data, further research is needed to actually determine the clinical utility of cefiderocol against Gram-negative bacilli with multiple resistance mechanisms. Of note, there are three pending trials examining cefiderocol in nosocomial pneumonia, cuti and bloodstream infections. Summary The emergence of CRE is a pressing concern in the fields of Infectious Diseases and Public Health. The antibiotics that have been used as mainstays of therapy have decreased activity against these MDR organisms. The concern is made even more palpable when the high mortality rates seen with these infections are taken into consideration. Historical treatment options have been quite limited, each with their own disadvantages. Two new combination agents, CAZ-AVI and MVB, have recently emerged as alternatives to treating CRE infections; we have more clinical experience with the former while the latter is fairly new. Though these agents have shown promising in vitro activity, their proposed clinical utility is limited by the scarcity of isolated CRE infections in registry trial data, as well as by widespread exclusion of patients with high comorbid burden within those trials who are likely to harbor a resistant pathogen. It therefore becomes difficult to link approval trial results to the patients who fit the proposed place in therapy for these new BL/BLI combinations. Of most concern are the rare, but growing reports of resistance seen with CAZ-AVI. Of note, noncarbapenemase resistance mechanisms such as decreased membrane permeability and increased drug efflux are gaining recognition as the weaknesses of these new antibiotics. With this in mind, it becomes all the more necessary to further investigate additional agents with novel mechanisms such as plazomicin, eravacycline, cefiderocol and imipenem/cilastatin with relebactam, which are currently in the drug pipeline. Though these potential therapeutics are still being studied, further information regarding their efficacy and safety is highly anticipated.

15 NEWSLETTER References: 1. Healthcare-Associated Infections. Centers for Disease Control and Prevention website Updated August Accessed November 4, Munoz-Price, LS, Poirel L, Bonomo RA, Schwaber MJ et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. The Lancet. 2013; 13: Kelly AM, Mathema B, Larson EL. Carbapenem-resistant Enterobacteriaceae in the community: a scoping review. International Journal of Antimicrobial Agents doi: /j.ijantimicag Centers for Disease Control. Facility Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE). Originally published: Updated: Nov Accessed Jul Cerceo E, Deitelzweig SB, Sherman BM, Amin AN. Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options. Microbial Drug Resistance. 2016; 22 (5): Nordmann P, Dortet L, Poirel L. Carbapenem resistance in Enterobacteriaceae: here is the storm! Trends in Molecular Medicine. 2012; 18 (5): Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology. 2015; 13: Tamma PD, Goodman KE, Harris AD, Tekle T, Roberts A, Taiwo A, Simner PJ. Comparing the Outcomes of Patients With Carbapenemase-Producing and Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Bacteremia. Clinial Infectious Diseases. 2017; 64(3): Martirosov DM, Lodise TP. Emerging trends in epidemiology and management of infections caused by carbapenem-resistant Enterobacteriaceae. Diagnostic Microbiology and Infectious Disease. 2016; 85: Doi Y, Iovleva A. Carbapenem-Resistant Enterobacteriaceae. Clin Lab Med. 2017; 37: Leavitt A, Navon-Venezia S, Chmelnitsky I, Schwaber MJ, Carmeli Y. Emergence of KPC-2 and KPC-3 in Carbapenem-Resistant Klebsiella pneumoniae Strains in an Israeli Hospital. Antimicrobial Agents and Chemotherapy. 2007; 51 (8): Lacace-Wiens P, Walkty A, Karlowsky J. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evidence. 2014; 9: Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infectious Diseases. Doi: /ofid.ofv Nordmann P, Gniadkowski M, Giske CG, Poirel L, Woodford N, Miriagou V, European Network on Carbapenemases. Identification and screening of carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2012; 18: Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem- resistant Enterobacteriaceae. Virulence. 2016; 8(4): Tzouvelekis LS, Markogiannaki A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014; 20: Bleasdale SC, Wenzler E, Sikka M, Bunnell KL, Finnemeyer M, Rosenkranz SL, Danziger LH,Rodvold KA. Phase I Study to Evaluate the Safety and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants. IDWeek "Conference Proceedings" 18. Hindler J, Humphries RM. Colistin MIC variability by method for contemporary clinical isolates of multi-drug resistant Gram-negative bacteria. J Clin Microbiol. 2013; 51(6): Avycaz [package insert]. Irvine, CA: Allergan Inc; Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, Pandey R, Doi Y, Kreiswirth BN, Hong Nguyen M, Clancy CJ. Emergency of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne bla KPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. Antimicrob Agents Chemother. 2017; 61:e Humphries RM, Hemarajata P. Resistance to Ceftazidime-Avibactam in Klebsiella pneumoniae Due to Porin Mutations and the Increased Expression of KPC-3. Antimicrob Agents Chemother. 2017; 61:e Nelson K, Hemarajata P, Sun D, Rubio-Aparicio D, Tsivkovski R, Yang S, Sebra R, Kasarskis A, Nguyen H, Hanson BM, Leopold S, Weinstock G, Lomovskaya O, Humphries RM. Resistance to Ceftazidime-Avibactam Is

16 NEWSLETTER Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity. Antimicrob Agents Chemother. 2017; 61:e Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, Newell P, Pachl J. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clinical Infectious Disease. 2016; 62(11): Torres A, Rank D, Rekeda L, Chen X, Riccobene T, Critchley IA, Lakkis HD, Melnick D, Chow J, Taylor D, Laud PJ, Talley AK. Phase 3, Randomized, Double-blind Noninferiority Study of Ceftazidime-Avibactam vs Meropenem in the Treatment of Patients With Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Analyses of the REPROVE Study per FDA Endpoints. IDWeek "Conference Proceedings" 25. Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, Press EG, Kreiswirth BN, Clancy CJ, Nguyen MH. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clinical Infectious Diseases. 2016; 63(12): King M, Heil E, Kuriakose S, Bias T, Huang V, El-Beyrouty C, McCoy D, Hiles J, Richards L, Gardner J, Harrington N, Biason K, Gallagher JC. Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapanem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother. 2017; 61:e Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, Doi Y, Kreiswirth BN, Clancy CJ. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumonia Bacteremia. Antimicrob Agents Chemother. 2017; 61:e Castanheira M, Rhomberg PR, Flamm RK, Jones RN. Effect of the β-lactamase Inhibitor Vaborbactam Combined Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae. Antimicrobial Agents and Chemotherapy. 2016; 60 (9): Wong D, van Duin D. Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy. Drugs. 2017; 77: Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Quale J, Landman D. Activity of Meropenem Combined with RPX7009, a Novel β-lactamase Inhibitor, against Gram-Negative Clinical Isolates in New York City. Antimicrob Agents Chemother. 2015; 59(8): Vabomere [package insert]. Teramo, Italy: Facta Famaceutici, S.p.A.; Loutit J, Fusaro K, Zhang S, Morgan E, Alexander E, Griffith D, Lomovskaya O, Dudley M. Meropenem- Vaborbactam (M-V) Compared With Piperacillin-Tazobactam (P-T) in the Treatment of Adults With Complicated Urinary Tract Infections (cuti), Including Acute Pyelonephritis (AP) in a Phase 3 Randomized, Double-Blind, Double-Dummy Trial (TANGO 1) [LB-7]. Open Forum Infectious Diseases. 2016; 1(S1): S KK. GR. Clinical microbiology review. Meropenem-vaborbactam. NDA# Remplex Pharmaceuticals. Division of Anti-Infective Products. Center or Drug Evaluation and Research. US Food and Drug Administration "Generic" 34. Kaye KS FT, Shorr A, Loutit J, Dudley M, Lomovskaya O, Zervos M. Clinical outcomes with meropenemvaborbactam (M-V) by extended-spectrum beta-lactamase (ESBL) production in TANGO 1, a Phase 3 randomized trial vs piperacillin-tazobactam (P-T). American Society for Microbiology Microbe "Conference Proceedings" 35. The Medicines Company. The Medicines Company announces TANGO-2 trial of meropenem-vaborbactam (formerly, Carbavance) stopped early for superior benefit-risk compared to best available therapy for CRE. Business Wire. trial-meropenem-vaborbactam-formerly-carbavance. July 25, Accessed September 17, Kaye KS VJ, Mathers A, Daikos G, Alexander E, Loutit JS, Zhang S, Dudley MN.. Clinical outcomes of serious infections due to carbapenem-resistant Enterobacteriaceae (CRE) in TANGO II, a Phase 3, randomized, multinational, open-label trial of meropenem-vaborbactam (M-V) versus best available therapy (BAT). IDWeek "Conference Proceedings" 37. Wunderink R G-BE, Rahav G, Mathers A, Bassetti M, Solomkin J, Alexander E, Loutit JS, Zhang S, Dudley MN, Kaye KS.. Meropenem-vaborbactam vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: primary outcomes by site of infection. IDWeek "Conference Proceedings"

17 NEWSLETTER 38. Paterson DL KE, Bhowmick T, Alexander E, Loutit JS, Zhang S, Dudley MN, Walsh TJ.. Meropenemvaborbactam vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: outcomes in immunocompromised patients. IDWeek "Conference Proceedings" 39. Alexander EL, Loutit J, Tumbarello M, et al. Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials. Open Forum Infect Dis 2017;2:ofx The Medicines Company. A Study of Meropenem-Vaborbactam Versus Piperacillin/Tazobactam in Participants With Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (TANGOIII). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2017 September 18]. Available from Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, Du J, Pedley A, Kartsonis NA, Paschke A. Prospective, randomized, double-blind, Phase 2 dose-randing study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. Journal of Antimicrobial Chemotherapy. doi: /jac/dkx Haidar G, Clancy CJ, Chen L, Samanta P, Shields RK, Kreiswirth BN, Nguyen MH. Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017; 61:e Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, Rizk ML, Brown ML, Losada MC, Pedley A, Kartsonis NA, Paschke A. Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection. Antimicrob Agents Chemother. 2016; 60(10): Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L. Assesing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Evaracycline (IGNITE 1) Trial. JAMA Surgery. 2017; 153 (3): Zhang Y, Lin X, Bush K. In Vitro susceptibility of β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE) to eravacycline. The Journal of Antibiotics. 2016; 69: Tetraphase Pharmaceuticals, Inc. Efficacy and Safety Study of Eravacycline Compared With Ertapenem in Participants With Complicated Urinary Tract Infections (IGNITE3). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2017 September 18]. Available from Galani I, Souli M, Daikos GL, Chrysouli Z, Poulakou G, Psichogiou M, Panagea T, Argyropoulou A, Stefanou I, Plakias G, Giamarellou H, Petrikkos. Activity of Plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. Journal of Chemotherapy. 2012; 24 (4): Zhanel GG, Lawson CD, Zelenitsky S, Findlay B, Schweizer F, Adam H, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther. 2012; 10(4): Achaogen, Inc. Study of Plazomicin (ACHN-490) Compared With Levofloxacin for the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2017 September 18]. Available from Achaogen, Inc. A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cuti) Including Acute Pyelonephritis (AP) (EPIC). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2017 September 18]. Available from McKinnell JA, Connolly LE, Pushkin R, Jubb AM, O Keeffe B, Serio AW, Smith A, Gall J, Riddle V, Krause KM, Pogue JM. Improved Outcomes With Plazomicin Compared With Colistin in Patients With Bloodstream Infections Caused by Carbapenem-resistant Enterobacteriaceae (CRE): Results From the CARE Study. IDWeek "Conference Proceedings" 52. Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowski JA, Sahm DF. In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, Against a Recent Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem Non-Susceptible Isolates: The SIDERO-WT-2014 Study.

18 NEWSLETTER Antimicrobial Agents and Chemotherapy. Accepted manuscript posted online 19 June Doi: /AAC Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R. Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function. Antimicrob Agents Chemother. 2017;61(1). ABOUT THE AUTHORS Josephine L. Tan is currently a PharmD Candidate at the University of Michigan College of Pharmacy. She is interested in continuing her training through a PGY1 general pharmacy practice residency in Sarah Jorgensen completed her Pharm. D. at the University of Florida, Gainesville, FL. She did her PGY1 Pharmacy Practice Residency at Tallahassee Memorial Hospital, Tallahassee, FL and an Infectious Diseases PGY2 Residency at Huntington Hospital/University of Southern California, Pasadena, CA. She is currently completing an Infectious Diseases Outcomes Research fellowship with Wayne State College of Pharmacy, Detroit, MI. Michael J. Rybak, PharmD, MPH, PhD, FCCP, FIDSA, FIDP is Professor of Pharmacy and Medicine and Director of the Anti-Infective Research Laboratory at the Eugene Applebaum College of Pharmacy and Health Sciences at Wayne State University. He is affiliated with Detroit Receiving Hospital and is a member of the Detroit Medical Center Antimicrobial Stewardship Committee.