2016 winter newsletter final - mad-id · mad-id newsletter volume 6, number 4 winter 2016 mad-id...

MAD-ID NEWSLETTER

Volume 6, Number 4 Winter 2016

MAD-ID www.mad-id.org 537 Calico Retreat Mt. Pleasant, SC 29464-2765

What’s inside this winter issue?

• Call for abstracts • MAD-ID workshops • Joint Commission ASP requirements • Surgeon and ASP

• Members in the news

• CE Article:

Six Reasons to Attend

The MAD-ID Annual Meeting The Meeting for Antimicrobial StewardshipTM

May 10-13, 2017

1. The keynote speaker Ramanan Laxminarayan MD., MPh. Director for the Center for Disease Dynamics, Economics & Policy is a TEDX speaker on “The coming crisis in antibiotics” https://www.ted.com/talks/ramanan_laxminarayan_the_coming_crisis_in_antibiotics and a TedX speaker on what it takes to deliver pediatric vaccines to 27 million children in India and TED radio hour speaker on “How Did A Medical Miracle (antibiotics) Turn Into A Global Threat?” http://www.npr.org/2015/07/17/421490567/how-did-a-medical-miracle-turn-into-a-global-threat With over 907,850 views on YouTube, the world is listening to him! 2. MAD-ID annual meeting is the ONLY meeting dedicated to antimicrobial stewardship. Not just one lecture or workshop but the entire 3½ day meeting is about antimicrobial stewardship. MAD-ID is The Antibiotic Stewardship MeetingTM! 3. Networking. MAD-ID annual meeting allows attendees to interact with each other. With over 400 attendees, MAD-ID has numerous opportunities to exchange ideas with colleagues and learn from each other. This networking opportunity is unlike other large meetings with 5,000-10,000 attendees where it is difficult to connect with others. 4. Formal antimicrobial stewardship education/training. The didactic portion of MAD-ID’s popular antimicrobial stewardship training program (ASP) is incorporated into annual meeting content. 5. Access to experts in ASP. The speaker line-up for 2017 includes experts in the field of ASP. Attendees can interact with the speakers in the hands on workshops or after their lecture. 6. Research. The poster session allows attendees to present their work, speak to other presenters, and exchange research ideas in a relaxed atmosphere.

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Call for Abstracts

Submission of abstracts related to antimicrobial therapy or infectious diseases pharmacotherapy are invited. Stewardship practitioners, including those who have completed the MAD-ID Antimicrobial Stewardship Training Program (ASP) are strongly encouraged to submit papers for presentation in our poster session. Those who have completed the MAD-ID ASP are particularly encouraged to share their stewardship projects/ initiatives as poster presentations. DEADLINE FOR ABSTRACT SUBMISSION IS APRIL 7, 2017.

Six MAD-ID Classrooms/Workshops (Attendees pick four)

The MAD-ID annual meeting workshops are focused on key ASP issues.

Evaluating the ID Literature Megan Winegardner, PharmD at Beaumont Hospital will be conducting a workshop titled “Critical Review of ID Literature” featuring timely articles. Learn from an expert!

Stressed out from Limited Resources to actually do ASP? Julie Ann Justo, PharmD, MS from University of South Carolina will help to you through the process in her MAD-ID workshop titled “Effective Stewardship in a Setting with Limited Resources”

Bad Behavior: how do you change it? From across the pond attend the MAD-ID workshop by Mark Gilchrist, MPharm, MSc from the Imperial College in London England will explain and provide exercises in bringing about change in antibiotic prescribing behavior.

Working with Antibiograms Join the workshop by Romney Humphries, PhD of UCLA Health to learn first hand the correct way to construct and use an antibiogram with hands-on exercises demonstrating various uses of this important tool.

The “low-hanging” Fruit of Stewardship; Capturing and Presenting Your Data

Julie Ann Justo, PharmD, MS returns to lead attendees in exploring simple and straightforward stewardship initiatives at their own institutions and ways to maximize impact in reporting their results to institutional leadership.

Using “Smart” Data Management Systems in Stewardship

Samuel L. Aitken, PharmD of the MD Anderson Cancer Center with work with participants in exploring ways in which they can effectively utilize clinical surveillance (or “smart” data management) systems in their institution’s ASP.

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Good Stewardship in Research Research Grant Recipients (awarded $90,000 total)

MAD-ID is pleased to announce the 2016 award of three $30,000 research grants to advance the science and practice of antimicrobial stewardship. Watch for the 2017 call for proposals.

Things Heard on Twitter Once again MAD-ID attendees will be busy tweeting live from the conference using the #madid17 Our keynote speaker is also active on Twitter. Follow him @CDDEP

New ASP Publication: Inquiring Minds Want to Know

Just published in Clinical Infectious Diseases early release is an article that every ASP will find of value as it answers an important question. In case you are wondering what the answer is, they found post-prescription review with feedback was more effective. The MAD-ID annual meeting workshops are focused on key ASP issues similar to this. Megan Winegardner, PharmD at Beaumont Hospital will be conducting a workshop titled “Critical Review of ID Literature” featuring timely articles such as the one above.

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2017 ASP Joint Commission Requirements ASP will be required in all hospitals effective January 2017. Is your hospital prepared to meet all the new standards? The 2017 Annual meeting will be addressing several required core elements. https://www.jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_Standard.pdf

Surgeon Speaker on the Microbiome As MAD-ID continues to build cross-collaboration between ASP and surgeons, John Alverdy MD. Professor of Surgery, University of Chicago and Director for Surgical Infection research will be sharing his expertise on the microbiome. He also tweets and can followed @JCAlverdy

At last year’s meeting we had trauma surgeon Christian Jones MD speak on how to do ASP with surgeons. He said, “You have to engage the surgeons,” not just mandate their actions.” His talk was so well received a medical reporter from Pharmacy Practice News wrote an article about his talk as it was the first time she observed a surgeon speaking to a non-surgical audience on the topic of antibiotic stewardship. Her article can be viewed at http://www.pharmacypracticenews.com/Clinical/Article/05-16/Tips-for-Getting-Surgeons-On-Board-With-Antibiotic-Stewardship/36213

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MAD-ID Members in the News MAD-ID member Debbie Goff PharmD was invited to give a TEDx Columbus talk on Nov 4, 2016. The TEDx theme was RISK and her talk was titled antibiotics “just-in-case”. Dr. Goff describes the risk of taking antibiotics. She engages the audience as she describes how consumers, patients, and healthcare providers can become antibiotic stewards. Help spread her message on how everyone can become an antibiotic steward. The twelve-minute talk may be viewed on YouTube by searching for TedX Columbus 2016 or use this link.

https://www.youtube.com/watch?v=ALryAB_AYiA&t=20s

Would you like your ASP to be featured in a future newsletter?

Our members enjoy learning about other members programs. It can be a big or small healthcare environment, community or academic setting, it just needs to be successful! If you’re willing to share your success story please contact [email protected] for details.

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MAD-ID 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 (http://mad-idtraining.org/newsletter/) at no cost for MAD-ID members. Non-members should print and mail the completed quiz, along with a $15.00 check made payable to MAD-ID to: MAD-ID, 537 Calico Retreat, Mt. Pleasant, SC 29464-2765. Your CE credit will be reported on CPE monitor within 4 weeks of receipt. ACPE UAN# 0485-0000-16-032-H01-P Knowledge-based activity. Target audience: pharmacists and other healthcare providers (expires 12/31/17)

MAD-ID is accredited by the Accreditation Council for Pharmacy Education as the provider of continuing pharmacy education. Existing and Emerging Treatment Options for Multidrug-Resistant

Pseudomonas aeruginosa Infections JC Wilson, WR Vincent, KD Brade

Disclosures: None of the authors have any conflicts of interest related to this learning activity to disclose. Learning Objectives: At the end of this activity, the learner will be able to:

1. Explain common mechanisms of resistance of Pseudomonas aeruginosa 2. Discuss pharmacology, dosing, and available evidence supporting ceftazidime-avibactam and

ceftolozane-tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa 3. Discuss the rationale and place in therapy for older drugs including fosfomycin and polymyxins

Introduction Multidrug-resistant (MDR) organisms, defined as non-susceptible to one or more agents in three or more antimicrobial classes, are perhaps the greatest infectious disease threat facing today’s society.1 Over two million patients are infected with MDR organisms annually, resulting in more than 23,000 deaths.2 Pseudomonas aeruginosa is a non-lactose fermenting Gram-negative rod implicated in 51,000 infections annually, with 13% attributed to MDR strains. The rate of P. aeruginosa infections in the United States has remained stable, but infections caused by MDR strains are on the rise. Traditional antibiotics are often rendered ineffective by multiple resistance mechanisms expressed by MDR P. aeruginosa strains, which limits available treatment options. P. aeruginosa is capable of developing resistance to antimicrobials through mechanisms including enzymatic degradation, target site modification, decreased permeability, and drug efflux pumps. Enzymatic degration, through production of beta-lactamase enzymes, is one of the primary mechanisms of resistance exhibited by P. aeruginosa. The expression of Ambler Class A enzymes (e.g. extended spectrum beta-lactamases (ESBLs)) confers resistance to penicillins, ceftazidime, and aztreonam; Class B enzymes (e.g. metallo-beta-lactamases [MBLs]) confer resistance to beta-lactams including carbapenems; Class C enzymes (e.g. AmpC) confer resistance to penicillins and cephalosporins; and

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class D enzymes (e.g. OXA48) confer resistance to penicillins, ceftazidime, and aztreonam. Beta-lactam and fluoroquinolone antibiotics gain access to P. aeruginosa by passing through porin channels in the outer membrane of the bacterial cell, allowing them to bind to their target site of action. However, P. aeruginosa is capable of decreasing the permeability of these agents through modifications or loss of porin channels, which affects the activity of nearly all antimicrobials. P. aeruginosa strains have been shown to express multiple efflux pumps, including oprD, which is active against carbapenems; mexAB-oprM and mexCD-oprJ, which are active against beta-lactams and fluoroquinolones; mexXY-oprM, which is active against aminoglycosides; and mexEF-oprN, which is active against fluoroquinolones. Although these efflux pumps are present in all strains of P. aeruginosa, the degree to which they are expressed will determine the development of resistance to the affected antibiotics.3 The emergence of MDR P. aeruginosa due to the expression of multiple resistance mechanisms has limited the use of traditional antimicrobials, prompted the development of new agents, and led to renewed use of older agents. Ceftolozane-tazobactam Ceftolozane-tazobactam (TOL-TAZ) is a beta-lactam beta-lactamase inhibitor combination approved by the FDA in 2014 for complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI), in combination with metronidazole. Ceftolozane is a novel cephalosporin that inhibits bacterial cell wall synthesis of P. aeruginosa through binding to penicillin-binding protein (PBP) 1b, PBP1c, and PBP3.4 Although structurally similar to ceftazidime, ceftolozane has a heavier side chain substitution in the 3-position, increasing its stability against AmpC beta-lactamases, reducing the MICs for P. aeruginosa strains expressing these enzymes.5 However, TOL-TAZ does not appear to be affected by oprD loss or the hyperexpression of efflux pumps and does not have activity against MBL-producing strains.

In vitro data have identified TOL-TAZ as a potent agent for the treatment of MDR P. aeruginosa. In a study evaluating 1,971 P. aeruginosa isolates across 32 US hospitals, susceptibility testing was performed for TOL-TAZ, ceftazidime, cefepime, piperacillin-tazobactam, aztreonam, levofloxacin, gentamicin, and colistimethate sodium.6 TOL-TAZ was the second most active agent, with activity against 96.1% of isolates at a MIC of <4 µg/mL, exceeded only by colistimethate sodium at 99.1%. TOL-TAZ also retained activity against 310 (16%) MDR strains with a MIC <8 µg/mL and 175 (0.09%) extensively-drug resistant (XDR) strains with a MIC <16 µg/mL. When tested against 1,019 P. aeruginosa isolates from 28 US and 31 European centers, TOL-TAZ inhibited 94.1% of isolates, including 78% of meropenem non-susceptible strains.7 The dosage of TOL-TAZ approved for cUTI or cIAI is 1.5 grams (ceftolozane 1 gram and tazobactam 0.5 grams) given every 8 hours over a 1 hour intravenous infusion.4 Ceftolozane and tazobactam have volumes of distribution (Vd) of 13.5 L and 18.2 L, and half-lives of 3 and 1 hours, respectively. More than 95% of ceftolozane is eliminated renally as unchanged drug, necessitating dose adjustments for patients with creatinine clearance of 50 mL/minute or less. Existing studies comparing TOL-TAZ to other agents for the treatment of cIAI and cUTI had very few isolates of P. aeruginosa. ASPECT-cIAI consisted of two randomized, double-blind, phase III trials which found TOL-TAZ plus metronidazole (n=487) to be non-inferior to meropenem (n=506) in achieving clinical cure (83% versus 87%, 95% CI: -8.91 to 0.54).8 The primary pathogen isolated was E. coli [525 isolates (65%]), with P. aeruginosa only being isolated in 52 (9%) patients. Of those 52 isolates, 3 were resistant and 6 were non-susceptible to three or more drug classes, but susceptibility rates remained high for TOL-TAZ, inhibiting 98.6% with an MIC <1 mg/L and meropenem, inhibiting 89.9% with an MIC <2 mg/L. ASPECT-cUTI was a randomized, double-blind, phase III trial which compared TOL-TAZ (n=398) to

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levofloxacin (n=402) in the treatment of cUTI.9 TOL-TAZ was non-inferior to levofloxacin in achieving the primary endpoint, a composite of clinical cure and microbiological eradication (76.9% versus 68.4%, 95% CI: 2.3 to 14.6). P. aeruginosa was isolated in 6 patients in the TOL-TAZ group and 7 patients in the levofloxacin group, of which 85.7% and 58.3% achieved microbiological eradication, respectively (95% CI: -15.9 to 56.3).

In addition to the above indications, TOL-TAZ is also being investigated for the treatment of ventilated nosocomial pneumonia at a dose of 3 grams every 8 hours in the ASPECT-NP trial, a randomized, phase III trial, which will compare TOL-TAZ to meropenem (NCT02070757). The results of this trial should provide useful clinical data supporting the use of TOL-TAZ for this indication. Although low rates of P. aeruginosa have been included in clinical trials, the in vitro data are supportive of the use of TOL-TAZ in the treatment of infections caused by MDR P. aeruginosa. Ceftazidime-avibactam Ceftazidime-avibactam (CAZ-AVI) is another beta-lactam beta-lactamase inhibitor combination FDA-approved in 2015 for the treatment of cUTI and cIAI in combination with metronidazole.10 Ceftazidime is a third-generation cephalosporin which inhibits bacterial cell-wall synthesis of P. aeruginosa through binding PBP3, resulting in filamentation and lysis of the bacterial cell.11 Avibactam is a novel beta-lactamase inhibitor that restores the activity of ceftazidime to enzyme-mediated resistant strains of P. aeruginosa. Unlike traditional beta-lactamase inhibitors, avibactam is a reversible inhibitor, allowing a single molecule of avibactam to inactivate multiple beta-lactamases.12 The addition of avibactam expands the activity of ceftazidime from Class A beta-lactamase enzymes to include Class C and some Class D enzymes; however, it is not active against MBL-producing organisms and may be affected by porin mutations and expression of efflux pumps.10

The ability of CAZ-AVI to overcome many mechanisms of resistance allows it to remain active against MDR P. aeruginosa. When evaluated in 5,328 P. aeruginosa isolates from 71 hospitals across the US, CAZ-AVI demonstrated activity against 96.8% of isolates at the breakpoint MIC of <8 µg/mL, exceeded only by amikacin at 97.4% and colistimethate sodium at >99.9%.13 When evaluated against strains non-susceptible to meropenem, CAZ-AVI retained activity against 67.4% of isolates. These results were similar to in vitro susceptibility demonstrated in other smaller studies, supporting the use of CAZ-AVI in the setting of MDR P. aeruginosa. The dosage of CAZ-AVI approved for the treatment of cUTI or cIAI is 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) given every 8 hours over a 2 hour intravenous infusion.10 Both ceftazidime and avibactam demonstrate linear kinetics and have similar Vds of 17 L and 22 L, and half-lives of 3 and 2 hours, respectively. Ceftazidime is eliminated renally as unchanged drug (80-90%), making it necessary to dose adjust in patients with a creatinine clearance of 50 mL/minute or less.10 Although the efficacy of CAZ-AVI has been evaluated in cIAI and cUTI, the existing studies include few patients with MDR P. aeruginosa isolates. A randomized, double-blind phase II trial comparing CAZ-AVI plus metronidazole (n=101) to meropenem (n=102) for the treatment of cIAI found that clinical response rates were similar between groups (82% versus 88%, 95% CI: -23.8% to 6.0%).14 The primary pathogen in the study was E. coli (111 isolates [50%]), with only 11 (0.05%) P. aeruginosa isolates. Of these, 2/11 had an MIC >8 µg/mL for CAZ-AVI, and 1/11 was resistant to meropenem. All patients in whom P. aeruginosa was isolated achieved a favorable microbiologic response. Two randomized, double-blind, phase III, non-inferiority trials, RECLAIM I and RECLAIM II, also compared CAZ-AVI plus metronidazole (n=413) to meropenem (n=410) for the treatment of cIAI with similar clinical cure (82% versus 85%, 95%

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CI: -8.64 to 1.58).15 In the CAZ-AVI plus metronidazole group, P. aeruginosa was isolated in 32 patients, of which 2 had a MIC >16 µg/mL to ceftazidime, both of which achieved clinical cure. In the meropenem group, P. aeruginosa was isolated in 36 patients, of which 4 isolates had a MIC >16 µg/mL to ceftazidime, and, again, both of which achieved clinical cure. Of note, a subgroup of patients in the CAZ-AVI group with baseline creatinine clearance of 30-50 mL/min had lower clinical cure rates (45% versus 74%, 95% CI: -50.05 to -5.36) than patients with a creatinine clearance of 50 mL/min. This difference was attributed to suboptimal dosing in the renally impaired subgroup, which received a 33% lower daily dose than recommended. Phase III, randomized, controlled trials evaluating the use of CAZ-AVI in the treatment of cUTI also found CAZ-AVI to be non-inferior to comparators, but had low rates of P. aeruginosa isolated. In the REPRISE trial, CAZ-AVI (n=165) was compared to best available therapy (n=168), most commonly meropenem as monotherapy (96%), for the treatment of cIAI or cUTI and achieved identical cure rates of 91% (95% CI: 85.6 to 94.7).16 86% of patients with P. aeruginosa in the cUTI group (n=14) treated with CAZ-AVI achieved clinical cure versus 100% of patients in the best available therapy group (n=5). In the cIAI population, P. aeruginosa was only isolated in 1 patient in each group. In the RECAPTURE trial, CAZ-AVI (n=393) was found to be non-inferior to doripenem (n=417) in symptom resolution (70% versus 66%, 95% CI: -2.39% to 10.42%) as well as combined symptom resolution and microbiologic eradication (71% versus 65%, 95% CI: 0.30% to 13.12%).17 Although E. coli was the primary pathogen [292 isolates (74%]), P. aeruginosa was isolated in 18 (4.6%) and 20 patients, of which 66.7% and 75% had a favorable response in the CAZ-AVI and doripenem groups, respectively. CAZ-AVI is also being investigated in a phase III trial comparing it to meropenem for the treatment of hospitalized adults with nosocomial pneumonia, including ventilator-associated pneumonia (NCT01808092). Future clinical trials will provide more information regarding the dosing of CAZ-AVI in nosocomial pneumonia and critically ill patients (NCT01808092; NCT02822950). Although existing clinical studies have low rates of P. aeruginosa isolates, in vitro data and an overall lack of active agents make CAZ-AVI a desirable option for the treatment of MDR P. aeruginosa. Fosfomycin As MDR P. aeruginosa infections become increasingly more challenging to manage, the use of fosfomycin outside of its FDA-approved indication of uncomplicated UTI has become a consideration.18 Fosfomycin remains active against many ESBL-producing Enterobacteriaceae isolates, and may be re-emerging as a treatment option for MDR P. aeruginosa infections. Fosfomycin is a derivative of phosphonic acid and exists as the only agent in its class of phosphonic antibiotics, inhibiting peptidoglycan synthesis, resulting in the inhibition of cell wall synthesis. In order to perform this activity, fosfomycin must be transported into the cell by the syn-glycerol-2-phosphate and hexose-6-transport systems produced by P. aeruginosa, modifications of which are a source of resistance. Although its activity may be affected by efflux pumps, fosfomycin is unaffected by enzymatic degradation. The intravenous and intramuscular formulation of this agent are not available in the US; however, these formulations are available and frequently utilized in Europe.18 In the UK, intravenous fosfomycin is indicated for the treatment of P. aeruginosa and may be used in the setting of acute osteomyelitis, cUTIs, nosocomial pneumonia, meningitis, and bacteremia associated with any of these sources. Doses widely vary, ranging from 8-24 grams/day in up to four divided doses.19 Fosfomycin has a Vd of 0.3 L/kg and distributes into the CNS with minimal protein binding. Its half-life is approximately 2 hours, with 80-90% of

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the dose being eliminated renally as unchanged drug, requiring renal dose adjustment at a creatinine clearance of <40 mL/min. A systematic review of 1,693 MDR P. aeruginosa isolates from 19 studies in Europe and Japan found that only 30% of isolates were susceptible to fosfomycin.20 An Australian trial evaluating the pharmacodynamic properties of fosfomycin in 64 MDR and non-MDR P. aeruginosa isolates, primarily from cystic fibrosis patients, found that 61% of isolates were susceptible to fosfomycin (MIC <64 mg/L).21 However, rapid emergence of resistance was noted, even at concentrations higher than can be attained clinically, causing concern for the use of fosfomycin as monotherapy. Although the low susceptibility rates and potential for development of resistance with fosfomycin are alarming, synergistic activity against both MDR and non-MDR P. aeruginosa strains has been observed with combinations of polymyxin, tobramycin, and ciprofloxacin in vitro.22 So, although high levels of resistance may preclude widespread use of fosfomycin monotherapy, its place in therapy against MDR P. aeruginosa likely exists in combination with other agents for synergistic activity. IV fosfomycin is currently being investigated in the treatment of cUTIs in the ZEUS trial (NCT02753946), which may pave the way for approval of IV fosfomycin in the US. Colistimethate sodium and polymyxin B Colistimethate sodium and polymyxin B, the two available antibiotics in the class of polymyxins, are generally reserved as last-line options for the treatment of MDR P. aeruginosa due to toxicities associated with their use. However, because of increasing resistance, there is a renewed interest in the use of polymyxins in the setting of MDR P. aeruginosa. Although the in vitro activities of colistimethate sodium and polymyxin B are nearly identical, their pharmacologic properties could not be more different.23 These positively charged antibiotics bind to the lipid A component of lipopolysaccharide (LPS), displacing divalent cations from the negatively charged phosphate groups present in membrane lipids. In addition, they have hydrophobic fatty acid tails which interact with LPS, creating a dual electrostatic and hydrophobic mechanism that ultimately causes disruption of the outer membrane, resulting in leakage of cell contents and death.24 The polymyxins are not affected by beta-lactamases, including MBLs, which confer resistance to all beta-lactams, including CAZ-AVI and TOL-TAZ.25–27 Common mechanisms by which P. aeruginosa develops resistance to the polymyxins include modification of lipid A on LPS, over-expression of the mexAB–oprM efflux pump system, and over-expression of the outer membrane protein oprH. The primary difference between these two polymyxins lies within their formulations. Whereas polymyxin B is administered in its pharmacologically active form, colistimethate sodium is administered as colistin methanesulfonate (CMS), a prodrug that must be converted colistimethate sodium within the kidneys.28 In patients with normal renal function, CMS is rapidly eliminated renally, resulting in the conversion to colistimethate of only 25% or less. Due to high rates of renal clearance, complex pharmacodynamic properties, and limited therapeutic experience, achieving desired plasma concentrations of colistimethate sodium is difficult in many patients.29 Even at the maximum recommended doses, many patients will not achieve adequate plasma concentrations; however, the use of higher doses is limited by adverse events, notably nephrotoxicity. Although the rapid renal clearance of CMS is undesirable for the treatment of most infections, this is a useful property of this drug in the treatment of UTIs. In contrast to the extreme variability of levels that result following colistimethate sodium dosing, the administration of polymyxin B achieves more reliable plasma concentrations. For this reason, many institutions use polymyxin B as their preferred polymyxin for systemic MDR Gram-negative infections.

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The recommended dose of colistimethate sodium is 2.5-5 mg/kg/day divided into 2-4 doses given as an IV infusion over 30 minutes.28 A loading dose of 5 mg/kg is recommended to achieve therapeutic concentrations more quickly; however, studies evaluating the use of this agent in critically ill populations have used loading doses ranging from 270 mg to 720 mg.30,31 The Vd of colistimethate sodium has been described in cystic fibrosis patients as 0.09 L/kg, with minimal protein binding. It has a half-life of approximately 1.5 hours, and the primary route of elimination is renal, with approximately 80% of the dose being renally excreted within 24 hours. Dose adjustments are recommended for patients with creatinine clearance < 80 mL/minute.28 The recommended dose of polymyxin B is 15,000 to 25,000 units/kg/day IV divided every 12 hours.32 A loading dose of 25,000-30,000 units/kg may be used to rapidly achieve target serum concentrations, followed by doses of 25,000-30,000 units/kg/day divided every 12 hours in critically ill patients.33,34 Dosing in renal impairment is largely unknown, with the manufacturer recommending <15,000 units/kg/day.32 Although polymyxin is nephrotoxic, the drug is primarily eliminated through non-renal routes and does not require adjustments in patients with renal dysfunction.34,35 When evaluated in critically ill patients, the Vd of polymyxin B was estimated to be 71–194 mL/kg with protein binding of 78.5–92.4%.36 Although clinical studies are limited, polymyxins are currently the most active agents against MDR P. aeruginosa. The SENTRY Antimicrobial Surveillance Program evaluated the activity of antimicrobial agents against Gram-negative organisms from 31 countries, which included 9,130 P. aeruginosa isolates.23 Of the antibiotics tested, polymyxin B and colistimethate sodium were the most active antibiotics with >99% susceptibility and a MIC50 and MIC90 of 1 mg/L. Multiple studies are in progress which will evaluate the safety and efficacy of polymyxin dosing regimens and compare the polymyxins to other antibiotics for the treatment of Gram-negative infections. Despite the dosing issues and risk of nephrotoxicity, the polymyxins remain a viable option as the most active agents in the setting of MDR P. aeruginosa. Emerging Agents Prior to the approval of ceftolozane/tazobactam in 2014 and ceftazidime/avibactam in 2015, several years lapsed without any new antibiotics in development targeting MDR Gram-negative bacteria. Now, several new antimicrobials have emerged and are in the various phases of clinical development. Meropenem/vaborbactam and imipenem-cilastatin/relebactam are two of these new agents in phase 3 of clinical testing which include a currently available carbapenem with new beta-lactamase inhibitors.37,38 Although mainly active against MDR Enterobacteriaceae, the new beta-lactamase inhibitors have been shown to potentiate the activity of carbapenems against strains of MDR P. aeruginosa. For isolates lacking oprD, and without other resistance mechanisms, relebactam reduced the MICs of unprotected imipenem from 16–64 mg/L to ≤2 mg/L in 7/8 isolates, and for strains with additional resistance mechanisms other than the loss of oprD, MICs were reduced to 4–8 mg/L.37 Additionally, by combining vaborbactam and meropenem, a 4-fold or greater decrease in MIC was seen in 9/98 and 6/98 meropenem-non-susceptible isolates with 4 and 8 µg/ml of the beta-lactamase inhibitor, respectively.38 However, an additional 23 meropenem non-susceptible isolates were tested, and there was no change in MICs regardless of the expression of ampC, oprD, mexA, mexC, mexE, and mexX. One of the more promising new agents being developed for the treatment of MDR P. aeruginosa is cefidericol, a siderophore cephalosporin. This agent utilizes a “trojan horse” strategy, which allows for accelerated influx of the antibiotic through active transport into the bacterial cell by exploiting the bacterial iron-siderophore uptake system, resulting in potent activity against carbapenemase-producing MDR isolates.39 It has been shown to be active against P. aeruginosa strains that are resistant to cefepime,

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meropenem, and piperacillin/tazobactam, including MBL-producing strains, with an MIC50 and MIC90 of 0.5 and 4 mg/L, respectively. Another potential option against these MDR pathogens, is BAL30072, a monosulfactam siderophore antibiotic.40 BAL30072 has been shown to have enhanced in vitro activity against Gram-negative isolates with Ambler class A, B, C or D carbapenemases, and was shown to be more active than other beta-lactam antibiotics against P. aeruginosa, A. baumannii and KPC-possessing K. pneumoniae. Its activity was enhanced even further when given with meropenem, tazobactam, and colistin. Although these data are promising, additional in vivo studies are needed for these newly developed agents to determine their clinical role in the treatment of MDR Gram-negative infections. Conclusion Due to the increasing prevalence of MDR P. aeruginosa and limited activity of traditional regimens, newer agents such as ceftolozane/tazobactam and ceftazidime/avibactam, as well as older agents, such as fosfomycin and the polymyxins, are becoming increasingly considered as treatment options for infections caused by MDR P. aeruginosa. Although not currently available in the US, the role of IV fosfomycin is unclear but may provide synergy when used in combination with active agents against MDR P. aeruginosa. The polymyxins remain the most active, currently available antimicrobials against these MDR strains and remain a viable treatment option despite limitations of dosing and toxicity. Emerging antibiotics currently under investigation may provide promising alternative treatment options in the future. As traditional antimicrobial agents become more and more limited, clinicians must consider the use of both old and new agents to combat the increasing frequency of MDR P. aeruginosa infections. References 1. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant

bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. doi:10.1111/j.1469-0691.2011.03570.x.

2. CDC. Antibiotic Resistance Threats in the United States, 2013.; 2013. doi:CS239559-B. 3. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin

Infect Dis. 2002;34(5):634-640. doi:10.1086/338782. 4. Ceftolozane-tazobactam (Zerbaxa) Prescribing Information. Merck. 2015. 5. Takeda S, Nakai T, Wakai Y, Ikeda F, Hatano K. In vitro and in vivo activities of a new cephalosporin, FR264205, against

Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2007;51(3):826-830. doi:AAC.00860-06 [pii]. 6. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam tested against

Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. hospitals (2011-2012). Antimicrob Agents Chemother. 2013;57(12):6305-6310. doi:10.1128/AAC.01802-13.

7. David J. Farrell∗, Helio S. Sader, Robert K. Flamm RNJ. Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates. Int J Antimicrob Agents. 2014;43:533-539.

8. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: Results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60(10):1462-1471. doi:10.1093/cid/civ097.

9. Huntington JA, Sakoulas G, Umeh O, Cloutier DJ, Steenbergen JN, Bliss C GE. Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial. J Antimicrob Chemother. 2016;71(7):2014-2021.

10. Allergan. Avyvaz (ceftazidime and avibactam) for injection, for intravenous use. 2016. 11. Hayes M V, Orr DC. Mode of action of ceftazidime: affinity for the penicillin-binding proteins of Escherichia coli K12,

Pseudomonas aeruginosa and Staphylococcus aureus. J Antimicrob Chemother. 1983;12(2):119-126. http://www.ncbi.nlm.nih.gov/pubmed/6413485.

12. Ehmann DE, Jahić H, Ross PL, et al. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012;109(29):11663-11668. doi:10.1073/pnas.1205073109.

13. Sader HS, Castanheira M, Farrell DJ, Flamm RK, Jones RN. Ceftazidime-avibactam activity when tested against ceftazidime-nonsusceptible Citrobacter spp., Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa from Unites States medical centers (2011-2014). Diagn Microbiol Infect Dis. 2015;83(4):389-394. doi:10.1016/j.diagmicrobio.2015.06.008.

14. Lucasti, C; Popescu, I; Ramesh, M; Lipka, J; Sable C. Comparative study of the efficacy and safety of

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ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68:1183-1192.

15. Mazuski, J; Gesink, L; Armstrong, J; Broadhurst, H; Stone, G; Rank, D; Llorens, L; Newell, P; Pachi 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. Clin Infect Dis. 2016;62:1380-1389.

16. Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): A randomised, pathogen-directed,. The Lancet Infectious Diseases. 2016.

17. Wagenlehner, F; Sobel, J; Armstrong, J; Huang, X; Stone, G; Yates K; Gasink L. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis. 2016;63:754-762.

18. Fosfomycin tromethamine. Monurol. Full prescribing information. Allergan. 19. Disodium fosfomycin. Fomicyt. Full prescribing information. Nord Pharma Limited. 2014. 20. Falagas M., Kastoris A., Karageorgopoulos D. RP. Fosfomycin for the treatment of infections caused by multidrug-resistant

non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009;34:111-120.

21. Walsh C., McIntosh M., Peleg A., Kirkpatrick C. BP. In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother. 2015.

22. Walsh C., Landersdorfer C., McIntosh M., Peleg A., Hirsch E., Kirkpatrick C. BP. Clinically relevant concentrations of fosfomycin combined with polymyxin, tobramycin, or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance. J Antimicrob Chemother. 2016;71:2218-2229.

23. Gales AC, Jones RN, Sader HS. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: Results from the SENTRY antimicrobial surveillance program (2006-09). J Antimicrob Chemother. 2011;66(9):2070-2074. doi:10.1093/jac/dkr239.

24. Velkov T, Roberts KD, Nation RL, Thompson PE, Li J. Pharmacology of polymyxins: new insights into an “old” class of antibiotics. Futur Microbiol. 2013;8(6):1-20. doi:10.2217/fmb.13.39.Pharmacology.

25. C Fernandez L, Jenssen H, Bains M, Wiegand I, Gooderham WJ HR. The two component system CprRS senses cationic peptides and triggers adaptive resistance in Pseudomonas aeruginosa independently of ParRS. Antimicrob Agents Chemother. 2012;56(12):6212-6222.

26. D Macfarlane EL, Kwasnicka A, Ochs MM HR. PhoP–PhoQ homologues in Pseudomonas aeruginosa regulate expression of the outer-membrane protein OprH and polymyxin B resistance. Mol Microbiol. 1999;34(2):305-316.

27. E Pamp SJ, Gjermansen M, Johansen HK T-NT. Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes. Mol Microbiol. 2008;68(1):223-240.

28. Colistimethate Sodium for injection and inhalation. Full prescribing information. Taj Pharm Limited. 2011. 29. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in

critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55(7):3284-3294. doi:10.1128/AAC.01733-10.

30. Mohamed AF, Karaiskos I, Plachouras D, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: Population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012;56(8):4241-4249. doi:10.1128/AAC.06426-11.

31. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009;53(8):3430-3436. doi:10.1128/AAC.01361-08.

32. Polymyxin B for injection. Full Prescribing Information. Xelia Pharm Inc. 2015. 33. Thamlikitkul V, Dubrovskaya Y, Manchandani P et al. Dosing and pharmacokinetics of polymyxin B in renal insufficiency.

2016.:013337-16. 34. Sandri AM, Landersdorfer CB, Jacob J, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill

patients: implications for selection of dosage regimens. Clin Infect Dis. 2013;57(4):524-531. doi:10.1093/cid/cit334. 35. Abdelraouf K, He J, Ledesma KR, Hu M, Tam VH. Pharmacokinetics and renal disposition of polymyxin B in an animal

model. Antimicrob Agents Chemother. 2012;56(11):5724-5727. doi:10.1128/AAC.01333-12. 36. Zavascki AP, Goldani LZ CG. Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients. Clin Infect Dis.

2008;47:1298-1304. 37. Livermore DM, Warner M, Mushtaq S. Activity of MK-7655 combined with imipenem against enterobacteriaceae and

Pseudomonas aeruginosa. J Antimicrob Chemother. 2013;68(10):2286-2290. doi:10.1093/jac/dkt178. 38. Lapuebla A, Abdallah M, Olafisoye O, et al. 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(June):AAC.00843-15. doi:10.1128/AAC.00843-15.

39. Ito-Horiyama T, Ishii Y, Ito A, Sato T, Nakamura R, Fukuhara N, Tsuji M, Yamano Y, Yamaguchi K TK. Stability of Novel

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Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases. Antimicrob Agents Chemother. 2016;60(7):4384-4386.

40. Landman D, Singh M, El-Imad B, Miller E, Win T QJ. In vitro activity of the siderophore monosuulfactam BAL30072 against comtemporary Gram-negative pathogens from New York City, including multidrug-resistant isolates. Int J Antimicrob Agents. 2014;43(6):527-532.

ABOUT THE AUTHORS

Jennifer C. Wilson, PharmD, MBA, is currently the PGY2 Critical Care Pharmacy Resident at Boston Medical Center. She received her Doctor of Pharmacy from Campbell University and completed a PGY1 Pharmacy Practice Residency at Vidant Medical Center.

William R. Vincent III, PharmD, BCCCP, is currently the Surgical ICU Clinical Pharmacy Specialist and PGY2 Critical Care Pharmacy Residency Program Director at Boston Medical Center. He received his Doctor of Pharmacy at Rutgers University and completed his PGY1 Pharmacy Practice Residency and PGY2 Critical Care Pharmacy Residency at the University of Kentucky Chandler Medical Center.

Karrine D. Brade, PharmD, BCPS, is the Antimicrobial Stewardship/Infectious Diseases Clinical Pharmacy Specialist and PGY2 Infectious Diseases Pharmacy Residency Program Director at Boston Medical Center. She received her Doctor of Pharmacy at the University of Colorado and completed her PGY1 at Memorial Hospital – University of Colorado Health and PGY2 Infectious Diseases Pharmacy Residency at Detroit Medical Center.

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SELF-ASSESSMENT QUESTIONS

(To be completed online or, in the case of non-MAD members, printed and mailed. You must achieve a grade of 80% of better to receive continuing education credit.)

1. What percentage of P. aeruginosa isolates in the U.S. is estimated to be multidrug- resistant? A. < 10% B. 10-19% C. 20-29% D. 30-39% E. ≥ 40

2. Which of the following agents may retain activity against AmpC beta-lactamase producing and

efflux pump hyperexpressing P. aeruginosa?

A. Ceftolozane-tazobactam B. Ceftazidime-avibactam C. Fosfomycin D. Both Ceftolozane-tazobactam and Ceftazidime-avibactam E. Both Ceftazidime-avibactam and Fosfomycin

3. Which of the following agents does not require dose reduction for patients with renal impairment?

A. Ceftolozane-tazobactam B. Ceftazidime-avibactam C. Colistimethate D. Fosfomycin E. Polymyxin B

4. Which of the following statements about avibactam is true?

A. Avibactam contains a heavier side chain substitution in the 3-position which allows it to

inhibit metallo-beta-lactamases B. Avibactam is a prodrug that requires bioactivation in the kidneys C. Avibactam resistance may develop if used as monotherapy D. Avibactam is reversible which allows one molecule to inhibit multiple beta lactamases E. Avibactam is marketed in combination with ceftolozane

5. Which of the following agents may be synergistic when used in combination with fosfomycin?

A. Only Tobramycin B. Only Ceftazidime-avibactam C. Only Ciprofloxacin D. Both Tobramycin and Ciprofloxacin E. Both Ciprofloxacin and Ceftazidime-avibactam

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LEARNING ACTIVITY ASSESSMENT

(Please provide your honest assessment of the value of this learning activity so that we can continue to improve our offerings.) Please indicate your degree of agreement or disagreement with the following statements regarding this learning activity by indicating strong agreement (a), general agreement (b), no opinion (c), mild disagreement (d), or strong disagreement (e):

1. The information presented was relevant to my practice a. b. c. d. e.

2. This program/session met the stated learning objectives a. b. c. d. e.

3. The information was presented in an objective and balanced manner without

commercial bias a. b. c. d. e.

4. The information presented will alter/affect the my practice (usefulness)

a. b. c. d. e.

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5. The educational materials enhanced my learning a. b. c. d. e.

6. The learning method was effective

a. b. c. d. e.

7. The learning assessment activity (self-assessment quiz) was appropriate a. b. c. d. e.

8. The faculty/authors were of appropriate quality

a. b. c. d. e.

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ABOUT MAD-ID MAD-ID is incorporated as a non-profit entity [501(c)(3)] in the state of South Carolina. MAD-ID provides continuing professional education in the general area of infectious diseases pharmacotherapy and the specific area of antimicrobial stewardship. Educational initiatives and content are determined by an eight-member Scientific Committee composed of infectious diseases experts from clinical pharmacy and medicine and are based upon ongoing needs assessments. The main venue for our programming is an annual meeting, which takes place in May of each year. Other MAD-ID initiatives have included regional programs related to specific topics and our Antimicrobial Stewardship Training Programs. OUR MISSION. The mission/purpose of the Foundation is to provide education, in the form of traditional continuing education, skills training, and other pertinent life-long learning methods, to pharmacists and other healthcare professionals concerning pharmacotherapy as it pertains to the prevention and treatment of infectious diseases and to do all things necessary or convenient to further these goals, with a special emphasis on antimicrobial stewardship. MEMBERSHIP. Membership in MAD-ID is available to all healthcare providers, including students and post-graduate trainees, interested and/or practicing in the area of infectious diseases. For more information, visit our webpage (www.mad-id.org).

MAD-ID SCIENTIFIC COMMITTEE John A. Bosso, PharmD, FCCP, FIDSA Medical University of South Carolina Colleges of Pharmacy and Medicine Charleston, SC Thomas M. File, Jr., MD, MSc, MACP, FIDSA, FCCP Summa Health System and Northeast Ohio Medical University Akron, OH Debra A. Goff, PharmD, FCCP The Ohio State University Wexner Medical Center Columbus, OH Keith S. Kaye, MD, MPH, FIDSA, FSHEA School of Medicine University of Michigan Ann Arbor, MI

Jason Newland, MD, MEd Washington University in St. Louis St. Louis Childrens Hospital St. Louis, MO Joseph A. Paladino, PharmD, FCCP University at Buffalo School of Pharmacy & Pharmaceutical Sciences Buffalo, NY Michael J. Rybak, PharmD, MPH, PhD, FCCP, FIDSA Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University Detroit, MI Jack D. Sobel, MD, FIDSA Wayne State University School of Medicine Detroit Medical Center Detroit, MI

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