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ACTIVITY DESCRIPTION

Target AudienceThis continuing pharmacy education activity is planned to meet the needs of pharmacists in a variety of practice settings, including large and small healthcare systems, outpatient clinics, managed care organizations, long-term care facilities, and academia. This program targets health-system pharmacists who are responsible for caring for patients with serious bacterial infections.

Learning ObjectivesUpon completing this activity, participants will be able to: • Explain current trends in antimicrobial resistance and identify patient risk factors for

infection • Assess the role of newer antimicrobial agents as part of the armamentarium in the

management of infections caused by multidrug-resistant Gram-negative bacteria and C. difficile

• Evaluate the utility of novel approaches that reduce the risk of recurrent C. difficile infection in high-risk patients

• Describe antimicrobial stewardship strategies that aim to minimize the burden of serious bacterial infections in healthcare institutions

ACCREDITATION

PharmacistsCenter for Independent Healthcare Education is accredited by theAccreditation Council for Pharmacy Education as a provider for continuing

pharmacy education. Center has assigned 1.0 contact hours (0.1 CEUs) of continuing pharmacy education credits for participating in this activity.

ACPE UAN: 0473-9999-18-001-L01-PActivity type: Application-based

To receive a Certificate of Credit, participants must complete and return the Activity Evaluation Form.

The information that you participated will be uploaded to CPE Monitor within 4 weeks and you will be able to access your credits from the profile you set up with NABP. For more information, please visit http://www.nabp.net/.

For questions regarding accreditation, please contact info@jointsponsor.com.

FACULTY

James S. Lewis II, PharmD, FIDSA ID Clinical Pharmacy Coordinator& Adjunct Associate ProfessorOregon Health and Science UniversityDepartments of Pharmacy & Infectious DiseasesPortland, OR

James S. Lewis, PharmD has relevant financial relationships with commercial interests:Consultant: Accelerate Diagnostics, Achaogen, Merck & Co., Inc., The Medicines Co.

Dr. Lewis intends to discuss the off-label uses for the following products: Use of fidaxomicin and bezlotoxumab in specific high risk subgroups.

No (other) speakers, authors, planners or content reviewers have any relevant financial relationships to disclose. Content review confirmed that the content was developed in a fair, balanced manner free from commercial bias. Disclosure of a relationship is not intended to suggest or condone commercial bias in any presentation, but it is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

Current Options for Antimicrobial-Resistant Gram-Negative Infections Trends in Antibiotic Resistance

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World Health Organization 2017

WHO. Available at: http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/.

MDR Pseudomonas aeruginosaAll HAIs, 2011‒2014

CDC Antibiotic Resistance Patient Safety Atlas. Available at: http://gis.cdc.gov/grasp/PSA/MapView.html.

National resistance: 14.2%

# Resistant: 3871 # Tested: 27,289

Mechanisms of Resistance in Gram-Negative Bacteria, and the Antibiotics Affected

Peleg A,, Hooper D. N Engl J Med. 2010;362:1804-1813.

Risk Factors

Effect of Prior Antibiotic Use on Pathogen Distribution and Resistance Profile Among Hospital-Onset UTIs

• 5,574 unique UTI episodes (2027 with and 3547 without prior antibiotic exposure) – E. coli (49.5%), K. pneumoniae (17.1%), and

P. aeruginosa (8.2%)

• P. aeruginosa was significantly more common in patients with ≥2 prior antibiotic exposures (12.6%) compared with no exposure (8.2%; p=0.036) or 1 prior exposure (7.9%; p=0.025).

• Suggested an increased risk for resistant Gram-negative pathogens among hospital patients with UTIs occurring ≥3 days after admission

Bidell M, et al. BMC Infect Dis. 2017;17:176. Bidell M, et al. BMC Infect Dis. 2017;17:176.

Pathogen Distribution by Prior Antibiotic Exposure

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Bidell M, et al. BMC Infect Dis. 2017;17:176.

Antibiotic Nonsusceptibility Phenotypes Across All Pathogens by Prior Antibiotic Exposure

Clinicians should assess prior antibiotic exposure when selecting empirical therapy for patients with hospital-onset urinary tract infections caused by Gram-negative pathogens.

Take Home Message

Newer Therapy Options

Ceftolozane-Tazobactam:Activity Against P. aeruginosa

• Demonstrated in vitro activity against P. aeruginosa isolates tested that had:‒ Chromosomal AmpC or‒ Loss of outer membrane porin (OprD) or‒ Up-regulation of efflux pumps (MexXY, MexAB)

• Not active against bacteria producing metallo-β-lactamases

Current FDA susceptibility interpretive criteria:

Ceftolozane and tazobactam for injection, for intravenous use - prescribing information, July 2015.Takeda S, et al. Int J Antimicrob Agents. 2007;30:443-445. Takeda S, et al. Antimicrob Agents Chemother. 2007;51:826-830.Castanheira M, et al. Antimicrob Agents Chemother. 2014;58:6844-6850.

Minimum Inhibitory Concentrations (µg/mL)

Pathogen Susceptible (S) Intermediate (I) Resistant (R)

Pseudomonas aeruginosa ≤4 / 4* 8 / 4* ≥16 / 4*

*Ceftolozane-tazobactam susceptibility testing performed with a fixed 4 µg/mL concentration of tazobactam

Evaluation of Ceftazidime-avibactam and Ceftolozane-tazobactam Against Meropenem-nonsusceptible

P. aeruginosa

• Compare in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible P. aeruginosa isolates– Non-duplicate clinical isolates from 34 US hospitals

using reference broth microdilution methods

– Isolates derived from blood, respiratory tract, and wound samples

Grupper M, et al. Antimicrob Agents Chemother. 2017;61(10). pii: e00875-17.

MIC Distribution Among Meropenem-nonsusceptible P. aeruginosa

MIC distribution (%) for ceftazidime-avibactam and ceftolozane-tazobactam 290 meropenem-nonsusceptible blood, respiratory and wound P. aeruginosa isolates.

The susceptibility breakpoints for ceftazidime-avibactam and ceftolozane-tazobactam are 8 mg/L (*) and 4 mg/L (#), respectively

Grupper M, et al. Antimicrob Agents Chemother. 2017;61(10). pii: e00875-17.

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Conclusions

• Both ceftazidime-avibactam and ceftolozane-tazobactam may serve as appropriate treatment options when encountering an infection caused by a carbapenem-nonsusceptible P. aeruginosa.

• Ceftolozane-tazobactam appears to have higher inhibitory activity than ceftazidime-avibactam. Further studies should include PK/PD plus clinical data to help translate these findings into the real-world clinical arena.

A population pharmacokinetic model with Monte Carlo simulations determined that for patients with normal renal function, a 3-g dose of ceftolozane-tazobactam will attain the required pulmonary drug levels needed to kill 90% of organisms with a MIC of ≤8 mg/L with a 98% probability.

Ceftolozane-Tazobactam for MDR P. aeruginosa Pneumonia

A Prospective, Randomized, Double-Blind, Multicenter, Phase 3 Study to Assess the Safety and Efficacy of Intravenous Ceftolozane-Tazobactam Compared With Meropenem in Adult Patients With Ventilated Nosocomial Pneumonia (Ongoing as of January 2018; anticipate completion June 2018)

Ceftolozane-tazobactam IV 3 gm every 8 hours for 8‒14 days, or 14 days for P. aeruginosa

compared to

Meropenem 1 gm every 8 hours for 8‒14 days, or 14 days for P. aeruginosa

Available at: https://clinicaltrials.gov/ct2/show/NCT02070757.

Ceftolozane-TazobactamCurrent Availability of Susceptibility Tests

• Disks MAST Disk: Hardy Diagnostics, commercially-available FDA-approved diameters:

Enterobacteriaceae: >21mm (S), 18-20mm (I), and <17mm (R)

P. aeruginosa: >21mm (S), 17-20mm (I), and <16mm (R)

• Gradient Strips Breakpoints published in the package insert and latest CLSI M100 document

Etest (Biomérieux) can be ordered from http://www.biomerieux-diagnostics.com/etest-ceftolozane-tazobactam-c-t-256 (FDA clearance pending)

MIC test strip (Liofilchem) C/T test strips can be ordered directly from Liofilchem(http://www.liofilchem.net/en/pdf/mic_brochure.pdf). (FDA cleared)

• Panels Vitek 2 (Biomérieux) card approved and will undergo beta-testing; not yet commercially

available, software updates started in March 2017

Microscan (Beckman Coulter) expect commercial availability in 2018

Phoenix (BD) expect commercial availability late 2018

Trek Panel (ThermoFisher Scientific) commercially available since Q1 2016

Ceftazidime-Avibactam

• Antipseudomonal cephalosporin plus beta-lactamase inhibitor

• Spectrum of activity: Gram-negatives, including MDR P. aeruginosa, ESBL-producing strains, KPCs

• FDA approval in February 2015 (based on Phase 2 data)‒ Complicated urinary tract infections, including pyelonephritis‒ Complicated intraabdominal infections (plus metronidazole)‒ IV dose: 2.5 g (2 g ceftazidime; 0.5 g avibactam) q8h (2-h

infusion)‒ For patients with limited or no alternative treatment options

Zhanel GG, et al. Drugs. 2013;73:159-177.Liscio JL, et al. Int J Antimicrob Agents. 2015;46:266-271.

The MIC90 remained below the susceptible breakpoint of ≤8.0 mg/L for the 4-year period:

% Susceptible MIC50 MIC90

Ceftazidime-avibactam 97.0 2 4

Ceftazidime 84.3 2 32

Cefepime 85.4 2 16

Piperacillin-tazobactam

80.5 4 >64

Meropenem 82.0 0.5 8

Ciprofloxacin 77.5 0.12 >4

Levofloxacin 74.9 0.5 >4

Gentamicin 88.3 ≤ 1 8

Amikacin 97.0 2 8

Colistin 99.4 1 2

MIC (mg/L), minimal inhibitory concentration to inhibit growth of 50% and 90% of isolatesCLSI Criteria for susceptible

Sader HS, et al. Antimicrob Agents Chemother. 2017;61;e02252-16.

Antimicrobial susceptibility patterns of 7452 Pseudomonas aeruginosa isolates from United States hospitals (INFORM, 2012‒2015):

Ceftazidime-Avibactam

Year %S

2015 98.0

2014 96.3

2013 96.8

2012 96.9

Ceftazidime-Avibactam

Ceftazidime-avibactam activity tested against Pseudomonas aeruginosa isolates

Cumulative (%) inhibitedat MIC in mg/L of: MIC50 / MIC90

(mg/L)4 8 16

All isolates (n=7452) 91.4 97.0 98.8 2 / 4

Ceftazidime – Nonsusceptible (n=1168) 59.9 81.0 92.2 4 / 16

Meropenem – Nonsusceptible (n=1341) 65.5 86.2 94.0 4 / 16

Piperacillin-tazobactam – Nonsusceptible (n=1449) 62.0 85.4 94.1 4 / 16

Levofloxacin – Nonsusceptible (n=1868) 75.1 90.4 95.8 4 / 8

Gentamicin – Nonsusceptible (n=873) 73.9 87.6 92.9 2 / 16

Amikacin – Nonsusceptible (n=224) 69.2 79.5 87.1 4 / 32

Colistin – Nonsusceptible (n=45) 86.7 88.9 95.6 2 / 16

Multidrug-resistant (MDR) (n=1151) 57.3 82.1 92.5 4 / 16

Extensively drug-resistant (XDR) (n=698) 46.0 75.8 92.4 8 / 32

Nonsusceptible to Meropenem, Ceftazidime,and Piperacillin-tazobactam (n=607)

42.5 71.2 88.4 8 / 32

Sader HS, et al. Antimicrob Agents Chemother. 2017;61;e02252-16.

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Ceftazidime-Avibactam vs Meropenem in Hospitalized Adults With Nosocomial Pneumonia (REPROVE)

Study Design: • Randomized, multicenter, double-blind, comparative study to determine the

efficacy, safety and tolerability of ceftazidime-avibactam (2.5 g q8h) vs meropenem (1 g q8h) for 7‒14 days • Nosocomial pneumonia including ventilator-associated pneumonia (N=879)• Pathogens identified in 355 patients (37% K. pneumoniae; 30% P.

aeruginosa)• 28% were ceftazidime-non-susceptible

mITT, modified Intent-to-Treat; TOC, test-of-cureTorres A, et al. Lancet Infect Dis. 2017;pii: S1473-3099(17)30747-8 [Epub ahead of print].Available at: https://clinicaltrials.gov/ct2/show/NCT01808092.

Clinically Cured at TOC (Day 21-25)

Difference; 95% CICeftazidime-Avibactam

n/N (%)Meropenem

n/N (%)

Clinically mITT 245/356 (68.8) 270/370 (73.0) ‒4.2%; [95% CI ‒10.8 to 2.5]

Clinically evaluable 199/257 (77.4) 211/270 (78.1) ‒0.7%; [95% CI ‒7.9 to 6.4]

Ceftazidime-AvibactamCurrent Availability of Susceptibility Tests

• Approved Tests KB Disks from Hardy Diagnostics and BD Custom Sensititre (ThemoFisher)

• Tests in Development Etest (Biomérieux) can be ordered from http://www.biomerieux-

diagnostics.com/etest-ceftazidime-avibactam-cza-256 (FDA clearance pending)

MIC test strip (Liofilchem) can be ordered directly from Liofilchem(http://www.liofilchem.net/en/pdf/mic_brochure.pdf). (Not cleared by FDA)

• Automated Tests Vitek 2: Software validation Q1 2017, expected approval Q2 2018 Microscan (Beckman Coulter): expect commercial availability in mid 2018 Phoenix (BD): FDA-approved, but not available yet

Meropenem-Vaborbactam

• Approved by FDA in August 2017 for complicated UTI, including pyelonephritis, for susceptible isolates of E. coli, K. pneumoniae, and E. cloacae species complex

• Excellent in vitro activity against common Enterobacteriaceae species producing serine carbapenemases

• Bactericidal against KPC-producing Enterobacteriaceae with in vitro hollow-fiber model (simulating human exposure, 2 g meropenem/2 g vaborbactam q8h 3-h infusion)

• In vivo efficacy in murine thigh infection model against KPC-producing isolates of K. pneumoniae, E. coli, and E. cloacae (MICs ranging from ≤0.06 to 8 µg/mL)

• Efficacy, Safety, Tolerability of Carbavance Compared to Best Available Therapy in Serious Infections Due to Carbapenem-Resistant Enterobacteriaceae in Adults (TANGO 2) Completed (NCT02168946; clinicaltrials.gov)

• A Study of Meropenem-Vaborbactam versus Piperacillin-Tazobactam in Participants with Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia Not yet recruiting as of January 2018 (NCT03006679; clinicaltrials.gov)

Falagas ME, et al. Expert Rev Anti-Infect Ther. 2016;14:747-63.Wenzler E, et al. Antimicrob Agents Chemother. 2015;59:7232-9.Griffith DC, et al. Antimicrob Agents Chemother. 2016;60:6326-32.Castanheira M, et al. Antimicrob Agents Chemother. 2016;60:5454-8.

Applying the Latest Approaches in the Management of C. difficile Infection

and Recurrence

What We’ll Cover

• The current state of C. difficile infection drug therapy

• Confusion surrounding diagnosis of CDI

• Possible ways to minimize recurrence & the cost of recurrence

• The role of FMT

• Future directions

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Lessa FC, et al. NEJM2015;372:825-34.

Age- & Sex-Standardized Incidence Rates/1000 Person-Years for CDI

Ma GK, et al. Ann Intern Med. 2017;167:152-8.

Diagnostic Issues

• Is the toxin “insensitive”?

• Does the PCR/NAAT “overcall”?

• Problems with toxin-negative but NAAT-positive

• Patients that are toxin-negative but NAAT-positive no different than negative-negative

• Are your rates getting overcalled? Is your staff confused?

Polage CR, et al. JAMA Intern Med. 2015;175:1792-801.Fang FC, et al. J Clin Microbiol. 2017;55:670-80.

The Mythical New IDSA C. difficile Guidelines

Available at: http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_by_Organism/Bacteria/Clostridium_difficile/ - accessed January 2018.

Is Everything We’ve Been Taught Wrong?

• 1250 cases of C. difficile infection evaluated• Over a 3-year period• 45% of cases were genetically distinct• Asymptomatic carriers play a major role in transmission• Mind Blown!

Eyre DW, et al. NEJM. 2013;369:1195-205.

Intervention = screening and isolation of asymptomatic carriers

Longtin Y, et al. JAMA Intern Med. 2016;176:796-804.

Estimate that intervention prevented 63 of the 101 (62.4%) expected cases

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• 188% increase in multiply recurrent CDI (mrCDI)

• 42.7% in overall incidence

• mrCDI patients– Older (median 56 vs. 49 years of age)

– More likely to be female

– More likely to have used each of the following• Antibiotics

• PPIs

• Steroids

– More likely to have chronic kidney disease

– More likely to live in a nursing home

Ma GK, et al. Ann Intern Med. 2017;167:152-8.

Who is at Risk of Recurrence?

• Scoring rule using logistic regression model

• Based on the fidaxomicin vs. vancomycin phase 3 studies

• 77 baseline factors classified

• 4 independent READILY AVAILABLE risk factors– Age <75 or ≥75 years

– Number of unformed bowel movements in previous 24 h (<10 vs ≥10)

– SCr <1.2 or ≥1.2 mg/dL

– Prior episode of CDI – yes vs. no

• Model also includes choice of treatment – vancomycin vs. fidaxomicin

D’Agostino RB, et al. Clin Infect Dis. 2014;58:1386-93.

Fidaxomicin vs. Vancomycin for CDI –Risk of Recurrence (NEJM)

15.4 13.3

25.3 24

0

20

40

60

80

100

mITT PP

Pat

ien

ts (

%)

Recurrence

Fidaxomicin Vancomycin

P=0.005 P=0.004

Louie TJ, et al. N Engl J Med. 2011;364:422-31.

What about BI/NAP1/027 and Recurrence Rates?

Fidaxomicin(mITT)

Vancomycin (mITT)

P

NEJM Paper 16/59 (27.1%) 14/67 (20.9%) 0.42

Lancet ID Paper 12/54 (22.2%) 19/50 (38%) 0.079

Louie TJ, et al. N Engl J Med. 2011;364:422-31.Cornely O, et al. Lancet Infect Dis. 2012;12:281-9.

Impact of Concomitant Antibiotics on Response to CDI Treatment

No CA FidaxoN=391

VancoN=416 P

Clinical cure 92% 93% 0.80

Recurrence 12% 23% <0.001

Sustained response 81% 69% <0.001

CA FidaxoN=90

VancoN=102 P

Clinical cure 90% 79% 0.04

Recurrence 17% 29% 0.05

Sustained response 72% 59% 0.02

Mullane KM, et al. Clin Infect Dis. 2011;53:440-7.

CA = concomitant antibiotics

Extended-Pulsed Fidaxomicin Versus Vancomycin for CDI in Older Patients (EXTEND)

• Randomized, controlled, open-label study of hospitalized patients ≥60 years with confirmed CDI (N=364)

• Patients randomized 1:1 to receive:– Fidaxomicin 200 mg PO BID on days 1‒5, then QD on alternate

days on days 7‒25, or– Vancomycin 125 mg PO four times daily on days 1‒10

EOT, end-of-treatmentGuery B, et al. Lancet Infect Dis. 2017; pii: S1473-3099(17)30751-X [Epub ahead of print].

Clinical Cure 30 days following EOT

DifferenceFidaxomicinn/N (%)

Vancomycinn/N (%)

Modified Full Analysis Set 124/177 (70%) 106/179 (59%)

11%; [95% CI 1.0 to 20.7];

p=0.030

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Bezlotoxumab

• ID gets its very own monoclonal antibody!

• Binds toxin B

• Dose of 10 mg/kg X 1

• Evaluated for the prevention of recurrence in patients with C. difficile infection

• No role in the treatment of disease – only for prevention of recurrence

Wilcox MH, et al. N Engl J Med. 2017;376:305-17.*p<0.001Wilcox MH, et al. N Engl J Med. 2017;376:305-17.

17 16 17

2826 27

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5

10

15

20

25

30

MODIFY I MODIFY II Pooled Data

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Bezlotoxumab Placebo

* **

Phase III Studies of Bezlotoxumab: CDI Recurrence

So How Do We Use This?

• “Use of this agent will need to be viewed in comparison with alternative options, including the new drugs and vaccines that are currently being evaluated in trials for the treatment and prevention of C. difficile infection.”

• “There are several important issues that are unresolved and need to be addressed to place this drug in perspective. Particularly important will be relative risk stratification and product cost.”

John G. Bartlett – N Engl J Med. 2017;376:381-2.

30-Day Readmission Post Bezlotoxumab vs. Placebo

• Pooled data from MODIFY 1 and 2 trials• Analysis performed on the mITT groups• Similar baseline demographics• BEZLO ‒ fewer all-cause readmissions

– (absolute difference, −3.7%; 95% CI, −9.0 to 1.5; relative difference, −12.1%) although the difference did not reach statistical significance

• In high-risk groups for rCDI ‒ fewer rCDIs with BEZLO vs. placebo (95% CIs for the difference included 0) – ≥65 years – With severe CDI– ≥1 CDI episode in the previous 6 months– Compromised immunity– Infection with the 027 strain

Prabhu VS, et al. Clin Infect Dis. 2017;65:1218-21.

The Status of Fecal Microbiota Transplantation

• Availability of freeze-dried capsules improving acceptance

• Many complications are procedure-related

• Response rates 70‒90% in multiple recurrence patients

• Still relatively unstudied

• Concerns over long-term effects

Youngster I, Gerding DN. Am J Gastroenterol. 2017;112:948-50.

STEWARDSHIP TO THE RESCUE?AKA – Fluoroquinolones are Evil… STILL!

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• Stewardship led to a major shift in ribotypes

• Rapid decreases in R027 & R001

• Rapidly falling rates due largely to disappearance of R027 & R001

• Of all the evil antibiotics, FQs were the most evil

• Interestingly, piperacillin-tazobactam appears protective… again…

Lawes T, et al. Lancet Infect Dis. 2017;17:194-206.

Conclusions

• C. difficile infection remains a major problem

• Diagnosis remains a challenge… even with PCR!

• Metronidazole remains recommended… for now…

• Vancomycin remains the gold standard – but those recurrences

• Fidaxomicin = vancomycin but better when recurrence factored in

• Bezlotoxumab is an option to prevent recurrence but questions remain

Q and A