Samantha Trumm, Pharm.D. PGY-1 Resident Avera McKennan Hospital and University Center

I have had no financial relationship over the past 12 months with any commercial sponsor with a vested interest in this presentation

Describe common factors causing the development of multidrug-resistant bacteria. Compare and contrast bacterial susceptibility of the following 3 new antibiotics used to treat multidrug-resistant gram-negative infections: AVYCAZ (ceftazidime and avibactam), VABOMERE (meropenem and vaborbactam), and ZERBAXA (ceftolozane and tazobactam).

Identify the antibiotic class of each of the components of the three medications presented for treating multidrug-resistant gram-negative infections. Compare and contrast the three medications in regards to administration, storage, and/or stability characteristics.

Multidrug-resistant (MDR)- nonsusceptible to at least 1 antimicrobial from 3 medication classes Extensively drug resistant (XDR)- nonsusceptible to at least 1 antimicrobial from 5 medication classes Walkty A, Adam H, Baxter M et al. In vitro activity of ceftolozane/tazobactam versus antimicrobial nonsusceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008 16. Journal of Antimicrobial Chemotherapy. 2017.

IDSA 10 x 20 Initiative launched in 2010 CDC issued Class 1a recommendation to monitor trends in the incidence of MDR Class 1b recommendation to make MDR prevention and control a patient safety priority -Boucher H, Talbot G, Benjamin Jr D et al. 10 20 Progress Development of New Drugs Active Against Gram- Negative Bacilli: An Update From the Infectious Disease Society of America. Clinical Infectious Diseases. 2013;56(12):1685-1694. -MDRO Management Guidelines Library Infection Control CDC. Cdcgov. 2017.

Khan Academy. Khan Academy. 2017.

Gram-negative bacteria Cocci Coccobacilli Rods Neisseria Haemophilus influenzae Lactose fermenting Non-lactose fermenting Escherichia coli Klebsiella Proteus Salmonella Pseudomonas

Efflux pump activation Enzyme production Porin reduction Target site protection + modification Environmental cell adaptation Munita J, Arias C. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2).

Munita J, Arias C. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2).

Indications: Complicated urinary tract infections and intra-abdominal infections Dose: 2.5 grams IV q8h *Renal* Adverse effects: Constipation, anxiety ( 10%) AVYCAZ [package insert]. Italy: GlaxoSmithKline, 2016.

International Network for Optimal Resistance Monitoring (INFORM) program Compared susceptibility of ceftazidime/avibactam for Gramnegative UTIs Total = 7,272 isolates Sader H, Castanheira M, Flamm R, Jones R. Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014. Antimicrobial Agents and Chemotherapy. 2016;60(7):4355-4360.

Sader H, Castanheira M, Flamm R, Jones R. Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014. Antimicrobial Agents and Chemotherapy. 2016;60(7):4355-4360.

Indication: Complicated urinary tract infections Dose: 4 grams IV q8h *Renal* Adverse effects: Headache, phlebitis, diarrhea ( 3%) Vabomere [package insert]. Italy: Facta Farmaceutici, 2017

Compared susceptibility of meropenemvaborbactam for Gram-negative bacilli Total = 14,304 isolates MDR = 1,210 isolates XDR = 161 isolates CRE = 264 isolates Castanheira M, Huband M, Mendes R, Flamm R. Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem- Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. Antimicrobial Agents and Chemotherapy. 2017;61(9):e00567-17.

Castanheira M, Huband M, Mendes R, Flamm R. Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. Antimicrobial Agents and Chemotherapy. 2017;61(9):e00567-17.

Ceftolozane/tazobactam Indications: Complicated urinary tract infections and intra-abdominal infections Dose: 1.5 grams IV q8h *Renal* Adverse effects: Nausea, diarrhea, headache, fever ( 5 %) Zerbaxa [package insert]. Massachusetts: Cubist Pharmaceuticals, 2015.

Pseudomonas aeruginosa isolates collected from 10-15 hospitals in Canada from 2008-2016 Total = 3,229 isolates MDR = 462 isolates (14.3%) XDR = 84 isolates (2.6%) Tested ceftolozane/tazobactam susceptibility Walkty A, Adam H, Baxter M et al. In vitro activity of ceftolozane/tazobactam versus antimicrobial nonsusceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008 16. Journal of Antimicrobial Chemotherapy. 2017.

Results: MDR: 90.5% susceptibility to ceftolozane/tazobactam XDR: 78.6% susceptibility to ceftolozane/tazobactam Walkty A, Adam H, Baxter M et al. In vitro activity of ceftolozane/tazobactam versus antimicrobial nonsusceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008 16. Journal of Antimicrobial Chemotherapy. 2017.

Preparation IV Compatibility Storage Avycaz Vabomere Zerbaxa Reconstituted and further diluted Reconstituted and further diluted Reconstituted and further diluted D5W, NS NS only D5W, NS Room temp: 12 h Refrigerated: 24 h Room temp: 4h Refrigerated: 22 h Room temp: 24 h Refrigerated: 7 d Cost per day $850-1100 $900-1200 $300-350 AVYCAZ [package insert]. Italy: GlaxoSmithKline, 2016. Vabomere [package insert]. Italy: Facta Farmaceutici, 2017 Zerbaxa [package insert]. Massachusetts: Cubist Pharmaceuticals, 2015.

Avycaz Vabomere Zerbaxa CRE CRE MDR Pseudomonas ESBL CRE: carbapenem-resistant Enterobacteriaceae

1. Which of the following are mechanisms in which bacteria develop resistance to antibiotics? A. Production of β-lactamase B. Activation of efflux pumps C. Decreased number of porins D. All of the above

2. Which of the following antibiotics would be the BEST option for treating a MDR Pseudomonas aeruginosa infection? A. Avycaz (ceftazidime/avibactam) B. Vabomere (meropenem/vaborbactam) C. Zerbaxa (ceftolozane/tazobactam)

1. Which of the following trade names are correctly matched up with its corresponding generic name? A. Vabomere (ceftazidime/vaboractam) B. Avycaz (ceftaroline/avibactam) C. Zerbaxa(ceftolozane/tazobactam) D. Vabomere (meropenem/avibactam)

2. Which of the following antibiotics has the longest stability in room temperature AND refrigeration? A. Avycaz (ceftazidime/avibactam) B. Vabomere (meropenem/vaborbactam) C. Zerbaxa (ceftolozane/tazobactam) D. All have the same BUD

Walkty A, Adam H, Baxter M et al. In vitro activity of ceftolozane/tazobactam versus antimicrobial nonsusceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008 16. Journal of Antimicrobial Chemotherapy. 2017. Boucher H, Talbot G, Benjamin Jr D et al. 10 20 Progress Development of New Drugs Active Against Gram- Negative Bacilli: An Update From the Infectious Disease Society of America. Clinical Infectious Diseases. 2013;56(12):1685-1694. MDRO Management Guidelines Library Infection Control CDC. Cdcgov. 2017. Munita J, Arias C. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2). AVYCAZ [package insert]. Italy: GlaxoSmithKline, 2016. Sader H, Castanheira M, Flamm R, Jones R. Antimicrobial Activities of Ceftazidime-Avibactam and Comparator Agents against Gram-Negative Organisms Isolated from Patients with Urinary Tract Infections in U.S. Medical Centers, 2012 to 2014. Antimicrobial Agents and Chemotherapy. 2016;60(7):4355-4360. doi:10.1128/aac.00405-16. Vabomere [package insert]. Italy: Facta Farmaceutici, 2017 Castanheira M, Huband M, Mendes R, Flamm R. Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. Antimicrobial Agents and Chemotherapy. 2017;61(9):e00567-17. Zerbaxa [package insert]. Massachusetts: Cubist Pharmaceuticals, 2015. Walkty A, Adam H, Baxter M et al. In vitro activity of ceftolozane/tazobactam versus antimicrobial nonsusceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008 16. Journal of Antimicrobial Chemotherapy. 2017.