Treatment of Multidrug-Resistant Gram-Negative Infections

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

Haemophilus Lactose Non-lactose Neisseria influenzae fermenting fermenting

Escherichia coli Klebsiella Pseudomonas Proteus Salmonella Efflux pump Enzyme Porin activation production reduction

Target site Environmental protection + cell adaptation modification

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 Gram- negative 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 meropenem- vaborbactam 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

Avycaz™ Vabomere™ Zerbaxa™ Preparation Reconstituted and Reconstituted Reconstituted further diluted and further and further diluted diluted IV D5W, NS NS only D5W, NS Compatibility Storage Room temp: 12 h Room temp: 4h Room temp: 24 h Refrigerated: 24 h Refrigerated: 22 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™

MDR CRE CRE 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

Efflux pump Enzyme Porin activation production reduction

Target site Environmental protection + cell adaptation modification

Munita J, Arias C. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2). 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 Avycaz™ Vabomere™ Zerbaxa™ Preparation Reconstituted and Reconstituted Reconstituted further diluted and further and further diluted diluted IV D5W, NS NS only D5W, NS Compatibility Storage Room temp: 12 h Room temp: 4h Room temp: 24 h Refrigerated: 24 h Refrigerated: 22 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.

 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.