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Antimicrobial Resistance: Highlights of New Antibiotics for Gram-negative Organisms
JNP
Antimicrobial Resistance: Highlights of New Antibiotics for Gram-negative Organisms Antimicrobial resistance poses a real threat in health care today, in part due to limiting therapeutic options for life-threatening infections and increasing the rates of morbidity and
PRESCRIPTION PAD Kanika Ballani, PharmD, and Jason Babby, PharmD, BCPS
mortality. According to the United States Centers for Disease Control and Prevention (CDC), each year approximately 2 million individuals in the US acquire serious bacterial infections. These individuals have resistance to at least one antibiotic that was originally aimed at treating those infections, ultimately resulting in 23,000 deaths.1 Furthermore, there is significant collateral damage caused by drug-resistant infections, including, but not limited to, increased health care costs, prolonged hospitalizations, superinfections, and loss of productivity.1 Generally, therapeutic drug development from the time of its discovery to final US Food and Drug Administration approval is a lengthy process that runs for about 10-15 years and requires extensive personnel and capital resources.2 The success rate for new drug development is very low; only 1 in 5 compounds studied in clinical trials are eventually approved by the FDA.2 This is one of the reasons why the current new drug development process fails to meet the demands of growing rates of antibiotic resistance. The Centers for Disease Control and Prevention prioritizes various bacteria with 354
The Journal for Nurse Practitioners - JNP
known rates of developing resistance into urgent, serious, or concerning threats.1 Clostridium difficile, carbapenem-resistant Enterobacteriaceae, multidrug-resistant (MDR) Neisseria gonorrhoeae are some microorganisms that fall under the urgent threat category. MDR Acinetobacter, Campylobacter, fluconazole-resistant Candida, extended spectrum b-lactamase‒producing enterobacteriaceae, vancomycin-resistant Enterococcus, MDR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and MDR Streptococcus pneumonia pose serious threats. Vancomycin-resistant Staphylococcus aureus is considered a concerning threat.1 Although over the past few decades, there has been significant antibiotic drug development for gram-positive infections, health care professionals are challenged in the treatment of MDR gram-negative infections as the current armamentarium of antimicrobials targeted against these organisms is limited. The recent Food and Drug Administration approval of 2 new b-lactam/b-lactamase inhibitors provides hope for the treatment of resistant gram-negative infections. These agents include: ceftolozane/tazobactam (Zerbaxa, Cubist Pharmaceuticals, Inc., Lexington, Massachusetts), a novel cephalosporin/b-lactamase inhibitor combination, approved in December 2014; and ceftazidime/avibactam (Avycaz, Forest Pharmaceuticals, Inc., Cincinnati, Ohio), a thirdgeneration cephalosporin and b-lactamase inhibitor combination, was approved in February 2015. What distinguishes these new antibiotics from other currently available antibiotics for gramnegative organisms is their extended spectrum of activity against MDR gram-negative organisms. Volume 12, Issue 5, May 2016
Table. Highlights of New Cephalosporin Antibiotics for Gram-negative Organisms3,4 Ceftolozane/Tazobactam (Zerbaxa)
Ceftazidime/Avibactam (Avycaz)
Indication
Treatment of CIAI in adults, in combination with metronidazole Treatment of cUTI (including pyelonephritis)
Dose
CIAI: 1.5 g IV every 8 hours for 4-14 days in combination with metronidazole cUTI (including pyelonephritis): 1.5 g IV every 8 hours for 7 days
Pregnancy category
B
Renal adjustment
Renal adjustment for CrCl 50 mL/min
Hepatic adjustment
No dose adjustment
Antimicrobial spectrum
CIAI: 2.5 g IV every 8 hours in combination with metronidazole for 5-14 days cUTI (including pyelonephritis): 2.5 g IV every 8 hours for 7-14 days
Enterobacter cloacae E coli Klebsiella oxytoca K pneumonia Proteus mirabilis P aeruginosa Bacteroides fragilis Streptococcus anginosus Streptococcus constellatus Streptococcus salivarius
Enterobacter cloacae E coli Klebsiella oxytoca K pneumonia Proteus mirabilis Providencia stuartii P aeruginosa Citrobacter freundii C koseri Enterobacter aerogenes E cloacae E coli Klebsiella pneumonia Proteus spp
CIAI ¼ complicated intra-abdominal infection; CrCl ¼ creatine clearance; cUTI ¼ complicated urinary urinary tract; UTI ¼ urinary track infection.
Ceftazidime/avibactam demonstrated in-vitro activity against Enterobacteriaceae, in the presence of some beta-lactamases and extended spectrum beta-lactamses (ESBLSs) which include TEM, SHV, CTX-M, some oxacillanases (OXA), Klebsiella pneumonia carbapenemases (KPCs) and AmpC. It is not active against bacteria that produce metallo-beta lactamases and other gram negative bacteria with resistance mechanisms involving overexpression of efflux pumps or porin mutations. Ceftolozane/tazobactam also demonstrated in vitro activity against Enterobacteriaceae in the presence of some ESBLs and other betalactamases of the TEM, SHV, CTX-M, and OXA groups. It is limited however in its activity against bacteria that produce serine carbapenemases (KPC) and metallo-beta-lactamases.3,4 The Table summarizes key aspects of both antibiotics. Although new drug development is certainly a focus of current clinical trials and research, it is essential to stress the importance of good infection control strategies, antimicrobial stewardship www.npjournal.org
practices, and undertaking effective infection preventive measures in an interdisciplinary environment. All these best practices will aid in addressing the problem of growing antimicrobial resistance across various health care settings. References 1. US Centers for Disease Control and Prevention. US Department of Health and Human Services. Antibiotic resistance threats in the United States. 2013. 2. US Department of Health and Human Services. http://directorsblog .nih.gov/therapeutic-pipeline. Accessed January 25, 2016. 3. Zerbaxa Prescribing Information. Cubist Pharmaceuticals, Inc., Lexington, MA; 2014. 4. Avycaz Prescribing Information. Forest Pharmaceuticals, Inc., Cincinnati, OH; 2015.
Kanika Ballani, PharmD, is an assistant director of pharmacy, clinical trials, at the NYU Langone Medical Center in New York City. She can be reached at [email protected]. Jason Babby, PharmD, BCPS, is a drug information clinical pharmacist at The Mount Sinai Hospital in New York City. Department Editor Timothy Nguyen, PharmD, BCPS, CCP, FASCP, who would like to hear your ideas for future columns, can be reached at [email protected].
1555-4155/16/$ see front matter © 2016 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2016.02.007
The Journal for Nurse Practitioners - JNP
355
Antimicrobial Resistance: Highlights of New Antibiotics for Gram-negative Organisms Antimicrobial resistance poses a real threat in health care today, in part due to limiting therapeutic options for life-threatening infections and increasing the rates of morbidity and
PRESCRIPTION PAD Kanika Ballani, PharmD, and Jason Babby, PharmD, BCPS
mortality. According to the United States Centers for Disease Control and Prevention (CDC), each year approximately 2 million individuals in the US acquire serious bacterial infections. These individuals have resistance to at least one antibiotic that was originally aimed at treating those infections, ultimately resulting in 23,000 deaths.1 Furthermore, there is significant collateral damage caused by drug-resistant infections, including, but not limited to, increased health care costs, prolonged hospitalizations, superinfections, and loss of productivity.1 Generally, therapeutic drug development from the time of its discovery to final US Food and Drug Administration approval is a lengthy process that runs for about 10-15 years and requires extensive personnel and capital resources.2 The success rate for new drug development is very low; only 1 in 5 compounds studied in clinical trials are eventually approved by the FDA.2 This is one of the reasons why the current new drug development process fails to meet the demands of growing rates of antibiotic resistance. The Centers for Disease Control and Prevention prioritizes various bacteria with 354
The Journal for Nurse Practitioners - JNP
known rates of developing resistance into urgent, serious, or concerning threats.1 Clostridium difficile, carbapenem-resistant Enterobacteriaceae, multidrug-resistant (MDR) Neisseria gonorrhoeae are some microorganisms that fall under the urgent threat category. MDR Acinetobacter, Campylobacter, fluconazole-resistant Candida, extended spectrum b-lactamase‒producing enterobacteriaceae, vancomycin-resistant Enterococcus, MDR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and MDR Streptococcus pneumonia pose serious threats. Vancomycin-resistant Staphylococcus aureus is considered a concerning threat.1 Although over the past few decades, there has been significant antibiotic drug development for gram-positive infections, health care professionals are challenged in the treatment of MDR gram-negative infections as the current armamentarium of antimicrobials targeted against these organisms is limited. The recent Food and Drug Administration approval of 2 new b-lactam/b-lactamase inhibitors provides hope for the treatment of resistant gram-negative infections. These agents include: ceftolozane/tazobactam (Zerbaxa, Cubist Pharmaceuticals, Inc., Lexington, Massachusetts), a novel cephalosporin/b-lactamase inhibitor combination, approved in December 2014; and ceftazidime/avibactam (Avycaz, Forest Pharmaceuticals, Inc., Cincinnati, Ohio), a thirdgeneration cephalosporin and b-lactamase inhibitor combination, was approved in February 2015. What distinguishes these new antibiotics from other currently available antibiotics for gramnegative organisms is their extended spectrum of activity against MDR gram-negative organisms. Volume 12, Issue 5, May 2016
Table. Highlights of New Cephalosporin Antibiotics for Gram-negative Organisms3,4 Ceftolozane/Tazobactam (Zerbaxa)
Ceftazidime/Avibactam (Avycaz)
Indication
Treatment of CIAI in adults, in combination with metronidazole Treatment of cUTI (including pyelonephritis)
Dose
CIAI: 1.5 g IV every 8 hours for 4-14 days in combination with metronidazole cUTI (including pyelonephritis): 1.5 g IV every 8 hours for 7 days
Pregnancy category
B
Renal adjustment
Renal adjustment for CrCl 50 mL/min
Hepatic adjustment
No dose adjustment
Antimicrobial spectrum
CIAI: 2.5 g IV every 8 hours in combination with metronidazole for 5-14 days cUTI (including pyelonephritis): 2.5 g IV every 8 hours for 7-14 days
Enterobacter cloacae E coli Klebsiella oxytoca K pneumonia Proteus mirabilis P aeruginosa Bacteroides fragilis Streptococcus anginosus Streptococcus constellatus Streptococcus salivarius
Enterobacter cloacae E coli Klebsiella oxytoca K pneumonia Proteus mirabilis Providencia stuartii P aeruginosa Citrobacter freundii C koseri Enterobacter aerogenes E cloacae E coli Klebsiella pneumonia Proteus spp
CIAI ¼ complicated intra-abdominal infection; CrCl ¼ creatine clearance; cUTI ¼ complicated urinary urinary tract; UTI ¼ urinary track infection.
Ceftazidime/avibactam demonstrated in-vitro activity against Enterobacteriaceae, in the presence of some beta-lactamases and extended spectrum beta-lactamses (ESBLSs) which include TEM, SHV, CTX-M, some oxacillanases (OXA), Klebsiella pneumonia carbapenemases (KPCs) and AmpC. It is not active against bacteria that produce metallo-beta lactamases and other gram negative bacteria with resistance mechanisms involving overexpression of efflux pumps or porin mutations. Ceftolozane/tazobactam also demonstrated in vitro activity against Enterobacteriaceae in the presence of some ESBLs and other betalactamases of the TEM, SHV, CTX-M, and OXA groups. It is limited however in its activity against bacteria that produce serine carbapenemases (KPC) and metallo-beta-lactamases.3,4 The Table summarizes key aspects of both antibiotics. Although new drug development is certainly a focus of current clinical trials and research, it is essential to stress the importance of good infection control strategies, antimicrobial stewardship www.npjournal.org
practices, and undertaking effective infection preventive measures in an interdisciplinary environment. All these best practices will aid in addressing the problem of growing antimicrobial resistance across various health care settings. References 1. US Centers for Disease Control and Prevention. US Department of Health and Human Services. Antibiotic resistance threats in the United States. 2013. 2. US Department of Health and Human Services. http://directorsblog .nih.gov/therapeutic-pipeline. Accessed January 25, 2016. 3. Zerbaxa Prescribing Information. Cubist Pharmaceuticals, Inc., Lexington, MA; 2014. 4. Avycaz Prescribing Information. Forest Pharmaceuticals, Inc., Cincinnati, OH; 2015.
Kanika Ballani, PharmD, is an assistant director of pharmacy, clinical trials, at the NYU Langone Medical Center in New York City. She can be reached at [email protected]. Jason Babby, PharmD, BCPS, is a drug information clinical pharmacist at The Mount Sinai Hospital in New York City. Department Editor Timothy Nguyen, PharmD, BCPS, CCP, FASCP, who would like to hear your ideas for future columns, can be reached at [email protected].
1555-4155/16/$ see front matter © 2016 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2016.02.007
The Journal for Nurse Practitioners - JNP
355