Pharmacy OneSource Blog

New Drugs for Bad Bugs: What the pharmacists needs to know about winning the war on antimicrobial resistance

Posted on 03/17/15

antimicrobial_stewarship_program_(1)

The healthcare buzz words for 2015 are most assuredly going to be “antimicrobial stewardship.” Antimicrobial stewardship programs will quickly become the standard across the nation, as a federal report recommended that antimicrobial stewardship programs be mandated within all healthcare facilities by 2017. 1

Antimicrobial stewardship serves to preserve our current armamentarium of antibiotics and will only suffice for a terminate period of time, as microbes can quickly develop resistance. The continuous war waged against microbes will need to be combated with new antimicrobials. Let us take stock of our newest weapons and see what is in the pipeline.  

The most recent FDA-approved antibacterial came in February 2015 with AvycazTM (ceftazidime-avibactam), indicated for complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis in adult patients. 2,4 This approval comes on the heels of four antibiotics approved in 2014: Dalvance TM (dalbavancin) and Sivextro TM (tedizolid), both approved in June 2014; Orbactiv TM (oritavancin) approved in August 2014; and Zerbaxa TM (ceftolozane + tazobactam), approved in December 2014.

The novel component of the Avycaz is the beta-lactamase inhibitor portion, avibactam. It is a synthetic non-beta-lactam, beta-lactamase inhibitor.6 Structurally, it is considered a diazabicyclooctane6 (see table 1 for a visualization of the structural difference of avibactam as compared to the previously available beta-lactamase inhibitors - clavulanic acid, tazobactam, and sulbactam.5,7,8,9,10) There are more than 850 beta-lactamases that have been identified and can be classified according to the Ambler classes A through D.6 Interestingly enough, an advantage of avibactam is that it combats the Ambler class A and C; and some Ambler class D enzymes,6 whereas currently available beta-lactamase inhibitors are mainly effective against class A and are generally less effective against class B, C, and D beta-lactamases.

 ClinicalOneSource-AMS-Mar2015

Although the antibiotic pipeline has historically been slim, it seems as if plans are in motion to remedy this lack of development, with proposals. For example, the Infectious Disease Society of America (IDSA)pushed for 10 new systemic antibiotics by the year 2020 and the creation of a sustainable global antibacterial drug R&D enterprise11. Additionally, one of the goals of the 2014 National Strategy for Combating Antibiotic-resistant Bacteria is to accelerate research and development for new antibiotics through economic incentives for manufacturers.12

According to The Pew Charitable Trusts, there are 10 antibiotics in phase I of clinical trials, 18 in phase II, and table 2 below provides a look at the eight antibiotics in phase III, five of which should be able to target gram-negative pathogens.13 The good news is drug developers seem to have gotten the memo. Two of the three microorganisms the CDC assigns the highest threat level, Clostridium difficile and carbapenem-resistant Enterobacteriaceae, are targeted by the antibiotics in phase III of clinical trials. 14 The bad news is even with those efforts, we are still left with limited and dwindling defenses against the vast majority of microbial threats to human health. More good news is that there are alternative therapies, such as fecal transplant used to treat C.diff infections and bio-debridement for necrotic wounds refractory to conventional treatment; neither of which contribute to resistance or increase antibiotic use.15,16 That said, these strategies, while proven efficacious and cost-efficient, are still not utilized on a grand scale and are left as a last resort, if tried at all.15,16,17,18,19

We, as pharmacists, must shift our paradigm of thinking about approving unnecessary antibiotic prescriptions. We are just as responsible for the state of affairs as anyone else. We would not dream of filling a prescription for an anticoagulant for a patient without the appropriate indication. Why is it that we find it perfectly acceptable to fill an antibiotic without an indication listed? Pharmacists are still in the top three most respected professions in the United States; along side nurses and physicians.20 We, as pharmacists, have the education, the authority, the responsibility and the duty to support our physicians and patients by verifying the indication of an antibiotic prescription; and driving policy to place newly approved antibiotics on the reserved and restricted list, preventing them from being rendered impotent for future use. Guard them as if your life or that of a loved one depends on it. It very well may.

Table 2. Antibiotics in Phase III of Clinical Trials13

Drug Name

Drug Class

Potential Indication

Company

Taksta (Fusidic acid)

Fusidane

Prosthetic joint infections, acute bacterial skin and skin structure infections

Cempra Inc.

Cadazolid

Quinolonyl-oxazolidinone

C. difficile-associated diarrhea

Actelion Pharmaceuticals

Carbavance (RPX709+meropenem)

Meropenem + novel boronic beta-lactamase inhibitor

Complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, febrile neutropenia, bacteremia, acute pyelonephritis (some indications specifically target infections caused by carbapenem-resistant Enterobacteriaceae)

Rempex Pharmaceuticals (wholly owned subsidiary of The Medicines Co.)

Delafloxacin

Fluoroquinolone

Acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, uncomplicated gonorrhea, hospital-acquired bacterial pneumonia, complicated urinary tract infections, complicated intra-abdominal infections

Melinta Therapeutics

Eravacycline

Tetracycline

Complicated intra-abdominal infections, complicated urinary tract infections, hospital-acquired bacterial pneumonia

Tetraphase Pharmaceuticals

Plazomicin

Aminoglycoside

Catheter-related bloodstream infections, hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, complicated intra-abdominal infections, complicated urinary tract infections (some indications specifically target infections caused by carbapenem-resistant Enterobacteriaceae

Achaogen

Solithromycin

Macrolide (fluroketolide)

Community-acquired bacterial pneumonia, uncomplicated urogenital gonorrhea, urethritis

Cempra Inc.

Surotomycin

Lipopeptide

C. difficile-associated diarrhea

Cubist Pharmaceuticals

 

References:

  1. President’s Council of Advisors on Science and Technology. Report to the President on Combating Antibiotic Resistance, September 2014.
  2. FDA Approved Drugs - 2015. CenterWatch Web site. http://www.centerwatch.com/drug-information/fda-approved-drugs/year/2014%20Accessed%203/6/2015 Accessed March 6, 2015.
  3. FDA Approved Drugs - 2015. CenterWatch Web site. http://www.centerwatch.com/drug-information/fda-approved-drugs/year/2014 Accessed March 6, 2015.
  4. AVYCAZTM (ceftazidime-avibactam) [prescribing information]. Cincinnati, OH: Forest Pharmaceuticals, Inc; 2015. https://www.avycaz.com/?guid=PPC%7CG%7C1&mkwid=sFAp7LUlB%7Cpcrid%7C69161635503%7Cpkw%7Cavycaz%7Cpmt%7Ce%7Cpdv%7Cc%7C Accessed March 6, 2015.
  5. Drawz SM, Bonomo RA. Three Decades of β-Lactamase Inhibitors. Clinical Microbiology Reviews. 2010;23(1):160-201. doi:10.1128/CMR.00037-09.
  6. Zhanel GG, Lawson CD, Adam H, et. al. Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination. Drugs. 2013;73(2):159-177. http://link.springer.com/article/10.1007/s40265-013-0013-7#page-2 Accessed March 6, 2015.
  7. Avibactam. ChemSpider: Search and share chemistry Web site. http://www.chemspider.com/Chemical-Structure.8010770.html Accessed March 6, 2015.
  8. Clavulanic Acid. ChemSpider: Search and share chemistry Web site. http://www.chemspider.com/Chemical-Structure.4444466.html?rid=8aea6f13-99c7-438b-8b8a-ede9e038aeb5 Accessed March 6, 2015.
  9. Tazobactam. ChemSpider: Search and share chemistry Web site. http://www.chemspider.com/Chemical-Structure.110216.html?rid=c1fa8487-2978-41b5-a44f-deb263c4934e Accessed March 6, 2015.
  10. Sulbactam. ChemSpider: Search and share chemistry Web site. http://www.chemspider.com/Chemical-Structure.110216.html?rid=c1fa8487-2978-41b5-a44f-deb263c4934e Accessed March 6, 2015.
  11. Infectious Diseases Society of America. The 10 x ’20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020. Clinical Infectious Diseases. 2010;50(8):1081-1083. doi: 10.1086/652237.
  12. The White House. National Strategy for Combating Antibiotic-resistant Bacteria, September 2014.
  13. Antibiotics Currently in Clinical Development. The Pew Charitable Trusts Web site. http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development Accessed March 6, 2015.
  14. Centers for Disease Control. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf Accessed March 16, 2015.
  15. Gough E, Shaikh H, and Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent clostridium difficile infection. Clinical Infectious Diseases 2011;53(10):994-1002.
  16. Sun X, Jiang K, Chen J, Wu L, Wang A, and Wang J. A systematic review of maggot debridement therapy for chronically infected wounds and ulcers. Int J Infect Dis. 2014 Aug;25:32-7. Doi: 10.1016/j.ijid.2014.03.1397.
  17. Sherman RA. Maggot therapy takes us back to the future of wound care: new and improved maggot therapy for the 21st century. J Diabetes Sci Technol 2009 Mar; 3(2): 336-344.
  18. Telephone conversation customer service representative. Monarch Labs (949) 679-3000. March 16, 2015.
  19. Feltman R. Good news: you can take your fecal transplant orally. The Washington Post. October 11, 2014. http://www.washingtonpost.com/news/speaking-of-science/wp/2014/10/11/good-news-you-can-take-your-fecal-transplants-orally/ Accessed March 16, 2015.
  20. Riffkin R. Americans rate nurses highest on honesty, ethical standards. Gallup. http://www.gallup.com/poll/180260/americans-rate-nurses-highest-honesty-ethical-standards.aspx Accessed March 16, 2015.

Topics: Antimicrobial Stewardship

About the Author

Mylinda Dill PharmD is a Pharmacy Fellow for Wolters Kluwer. She is a graduate from Harding University College of Pharmacy. Before pursuing her career in pharmacy, Dr. Dill proudly served in the United States Navy, where she received a Navy Achievement Medal. She also brings a strong research background and a commitment to volunteerism. She is a member of the International Society For Pharmacoeconomics and Outcomes Research (ISPOR), the American Society of Health-System Pharmacists (ASHP), and the American Pharmacists Association (APhA).