Getting a Handle on Antimicrobial Resistance

Joanna Lewis, PharmD, MBA
Wednesday December 19, 2018
Antimicrobial resistance is a worldwide problem, with new resistance mechanisms emerging and spreading that threaten our ability to treat common diseases.1,2
 
The CDC estimates that each year in the United States, drug-resistant bacteria are responsible for more than 2 million infections and 23,000 deaths.3 Antibiotic-resistant bacterial infections more than doubled between 2002 and 2014, rising from 5.2% to 11.0%, according to a recent study in Health Affairs.4,5
 
Improper management of resistant organisms may result in death, disability, and prolonged illness. Without effective antibiotics to prevent and treat infections, rates of medical procedures and surgery become very high risk. Antimicrobial resistance also leads to higher health care costs, with lengthier hospital stays and more intensive care required.1 Results from a recent study found that antibiotic resistance added about $1400 to the cost of treating a patient, with an estimated yearly cost of $2 billion.4
 
What Is Being Done?
Resistance to antimicrobials occurs naturally through genetic changes over time. However, the misuse and overuse of antimicrobials is accelerating this process. 


In response to antibiotic resistance, the Infectious Diseases Society of America launched the 10 x ’20 Initiative as a global collaboration to develop 10 new systemic antibacterial drugs by 2020.6 In 2012, Congress approved the Generating Antibiotic Incentives Now (GAIN) Act to encourage new antibiotic drug development. Through the GAIN Act, a drug is designated as a qualified infectious disease product (QIDP) and granted priority review, fast track status, and longer exclusive marketing rights, which gives companies incentive to produce new antibiotics and antifungals to treat life-threatening infections.
 
The CDC’s Antibiotic Resistance Solutions Initiative is a national collaborative approach that includes responses to outbreaks and research as well as investments in infection prevention and control.7 It also provides resources and tools to health care facilities and providers. The CDC recommends fighting resistance in 4 ways: immunizations and infection prevention to prevent illness in the first place, surveillance and tracking, antibiotic stewardship, and development of new diagnostic tests and drugs.7
 
Recent Drug Approvals
Through 2017, the FDA had granted 147 drugs QIDP status, with 12 of those products approved through the GAIN Act and now on the market. Of the 12, several stand out as options with a broad spectrum of coverage for hard-to-treat resistant infections.
 
The novel cephalosporin ceftolozane, combined with the β-lactamase inhibitor tazobactam (Zerbaxa), is approved to treat complicated intra-abdominal infections (cIAIs) in combination with metronidazole and complicated urinary tract infections (cUTIs), including pyelonephritis.8,9 It provides coverage against gram-negative bacteria such as Enterobacteriaceae and Pseudomonas aeruginosa. Ceftolozane/tazobactam also has coverage against Bacteroides fragilis and the gram-positive organisms Streptococcus constellatus, Streptococcus salivarius, and Streptococcus anginosus.8,9
 
Ceftazidime combined with the β-lactamase inhibitor avibactam (Avycaz) is approved for treatment of cIAI in combination with metronidazole and cUTI, including pyelonephritis. It has broad gram-negative activity, including coverage of Escherichia coli, Klebsiella pneumoniae, and P aeruginosa.10,11 The presence of avibactam allows ceftazidime to keep activity against certain resistance mechanisms. Ceftazidime has minimal anaerobic and gram-positive activity.


Delafloxacin (Baxdela) is a fluoroquinolone antibiotic approved in 2017 to treat acute bacterial skin and skin structure infections. Delafloxacin has staphylococci coverage, including some methicillin-resistant and methicillin-susceptible strains.12 It also has gram-negative activity, including coverage of Enterobacter cloacae and P aeruginosa, as well as some anaerobic coverage, including Clostridium difficile.12 Approval was based on 2 phase 3 trials showing noninferiority to the combination of aztreonam and vancomycin at the endpoint of early clinical response at 48 to 72 hours. 

Meropenem/vaboractam is a combination carbapenem and novel β-lactamase inhibitor marketed under the trade name Vabomere and approved to treat cUTIs, including pyelonephritis, in adults. With coverage against Acinetobacter baumannii, Enterobacteriaceae (such as E coli and K pneumoniae), P aeruginosa, and Stenotrophomonas maltophilia, Vabomere is an option for a group of bacteria that have a limited number of treatment options.13 Approval was based on the results of the TANGO 1 trial, a phase 3, multicenter, randomized, double-blind, double-dummy study with 550 enrolled patients. Participants were randomized to receive either Vabomere or piperacillin 4 g/tazobactam 500 mg every 8 hours for up to 10 days. At the end of treatment, about 98% of patients treated with Vabomere were cured or saw improved symptoms compared with about 94% of those treated with piperacillin/tazobactam. At 7 days after antibiotic completion, about 77% of patients treated with Vabomere had resolved symptoms and a negative urine culture compared with 73% of patients treated with piperacillin/tazobactam.

Are New Antibiotics Superior?
Many newer antibiotics have gained approval by proving noninferiority without evaluating direct patient outcomes as their endpoints. Some experts argue that with a noninferiority designation, these drugs are just new additions to existing classes without any presumable benefit and are not appropriate treatment in patients when superior efficacy has not been proved.14,15
 
However, others argue that superiority study designs require different processes, some of which may result in patient harm and cause serious ethical concerns by exposing patients to potentially less effective drugs. Superiority of an investigational antibiotic over a properly dosed comparator antibiotic is unlikely to be seen if the pathogen is susceptible to both. Progress has been shown with some newer antibiotics, as they have demonstrated shortened durations of therapy and less frequent dosing than some traditionally used antibiotics, thus supporting antibiotic stewardship.
 
In the meantime, payers are also unlikely to reimburse for a more expensive, new product if superiority has not been shown. To show where the benefit is, future studies and experience are needed in patients with resistant bacteria who lack effective options.14-16
 
Antimicrobial Stewardship
Antimicrobial stewardship programs are also a vital component in preventing resistance. By reducing unnecessary antibiotic prescribing, stewardship programs can improve the treatment of infections and prevent avoidable adverse effects and reactions.7 Through education in the proper treatment, duration, and dose, stewardship programs also decrease C difficile antibiotic resistance, costs, and infections.7,17 Programs have consistently shown annual savings of $200,000 to $400,000 in hospitals, and the results of a study by the University of Maryland showed that implementation of an antimicrobial stewardship program saved one hospital $17 million over 8 years.7 The benefits of antimicrobial stewardship programs are widely recognized, and the Joint Commission recently added antimicrobial stewardship to its medication management standards.17
 
Conclusion
Antibiotics have transformed modern medicine, but they are becoming less effective because of resistant mechanisms. A strong drug research pipeline, as well as a collaborative effort in improving antibiotic use, is important to combat future resistant organisms.
 
Pharmacists should be key stakeholders in antimicrobial stewardship programs, as their drug expertise can aid in policy development supporting optimal antibiotic use that includes proper selection and automatic substitutions from intravenous to by mouth, when appropriate.17 They are also valuable resources for dose adjustment, duration of treatment, and education of patients and providers on proper antibiotic prescribing.17



Joanna Lewis, PharmD, MBA, is a clinical pharmacist who is passionate about medication safety, clinical quality, leadership development, and regulatory affairs. She received her pharmacy degree from the Medical University of South Carolina and is an active member of the American Society of Health-System Pharmacists. She has worked in a variety of practice settings, most recently as a coordinator at Duke University Hospital in Durham, North Carolina.

References
  1. Antimicrobial resistance. World Health Organization website. who.int/mediacentre/factsheets/fs194/en/. Published February 15, 2018. Accessed March 22, 2018.
  2. Laxminarayan R, Marsoso P, Pant S, et al. Access to effective antimicrobials: a worldwide challenge. Lancet. 2016;387(10014):168-175. doi: 10.1016/S0140-6736(15)00474-2.
  3. Antibiotic/antimicrobial resistance (AR/AMR). CDC website. cdc.gov/drugresistance/index.html. Updated September 10, 2018. Accessed October 16, 2018.
  4. Thorpe KE, Joski P, and Johnston KJ. Antibiotic-resistant infection treatment costs have doubled since 2002, now exceeding $2 billion annually. Health Aff (Millwood). 2018;37(4):662-669. healthaffairs.org/doi/abs/10.1377/hlthaff.2017.1153. Accessed March 22, 2018.
  5. Dall C. Price to pay: antibiotic-resistant infections cost $2 billion a year. University of Minnesota’s Center for Infectious Disease Research and Policy website. cidrap.umn.edu/news-perspective/2018/03/price-pay-antibiotic-resistant-infections-cost-2-billion-year. Published March 22, 2018. Accessed March 22, 2018.
  6.  Antibiotic development: the 10 x ’20 initiative. Infectious Diseases Society of America website. idsociety.org/10x20/. Accessed March 28, 2018.
  7. Antibiotic prescribing and use in the U.S. CDC website. cdc.gov/antibiotic-use/stewardship-report/index.html. Updated April 6, 2018. Accessed October 16, 2018.
  8. Zerbaxa (ceftolozane + tazobactam). CenterWatch website. centerwatch.com/drug-information/fda-approved-drugs/drug/100057/zerbaxa-ceftolozane--tazobactam-. Accessed March 29, 2018.
  9. Zerbaxa. Merck Connect website. zerbaxa.com. Accessed March 29, 2018.
  10. Avycaz. Allergan website. avycaz.com. Accessed March 28, 2018.
  11. Avycaz (ceftazidime-avibactam). CenterWatch website. centerwatch.com/drug-information/fda-approved-drugs/drug/100071/avycaz-ceftazidime-avibactam. Accessed March 28, 2018.
  12. Baxdela (delafloxacin) tablets and injection. CenterWatch website. centerwatch.com/drug-information/fda-approved-drugs/drug/100207/baxdela-delafloxacin-tablets-and-injection. Accessed March 29, 2018.
  13. Vabomere. Melinta Therapeutics website. vabomere.com. Accessed March 29, 2018.
  14. Deak D, Outterson K, Powers JH, and Kesselheim AS. Progress in the fight against multidrug-resistant bacteria? A review of U.S. Food and Drug Administration–approved antibiotics, 2010-2015. Ann Intern Med. 2016;165(5):363-372. doi: 10.7326/M16-0291.
  15. Powers JH, Evans SR, Kesselheim AS. Studying new antibiotics for multidrug resistant infections: are today’s patients paying for unproved future benefits? BMJ. 2018;360:k587. doi: 10.1136/bmj.k587.
  16. Gentile I, Maraolo AE, Borgia G. What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazadime/avibactam? Expert Rev Anti Infect Ther. 2016;14(10):875-878. doi: 10.1080/14787210.2016.1233060.
  17. Core elements of hospital antibiotic stewardship programs. CDC website. cdc.gov/antibiotic-use/healthcare/implementation/core-elements.html. Updated February 23, 2017. Accessed March 30, 2018.


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