Avoiding Antimicrobial Misuse: Delaying the Postantibiotic Era

Wendy Jung, PharmD
Published Online: Sunday, February 1, 2009
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Dr. Jung is a clinical assistant professor at Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, and an infectious diseases clinical specialist at Robert Wood Johnson University Hospital.


Antibiotic resistance became a pressing issue the moment Alexander Fleming discovered penicillin in the early 1940s, but never more so than today. As we enter a time that some fear may be the "postantibiotic era,"1 appropriate antimicrobial use is even more critical than ever. Approximately 70% of bacterial infections resulting in mortality are resistant to at least one antimicrobial, and complications resulting from drug-resistant infections cost society almost $5 billion annually, according to estimates by the Centers for Disease Control and Prevention (CDC).2

"No Drugs"

Up until the last decade, bacterial resistance to antimicrobials has only led to further research and development of novel drugs to counteract some of this resistance. A 2004 report by the Infectious Diseases Society of America (IDSA), Bad bugs, No drugs, highlights the alarming fact that the formerly prodigious antibiotic pipeline is now drying up. Only 3 novel antibiotics have come onto the market in the last 11 years, and only one of those has activity against gram-negative organisms, where the greatest need for a novel antibiotic agent lies.2 Sadly, as much as society would like to believe that health care and the pharmaceutical industry are a basic human right, it is, at the end of the day, still a business.2,3

Antibiotics often provide a weak investment return, because they are usually only prescribed for 3 to 14 days for most infections, 6 weeks for more severe infections, such as endocarditis and osteomyelitis, and rarely for longer than that timeframe. In addition, the trend in recommendations for therapeutic duration is crawling toward shortening therapies as much as possible to combat rising resistance issues.3 With the large amount of resources required for the research and development of a new drug, many companies prefer developing drugs that will be taken chronically, as they bring more promise of investment return.2

Bad Bugs

On the opposing end, bacteria have been quickly and steadily increasing their resistance armamentarium. In the early 1980s, the first extended-spectrum beta-lactamases were identified, most of which conferred resistance to, functionally, the entire beta-lactam class except carbapenems. By the late 1980s, the AmpC class of beta-lactamases emerged, which also conferred resistance to most of the beta-lactam class, but again, spared the carbapenems.4

In the earlier part of this century, however, an epidemic of what is now identified as the Klebsiella pneumoniae Carbapenemase (KPC) class spread throughout New York City and some surrounding areas. These KPCs conferred resistance to not only the entire beta-lactam class, including carbapenems, but demonstrated resistance toward many other classes of antibiotics as well, including fluoroquinolones, aminoglycosides, tetracyclines, etc.5-7 As a result, hospitals worldwide have been battling aptly named multidrugresistant organisms, while new resistance mechanisms, such as CTX-M, are being identified much more rapidly than novel agents are being developed to counter them.2,8

Battling the Resistance

With the barrenness of the antibiotic pipeline in terms of novel antimicrobial agents to combat growing resistance, different strategies have been employed as an attempt at curtailing this problem of resistance—strategies that have largely failed thus far.

One popular method is to "double cover" highly resistant organisms, even after susceptibilities are known. Unfortunately, very little, if any, data show any benefit resulting from this method. Either the organism has or will develop resistance to one or more of the agents used, or agents used will co-select resistance to other classes of antibiotics.3,9 The bottom line is that greater use of antibiotics results in greater probability of resistance emergence.

Another failed attempt is antibiotic cycling. This is when one antibiotic is chosen as the antibiotic of choice or "workhorse" antibiotic for certain infections until susceptibilities to that agent decline. Another agent is then selected as the new agent of choice to let the susceptibilities of the original workhorse recover. Rice et al humorously, yet accurately, point out that this type of management is "like offering an alcoholic the choice to rotate beer, wine, gin, and whiskey as a strategy to prevent liver disease."3

Strategies for Clinicians

The most effective strategy to combat the emergence of resistant bacteria is to encourage the appropriate use of antibiotics—start at the right time, and stop at the right time. Development of resistance depends largely on inappropriate doses of drug, inappropriate durations of treatment, inappropriate exposures to antibiotics, and inappropriate selection of antibiotics used.10

Starting properly dosed antibiotics at the right time is vital in treating patients with true infections and preventing exposure in those patients who do not require antibiotic therapy. Although data are showing decreased mortality when antibiotics are administered as soon as possible to patients with severe and overwhelming bacterial infection, antibiotics should not be prescribed where there is a low suspicion of bacterial infection.

In the outpatient setting, approximately 55% of all antibiotics prescribed for acute respiratory tract infections were unnecessary due to the viral nature of many of these infections.10 This large percentage of inappropriate use of antibiotics fueled a study by Dagan et al, which demonstrated decreased resistance rates with decreased inappropriate antibiotic use in children with acute otitis media.11

Currently, the CDC is involved in encouraging appropriate prescribing of antibiotics through their Get Smart campaign. This program promotes appropriate prescribing, decreasing demand for antibiotics by the general public, and proper adherence and duration of therapy once an antibiotic is initiated appropriately.10

Discontinuation of antibiotics at the appropriate end point is the second and perhaps the more difficult concept to encourage, yet the most effective. Because there are not enough data supporting current durations of treatment nor a lot of data supporting the shortening of current durations of treatment, practitioners are often caught between the fear of undertreating a patient and the fear of promoting bacterial resistance by overtreating them.3,12 De-escalation of empiric therapy to narrow-spectrum therapy once identification and susceptibility of an organism is known is one practical way of discontinuing broad-spectrum antibiotics appropriately. Following end points recommended by guidelines put forth by the IDSA also is one way to remain consistent in practice.

Determining appropriate treatment will be an exercise in determining when the period of adequate treatment ends and the period of increasing antimicrobial selective pressure begins. To further complicate this issue, adequate treatment for the same disease state may differ between those patients who are immunocompetent and those who are immunocompromised, such as patients who are neutropenic. Clearly, more prospective studies are needed in this area before definitive end points of therapy can be enforced.

References

  1. Falagas ME, Bliziotis IA. Pandrug-resistant Gram-negative bacteria: Dawn of the post-antibiotic era? Int J of Antimicrob Agents. 2007;29(6):630-636.
  2. Bad bugs, no drugs: As antibiotic discovery stagnates?A public health crisis brews Infectious Diseases Society of America Web site. www.idsociety.org/badbugsnodrugs.html. Accessed Dec 1, 2008.
  3. Rice LB. The Maxwell Finland Lecture: For the duration?rational antibiotic administration in an era of antimicrobial resistance and clostridium difficile. Clin Infect Dis. 2008;46(4):491-496.
  4. Thomson KS. Controversies about extended-spectrum and AmpC beta-lactamases. Emerg Infect Dis. 2001;7(2):333-336.
  5. Yigit H, Queenan AM, Anderson G, et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumonia. Antimicrob Agents and Chemother. 2001;45(4):1151-1161.
  6. Woodford N, Tierno PM Jr, Young K, et al. Outbreak of Klebsiella pneumoniae producing a new carbapenem-hydrolyzing class A beta-lactamase, KPC-3, in a New York medical center. Antimicrob Agents Chemother. 2004;48(12):4793-4799.
  7. Smith Moland E, Hanson ND, Herrera VL, et al. Plasmid-mediated, carbapenem-hydrolysing beta-lactamase, KPC-2, in Klebsiella pneumoniae isolates. J Antimicrob Chemother. 2003;51(3):711-714.
  8. Lewis JS 2nd, Herrera M, Wickes B, Patterson JE, Jorgensen JH. First report of the emergence of CTX-M-type extended-spectrum beta-lactamases (ESBLs) as the predominant ESBL isolated in a US health care system. Antimicrob Agents Chemother. 2007;51(11):4015-4021.
  9. Mandell GL, Bennett JE, Dolin R, eds. In: Mandell, Bennett, & Dolin: Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005:2600-2608.
  10. Friedman CR, Whitney CG. It?s time for a change in practice: reducing antibiotic use can alter antibiotic resistance. J Infect Dis. 2008;197(8):1082-1083.
  11. Dagan R, Barkai G, Givon-Lavi N, et al. Seasonality of antibiotic-resistant streptococcus pneumoniae that causes acute otitis media: A clue for an antibiotic-restriction policy? J Infect Dis. 2008;197(8):1094-1102.
  12. Bronzwaer SL, Cars O, Buchholz U, et al. A European study on the relationships between antimicrobial use and antimicrobial resistance. Emerg Infect Dis. 2002;8(3):278-282.


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