Combating Antimicrobial Resistance

Multi-drug resistant organisms arent going away. The impact of these pathogens continues to be felt throughout healthcare facilities of all kinds, and their presence in local communities is more and more widespread. The battle to minimize their impact is waged on many fronts, including the search for new antimicrobial mechanisms and the promotion of proper antimicrobial usage.

A recent study evaluated the effects of recommended practices to control the use of antibiotics on antimicrobial resistance rates in hospitals.¹ A survey instrument was sent to the person responsible for infection control at a sample of 670 U.S. hospitals. The outcome measured the prevalence of four drug-resistant pathogens: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), ceftazidime-resistant Klebsiella species, and quinolone (ciprofloxacin)-resistant Escherichia coli.

Five variables relating to hospital practices were selected from the survey the extent to which hospitals:

• Implement clinical practice guidelines and ensure best practices for antimicrobial use 

• Disseminate information on clinical practice guidelines for antimicrobial use 

• Use information technology related to antimicrobials 

• Use decision-support tools 

• Communicate to prescribers about antimicrobial use 

Survey instruments were returned by 448 hospitals (67 percent). The authors determined that implementation of recommended practices for antimicrobial use and optimization of the duration of antibiotic prophylaxis were associated with a lower prevalence of antimicrobial resistance. Use of restrictive formularies and dissemination of clinical practice guideline information were associated with higher prevalence of resistance. They concluded that implementation of guideline-recommended practices to control antimicrobial use and optimize the duration of therapy appears to help control antimicrobial resistance rates, and highlighted the need for systems interventions and reengineering to ensure more consistent application of guideline-recommended measures for antimicrobial use.²

The Infectious Diseases Society of America (IDSA) specifies two major principles to limit the impact of antimicrobial resistance:³

• Good antimicrobial stewardship the optimal selection of antimicrobial agents for the appropriate indication, dosage, and duration of therapy that results in the maximum benefit and minimum of adverse events for the patient and minimizes the development of antimicrobial resistance 

• Control and prevention including the consistent development and application of infection control and immunization policies and practices to prevent transmission and infection caused by resistant organisms IDSA also offers the following strategies intended to rapidly achieve control of the problem of antibiotic resistance and/or provide the scientific basis to manage it in a rational manner:⁴

• Rigorous measurement and mandatory industry reporting to the Department of Health and Human Services of antimicrobial agent usage in human, animal, plant, and inanimate applications. Surveillance for antimicrobial resistance rates in key microorganisms found in humans, animals, plants, food products, and the environment 

• Continued availability of high-quality diagnostic microbiology laboratories in human and animal healthcare facilities 

• Improved diagnostic testing in humans and in animals to aid practitioners in better identifying those subjects with infections who will and who will not benefit from antimicrobial treatment 

• Steadfast support for infection control programs in all healthcare settings 

• Education of the public and of professionals to change expectations and to increase awareness of the risks of antimicrobial resistance when these agents are used 

• Development of decision-support tools for clinicians including computer and Internet technology to deliver best practice information at the time the clinical antimicrobial treatment decision is made 

• Development and application of vaccines to prevent infections caused by a broader array of organisms, thus reducing the need for the use of antimicrobial agents 

• Development of new antimicrobial agents for the treatment of antimicrobial-resistant microorganisms 

• Responsible marketing and promotion of antimicrobial agents that incorporate concern about the potential for development of antimicrobial resistance 

• Support for good antimicrobial stewardship and improved hygiene in food animal production that promotes animal health 

• Support for legislation to phase out nontherapeutic use of certain antimicrobial drugs in food animals, including all antimicrobial drugs classified as critically important or highly important for human therapeutic use by the Food and Drug Administration (FDA) 

• Support for adequate resources to apply FDAs Guidance for Industry document #152: Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria on Human Health Concern, to all antimicrobial agents used in food animals including those previously approved by FDA 

IDSA and other organizations have also raised concerns regarding the relative lack of development of new kinds of antimicrobials. There has been recent activity in this regard, however. Researchers at the University of Minnesota and the University of Michigan have reported discovery of a new method of developing antibiotics, which could be an important step in fighting the growing number of drug-resistant infections.

In articles from Nature Chemical Biology, the researchers describe an approach that may be more efficient in developing new antibiotics. Were striving to create new drugs that can have a positive impact on the growing threat of infectious diseases, said Robert Fecik, PhD, an assistant professor of medicinal chemistry at the University of Minnesota College of Pharmacy and one of the lead authors of the study, in a press release. This type of research can help us make new antibiotic molecules.⁵

Most antibiotics in use today are molecules made by bacteria to kill their enemies. The bacteria use enzymes to make these ring-shaped antibiotic molecules. One way to increase the number of antibiotics, according to the release, is to engineer enzymes to produce new molecules, and thus new antibiotics. To do this more effectively, scientists need a clearer picture of how the enzyme molecules act upon the precursor to the antibiotic.

The team of scientists, including research professors David H. Sherman and Janet L. Smith from the University of Michigans Life Sciences Institute and Fecik of University of Minnesota College of Pharmacy, is the first to crystallize an enzyme in the process of closing the antibiotic ring, which shows how the ring is formed. Their work creates potential opportunities for new drug discovery.

Having the tools to make the next generation of macrolide antibiotics is crucial because these drugs are so well tolerated and have so few side effects, Smith says. They are really a great class of antibiotics, so we need more of them.⁶

These types of antibiotics are of particular interest because bacteria make them in a way that potentially allows for thousands of slightly different compounds to be synthesized and tested for antibiotic activity. The structure of macrolides is a large ring, itself constructed from a linear molecule, which is built in an assembly-line fashion from smaller molecules. An enzyme at the end of the chain triggers the ring formation that results in antibiotic formation.

These findings are likely to enable the development of powerful new methods to build structural diversity into large ring systems that are a key component of many types of macrolide antibiotic molecules. This will provide yet another strategy to stay ahead of the emerging and persistent antibiotic resistance threat, Sherman says.⁷

At Purdue University, a scientist recently determined the structure of a protein that controls the starvation response of E. coli, which may provide another possible avenue of new antibiotic research. This is an important discovery for the field of antibiotics, which was greatly in need of something new, says David Sanders, an associate professor of biology at Purdue, in a press release. This research suggests a whole new approach to combat bacterial infections. In addition, this protein is an excellent antibiotic target because it only exists in bacteria and some plants, which means the treatment will only affect the targeted bacterial cells and will be harmless to human cells.⁸

Sanders and his collaborator, Miriam Hasson, studied the structure of exopolyphosphatase, a protein in E. coli that functions as an enzyme and catalyzes chemical reactions within the bacteria. This enzyme provides the signal for bacteria to enter starvation mode, thus limiting reproduction.

Researchers may be able to design drugs to bind to the protein and keep it from being used by bacteria, making the bacteria unable to survive a lack of nutrients, the researchers said. Alternatively, a drug to mimic the protein may be a possibility, causing the bacteria to react as if it were starving even in the presence of nutrients.

Fundamental basic research is the engine that drives the development of technology such as antibiotics, Saunders says. The next step in this research will be working to develop inhibitors for this protein and studying the applications to other bacteria.^9 

References:

1. Zillich AJ, et al. Antimicrobial Use Control Measures to Prevent and Control Antimicrobial Resistance in US Hospitals. Infect Control Hosp Epidemiol. 2006 Oct;27(10):1088- 95. Epub 2006 Sep 18.

2. Ibid.

3. Principles and Strategies Intended to Limit the Impact of Antimicrobial Resistance. http://www.idsociety.org/Template.cfm?Section=Antimicrobial_Resistance&CONTENTID=16248&TEMPLATE=/ContentManagement/ContentDisplay.cfm   

4. Ibid.

5. Minnesota and Michigan Researchers Discover New Insights for Antibiotic Drug Development. http://www.ahc.umn.edu/news/releases/antibiotic091106/home.html 

6. Ibid.

7. Ibid.

8. Researcher hits bulls-eye for antibiotic target. http:// www.purdue.edu/UNS/html4ever/2006/060821.Sanders.ecoli.html 

9. Ibid.