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Reduce antibiotic resistance [VIDEO]


Stewardship includes influences of prescribing patterns through guidelines and incentives

Antibiotics target bacterial cell walls that our human cells do not have. How does resistance develop to antibiotics? A simplified explanation is that some bacteria were “born” with resistant genes.

Increasingly, resistant organisms are no longer limited to the confines of hospitals, and represent a significant threat to the community. Therefore, all sites that care for patients should be aware of the causes and have a plan for addressing resistance.

Antibiotic use=Antibiotic resistance

The single most important cause of resistance is the overall use of antibiotics. This includes use of antibiotics in people as well as in food animals.

The Centers for Disease Control and Prevention (CDC) reported that a total of 258 million courses of outpatient antibiotics were prescribed in the U.S. in 2010. This translates to 833 prescriptions per 1,000 persons. Antibiotics are the number one type of prescribed drugs to children and ~75% of antibiotics are prescribed in the outpatient setting for respiratory tract infections.

Reviews suggest that 50% of antibiotic prescriptions are unnecessary. Azithromycin is the most commonly prescribed antibiotic, and with increasing resistance issues for targeted organisms (Streptococcus pneumoniae), some guidelines recommend avoiding this broad-spectrum macrolide entirely. Antibiotic prescription trends are generally decreasing for pediatric populations, perhaps from use of pneumococcal vaccination. However, in a report published in JAMA, the aged 50-year-and-older population saw an increase in antibiotic prescriptions between 1995 to 1996 and 2005 to 2006. Antibiotic use in hospitals is also increasing, and is often not evidenced-based. 

Overuse of antibiotics includes several scenarios. The most egregious overuse of antibiotics is against viral illnesses or other non-bacterial infections. Additionally, overuse includes antibiotics prescribed for an extended time when evidence supports shorter durations. Overuse also occurs when the main culprit of an infection is known, but a broader-than-necessary spectrum agent is selected. The JAMA study above also identified that between 1995 to 1996 and 2005 to 2006 there was a notable increase in prescribing broad-spectrum macrolides and fluoroquinolones. Another study confirmed an increase in the use of broad-spectrum agents from 2000 to 2010. Broad-spectrum agents contribute specifically to selective pressure for resistance. The concerns of overuse of antibiotics relative to resistance are addressed in many available guidelines for treating common infections. 

When compared with infections caused by susceptible bacteria, multidrug-resistant bacterial infections prolong hospital stay and have a higher incidence of mortality. The CDC’s report estimated that antibiotic-resistant infections have caused more than 2 million illnesses and 23,000 deaths every year in the United States. The economic burden is significant with estimates as high as $20 billion in direct costs above ordinary costs of care. Antibiotics are often not prescribed appropriately, and there are negative economic and ecological impacts. 

Guidelines for managing infectious diseases have long heralded that a consequence of antibiotic use is increased resistance. However, ensuring appropriate antibiotic use is complicated and only part of the evolving equation of addressing pre-existing resistance. The following are recommendations for addressing resistance from the CDC: 

  • Prevent infections and prevent the spread of resistance;

  • Track resistant bacteria;

  • Improve antibiotic use through stewardship; 

  • Promote development of new antibiotics as well as diagnostic tests for resistant bacteria.

Preventing all infections is a noble, albeit likely impossible, action plan in the hospital setting. Preventing infections and containing the spread of resistance is the main goal of any infection prevention program. A unifying principle between infection prevention and antibiotic stewardship is tracking bacterial susceptibility rates through a hospital or local antibiogram.

Antibiograms provide necessary information for prescribers to make informed decisions about initial/empiric antibiotic use. For example, if Escherichia Coli’s susceptibility rate is 89% against levofloxacin, that would not be a valuable empiric choice due to the relative clinical rate of failure at percentages less than 90. 

Antimicrobial Stewardship Programs (ASPs) are recommended specifically to measure and improve antibiotic use. ASP teams in acute care settings are typically comprised of a physician, a pharmacist, a clinical microbiologist and an infection preventionist. There is an initiative to define what the optimal model should be for outpatient ASPs, but clear opportunity exists for wide scale implementation. Basic ASP goals are:

  • Optimize formulary choices of antimicrobials;

  • Implement local guidelines for treating common infections;

  • Eliminate redundant antibiotics (e.g. double anaerobe coverage)

  • Educate when antibiotics are not appropriate (e.g. viral infections or contamination of blood cultures); and

  • Narrow therapy for culture-confirmed pathogens.  



Best practices

Successful interventions to improve prescribing habits include both restricting access to and persuasive suggestions of antibiotic selection. ASPs in both the inpatient and outpatient settings may educate and/or steward prescribers via these two main methods. Restriction essentially limits the available antibiotics for use, directing prescribers away from targeted antibiotics (e.g. quinolones and carbapenems) to locally-determined appropriate treatments. Restriction appears to have a more rapid impact in decreasing the number of resistant bacteria.

Persuasion includes education and real-time feedback via prospective prescribing review but is limited by acceptance and may be less effective on minimizing collateral damage of antibiotic use in the short term. An effective persuasion program, applicable to both outpatient and inpatient settings, is prescribing audit with real-time feedback.

In a study published in JAMA last June, a large pediatric primary care network was able to statistically significantly reduce broad-spectrum antibiotic prescribing by 6.7%, off-guideline prescribing for pneumonia by 10.7% and acute sinusitis by 14% through provider education and patient-specific feedback from an infectious diseases specialist. Restrictive measures are more effective for immediate results, but persuasive techniques are equal at six months. Guideline recommendations provide the framework for developing both methods. Implementation of these recommendations needs to be catered to the needs of each location. 

Physician leadership is essential to crafting and implementing specific antibiotic-based treatment strategies. Leadership greatly influences local level “prescriber etiquette.” All strategies in concert can reduce antibiotic overuse, resistance and improve clinical outcomes.

Unfortunately, a disappointingly modest decrease of ~10% of antibiotic use has been demonstrated with various intervention strategies.  Typically, prescriber knowledge of guidelines is not the issue. Embracing key beliefs of prescriber success is necessary. Behavior change theory suggests that verbal persuasion does not usually alter practice. Revamping clinicians’ approach to antibiotics, such as prescribing delayed antibiotics, can be very successful in reducing antibiotic use without significant patient impact. However, there is a strong incentive for the prescriber to balance clinical appropriateness with patient satisfaction. Prescriptions validate patient suffering and confirm the appropriateness of patients to seek medical attention. The “fear of omission” (not treating effectively) is significantly greater than the “fear of commission” (antibiotic overuse). 

One strategy that may bridge the overuse belief and resistance impact gap is delay-fill antibiotics. Patients are provided prescriptions at the initial visit with explicit instructions on clinical circumstances and when to fill. This prevents the need for patients to return to the prescriber’s office for a second time and allows the patient to have both security and control.

Patients’ primary reason for seeking outpatient treatment is cough which is also the primary reason for dispensing antibiotics. Physicians often state they feel pressure by patients to prescribe antibiotics. That pressure may be vocalized by the patient or only a perception of the clinician. Patient opinion of the need for antibiotics has been found to not be associated with true illness severity. But, prescribers should be clear with patients about individual risks and benefits. 

In general, antibiotics for respiratory infections may only reduce symptoms by around half a day but confers a 5% to 25% adverse drug reaction rate (ADR). Around 1 in 1,000 antibiotic prescriptions results in a visit to the emergency department due to a serious ADR. One approach is to not engage the patient in a societal discussion about the ecological impacts on resistance, but to simply state “this medicine is more likely to hurt you than help you.”

Restriction and persuasion at the prescriber and patient level may only have a small impact on improving antibiotic prescribing. Thus, larger, financially-driven tactics have been put in place to “force” appropriate institutional prescribing for specific populations.



Pay for performance

In October 2012, CMS began requiring hospitals to report the following Value-Based Purchasing Program antibiotic-related areas: 

  • Percent of pneumonia patients who had a blood culture taken before they were given antibiotics;

  • Percent of pneumonia patients that received the correct kind of antibiotics;

  • Percent of patients that received an antibiotic within an hour of surgery;

  • Percent of surgical patients that received the correct kind of antibiotic; and

  • Percent of patients who had their antibiotics stopped within 24 hours after surgery ended.

For acute-care facilities held to the standards of CMS, compliance with the specified targets results in monetary rewards and noncompliance results in reduced payments. However, these patient populations do not represent all antibiotic use, thus broader strategies such as ASPs are critical.

Unfortunately, the drive to reach 100% compliance may lead to inaccurate reporting. Establishing an evidenced-based compliance benchmark may provide a more realistic picture. The impacts of these CMS requirements are being studied, and the hope is that outcomes are truly improved for patients. 

Other mandated CMS initiatives have not necessarily demonstrated value. In October 2008, CMS ceased paying hospitals for specified healthcare-associated infections such as central line-associated bloodstream infection (CLABSI), ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI). Harvard investigators examined 398 hospitals and found CMS targeted infections as well as other infections trended downward, long before the penalties for reimbursement were put into place. No changes were identified in the quarterly rates for CLABSI, VAP or CAUTI in pre- or post-implementation of the CMS “Never Events.”

New antibiotic development

The antibiotic pipeline has waned considerably over the preceding decades. Differing antibiotic mechanisms require significant investment into research and development and have a projected loss of return of investment. As of the end of 2013, 18 antibiotics were identified in phase III trials or had applied for a New Drug Application. However, three are specific anti-tuberculosis agents and the remaining agents are part of existing categories of antibiotics. 

Based on the surge of multi-drug-resistant pathogens and the lack of new treatments, FDA crafted and President Obama signed into law Generating Antibiotics Incentive Now (GAIN) in July 2012. This law aims to incentivize the research and development of new antibiotics by: 1) fast tracking new compounds for FDA approval; 2) extending patent exclusivity by an additional five years; and 3) requiring FDA to specify target organisms and clinical trials of need with continual updates. 

Additional legislation was introduced in December 2013, called the Antibiotic Development to Advance Patient Treatment Act of 2013. It is essentially a follow-up to GAIN and proposes developing an accelerated pathway for approval of antibiotics and antifungals, increasing oversight by the CDC and FDA.  

Even with new agents in the pipeline, if manufacturers continue to promote antibiotic prescribing with historical precedent, these antibiotics will fall victim to the same use-associated resistance. A profit-driven incentive to sell antibiotics without limits often conflicts with appropriate use driven by antimicrobial stewardship. Reimbursement for manufacturers could be changed with additional legislation and tied with public health goals and rational use of antibiotics. Evidence based medicine provides necessary direction for guiding appropriate antibiotic use and should be incorporated in these goals. 

Gina Lumbard Harper, PharmD, BCPS, is the clinical coordinator and residency program director at Poudre Valley Hospital.

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