May/Jun 2015 Vol 16 No 3 RxPress TABLE OF CONTENTS The White House Releases Plan to Combat Antibiotic-Resistant Bacteria 1-2 FDA Requests New Data on Health Care Antiseptics 2-4 Penicillin Allergies and Skin Testing: Implications for Antimicrobial Stewarship 3-5 The White House Releases Plan to Combat Antibiotic-Resistant Bacteria In 2013, the Centers for Disease Control and Prevention (CDC) released its first report on antibiotic resistance threats in the United States. The report estimated that there are at least 2 million infections and 23,000 deaths annually that are attributed to antibiotic resistance. The report also classified the threat level of current resistant bacteria into 3 categories: urgent, serious, and concerning. Clostridium difficile, carbapenem-resistant Enterobacteriaceae (CRE), and drug-resistant Neisseria gonorrhoeae were classified as urgent threats that require immediate and aggressive action. Unlike CRE and N. gonorrhoeae infections, which are concerning due to antibiotic resistance, C. difficile infections are included in this category based on their association with overuse of antibiotics, increasing incidence, and risk of morbidity and mortality. The overall goal of this report was to raise awareness and to encourage national efforts to help prevent the further spread of resistance and to preserve future treatment options for bacterial infections. In response to the CDC report, President Barack Obama signed Executive Order 13676 in September 2014 which established efforts to address the increasing emergence of antibiotic-resistant bacteria. The Executive Order established the Task Force for Combating Antibiotic- Resistant Bacteria (CARB), whose objective was to create a National Action Plan to implement the National Strategy for CARB that was released concurrently with the Executive Order. The National Strategy for CARB addresses prevention, detection, and managing outbreaks of resistant bacteria and introduces goals and objectives to have effective antibiotics for these infections in the future. The Strategy focuses on reducing the number of resistant bacterial infections caused by organisms on the CDC s Urgent and Serious Threats list. The National Action Plan, released in March 2015, provides the framework to achieve the 5 main goals laid out by the National Strategy. Goals and selected objectives to achieve goals that are most relevant to healthcare providers are provided in Table 1. Additional objectives of the National Action Plan focus on antibiotics used in the agricultural industry. The overarching goal for animal agriculture is to eliminate antibiotics as a method for growth promotion, but still allow their use in the treatment and control of disease. One key objective of the National Action Plan is implementation of antibiotic stewardship activities in all inpatient, outpatient, and long-term care settings by 2020. Additionally for hospitals, antibiotic stewardship programs will have to comply with the CDC s Core Elements of Hospital antibiotic stewardship programs as a condition of participation for Medicare and Medicaid programs by 2018. The CDC Core Elements guidance provides a framework that allows an antibiotic stewardship program to ensure it is operating effectively to optimize antibiotic prescribing and reduce antibiotic overuse. The guidance has several elements including presence of support from hospital leadership; an established physician leader for antibiotic stewardship; support of a multidisciplinary team including pharmacy co-leaders, existence of active interventions to optimize antibiotic prescribing, tracking of prescribing and resistance, and active education. A checklist is available on the CDC website that existing antibiotic stewardship programs can use to ensure that their program is meeting these standards (available at: http://www.cdc.gov/getsmart/ healthcare/implementation/checklist.html). Overall, the National Action Plan provides actionable objectives and metrics for the US government to help address the national crisis of increasing antibiotic resistance. The hope is that this action by the White House will help increase concerted efforts in improving antibiotic prescribing habits, increasing the ability to detect and track resistant infections, and incentivizing key stakeholders to develop new antibiotics and alternative therapeutics, such as vaccines. 1
Table 1. Goals and Selected Objectives in the National Action Plan for Combating Antibiotic-Resistant Bacteria. Goals Slow emergence of resistant bacteria and prevent the spread of resistant infections Strengthen national onehealth surveillance efforts to combat resistance Advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria Accelerate basic and applied research and development of new antibiotics, other therapeutics, and vaccines Improve international collaboration and capacities for antibiotic-resistance prevention, surveillance, control, and antibiotic research and development Selected Objectives Relevant to Healthcare Providers Strengthen antimicrobial stewardship: Hospitals will have to establish or enhance ASP by implementing CDC recommendations. a Establish state AR prevention programs: Creation of local networks with healthcare facilities and the state health department to help slow the regional spread of resistant organisms. Increase reporting of incidence of resistant infections and specific use of antibiotics to the National Health Safety Network. Create regional public health laboratory network: Sites will help in detection of outbreaks by MDROs and track their incidence and resistance mechanisms. Create repository and maintain database of genomic sequences for MDROs: Government agencies will maintain these and provide information or samples to aid in development of new antibiotics or diagnostic tests. Establish incentives for timely reporting of AR and antibiotic use data: Reporting these data to the National Health Safety Network will become part of the CMS hospital inpatient quality reporting program. Increase funding for the development of rapid diagnostics: Targets for funding include both tests that can differentiate between bacterial and viral infections and tests that can quickly analyze susceptibility profiles. Create incentives to increase use of these diagnostics in the healthcare setting. Increase support for research: Topics of interest include antibiotic resistance, mapping the gut microbiome, novel classes of antibiotics, vaccines, or non-traditional, innovative therapeutics. Create partnerships between stakeholders to encourage development of new antibiotics: Key stakeholders include the FDA, CDC, NIH, HHS, pharmaceutical companies, biotechnology companies, and academic researchers. Develop or strengthen relationships with other countries: Goals of collaboration with global health partners include increasing proficiency in detecting the WHO priority antimicrobial resistant pathogens c, increasing surveillance of AR in both humans and animals, developing a system to communicate significant threats quickly, and disseminating information to countries to promote interventions to fight AR. Support development of national action plans in other countries and provide assistance to developing nations so they can participate in AR surveillance. a Centers for Disease Control and Prevention s Core Elements of Hospital Antibiotic Stewardship Programs. b The goal of this network is to allow the CDC to monitor changes regionally and nationally in order to provide national estimates and provide benchmarking on antibiotic use to healthcare facilities. c WHO priority antimicrobial resistant pathogens: Escherichia coli (resistant to 3rd generation cephalosporins and fluoroquinolones), Klebsiella pneumoniae (resistant to 3rd generation cephalosporins and carbapenems), methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, fluroquinolone-resistant non-typhoidal Salmonella, fluoroquinolone-resistant Shigella, and Neisseria gonorrhoeae (reduced susceptibility to 3rd generation cephalosporins). Abbreviations: AR, antibiotic resistance; ASP, antibiotic stewardship program; CDC; Centers for Disease Control and Prevention; CMS, Centers for Medicare & Medicaid Services; FDA, Food and Drug Administration; HHS, Health and Human Services Department; MDRO, multi-drug resistant organism; NIH, National Institutes of Health; WHO, World Health Organization. FDA Requests New Data on Health Care Antiseptics The U.S. Food and Drug Administration (FDA) released a proposed rule for antiseptic drug products on April 30, 2015. New safety and efficacy data will be required for antiseptics used in the health care setting, including hand rubs, hand washes, surgical hand rubs, surgical hand scrubs, and preoperative skin preparations. Antiseptics used by consumers are excluded from the rule. 2
The proposed rule will affect health care antiseptics approved under the over-the-counter drug monograph. Active ingredients of affected antiseptics include alcohol (60% to 95%), povidone-iodine, iodine tincture, iodine topical solution, and isopropyl alcohol. A complete list of affected active ingredients can be found on the Federal Register (www.federalregister.gov). Proper hand hygiene has become an essential element of prevention of nosocomial infections. The 2002 CDC hand hygiene guidelines recommend regular use of alcoholbased antiseptics for decontamination to prevent the spread of infection in the health care setting. Similarly, the 2009 World Health Organization guidelines select alcohol-based hand rub as the preferred antiseptic for hand hygiene (except when hands are visibly soiled or there is a strong suspicion for Clostridium difficile). Appropriate hand hygiene is recommended before and after direct contact with a patient, as well as before and after contact with invasive devices, bodily fluids, wound dressings, and medical equipment in the vicinity of a patient, and before and after removal of gloves. Furthermore, The Joint Commission highlights hand hygiene as a priority in their 2015 National Patient Safety Goals. Health care frequent use of antiseptics has become routine. Although the actual frequency of hand antiseptic use by health care has not been defined, studies have estimated an average of 5 to 30 applications per hour, with potentially more than 100 applications in an 8-hour shift. Health care antiseptics such as alcohol hand rubs are considered to be safe and effective for regular use. However, there are limited data on the effects of frequent and chronic use at the rates currently reported by health care. In 1994, health care antiseptic products were determined by the FDA to be generally recognized as safe and effective (GRASE). Since that time, reports have been published suggesting that antiseptics may have systemic exposure. Improvements in laboratory technology have made it possible to detect lower levels of active ingredients in the blood or tissue of health care. Considering the frequent and chronic use of antiseptics by health care, the FDA is requesting new evaluations of these products in order to reexamine their classification as GRASE. To demonstrate efficacy, antiseptics will need to have sufficient bacterial log reduction. The safety studies will need to provide data on frequent and long-term exposure to the antiseptic, reproductive toxicity, hormonal effects, and the development of antimicrobial resistance. There are several published studies that have evaluated the absorption of alcohol hand rubs using various frequencies and durations of exposure (Table 2). These studies have been limited by small numbers of participants and brief durations of exposure. While most studies found detectable levels of alcohol in the serum or breath, all levels were below the known threshold for intoxication. Limited information is available on the effects of repeated exposure to low levels of alcohol in health care over the course of their entire career; whether this may be a concern remains unknown. Additional concerns exist over the effects of any measurable levels of alcohol in pregnant or lactating health care. During the collection of additional data, the FDA recommends that health care continue to use antiseptics according to current infection control guidelines. There is no information to indicate that currently available health care antiseptics are unsafe or ineffective. The rule is expected to be finalized in October 2015, after which manufacturers will have 1 year to provide the requested data. Marketed health care antiseptics will continue to be available during this review. Penicillin Allergies and Skin Testing: Implications for Antimicrobial Stewardship One of the most common causes of hypersensitivity reactions is beta-lactam antibiotics. Penicillin, a beta-lactam antibiotic, can cause an allergic reaction that presents as urticaria, shortness of breath, and angioedema. Reactions to penicillin can be classified as immediate (within 1 hour) or delayed (days to weeks). Immediate anaphylactic reactions are mediated by immunoglobulin E (IgE), while non-ige mediated reactions may have additional causes. Penicillin is metabolized into major and minor determinants, which may illicit the immune response to form the antibodies that would cause a reaction. Since penicillin is structurally related to other beta-lactams, including cephalosporins and carbapenems, hypersensitivity reactions can also occur in patients with penicillin allergies that receive these antibiotics. Although the cross-reactivity between agents is low, many clinicians avoid beta-lactam antibiotics in the event of a documented allergy to avoid harming a patient. Previous studies have shown that not all patients with documented penicillin allergies have a true allergy. Up to 10% of patients are reported to have an allergy to penicillin, with some reactions proving to be more severe than others. Many patients report their reactions as a non-specific rash during childhood. If they received the antibiotic as an adult, adverse events such as vomiting are sometimes reported as an allergy, which may not reflect a true IgE-mediated reaction. However, 90% of patients with a documented allergy can tolerate administration of penicillin. Over time, there can be a loss of the anti-penicillin antibodies that formed from the initial penicillin exposure, rendering the patient non-allergic. When the reaction is unknown in a penicillin-allergic patient, clinicians generally choose broad spectrum antibiotics, which are reserved for multi-drug resistant organisms. In patients with an inappropriately labeled penicillin allergy, reports have shown increased medical 3
Table 2. Studies on Systemic Exposure of Alcohol Hand Rubs Used in Healthcare. Sample Antiseptic Exposure Extent of Systemic Absorption 10 healthy adults 52.6% isopropyl alcohol Every 10 minutes for 4 hrs 1 physician 62% ethanol 25 times over 2 hrs Not detectable in blood 5 adult healthcare 62% ethanol 50 times over 4 hrs Not detectable in blood 20 healthcare 12 adult volunteers 70% ethanol or 70% isopropanol 95% ethanol, 85% ethanol, or 55% ethanol with 10% propan-1-ol 1 volunteer 70% ethanol or 56% ethanol with 9% isopropanol 32 adults 63.14% propan-2-ol or 45% propan-2-ol with 30% propan-1-ol 12 healthcare 70% ethanol 30 times over 1 hr, applied 70% isopropanol 30 times over 1 hr 20 times over 30 minutes for hygienic hand disinfection; applied 10 times over 30 minutes for surgical hand disinfection Once over 30 seconds for hygienic hand disinfection; applied twice for 45 seconds for each surgical hand disinfection 20 times over 30 minutes for hygienic hand rub; applied 10 times over 80 minutes for surgical hand rub 70% ethanol Twice over 10 minutes, 3 times over 8 minutes, or 9 times over 50 minutes for hygienic hand rub; applied twice over 2 minutes for surgical hand rub Ethanol detectable on breath and in blood (not toxic); isopropanol not detectable Detectable vapor in air; estimated absorption not toxic Detectable in vapor in air; estimated absorption not toxic costs, risk of antibiotic resistance, length of stay, and intensive care unit (ICU) admission in addition to higher mortality. One of the most useful and reliable detection methods for a true penicillin allergy is the penicillin skin test. Skin testing can demonstrate the presence of penicillin-specific IgE in the body. In patients with a non-ige mediated reaction, skin testing is contraindicated. Examples of non-ige mediated reactions include Stevens-Johnson Syndrome, serum sickness, or drug rash with eosinophilia and systemic symptoms. To complete a skin test, a patient is exposed to a positive and negative control, and major and minor penicillin determinants. These reagents are pricked into the skin, and the reaction is measured. If there is a positive reaction to the skin test, defined as >3 mm of erythema surrounding the injection site, a patient should not receive the intradermal test. If there is no growth around the site, the reagents are intradermally injected. If the intradermal test also has no reaction, an oral challenge with penicillin or amoxicillin may follow, with 60 minutes of observation time. The test has been found to have a high specificity to exclude the allergy correctly (97% to 100%), but lower sensitivity to identify the allergy correctly (29% to 68%). There are few adverse events reported in patients with a negative skin test, however events are dependent on if the patient had a previous IgE-mediated reaction. There are multiple patient care settings where penicillin skin testing can have an impact on antimicrobial stewardship and patient care, including the ICU, the emergency department (ED), and cardiac surgery. Approximately 90% of patients in various ICUs who received a penicillin skin test had a negative result. These negative results can lead to changes in the patients therapy to include a beta-lactam antibiotic if necessary. Use of beta-lactams reduces the use of antibiotics reserved for multi-drug resistant organisms, including fluoroquinolones, vancomycin, and carbapenems. In a study of patients with self-reported penicillin allergies in the ED, 137 patients out of a sample of 150 patients (91%) had a negative penicillin skin test result and not a true IgE-mediated allergy. The test only took 30 minutes to produce a result, which was efficient for an ED setting. In patients undergoing cardiac surgery, the appropriate antibiotic choice is essential to avoid potential toxicities that may result in negative cardiovascular outcomes. In a study of 276 patients with a penicillin allergy referred for testing prior to cardiac surgery, 38 had a positive skin test result. After testing, there was a 91% reduction in the 4
amount of vancomycin used in the operating room prior to cardiac surgery, thus reducing unnecessary vancomycin. There were no adverse events reported in patients with negative results. However, penicillin skin testing is not appropriate for all patients. If there is a recent history of an IgE-mediated reaction or severe dermatologic reaction to a beta-lactam, testing should be avoided to reduce the chance of an adverse reaction. Penicillin skin testing is a cost-effective way to determine if a patient has a true penicillin allergy, since the cost of broad spectrum antibiotics used in place of penicillin is higher. The cost of reagent and testing equipment can be up to $130, and the time to a result is approximately 30 to 60 minutes. In a 4 month prospective chart review, 146 patients with a reported penicillin allergy were given a penicillin skin test as part of an antimicrobial stewardship program. Patients were identified from the antimicrobial stewardship database. The decision to alter the therapy to a beta-lactam antibiotic was based on microbiologic data, IgE-mediated reaction, infection, and laboratory values. Patients with certain skin conditions, non-ige mediated reactions, additional or unknown allergies to antibiotics or recent anaphylaxis were excluded. Patients were initially given a skin prick test and monitored. If there was a negative result, the patient was then exposed to the intradermal reagent, and then an oral penicillin challenge based on response. Out of all the patients tested, only 1 had a positive reaction; the other 145 were negative to both the skin test and a subsequent oral challenge. Patients with a negative result were transitioned to a betalactam antibiotic. There were no reactions at 24 hours for these patients, which resulted in a negative predictive value of 100%. The cost reduction with use of a penicillin skin test was approximately $520 per patient. Additional costs associated with catheters, laboratory work, wound dressing changes, and other medications were avoided. The estimated cost of therapy if the penicillin skin test had not been performed was $113,991. The cost after the betalactam transition was $81,180, resulting in a difference of $225 saved per patient during the study period. In patients with a negative skin test, there is a potential for up to an $82,000 savings per year by switching to a betalactam. The authors concluded that the use of skin testing can improve antimicrobial stewardship and save costs associated with antibiotic use. Integrating penicillin skin testing into an antimicrobial stewardship program is one way to ensure that patients with documented penicillin allergies are tested. By incorporating penicillin skin testing into an antimicrobial stewardship program and making it a standard of care, there are many opportunities to prevent unnecessary adverse events, reduce costs, and ensure antibiotics used for multi-drug resistant infections are preserved. Incorporating histories and risk stratification provide important information so that patients can be properly tested. One proposed model can be remembered by the 3 A s: alert, assessment, and action. By identifying patients with antibiotic allergies and alerting clinicians that are part of the antimicrobial stewardship team, those patients can be assessed. After the in vitro and in vivo data from the patient have been assessed, the patient s allergy status can be determined: IgE-mediated or non-allergic. Lastly, the action can take place: the patient can be tested or desensitized. Based on the results from the test, appropriate therapy can be administered to the patient. Pharmacists can play an important role in antimicrobial stewardship by interacting with patients and other healthcare providers. By taking detailed allergy histories and discussing the reaction with patients they can help to identify patients that would be appropriate for testing. They can also recommend appropriate therapy after the patient has been tested. By integrating penicillin skin testing with antimicrobial stewardship, there are many opportunities for pharmacists and physicians to reduce broad spectrum antibiotic use, adverse events, and costs. More appropriate antibiotics can be prescribed and monitored, all while improving patient outcomes. Authors: Nicole Mueller PharmD, BCPS Samantha Spencer PharmD Carol Poskay PharmD Editors: Ryan Rodriguez PharmD, BCPS Lara Ellinger PharmD, BCPS 5