Antibiotics and vaccines are undoubtedly among the most significant discoveries in human history. Their use has saved countless lives from once-lethal infections. Unfortunately, antibiotics are also the only drugs in which widespread use decreases their utility. In contrast to medications that alter human biochemical processes, such as the clotting cascade and heart rate, antibiotics are engaged in a war with an enemy that is fighting back. Bacteria alter themselves to resist the effects of antibiotics, allowing them to multiply and continue spreading disease. This issue has become one of the nation's most pressing health problems, and its magnitude is accelerating. In order to combat antibiotic resistance and preserve our miracle drugs, pharmacists must be knowledgeable about the issue and actively involved in the solution.
Increasing Antibiotic Resistance
According to the Centers for Disease Control & Prevention (CDC), nearly 2 million people in the United States acquire bacterial infections during their hospital stay annually, and over 70% of the bacteria that cause these infections are resistant to at least one of the drugs normally used to treat them.1 These drug-resistant bacteria include not only well-known offenders such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, but also strains of Klebsiella pneumoniae that have developed resistance to all available beta-lactams.2 For some organisms, clinicians have been forced to turn to polymyxins, an older class of antibiotics that was previously abandoned, in lieu of the “safer” aminoglycosides.3
Resistance in the community setting is just as concerning. In one national cohort, community-associated MRSA was the most common identified cause of skin infections among patients who visited emergency rooms.4 Common pathogens seen in the community setting such as Escherichia coli and Neisseria gonorrhoeae have become resistant to fluoroquinolones, agents that were considered first-line therapies for infections caused by these pathogens in the past.5,6
Possibly more unsettling than the increase in antibiotic resistance is the decrease in antibiotic research and development. As of 2009, no new classes of antibiotics were in late-stage development, and only 16 antibiotics are in late-stage development at all.2 Not all of these 16 agents will be approved, as evidenced by the fact that of the six that have undergone FDA review, only two were approved (telavancin and ceftaroline). The oxazolidinones (linezolid) in 2000 and the lipopeptides (daptomycin) in 2003 were the only novel systemic antibiotic classes developed since 1968.7
There are many reasons for the lack of antibiotic development. Antibiotics are typically only taken for days at a time, which does not guarantee substantial profit for drug companies. When antibiotics are approved, the natural inclination of many practitioners is to reserve them for more resistant or serious infections, which ironically compounds the economic disincentive for further antibiotic development. Additionally, clinical trials for antibiotics are not easily conducted. As antibiotics must be given acutely for most infections, prior antimicrobial use significantly confounds any measurable benefit. Also, since multiple organisms can cause most infections, companies seeking approval for candidate antibiotics often must include other antibiotics in combination with the candidate drug in clinical trials, which may contribute to the therapeutic effect and make the effect of the candidate antibiotic difficult to measure. The difficulty in finding patients with infections caused by microorganisms of interest is another concern. This issue was recently demonstrated by a trial of linezolid (Zyvox-Pfizer, Inc.) in MRSA pneumonia, where ~1,200 patients were enrolled and treated to find ~400 that were eligible, and the number of patients screened was likely even higher.8 Antibiotics must be studied for each infection in which they are indicated, which presents the issue of small sample sizes since infections are not typically chronic or nearly as widespread as diseases such as hypertension.
Investigating clinical utility in the treatment of resistant bacteria is even more difficult to study. Enrolling patients in studies of new antibiotics who have organisms that are resistant to active controls is not ethical. This presents a true concern, since it is these resistant strains that require new options. New types of studies for alternative drug approval may be needed to increase the availability of antibiotics for these infections.
Society Undervalues Antibiotics
In the 21st century, most people lack the historic perspective of what society was like before antibiotics became widely available. Antibiotics transformed medicine, yet in an era where the majority of bacterial infections are routinely treatable this is easily forgotten. Infections that are easily treated today were frequently lethal in the pre-antibiotic era. A review of historically controlled studies of early antibiotics showed a decline in mortality from community-associated pneumonia (CAP) from 38% to 12% due to antibiotic use, corresponding to a number needed to treat to save one life of four.9 Even young, otherwise healthy patients had mortality rates from CAP of 10% in the pre-antibiotic era, much higher than the <1% with antibiotics.9 Penicillin reduced the mortality rate from cellulitis from 11% to <1%.10 These common infections were feared in the pre-antibiotic era but are now routinely treated.
“You didn't pay for the germs. Why pay for the antibiotics?” This is one of the tag lines used to promote free antibiotic programs found at various pharmacies that allow patients to receive generic antibiotics for free. In a time of economic instability, the notion of pharmacies extending generosity towards customers by giving away medicine seems refreshing. However, it may contribute to the undervaluing of antibiotics by society. By making antibiotics available to patients for free, their perceived value may be lessened.
Since antibiotics are highly effective at curing many once-lethal diseases, the economic value of antibiotics is difficult to measure. In oncology, a drug that prolongs life by several months is considered a success and is likely to become a standard of care, probably at a substantial cost. A successful antibiotic cures infection and prolongs life indefinitely, but the price that payers are willing to pay is substantially lower. Per-unit costs with newly approved antibiotics may be higher than in other disease states but may be justified by the short courses of therapy that most infections require. For example, a patient with sinusitis may take an antibiotic for 5 to 10 days, but the same patient may take a cholesterol-lowering agent or antihypertensive drug for the rest of his or her life. These economic disincentives prevent further antibiotic development.
The Pharmacist's Role
The pharmacist's role in combating and preventing infectious diseases is essential as antibiotic and vaccine regimens become more complex due to the continuously evolving epidemiology of infections. The decrease in drug development makes the preservation of currently available antibiotics paramount, highlighting the roles that pharmacists play in maximizing the utility of available drugs. While further training in infectious diseases may be necessary for some pharmacist roles in preventing antibiotic resistance, many others exist that all pharmacists can embrace.
Pharmacist-directed antibiotic stewardship programs (ASPs) have proliferated considerably in the past decade. After evidence emerged that these programs improve patient care, the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America published a guideline for the development of ASPs specifying that an infectious diseases-trained clinical pharmacist was an essential core member.11,12 As resistance has increased and antibiotic development has lagged, ASPs have become important to improve clinical outcomes, prevent resistance, and decrease adverse events such as Clostridium difficile infections.13 ASPs take many forms, but all utilize a team approach to improve the utilization of antibiotics through means such as interventions on individual patients, guideline development, and system-wide improvement (TABLE 1). Over time, ASPs may become a standard for all hospitals and long-term-care facilities across the nation; however, at this time only California has developed a statewide initiative to require ASPs.14
Various methods may be employed for ASPs, and pharmacists are generally the key personnel members following the patients and intervening when necessary. While some of these interventions require an in-depth knowledge of infectious diseases, others are within the scope of general pharmacy practice. For example, it has been reported that dosing of vancomycin may be inadequate in obese patients.15 Since it has been suggested that inadequate vancomycin dosing may be associated with the promotion of resistance in Staphylococcus aureus, this represents an opportunity for nonspecialist pharmacists to intervene.16 More complex antibiotic selection or dose optimization methods may be utilized by those pharmacists with a comprehensive understanding of diagnostic tests or antibiotic pharmacokinetics and pharmacodynamics.17-19 Each intervention is an opportunity to provide feedback and education to the prescriber, which is vital to the maintenance of a stewardship program and further promotes the improvement of antibiotic utilization. Further, pharmacists frequently collect and report data about interventions and antibiotic-use patterns at hospital committees in order to assess the effectiveness of the program, identify areas for improvement, and garner continued support for stewardship.
Community Pharmacists as Gateway Practitioners
As gateway practitioners, community pharmacists have some of the most significant opportunities to intervene and prevent unnecessary antibiotic use, which is strongly associated with increased resistance. Patients often go to their community pharmacy first to seek advice regarding infections and OTC medications to alleviate their symptoms. Pharmacists may counsel patients on viral infections, the futility of antibacterials for them, and recommend appropriate OTC products for supportive care. Avoiding an unnecessary trip to a physician's office can prevent the pressure that physicians may feel to prescribe antibiotics that they do not believe are necessary. Of course, pharmacists should refer a patient to see a physician if a bacterial infection is suspected, the patient is severely ill or complicated by significant comorbidities, the infection is prolonged, or the pharmacist is not comfortable judging that a mild viral infection is present. A useful resource for pharmacists regarding these counseling points is the CDC Web site Get Smart: Know When Antibiotics Work.20
Pharmacists are crucial to promoting currently available vaccines. Vaccines can decrease the use of antibiotics directly by preventing primary infection and indirectly by preventing bacterial superinfection after a primary vaccine-preventable illness, such as influenza.21 Pharmacists can screen patients and identify those in need of immunizations at various time points and places: admission to a health care facility; visits to community pharmacies; at a specific age; for certain chronic conditions, medical or surgical procedures; and at certain times of the year.22 Pharmacists can also now administer vaccines in the community setting in every state.23
Perhaps the most important pharmacist role in preventing antibiotic resistance is that of an educator. Due to many misconceptions that exist about antibiotics and vaccines, addressing patient and clinician concerns is vital to increasing the understanding of the appropriate use of these agents. Some parents are hesitant about vaccinating their children because of the concern for side effects, both real and imagined. Pharmacists can help patients to separate fact from fiction regarding immunizations. They may also educate on antibiotic resistance, act as gateway practitioners as mentioned previously, and provide resources for clinical decision making so appropriate choices are made regarding antibiotics.
Education regarding infection-control practices is also an important avenue for pharmacist involvement. Pharmacists may be proactive in regard to educating the public about important infection-control practices such as general hygiene, hand hygiene, cough etiquette, immunizations, and staying home when sick.24,25 These topics may seem like common sense, but patient understanding of these basic infection-control practices should not be overestimated. Various tools are available online to support pharmacists in these endeavors. Pharmacists can access both print materials and tips on how to communicate with patients about respiratory viral infections, appropriate antibiotic use, and other relevant topics.20
Pharmacists have a responsibility to assist in the war on antibiotic resistance. They have the knowledge and resources at their fingertips to raise awareness and to act. There are multiple opportunities for pharmacists to assist in this campaign. The recognition of pharmacists as key members of antibiotic stewardship teams in health systems is a milestone in infectious-diseases pharmacy practice. Community pharmacists have a critical role to play in combating antibiotic resistance as front-line practitioners who can educate and vaccinate patients.
Without significant intervention, we are coming to the end of the days where 10 different antibiotics can be utilized to treat a serious E coli infection. If we do not make it our problem now, it will certainly be our problem later when we are asked what antibiotic to use for a pan-resistant E coli infection and the answer is: nothing.
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5. Centers for Disease Control and Prevention (CDC). Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep. 2007;56(14):332-336.
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8. Kunkel M, Chastre JE, Kollef M, et al. Linezolid vs vancomycin in the treatment of nosocomial pneumonia proven due to methicillin-resistant Staphylococcus aureus. Presented at the 48th Annual Meeting of the Infectious Diseases Society of America; October 21-24, 2010; Vancouver, BC, Canada.
9. Spellberg B, Talbot GH, Brass EP, et al. Position paper: recommended design features of future clinical trials of antibacterial agents for community-acquired pneumonia. Clin Infect Dis. 2008;47(suppl 3):S249-S265.
10. Spellberg B, Talbot GH, Boucher HW, et al. Antimicrobial agents for complicated skin and skin-structure infections: justification of noninferiority margins in the absence of placebo-controlled trials. Clin Infect Dis. 2009;49(3):383-391.
11. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.
12. Gross R, Morgan AS, Kinky DE, et al. Impact of a hospital-based antimicrobial management program on clinical and economic outcomes. Clin Infect Dis. 2001;33(3):289-295.
13. Charani E, Cooke J, Holmes A. Antibiotic stewardship programmes--what's missing? J Antimicrob Chemother. 2010;65(11):2275-2277.
14. California Department of Public Health, State of California. The California antimicrobial stewardship program initiative. www.cdph.ca.gov/programs/hai/Pages/AntimicrobialStewardshipProgramInitiative.aspx. Accessed November 29, 2010.
15. Hall RG, 2nd, Payne KD, Bain AM, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. 2008;121(6):515-518.
16. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009;66(1):82-98.
17. Bauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program's impact with rapid polymerase chain reaction methicillin-resistant Staphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis. 2010;51(9):1074-1080.
18. Forrest GN, Roghmann MC, Toombs LS, et al. Peptide nucleic acid fluorescent in situ hybridization for hospital-acquired enterococcal bacteremia: delivering earlier effective antimicrobial therapy. Antimicrob Agents Chemother. 2008;52(10):3558-3563.
19. Mohr JF, Wagner A, Rex JH. Pharmacokinetic/pharmacodynamic modeling can help guide targeted antimicrobial therapy for nosocomial gram-negative infections in critically ill patients. Diagn Microbiol Infect Dis. 2004;48(2):125-130.
20. Centers for Disease Control and Prevention. Get smart: know when antibiotics work. www.cdc.gov/getsmart/index.html. Accessed November 18, 2010.
21. Kwong JC, Maaten S, Upshur RE, et al. The effect of universal influenza immunization on antibiotic prescriptions: an ecological study. Clin Infect Dis. 2009;49(5):750-756.
22. American Society of Health System Pharmacists Council on Professional Affairs. ASHP guidelines on the pharmacist's role in immunization. Am J Health Syst Pharm. 2003;60(13):1371-1377.
23. American Pharmacists Association. States where pharmacists can immunize as of June 2009. www.pharmacist.com/AM/Template.cfm?Section=
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24. Society for Healthcare Epidemiology of America. Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals. www.shea-online.org/about/compendium.cfm. Accessed November 18, 2010.
25. Centers for Disease Control and Prevention. 12 steps to prevent antimicrobial resistance among long-term care residents. www.cdc.gov/drugresistance/healthcare/ltc/12steps_ltc.htm. Accessed October 4, 2010.
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