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Infections, bacterial resistance, and antimicrobial stewardship: The emerging role of hospitalists
Author(s)
David J. Rosenberg, MD, MPH, FACP, SFHM

Healthcare‐associated infections (HAIs) are important causes of morbidity and mortality in the United States and other countries.13 Moreover, treatment of HAIs is frequently complicated by involvement of bacterial pathogens resistant to 1 or more antibiotics or antibiotic classes,4 and sometimes bacteria resistant to all or nearly all currently available agents.57 The rapid emergence of resistant bacteria both in and out of the hospital setting can affect empiric antimicrobial choices across all patients. The effort to avoid undertreating or not covering resistant bacteria can lead to overuse of wide‐spectrum antimicrobials. Antimicrobial useand especially antimicrobial overuse or misusehas been linked with increased antimicrobial resistance,817 leading to worsened clinical outcomes with increased length of hospital stay and healthcare costs. Table 1 defines the various lines of evidence supporting a causal relationship between antibiotic use and emergence of antimicrobial resistance.18, 19

Observations That Support Causal Associations Between Antimicrobial Use and Emergence of Antimicrobial Resistance

  • NOTE: Adapted from Dellit et al.18

Changes in antimicrobial use are paralleled by changes in the prevalence of resistance
Antimicrobial resistance is more prevalent in healthcare‐associated bacterial infections vs community‐acquired infections
Patients with healthcare‐associated infections caused by resistant strains are more likely than control patients to have received prior antimicrobials
Areas within hospitals that have the highest rates of antimicrobial resistance also have the highest rates of antimicrobial use
Increasing duration of patient exposure to antimicrobials increases the likelihood of colonization with resistant organisms

Optimal management of patients with bacterial infections, both HAIs and those that originate in the community, involves a focus on treatment that maximizes clinical outcomes for the individual patient, while also inhibiting or slowing the development of antimicrobial resistance and its spread to other patients. Antimicrobial stewardship is a term describing the various clinical strategies that have been devised to maximize the benefits and minimize the costs of antimicrobial therapy through judicious use of these agents.18, 20, 21 This article examines the developing patterns of resistance among key bacterial pathogens in the hospital and associated healthcare settings, the costs associated with HAIs (specifically, those caused by resistant pathogens), and the various strategies or programs that have been developed by governmental agencies, individual healthcare institutions, and other organizations to optimize the use of antibiotics to improve patient outcomes and minimize healthcare costs. The value that the hospitalist can bring to the development and/or implementation of institutional antimicrobial stewardship programs is explored.

ANTIMICROBIAL RESISTANCE AND HAI TRENDS FOR KEY BACTERIAL PATHOGENS

Bacterial pathogens including Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp, Escherichia coli, and Proteus spp, among others), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium22, 23 are increasingly prevalent in healthcare settings, and particularly troublesome to manage due to increasing resistance. Data from the Centers for Disease Control and Prevention's (CDC) National Healthcare Safety Network (NHSN) have shown that, in intensive care units (ICUs), 16% of HAIs are due to multidrug‐resistant (MDR) pathogens.4 These 16% have the highest mortality and length of hospital stay, and are associated with the highest healthcare costs.24, 25 Infections caused by MDR pathogens are more important than their actual numbers, because treatment decisions are driven by the intent to cover these MDR pathogens, even if that means providing excessively broad coverage for most patients. Moreover, the 16% mentioned above are only the tip of the iceberg, as many more HAIs will occur outside of the ICU, particularly catheter‐associated urinary tract infections (CAUTI) and surgical site infections, as these patients are often not sick enough to require ICU care. There is little information on the prevalence of HAIs outside of the ICU setting, the role of MDR bacteria in these infections, and the associated costs, mortality, and effects on length of stay.

K pneumoniae Carbapenemases and Community‐Acquired Methicillin‐Resistant Staphylococcus aureus

K pneumoniae carbapenemase (KPC) is a prime example of the emergence and rapid spread of a new resistance pattern that affects prescribing patterns. Emergence of KPC as the primary source of carbapenem resistance in Enterobacteriaceae26 is critically significant, as carbapenems are recommended first‐line therapy for serious infections caused by extended‐spectrum ‐lactamase (ESBL)‐producing K pneumoniae or other Enterobacteriaceae. One particularly remarkable fact about KPC‐producing bacteria is the speed at which they have spread since first emerging. Figure 1 from the CDC illustrates the rapid spread of KPC‐producing bacteria within the United States, from winter 2008 to May 2010. International spread has also been rapid and extensive. The first case of a KPC‐producing bacteria outside the United States was reported in France in February 2005, in an 80‐year‐old man who was admitted to a Parisian hospital 2 to 3 months after having a medical procedure performed in a New York City hospital, suggesting intercontinental transfer from the United States.27 Since then, KPC‐producing pathogenic bacteria have been identified in the Caribbean, South America, Europe, Israel, and China.2830 It is clear that once resistant bacteria emerge, they have the potential to spread very rapidly within and between countries, challenging currently available antimicrobial agents and complicating the treatment of serious infections.

Figure 1
Rapid spread of Klebsiella pneumoniae carbapenemase‐producing bacteria within the United States, from winter 2008 to May 2010. (CDC unpublished data).

Consideration of S aureus skin and skin‐structure infections highlights the fact that the barrier between hospital and community is now beginning to be crossed, further complicating prescribing decisions. The classic risk factors for resistance may no longer be reliable in determining best empiric treatment. In a landmark study, Moran et al. demonstrated the large percentages of outpatients in the United States with skin or soft‐tissue infections (SSTIs) involving community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA).31 S aureus was isolated from 76% (320/422) of adults presenting to 11 university‐affiliated emergency departments with acute, purulent SSTIs in August 2004, 59% of whom were infected with MRSA. More than half the patients in the study (57%) were initially treated with antibiotics to which MRSA isolates were not susceptible.31 In the hospital, it has been shown that most invasive MRSA infections now actually have their onset outside of the healthcare setting,32 and that increasing numbers of hospitalized patients are now developing infections associated with CA‐MRSA strains >72 hours after admission.3338 Thus, it is becoming increasingly difficult to determine whether an invasive S aureus infection encountered in either a healthcare facility or community setting involves a sensitive organism, healthcare‐associated MRSA, or a CA‐MRSA pathogen, directly impacting treatment choices across all patients we care for with skin and skin‐structure infections.

Clostridium difficile‐Associated Disease

Indiscriminate and unnecessary use of antibiotics offer our patients no benefit, while exposing them to adverse effects of antibiotics, including allergies, rashes, and diarrhea among many potential other unintended consequences. C difficile‐associated disease is an increasingly problematic pathogen in the hospital setting that has been linked to unintended antibiotic effects.22, 39, 40 C difficile infection is not only costly in dollars, it is also a potentially fatal condition and has been linked to prolonged hospital stays and increased healthcare costs.4144 Improved infection control measures4549 and better use of antibiotics through antibiotic stewardship programs5055 have been shown to reduce the incidence of C difficile infection.

COSTS OF HAIs AND ANTIMICROBIAL RESISTANCE

HAIs are an important and growing problem in the United States.56 Klevens et al. estimated that approximately 1.7 million individuals hospitalized in the United States in 2002 had HAI, leading to 98,987 deaths.1 Estimates of annual hospital costs in the United States related to HAIs range from $28 to $48 billion.57 Antimicrobial resistance is a major driver of mortality, increased length of hospital stay, and hospital costs associated with HAIs.24, 25 A recent review by Sipahi25 summarizes recent studies examining the impact of resistant and MDR bacterial infections (Figure 2).5866 It is dramatically clear that infections due to resistant and MDR bacteria more often result in death, are associated with longer hospital stays, and are considerably more expensive to treat.

Figure 2
Association of multidrug resistance of several MDR bacteria with (A) length of stay, (B) mortality, and (C) cost of hospitalization. (Data from Sipahi, 2008) (ESBL, extended‐spectrum β‐lactamase; MDR, multidrug resistant; MRSA, methicillin‐resistant S aureus; MSSA, methicillin‐susceptible S aureus; VRE, vancomycin‐resistant Enterococcus; VSE, vancomycin‐susceptible Enterococcus.) aRepresents additional hospital days attributable to infection with MDR A baumannii, as determined in a multivariate model including all variables predictive of duration of hospitalization. bRepresents additional mean increase in hospitalization cost attributable to infections with a MDR‐resistant versus susceptible bacteria.

A number of factors can lead to the increased hospital costs associated with infection with a resistant or MDR bacteria. These include the need to use more expensive antibiotics, increased length of hospital stay, delayed appropriate antibiotic therapy, increased treatment toxicity (and costs associated with managing these toxicities), and increased frequency of surgical interventions required to control infection.25, 67

The savings that could be realized through reduction in antimicrobial resistance was evaluated recently by Roberts et al.68 Using a sensitivity analysis for a sample of high‐risk adult patients hospitalized in an urban public teaching hospital in 2000, the authors determined that reducing the antimicrobial‐resistant infection rate by 3.5% (from 13.5% to 10.0%) would have saved the study hospital $910,812 (in 2008 US$), when using lowest cost and length of stay figures. The calculated societal savings, for reduced mortality and lost productivity associated with the reduced antimicrobial‐resistant rate, was $1.8 million. Hence, the analysis showed a minimum overall medical (hospital) and societal savings of $2.7 million for this single hospital with a cohort of 1391 patients. The projected savings would be dramatically higher if the reduced antimicrobial‐resistant rate was generalized to all hospitals throughout the United States.

ORGANIZATIONAL AND GOVERNMENTAL EFFORTS ADDRESSING ANTIMICROBIAL RESISTANCE AND HAIs

Given the relationships between antimicrobial use and resistance, and between antimicrobial resistance and morbidity, mortality, length of hospital stay, and healthcare costs, it is not surprising that we have seen a variety of programs and initiatives begun by either government agencies or healthcare organizations aimed at reducing antimicrobial resistance and HAIs.

The Joint Commission

The Joint Commission is an independent, not‐for‐profit organization that accredits and certifies >18,000 healthcare organizations/programs in the United States.69 The Joint Commission issues annual National Patient Safety Goals (NPSG). Hospital compliance with these goals is a critical component of the accreditation process.70

The seventh goal of The Joint Commission's NPSG is to reduce the risk of HAIs,70 the key features of which are listed in Table 2. The methodology recommended to achieve compliance includes infection control programs and implementation of evidence‐based practices to prevent HAIs due to MDR microorganisms in acute‐care hospitals. This presumably could include development and implementation of an institutional antimicrobial stewardship, or components of a program, to reduce antimicrobial resistance within the hospital.

National Patient Safety Goals (NPSG)
Goal 7: Reduce the Risk of Healthcare‐Associated Infections

  • NOTE: Available at: http://www.jointcommission.org/npsg_7_healthcare‐associated_infections_webinar/

NPSG.07.03.01
Implement evidence‐based practices to prevent healthcare‐associated infections due to multidrug‐resistant organisms in acute‐care hospitals
Note: This requirement applies to, but is not limited to, epidemiologically important organisms such as methicillin‐resistant Staphylococcus aureus, Clostridium difficile, vancomycin‐resistant enterococci (VRE), and multidrug‐resistant Gram‐negative bacteria
NPSG.07.04.01
Implement evidence‐based practices to prevent central line‐associated bloodstream infection
Note: This requirement covers short‐ and long‐term central venous catheters and peripherally inserted central catheter (PICC) lines

Centers for Medicare and Medicaid Services

The Deficit Reduction Act of 2005, Section 5001(c), requires the Secretary of Health and Human Services to identify conditions that are: (1) high cost or high volume, or both; (2) result in assignment of a case to a diagnosis‐related group that has higher payment when the code is present as a secondary diagnosis; and (3) could reasonably have been prevented through application of evidence‐based guidelines.71 The Centers for Medicare and Medicaid Services (CMS), which develops and administers Medicare and Medicaid payment and coverage policies, encourages hospitals to reduce the occurrence of these preventable problems through reduced payments when these events occur. Among the Hospital Acquired Conditions (HAC) that CMS considers reasonably preventable are a number of HAIs, particularly CAUTI, vascular catheter‐associated infections, and various surgery‐related SSTIs. Importantly, the CMS policy is still in effect as of April 2011, and there are no signs of its being repealed or modified in the foreseeable future.

The CDC Get Smart and Get Smart for Healthcare Programs

The Get Smart campaign, initiated by the CDC in 1995, focused on providing information to parents about the appropriate and inappropriate use of antibiotics to treat common childhood infections, as well as about the dangers of antibiotic resistance.72 The goal of Get Smart is to reduce unnecessary antibiotic use and the spread of antibiotic resistance in the community by reducing the pressure exerted by parents on physicians to overuse or misuse antibiotics. Hence, the primary focus in this setting is on patient/parent education. The Get Smart campaign has been highly successful, with a significant reduction in antibiotic prescriptions after initiation of the campaign, across a range of infections for which antibiotics are generally or often not warranted.73 The success of Get Smart is also largely responsible for the improvement in antibiotic prescribing for childhood middle ear infections observed in the CDC Healthy People 2010 program.74 The actual performance achieved in 2007 (the latest year reported) exceeded the Healthy People 2010 target.75

Building on the success of Get Smart for community‐acquired infections, a similar CDC campaign (Get Smart for Healthcare) has been undertaken to improve antibiotic usage and reduce antibiotic resistance in inpatient healthcare facilities.76 The specific goals of Get Smart for Healthcare are to improve patient safety through better treatment of infections, reduce emergence of antimicrobial‐resistant pathogens and C difficile, and heighten awareness of the challenges posed by antimicrobial resistance in healthcare settings. To help accomplish these ends, the CDC has partnered with the Institute for Healthcare Improvement (IHI), an independent, not‐for‐profit organization dedicated to closing the gap between the healthcare that currently exists and the healthcare that should exist.77 Together, they have identified a number of primary drivers to improve antibiotic use: timely and appropriate initiation of antibiotics; appropriate administration and de‐escalation; data monitoring and transparency; and improving knowledge of, and engagement in, antimicrobial stewardship efforts, which are the focus of the next section. With respect to data monitoring, many in the healthcare community hope that, through the Get Smart program, we will soon have better sources of data, not just for the ICU, but across the entire hospital setting. This would help providers get a better sense of where resistance is located, thereby enabling better development of action plans to deal with the problem.

The CDC has recently expanded its Web site on antimicrobial stewardship, now providing extensive support and resources for program development and implementation at: http://www.cdc.gov/getsmart/healthcare/. In addition to urging the development of stewardship programs at all healthcare facilities, they propose 2 novel tools for use with every hospitalized patient who is prescribed antibiotics. According to the CDC78:

All Clinicians Should:

Dose, Duration, Indication

Too often antibiotics in hospitals are continued unnecessarily simply because clinicians caring for the patient do not have information indicating why the antibiotics were started initially or for how long they were to be continued. This challenge is compounded in today's healthcare system where primary responsibility for patient care is frequently transitioned from one clinician to another. Ensuring that all antibiotic orders are always accompanied by a dose, duration, and indication will help clinicians change or stop therapy when appropriate.

Get Cultures

Antibiotic therapy can be best optimized when it can be tailored to specific culture results. Knowing the susceptibility of the infecting organisms can lead to narrowing of broad‐spectrum therapy, changing therapy to better treat resistant pathogens and to stopping antibiotics when cultures suggest an infection is unlikely.

A number of other government initiatives have been developed to address the issues of HAIs, antimicrobial resistance, and improved antimicrobial stewardship. These are beyond the scope of the present article, but include the United States Department of Health and Human Services (HHS) action plan to prevent HAIs,79 and the CDC campaign and action plan to prevent and combat antimicrobial resistance,80, 81 among others.

ANTIMICROBIAL STEWARDSHIP IN HOSPITALS AND THE HOSPITALIST'S ROLE

As recently defined, antimicrobial stewardship is a system of personnel, informatics, data collection, and policy/procedures that promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use.20 In simple words, the right antibiotic, at the right dose, at the right time, and for the right duration. The primary goals of antimicrobial stewardship are to reduce patient morbidity and mortality, prevent or slow the emergence of antimicrobial resistance, and reduce adverse drug effects, including secondary infections, such as C difficile‐associated diarrhea.18, 20 Secondary goals include a reduction in hospital length of stay and healthcare expenditures, without adversely impacting quality of care. These goals are entirely in line with those of the hospitalist, who can play a critical role in the prevention and successful management of these infections. Optimal effects are expected when antimicrobial stewardship is combined with implementation of effective infection control measures within the hospital setting.

Antimicrobial Stewardship Strategies

Table 3 provides an overview of various general strategies/procedures employed as components of antimicrobial stewardship programs.82 The 2 most common are: (1) formulary restriction and preauthorization for specific agents; and (2) prospective audit with intervention and feedback.18, 20 Both approaches can and have been used to improve antimicrobial stewardship and to achieve at least some of its goals, and each is associated with advantages and disadvantages, as outlined in Table 3 and reviewed elsewhere.18, 20, 21, 83 Other strategies, such as education and use of guidelines and clinical pathways, tend to be used to supplement or complement either a general formulary restriction/preauthorization, or prospective audit/review and feedback approach to antimicrobial stewardship. It is important to note that, as in other areas such as venous thromboembolism prophylaxis, education alone is insufficient to drive changes in prescribing patterns and thereby reduce resistance. Healthcare informatics are increasingly being utilized to improve the management of infectious diseases. These can be simple programs that better assemble information about hospital‐pathogen epidemiology. They can also be sophisticated systems, designed to standardize the antimicrobial order sets and medical logic modules, that guide treatment options by connecting patient‐specific information with guideline recommendations and local resistance patterns.18, 20, 84, 85

Summary of Antimicrobial Stewardship Strategies
Strategy Procedure Personnel Advantages Disadvantages

  • NOTE: Adapted from MacDougall and Polk.82

Education/ guidelines Creation of guidelines for antimicrobial use Antimicrobial committee to create guidelines May alter behavior patterns Passive education likely ineffective
Group or individual education of clinicians by educators Educators (physicians, pharmacists) Avoids loss of prescriber autonomy
Formulary restriction Restrict dispensing of targeted antimicrobials to approved indications Antimicrobial committee to create guidelines Approval personnel (physician, infectious diseases fellow, clinical pharmacist) Most direct control over antimicrobial use Individual educational opportunities Perceived loss of autonomy for prescribers Need for all‐hours consultant availability
Review and feedback Daily review of targeted antimicrobials for appropriateness Contact prescribers with recommendations for alternative therapy Antimicrobial committee to create guidelines Review personnel (usually clinical pharmacist) Avoids loss of autonomy for prescribers Individual educational opportunities Compliance with recommendations
Computer assistance Use of information technology to implement previous strategies Antimicrobial committee to create rules for computer systems Provides patient‐specific data where most likely to impact care (point of care) Significant time and resource investment to implement sophisticated systems
Expert systems provide patient‐specific recommendations at point of entry (order entry) Personnel for approval or review (physicians, pharmacists) Computer programmers Facilitates other strategies

Two early, randomized, prospective studies illustrate the potential benefits and general receptiveness of clinicians to use of an audit/review and feedback approach to institutional antimicrobial stewardship. The first study randomized adult inpatients receiving 1 parenteral antibiotic for 3 days to an intervention (n = 141) or control group (n = 111).86 In the intervention group, a clinical pharmacist and infectious diseases fellow reviewed the initial therapy prescribed by the primary care physician and the patient's progress 3 days after therapy initiation, and at that point offered suggestions for subsequent antibiotic therapy. The feedback or suggestions were communicated via nonpermanent chart note. In total, 85% of the physicians implemented the suggestions, and there were no significant differences between the intervention and control group for clinical or microbiologic endpoints. However, per‐patient antibiotic charges were significantly lower in the intervention versus control group ($1287.17 vs $1673.97; P = 0.05), which yields an estimated $390,000 in annualized savings for the 600‐bed tertiary‐care hospital.

Similarly, a randomized, prospective study by Gums et al. showed that therapeutic intervention by a multidisciplinary antimicrobial team for inpatients receiving suboptimal intravenous antibiotic therapy was associated with a median hospital cost savings of $2642 per intervention, compared with costs for similar inpatients who did not receive such intervention.87 The multidisciplinary team in the study consisted of pharmacists, a clinical microbiologist, and an infectious diseases specialist, who provided the treating physician with recommendations of possible optimal antibiotics, dosages, and rationales based on timely, detailed reviews of relevant microbiologic and clinical data. In total, 89% of physicians in the study implemented the suggestions from the multidisciplinary antimicrobial team. In addition to reduced costs, the intervention versus control group was also associated with significant reductions in the overall length of stay (10.1 vs 14.5 days; P = 0.0001), and total non‐ICU length of stay (5.7 vs 9.0; P = 0.0001). There was no significant difference between the 2 groups for mortality rate.

The results from these studies86, 87 demonstrate how a prospective audit/review and feedback approach to antimicrobial stewardship can be associated with high physician participation and significant cost reductions for participating hospitals,88 and potentially improve patient outcomes. Antimicrobial stewardship programs overall have a long track record in improving patient outcomes and reducing antimicrobial resistance at the patient level.8991

The Hospitalist's Role in Antimicrobial Stewardship

Hospitalists can participate in antimicrobial stewardship at a number of levels. On the direct patient care level, they can consistently apply the principles of appropriate empiric therapy, de‐escalation, and duration of therapy as presented by Drs Snydman, Kaye, and File in this supplement. As hospitalists assume a continually increasing role in the care of hospitalized patients throughout the United States,92 they can directly influence the way medicine is practiced on a daily basis, patient by patient. A 2007 survey conducted by the American Hospital Association (AHA) showed that 58% of the 4897 community hospitals surveyed had hospital medicine programs, and that 83% of hospitals with 200 or more beds had such a program.93, 94 Estimates from the Society of Hospital Medicine (SHM) in July 2010 indicated that currently there were more than 30,000 hospitalists, practicing in 3300 large hospitals.95 This affords hospitalists the opportunity to improve care across a huge segment of hospitalized patients.

On a departmental or institutional level, hospitalists appear to be especially well positioned to contribute to, and in some cases direct, a hospital's antimicrobial stewardship program. Unique to hospital medicine, and incorporated into the definition of the profession, is the commitment to quality and process improvement, efficient use of hospital and healthcare resources, and an interdisciplinary approach to care.96 In line with this, hospitalists frequently serve on hospital committees and task forces, are experienced in developing and implementing clinical guidelines, and lead multidisciplinary teams to optimize patient care. For example, as reported in a recent review, a 2007 Pediatric Research in the Inpatient Setting survey of 208 pediatric hospitalists in the United States and Canada indicated that 92% spend at least some time in administration, 85% serve on hospital committees, and 61% and 52% lead initiatives in practice guidelines and quality improvement, respectively.97 Hospitalists are therefore especially well positioned to participate, and provide leadership, in hospital antimicrobial stewardship programs.

In 2007, the Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) released guidelines for developing institutional programs to enhance antimicrobial stewardship.18 According to these guidelines, the ideal institutional antimicrobial stewardship program contains an infectious diseases physician and clinical pharmacist with infectious diseases training as core members, along with a clinical microbiologist, an information system specialist, infection control professional, and a hospital epidemiologist. The infectious diseases physician and clinical pharmacist with infectious diseases training are expected to serve as leaders of the team and should be appropriately compensated for time dedicated to the program. Clearly, this is an extensive team requiring a lot of staff. Although optimal, many institutions do not have an infectious diseases physician on staff or an attending who is interested and willing to participate. For many institutions, an even bigger issue is identifying an infectious diseases pharmacist with sufficient skill to manage an antimicrobial stewardship program. As a consequence, many institutions wanting to develop an antimicrobial stewardship program to improve clinical outcomes, reduce antimicrobial resistance, and lower costs will need to think outside the box and look for nontraditional leaders to champion and lead their programs. Potential nontraditional leaders include general clinical pharmacists, intensivists, and hospitalists.98

Although hospitalists are not explicitly mentioned in the IDSA/SHEA guidelines, they seem to be implicitly included. The guidelines state that the development, maintenance, and ultimate success of such programs fundamentally depends on the support and collaboration of hospital administration, medical staff leadership, and local providers.18 Furthermore, they indicate the desirability for antimicrobial stewardship programs to function under the auspices of quality assurance and patient safety. As defined above, these are characteristics that are inherent to hospital medicine. Hence, there appears to be a good match between the activities performed by hospitalists and what the 2007 guidelines indicate is important for an effective antimicrobial stewardship program.

Now is the time for individuals to begin thinking about how best to prepare hospitalists for leadership roles in hospital antimicrobial stewardship programs. We need a well‐defined process for either training hospitalists for independent establishment of stewardship programs or establishing partnership with infectious disease specialists for the development of these programs. We need high‐level training programs in focused areas of infectious diseases that hospitalists encounter frequently (skin and skin‐structure infections, pneumonia, catheter‐associated infections, among others). Detailed understanding of the pathogens and their optimal treatment could form the core of such training. Additional education in infection control and the antimicrobial stewardship processes would round out the knowledge needed for a hospitalist to best implement and provide leadership for an antimicrobial stewardship program at his/her own institution. These training programs could be developed and delivered locally, or preferably they could be provided at national training sessions developed and supported through SHM, infectious disease societies, or the CDC.

Partnering with infectious diseases specialists is essential for protocol development and clinical support. This could allow the hospitalist to start a stewardship program on a small scale. It begins with identifying a single important problematic infection area, based on available local data (antibiotic usage, resistance levels, length of stay, C difficile rates, mortality, etc). The hospitalist would then work with the infectious disease department/staff to establish a protocol focusing on several of the key areas: diagnosis, optimal empiric therapy, de‐escalation (based on cultures and clinical response), transitioning intravenous antibiotics to oral, optimal duration of therapy, and transitioning therapy to the posthospital setting. The protocol would establish best treatment practices and the strategies to implement them (education, standardized order sets, computer decision support, monitoring and feedback, etc). The level of complexity and targeted outcomes need to be tailored to the resources available for implementation. Successful implementation and goal achievement in a small area could then be used to justify additional resources to expand the program. If hospitalists can be engaged in antimicrobial stewardship, both through individual patient care as well as program development, the large and growing number of hospitalists throughout the United States should allow for widespread implementation of antimicrobial stewardship programs.

CONCLUSIONS

Healthcare‐associated infections are increasingly a cause of morbidity and mortality in the United States and other countries, and the management of HAIs is increasingly complicated by involvement of MDR pathogens. Antimicrobial‐resistant pathogens are also increasingly involved in infections occurring outside the hospital setting. Infections caused by resistant or MDR pathogens are associated with increased mortality, longer length of hospital stay, and higher healthcare costs. The prevalence of these dangerous bacteria affects antimicrobial choices across a wider range of patients, particularly when choosing empiric therapy. Together with infection control, antimicrobial stewardship is an attractive solution to the challenges posed by antimicrobial resistance. Development and implementation of an effective institutional antimicrobial stewardship program can improve clinical outcome, reduce antimicrobial resistance and other unintended consequences of antimicrobial overuse/misuse, and lower healthcare costs.

At the forefront of inpatient care, hospitalists are positioned as excellent champions of the principles and practices of antimicrobial stewardship. By adhering to the principles of optimal antimicrobial therapy in their clinical practice, hospitalists can improve care and help reduce resistance on a patient‐by‐patient basis. At the same time, they may achieve other key hospitalist goals by reducing length of stay and decreasing costs and utilization. Moreover, they are well positioned to participate in, and at times lead, hospital‐based antimicrobial stewardship programs. As such, hospitalists are expected to play a critical role in helping to solve the problems of antimicrobial resistance and suboptimal inpatient care, as we move further into the 21st century.

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References
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  27. Naas T,Nordmann P,Vedel G,Poyart C.Plasmid‐mediated carbapenem‐hydrolyzing beta‐lactamase KPC in a Klebsiella pneumoniae isolate from France.Antimicrob Agents Chemother.2005;49:4423–4424.
  28. Akpaka PE,Swanston WH,Ihemere HN, et al.Emergence of KPC‐producing Pseudomonas aeruginosa in Trinidad and Tobago.J Clin Microbiol.2009;47:2670–2671.
  29. Navon‐Venezia S,Leavitt A,Schwaber MJ, et al.First report on a hyperepidemic clone of KPC‐3‐producing Klebsiella pneumoniae in Israel genetically related to a strain causing outbreaks in the United States.Antimicrob Agents Chemother.2009;53:818–820.
  30. Nordmann P,Cuzon G,Naas T.The real threat of Klebsiella pneumoniae carbapenemase‐producing bacteria.Lancet Infect Dis.2009;9:228–236.
  31. Moran GJ,Krishnadasan A,Gorwitz RJ, et al.Methicillin‐resistant S. aureus infections among patients in the emergency department.N Engl J Med.2006;355:666–674.
  32. Klevens RM,Morrison MA,Nadle J, et al.Invasive methicillin‐resistant Staphylococcus aureus infections in the United States.JAMA.2007;298:1763–1771.
  33. Jenkins TC,McCollister BD,Sharma R, et al.Epidemiology of healthcare‐associated bloodstream infection caused by USA300 strains of methicillin‐resistant Staphylococcus aureus in 3 affiliated hospitals.Infect Control Hosp Epidemiol.2009;30:233–241.
  34. Klein E,Smith DL,Laxminarayan R.Community‐associated methicillin‐resistant Staphylococcus aureus in outpatients, United States, 1999‐2006.Emerg Infect Dis.2009;15:1925–1930.
  35. Maree CL,Daum RS,Boyle‐Vavra S,Matayoshi K,Miller LG.Community‐associated methicillin‐resistant Staphylococcus aureus isolates causing healthcare‐associated infections.Emerg Infect Dis.2007;13:236–242.
  36. Park SH,Park C,Yoo JH, et al.Emergence of community‐associated methicillin‐resistant Staphylococcus aureus strains as a cause of healthcare‐associated bloodstream infections in Korea.Infect Control Hosp Epidemiol.2009;30:146–155.
  37. Popovich KJ,Weinstein RA,Hota B.Are community‐associated methicillin‐resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains?Clin Infect Dis.2008;46:787–794.
  38. Seybold U,Kourbatova EV,Johnson JG, et al.Emergence of community‐associated methicillin‐resistant Staphylococcus aureus USA300 genotype as a major cause of health care‐associated bloodstream infections.Clin Infect Dis.2006;42:647–656.
  39. Riddle DJ,Dubberke ER.Clostridium difficile infection in the intensive care unit.Infect Dis Clin North Am.2009;23:727–743.
  40. Vaishnavi C.Established and potential risk factors for Clostridum difficile infection.Indian J Med Microbiol.2009;27:289–300.
  41. Ricciardi R,Rothenberger DA,Madoff RD,Baxter NN.Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States.Arch Surg.2007;142:624–631.
  42. Zilberberg MD,Shorr AF,Kollef MH.Increase in adult Clostridium difficile‐related hospitalizations and case‐fatality rate, United States, 2000‐2005.Emerg Infect Dis.2008;14:929–931.
  43. Zilberberg MD,Shorr AF,Kollef MH.Increase in Clostridium difficile‐related hospitalizations among infants in the United States, 2000‐2005.Pediatr Infect Dis J.2008;27:1111–1113.
  44. Kyne L,Hamel MB,Polavaram R,Kelly CP.Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile.Clin Infect Dis.2002;34:346–353.
  45. Cohen SH,Gerding DN,Johnson S, et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol.2010;31:431–455.
  46. Hsu J,Abad C,Dinh M,Safdar N.Prevention of endemic healthcare‐associated Clostridium difficile infection: reviewing the evidence.Am J Gastroenterol.2010;105:2327–2340.
  47. Loo VG,Poirier L,Miller MA, et al.A predominantly clonal multi‐institutional outbreak of Clostridium difficile‐associated diarrhea with high morbidity and mortality.N Engl J Med.2005;353:2442–2449.
  48. Salgado CD,Mauldin PD,Fogle PJ,Bosso JA.Analysis of an outbreak of Clostridium difficile infection controlled with enhanced infection control measures.Am J Infect Control.2009;37:458–464.
  49. Weiss K,Boisvert A,Chagnon M, et al.Multipronged intervention strategy to control an outbreak of Clostridium difficile infection (CDI) and its impact on the rates of CDI from 2002 to 2007.Infect Control Hosp Epidemiol.2009;30:156–162.
  50. Climo MW,Israel DS,Wong ES,Williams D,Coudron P,Markowitz SM.Hospital‐wide restriction of clindamycin: effect on the incidence of Clostridium difficile‐associated diarrhea and cost.Ann Intern Med.1998;128:989–995.
  51. Fowler S,Webber A,Cooper BS, et al.Successful use of feedback to improve antibiotic prescribing and reduce Clostridium difficile infection: a controlled interrupted time series.J Antimicrob Chemother.2007;59:990–995.
  52. Khan R,Cheesbrough J.Impact of changes in antibiotic policy on Clostridium difficile‐associated diarrhoea (CDAD) over a five‐year period in a district general hospital.J Hosp Infect.2003;54:104–108.
  53. Ludlam H,Brown N,Sule O,Redpath C,Coni N,Owen G.An antibiotic policy associated with reduced risk of Clostridium difficile‐associated diarrhoea.Age Ageing.1999;28:578–580.
  54. O'Connor KA,Kingston M,O'Donovan M,Cryan B,Twomey C,O'Mahony D.Antibiotic prescribing policy and Clostridium difficile diarrhoea.Q J Med.2004;97:423–429.
  55. Valiquette L,Cossette B,Garant MP,Diab H,Pepin J.Impact of a reduction in the use of high‐risk antibiotics on the course of an epidemic of Clostridium difficile‐associated disease caused by the hypervirulent NAP1/027 strain.Clin Infect Dis.2007;45(suppl 2):S112–S121.
  56. Stone PW.Economic burden of healthcare‐associated infections: an American perspective.Expert Rev Pharmacoecon Outcomes Res.2009;9:417–422.
  57. Scott RD.The Direct Medical Costs of Healthcare‐Associated Infections in US Hospitals and the Benefits of Prevention. Division of Healthcare Quality Promotion, National Center for Preparedness, Detection, and Control of Infectious Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention. Polock DA, Stone PW, eds.London, UK:Economist;2009.
  58. Aloush V,Navon‐Venezia S,Seigman‐Igra Y,Cabili S,Carmeli Y.Multidrug‐resistant Pseudomonas aeruginosa: risk factors and clinical impact.Antimicrob Agents Chemother.2006;50:43–48.
  59. Cosgrove SE,Qi Y,Kaye KS,Harbarth S,Karchmer AW,Carmeli Y.The impact of methicillin resistance in Staphylococcus aureus bacteremia on patient outcomes: mortality, length of stay, and hospital charges.Infect Control Hosp Epidemiol.2005;26:166–174.
  60. Kwon KT,Oh WS,Song JH, et al.Impact of imipenem resistance on mortality in patients with Acinetobacter bacteraemia.J Antimicrob Chemother.2007;59:525–530.
  61. Lautenbach E,Patel JB,Bilker WB,Edelstein PH,Fishman NO.Extended‐spectrum beta‐lactamase‐producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes.Clin Infect Dis.2001;32:1162–1171.
  62. Lodise TP,McKinnon PS.Clinical and economic impact of methicillin resistance in patients with Staphylococcus aureus bacteremia.Diagn Microbiol Infect Dis.2005;52:113–122.
  63. Schwaber MJ,Navon‐Venezia S,Kaye KS,Ben‐Ami R,Schwartz D,Carmeli Y.Clinical and economic impact of bacteremia with extended‐spectrum‐beta‐lactamase‐producing Enterobacteriaceae.Antimicrob Agents Chemother.2006;50:1257–1262.
  64. Vergis EN,Hayden MK,Chow JW, et al.Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia: a prospective multicenter study.Ann Intern Med.2001;135:484–492.
  65. Wilson SJ,Knipe CJ,Zieger MJ, et al.Direct costs of multidrug‐resistant Acinetobacter baumannii in the burn unit of a public teaching hospital.Am J Infect Control.2004;32:342–344.
  66. Young LS,Sabel AL,Price CS.Epidemiologic, clinical, and economic evaluation of an outbreak of clonal multidrug‐resistant Acinetobacter baumannii infection in a surgical intensive care unit.Infect Control Hosp Epidemiol.2007;28:1247–1254.
  67. Cosgrove SE.The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs.Clin Infect Dis.2006;42(suppl 2):S82–S89.
  68. Roberts RR,Hota B,Ahmad I, et al.Hospital and societal costs of antimicrobial‐resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship.Clin Infect Dis.2009;49:1175–1184.
  69. The Joint Commission. About The Joint Commission. Available at: http://www.jointcommission.org/facts_about_the_joint_commission/. Accessed March 29,2011.
  70. The Joint Commission. Accreditation Program: Hospital. National Patient Safety Goals. Effective January 1, 2011. Available at: http://www.jointcommission.org/assets/1/6/2011_NPSGs_HAP.pdf. Accessed January 24,2011.
  71. Deficit Reduction Act. Sec. 5001. Hospital Quality Improvement. Available at: http://www.cms.gov/HospitalAcqCond/Downloads/DeficitReductionAct2005. pdf. Accessed March 29,2011.
  72. Centers for Disease Control and Prevention (CDC). Get Smart: Know When Antibiotics Work. Available at: http://www.cdc.gov/getsmart/. Accessed March 30,2011.
  73. Centers for Disease Control and Prevention (CDC). National Ambulatory Medical Care Survey. Available at: http://www.cdc.gov/nchs/ahcd. Accessed March 30,2011.
  74. Centers for Disease Control and Prevention (CDC). About Healthy People 2010. Available at: http://www.cdc.gov/nchs/healthy_people/hp2010.htm. Accessed March 30,2011.
  75. Centers for Disease Control and Prevention (CDC). DATA2010…the Healthy People 2010 Database. Available at: http://wonder.cdc.gov/DATA2010/ by searching for antibiotic. Accessed March 30,2011.
  76. Centers for Disease Control and Prevention (CDC). Get Smart for Healthcare. Available at: http://www.cdc.gov/getsmart/healthcare/. Accessed March 29,2011.
  77. The Institute for Healthcare Improvement (IHI). About IHI. Available at: http://www.ihi.org/ihi/about. Accessed March 29,2011.
  78. Centers for Disease Control and Prevention (CDC). Get Smart for Healthcare: All Clinicians Should…. Available at: http://www. cdc.gov/getsmart/healthcare/improve‐efforts/clinicians.html. Accessed May 3,2011.
  79. United States Department of Health 18:638–656.
  80. Owens RC.Antimicrobial stewardship: application in the intensive care unit.Infect Dis Clin North Am.2009;23:683–702.
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  84. Gums JG,Yancey RW,Hamilton CA,Kubilis PS.A randomized, prospective study measuring outcomes after antibiotic therapy intervention by a multidisciplinary consult team.Pharmacotherapy.1999;19:1369–1377.
  85. Centers for Disease Control and Prevention (CDC). Get Smart for Healthcare: Impact of Antibiotic Stewardship Program Interventions on Costs. Available at: http://www.cdc.gov/getsmart/healthcare/support‐efforts/asp‐int‐costs.html. Accessed May 3,2011.
  86. Carling P,Fung T,Killion A,Terrin N,Barza M.Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years.Infect Control Hosp Epidemiol.2003;24:699–706.
  87. Singh N,Rogers P,Atwood CW,Wagener MM,Yu VL.Short‐course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription.Am J Respir Crit Care Med.2000;162:505–511.
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  89. Kuo YF,Sharma G,Freeman JL,Goodwin JS.Growth in the care of older patients by hospitalists in the United States.N Engl J Med.2009;360:1102–1112.
  90. Society of Hospital Medicine (SHM). Information About SHM and Hospitalists. Available at: http://www.hospitalmedicine.org/. Accessed April 1,2011.
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  92. Srinivasan A.Engaging hospitalists in antimicrobial stewardship: the CDC perspective.J Hosp Med.2011;6(suppl 1):S31–S33.
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Healthcare‐associated infections (HAIs) are important causes of morbidity and mortality in the United States and other countries.13 Moreover, treatment of HAIs is frequently complicated by involvement of bacterial pathogens resistant to 1 or more antibiotics or antibiotic classes,4 and sometimes bacteria resistant to all or nearly all currently available agents.57 The rapid emergence of resistant bacteria both in and out of the hospital setting can affect empiric antimicrobial choices across all patients. The effort to avoid undertreating or not covering resistant bacteria can lead to overuse of wide‐spectrum antimicrobials. Antimicrobial useand especially antimicrobial overuse or misusehas been linked with increased antimicrobial resistance,817 leading to worsened clinical outcomes with increased length of hospital stay and healthcare costs. Table 1 defines the various lines of evidence supporting a causal relationship between antibiotic use and emergence of antimicrobial resistance.18, 19

Observations That Support Causal Associations Between Antimicrobial Use and Emergence of Antimicrobial Resistance

  • NOTE: Adapted from Dellit et al.18

Changes in antimicrobial use are paralleled by changes in the prevalence of resistance
Antimicrobial resistance is more prevalent in healthcare‐associated bacterial infections vs community‐acquired infections
Patients with healthcare‐associated infections caused by resistant strains are more likely than control patients to have received prior antimicrobials
Areas within hospitals that have the highest rates of antimicrobial resistance also have the highest rates of antimicrobial use
Increasing duration of patient exposure to antimicrobials increases the likelihood of colonization with resistant organisms

Optimal management of patients with bacterial infections, both HAIs and those that originate in the community, involves a focus on treatment that maximizes clinical outcomes for the individual patient, while also inhibiting or slowing the development of antimicrobial resistance and its spread to other patients. Antimicrobial stewardship is a term describing the various clinical strategies that have been devised to maximize the benefits and minimize the costs of antimicrobial therapy through judicious use of these agents.18, 20, 21 This article examines the developing patterns of resistance among key bacterial pathogens in the hospital and associated healthcare settings, the costs associated with HAIs (specifically, those caused by resistant pathogens), and the various strategies or programs that have been developed by governmental agencies, individual healthcare institutions, and other organizations to optimize the use of antibiotics to improve patient outcomes and minimize healthcare costs. The value that the hospitalist can bring to the development and/or implementation of institutional antimicrobial stewardship programs is explored.

ANTIMICROBIAL RESISTANCE AND HAI TRENDS FOR KEY BACTERIAL PATHOGENS

Bacterial pathogens including Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp, Escherichia coli, and Proteus spp, among others), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium22, 23 are increasingly prevalent in healthcare settings, and particularly troublesome to manage due to increasing resistance. Data from the Centers for Disease Control and Prevention's (CDC) National Healthcare Safety Network (NHSN) have shown that, in intensive care units (ICUs), 16% of HAIs are due to multidrug‐resistant (MDR) pathogens.4 These 16% have the highest mortality and length of hospital stay, and are associated with the highest healthcare costs.24, 25 Infections caused by MDR pathogens are more important than their actual numbers, because treatment decisions are driven by the intent to cover these MDR pathogens, even if that means providing excessively broad coverage for most patients. Moreover, the 16% mentioned above are only the tip of the iceberg, as many more HAIs will occur outside of the ICU, particularly catheter‐associated urinary tract infections (CAUTI) and surgical site infections, as these patients are often not sick enough to require ICU care. There is little information on the prevalence of HAIs outside of the ICU setting, the role of MDR bacteria in these infections, and the associated costs, mortality, and effects on length of stay.

K pneumoniae Carbapenemases and Community‐Acquired Methicillin‐Resistant Staphylococcus aureus

K pneumoniae carbapenemase (KPC) is a prime example of the emergence and rapid spread of a new resistance pattern that affects prescribing patterns. Emergence of KPC as the primary source of carbapenem resistance in Enterobacteriaceae26 is critically significant, as carbapenems are recommended first‐line therapy for serious infections caused by extended‐spectrum ‐lactamase (ESBL)‐producing K pneumoniae or other Enterobacteriaceae. One particularly remarkable fact about KPC‐producing bacteria is the speed at which they have spread since first emerging. Figure 1 from the CDC illustrates the rapid spread of KPC‐producing bacteria within the United States, from winter 2008 to May 2010. International spread has also been rapid and extensive. The first case of a KPC‐producing bacteria outside the United States was reported in France in February 2005, in an 80‐year‐old man who was admitted to a Parisian hospital 2 to 3 months after having a medical procedure performed in a New York City hospital, suggesting intercontinental transfer from the United States.27 Since then, KPC‐producing pathogenic bacteria have been identified in the Caribbean, South America, Europe, Israel, and China.2830 It is clear that once resistant bacteria emerge, they have the potential to spread very rapidly within and between countries, challenging currently available antimicrobial agents and complicating the treatment of serious infections.

Figure 1
Rapid spread of Klebsiella pneumoniae carbapenemase‐producing bacteria within the United States, from winter 2008 to May 2010. (CDC unpublished data).

Consideration of S aureus skin and skin‐structure infections highlights the fact that the barrier between hospital and community is now beginning to be crossed, further complicating prescribing decisions. The classic risk factors for resistance may no longer be reliable in determining best empiric treatment. In a landmark study, Moran et al. demonstrated the large percentages of outpatients in the United States with skin or soft‐tissue infections (SSTIs) involving community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA).31 S aureus was isolated from 76% (320/422) of adults presenting to 11 university‐affiliated emergency departments with acute, purulent SSTIs in August 2004, 59% of whom were infected with MRSA. More than half the patients in the study (57%) were initially treated with antibiotics to which MRSA isolates were not susceptible.31 In the hospital, it has been shown that most invasive MRSA infections now actually have their onset outside of the healthcare setting,32 and that increasing numbers of hospitalized patients are now developing infections associated with CA‐MRSA strains >72 hours after admission.3338 Thus, it is becoming increasingly difficult to determine whether an invasive S aureus infection encountered in either a healthcare facility or community setting involves a sensitive organism, healthcare‐associated MRSA, or a CA‐MRSA pathogen, directly impacting treatment choices across all patients we care for with skin and skin‐structure infections.

Clostridium difficile‐Associated Disease

Indiscriminate and unnecessary use of antibiotics offer our patients no benefit, while exposing them to adverse effects of antibiotics, including allergies, rashes, and diarrhea among many potential other unintended consequences. C difficile‐associated disease is an increasingly problematic pathogen in the hospital setting that has been linked to unintended antibiotic effects.22, 39, 40 C difficile infection is not only costly in dollars, it is also a potentially fatal condition and has been linked to prolonged hospital stays and increased healthcare costs.4144 Improved infection control measures4549 and better use of antibiotics through antibiotic stewardship programs5055 have been shown to reduce the incidence of C difficile infection.

COSTS OF HAIs AND ANTIMICROBIAL RESISTANCE

HAIs are an important and growing problem in the United States.56 Klevens et al. estimated that approximately 1.7 million individuals hospitalized in the United States in 2002 had HAI, leading to 98,987 deaths.1 Estimates of annual hospital costs in the United States related to HAIs range from $28 to $48 billion.57 Antimicrobial resistance is a major driver of mortality, increased length of hospital stay, and hospital costs associated with HAIs.24, 25 A recent review by Sipahi25 summarizes recent studies examining the impact of resistant and MDR bacterial infections (Figure 2).5866 It is dramatically clear that infections due to resistant and MDR bacteria more often result in death, are associated with longer hospital stays, and are considerably more expensive to treat.

Figure 2
Association of multidrug resistance of several MDR bacteria with (A) length of stay, (B) mortality, and (C) cost of hospitalization. (Data from Sipahi, 2008) (ESBL, extended‐spectrum β‐lactamase; MDR, multidrug resistant; MRSA, methicillin‐resistant S aureus; MSSA, methicillin‐susceptible S aureus; VRE, vancomycin‐resistant Enterococcus; VSE, vancomycin‐susceptible Enterococcus.) aRepresents additional hospital days attributable to infection with MDR A baumannii, as determined in a multivariate model including all variables predictive of duration of hospitalization. bRepresents additional mean increase in hospitalization cost attributable to infections with a MDR‐resistant versus susceptible bacteria.

A number of factors can lead to the increased hospital costs associated with infection with a resistant or MDR bacteria. These include the need to use more expensive antibiotics, increased length of hospital stay, delayed appropriate antibiotic therapy, increased treatment toxicity (and costs associated with managing these toxicities), and increased frequency of surgical interventions required to control infection.25, 67

The savings that could be realized through reduction in antimicrobial resistance was evaluated recently by Roberts et al.68 Using a sensitivity analysis for a sample of high‐risk adult patients hospitalized in an urban public teaching hospital in 2000, the authors determined that reducing the antimicrobial‐resistant infection rate by 3.5% (from 13.5% to 10.0%) would have saved the study hospital $910,812 (in 2008 US$), when using lowest cost and length of stay figures. The calculated societal savings, for reduced mortality and lost productivity associated with the reduced antimicrobial‐resistant rate, was $1.8 million. Hence, the analysis showed a minimum overall medical (hospital) and societal savings of $2.7 million for this single hospital with a cohort of 1391 patients. The projected savings would be dramatically higher if the reduced antimicrobial‐resistant rate was generalized to all hospitals throughout the United States.

ORGANIZATIONAL AND GOVERNMENTAL EFFORTS ADDRESSING ANTIMICROBIAL RESISTANCE AND HAIs

Given the relationships between antimicrobial use and resistance, and between antimicrobial resistance and morbidity, mortality, length of hospital stay, and healthcare costs, it is not surprising that we have seen a variety of programs and initiatives begun by either government agencies or healthcare organizations aimed at reducing antimicrobial resistance and HAIs.

The Joint Commission

The Joint Commission is an independent, not‐for‐profit organization that accredits and certifies >18,000 healthcare organizations/programs in the United States.69 The Joint Commission issues annual National Patient Safety Goals (NPSG). Hospital compliance with these goals is a critical component of the accreditation process.70

The seventh goal of The Joint Commission's NPSG is to reduce the risk of HAIs,70 the key features of which are listed in Table 2. The methodology recommended to achieve compliance includes infection control programs and implementation of evidence‐based practices to prevent HAIs due to MDR microorganisms in acute‐care hospitals. This presumably could include development and implementation of an institutional antimicrobial stewardship, or components of a program, to reduce antimicrobial resistance within the hospital.

National Patient Safety Goals (NPSG)
Goal 7: Reduce the Risk of Healthcare‐Associated Infections

  • NOTE: Available at: http://www.jointcommission.org/npsg_7_healthcare‐associated_infections_webinar/

NPSG.07.03.01
Implement evidence‐based practices to prevent healthcare‐associated infections due to multidrug‐resistant organisms in acute‐care hospitals
Note: This requirement applies to, but is not limited to, epidemiologically important organisms such as methicillin‐resistant Staphylococcus aureus, Clostridium difficile, vancomycin‐resistant enterococci (VRE), and multidrug‐resistant Gram‐negative bacteria
NPSG.07.04.01
Implement evidence‐based practices to prevent central line‐associated bloodstream infection
Note: This requirement covers short‐ and long‐term central venous catheters and peripherally inserted central catheter (PICC) lines

Centers for Medicare and Medicaid Services

The Deficit Reduction Act of 2005, Section 5001(c), requires the Secretary of Health and Human Services to identify conditions that are: (1) high cost or high volume, or both; (2) result in assignment of a case to a diagnosis‐related group that has higher payment when the code is present as a secondary diagnosis; and (3) could reasonably have been prevented through application of evidence‐based guidelines.71 The Centers for Medicare and Medicaid Services (CMS), which develops and administers Medicare and Medicaid payment and coverage policies, encourages hospitals to reduce the occurrence of these preventable problems through reduced payments when these events occur. Among the Hospital Acquired Conditions (HAC) that CMS considers reasonably preventable are a number of HAIs, particularly CAUTI, vascular catheter‐associated infections, and various surgery‐related SSTIs. Importantly, the CMS policy is still in effect as of April 2011, and there are no signs of its being repealed or modified in the foreseeable future.

The CDC Get Smart and Get Smart for Healthcare Programs

The Get Smart campaign, initiated by the CDC in 1995, focused on providing information to parents about the appropriate and inappropriate use of antibiotics to treat common childhood infections, as well as about the dangers of antibiotic resistance.72 The goal of Get Smart is to reduce unnecessary antibiotic use and the spread of antibiotic resistance in the community by reducing the pressure exerted by parents on physicians to overuse or misuse antibiotics. Hence, the primary focus in this setting is on patient/parent education. The Get Smart campaign has been highly successful, with a significant reduction in antibiotic prescriptions after initiation of the campaign, across a range of infections for which antibiotics are generally or often not warranted.73 The success of Get Smart is also largely responsible for the improvement in antibiotic prescribing for childhood middle ear infections observed in the CDC Healthy People 2010 program.74 The actual performance achieved in 2007 (the latest year reported) exceeded the Healthy People 2010 target.75

Building on the success of Get Smart for community‐acquired infections, a similar CDC campaign (Get Smart for Healthcare) has been undertaken to improve antibiotic usage and reduce antibiotic resistance in inpatient healthcare facilities.76 The specific goals of Get Smart for Healthcare are to improve patient safety through better treatment of infections, reduce emergence of antimicrobial‐resistant pathogens and C difficile, and heighten awareness of the challenges posed by antimicrobial resistance in healthcare settings. To help accomplish these ends, the CDC has partnered with the Institute for Healthcare Improvement (IHI), an independent, not‐for‐profit organization dedicated to closing the gap between the healthcare that currently exists and the healthcare that should exist.77 Together, they have identified a number of primary drivers to improve antibiotic use: timely and appropriate initiation of antibiotics; appropriate administration and de‐escalation; data monitoring and transparency; and improving knowledge of, and engagement in, antimicrobial stewardship efforts, which are the focus of the next section. With respect to data monitoring, many in the healthcare community hope that, through the Get Smart program, we will soon have better sources of data, not just for the ICU, but across the entire hospital setting. This would help providers get a better sense of where resistance is located, thereby enabling better development of action plans to deal with the problem.

The CDC has recently expanded its Web site on antimicrobial stewardship, now providing extensive support and resources for program development and implementation at: http://www.cdc.gov/getsmart/healthcare/. In addition to urging the development of stewardship programs at all healthcare facilities, they propose 2 novel tools for use with every hospitalized patient who is prescribed antibiotics. According to the CDC78:

All Clinicians Should:

Dose, Duration, Indication

Too often antibiotics in hospitals are continued unnecessarily simply because clinicians caring for the patient do not have information indicating why the antibiotics were started initially or for how long they were to be continued. This challenge is compounded in today's healthcare system where primary responsibility for patient care is frequently transitioned from one clinician to another. Ensuring that all antibiotic orders are always accompanied by a dose, duration, and indication will help clinicians change or stop therapy when appropriate.

Get Cultures

Antibiotic therapy can be best optimized when it can be tailored to specific culture results. Knowing the susceptibility of the infecting organisms can lead to narrowing of broad‐spectrum therapy, changing therapy to better treat resistant pathogens and to stopping antibiotics when cultures suggest an infection is unlikely.

A number of other government initiatives have been developed to address the issues of HAIs, antimicrobial resistance, and improved antimicrobial stewardship. These are beyond the scope of the present article, but include the United States Department of Health and Human Services (HHS) action plan to prevent HAIs,79 and the CDC campaign and action plan to prevent and combat antimicrobial resistance,80, 81 among others.

ANTIMICROBIAL STEWARDSHIP IN HOSPITALS AND THE HOSPITALIST'S ROLE

As recently defined, antimicrobial stewardship is a system of personnel, informatics, data collection, and policy/procedures that promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use.20 In simple words, the right antibiotic, at the right dose, at the right time, and for the right duration. The primary goals of antimicrobial stewardship are to reduce patient morbidity and mortality, prevent or slow the emergence of antimicrobial resistance, and reduce adverse drug effects, including secondary infections, such as C difficile‐associated diarrhea.18, 20 Secondary goals include a reduction in hospital length of stay and healthcare expenditures, without adversely impacting quality of care. These goals are entirely in line with those of the hospitalist, who can play a critical role in the prevention and successful management of these infections. Optimal effects are expected when antimicrobial stewardship is combined with implementation of effective infection control measures within the hospital setting.

Antimicrobial Stewardship Strategies

Table 3 provides an overview of various general strategies/procedures employed as components of antimicrobial stewardship programs.82 The 2 most common are: (1) formulary restriction and preauthorization for specific agents; and (2) prospective audit with intervention and feedback.18, 20 Both approaches can and have been used to improve antimicrobial stewardship and to achieve at least some of its goals, and each is associated with advantages and disadvantages, as outlined in Table 3 and reviewed elsewhere.18, 20, 21, 83 Other strategies, such as education and use of guidelines and clinical pathways, tend to be used to supplement or complement either a general formulary restriction/preauthorization, or prospective audit/review and feedback approach to antimicrobial stewardship. It is important to note that, as in other areas such as venous thromboembolism prophylaxis, education alone is insufficient to drive changes in prescribing patterns and thereby reduce resistance. Healthcare informatics are increasingly being utilized to improve the management of infectious diseases. These can be simple programs that better assemble information about hospital‐pathogen epidemiology. They can also be sophisticated systems, designed to standardize the antimicrobial order sets and medical logic modules, that guide treatment options by connecting patient‐specific information with guideline recommendations and local resistance patterns.18, 20, 84, 85

Summary of Antimicrobial Stewardship Strategies
Strategy Procedure Personnel Advantages Disadvantages

  • NOTE: Adapted from MacDougall and Polk.82

Education/ guidelines Creation of guidelines for antimicrobial use Antimicrobial committee to create guidelines May alter behavior patterns Passive education likely ineffective
Group or individual education of clinicians by educators Educators (physicians, pharmacists) Avoids loss of prescriber autonomy
Formulary restriction Restrict dispensing of targeted antimicrobials to approved indications Antimicrobial committee to create guidelines Approval personnel (physician, infectious diseases fellow, clinical pharmacist) Most direct control over antimicrobial use Individual educational opportunities Perceived loss of autonomy for prescribers Need for all‐hours consultant availability
Review and feedback Daily review of targeted antimicrobials for appropriateness Contact prescribers with recommendations for alternative therapy Antimicrobial committee to create guidelines Review personnel (usually clinical pharmacist) Avoids loss of autonomy for prescribers Individual educational opportunities Compliance with recommendations
Computer assistance Use of information technology to implement previous strategies Antimicrobial committee to create rules for computer systems Provides patient‐specific data where most likely to impact care (point of care) Significant time and resource investment to implement sophisticated systems
Expert systems provide patient‐specific recommendations at point of entry (order entry) Personnel for approval or review (physicians, pharmacists) Computer programmers Facilitates other strategies

Two early, randomized, prospective studies illustrate the potential benefits and general receptiveness of clinicians to use of an audit/review and feedback approach to institutional antimicrobial stewardship. The first study randomized adult inpatients receiving 1 parenteral antibiotic for 3 days to an intervention (n = 141) or control group (n = 111).86 In the intervention group, a clinical pharmacist and infectious diseases fellow reviewed the initial therapy prescribed by the primary care physician and the patient's progress 3 days after therapy initiation, and at that point offered suggestions for subsequent antibiotic therapy. The feedback or suggestions were communicated via nonpermanent chart note. In total, 85% of the physicians implemented the suggestions, and there were no significant differences between the intervention and control group for clinical or microbiologic endpoints. However, per‐patient antibiotic charges were significantly lower in the intervention versus control group ($1287.17 vs $1673.97; P = 0.05), which yields an estimated $390,000 in annualized savings for the 600‐bed tertiary‐care hospital.

Similarly, a randomized, prospective study by Gums et al. showed that therapeutic intervention by a multidisciplinary antimicrobial team for inpatients receiving suboptimal intravenous antibiotic therapy was associated with a median hospital cost savings of $2642 per intervention, compared with costs for similar inpatients who did not receive such intervention.87 The multidisciplinary team in the study consisted of pharmacists, a clinical microbiologist, and an infectious diseases specialist, who provided the treating physician with recommendations of possible optimal antibiotics, dosages, and rationales based on timely, detailed reviews of relevant microbiologic and clinical data. In total, 89% of physicians in the study implemented the suggestions from the multidisciplinary antimicrobial team. In addition to reduced costs, the intervention versus control group was also associated with significant reductions in the overall length of stay (10.1 vs 14.5 days; P = 0.0001), and total non‐ICU length of stay (5.7 vs 9.0; P = 0.0001). There was no significant difference between the 2 groups for mortality rate.

The results from these studies86, 87 demonstrate how a prospective audit/review and feedback approach to antimicrobial stewardship can be associated with high physician participation and significant cost reductions for participating hospitals,88 and potentially improve patient outcomes. Antimicrobial stewardship programs overall have a long track record in improving patient outcomes and reducing antimicrobial resistance at the patient level.8991

The Hospitalist's Role in Antimicrobial Stewardship

Hospitalists can participate in antimicrobial stewardship at a number of levels. On the direct patient care level, they can consistently apply the principles of appropriate empiric therapy, de‐escalation, and duration of therapy as presented by Drs Snydman, Kaye, and File in this supplement. As hospitalists assume a continually increasing role in the care of hospitalized patients throughout the United States,92 they can directly influence the way medicine is practiced on a daily basis, patient by patient. A 2007 survey conducted by the American Hospital Association (AHA) showed that 58% of the 4897 community hospitals surveyed had hospital medicine programs, and that 83% of hospitals with 200 or more beds had such a program.93, 94 Estimates from the Society of Hospital Medicine (SHM) in July 2010 indicated that currently there were more than 30,000 hospitalists, practicing in 3300 large hospitals.95 This affords hospitalists the opportunity to improve care across a huge segment of hospitalized patients.

On a departmental or institutional level, hospitalists appear to be especially well positioned to contribute to, and in some cases direct, a hospital's antimicrobial stewardship program. Unique to hospital medicine, and incorporated into the definition of the profession, is the commitment to quality and process improvement, efficient use of hospital and healthcare resources, and an interdisciplinary approach to care.96 In line with this, hospitalists frequently serve on hospital committees and task forces, are experienced in developing and implementing clinical guidelines, and lead multidisciplinary teams to optimize patient care. For example, as reported in a recent review, a 2007 Pediatric Research in the Inpatient Setting survey of 208 pediatric hospitalists in the United States and Canada indicated that 92% spend at least some time in administration, 85% serve on hospital committees, and 61% and 52% lead initiatives in practice guidelines and quality improvement, respectively.97 Hospitalists are therefore especially well positioned to participate, and provide leadership, in hospital antimicrobial stewardship programs.

In 2007, the Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) released guidelines for developing institutional programs to enhance antimicrobial stewardship.18 According to these guidelines, the ideal institutional antimicrobial stewardship program contains an infectious diseases physician and clinical pharmacist with infectious diseases training as core members, along with a clinical microbiologist, an information system specialist, infection control professional, and a hospital epidemiologist. The infectious diseases physician and clinical pharmacist with infectious diseases training are expected to serve as leaders of the team and should be appropriately compensated for time dedicated to the program. Clearly, this is an extensive team requiring a lot of staff. Although optimal, many institutions do not have an infectious diseases physician on staff or an attending who is interested and willing to participate. For many institutions, an even bigger issue is identifying an infectious diseases pharmacist with sufficient skill to manage an antimicrobial stewardship program. As a consequence, many institutions wanting to develop an antimicrobial stewardship program to improve clinical outcomes, reduce antimicrobial resistance, and lower costs will need to think outside the box and look for nontraditional leaders to champion and lead their programs. Potential nontraditional leaders include general clinical pharmacists, intensivists, and hospitalists.98

Although hospitalists are not explicitly mentioned in the IDSA/SHEA guidelines, they seem to be implicitly included. The guidelines state that the development, maintenance, and ultimate success of such programs fundamentally depends on the support and collaboration of hospital administration, medical staff leadership, and local providers.18 Furthermore, they indicate the desirability for antimicrobial stewardship programs to function under the auspices of quality assurance and patient safety. As defined above, these are characteristics that are inherent to hospital medicine. Hence, there appears to be a good match between the activities performed by hospitalists and what the 2007 guidelines indicate is important for an effective antimicrobial stewardship program.

Now is the time for individuals to begin thinking about how best to prepare hospitalists for leadership roles in hospital antimicrobial stewardship programs. We need a well‐defined process for either training hospitalists for independent establishment of stewardship programs or establishing partnership with infectious disease specialists for the development of these programs. We need high‐level training programs in focused areas of infectious diseases that hospitalists encounter frequently (skin and skin‐structure infections, pneumonia, catheter‐associated infections, among others). Detailed understanding of the pathogens and their optimal treatment could form the core of such training. Additional education in infection control and the antimicrobial stewardship processes would round out the knowledge needed for a hospitalist to best implement and provide leadership for an antimicrobial stewardship program at his/her own institution. These training programs could be developed and delivered locally, or preferably they could be provided at national training sessions developed and supported through SHM, infectious disease societies, or the CDC.

Partnering with infectious diseases specialists is essential for protocol development and clinical support. This could allow the hospitalist to start a stewardship program on a small scale. It begins with identifying a single important problematic infection area, based on available local data (antibiotic usage, resistance levels, length of stay, C difficile rates, mortality, etc). The hospitalist would then work with the infectious disease department/staff to establish a protocol focusing on several of the key areas: diagnosis, optimal empiric therapy, de‐escalation (based on cultures and clinical response), transitioning intravenous antibiotics to oral, optimal duration of therapy, and transitioning therapy to the posthospital setting. The protocol would establish best treatment practices and the strategies to implement them (education, standardized order sets, computer decision support, monitoring and feedback, etc). The level of complexity and targeted outcomes need to be tailored to the resources available for implementation. Successful implementation and goal achievement in a small area could then be used to justify additional resources to expand the program. If hospitalists can be engaged in antimicrobial stewardship, both through individual patient care as well as program development, the large and growing number of hospitalists throughout the United States should allow for widespread implementation of antimicrobial stewardship programs.

CONCLUSIONS

Healthcare‐associated infections are increasingly a cause of morbidity and mortality in the United States and other countries, and the management of HAIs is increasingly complicated by involvement of MDR pathogens. Antimicrobial‐resistant pathogens are also increasingly involved in infections occurring outside the hospital setting. Infections caused by resistant or MDR pathogens are associated with increased mortality, longer length of hospital stay, and higher healthcare costs. The prevalence of these dangerous bacteria affects antimicrobial choices across a wider range of patients, particularly when choosing empiric therapy. Together with infection control, antimicrobial stewardship is an attractive solution to the challenges posed by antimicrobial resistance. Development and implementation of an effective institutional antimicrobial stewardship program can improve clinical outcome, reduce antimicrobial resistance and other unintended consequences of antimicrobial overuse/misuse, and lower healthcare costs.

At the forefront of inpatient care, hospitalists are positioned as excellent champions of the principles and practices of antimicrobial stewardship. By adhering to the principles of optimal antimicrobial therapy in their clinical practice, hospitalists can improve care and help reduce resistance on a patient‐by‐patient basis. At the same time, they may achieve other key hospitalist goals by reducing length of stay and decreasing costs and utilization. Moreover, they are well positioned to participate in, and at times lead, hospital‐based antimicrobial stewardship programs. As such, hospitalists are expected to play a critical role in helping to solve the problems of antimicrobial resistance and suboptimal inpatient care, as we move further into the 21st century.

Healthcare‐associated infections (HAIs) are important causes of morbidity and mortality in the United States and other countries.13 Moreover, treatment of HAIs is frequently complicated by involvement of bacterial pathogens resistant to 1 or more antibiotics or antibiotic classes,4 and sometimes bacteria resistant to all or nearly all currently available agents.57 The rapid emergence of resistant bacteria both in and out of the hospital setting can affect empiric antimicrobial choices across all patients. The effort to avoid undertreating or not covering resistant bacteria can lead to overuse of wide‐spectrum antimicrobials. Antimicrobial useand especially antimicrobial overuse or misusehas been linked with increased antimicrobial resistance,817 leading to worsened clinical outcomes with increased length of hospital stay and healthcare costs. Table 1 defines the various lines of evidence supporting a causal relationship between antibiotic use and emergence of antimicrobial resistance.18, 19

Observations That Support Causal Associations Between Antimicrobial Use and Emergence of Antimicrobial Resistance

  • NOTE: Adapted from Dellit et al.18

Changes in antimicrobial use are paralleled by changes in the prevalence of resistance
Antimicrobial resistance is more prevalent in healthcare‐associated bacterial infections vs community‐acquired infections
Patients with healthcare‐associated infections caused by resistant strains are more likely than control patients to have received prior antimicrobials
Areas within hospitals that have the highest rates of antimicrobial resistance also have the highest rates of antimicrobial use
Increasing duration of patient exposure to antimicrobials increases the likelihood of colonization with resistant organisms

Optimal management of patients with bacterial infections, both HAIs and those that originate in the community, involves a focus on treatment that maximizes clinical outcomes for the individual patient, while also inhibiting or slowing the development of antimicrobial resistance and its spread to other patients. Antimicrobial stewardship is a term describing the various clinical strategies that have been devised to maximize the benefits and minimize the costs of antimicrobial therapy through judicious use of these agents.18, 20, 21 This article examines the developing patterns of resistance among key bacterial pathogens in the hospital and associated healthcare settings, the costs associated with HAIs (specifically, those caused by resistant pathogens), and the various strategies or programs that have been developed by governmental agencies, individual healthcare institutions, and other organizations to optimize the use of antibiotics to improve patient outcomes and minimize healthcare costs. The value that the hospitalist can bring to the development and/or implementation of institutional antimicrobial stewardship programs is explored.

ANTIMICROBIAL RESISTANCE AND HAI TRENDS FOR KEY BACTERIAL PATHOGENS

Bacterial pathogens including Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp, Escherichia coli, and Proteus spp, among others), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium22, 23 are increasingly prevalent in healthcare settings, and particularly troublesome to manage due to increasing resistance. Data from the Centers for Disease Control and Prevention's (CDC) National Healthcare Safety Network (NHSN) have shown that, in intensive care units (ICUs), 16% of HAIs are due to multidrug‐resistant (MDR) pathogens.4 These 16% have the highest mortality and length of hospital stay, and are associated with the highest healthcare costs.24, 25 Infections caused by MDR pathogens are more important than their actual numbers, because treatment decisions are driven by the intent to cover these MDR pathogens, even if that means providing excessively broad coverage for most patients. Moreover, the 16% mentioned above are only the tip of the iceberg, as many more HAIs will occur outside of the ICU, particularly catheter‐associated urinary tract infections (CAUTI) and surgical site infections, as these patients are often not sick enough to require ICU care. There is little information on the prevalence of HAIs outside of the ICU setting, the role of MDR bacteria in these infections, and the associated costs, mortality, and effects on length of stay.

K pneumoniae Carbapenemases and Community‐Acquired Methicillin‐Resistant Staphylococcus aureus

K pneumoniae carbapenemase (KPC) is a prime example of the emergence and rapid spread of a new resistance pattern that affects prescribing patterns. Emergence of KPC as the primary source of carbapenem resistance in Enterobacteriaceae26 is critically significant, as carbapenems are recommended first‐line therapy for serious infections caused by extended‐spectrum ‐lactamase (ESBL)‐producing K pneumoniae or other Enterobacteriaceae. One particularly remarkable fact about KPC‐producing bacteria is the speed at which they have spread since first emerging. Figure 1 from the CDC illustrates the rapid spread of KPC‐producing bacteria within the United States, from winter 2008 to May 2010. International spread has also been rapid and extensive. The first case of a KPC‐producing bacteria outside the United States was reported in France in February 2005, in an 80‐year‐old man who was admitted to a Parisian hospital 2 to 3 months after having a medical procedure performed in a New York City hospital, suggesting intercontinental transfer from the United States.27 Since then, KPC‐producing pathogenic bacteria have been identified in the Caribbean, South America, Europe, Israel, and China.2830 It is clear that once resistant bacteria emerge, they have the potential to spread very rapidly within and between countries, challenging currently available antimicrobial agents and complicating the treatment of serious infections.

Figure 1
Rapid spread of Klebsiella pneumoniae carbapenemase‐producing bacteria within the United States, from winter 2008 to May 2010. (CDC unpublished data).

Consideration of S aureus skin and skin‐structure infections highlights the fact that the barrier between hospital and community is now beginning to be crossed, further complicating prescribing decisions. The classic risk factors for resistance may no longer be reliable in determining best empiric treatment. In a landmark study, Moran et al. demonstrated the large percentages of outpatients in the United States with skin or soft‐tissue infections (SSTIs) involving community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA).31 S aureus was isolated from 76% (320/422) of adults presenting to 11 university‐affiliated emergency departments with acute, purulent SSTIs in August 2004, 59% of whom were infected with MRSA. More than half the patients in the study (57%) were initially treated with antibiotics to which MRSA isolates were not susceptible.31 In the hospital, it has been shown that most invasive MRSA infections now actually have their onset outside of the healthcare setting,32 and that increasing numbers of hospitalized patients are now developing infections associated with CA‐MRSA strains >72 hours after admission.3338 Thus, it is becoming increasingly difficult to determine whether an invasive S aureus infection encountered in either a healthcare facility or community setting involves a sensitive organism, healthcare‐associated MRSA, or a CA‐MRSA pathogen, directly impacting treatment choices across all patients we care for with skin and skin‐structure infections.

Clostridium difficile‐Associated Disease

Indiscriminate and unnecessary use of antibiotics offer our patients no benefit, while exposing them to adverse effects of antibiotics, including allergies, rashes, and diarrhea among many potential other unintended consequences. C difficile‐associated disease is an increasingly problematic pathogen in the hospital setting that has been linked to unintended antibiotic effects.22, 39, 40 C difficile infection is not only costly in dollars, it is also a potentially fatal condition and has been linked to prolonged hospital stays and increased healthcare costs.4144 Improved infection control measures4549 and better use of antibiotics through antibiotic stewardship programs5055 have been shown to reduce the incidence of C difficile infection.

COSTS OF HAIs AND ANTIMICROBIAL RESISTANCE

HAIs are an important and growing problem in the United States.56 Klevens et al. estimated that approximately 1.7 million individuals hospitalized in the United States in 2002 had HAI, leading to 98,987 deaths.1 Estimates of annual hospital costs in the United States related to HAIs range from $28 to $48 billion.57 Antimicrobial resistance is a major driver of mortality, increased length of hospital stay, and hospital costs associated with HAIs.24, 25 A recent review by Sipahi25 summarizes recent studies examining the impact of resistant and MDR bacterial infections (Figure 2).5866 It is dramatically clear that infections due to resistant and MDR bacteria more often result in death, are associated with longer hospital stays, and are considerably more expensive to treat.

Figure 2
Association of multidrug resistance of several MDR bacteria with (A) length of stay, (B) mortality, and (C) cost of hospitalization. (Data from Sipahi, 2008) (ESBL, extended‐spectrum β‐lactamase; MDR, multidrug resistant; MRSA, methicillin‐resistant S aureus; MSSA, methicillin‐susceptible S aureus; VRE, vancomycin‐resistant Enterococcus; VSE, vancomycin‐susceptible Enterococcus.) aRepresents additional hospital days attributable to infection with MDR A baumannii, as determined in a multivariate model including all variables predictive of duration of hospitalization. bRepresents additional mean increase in hospitalization cost attributable to infections with a MDR‐resistant versus susceptible bacteria.

A number of factors can lead to the increased hospital costs associated with infection with a resistant or MDR bacteria. These include the need to use more expensive antibiotics, increased length of hospital stay, delayed appropriate antibiotic therapy, increased treatment toxicity (and costs associated with managing these toxicities), and increased frequency of surgical interventions required to control infection.25, 67

The savings that could be realized through reduction in antimicrobial resistance was evaluated recently by Roberts et al.68 Using a sensitivity analysis for a sample of high‐risk adult patients hospitalized in an urban public teaching hospital in 2000, the authors determined that reducing the antimicrobial‐resistant infection rate by 3.5% (from 13.5% to 10.0%) would have saved the study hospital $910,812 (in 2008 US$), when using lowest cost and length of stay figures. The calculated societal savings, for reduced mortality and lost productivity associated with the reduced antimicrobial‐resistant rate, was $1.8 million. Hence, the analysis showed a minimum overall medical (hospital) and societal savings of $2.7 million for this single hospital with a cohort of 1391 patients. The projected savings would be dramatically higher if the reduced antimicrobial‐resistant rate was generalized to all hospitals throughout the United States.

ORGANIZATIONAL AND GOVERNMENTAL EFFORTS ADDRESSING ANTIMICROBIAL RESISTANCE AND HAIs

Given the relationships between antimicrobial use and resistance, and between antimicrobial resistance and morbidity, mortality, length of hospital stay, and healthcare costs, it is not surprising that we have seen a variety of programs and initiatives begun by either government agencies or healthcare organizations aimed at reducing antimicrobial resistance and HAIs.

The Joint Commission

The Joint Commission is an independent, not‐for‐profit organization that accredits and certifies >18,000 healthcare organizations/programs in the United States.69 The Joint Commission issues annual National Patient Safety Goals (NPSG). Hospital compliance with these goals is a critical component of the accreditation process.70

The seventh goal of The Joint Commission's NPSG is to reduce the risk of HAIs,70 the key features of which are listed in Table 2. The methodology recommended to achieve compliance includes infection control programs and implementation of evidence‐based practices to prevent HAIs due to MDR microorganisms in acute‐care hospitals. This presumably could include development and implementation of an institutional antimicrobial stewardship, or components of a program, to reduce antimicrobial resistance within the hospital.

National Patient Safety Goals (NPSG)
Goal 7: Reduce the Risk of Healthcare‐Associated Infections

  • NOTE: Available at: http://www.jointcommission.org/npsg_7_healthcare‐associated_infections_webinar/

NPSG.07.03.01
Implement evidence‐based practices to prevent healthcare‐associated infections due to multidrug‐resistant organisms in acute‐care hospitals
Note: This requirement applies to, but is not limited to, epidemiologically important organisms such as methicillin‐resistant Staphylococcus aureus, Clostridium difficile, vancomycin‐resistant enterococci (VRE), and multidrug‐resistant Gram‐negative bacteria
NPSG.07.04.01
Implement evidence‐based practices to prevent central line‐associated bloodstream infection
Note: This requirement covers short‐ and long‐term central venous catheters and peripherally inserted central catheter (PICC) lines

Centers for Medicare and Medicaid Services

The Deficit Reduction Act of 2005, Section 5001(c), requires the Secretary of Health and Human Services to identify conditions that are: (1) high cost or high volume, or both; (2) result in assignment of a case to a diagnosis‐related group that has higher payment when the code is present as a secondary diagnosis; and (3) could reasonably have been prevented through application of evidence‐based guidelines.71 The Centers for Medicare and Medicaid Services (CMS), which develops and administers Medicare and Medicaid payment and coverage policies, encourages hospitals to reduce the occurrence of these preventable problems through reduced payments when these events occur. Among the Hospital Acquired Conditions (HAC) that CMS considers reasonably preventable are a number of HAIs, particularly CAUTI, vascular catheter‐associated infections, and various surgery‐related SSTIs. Importantly, the CMS policy is still in effect as of April 2011, and there are no signs of its being repealed or modified in the foreseeable future.

The CDC Get Smart and Get Smart for Healthcare Programs

The Get Smart campaign, initiated by the CDC in 1995, focused on providing information to parents about the appropriate and inappropriate use of antibiotics to treat common childhood infections, as well as about the dangers of antibiotic resistance.72 The goal of Get Smart is to reduce unnecessary antibiotic use and the spread of antibiotic resistance in the community by reducing the pressure exerted by parents on physicians to overuse or misuse antibiotics. Hence, the primary focus in this setting is on patient/parent education. The Get Smart campaign has been highly successful, with a significant reduction in antibiotic prescriptions after initiation of the campaign, across a range of infections for which antibiotics are generally or often not warranted.73 The success of Get Smart is also largely responsible for the improvement in antibiotic prescribing for childhood middle ear infections observed in the CDC Healthy People 2010 program.74 The actual performance achieved in 2007 (the latest year reported) exceeded the Healthy People 2010 target.75

Building on the success of Get Smart for community‐acquired infections, a similar CDC campaign (Get Smart for Healthcare) has been undertaken to improve antibiotic usage and reduce antibiotic resistance in inpatient healthcare facilities.76 The specific goals of Get Smart for Healthcare are to improve patient safety through better treatment of infections, reduce emergence of antimicrobial‐resistant pathogens and C difficile, and heighten awareness of the challenges posed by antimicrobial resistance in healthcare settings. To help accomplish these ends, the CDC has partnered with the Institute for Healthcare Improvement (IHI), an independent, not‐for‐profit organization dedicated to closing the gap between the healthcare that currently exists and the healthcare that should exist.77 Together, they have identified a number of primary drivers to improve antibiotic use: timely and appropriate initiation of antibiotics; appropriate administration and de‐escalation; data monitoring and transparency; and improving knowledge of, and engagement in, antimicrobial stewardship efforts, which are the focus of the next section. With respect to data monitoring, many in the healthcare community hope that, through the Get Smart program, we will soon have better sources of data, not just for the ICU, but across the entire hospital setting. This would help providers get a better sense of where resistance is located, thereby enabling better development of action plans to deal with the problem.

The CDC has recently expanded its Web site on antimicrobial stewardship, now providing extensive support and resources for program development and implementation at: http://www.cdc.gov/getsmart/healthcare/. In addition to urging the development of stewardship programs at all healthcare facilities, they propose 2 novel tools for use with every hospitalized patient who is prescribed antibiotics. According to the CDC78:

All Clinicians Should:

Dose, Duration, Indication

Too often antibiotics in hospitals are continued unnecessarily simply because clinicians caring for the patient do not have information indicating why the antibiotics were started initially or for how long they were to be continued. This challenge is compounded in today's healthcare system where primary responsibility for patient care is frequently transitioned from one clinician to another. Ensuring that all antibiotic orders are always accompanied by a dose, duration, and indication will help clinicians change or stop therapy when appropriate.

Get Cultures

Antibiotic therapy can be best optimized when it can be tailored to specific culture results. Knowing the susceptibility of the infecting organisms can lead to narrowing of broad‐spectrum therapy, changing therapy to better treat resistant pathogens and to stopping antibiotics when cultures suggest an infection is unlikely.

A number of other government initiatives have been developed to address the issues of HAIs, antimicrobial resistance, and improved antimicrobial stewardship. These are beyond the scope of the present article, but include the United States Department of Health and Human Services (HHS) action plan to prevent HAIs,79 and the CDC campaign and action plan to prevent and combat antimicrobial resistance,80, 81 among others.

ANTIMICROBIAL STEWARDSHIP IN HOSPITALS AND THE HOSPITALIST'S ROLE

As recently defined, antimicrobial stewardship is a system of personnel, informatics, data collection, and policy/procedures that promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use.20 In simple words, the right antibiotic, at the right dose, at the right time, and for the right duration. The primary goals of antimicrobial stewardship are to reduce patient morbidity and mortality, prevent or slow the emergence of antimicrobial resistance, and reduce adverse drug effects, including secondary infections, such as C difficile‐associated diarrhea.18, 20 Secondary goals include a reduction in hospital length of stay and healthcare expenditures, without adversely impacting quality of care. These goals are entirely in line with those of the hospitalist, who can play a critical role in the prevention and successful management of these infections. Optimal effects are expected when antimicrobial stewardship is combined with implementation of effective infection control measures within the hospital setting.

Antimicrobial Stewardship Strategies

Table 3 provides an overview of various general strategies/procedures employed as components of antimicrobial stewardship programs.82 The 2 most common are: (1) formulary restriction and preauthorization for specific agents; and (2) prospective audit with intervention and feedback.18, 20 Both approaches can and have been used to improve antimicrobial stewardship and to achieve at least some of its goals, and each is associated with advantages and disadvantages, as outlined in Table 3 and reviewed elsewhere.18, 20, 21, 83 Other strategies, such as education and use of guidelines and clinical pathways, tend to be used to supplement or complement either a general formulary restriction/preauthorization, or prospective audit/review and feedback approach to antimicrobial stewardship. It is important to note that, as in other areas such as venous thromboembolism prophylaxis, education alone is insufficient to drive changes in prescribing patterns and thereby reduce resistance. Healthcare informatics are increasingly being utilized to improve the management of infectious diseases. These can be simple programs that better assemble information about hospital‐pathogen epidemiology. They can also be sophisticated systems, designed to standardize the antimicrobial order sets and medical logic modules, that guide treatment options by connecting patient‐specific information with guideline recommendations and local resistance patterns.18, 20, 84, 85

Summary of Antimicrobial Stewardship Strategies
Strategy Procedure Personnel Advantages Disadvantages

  • NOTE: Adapted from MacDougall and Polk.82

Education/ guidelines Creation of guidelines for antimicrobial use Antimicrobial committee to create guidelines May alter behavior patterns Passive education likely ineffective
Group or individual education of clinicians by educators Educators (physicians, pharmacists) Avoids loss of prescriber autonomy
Formulary restriction Restrict dispensing of targeted antimicrobials to approved indications Antimicrobial committee to create guidelines Approval personnel (physician, infectious diseases fellow, clinical pharmacist) Most direct control over antimicrobial use Individual educational opportunities Perceived loss of autonomy for prescribers Need for all‐hours consultant availability
Review and feedback Daily review of targeted antimicrobials for appropriateness Contact prescribers with recommendations for alternative therapy Antimicrobial committee to create guidelines Review personnel (usually clinical pharmacist) Avoids loss of autonomy for prescribers Individual educational opportunities Compliance with recommendations
Computer assistance Use of information technology to implement previous strategies Antimicrobial committee to create rules for computer systems Provides patient‐specific data where most likely to impact care (point of care) Significant time and resource investment to implement sophisticated systems
Expert systems provide patient‐specific recommendations at point of entry (order entry) Personnel for approval or review (physicians, pharmacists) Computer programmers Facilitates other strategies

Two early, randomized, prospective studies illustrate the potential benefits and general receptiveness of clinicians to use of an audit/review and feedback approach to institutional antimicrobial stewardship. The first study randomized adult inpatients receiving 1 parenteral antibiotic for 3 days to an intervention (n = 141) or control group (n = 111).86 In the intervention group, a clinical pharmacist and infectious diseases fellow reviewed the initial therapy prescribed by the primary care physician and the patient's progress 3 days after therapy initiation, and at that point offered suggestions for subsequent antibiotic therapy. The feedback or suggestions were communicated via nonpermanent chart note. In total, 85% of the physicians implemented the suggestions, and there were no significant differences between the intervention and control group for clinical or microbiologic endpoints. However, per‐patient antibiotic charges were significantly lower in the intervention versus control group ($1287.17 vs $1673.97; P = 0.05), which yields an estimated $390,000 in annualized savings for the 600‐bed tertiary‐care hospital.

Similarly, a randomized, prospective study by Gums et al. showed that therapeutic intervention by a multidisciplinary antimicrobial team for inpatients receiving suboptimal intravenous antibiotic therapy was associated with a median hospital cost savings of $2642 per intervention, compared with costs for similar inpatients who did not receive such intervention.87 The multidisciplinary team in the study consisted of pharmacists, a clinical microbiologist, and an infectious diseases specialist, who provided the treating physician with recommendations of possible optimal antibiotics, dosages, and rationales based on timely, detailed reviews of relevant microbiologic and clinical data. In total, 89% of physicians in the study implemented the suggestions from the multidisciplinary antimicrobial team. In addition to reduced costs, the intervention versus control group was also associated with significant reductions in the overall length of stay (10.1 vs 14.5 days; P = 0.0001), and total non‐ICU length of stay (5.7 vs 9.0; P = 0.0001). There was no significant difference between the 2 groups for mortality rate.

The results from these studies86, 87 demonstrate how a prospective audit/review and feedback approach to antimicrobial stewardship can be associated with high physician participation and significant cost reductions for participating hospitals,88 and potentially improve patient outcomes. Antimicrobial stewardship programs overall have a long track record in improving patient outcomes and reducing antimicrobial resistance at the patient level.8991

The Hospitalist's Role in Antimicrobial Stewardship

Hospitalists can participate in antimicrobial stewardship at a number of levels. On the direct patient care level, they can consistently apply the principles of appropriate empiric therapy, de‐escalation, and duration of therapy as presented by Drs Snydman, Kaye, and File in this supplement. As hospitalists assume a continually increasing role in the care of hospitalized patients throughout the United States,92 they can directly influence the way medicine is practiced on a daily basis, patient by patient. A 2007 survey conducted by the American Hospital Association (AHA) showed that 58% of the 4897 community hospitals surveyed had hospital medicine programs, and that 83% of hospitals with 200 or more beds had such a program.93, 94 Estimates from the Society of Hospital Medicine (SHM) in July 2010 indicated that currently there were more than 30,000 hospitalists, practicing in 3300 large hospitals.95 This affords hospitalists the opportunity to improve care across a huge segment of hospitalized patients.

On a departmental or institutional level, hospitalists appear to be especially well positioned to contribute to, and in some cases direct, a hospital's antimicrobial stewardship program. Unique to hospital medicine, and incorporated into the definition of the profession, is the commitment to quality and process improvement, efficient use of hospital and healthcare resources, and an interdisciplinary approach to care.96 In line with this, hospitalists frequently serve on hospital committees and task forces, are experienced in developing and implementing clinical guidelines, and lead multidisciplinary teams to optimize patient care. For example, as reported in a recent review, a 2007 Pediatric Research in the Inpatient Setting survey of 208 pediatric hospitalists in the United States and Canada indicated that 92% spend at least some time in administration, 85% serve on hospital committees, and 61% and 52% lead initiatives in practice guidelines and quality improvement, respectively.97 Hospitalists are therefore especially well positioned to participate, and provide leadership, in hospital antimicrobial stewardship programs.

In 2007, the Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) released guidelines for developing institutional programs to enhance antimicrobial stewardship.18 According to these guidelines, the ideal institutional antimicrobial stewardship program contains an infectious diseases physician and clinical pharmacist with infectious diseases training as core members, along with a clinical microbiologist, an information system specialist, infection control professional, and a hospital epidemiologist. The infectious diseases physician and clinical pharmacist with infectious diseases training are expected to serve as leaders of the team and should be appropriately compensated for time dedicated to the program. Clearly, this is an extensive team requiring a lot of staff. Although optimal, many institutions do not have an infectious diseases physician on staff or an attending who is interested and willing to participate. For many institutions, an even bigger issue is identifying an infectious diseases pharmacist with sufficient skill to manage an antimicrobial stewardship program. As a consequence, many institutions wanting to develop an antimicrobial stewardship program to improve clinical outcomes, reduce antimicrobial resistance, and lower costs will need to think outside the box and look for nontraditional leaders to champion and lead their programs. Potential nontraditional leaders include general clinical pharmacists, intensivists, and hospitalists.98

Although hospitalists are not explicitly mentioned in the IDSA/SHEA guidelines, they seem to be implicitly included. The guidelines state that the development, maintenance, and ultimate success of such programs fundamentally depends on the support and collaboration of hospital administration, medical staff leadership, and local providers.18 Furthermore, they indicate the desirability for antimicrobial stewardship programs to function under the auspices of quality assurance and patient safety. As defined above, these are characteristics that are inherent to hospital medicine. Hence, there appears to be a good match between the activities performed by hospitalists and what the 2007 guidelines indicate is important for an effective antimicrobial stewardship program.

Now is the time for individuals to begin thinking about how best to prepare hospitalists for leadership roles in hospital antimicrobial stewardship programs. We need a well‐defined process for either training hospitalists for independent establishment of stewardship programs or establishing partnership with infectious disease specialists for the development of these programs. We need high‐level training programs in focused areas of infectious diseases that hospitalists encounter frequently (skin and skin‐structure infections, pneumonia, catheter‐associated infections, among others). Detailed understanding of the pathogens and their optimal treatment could form the core of such training. Additional education in infection control and the antimicrobial stewardship processes would round out the knowledge needed for a hospitalist to best implement and provide leadership for an antimicrobial stewardship program at his/her own institution. These training programs could be developed and delivered locally, or preferably they could be provided at national training sessions developed and supported through SHM, infectious disease societies, or the CDC.

Partnering with infectious diseases specialists is essential for protocol development and clinical support. This could allow the hospitalist to start a stewardship program on a small scale. It begins with identifying a single important problematic infection area, based on available local data (antibiotic usage, resistance levels, length of stay, C difficile rates, mortality, etc). The hospitalist would then work with the infectious disease department/staff to establish a protocol focusing on several of the key areas: diagnosis, optimal empiric therapy, de‐escalation (based on cultures and clinical response), transitioning intravenous antibiotics to oral, optimal duration of therapy, and transitioning therapy to the posthospital setting. The protocol would establish best treatment practices and the strategies to implement them (education, standardized order sets, computer decision support, monitoring and feedback, etc). The level of complexity and targeted outcomes need to be tailored to the resources available for implementation. Successful implementation and goal achievement in a small area could then be used to justify additional resources to expand the program. If hospitalists can be engaged in antimicrobial stewardship, both through individual patient care as well as program development, the large and growing number of hospitalists throughout the United States should allow for widespread implementation of antimicrobial stewardship programs.

CONCLUSIONS

Healthcare‐associated infections are increasingly a cause of morbidity and mortality in the United States and other countries, and the management of HAIs is increasingly complicated by involvement of MDR pathogens. Antimicrobial‐resistant pathogens are also increasingly involved in infections occurring outside the hospital setting. Infections caused by resistant or MDR pathogens are associated with increased mortality, longer length of hospital stay, and higher healthcare costs. The prevalence of these dangerous bacteria affects antimicrobial choices across a wider range of patients, particularly when choosing empiric therapy. Together with infection control, antimicrobial stewardship is an attractive solution to the challenges posed by antimicrobial resistance. Development and implementation of an effective institutional antimicrobial stewardship program can improve clinical outcome, reduce antimicrobial resistance and other unintended consequences of antimicrobial overuse/misuse, and lower healthcare costs.

At the forefront of inpatient care, hospitalists are positioned as excellent champions of the principles and practices of antimicrobial stewardship. By adhering to the principles of optimal antimicrobial therapy in their clinical practice, hospitalists can improve care and help reduce resistance on a patient‐by‐patient basis. At the same time, they may achieve other key hospitalist goals by reducing length of stay and decreasing costs and utilization. Moreover, they are well positioned to participate in, and at times lead, hospital‐based antimicrobial stewardship programs. As such, hospitalists are expected to play a critical role in helping to solve the problems of antimicrobial resistance and suboptimal inpatient care, as we move further into the 21st century.

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Journal of Hospital Medicine - 7(1)
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Journal of Hospital Medicine - 7(1)
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Infections, bacterial resistance, and antimicrobial stewardship: The emerging role of hospitalists
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Infections, bacterial resistance, and antimicrobial stewardship: The emerging role of hospitalists
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David J. Rosenberg, MD, MPH, FACP, SFHM
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