Download Elements of an Antimicrobial Stewardship Program

Elements of an Antimicrobial Stewardship Program
By John Zaccardelli, Pharm.D., Postgraduate Year 1 resident, Henry Ford Macomb Hospital
Target Audience
This continuing education activity was designed specifically for pharmacists.
Disclosure Statement
The author has indicated that he does not have any conflicts of interest, nor does he have financial
relationships with a commercial interest, related to this activity.
Learning Objectives
At the end of this activity, participants should be able to:
 describe the elements of an antimicrobial stewardship program.
 explain the importance of an antimicrobial stewardship program within a hospital.
 discuss examples of antimicrobial stewardship activities.
Introduction
Antimicrobial agents are important to the practice of medicine because of their ability to
cure infections, but it is estimated that as much as 50 percent of antibiotic prescriptions may be
unnecessary.1 A normal risk for antimicrobial use is adverse effects such as diarrhea and nephritis,
but a serious adverse event, Clostridium difficile infection, can develop from overuse of antibiotics.2
This can lead to increased health care costs. In a systematic review by Nanwa and colleagues, total
health care costs to treat a C. difficile infection can be as high as $30,000.3 Antimicrobial resistance
can also develop over time when broad-spectrum antibiotics are used instead of more targeted
therapies. Superinfections or organisms resistant to multiple anti-infectives can lead to treatment
failure and even death. A recent incident of carbapenem-resistant enterobacteriaceae at Ronald Reagan
UCLA Medical Center highlights the real danger in allowing organisms to develop resistance to
antimicrobial agents.4 Seven patients were infected, while two patients died from the resistant
infection.4 An antimicrobial stewardship program (ASP) is a way to help prevent these negative
consequences.
The main goal of antimicrobial stewardship is to optimize positive clinical outcomes such as
curing the infectious disease while minimizing negative consequences of antimicrobial use.5 The
majority of hospitals in the United States have some strategies to promote antimicrobial stewardship
but, in particular, smaller community hospitals may not have a well-developed program.6 It will be
important for all health care facilities to develop antimicrobial stewardship programs because the
government has set future goals to require certain antimicrobial stewardship activities.
On Sept. 18, 2014, President Barack Obama gave an executive order on combating antibiotic
resistance.7 It outlined a Task Force to identify future national goals and strategies to decrease
antibiotic resistance and to improve antimicrobial use through ASPs. By the end of 2016, new
regulations will be implemented to require health care facilities to have robust ASPs.7 The Centers
for Medicare and Medicaid Services (CMS) has also indicated future requirements for antimicrobial
stewardship activities.8 These activities will be tied to CMS reimbursement payments to health care
facilities. Health care facilities will likely have to designated leaders responsible for ASP, develop
policies and procedures, require documentation of indication for all antimicrobials, and monitor
antimicrobial use.8 Implementing or improving elements of an ASP will be vital to a hospital’s
growth and success.
Elements of Antimicrobial Stewardship Program
The Infectious Diseases Society of America (IDSA) recommends certain elements or tools
when developing an antimicrobial stewardship program.5 There are two core elements and several
supplemental elements for a health care facility to perform when creating an enhanced ASP. The
first core function of an ASP is prospective audit with intervention and feedback. A patient’s chart is
reviewed during the hospital admission then discussed with the patient’s prescriber for potential
recommendations to optimize the patient’s antimicrobial therapy. This can occur during daily rounds
or through consultation with the prescriber, as needed, either verbally or in writing. It is
recommended that an infectious disease physician or an infectious disease pharmacy specialist
reviews the patient’s chart.5 The objective of the prospective review is to reduce unnecessary
antimicrobial agents based on organism coverage or duration of therapy.
An example of this is a patient with pneumonia who lives in a nursing home and is
empirically treated with moxifloxacin. The admitting physician will likely change the patient’s
therapy to include broader spectrum agents such as vancomycin and cefepime due to the patient’s
risk for health care-associated pneumonia (HCAP). Later in the hospital stay, the microbiology data
shows only Gram-positive organisms growing in the lungs. The antimicrobial stewardship pharmacy
specialist can recommend to the attending physician to discontinue cefepime and continue with
vancomycin alone. The antimicrobial stewardship pharmacy specialist is decreasing antimicrobial
exposure since cefepime covers Gram-negative organisms and is no longer needed. This antibiotic
review not only decreases unnecessary antimicrobial exposure but saves cost on unnecessary
medications.
Prospective audit has shown cost savings in both large teaching hospitals and small
community hospitals. A study by Frazer and colleagues done in a 600-bed tertiary teaching hospital
randomized patients to either be reviewed by an infectious disease fellow or pharmacist or not
reviewed. The study showed an average cost savings of $400 per patient compared to the patients
who were not reviewed.9 In another study by Yu and colleagues, pharmacists on an antimicrobial
stewardship team providing recommendations to physicians on antimicrobial therapy showed a cost
savings of more than $127,000 when compared to hospitals without antimicrobial stewardship.10 In
hospitals where daily review of antimicrobial therapy is not realistic due to limited resources, less
frequent reviews can still be beneficial. In a study done at a 120-bed community hospital, an
infectious disease physician or clinical pharmacist focused on reviewing patients with multiple
antimicrobials. They would review the patients’ antimicrobial regimens three times weekly. The
study found a 19 percent reduction in antimicrobial cost and estimated annual cost savings of more
than $175,000.11 As health care costs rise over time, there will be more pressure to audit
antimicrobial therapies and restrict antimicrobial prescribing.
Formulary restriction and preauthorization is another core element to an ASP.5 A hospital
should have a Pharmacy and Therapeutics Committee or equivalent group to review medications
that should be included in the hospital formulary. The formulary is the first line of defense to
control antimicrobial usage and cost. The Committee should evaluate the efficacy, safety and
placement on the formulary. A new antimicrobial agent may be added to the formulary even though
it is expensive but useful in treatment in a specific type of infection. If the medication is expensive
but does not have better efficacy than other cheaper options, it may not be added to the formulary.
Preauthorization requirements such as requiring a consult to an infectious disease physician
or allowing only certain physicians to prescribe certain antimicrobial agents allows the hospital to
control usage and cost. A study by Seligman demonstrated a 29 percent decrease in antibiotic cost
when requiring an infectious disease consult for an oral cephalosporin agent, which accounted for 31
percent of total antibiotic expenditure.12 The cost savings from antimicrobial medications can be
used in another aspect of the patient’s care or help the hospital overall with care to its patients. More
importantly, antimicrobial resistance with overuse of broad-spectrum antimicrobial medications is a
concern. Agents such as vancomycin and carbapenems have developed resistance to Enteroccous and
Enterobacteriaceae strains.13 A study by Quale and colleagues showed a significant decrease in
vancomycin-resistant Enterococci after restricting cefotaxime and vancomycin use.13 Preventing
resistance is vital because the pharmaceutical market has only produced a few new antimicrobial
agents over the past decade.14 There is a real threat of superinfections to become more common
because current agents are losing efficacy to new resistant infections.2
STOP AND REFLECT
What government organization will be requiring antimicrobial stewardship
activities for health care facilities to participate with them and receive reimbursement
payments? What is the goal behind these activities?
Education is a supplemental element to a successful ASP. The education is designed to
influence prescribing behavior. Passive activities such as lectures, informational booklets, signs and
e-mail alerts remind and reinforce proper antimicrobial use and stewardship. An example is a
hospital antibiogram given out to physicians to educate them on the hospital’s formulary antibiotic
agents and sensitivity against different pathogens seen within the hospital. However, passive
activities have a limit to their effectiveness. Passive activities have a more direct effect on health care
providers when combined with active interventions. In one study by Bantar and colleagues, passive
education was followed by active prospective reviews, which showed more than $900,000 in savings
and more than 45 percent of interventions resulted in changing to narrower spectrum of activity.15
Guidelines and clinical pathways are supplemental strategies in antimicrobial stewardship.
Guidelines such as those from the IDSA can help direct a prescriber on the proper treatment for a
certain infectious disease. It is important to note that guidelines are recommendations given for a
certain disease or condition, but the prescriber can vary on the final treatment choice based on the
patient’s specific characteristics. Guidelines also can help create policies within a hospital or health
system on how to use antimicrobial agents. A study by Dranitsaris and colleagues evaluated an
institutional guideline concerning ceftotaxime usage. Pharmacists promoting the institutional
guidelines showed more appropriate use of the antibiotic agent better than without the
intervention.16
Clinical pathways can also narrow the selection of antimicrobial agents. A clinical pathway is
a stepwise guide to certain treatments depending on the patient’s signs and symptoms. This allows
clinicians to make quicker and more educated decisions about treatment. It can lead to decreased
hospital length of stay and days on antibiotics, as found in the study by Marrie and colleagues. A
clinical pathway was randomly implemented among 20 hospitals and it showed a 1.7-day decrease in
hospital length of stay and a decrease mean of 1.7 days of intravenous therapy without increasing
readmissions or mortality.17 Clinical pathways can also lead to cost savings. Singh and colleagues
implemented an algorithm in an intensive care unit to direct antibiotic therapy with pulmonary
infection scores. The score would direct how long the patient should be on antimicrobial agents.
The study showed a decrease in antimicrobial-resistant infections and duration of therapy but no
difference in mortality.18
Dose optimization is another supplemental element to antimicrobial stewardship. It is the
use of a patient’s characteristics along with a drug’s pharmacodynamic and pharmacokinetic
properties to optimize therapy5. A common example of this is β-lactam agents being dose adjusted
for renal function. β-lactam agents such as amoxicillin and cefepime have bactericidal activity that
correlates with time above the minimum inhibitory concentration. The antibiotic agents can be given
over longer intervals if the patient has poor renal function. This would have a pharmacokinetic
effect to maintain antibiotic concentrations but given in fewer doses. A pharmacodynamic effect
would be using single-dose fosfomycin instead of four times daily dose cephalexin for an
uncomplicated urinary tract infection due to fosfomycin’s high concentration in the urine with a
single dose.19
Antimicrobial de-escalation or streamlining is another tool to be used along with the core
elements of antimicrobial stewardship. The action can be described as switching empiric
antimicrobial therapy to targeted therapy.5 Microbiology data such as culture results and
susceptibility data can streamline empiric antimicrobial therapy to the causative pathogen and
eliminate unnecessary or redundant medications. Broad-spectrum antimicrobial agents are often
changed to narrow-spectrum agents, though this is not always the case. An example is a patient who
is treated with ceftriaxone when the susceptibility data indicates Klebsiella pneumoniae sensitive to only
cefepime. The key to antimicrobial de-escalation is to use the most effective agent for the infecting
organism while limiting exposure to other antimicrobial agents to prevent the development of
resistance. Continuous broad-spectrum empiric therapy has shown to contribute to antimicrobialresistant organisms.20 When microbiology data becomes available, this is the time to choose a more
selective antimicrobial agent. This can lead to overall cost savings, as multiple agents are removed
and more expensive agents are switched with cheaper generic agents. A study by Briceland and
colleagues concerning streamlining by an infectious disease physician and pharmacist showed a
projected annual savings of more than $100,000.21
STOP AND REFLECT
A patient comes into the emergency department and is diagnosed with HCAP.
The physician orders empiric treatment with vancomycin and cefepime. Respiratory
cultures are taken and later show Gram-negative organism growth. The patient is
transferred to the general practice unit where the clinical pharmacist reviews the patient’s
chart. What action should the clinical pharmacist take on this patient’s medications?
Conversion from parenteral to oral dosage form is another supplemental element to
antimicrobial stewardship. Patients with serious infections or when oral bioavailability is uncertain
are often started on parenteral therapy.22 Intravenous antibiotics may initially be more beneficial
because they have a 100 percent bioavailability in the blood stream and may quicken the onset of the
medication. However, intravenous medications can be burdensome if the patient has poor
intravenous access or if a medication has to be infused over several hours. Conversion to oral
therapy may be preferred since it is easier to administer, causes less frequent adverse effects and
saves cost.22 Routine monitoring for conversion has shown to decrease length of hospital stay and
health care costs while not compromising patient care.22 One ideal time to have the conversion from
parenteral to oral therapy is when the patient is being transferred out of an intensive care unit onto a
general practice unit. The patient’s condition is less serious and more likely to tolerate oral
medications.
Antimicrobial order sets are another tool to be used for ASP. Pre-specified order sets can be
developed by the antimicrobial stewardship team. An order set can limit the overuse of
antimicrobials through automatic stop times and physician requirements to justify the continued use
of the antimicrobial agent. Order sets were found to be particularly useful on perioperative antibiotic
orders in a study by Durbin and colleagues. The study showed a decrease in mean duration of
antimicrobial use from 4.9 days to 2.9 days when automatic two-day discontinuation order sets were
used.23
Combination antimicrobial therapy is another strategy to help improve clinical outcomes. A
study by Harbarth and colleagues focusing on sepsis showed inadequate initial therapy is associated
with increased mortality.24 The goal of combination therapy is to use broad-spectrum empiric
therapies for serious infections especially for multidrug-resistant organism infections.5 The concern
with combination therapy is unnecessary and redundant coverage, which may lead to antimicrobial
resistance.25 An example is the combination of a β-lactam and an aminoglycoside. A meta-analysis by
Bliziotis and colleagues reviewed the combination versus β-lactam monotherapy. Monotherapy was
associated with less treatment failure and superinfections compared to the combination.25
Antimicrobial cycling is one activity that is not recommended in an ASP. Cycling is
described as scheduled removing and switching of similar antimicrobial agents or classes within a
facility.5 It was thought to have a benefit to antimicrobial stewardship by decreasing the occurrence
of antimicrobial resistance. Though, studies have mixed support for the use of antimicrobial
cycling.26,27 Mathematical modeling has suggested the only benefit is slowing the spread of resistance
but not preventing it.28
The Pharmacist’s Impact
Pharmacists can play an important role in antimicrobial stewardship. Staff pharmacists play a
daily role in verifying anti-infective medications. They can be involved in the core elements of
prospective antibiotic review and formulary restriction, along with supplemental elements such as
intravenous to oral dosage form conversion. Ideally, a pharmacist with infectious disease training
should be working with the hospital’s infectious disease physicians to optimize antibiotic
stewardship.5 Clinical pathways can assist staff pharmacists in providing recommendations for the
most suitable antibiotic for the patient and restrict overuse of certain antibiotics.16 A study by
Lancaster and colleagues showed a pharmacist-driven intervention led to improved hospital-acquired
pneumonia (HAP) therapy.29 Pharmacists used an approved HAP protocol to review antibiotic
therapy for appropriate empiric antibiotic coverage and recommend when to de-escalate therapy.
The pharmacists made 59 interventions in 29 patients with about a 50 percent physician accepted
recommendation rate.29
Pharmacists can promote optimal use of antimicrobial agents. There are several ways this
can be achieved.27 First, pharmacists need to encourage multidisciplinary collaboration within the
health care system. Pharmacists should assist in appropriate selection, optimal dosing, proper
monitoring and de-escalation when on rounds or verifying medication orders. Pharmacists should be
involved in the hospital Therapeutics Committee and Infectious Disease Subcommittees to help
develop policies such as therapeutic interchange and restricted antimicrobial-use.30 Collaboration
with microbiology laboratory personnel is also important to have appropriate microbiology and
susceptibility data communicated in a timely fashion to the health care provider.30 The goal is to
have open communication to help mitigate any delays or issues when trying to determine the
infectious disease origins.
Pharmacists can collect antimicrobial data from the electronic health record (EHR) to
analyze clinical and economic outcomes.30 This data can be used to create or optimize antimicrobial
guidelines, policies and procedures. The data can be individualized to specific hospitals within a
health-system to help lead physicians to the most effective antimicrobial agents at their facility.
Pharmacists can also use the EHR to track and monitor antimicrobial utilization. This can lead to
improved antimicrobial therapy, as showed by Evans and colleagues.31 A monitoring system
identified changes in renal function for patients on specific antibiotics. Pharmacists would review
the list and adjust doses of the patients’ medications when warranted. When a guideline embedded
computer-assisted system was implemented at a 520-bed hospital, it resulted in a pharmacy
antimicrobial drug expenditure decrease from 24.8 to 12.9 percent, while showing a 30 percent
decrease in antimicrobial-associated adverse events.32
Pharmacists should participate in the prevention and reduction of the transmission of
infections. Pharmacists play an important role, as compounding of intravenous medications start in
the pharmacy. Policies and procedures can be created and put in place to ensure sterility of drug
products. Pharmacist should encourage the use of single-dose vials as opposed to multiple-dose
containers.30 Along with compounding, they can ensure proper handling and storage of sterile
products. Pharmacists should ensure proper standard precautions such as hand washing and routine
immunizations of health care workers.30 Other areas where a pharmacist can be involved are
preventing surgical site infections, catheter-associated infections and ventilator-associated
pneumonia by following proper procedures and policies. An example is a pharmacist making sure
pre-operation antibiotics are given on time before starting a surgical procedure.
The pharmacist’s role should also include educational activities. Pharmacists should be
knowledgeable in recent news and developments in antimicrobial use. The pharmacist can give
presentations, create newsletters or give topic discussions to health care professionals to spread
current knowledge in antimicrobial use. Education should include patients and caregivers, not only
in the inpatient setting but in ambulatory and home care settings as well. Antimicrobial education
can be presented at public health awareness events such as at senior centers and conferences.
Prudent use of antimicrobial agents, immunization and proper hand hygiene should be emphasized
at health awareness events.30
Conclusion
Antimicrobial stewardship plays a vital role in health care. It can improve infectious disease
outcomes while decreasing C. difficile infections and antimicrobial resistance. The presidential
executive order on combating antibiotic resistance highlights the importance of ASPs, and CMS will
be tying financial reimbursement to antimicrobial stewardship activities at health care facilities. Large
academic centers along with smaller community hospitals will need to have an ASP in place. The
core elements for stewardship are prospective review and formulary restriction. Supplemental
elements are education, guidelines, dose optimization and de-escalation among others. Pharmacists
can play an important role with these core elements, along with the supplemental elements.
Pharmacists can be actively involved with infectious disease rounding, Therapeutic Committees and
antimicrobial de-escalation. Pharmacists are directly involved with preventing hospital-acquired
infections with maintaining product sterility. Lastly, antimicrobial education through presentations
and patient interaction is another example of how pharmacists can be actively involved in
antimicrobial stewardship. As government agencies communicate more specific information for
requirements, pharmacists can play an important role in ASPs.
Continuing Education Self-assessment Questions
1. What is a positive outcome of antimicrobial stewardship?
a. Cure disease
b. Clostridium difficile infections
c. Antimicrobial resistance
d. Extended broad-spectrum antimicrobial therapy
2. What is a core component of an antimicrobial stewardship program?
a. Antimicrobial de-escalation
b. Education
c. Formulary restriction
d. Dose optimization
3. What government agency will be tying reimbursement payments to stewardship activities?
a. Center for Disease Control and Prevention (CDC)
b. Centers for Medicare and Medicaid Services (CMS)
c. The White House
d. Infectious Diseases Society of America (IDSA)
4. Which of the following describes antimicrobial de-escalation?
a. Empiric therapy changed to targeted therapy
b. Only using monotherapy
c. Adding a medication to cover for suspected Pseudomonas aeruginosa
d. Narrow therapy changed to empiric therapy
5. Who should be involved in prospective review and audit?
a. Only the prescribing physician
b. A pharmacist with infectious disease training
c. Nurse’s aide
d. Laboratory personnel
6. What activity can guide health care providers to appropriate antimicrobial choices?
a. Intravenous to oral medication conversion
b. Clinical pathway
c. Antimicrobial de-escalation
d. Antimicrobial cycling
7. Pharmacists should be involved in what Committee(s)?
a. Physician and Therapeutics Committee
b. Laboratory Subcommittee
c. Infectious Disease Subcommittee
d. A and C
8. Which of the following is an example of passive education?
a. Presentations
b. E-mail alerts
c. Prospective audit
d. A and B
9. What activity has not been shown to be beneficial to antimicrobial stewardship?
a. Antimicrobial de-escalation
b. Formulary restriction
c. IV to PO conversation
d. Antibiotic cycling
10. How can pharmacists impact antimicrobial stewardship?
a. Promote optimal antimicrobial use
b. Input on antimicrobial guidelines and policies
c. Antimicrobial de-escalation
d. All of the above
References:
1. U.S. Outpatient Antibiotic Prescribing, 2010, New England Journal of Medicine, 2013, 368, pp.
1461-1462.
2. Hensgens, M.P., Goorhuis, Dekkers, O.M., et al., Time interval of increased risk for
clostridium difficile infections after exposure to antibiotics, Journal of Antimicrobial
Chemotherapy, 2012, 67 (3), pp. 742-748.
3. Nanwa, N., Kendzerska, T., Krahn, M., et al., The economic impact of Clostridium difficile
infection: A systematic review, American Journal of Gastroenterology, 2015, 110 (40), pp. 511-519.
4. UCLA Statement on Notification of Patients Regarding Endoscopic Procedures, Health and
Medicine News, UCLA Health, March 10, 2015, www.UCLAhealth.org/news/uclastatement-on-notification-of-patients-regarding-endoscopic-procedures , May 5, 2015.
5. Dellit, T.H., Owens, R.C., McGowan, J.E., et al,. Infectious Diseases Society of America and
the Society for Healthcare Epidemiology of America Guidelines for Developing an
Institutional Program to Enhance Antimicrobial Stewardship, Clinical Infectious Diseases, 2007,
44, pp. 159-177.
6. Pedersen, C.A., Schneider, P.J., Scheckelhoff, D.J., ASHP National Survey of Pharmacy
Practice in Hospital Settings: Prescribing and Transcribing, 2013, American Journal of HealthSystem Pharmacy, 2014, 71 (11), pp. 924-942.
7. Executive Order—Combating Antibiotic-Resistant Bacteria, Presidential Actions, The White
House, Sept. 18, 2014, www.whitehouse.gov/the-press-office/2014/09/18/executive-ordercombating-antibiotic-resistant-bacteria, April 24, 2015.
8. CMS Sets the Table for Regulation Requiring Antibiotic Stewardship Programs, AHC Media,
Feb. 13, 2015, www.ahcmedia.com/articles/134561-cms-sets-the-table-for-regulationrequiring-antibiotic-stewardship-programs, March 24, 2015.
9. Fraser, G.L., Stogsdill, P., Dickens, J.D., Jr., et al., Antibiotic Optimization: An Evaluation of
Patient Safety and Economic Outcomes, Archives of Internal Medicine, 1997, 157, pp. 16891694.
10. Yu, K., Rho, J., Morcos, M., et al., Evaluation of Dedicated Infectious Diseases Pharmacists
on Antimicrobial Stewardship Teams, American Journal of Health-System Pharmacy, 2014, 71, pp.
1019-1028.
11. LaRocco, A., Concurrent Antibiotic Review Programs—A Role for Infectious Diseases
Specialists at Small Community Hospitals, Clinical Infectious Diseases, 2003, 37, pp. 742-743.
12. Seligman, S.J., Reduction in Antibiotic Costs by Restricting use of an Oral Cephalosporin,
American Journal of Medicine, 1981, 71, pp. 941-944.
13. Quale, J., Landman, D., Aurina, G., et al., Manipulation of a Hospital Antimicrobial
Formulary to Control an Outbreak of Vancomycin-resistant Enterococci, Clinical Infectious
Diseases, 1996, 23, pp. 1020-1025.
14. Boucher, H.W., Talbot, G.H., Bradley, J.S., et al., Bad Bugs, No Drugs: No ESKAPE! An
Update from the Infectious Diseases Society of America, Clinical Infectious Diseases, 2009, 48
(1), pp. 1-12.
15. Bantar, C., Sartori, B., Vesco, E., et al., A Hospitalwide Intervention Program to Optimize
The Quality of Antibiotic Use: Impact on Prescribing Practice, Antibiotic Consumption,
Cost Saving and Bacterial Resistance, Clinical Infectious Diseases, 2003, 37, pp. 180-186.
16. Dranitsaris, Spizzirri, D., Pitre, M., et al,. A Randomized Trial to Measure the Optimal Role
of the Pharmacist in Promoting Evidence-based Antibiotic Use in Acute Care Hospitals,
International Journal of Technology Assessment in Health Care, 2001, 17 (2), pp. 171-180.
17. Marrie, T.J., Lau, C.Y., Wheeler, S.L., et al., A Controlled Trial of a Critical Pathway for
Treatment of Community-Acquired Pneumonia, Journal of the American Medical Association,
2000, 283 (6), pp. 749-755.
18. Singh, N., Rogers, P., Atwood, C.W., et al., Short-course Empiric Antibiotic Therapy for
Patients with Pulmonary Infiltrates in the Intensive Care Unit, A Proposed Solution for
Indiscriminate Antibiotic Prescription, American Journal of Respiratory Critical Care Medicine,
2000, 162, pp. 505-511.
19. Stein, G.E., Comparison of Single-dose Fosfomycin and a 7-day Course of Nitrofurantoin in
Female Patients with Uncomplicated Urinary Tract Infection, Clinical Therapeutics, 1999, 21,
pp. 1864-1872.
20. Paterson, D.L., Rice, L.B., Empirical Antibiotic Choice for the Seriously Ill Patients: Are
Minimization of Selection of Resistant Organisms and Maximization of Individual Outcome
Mutually Exclusive?, Clinical Infectious Diseases, 2003, 36, pp. 1006-1012.
21. Briceland, L.L., Nightingale, C.H., Quintiliani, R., et al., Antibiotic Streamlining from
Combination Therapy to Monotherapy Utilizing an Interdisciplinary Approach, Archives of
Internal Medicine, 1988, 148, pp. 2019-2022.
22. Przybylski, K.G., Rybak, M.J., Martin, P.R., et al., A Pharmacist-initiated Program of
Intravenous to Oral Antibiotic Conversion, Pharmacotherapy, 1997, 17, pp. 271-276.
23. Durbin, W.A., Lapidas, B., Goldmann, D.A., Improved Antibiotic Usage Following
Introduction of a Novel Prescription System, Journal of the American Medical Association, 1981,
246, pp. 1796-1800.
24. Harbarth, S., Barbino, J., Pugin, J., et al., Inappropriate Initial Antimicrobial Therapy and its
Effect on Survival in a Clinical Trial of Immunomodulating Therapy for Severe Sepsis,
American Journal of Medicine, 2003, 115 (7), pp. 529-535.
25. Bliziotis, I.A., Samonis, G., Vardakas, K.Z., et al., Effect of Aminoglycoside and Beta-lactam
Combination Therapy Versus Β-lactam Monotherapy on the Emergence of Antimicrobial
Resistance: A Meta-Analysis of Randomized, Controlled Trials, Clinical Infectious Diseases,
2005, 41, pp. 149-158.
26. Gerding, D.N., Larson, T.A., Hughes, R.A., et al., Aminoglycoside Resistance and
Aminoglycoside Usage: Ten Years of Experience in One Hospital, Antimicrobial Agents
Chemotherapy, 1991, 35, pp. 1284-1290.
27. Martinez, J.A., Nicolas, J.M., Marco, F., Comparison of Antimicrobial Cycling and Mixing
Strategies in Two Medical Intensive Care Units, Critical Care Medicine, 2006, 34, pp. 329-336.
28. Bergstrom, C.T., Lo, M., Lipsitch, M., Ecological Theory Suggests That Antimicrobial
Cycling Will not Reduce Antimicrobial Resistance in Hospitals, Proceedings of the National
Academy of Sciences, USA, 2004, 101 (36), pp. 13285-132890.
29. Lancaster, J.W., Lawrence, K.R., Fong, J.J., et al., Impact of an Institution-specific Hospitalacquired Pneumonia Protocol on the Appropriateness of Antibiotic Therapy and Patient
Outcomes, Pharmacotherapy, 2008, 28 (7), pp. 852-862.
30. ASHP Statement on the Pharmacist’s Role in Antimicrobial Stewardship and Infection
Prevention and Control, American Journal of Health-System Pharmacy, 2010, 67 (7), pp. 575-577.
31. Evan, R.S., Pestotnik, S.L., Classen, D.C., et al., Evaluation of a Computer-assisted
Antibiotic-dose Monitor, Annals of Pharmacotherapy, 1999, 33, pp. 1026-1031.
32. Pestotnik, S.L., Classen, D.C., Evans, R.S., et al., Implementing Antibiotic Practice
Guidelines Through Computer-assisted Decision Support; Clinical and Financial Outcomes,
Annals of Internal Medicine, 1996, 124, pp. 884-890.