Antimicrobial Resistance and Antimicrobial

Stewardship Program
Learning Objectives: To recognize

▪ Important terms related to antimicrobial resistance

▪ Epidemiology and etiology of antimicrobial resistance.
▪ Guideline for developing a program to enhance antimicrobial stewardship.
▪ Prevention and control of multidrug resistant organisms.

I. Important Terms

Multidrug-resistant (MDR) bacteria: CDC typically uses this term to refer to a bacterial
isolate that is not susceptible to at least one antibiotic in three or more drug classes.
Extensively drug-resistant (XDR) bacteria: non-susceptibility to at least one agent in all
classes but two or fewer antimicrobial classes (i.e. bacterial isolate remains susceptible to only
one or two classes).
Pandrug-resistant (PDR) bacteria: non-susceptibility to all agents in all antimicrobial
categories.

II. Epidemiology of Antimicrobial Resistance

The emergence and spread of drug-resistant pathogens that have acquired new resistance
mechanisms, leading to antimicrobial resistance, continues to threaten our ability to treat
common infections. Especially alarming is the rapid global spread of multi- and pan-resistant
bacteria (also known as “superbugs”) that cause infections that are not treatable with existing
antimicrobial medicines such as antibiotics.
MDR in various bacterial pathogens has reached to a pandemic level during the last 2
decades. CDC estimates that in the US more than 2 million people are infected every year with
antibiotic resistant microbes and at least 23.000 die due to these infections.
The calculated price tag is $20 billion in direct healthcare costs, with far more costs in lost
productivity. A similar report from Britain predicts that the toll of global antimicrobial resistance
will be 10 million deaths per year and up to $100 trillion lost to the global economy by 2050. A

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recent study revealed that 30% reduction of efficacy of antibiotics for antibacterial prophylaxis
in surgery and cancer chemotherapy may result in 120.000 additional surgical site- and post-
chemotherapy-infections per year in the US and 6300 infection-related deaths.

III. Etiology of Resistance

Though resistance to antimicrobials is a natural biological phenomenon, yet it can be

amplified or accelerated by a variety of factors, including human practices.

Contributing factors:
A‐ Increased infection transmission, coupled with
B‐ Inappropriate antibiotic use.
“A vicious cycle: more infections and antibiotic overuse”

A) Causes for the increased infections:

• Urbanization with its concomitant overcrowding and poor sanitation.

• Pollution, environmental degradation, and changing weather.

• Demographic changes, ensuing a growing proportion of elderly people needing

hospitalization and thus at risk of exposure to highly resistant pathogens.

• Resurgence of old enemies, as malaria and TB.

• Enormous growth of global trade and travel and resistant microorganisms can
spread amongst continents.

• People on chemotherapy and transplant recipients taking immunosuppressive drugs are at

greater risk of infection.

• Increased use of day‐care facilities.

• Advances in modern medicine (Endoscopy, dialysis, transplant ,...etc) have made more people
predisposed to infection.

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B) Inappropriate antibiotic use:
• The unrestricted sale with subsequent uncontrolled.

• Paradoxically, underuse through lack of access, inadequate dosing, poor adherence, may
play as important a role as overuse.

• Misuse and overuse of antimicrobials is one of the world’s most pressing public health
problems. Infectious organisms adapt to the antimicrobials designed to kill them, making
the drugs ineffective. People infected with antimicrobial-resistant organisms are more
likely to have longer, more expensive hospital stays, and may be more likely to die as a
result of an infection.

• In addition, the enhanced food requirements of an expanding world population have led to
the widespread routine use of antimicrobials as growth promoters or preventive agents in
food‐producing animals. Such practices have likewise contributed to the rise in resistant
microbes, which can be transmitted from animals to man.

IV. Prevention and Control of Multidrug-Resistant Organisms (MDROs)

Although certain MDROs describe resistance to only one agent e.g., methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), these pathogens
are frequently resistant to most available antimicrobial agents.
Also, certain gram-negative bacilli (e.g. Escherichia coli, Klebsiella pneumoniae),
including those producing extended spectrum beta-lactamases (ESBLs) or carbapenem resistant
Enterobacteriaceae (CRE) are of particular concern, in addition to certain bacteria such as
Acinetobacter baumannii that are intrinsically resistant to the broadest-spectrum antimicrobial
agents.

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A) Prevention of MDROs:

Figure (1): CDC key prevention strategies for antimicrobial resistance

(CDC campaign to prevent antimicrobial resistance pocket card)

B) Control of MDROs:

Successful control of MDROs has been documented using a variety of combined

interventions.

Interventions used to control or eradicate MDROs

They may be grouped into seven categories:

1. Administrative support.
2. Education
3. Judicious use of antimicrobial agents
4. Surveillance for MDROs
5. Infection Control Precautions
6. Environmental measures
7. Decolonization
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1. Administrative support:
There are several control interventions that require administrative commitment of
financial and human resources;
• Building capacities of micro labs and providing necessary supplies for standardized micro
workup.
• The use of Active Surveillance Cultures (ASC).
• Implementing system changes to ensure prompt and effective communications e.g.,
computer alerts.
• Providing necessary number and appropriate placement of hand washing sinks and
alcohol-containing hand rub dispensers in the facility.
• Enforcing adherence to recommended IC practices (e.g., Hand hygiene, Standard and
Contact Precautions) for MDRO control.
• Direct observation with feedback to HCP on adherence to recommended precautions and
keeping HCP informed about changes in transmission rates.
• Participation in existing, or the creation of new, Local, or National coalitions, to combat
emerging or growing MDRO problems.
2. Education:
Educational campaigns to enhance adherence to hand hygiene, antibiotic prescribing
patterns…etc, in conjunction with other control measures have been associated with decreases
in MDRO transmission in various healthcare settings.

3. Judicious use of antimicrobial agents:

Limiting antimicrobial use alone may fail to control resistance due to a combination of
factors:
a) Relative effect of antimicrobials on providing initial selective pressure;
b) Inadequate limits on usage; or
c) Insufficient time to observe the impact of this intervention.

Evidence-based principles for judicious use of antimicrobials; should target all

healthcare settings and focus on:
• Effective antimicrobial treatment of infections,

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 • Use of narrow spectrum agents,
• Treatment of infections and not contaminants,
• Avoiding excessive duration of therapy, and
• Restricting use of broad-spectrum or more potent antimicrobials to treatment of
serious infections.
Achieving these objectives would likely diminish the selective pressure that favors
proliferation of MDROs.

4. Surveillance for MDROs:

Surveillance is an important component of any MDRO control program, allowing
detection of emerging pathogens, monitoring trends, and measuring effectiveness of
interventions.
Multiple MDRO surveillance strategies have been employed, ranging from surveillance
of clinical micro lab results obtained from routine clinical care, to use of ASC to detect
asymptomatic colonization.

i. Surveillance for MDROs isolated from routine clinical cultures

- The simplest form of MDRO surveillance is monitoring of clinical microbiology isolates
resulting as part of routine clinical care.
- This method is useful to detect emergence of new MDROs not previously detected, either
within an individual healthcare facility or community-wide.

ii. Surveillance for MDROs using ASC for Detecting Asymptomatic Colonization

Active surveillance cultures (ASCs) are targeted microbiological screening cultures for
patients admitted to a hospital.
- The most commonly tracked antimicrobial resistance organisms in surveillance programs are
MRSA, VRE, Clostridium difficile, ESBL producing gram-negative bacilli, and CRE.
- ASC is used to identify patients who are colonized with a targeted MDRO.
- ASC have been used when new pathogens emerge, in order to define the epidemiology of
that particular agent.

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- ASC, in combination with Contact Precautions for colonized patients, contributed directly to
the decline or eradication of the target MDRO.
- However, not all studies have reached the same conclusion. Poor control of MRSA was
reported despite use of ASC.

5. Infection control precautions:

• Since 1996 CDC recommended the use of Standard and Contact Precautions for MDROs.
• This recommendation was based on general consensus and was not necessarily evidence-
based.
• No studies have compared the efficacy of Standard Precautions alone versus Standard
Precautions and Contact Precautions, with or without ASC, for control of MDROs.

Contact Precautions
– A single-patient room is preferred for patients who require contact precautions.
– When a single-patient room is not available, it is necessary to assess the various risks
associated with other placement options (e.g., cohorting).
– Donning gown and gloves upon room entry and discarding before exiting is done to
contain pathogens implicated in transmission (e.g.VRE, C. diff. and other intestinal tract
agents).
– Duration of contact precautions: contact precautions can be used indefinitely for all
previously infected and known colonized patients. If ASC are used to detect and isolate
patients colonized with MRSA or VRE, it is logical to use contact precautions for the
duration of stay in the setting. Discontinue contact precautions when three or more
surveillance cultures are repeatedly negative for a week or two in a patient who:
• Has not received antimicrobial therapy for weeks
• with absence of evidence implicating patient in ongoing transmission of the
MDRO within the facility.
• And absence of draining wound and profuse respiratory secretions.
– Impact of contact precautions on patient care: It was reported that patients in private
rooms, on barrier precautions for MDRO had increased anxiety and depression. Another
study found that patients on Contact Precautions for MRSA had more preventable

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 adverse events and expressed greater dissatisfaction with their treatment.
Therefore, when patients are placed on Contact Precautions, efforts must be made to
counteract these potential adverse effects.

6. Environmental measures:
• The potential role of environmental reservoirs, such as surfaces and medical equipment, in
transmission of MDROs, has been reported.
• While environmental cultures are not routinely recommended, they were used to document
contamination.
• A common reason for environmental contamination with a MDRO was the lack of
adherence to cleaning and disinfection procedures. These organisms need thorough and
meticulous cleaning of surfaces.

7. Decolonization
o Decolonization entails treatment of persons colonized with a MDRO to eradicate carriage
of that organism.
o Decolonization of persons carrying MRSA in their nares has proved possible with topical
mupirocin alone or in combination with oral antibiotics (e.g., rifampin with
trimethoprim- sulfamethoxazole) plus an antimicrobial soap for bathing.
o Decolonization regimens are not sufficiently effective to warrant routine use; several
factors limit the utility of this control measure:
a. Identification of candidates for decolonization requires surveillance cultures;
b. Candidates for decolonization treatment must receive follow-up cultures to ensure
eradication; and
c. Recolonization with the same strain and emergence of resistance to mupirocin
during treatment can occur.
o HCP implicated in transmission of MRSA are candidates for decolonization and should
be treated and culture negative before returning to direct patient care.
o In contrast, HCP who are colonized with MRSA, but are asymptomatic, and have not
been linked to transmission, do not require decolonization.

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 V. Antimicrobial Stewardship

Looking at other disciplines on Web of Science, ‘stewardship’ has mostly been used in
the ethics, policy, economics, theology and environment domains, and it had rarely been used
until the 1990s. According to the Merriam-Webster dictionary, stewardship refers to:
1) The office, duties, and obligations of a steward
2) The conducting, supervising, or managing of something; especially the careful and
responsible management of something entrusted to one's care.

The Infectious Diseases Society of America (IDSA) and the Society for Healthcare
Epidemiology of America (SHEA) issued guidelines in 2007 for developing an institutional
antimicrobial stewardship program to enhance antimicrobial stewardship and help prevent
antimicrobial resistance in hospitals. The antimicrobial stewardship program may vary among
facilities based on available resources.

Definition:
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of
antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance,
and decreases the spread of infections caused by multidrug-resistant organisms.
It is an activity that includes appropriate selection, dosing, route, and duration of antimicrobial
therapy.

Goals:

• The primary goal of antimicrobial stewardship is to optimize clinical outcomes while

minimizing unintended consequences of antimicrobial use. The combination of effective
antimicrobial stewardship with a comprehensive IC program can limit the emergence and
transmission of antimicrobial-resistant bacteria.

• A secondary goal of antimicrobial stewardship is to reduce health care costs without

adversely impacting quality of care.

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The antimicrobial stewardship team (AST) and administrative support:

The Antimicrobial stewardship program should be administered by multidisciplinary

team (AST) composed of:

1. An infectious diseases (ID) physician

2. A clinical pharmacist with ID training

3. A clinical microbiologist

4. An IC professional

5. An information system specialist (if possible)

6. A hospital epidemiologist.

– The AST should obtain adequate authority.

– It should maintain responsibility for antimicrobial policy and formulary management, in

response to national guidance and local susceptibility data.

– The main tasks of the AST are:

o To establish a drug formulary (after full consultation with the clinical staff).

o To formulate guidelines for prophylaxis and therapy of infection .

o To review antibiotic use.

o To provide feedback to clinicians on appropriate usage.

o To be responsible for education and dissemination of information.

o To work closely with the ICT in the hospital.

– Collaboration between the AST and the hospital infection control and pharmacy and
therapeutics committees is essential.

– The support and collaboration of hospital administration, medical staff leadership, and
local providers in the development and maintenance of antimicrobial stewardship
programs is essential.

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– Hospital administrative support for the necessary infrastructure to measure and track
antimicrobial use on an ongoing basis is essential.

Elements of an antimicrobial stewardship program:

A comprehensive evidence-based antimicrobial stewardship program to combat

antimicrobial resistance includes elements chosen from among the following strategies,
which are based on local antimicrobial use and resistance problems, and on available
resources.

Figure (2): Core Elements of Any Antimicrobial Stewardship.

HCAIs, Health Care Associated Infections

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 1) Active Antimicrobial Stewardship Strategies

a. Prospective audit with intervention and feedback

Prospective audit of antimicrobial use with direct interaction and feedback to the
prescriber, performed by either an ID physician or the clinical pharmacist, can result in
reduced inappropriate use of antimicrobials.

b. Formulary restriction and preauthorization requirements for specific agents

• The strategy of formulary restriction and pre-authorization involves limiting the use of
specified antimicrobials to certain approved indications.

• An antimicrobial committee creates guidelines to the approved use of agents. If necessary,

designated personnel are made available for the approval process.

• However, monitoring overall trends in antimicrobial use is necessary to assess and respond
to shift to alternative agents.

• Antibiotics may be conveniently put into categories according to usage:

- Unrestricted antibiotics: can be prescribed by all grades of medical staff.

- Restricted antibiotics: prescribed only on the advice of the consultant.

- Reserve antibiotics: for specific diseases e.g., tuberculosis.

- Withdrawn antibiotics: discontinued from use in the hospital.

2) Supplemental Antimicrobial Stewardship Strategies

a. Education

• Education is an essential element of any program designed to influence prescribing

behavior and can provide knowledge that will enhance and increase the acceptance of
stewardship strategies.

• However, education alone, without incorporation of active intervention, is marginally

effective and not sustainable in changing prescribing practices.

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b. Guidelines and clinical pathways
• Multidisciplinary development of evidence‐based practice guidelines incorporating local
microbiology and resistance patterns can improve antimicrobial utilization.

• Guideline implementation can be facilitated through provider education and feedback on

antimicrobial use and patient outcomes.

c. Empirical therapy
• Consider whether or not the patient actually requires an antibiotic.
• In general, do not change empirical antibiotic therapy if the clinical condition indicates
improvement.
• If there is no clinical response in 72 hours, the clinical diagnosis, the choice of antibiotic
(culture &sensitivity) and a secondary infection should be reconsidered.
• Review the duration of antibiotic therapy (e.g. after 7 or 10 days).

d. Antimicrobial cycling and scheduled antimicrobial switch

• The routine use of antimicrobial cycling is recommended as a means of preventing or
reducing antimicrobial resistance over a prolonged period of time.
• Substituting one antimicrobial for another may transiently decrease selection pressure and
reduce resistance to the restricted agent.

e. Antimicrobial order forms

• Antimicrobial order forms can be an effective component of antimicrobial stewardship and
can facilitate implementation of practice guidelines.
• The use of order forms, with an automatic stop function, requiring a prescriber to justify
his decision has been shown to be beneficial.

f. Combination therapy
• Combination therapy does have a role in certain clinical contexts, e.g. critically ill patients
at risk of infection with multidrug resistant pathogens; to increase the coverage and the
likelihood of adequate initial therapy.
• But, there are insufficient data to recommend the routine use combination therapy to
prevent the emergence of resistance.

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 Possible reasons for using two or more antimicrobials as follows:
- To delay the emergence of microbial mutants resistant to one drug in chronic
infections e.g. tuberculosis.
- To treat mixed infections e.g. those following massive trauma.
- To achieve bactericidal synergism.
- To give prompt treatment conditioned by desperately ill patients suspected of
having a serious microbial infection.

Disadvantages of combined antimicrobial therapy:

- It may give a false sense of security when the physician feel that since several
drugs are already being given, everything possible has been done for the patient.
- The more drugs that are administered, the greater the chance for drug reactions to
occur.
- Very rarely, one drug may antagonize a second one given simultaneously.
- Mostly it is costly.

g. Streamlining or de‐escalation of therapy

Streamlining or de‐escalation of empirical antimicrobial therapy, on the basis of

culture results, can more effectively target the causative pathogen, resulting in decreased
antimicrobial exposure and substantial cost savings.

h. Dose optimization

Optimization of antimicrobial dosing based on individual patient characteristics, causative

organism, site of infection, and pharmacokinetic and pharmacodynamic characteristics of the
drug is an important part of antimicrobial stewardship.

i. Conversion from parenteral to oral therapy

A systematic plan for parenteral to oral conversion of antimicrobials, when the patient’s
condition allows, can decrease length of hospital stay and health care costs.

Development of clinical criteria and guidelines allowing conversion to use of oral

agents can facilitate implementation at the institutional level.

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References:

➢ Akova M. Epidemiology of antimicrobial resistance in bloodstream infections. Virulence.

2016;7(3):252-66.

➢ Barlam TF, et al. Implementing an antibiotic stewardship program: guidelines by the

Infectious Diseases Society of America and the Society for Healthcare Epidemiology of
America. Clinical infectious diseases. 2016; 62(10):e51-77.

➢ Dellit TH, 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(2):159-77.

➢ Centers for Disease Control and Prevention campaign to prevent antimicrobial resistance
pocket card, 2002.

➢ ABCs of infection prevention and control. Egyptian society for infection control.
APIC/Egypt chapter.1st ed, 2017.

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