1

AMSP COURSE CURRICULUM

This Antimicrobial Stewardship Program (AMSP) curriculum has been developed to educate health care

workers on the principles of judicious antibiotic use, helping them apply guidelines and algorithms in

ensuring improved patient outcomes, preventing antibiotic misuse and minimizing antimicrobial

resistance. The curriculum primarily targets hospital doctors (especially junior doctors, practicing

physicians and surgeons) and nurses involved in infection control and prevention. It is intentionally

concise and deals with the basic aspects of antimicrobial use and focuses on practical aspects of

implementing an AMSP. This curriculum is only an adjunct to the one day contact program on AMSP, as

part of the pilot initiative conducted by the ICMR for the relevant members of the AMSP representing

select hospitals.

The program goals/learning objectives are the following:

Introduce the scope and implications of antibiotic misuse and the impact of antimicrobial

resistance

Outline the essentials of clinical microbiology, pharmacology, pharmacokinetics,

pharmacodynamics, and infectious disease state management necessary in Antimicrobial

Stewardship.

Understanding the Hospital Antibiogram.

Describe the development of evidence-based guidelines to implement clinical pathways.

Define and set the goals for AMSP

Describe how to justify the benefits of an antimicrobial stewardship program to administrative

and clinical leadership.

Identify potential financial and institutional barriers to implementation of an antibiotic

stewardship program.

Implement interventions to improve patient care, minimize resistance and cost, and prolong the

longevity of antimicrobials as strategies of AMSP.

Identify barriers to implementing components of an antimicrobial stewardship project.

Outline strategies to overcome barriers identified for an antimicrobial stewardship project.

Explain how to evaluate the effectiveness of an antimicrobial stewardship program through the

measurement of outcomes.

Define the interaction between AMSP and infection control.

2

Introduction

Tragic Irony of a Miracle

The serendipitous observation by Alexander Fleming on the morning of September 3, 1928 that there

was a halo of inhibition of bacterial growth around a contaminant blue-green mould on a staphylococcal

plate culture paved the way for the discovery of a miracle. Penicillium notatum, from which penicillin

was produced, was the first step in the journey towards the antibiotic revolution. Antibiotics helped

transform the practice of medicine in the fight against bacterial infections. The heady euphoria created

by the discovery of various antibiotics in the 1950s prompted Dr William Stewart, the Surgeon General

of the United States to remark, ‘The time has come to close the book on Infectious Diseases. We have

basically wiped out infections in the United States’. But we failed to realize the resilience of the

microbes; their survival skills, characterized by their ability to develop resistance. This evolutionary

adaptation, in the face of antibiotic pressure has led to us losing a miracle.

Defining scope and implications of antibiotic misuse

The prompt initiation of antibiotics to treat infections has been proven to reduce morbidity and save

lives. Roughly 50% of patients in health-care facilities are prescribed antimicrobials. However, over half

of all antibiotics prescribed in acute care hospitals are either unnecessary or inappropriate. Moreover,

up to 85% of antibiotics have a non-human use and up to 75% have a non-therapeutic use. Like all

medications, antibiotics have serious side effects, including adverse drug reactions and Clostridium

difficile infection (CDI). Patients who are unnecessarily exposed to antibiotics are placed at risk for

serious adverse events with no clinical benefit. The misuse of antibiotics has also contributed to the

growing problem of antibiotic resistance, which has become one of the most serious and growing

threats to public health. Even though antibiotics do not generally induce resistance, they select out

resistant genes which offer a survival benefit. These genes can be horizontally transferred between

bacteria. Unlike other medications, the potential for spread of resistant organisms means that the

misuse of antibiotics can adversely impact the health of patients who are not even exposed to them.

Antimicrobial Resistance

The resistance phenomenon can be characterized as follows:

o Given sufficient time and drug use, resistance will emerge

o Resistance is progressive, evolving from low levels to high levels

o Organisms resistant to one drug are likely to develop resistance to others

o Once resistance appears, it declines slowly if at all

o Use of antibiotics in one person affects others

Even though our learning curve has been steep, we failed to understand the implications for the future.

Antibiotic resistance can be spontaneous, but is usually induced by evolutionary selection pressure on

exposure to an antibiotic.

The mechanisms of antibiotic resistance:

3

Modification of antibiotic receptor

Loss of porin channels

Development of efflux pumps

Production of enzymes to destroy antibiotics

Genes that confer resistance can be transferred between bacteria by conjugation, transduction or

transformation. This enables a rapid spread of resistance genes between colonies of the same bacteria

and at times to similar bacterial populations.

In the United States, antimicrobial resistant (AMR) organisms cause more than 2 million infections and

are associated with approximately 23 000 deaths each year. In Europe, AMR is associated with

approximately 25 000 deaths annually. The economic costs of AMR are also substantial, estimated at

$20 billion in excess medical spending each year in the United States. The full global impact of AMR is

more difficult to quantify, as epidemiological data are sparse in many areas of the world. However, data

that are available from India are cause for significant concern.

Improving the use of antibiotics is an important patient safety and public health issue as well as a

national priority. A growing body of evidence demonstrates that hospital based programs dedicated to

improving antibiotic use, commonly referred to as “Antibiotic Stewardship Programs (ASPs)”, can both

optimize the treatment of infections and reduce adverse events associated with antibiotic use. These

programs help clinicians improve the quality of patient care and improve patient safety through

increased infection cure rates, reduced treatment failures, and increased frequency of correct

prescribing for therapy and prophylaxis. They also significantly reduce hospital rates of CDI and

antibiotic resistance. Moreover these programs often achieve these benefits while saving hospitals

money.

Understanding Clinical Microbiology

Antibiogram for the physician

An antibiogram is a result of a laboratory testing for the sensitivity of an isolated bacterial strain to

different antibiotics. Antibiograms help to determine the correct choice and dose of the antibiotic. They

are also used to study epidemiology of resistance and to evaluate the efficacy of a new antibiotic.

Antibiograms are an important resource for health care providers. The development of an antibiogram

should be a collaborative effort between microbiology, pharmacy, physicians and the hospital policy

committees. It is an overall profile of antimicrobial susceptibility results of a microbial species to a

battery of antimicrobial agents. Data from antibiograms are useful for initiating empiric therapy and

when tracking antimicrobial resistance trends over time within a hospital or healthcare system.

Once a culture is established, there are two possible ways to get an antibiogram:

-A semi-quantitative way based on diffusion (Kirby-Bauer method)

-A quantitative way based on dilution – MIC (minimum inhibitory concentration)

4

The basic idea of diffusion assays is as follows:

The tested antibiotics are impregnated in paper discs which are placed on plate of agar medium

inoculated with the bacteria in question. Following diffusion of the compounds through the agar, a

"halo" or zone of inhibition forms where concentrations of the specific diffused antibiotic are sufficient

to inhibit that microbial growth. Therefore, it is often assumed that the larger the diameter of the zone

of inhibition, the more potent the antimicrobial. A number of factors however, may interfere with this

interpretation. Firstly, the concentration of the antibiotic in the disc must be taken into account. The

higher the concentration in the disc, the more concentrated the compound will be at a given distance

from the disc itself. Also, the length of time allowed for the process to occur can greatly influence the

diameter of the zone of inhibition, as the longer diffusion is allowed to take place the higher the

concentrations at any given point in the gradient will be. In addition, the extent of the growth of the

microbe, in relation to the degree of diffusion, can influence the resulting zone of inhibition, such that

the timing of the both factors, microbial growth and diffusion, interplay.

Interpreting an antibiogram can be simplified by understanding some basic principles. The knowledge of

a select few antibiotics referred to as indicator antibiotics can be applied to aid choice of appropriate

therapy.

Susceptibility breakpoint: A susceptibility breakpoint may be defined as the minimum inhibitory

concentration (MIC) value for an antibiotic to a specific pathogen. The MIC value determines whether

the particular bacteria will be classified as S, I or R.

NATURAL RESISTANCES TYPICAL OF COMMON PATHOGENS

ORGANISMS NATURAL RESISTANCES TO

All Enterobacteriaceae Penicillin G, glycopeptides, fusidic acid, macrolides, clindamycin, linezolid,

mupirocin

Acinetobacter baumannii Ampicillin, amoxycillin, first-generation cephalosporins

P. aeruginosa Ampicillin, amoxycillin, co-amoxiclav, first-generation cephalosporins,

second-generation cephalosporins, cefotaxime, ceftriaxone, nalidixic acid,

trimethoprim

B. cepacia Ampicillin, amoxycillin, first-generation cephalosporins, colistin,

aminoglycosides

Stenotrophomonas maltophilia All β-lactams except ticarcillin/clavulanate, aminoglycosides

Flavobacterium

(Chryseobacterium)

Ampicillin, amoxycillin, first-generation cephalosporins

Salmonella spp. Cefuroxime, aminoglycosides (active in vitro, not active in vivo)

5

Klebsiella spp., Citrobacter diversus Ampicillin, amoxycillin, carbenicillin, ticarcillin

Enterobacter spp., C. freundii Ampicillin, amoxycillin, co-amoxiclav, first-generation cephalosporins,

cefoxitin

M. morganii Ampicillin, amoxycillin, co-amoxiclav, first-generation cephalosporins,

cefuroxime, colistin, nitrofurantoin

Providenicia spp. Ampicillin, amoxycillin, co-amoxiclav, first-generation cephalosporins,

cefuroxime, gentamicin, netilmicin, tobramycin, colistin, nitrofurantoin

Proteus mirabilis Colistin, nitrofurantoin

Proteus vulgaris Ampicillin, amoxycillin, cefuroxime, colistin, nitrofurantoin

Serratia spp. Ampicillin, amoxycillin, co-amoxiclav, first-generation cephalosporins,

cefuroxime, colistin

Yersinia enterocolitica Ampicillin, amoxycillin, carbenicillin, ticarcillin, first-generation

cephalosporins

Campylobacter jejuni,

Campylobacter coli

Trimethoprim

H. influenzae Penicillin G, erythromycin, clindamycin

M. catarrhalis Trimethoprim

All Gram-positive bacteria Aztreonam, temocillin, colistin, nalidixic acid

Streptococci Fusidic acid, aminoglycosides (except as synergists)*

S. pneumoniae Trimethoprim, aminoglycosides

Methiciilin-resistant S.aureus All β-lactams

Enterococci Penicillin G, carbenicillin, ticarcillin, all cephalosporins, aminoglycosides*,

mupirocin

Listeria Third-generation cephalosporins, fluoroquinolones

*Low-level resistance: aminoglycosides are useful for synergy with penicillins against typical streptococci

and enterococci

6

USEFUL INDICATOR ANTIBIOTICS

ORGANISM

RESISTANCE TO

INFERENCE/ACTION

Staphylococci Cefoxitin or oxacillin or methicillin Resistant to all β-lactams (MRSA)

Staphylococci erythromycin Inducible clindamycin resistance likely; avoid clindamycin or use with caution

Pneumococci oxacillin (zone ≤ 19 mm) Probably penicillin resistant. Perform E-test for penicillin or cephalosporin to be used.

E. faecalis (usually penicillin sensitive)

ampicillin Probably E. faecium, but may be less frequent species or (just possibly) may have acquired resistance: check speciation or refer.

H. influenzae cefaclor Likely non-β-lactamase-type resistance (better indicator than ampicillin)

N. gonorrhoeae/ H. influenzae nalidixic acid Indicates reduced susceptibility or resistance to fluoroquinolones

Klebsiella / E. coli ceftazidime or cefpodoxime Likely ESBL producer. Avoid all third generation cephalosporins; Carbapenems drugs of choice; βL-βLI in stable patients

Any Enterobacteriaceae any second-generation cephalosporin

Likely to have potent β-lactamase; avoid first-generation cephalosporins

Any Enterobacteriaceae any third-generation cephalosporin Likely to have potent β-lactamase; avoid first- and second-generation cephalosporins; Carbapenems drugs of choice; βL-βLI in stable patients

Any Enterobacteriaceae resistant to any β-lactamase inhibitor combinations

AmpC producer, assume resistance to the corresponding unprotected penicillin; Carbapenems drugs of choice

7

Mechanism Isolates Affected Unaffected

Common plasmid TEM, SHV

Most Gram negatives Ampicillin Cephalosporins 3 BL / BLI Carbapenems

Extended spectrum beta lactamase (ESBL)

Kleb, E.Coli Serratia Enterobacter

Above + 2/3 ceph monobactam

Carbapenem BL / BLI Cefoxitin

Amp C Enterobacter, pseudo, serratia, citro, proteus

Above + BL / BLI cefoxitin

? Cefepime carbapenem

Zinc metallo beta lactamase

S.malto P.aeruginosa

Above + carbapenem

? Aztreonam

Pharmacokinetics and dynamics

Antibiotics can act by a time dependent fashion (beta lactams, cephalosporins, macrolides, tetracyclines,

etc.) wherein you need to ensure that the levels of antibiotics are maintained above the minimum

inhibitory concentration (MIC) consistently. This is done by frequent dosing of the antibiotic or by

extended infusions. Certain other antibiotics (aminoglycosides, fluoroquinolones, daptomycin etc.) act

by a concentration dependent fashion, where, a high initial dose will ensure effective destruction of the

bacteria through a post-antibiotic effect, even though the level of the antibiotic may drop below MIC

subsequently.

Certain antibiotics like aminoglycosides and glycopeptides (vancomycin) and voriconazole may require

measurement of therapeutic drug levels (TDM) to ensure optimal action.

There is enough evidence available to confirm that there is no superiority in combination therapy over

monotherapy except in treating polymicrobial infections and certain specific infections like tuberculosis

and HIV. But evidence is now accumulating on the use of combination therapy for multidrug resistant

organisms like carbapenemase producers, with superior outcomes.

8

What is Antimicrobial stewardship?

AMSP refers to coordinated interventions designed to improve and measure the appropriate use of

antimicrobial agents by promoting the selection of the optimal antimicrobial drug regimen, including

dosing, duration of therapy, and route of administration, that results in the best clinical outcome for the

treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on

subsequent resistance.

Goals of AMSP

Antimicrobial stewardship (AMS) programs aim to provide assistance with optimal choice, dosage,

pharmacokinetic–pharmacodynamic (PK/PD) characteristics and duration of antibiotics in order to

improve patient outcomes, ensure patient safety, reduce costs, adverse events and the development of

resistance.

The first goal is to work with health care practitioners to help each patient receiving the most

appropriate antimicrobial with the correct dose and duration. The4 D’s of optimal antimicrobial therapy

are: right drug, right dose, de-escalation to pathogen-directed therapy, and right duration of therapy.

The second goal is to prevent antimicrobial overuse, misuse, and abuse.

The third goal is to minimize the development of resistance.

These measures are only effective if all stakeholders, supported by the relevant authorities, accept

implementation and incorporate audits and feedback mechanisms

Pitching AMSP to the Hospital A business case for an AMSP should address the following important questions:

• Will the proposed strategy for antimicrobial stewardship actually result in improved care?

• Is the improvement that an AMSP will bring considered central to healthcare or an optional feature?

• Will revenue increase for the organization as a result of the AMSP?

• What nonfinancial consequences of the improvement are important?

Even though there is global recognition for the AMR crisis, hospital administrators in India need

convincing regarding AMSP as an essential intervention.

The following are perceived barriers to a successful AMSP:

Insufficient resources, including funding, time, and people

Competing initiatives

Leaders unaware of the value of an AMSP

Opposition from prescribers

Lack of information technology support and/or inability to get data

Other specialties antagonized by an AMSP

Multiple infectious disease groups within a facility

The following eight approaches can be used to address these common barriers:

9

Acquire evidence-based data to ensure the success of an AMSP

Prioritize leadership strategic initiatives

Establish a clear vision for antimicrobial stewardship

Establish a multidisciplinary team

Identify a lead physician champion

Establish a business case and return on investment

Justify the investment

Pilot test the AMSP for justification and seek administrative approval

The following arguments highlight AMSP as an attractive business model.

There is global need to preserve antibiotic therapy in view of increasing AMR and declining

antibiotic pipeline, definitely more so in the Indian context

AMSP will help reduce antibiotic days of therapy, length of therapy and associated antibiotic

expense

AMSP will attenuate and/or reverse the rate of emergence of resistant bacteria

It will result in better patient care and fewer readmissions

In short, funding an AMSP will result in a solid return on investment, manifest as, better patient

care coupled with less antibiotic exposure. The results will include fewer adverse drug reactions,

less antibiotic resistance, and less expense to the medical center

10

Formulating local antibiotic guidelines, suggestion framework

Primary therapy Alternative

Ac osteomyelitis Cloxacillin/Cefazolin/Co-

amoxyclavGentamicin/ tobramycin

Clindamycin

Mastitis/ breast abscess Cloxacillin/Cefazolin Clindamycin / Co-

amoxyclav

Diabetic foot:

Early

Chronic

Severe

Clindamycin

Clindamycin+ cefaperazone- sulbactum

Ertapenem

Co-amoxyclav/

cefaperazone- sulbactum

Cellulitis Clindamycin/Cefazolin Co-amoxyclav

Decubitis ulcer Clindamycin + Cefaperazone- sulbactum

Gallblader Piperacillin tazobactum ampi + gentamicin +

metrogyl

Cefaperazone- sulbactum /

Ertapenem

Diverculitis Metrogyl + Cefaperazone- sulbactum Clindamycin + gentamicin

Perirectal abscess Clinda or metrogyl + Gentamicin or ceph 3

Joint Monoarticular

sexually active

> 40 yrs

Ceftriaxone/ ofloxacin clox + ceph 3 or

amikacin

Cloxacillin + Cefuroxime if

GPC

Adult polyarticular Ceftriaxone

Prosthetic / post-op Vancomycin + ceph 3 Ofloxacin + rifampicin

Liver abscess Ampi cillin+ gentamicin + metrogyl Imepenem

Ampicillin + ciprofloxacin or

ceph3

Muscle gangrene /

necrotisingfascitis

Clindamycin + penicillin Co-amoxyclav + gentamicin

11

Pancreas Co-amoxyclav, piperacillin-tazobactam Imepenem or meropenem

Peritonitis (secondary) Ceph 3 + clindamycin or metrogyl Cefaperazone- sulbactum

or ertapenem

Uncomplicated UTI Norfloxacin or ciprofloxacin

Pyelonephritis Ampicillin + gentamicin/ iv cipro / co-

amoxyclav

Cefaperazone- sulbactum

Brain abscess Primary or

contiguous

Ceftriaxone or cefotaxime pen + metrogyl

Post traumatic / surgical Cloxacillin + ceph3 Vancomycin + ceph3

Meningitis

7-50

>50

Ceftriaxone/ ceftotaxime

Add ampicillin

Endocarditis native valve Penicillin on ampicillin + gentamicin

cloxacillin

Vancomycin + gentamicin

COPD inf exacerbation Doxycycline/ co-amoxyclav/newer

macrolides or quinolones

CAP age 5-60 OP Clarithromycin / azithromycin Doxycycline

CAP > 60 Same or ceph 2

CAP hospitalized Ceph 2 + macrolides

CAP hosp severe Ceph 3 + iv azithromycin or clarithromycin

HAP L + L1

Aspiration Clindamycin Co- amoxyclav

Sepsis unknown L + L1 Ceph3 + gentamicin +

clindamycin or metrogyl

Sepsis burns Vancomycin + L + L1 Carbapenem

Enteric fever Ceftriaxone Cefuroxime or

azithromycin

12

Prophylactic antibiotic regimen selection for surgery

Surgical procedure Approved antibiotics

CABG, other cardiac or vascular Cefuroxime 1.5g

If –lactum allergy: Vancomycin* or Clindamycin* 600mg

Orthopaedic, hip/ knee

arthroplasty

Cefazolin 1-2 g or cefuroxime 1.5g or co-amoxyclav 1.2g

If –lactum allergy: Vancomycin* or Clindamycin*

Colon Co-amoxyclav or Cephazolin + Metronidazole

If –lactum allergy: Clindamycin + Gentamicin /Aztreonam

Hysterectomy & other gynaec

procedures

Cephazolin, cefuroxime or Co-amoxyclav

If –lactam allergy: Clindamycin + Gentamicin or clindamycin +

Aztreonam

Special considerations Dose to be increased appropriate to body weight

For all other major clean surgeries (gastro- duodenal, biliary, head &

neck, ENT, Neurosurgical, urologic) : cefazolin or cefuroxime.

Sinusitis Co-amoxyclav/ cefaclor Cefuroxime

Pharyngitis Amoxycillin/newer macrolides Cefuroxime

Orbital cellulites Cephalexin / co- amoxyclav Cefuroxime

Mastoditis acute Co-amoxyclav / cefuroxime

Mastoditis chronic Clindamycin + ceph3

13

Selecting appropriate course and duration of antibiotic therapy

Community acquired pneumonia 5 – 7days

Health care acquired pneumonia 8 days

SSI 5 days

UTI

Cystitis

Pyelonephritis

Catheter associated

3 – 5 days 14 days 7 days

S. aureus bacteremia

Uncomplicated

Complicated

2 weeks 4 – 6 weeks

Intra-abdominal infection 4 – 7 days

Surgical antimicrobial prophylaxis 1 dose (not longer than 24 hrs)

Summary of Core Elements of Hospital Antibiotic Stewardship Programs

Assess motivation: Deconstruct the issue of AMR, define problem to address, adapt appropriate

interventions and promote education

Leadership Commitment: Dedicating necessary human, financial and information technology

resources

Accountability: Appointing a single leader responsible for program outcomes. Experience with

successful programs show that a physician leader is effective

Action: Dedicate resources, appoint a multi-disciplinary team and incorporate quality

improvement and patient safety governance.

Identify and prioritize interventions: Implementing at least one recommended action, such as

systemic evaluation of ongoing treatment need after a set period of initial treatment (i.e.

“antibiotic time out” after 48 hours)

Tracking: Monitoring antibiotic prescribing and resistance patterns

Reporting: Regular reporting information on antibiotic use and resistance to doctors, nurses and

relevant staff

Education: Educating clinicians about resistance and optimal prescribing

14

AMSP Team

Every hospital should work according to the resources available to create a multidisciplinary inter-

professional antimicrobial management team that is physician directed or supervised. At a minimum, 1

or more members of the team should have training in ASP. The number of team members may vary on

the basis of the size and complexity of the facility.

Team members should include but are not limited to: i) a physician; ii) a pharmacist; iii) a clinical

microbiologist; iv) an infection preventionist (nurse or doctor).The 2007 IDSA/Society for Healthcare

Epidemiology of America (SHEA) guidelines for AMSPs defined the ideal antimicrobial program as led by

an ID physician and clinical pharmacist with ID training, together with a list of other important staff:

clinical microbiologist, information systems specialist, infection control professional, and hospital

epidemiologist. Although optimal, many institutions do not have an ID physician or an ID pharmacist

with sufficient skill to manage an AMSP. As a consequence, many institutions wanting to develop an

AMSP to improve clinical outcomes, reduce antimicrobial resistance, and lower costs will need to think

outside the box and look for progressive leaders to champion and lead their programs. Potential

nontraditional leaders include general clinical pharmacists, intensivists and internists. Internists with an

interest in infectious disease can be ideal physician leaders for efforts to improve antibiotic use given

their increasing presence in in patient care, the frequency with which they use antibiotics and their

commitment to quality improvement. Collaboration between ID specialists and internists in ASP is a vast

and mostly untapped resource.

It is recommended that the AMSP team meet periodically to evaluate the program performance, assess

efficacy and come up with innovative methods to deal with non-compliant health care workers.

Excellent channels of communication have to be maintained with the administrative leaders responsible

for supporting the program to help sort out sticky issues. Periodic feedback should also be given to the

ICMR in order to ensure uniformity of care and progress is maintained in the network of hospitals.

AMSP Strategies

A range of stewardship interventions have been explored for an effective program. These can be

categorized as core strategies and supplemental strategies.

Core strategies

The core strategies can be in the form of 2 major approaches, with the most successful programs

generally implementing a combination of both. The frontend or pre-prescription approach to

stewardship uses restrictive prescriptive authority. Certain antimicrobials are considered restricted and

require prior authorization for use by all except a select group of clinicians.This intervention requires the

availability of expertise in antibiotic use and infectious diseases and authorization needs to be

completed in a timely manner. So, this may not be practical in the Indian scenario. The backend or post-

prescription approach to stewardship uses prospective review and feedback. The antimicrobial steward

reviews current antibiotic orders and provides clinicians with recommendations to continue, adjust,

change, or discontinue the therapy based on the available microbiology results and clinical features of

15

the case. Even though the front-end strategies result in immediate reduction in use and expenditure of

restricted antibiotics, the back-end strategies are more easily accepted, widely used and have a more

sustained impact due to better educational opportunities.

A multi-disciplinary team is intrinsic to the implementation of the core strategies.

Supplemental antimicrobial stewardship strategies

Dose optimization

Optimization of antimicrobial dosing that accounts for individual patient characteristics (e.g., age, renal

function, and weight), causative organism and site of infection (e.g., endocarditis, meningitis, and

osteomyelitis), and pharmacokinetic and pharmacodynamic characteristics of the drug is an important

part of antimicrobial stewardship.

Intravenous-to-oral switch therapy

Antimicrobial therapy for patients with serious infections requiring hospitalization is generally initiated

with parenteral therapy. Enhanced oral bioavailability among certain antimicrobials, such as

fluoroquinolones, oxazolidinones, metronidazole, clindamycin, trimethoprim-sulfamethoxazole,

fluconazole, and voriconazole, allows conversion to oral therapy once a patient meets defined clinical

criteria. A systematic plan for parenteral to oral conversion of antimicrobials with excellent

bioavailability, when the patient’s condition allows, can decrease length of hospital stay, health care

costs and potential complications due to intravenous access.

Streamlining or de-escalation of therapy

Streamlining or de-escalation of empirical antimicrobial therapy on the basis of culture results and

elimination of redundant combination therapy can more effectively target the causative pathogen,

resulting in decreased antimicrobial exposure and substantial cost savings.

Guidelines and clinical pathways

Clinical practice guidelines are being produced with increasing frequency, with the goal of ensuring high quality care. However, the impact on provider behavior and improved clinical outcomes has been difficult to measure. Although physicians usually agree, in principle, with national guidelines, the absence of accompanying strategies for local implementation often presents a formidable barrier. Each Health Care Institute and each dept should customize their own guidelines in line with national guidelines but based on local antibiograms and not national data.

Antimicrobial order forms

Introduction of order forms especially for the high-end, broad spectrum agents can act as a deterrent in

prescription. Any intervention requiring extra effort will serve as discouragement.

Education

16

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

behavior and can provide a foundation of knowledge that will enhance and increase the acceptance of

stewardship strategies. However, education alone, without incorporation of active intervention, is only

marginally effective in changing antimicrobial prescribing practices and has not demonstrated a

sustained impact.

Antimicrobial cycling

There are insufficient data to recommend the routine use of antimicrobial cycling as means of

preventing or reducing antimicrobial resistance over a prolonged period of time.

Combination therapy

The rationale for combination antimicrobial therapy includes broad-spectrum empirical therapy for

serious infections, improved clinical outcomes, and the prevention of resistance. However, in many

situations, combination therapy is redundant and unnecessary. Moreover there are insufficient data to

recommend the routine use of combination therapy to prevent the emergence of resistance.

Rapid microbiological diagnosis

Rapid diagnostic tests such as procalcitonin, fluorescence in situ hybridization using peptide nucleic acid

probes, and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometric

analysis have been successfully incorporated by some stewardship programs and may become

important additions to stewardship efforts.

Laboratory surveillance and feedback

Periodic feedback to clinicians on the prevailing trends on bacteria causing nosocomial infections and

their resistance patterns will help guide clinicians use of antibiotics. Ensuring active participation

through empowerment will sustain the stewardship program.

Implement Policies and Interventions to Improve Antibiotic Use

Key points

Implement policies that support optimal antibiotic use

Utilize specific interventions that can be divided into three categories: broad, pharmacy driven

and infection and syndrome specific

Avoid implementing too many policies and interventions simultaneously; always prioritize

interventions based on the needs of the hospital as defined by measures of overall use and

other tracking and reporting metrics.

Policies that support optimal antibiotic use

Implement policies that apply in all situations to support optimal antibiotic prescribing, for example:

17

Document dose, duration, and indication. Specify the dose, duration and indication for all

courses of antibiotics so they are readily identifiable. Making this information accessible helps

ensure that antibiotics are modified as needed and/or discontinued in a timely manner

Develop and implement facility specific treatment recommendations. Facility-specific treatment

recommendations, based on national guidelines and local susceptibilities and formulary options

can optimize antibiotic selection and duration, particularly for common indications for antibiotic

use like community-acquired pneumonia, urinary tract infection, intra-abdominal infections,

skin and soft tissue infections and surgical prophylaxis.

Interventions to improve antibiotic use

Choose interventions based on the needs of the facility as well as the availability of resources and

content expertise; stewardship programs should be careful not to implement too many interventions at

once. Many potential interventions are highlighted in the CDC/Institute for Healthcare Improvement

“Antibiotic Stewardship Driver Diagram and Change Package”. Assessments of the use of antibiotics as

mentioned in the “Process Measures” section of this document can be a starting point for selecting

specific interventions.

Stewardship interventions are listed in three categories below: broad, pharmacy-driven; and infection

and syndrome specific.

Broad interventions

Antibiotic “Time outs”. Antibiotics are often started empirically in hospitalized patients while

diagnostic information is being obtained. However, providers often do not revisit the selection

of the antibiotic after more clinical and laboratory data (including culture results) become

available. An antibiotic “time out” prompts a reassessment of the continuing need and choice

of antibiotics when the clinical picture is clearer and more diagnostic information is available. All

clinicians should perform a review of antibiotics 48 hours after antibiotics are initiated to answer

these key questions:

o Does this patient have an infection that will respond to antibiotics?

o If so, is the patient on the right antibiotic(s), dose, and route of administration?

o Can a more targeted antibiotic be used to treat the infection (de-escalate)?

o How long should the patient receive the antibiotic(s)?

Prior authorization- Some facilities restrict the use of certain antibiotics based on the spectrum

of activity, cost, or associated toxicities to ensure that use is reviewed with an antibiotic expert

before therapy is initiated. This intervention requires the availability of expertise in antibiotic

use and infectious diseases and authorization needs to be completed in a timely manner.

18

Prospective audit and feedback- External reviews of antibiotic therapy by an expert in antibiotic

use have been highly effective in optimizing antibiotics in critically ill patients and in cases where

broad spectrum or multiple antibiotics are being used. Prospective audit and feedback is

different from an antibiotic ”time out” because the audits are conducted by staff other than the

treating team. Audit and feedback requires the availability of expertise and some smaller

facilities have shown success by engaging external experts to advise on case reviews.

Pharmacy-driven Interventions

Automatic changes from intravenous to oral antibiotic therapy in appropriate situations and for

antibiotics with good absorption (e.g., fluoroquinolones, trimethoprim-sulfamethoxazole,

linezolid, etc.), which improves patient safety by reducing the need for intravenous access

Dose adjustments in cases of organ dysfunction (e.g. renal adjustment)

Dose optimization including dose adjustments based on therapeutic drug monitoring, optimizing

therapy for highly drug-resistant bacteria, achieving central nervous system penetration,

extended-infusion administration of beta-lactams, etc.

Automatic alerts in situations where therapy might be unnecessarily duplicative including

simultaneous use of multiple agents with overlapping spectra e.g. anaerobic activity, atypical

activity, Gram-negative activity and resistant Gram-positive activity

Time-sensitive automatic stop orders for specified antibiotic prescriptions, especially antibiotics

administered for surgical prophylaxis

Detection and prevention of antibiotic-related drug-drug interactions- e.g. interactions between

some orally administered fluoroquinolones and certain vitamins.

Infection and syndrome specific interventions

The interventions below are intended to improve prescribing for specific syndromes; however, these

should not interfere with prompt and effective treatment for severe infection or sepsis.

Community-acquired pneumonia. Interventions for community-acquired pneumonia have

focused on correcting recognized problems in therapy, including: improving diagnostic accuracy,

tailoring of therapy to culture results and optimizing the duration of treatment to ensure

compliance with guidelines.

Urinary tract infections (UTIs). Many patients who get antibiotics for UTIs actually have

asymptomatic bacteriuria and not infections. Interventions for UTIs focus on avoiding

unnecessary urine cultures and treatment of patients who are asymptomatic and ensuring that

patients receive appropriate therapy based on local susceptibilities and for the recommended

duration.

19

Skin and soft tissue infections. Interventions for skin and soft tissue infections have focused on

ensuring patients do not get antibiotics with overly broad spectra and ensuring the correct

duration of treatment.

Empiric coverage of methicillin-resistant Staphylococcus aureus (MRSA) infections. In many

cases, therapy for MRSA can be stopped if the patient does not have an MRSA infection or

changed to a beta-lactam if the cause is methicillin-sensitive Staphylococcus aureus.

Clostridium difficile infections. Treatment guidelines for CDI urge providers to stop unnecessary

antibiotics in all patients diagnosed with CDI, but this often does not occur. Reviewing

antibiotics in patients with new diagnoses of CDI can identify opportunities to stop unnecessary

antibiotics which improve the clinical response of CDI to treatment and reduce the risk of

recurrence.

Treatment of culture proven invasive infections. Invasive infections (e.g. blood stream

infections) present good opportunities for interventions to improve antibiotic use because they

are easily identified from microbiology results. The culture and susceptibility testing often

provides information needed to tailor antibiotics or discontinue them due to growth of

contaminants.

Activities That Can Potentially Optimize and Improve Antimicrobial Use

Category Activities

Patient-specific

• Prospective audit and feedback • Clinical decision support • Rapid diagnostic utilization • Microbiology laboratory selective reporting of susceptibilities • Identifying bug-drug mismatches • Culture-specific audit and feedback (eg, asymptomatic bacteriuria and tracheal colonization)

Physician-specific

• Formulary restriction/preauthorization • Antimicrobial-specific audit and feedback • Clinical decision support • Medication use evaluations (peer comparison) • One-on-one education • Antimicrobial order forms

General facility or healthcare system • Education for large groups • Guidelines/pathway development • Care bundles or change bundles/packages • Benchmarking

20

Monitoring antibiotic use and other metrics for audit

Monitoring trends in antimicrobial resistance and antimicrobial usage is essential for guiding a

successful stewardship program. This helps to adapt empiric treatment, demonstrate changes in

practice and also helps to identify hospital settings where targeted interventions will help. This will help

to identify key measurements for improvement.

Defined Daily Dose (DDD) is a measure which represents the average daily maintenance dose of

an antimicrobial for its main indication in adults. For example, the DDD of oral amoxicillin is

1000 mg, so a patient receiving 500 mg every 8 hours for 5 days consumes 7.5 DDDs. The usage

data may then be divided by a measure of hospital activity such as number of admissions or in-

patient bed days to provide more meaningful trend analysis.

ABC Calc is a simple computer tool to measure antibiotic consumption in hospitals. It transforms

aggregated data provided by hospital pharmacies (generally as a number of packages or vials)

into meaningful antibiotic utilization rates.

(http://www.escmid.org/research_projects/study_groups/esgap/abc_calc/)

Pareto charts are useful to provide an overview of antimicrobial usage at ward level and identify

wards with that have high total usage or high use of restricted antimicrobials.

Resistance data is obtained from the Microbiology Laboratory through computer systems as

antibiograms.

AMSP measures for Quality Improvement

Structural Indicators

Availability of multi-disciplinary antimicrobial stewardship team

Availability of guidelines for empiric treatment and surgical prophylaxis

Provision of education in the last 2 years

Process Measures

Amount of antibiotics in DDD/100 bed days

Compliance with acute empiric guidance

% appropriate de-escalation; appropriate switch from iv to oral

Compliance with surgical prophylaxis

Compliance with “care bundles” (3 day antibiotic review bundle, Ventilator Associated Pneumonia VAP bundle)

Outcome Measures

C. difficile rates

SSI rates

Readmission within 30 days of discharge

Surveillance of resistance

Mortality: Standardized Mortality rates (SMR) Balancing Measures

Mortality

21

SSI rates

Readmission within 30 days of discharge

Admission to ICU

Rates of complications

Treatment related toxicity

AMSP as part of Hospital Infection Control and prevention

Both antimicrobial stewardship program (AMSP) and the infection control programs (ICP) are strategic

partners in the efforts to reduce hospital acquired infection and drug resistance. There should be a close

liaison between the AMSP and ICP with the hospital Microbiology Lab to gain insight into the scope of

resistance and infection prevalence. Colonized or infected patients are the primary source of MDRO and

C difficile transmission in hospitals. Transmission of antimicrobial resistant organisms occur via three

routes

1) Transmission via the animate environment: A healthcare worker’s hands may become transiently

contaminated with an MDRO or C difficile spores after having contact with a colonized or infected

patient, then transfer the pathogen to another.

2) Transmission via the inanimate environment: Equipment, such as a stethoscope, becomes

contaminated after contact with the skin or mucous membranes of a colonized patient and transfers the

pathogen when it is used on another patient.

3) Transmission involving animate and inanimate environments: MDROs and C difficile are transmitted

to surfaces and items in a colonized or infected patient’s hospital room (eg, an infusion pump) first and

are subsequently transferred to the hands of HCP who, in turn, transmit the pathogen to previously

noncolonized patients.

Therefore, an important step in mitigating the impact of the inanimate environment in the transmission

of MDROs and C difficileis to ensure that “high-touch” surfaces, such as door knobs,bed rails, light

switches, and wall are as around the toilet in the patient’s room, are cleaned on a regular basis. Isolating

patients infected or colonized with drug resistant organisms should be undertaken.

The Hospital Infection Control Committee (HICC) has to actively interact with the AMSP team to ensure

control of resistant pathogens. Having overlapping members in both the teams will help in this

endeavor.

22

Bibliography

1. Fauci JAMA September 20, 2016 Volume 316, Number 11

2. Gerding DN. The search for good antimicrobial stewardship. Jt Comm J Qual Improv 2001; 27: 403404

3. Livermore D M, Winstanley T G, Shannon K P, J Antimicrob Chem 48: S1, 87-102

4. Wlodover et al., Infect.Dis.Clin. Pract. 2012;20: 12-17

5. Dellit TH, Robert C Owens, John E McGowan et al, IDSA & SHEA Guidelines for Antimicrobial

Stewardship Cl Infect Dis 2007: 44: 157 – 177

6. Massimo Giusti, Elena Cerutti Antibiotic stewardship program and the Internist’s role: Italian Journal

of Medicine 2016; volume 10:329-338

7. Drew RH Antimicrobial stewardship programs J Manag Care Pharm, 2009: 15 (Supp 2) S18 - 23

8. Dumartin et al J. Antimicrob Chemother 2011;66: 1631-7: Morris et al Inf. Control. Hosp. Epidemiol.

2012;33 [3]:500-506