Appropriate Antibiotic

Prescribing
Prudent prescribing to reduce resistance
 Aristotle said

“Anybody can become angry - that is easy;

but to be angry with the right person and to the right degree
and at the right time and for the right purpose, and in the
right way –
that is not easy”

When it comes to Antimicrobials…

“Anybody can prescribe antibiotics - that is easy;

but to prescribe the right drug to the right person and at the
right dose and for the right time and for the right
purpose, and in the right way –
that is not easy”

Aristotle quotes . Available at: http://philosiblog.com/2013/08/07/anybody-can-become-angry-but-to-be-angry-at-the-right-

time-and-for-the-right-purpose-is-not-within-everybodys-power/. Accessed: June 2016
Overview

• Antimicrobial resistance: global challenge, dynamics, impact

• Appropriate Antibiotic Prescribing (AAP) or Optimal Treatment
• Principles of appropriate antibiotic prescribing
• Treat bacterial Infection; colonisation vs. infection
• Optimise: accurate diagnosis and severity assessment
• Maximise: therapy should reduce maximally or eradicate the bacterial load
• Recognise: antibiotic choices must reflect local resistance prevalence
• Utilise: Pharmacokinetic (PK)/pharmacodynamic (PD) – effective choice of agent and
dose
• Importance of adequate dosing

• Duration of therapy
• Guidelines: implementation in clinical practice
• Advantages of appropriate antibiotic prescribing
The global challenge of
antimicrobial resistance
“There are few public health issues of
potentially greater importance for society
than antibiotic resistance.”

Professor Dame Sally Davies.

Lecky DM, McNulty CAM. J Antimicrob Chemother 2013;68:2428–2430.
Resistance: A global challenge making headlines

No action today,
no cure tomorrow4

1. Time Magazine cover. August 3rd. 1998; 2. Time Magazine cover. September 12th. 1994; 3. Harvard
Magazine cover. May-June 2014; 4. World Health Today cover. April 2014
How much could antimicrobial resistance
cost the world (deaths)?

Source: Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of
Nations. 2014. Chaired by Jim O’Neill.
 The root problem: increasing resistance but fewer new
antibiotics

“Antibiotics- the perfect storm”1

Companies
20
Number of antibiotics approved2

researching
antibiotics
18 18
16
ceftazidime-R Enterobacteriaceae levofloxacin-R pneumococcus PDR-Acinetobacter
14
vancomycin-R Enterococcus imipenem-R Enterobacteriaceae
12 PDR-Pseudomonae
methicillin-R Stephylococcus
PDR-Enterobacteriaceae
10 XDR tuberculosis
penicillin-R pneumococcus
8 linezolid-R Staphylococcus
Companies
6 vancomycin-R Staphylococcus researching
antibiotics
4 4
2
0
Pre 1980 1980-84 1985-89 1990-94 1995-99 2000-04 2005-09 2010-12
XDR – Extensively Drug Resistant PDR – Pan Drug Resistant

1. Cooper MA, Shlaes D. Nature 2011;472:32; 2. Antibiotic Resistance Threats in the

United States, 2013. CDC.
CDC warns of impending post antibiotic era - doomsday
When did the miracle become a crisis?

“The problem of AMR is so serious that it threatens the achievements of

modern medicine. A post-antibiotic era - in which common infections and
minor injuries can kill - is a very real possibility for the 21st century.”
World Health Organization2
1. http://www.cdc.gov/media/releases/2013/t0916_health-threats.html
2. World Health Organization. Antimicrobial Resistance. Global report on surveillance, 2014;
The consequences of indiscriminate antibiotic
prescription

Patient level Community level

• Adverse events
• Unnecessary cost
• Drug-drug interactions
• Increased risk of infection with
antibiotic resistant strain
• Increased antibiotic resistance
– Infections becoming more difficult
to treat
– Epidemics harder to control
• Increased healthcare cost

Gonzales R, et al. Annals of Emer Med 2001;37(6):690-7

Optimal treatment

AAP – Appropriate AMS – Antimicrobial

Antibiotic Prescribing Stewardship

FAQs Antimicrobial Stewardship Clinical Care Standard November 2014. Available at:
http://www.safetyandquality.gov.au/wp-content/uploads/2014/12/FAQs-Antimicrobial-10
Stewardship-CCS.pdf [accessed 16th February 2016]
Appropriate Antibiotic
Prescribing
Principles of appropriate antibiotic prescribing

TREAT Bacterial infection only

OPTIMISE Diagnosis/severity assessment

MAXIMISE Bacterial eradication only (or reduction)

RECOGNISE (Local) resistance prevalence

UTILISE PK/PD – effective choice agent and dose

INTERGRATE Local resistance, efficacy cost & effectiveness

Appropriate prescribing conforms to these criteria

Ball P et al. J Antimicrob Chemother 2002;49:31–40.
 It’s pointless taking

antibiotics for colds and flu

TREAT BACTERIAL INFECTION ONLY

Correct diagnosis is the key
Acute respiratory tract infections
When are antibiotics indicated?

Inappropriate prescribing of antibiotics for acute RTIs

contributes to the increasing prevalence of antibiotic
resistance.
• More than half of all antibiotics prescribed for acute RTIs are
unnecessary because these infections are most likely viral and therefore
not treatable with antibiotics
• Clinicians in ambulatory-care settings prescribe antibiotics for patients
with a viral acute RTI in 40% to 50% of cases
• Studies have demonstrated that clinician and patient education is a vital
component of reducing inappropriate antibiotic use

Werner K, Deasy JA. JAAPA 2009;22(4):22–26.

Patients/parents also need to be targeted

http://www.cdc.gov/getsmart/community/materials-references/print-materials/parents-young-children/index.html.
Reinforcing the message with guideline recommendations

Guidelines also suggest “watchful waiting” and that antibiotics

should be prescribed only when warranted.

Clinical Practice Guideline (Update): Adult Sinusitis

• Emphasis on patient education and counseling with new

explanatory tables

• Extension of watchful waiting (without antibiotic therapy) as

an initial management strategy to all patients with
uncomplicated acute bacterial rhinosinusitis (ABRS)
regardless of severity, not just patients with “mild illness”
(prior guideline)

Rosenfeld RM et al. Otolaryngology-Head and Neck Surgery

2015;152(2S):S1–S39.
Colonisation vs. infection: common clinical scenario

• Sputum/respiratory specimen showing organisms in a patient with

suspected pneumonia.
– Assessing sputum quality uses a grading system based on neutrophils,
epithelial cells and mucus
– This helps to interpret results of sputum culture (distinguish commensals
from saliva vs. pathogens from sputum)

Soman R. Colonization Versus Infection. Chapter 42; 330-333. In Medicine Update Vol 18, 2008.
OPTIMISE - ACCURATE
DIAGNOSIS AND
SEVERITY ASSESSMENT
Correct Diagnosis is the Key

Treat with antibiotics only when bacterial

Infection is proven or strongly suspected
Rational Antibiotic Therapy

“Successful chemotherapy must be rational, and rational treatment

demands a diagnosis. This may only be provisional, and it may later be
proved wrong, but the treatment chosen should be based on some
explicit assumption as to the nature of the disease process”

- Antibiotics and Chemotherapy, 2nd edition

Simpson AJH. Surg 2002;20:177-9.

Diagnostic and other measures to reduce prescribing

Accurate clinical diagnosis is key to limit

antibiotic prescribing1
• Guidelines should offer practical criteria to identify those bacterial
infections requiring antibiotic therapy1
• A study from the United States (led by a family physician) shows that
antibiotics are prescribed for 65% of episodes of URTI, 78% of acute
bronchitis, 65% of acute pharyngitis, and 81% of acute sinusitis2
• In a survey of 298 patients with a sore throat, the 3 most common
reasons for consulting the physician were to find out the cause of the
symptoms, pain relief, and information about the course of the illness.
Hope for an antibiotic was ranked 11 out of 13 reasons!2

1.Ball P et al. J Antimicrob Chemother 2002;49:31–40.

2.Hickner J. Ann Fam Med 2006;4(6):484–485.
Acute Uncomplicated Bronchitis – Initiation of
Antibiotic therapy

Acute uncomplicated bronchitis is defined as a self-limited inflammation of the large

airways (bronchi) with a cough lasting up to 6 weeks.
• Determining the Likelihood of a Bacterial Infection
More than 90% of otherwise healthy patients presenting to their outpatient providers with
an acute cough have a syndrome caused by a virus
• Appropriate Management Strategies
A randomized, placebo-controlled trial (not included in the Cochrane review) comparing
ibuprofen, amoxicillin–clavulanic acid, and placebo showed no significant differences in the
number of days to cough resolution. Although macrolides (azithromycin) are frequently
prescribed for patients with a cough, one study showed that patients with acute bronchitis
treated with a macrolide had significantly more adverse events than those receiving
placebo

Clinicians should not perform testing or initiate antibiotic therapy in patients

with bronchitis unless pneumonia is suspected

Harris AM. Ann Intern Med. 2016;164(6):425-434.

 The British Thoracic Society guidelines for the management
of community acquired pneumonia in adults update 2009

Avoiding inappropriate antibiotic prescribing

1. The diagnosis of CAP and the decision to start antibiotics should be reviewed
by a senior clinician at the earliest opportunity.
2. There should be no barrier to discontinuing antibiotics if they are not indicated
3. The indication for antibiotics should be clearly documented in the medical
notes
4. The need for intravenous antibiotics should be reviewed daily
5. De-escalation of therapy, including the switch from intravenous to oral
antibiotics, should be considered as soon as is appropriate, taking into account
response to treatment and changing illness severity
6. Strong consideration should be given to narrowing the spectrum of antibiotic
therapy when specific pathogens are identified, or when the patient’s condition
improves.
7. Where appropriate, stop dates should be specified for antibiotic prescriptions
The British Thoracic Society guidelines for the management of community acquired pneumonia in adults update 2009. Available at:https://www.brit-thoracic.org.uk/document-
library/clinical-information/pneumonia/adult-pneumonia/a-quick-reference-guide-bts-guidelines-for-the-management-of-community-acquired-pneumonia-in-adults/
 Increasing use of third-generation cephalosporins
for pneumonia in the emergency department

• Design- retrospective study of patients treated for community-acquired pneumonia in

an emergency department, and subsequently hospitalized in non ICU wards.
• Third-generation cephalosporin prescriptions were presumed unavoidable if they met
both criteria: (i) age ≥ 65 yr or comorbid condition, and (ii) allergy or intolerance to
penicillin, or failure of penicillin first-line therapy, or treatment with penicillin in three
previous months.
• The proportion of patients treated with a third generation cephalosporin increased
significantly from 13.9 % (6.9-24.1 %) in 2002 to 29.5 % (18.5-42.6 %) in 2012
(OR = 1.07 [1.01-1.14] , P = 0.02).
• This increase was independent from other factors associated with the prescription of
a third-generation cephalosporin (immunocompromising condition, antibacterial
therapy in three previous months, fluid resuscitation).
• Treatment with third-generation cephalosporin was avoidable in 118 out of 147
patients (80.3 % [72.7-86.2 %]).
• Conclusion - Antibiotic stewardship programs should be implemented to restrict the
third-generation cephalosporins use for pneumonia in the emergency department.

Goffinet N, et al.European journal of clinical microbiology & infectious diseases. 2014 Jul 1;33(7):1095-9.
 Criteria for initial antibacterial agent treatment or observation
in children with acute otitis media (AOM)

The diagnosis and management of acute otitis media

• 6 months – 2 years
– Otorrhea with AOM*
– Unilateral or bilateral AOM* with severe symptoms** Antibiotic therapy
– Bilateral AOM* without otorrhea
Antibiotic therapy or
– Unilateral AOM* without otorrhea additional observation†

• 2 years and over

– Otorrhea with AOM* Antibiotic therapy
– Unilateral or bilateral AOM* with severe symptoms**
– Bilateral AOM* without otorrhea
Antibiotic therapy or
– Unilateral AOM* without otorrhea additional observation†
*Applies only to children with well-documented AOM with high certainty of diagnosis.
** A toxic appearing child, persistent otalgia more than 48 h, temperature ≥ 39°C (102 2° F) in the past 48 h, or if there is uncertain access to follow-up
after the visit.
This plan of initial management provides an opportunity for shared decision-making with the child’s family for those categories appropriated for
additional observation. If observation is offered, a mechanism must be in place to ensure follow-up and begin antibiotics if the child worsens or fails to
improve within 48-72 h of AOM onset.

Adapted from Lieberthal AS et al. Pediatrics 2013;131(3):e964–999.

ESCMID guideline for the management of acute sore
throat
Scoring system
ESCMID Sore Throat Guideline Signs/symptom Risk of group A streptococcal infection =
Group s=4 56%
Signs/symptom Risk of group A streptococcal infection =
• Centor clinical scoring system or s=3 32%
rapid antigen test can be helpful
Signs/symptom Risk of group A streptococcal infection =
in targeting antibiotic use s=2 15%

• In patients with high likelihood of Signs/symptom Risk of group A streptococcal infection =

s=1 6.5%
Group A streptococcal infection
Signs/symptom Risk of group A streptococcal infection =
(e.g. 3–4 Centor criteria)
s=0 2.5%
physicians can consider the use
of rapid antigen test (RAT)

• Antibiotics should not be used in patients with less severe presentation of

sore throat, e.g. 0–2 Centor criteria to relieve symptoms

Pelucchi C et al. Clin microbiol infect 2012;18(S1):1–27.

MAXIMISE
Therapy should reduce maximally or
eradicate the bacterial load
MAXIMISE bacterial eradication

Appropriate
treatment
Infection

Bacterial
Increasing Inappropriate eradication
resistance treatment

Spread Failed bacterial

eradication

Selection
Maximise clinical cure
of resistant Minimise potential for resistance
bacteria
1. Dagan R et al. J Antimicrob Chemother 2001;47:129–140;
2. Ball P et al. J Antimicrob Chemother 2002;49:31–40.
Image courtesy of GSK
Clinical failures are higher in patients with bacteriologic
failures

Failure to achieve early bacterial eradication increases

clinical failure rate in acute otitis media in young children
Dagan et al 2008.
• BACKGROUND:
– This study determined the association between early bacteriologic failure and clinical
failure in AOM

• METHODS:
– Children aged 3-35 months with AOM were enrolled in studies reporting on
bacteriologic outcomes by tympanocentesis on day 4-6 and clinical outcomes on day
11-16 (immediate post-treatment visit). Bacteriologic outcomes were studied for
children with AOM caused by Streptococcus pneumoniae, non-typeable Haemophilus
influenzae or both

• RESULTS:
– Clinical failure occurred in 7.3% of 660 patients with bacterial eradication versus
32.8% of 247 patients with bacteriologic failures

Dagan R et al. Pediatr Infect Dis J. 2008;27(3):200–206.

Bacteriologically confirmed clinical failures in
pneumococcal pneumonia

• Bacteriologically confirmed clinical failures have been reported in

pneumococcal pneumonia with both macrolides and older
fluoroquinolones (ciprofloxacin, ofloxacin, and levofloxacin).
• These failures were due to the involvement of resistant pathogens
(macrolides) or suboptimal pharmacokinetics/pharmacodynamics
(PK/PD) (quinolones).
• However, persistent positive blood cultures have not been reported
during therapy with adequate doses of benzylpenicillins or
aminopenicillins.

Garau J. Why do we need to eradicate pathogens in respiratory tract infections?. International journal of infectious
diseases. 2003 Mar 31;7:S5-12.
RECOGNISE- ANTIBIOTIC
CHOICES MUST REFLECT
LOCAL RESISTANCE
PREVALENCE
Take account of local susceptibility data and
their resistance patterns when selecting an
antibiotic
Using the surveillance data to guide empirical antibiotic use
For both hospitals and community
Systematic monitoring and surveillance of antibiotic susceptibility
of bacterial pathogens
This information would enable authorities to design and
implement early interventions that halt the spread of resistant
strains

Masterton RG. J Antimic Chemo 2000;46 (Topic T2):53-8

An example: Antimicrobial resistance surveillance in Europe
2012

• The reported susceptibility of S. pneumoniae

showed large variations between European
countries
• A majority of the reporting countries had
percentages of penicillin non-susceptibility
below 10%, but four countries reported
percentages above 25%
• Serogroups 1, 3, 7 and 19 dominate among
pneumococcal isolates.
– A large majority of serogroups 1, 3 and 7 were
susceptible to both penicillin and macrolides
– Serogroup 19 - 27% of the isolates had a decreased
susceptibility to penicillin and/or macrolides

European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2012. Annual
Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net).
UTILISE- PK/PD – EFFECTIVE
CHOICE OF AGENT AND DOSE
Apply pharmacodynamic parameters in
choice of effective agents and dosage
Sir Alexander Fleming
Nobel lecture, 1945

“It is not difficult to make microbes resistant to penicillin

in the laboratory by exposing them to concentrations not
sufficient to kill them… there is the danger that the ignorant
man may easily under dose himself and by exposing his
microbes to non-lethal quantities of the drug, make them
resistant”

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/
fleming-lecture.pdf
PK/PD profiles of antimicrobials

•Provides information on the ability to eradicate bacteria at drug

concentration attained during therapy

1. Craig WA. Adv St Med 2002;2(4):126‒134; 2. Craig WA , Andes D. Pediatr Inf Dis 1996;15(10):944‒948.
Images created to illustrate principles of PK/PD,
DURATION OF THERAPY

What we need to know…

Longer or shorter antibiotic course?

• Defining the optimal duration of antibiotic treatment is often

a dilemma

• Longer than necessary duration of antibiotics can result in:

– greater risk of toxicity, higher rate of adverse events
– increased risk of resistance
– increased days of hospitalisation, morbidity or mortality
– reduction in patient compliance – compliance is better with shorter
course

Rafailidis P. Infect Dis Clin North Am. 2009;23(2):269–276.

Duration of therapy: what we need to know

Meta analyses of Acute Otitis Media (AOM), Acute Bacterial sinusitis (ABS), Acute
exacerbation of chronic bronchitis (AECB), Community acquired pneumonia (CAP)
• AOM: 5 vs. 8–10 day therapy: No significant difference in clinical outcomes
• ABS: 3–7 vs. 6–10d NS (AE less in former)
• COPD: 5 vs. 7–10d NS (AE less in former)
• CAP: Adults: 3-7 vs. 7-10d: NS; children: 3 vs. 5d NS in clinical or microbiologic
success, mortality, AE or withdrawals
• The above meta-analyses indicate that a short-duration treatment
seems to be as effective as a longer course of antibiotic treatment in
such infections as acute otitis media, acute bacterial sinusitis, CAP and
infectious exacerbations of chronic bronchitis

NS: No significant difference in clinical outcomes

Rafailidis P. Infect Dis Clin North Am. 2009;23(2):269–276.
GUIDELINES

Implementation in clinical practice

Reasons why antibiotic prescribing guidelines are not
followed

CURE

Belief that non- Concern for parent or Fear of infection

recommended agents may patient satisfaction, a complications and
be more likely to cure an common method by which related negative
infection clinicians are evaluated consequence

Sanchez G et al. Emerg Infect Dis 2014;20(12):2041–2047

 CRB 65 Score

1. McNally M et al. Validity of British Thoracic Society guidance (the CRB-65 rule) for predicting the severity of pneumonia in general
practice: systematic review and meta-analysis. Br J Gen Pract. Oct 2010;60(579):e423-33.
 Empirical therapy for CAP ¥ in India in Outpatients

* ICS/NCCP: The Indian Chest Society and the National College of Chest Physicians (India).;
¥¥ ICS/NCCP(I)* 2012 guidelines:3 Level: Level of evidence 1: High-quality evidence backed by consistent results from well-performed randomized controlled trials, or overwhelming evidence from well-
executed observational studies with strong eects. Quality of evidence: Grade A: Strong recommendation to do (or not to do) where the benefits clearly outweighs the risk (or vice versa) for most, if not al
patients
¥ CAP - Community Acquired Pneumonia

3. Gupta D et al. Guidelines for diagnosis and management of community- and hospital-acquired pneumonia in adults: Joint ICS/NCCP(I) recommendations. Lung India. Jul 2012;29(Suppl 2):S27-62.
Influence of deviation from guidelines on the outcome
of community-acquired pneumonia

• Study investigated: (1) the degree of adherence to American Thoracic Society (ATS) and
the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) guidelines; and (2)
influence of adhering to guidelines on mortality and length of hospitalisation.

• Patients (n=295) with CAP were investigated and the antibiotic regimen prescribed in the
first 24 hours was evaluated as to whether or not it adhered to treatment guidelines.

• There were no significant differences in mortality or duration of hospitalisation between

adherent and non-adherent regimens in mild or moderate CAP.

• Mortality in severe CAP was significantly higher in patients with non-adherent

treatments.

This study demonstrated that severe CAP had a significantly higher

mortality when the guidelines (both ATS and SEPAR) were not followed

Menéndez R et al. Chest. 2002;122(2):612–617.

Embrace antibiotic stewardship

• Improve antibiotic use in private practice as well as in hospitals—

regardless of size—through stewardship interventions and programs,
which will:
• improve individual patient outcomes
• reduce the overall burden of antibiotic resistance
• save healthcare cost
• Refer to standard treatment guidelines
• Practice rational use of antibiotics

CDC. https://www.cdc.gov/getsmart/week/downloads/gsw-factsheet-cost.pdf[cited May 2016

CONCLUSION
SUMMARY
Summary

• Antibiotic resistance is a global problem and multi-factorial

• Much of the increase in MDR bacteria can be attributed to the overuse of
broad-spectrum antimicrobials
• Efforts to develop new antimicrobials over the past two decades have
lagged behind the rapid evolution of resistance developing in both Gram-
positive and Gram-negative pathogens
• AAP has a direct impact on optimal clinical outcomes with fewer adverse
effects
• Is cost effective and helps to prevent the emergence of resistance
Safety Information of Oral Formulations

• Very common undesirable side (≥1/10); Diarrhea (adults)

• Common undesirable side (≥1/100 and <1/10); Mucocutaneous

candidiasis, diarrhea (children), nausea, vomiting

Prescribing Information of AUGMENTIN 625/1000 DUO. GlaxoSmithKline, India. Version: AUG-TAB/PI/IN/2018/02 dated 10
Sep 2018
Prescribing Information of AUGMENTIN DDS (oral suspension). GlaxoSmithKline, India. Version: AUG-DDS/PI/IN/2018/01
dated 29 October 2018
Prescribing Informations of AUGMENTIN DUO (oral suspension): GlaxoSmithKline, India. Version: AUG-SUS/PI/IN/2017/02
dated 12-Dec-2017.
 For the use only of Registered Medical Practitioners or
a Hospital or a Laboratory

Registered medical practitioners can refer company website

http://india-pharma.gsk.com/en-in/products/prescribing-information/
for full Product Information.

Please report adverse events with any GSK product to the company
at india.pharmacovigilance@gsk.com
 Registered medical practitioners can refer company website
http://india-pharma.gsk.com/en-in/products/prescribing-information/ for full
Product Information.
For the use only of Registered Medical Practitioners or a Hospital or a Laboratory

Full prescribing information available on request from

GlaxoSmithKline Pharmaceuticals Ltd.,

Dr. Annie Besant Road, Worli,
Mumbai- 400 030. (India)

Please report adverse events with any GSK

product to the company
at india.pharmacovigilance@gsk.com
Trademarks are owned by or licensed to the GSK group of companies

• Date of preparation: Feb 2019

• Zinc Code: IN/CAM/0046/18a
 TO USE OR NOT TO USE ANTIBIOTICS?
The answer is in OUR hands

Use antibiotics
responsibly
; Date of Preparation: May ; For the use of a registered medical practitioner only
GlaxoSmithKline Pharmaceuticals Limited, Dr Annie Besant Road, Worli, Mumbai, 400030
Please report adverse events with any GSK product to the company at india.pharmacovigilance@gsk.com