Special Winter School

Towards Excellence in Higher Education

University of Kashmir

Prof. Anita Kotwani, Department of Pharmacology

V. P. Chest Institute, University of Delhi, Delhi, India

Antimicrobial Resistance: Inappropriate Use

of Antibiotics in the Community

Feb 28, 2017

Presentation outline

Setting the scene

Antimicrobial resistance

Inappropriate antibiotic use

Surveillance system in developed and developing

countries to tackle AMR

Indian Experience: Studies conducted for

methodology development & validation for

antibiotic use; access to antibiotics in the community

Way forward

Definitions

ANTIBIOTIC is produced by a microorganism, at a low conc.

inhibits or kills other microorganisms. E.g., penicillin

ANTIMICROBIAL is any substance of natural, semisynthetic

(amoxycyllin) or synthetic origin (quinolone)that kills or inhibits

the growth of microorganisms

Antimicrobials include all agents that act against all types of

microorganisms – bacteria (antibacterial), viruses (antiviral),

fungi (antifungal) and protozoa (antiprotozoal)

Antibacterials being the largest class of antimicrobials, is often

used interchangeably with the term “antimicrobials” and

usually referred as “antibiotics” in the community

Antimicrobials, Antimicrobial resistance,

Post antibiotic era

Discovery of antimicrobials/antibiotics

(wonder drugs) revolutionized

treatment of infectious diseases

Antibiotics, have been a mainstay of modern

medicine for the last eight decades

Soon realized bacteria could

develop antimicrobial resistance

What is antimicrobial resistance?

(AMR)

AMR happens when microorganisms (such as

bacteria, fungi, viruses, and parasites) change when

they are exposed to antimicrobial drugs (such as

antibiotics, antifungals, antivirals, antimalarials, and

anthelmintics)

As a result, the medicines become ineffective and

infections persist in the body, increasing the risk of

spread to others

Microorganisms that develop AMR resistance are

sometimes referred to as “superbugs”

AMR

Among AMR, the biggest threat is antibacterial

resistance (ABR):

common infections (respiratory, skin, wound, diarrheal

infections) could become untreatable

Many common and safe surgical or medical interventions

(cancer therapy, caesarean section) would become at risk

AMR increases the cost of health care with lengthier

stays in hospitals and more intensive care required

Impact on mortality and economic losses

Downward trend in development of

new antibiotics

After 1970 very few new classes of antibiotics

launched

Topical antibiotic

- Mupirocin 1985

- Retapamulin 2007

Systemic antibiotic

- Linezolid 2000

- Daptomycin 2003

7

Butler & Cooper. Antibiotics in the ….J Antibiotics 211;64:413-425

Post-antibiotic era

Bacteria, not humans or animals, become antibiotic-

resistant. These bacteria may infect humans and

animals, and the infections they cause are harder to

treat than those caused by non-resistant bacteria

Infections could again become serious health

problem; AMR, a serious public health problem

worldwide

Current rise of AMR poses the threat of POST-

ANTIBIOTIC ERA?

What accelerates the emergence and

spread of antimicrobial resistance?

Resistance to antibiotic a natural phenomenon

Overuse and misuse in people, agriculture & in

animals; often given without professional oversight

Inappropriate use of antibiotics

result in rapid increase and spread of AMR

Antimicrobial resistance: a global issue

needs immediate action

Antimicrobial resistance (AMR) is a growing problem

Main contributor of AMR – Antibiotic (AB) use

Paradoxically this selective pressure comes from

Overuse

Poor use

Misuse

Underuse

Lack of access to affordable health care: Self medication

Widespread non-human use

Global trade and Travel

Rising antibiotic use

Between 2005 and 2009, the units of antibiotic sold

increased by about 40% in India (IMS data)

Increased sales of cephalosporins were particularly

striking, the sales increased by 60%

Survey conducted in part of Delhi in 2004* and

2008# showed increase in use of cephalosporins

11

*Kotwani A, Holloway K, Roy Chaudhury R. Methodology for surveillance of antimicrobials use

among out-patients in Delhi. Indian Journal of Medical Research 2009; 129: 555-560

#Kotwani A, Holloway K. Trends in antibiotic use among outpatients in New Delhi, India. BMC

Infectious Diseases 2011;11.

Appropriate use of medicine

Patients receive the appropriate medicines, in doses

that meet their own individual requirements, for an

adequate period of time and at the lowest cost,

both to them and to the community (WHO))

Definition true for antibiotic

Inappropriate use of antibiotic when one or more of

or more of these conditions are not met

Appropriate antibiotic prescribing &

inappropriateness in antibiotic use

I. Prescriber Appropriate indication

Appropriate antibiotic

Appropriate patient

Appropriate information

2. Pharmacists

Prescribe and dispense antibiotics in developing countries

3. Patients Incomplete doses

Self-medication

4. Non-human Use

13

How to evaluate & tackle use

(inappropriate) of antibiotics?

Need to provide evidence to stakeholders

Surveillance/measure antibiotic use

Investigating the reasons and factors underlying

Identify the barriers to behaviour change

Education and awareness of all stakeholders

Implementing suitable and sustainable interventions

Continuous monitoring and evaluation

Each country needs to measure AB use and AMR and

have a policy for their state or country

Developed country settings

Extensive surveillance programs to track pattern of

antibiotic use and AMR over time

Provides information, insights, & tools needed to

guide policy & evaluate measures taken to promote

appropriate ABs use at all levels: local to global

Successful Programs

Swedish program – STRAMA

European program – ESAC and EARSS

ASPs in U.S.A

Developing country settings

Complexity – dynamics of resistance and use

AMR not a priority area

Lack of knowledge for inappropriate AB use & AMR

Unregulated access in many settings

Lack of reliable diagnostic tools & lab facilities

Overcrowding in hospitals & communities

Lack of record keeping on AB use & quality data on AMR

Lack of resources for extensive surveillance

The current statusDeveloping country settings

Countries have recognized the need for containment

of AMR but the surveillance system still not in place

Fragmented data available (high use of AB)

Obtaining data are often problematic, more so for

community where about 80% ABs are used

A reproducible and sustainable surveillance

methodology needed for quantifying antibiotic use

and resistance in the community

Steps in right direction…

Indian Experience

WHO collaborated 5 pilot projects to develop

validated reproducible and sustainable

surveillance methodology for AB use (2002-05)

Pilot project at New Delhi: Data on AB use collected

monthly over one year from 30 retail pharmacies

Antibiotic use data was collected by two methods –

1. Bulk purchase data for each pharmacy (Defined Daily Dose,

DDD/1000 population)

2. Patient exit interviews at pharmacies (DDD/1000 patients

and % of patient receiving antibiotic)

Conclusions from Pilot study

Bulk purchase and exit interview methodologies

showed a similar pattern of antibiotic use

Patient exit interviews methodology allows collection

of additional information from patients

Standardized units of measure was used

ATC/DDD classification

1. Kotwani A, Holloway K, Roy Chaudhury R. Methodology for surveillance of antimicrobials use among out-patients in Delhi. Indian Journal of Medical Research 2009; 129: 555-560

2. World Health Organization. 2009. Community-based surveillance of antimicrobial use and resistance in resource-constrained settings. Report on five pilot projects.

Expanded AB use survey

New Delhi (Dec 2007-Nov 2008)

Surveillance of AB use in the community using the

established methodology of Exit Interviews

Antibiotic use data was collected from

- Public facilities (10)

- Private retail pharmacies (20)

- Private practitioners (20)

ATC/DDD measurement units were assigned; AB use

was measured as DDD/1000 patients visiting the

facility & also the % of patients receiving an AB

Salient findings of the survey

New Delhi (Dec 2007-Nov 2008)

High use of antibiotics: 39% patients visiting public

facilities and private retail pharmacies received AB;

43% patients at private clinics got an AB

The surveillance system successfully captured

the pattern of antibiotic use (newer AB used)

Repeat survey could catch change in trend of AB

use over a period of time-cephalosporins use

increased & macrolides use decreased since 2004

Methodology for surveillance of AB use in the out-

patient setting is working well

Annual use of antibiotics by facility type measured

as percentage of prescriptions containing a

specific antibiotic

0

5

10

15

20

25

30

35

40

PS PrS PrC

Facility type

Pe

rce

nta

ge

Ce

F

P

M

T

Co

AG

PS- Public Sector, PrS- Private Sector retail pharmacies, PrC- Private Clinics

M - Macrolides, P - Penicillins, Ce - Cephalosporins, F - Fluoroquinolones, Co - Cotrimoxazole,

T - Tetracyclines, AG - Aminoglycosides

Trends in antibiotic use (DDD/ 1000 patients) in the

areas surveyed in New Delhi (Dec 2007- Nov 2008)

Antibiotic name Public

sector

Private

retail

Private

clinic

Cephalosporins

Cefuroxime (2nd Gen)

Cephalexin (1st Gen)

Cefixime (3rd Gen)

Cefixime + clavulanic acid

3132

971

-

-

13511

-

8065

4127

8987

-

5919

2896

Fluoroquinolones

Ofloxacin

Ciprofloxacin

Levofloxacin

Norfloxacin

5516

4367

-

2590

15652

7557

5559

3332

13222

5434

4586

-

Penicillins

Amoxicillin

Amoxicillin+Clavulanic acid

Amoxicillin+Cloxacillin

Ampicillin

6403

2873

-

2234

8240

16299

4082

-

2263

14370

3065

-

Trends in antibiotic use (DDD/ 1000 patients) in the

areas surveyed in New Delhi (Dec 2007- Nov 2008)

Antibiotic name Public sector Private retail Private clinic

Macrolides

Roxithromycin

Azithromycine

Erythromycin

3995

-

2286

6836

5404

2535

3353

3648

-

Tetracycline

Doxicycline

Tetracycline

4210

1759

6147

949

4440

-

Kotwani A, Holloway K. Trends in antibiotic use among outpatients in New Delhi, India. BMC Infectious Diseases 2011;11:99

Methodology (absence of - community-based databases on AB

use, disease-code classification and doctors often not writing the name of

disease on the prescription)

After consultation with a prescriber, patients of

common cold/sore throat/cough for not more than

five days (symptoms of acute uncomplicated RTIs) or

acute diarrhoea (1-2 days) without any blood &

mucus were enrolled for exit interview

Antibiotic use data was collected per month over one

year (December 2007–November 2008)

Use of antibiotics for acute

uncomplicated RTIs

At public facilities 45% and at private facilities 57% of patients with acute uncomplicated RTIs were prescribed at least one antibiotic

Public sector-penicillins followed by macrolide, fluoroquinolone, and cephalosporins while at

Private facilities - cephalosporins, followed by fluoroquinolone, penicillins, and macrolide were prescribed

Pattern of AB use for acute uncomplicated RTIs

Antibiotic name Public sector (% 0f total

DDDs of AB

prescribed)

Private clinic (% of

total AB

prescribed)

Cephalosporins (J01DA)

Cefuroxime (2nd gen.)

Cefpodoxime Proxetil(3rd gen.)

Cefixime (3rd gen.)

Cefixime + clavulanic acid

Cephalexin (1st gen.)

Cefaclor

10.4

6.7

-

-

-

3.7

-

39.1

11.9

8.6

8.5

8.2

0.6

0.4

Fluoroquinolones (J01MA)

Levofloxacin

Ofloxacin

Ciprofloxacin

Norfloxacin

19.7

-

15.6

3.7

0.4

23.6

12.7

8.7

2.2

-

Penicillins J01C

Amoxicillin+Clavulanic acid

Amoxicillin

31.0

7.5

15.9

19.1

14.0

3.0

Pattern of AB use for acute uncomplicated RTIs

Antibiotic name Public sector (% 0f

total DDDs of AB

prescribed)

Private clinic (% of

total AB

prescribed)

Macrolides J01FA

Roxithromycin

Azithromycine

Erythromycin

24.6

14.7

-

9.9

15.5

11.4

4.0

0.1

Tetracycline (J01AA)

Doxicycline

Tetracycline

9.5

7.1

2.3

2.7

2.7

-

Cotriamoxazole (J01EE)4.8 0.03

Kotwani A, Holloway K. Antibiotic prescribing practice for acute, uncomplicated respiratory tract infections in primary care settings in New Delhi, India. Tropical medicine & International Health 2014; doi: 10.1111/tmi.12327. Online published 22 April, 2014.

Use of antibiotics for

acute diarrhoea

Patient exit interview methodology showed at public facilities

43% and at private facilities 69%, of patients with acute

diarrhoea were prescribed at least one antibiotic in New Delhi

The main antibiotic class that was prescribed in both public and

private sector facilities was fluoroquinolones, J01MA (91.5%

and 96%)*

Another study showed low adherence to standard treatment

guidelines for management of acute diarrhoea in children by

all healthcare providers in Ujjain city (India)#

*Kotwani A, Roy Chaudhury R, Holloway K. Antibiotic prescribing practices of primary care prescribers for acute

diarrhoea in New Delhi, India. Value in Health, 2012; 15: S116-S119.

#Pathak D,…Lundborg C .Adherence to treatment guidelines for acute diarrhoea in children up to age of 12 in

Ujjain, India. BMC Infectious Diseases 2011; 11: 32

Moving ahead…

qualitative studies

FGDs were conducted with doctors*, pharmacists#,

community, high school children. Salient findings:

1. Lack of microbiology testing; peer & commercial pressure

2. Doctors’ perceived demand and expectation

3. Retail pharmacists copying the prescription of neighbourhood

doctors and dispensing antibiotics for common conditions like

cold, sore throat, and diarrhoea

4. Incentives for pharmacists to make a profit

#Kotwani A, et al. Irrational use of antibiotics and role of pharmacists:…..qualitative study New

Delhi, India. Journal of Clinical Pharmacy Therapeutics 2011 Online published 23 AUG 2011

*Kotwani A, et al. Antibiotic use in the community: what factors influence primary care physicians

to prescribe antibiotics in Delhi, India? Family Practice 2010; 27: 684-690

Qualitative studies with high school

teachers & students

Salient findings*-

Students had poor knowledge regarding antibiotics

and antibiotic resistance, while only some teachers

had a basic understanding.

Broad themes needing attention emerged: antibiotic

use behavior, doctor–patient relationship, suggested

a multipronged approach - robust public awareness

campaigns also involving schools, better doctor–

patient relationships, and stronger regulations

*Kotwani A, et al. Knowledge and perceptions on……..a qualitative study. Indian Journal of Pharmacology 2016; 48: 365-371.

Access to antibiotics in

New Delhi (2011)

Data on price and availability of a basket of 24

essential ABs and 8 high-end ABs from public and

private sector was collected using a standardized

WHO/HAI methodology

Public sector: total of 83 public facilities, 68

primary care, 10 secondary care and 5 tertiary

care facilities under 3 public health care providers

Private sector: 40 private retail and 40 retail chain

pharmacies were enrolled

Kotwani A, Holloway K. Access to antibiotics in New Delhi, India: implications for antibiotic policy. Journal of Pharmaceutical Policy and Practice.2013, 6:6.

Salient findings from access survey for

policy implications

Public sector: Delhi state government has its essential medicine

list and was using Delhi state EML 2007 for procurement; the

other two agencies had their own procurement list not the EML

All ABs procured including second and third generation

antibiotics were available at primary care facilities. Antibiotic

available were on the basis of supply rather than rationality

or the Delhi state EML and none was 100% available

Availability of ABs at tertiary care facilities was sub-optimal

Private sector: Availability of ABs was good. For most of the

antibiotics the most expensive and popular trade names were

often available. High-end antibiotics, meropenam,

gemifloxacin, and moxifloxacin were commonly available.

For Community-acquired pneumonia

Antibiotic use in tertiary care

hospitals

Antibiotic drug use in hospitalised

patients

WHO recommends use of simple indicators to follow trends in

antibiotic use that provides guidance for local agencies in the

identification of deficiencies and priority areas for intervention

Community-acquired pneumonia (CAP) is an infectious disease

needs treatment with AB

Study was conducted: To determine patterns and frequency of

antimicrobial drug use for hospitalised patients with CAP

A retrospective five-year (April 2007-March 2012) medical

record review of patients discharged to home with a diagnosis

of CAP from non-ICU respiratory medicine wards of two public

tertiary care hospitals of Delhi was performed

Important findings from in-patient study

of CAP

For two antimicrobials, beta-lactam and macrolide;

For three antimicrobials, usually a beta-lactam,

macrolide and aminoglycoside were prescribed

Reasons for prescribing various ABs, previous history

of AB use, often discharge treatment were not

mentioned in the medical records

Hospitals did not have treatment guidelines or AB

policy to be followed and a variety of antimicrobial

regimens were prescribed at both the hospitals

Suggested interventions and Way forward

Main findings from the studies

Important conclusions from the various

studies

Community-based surveillance of AB use is possible in

resource-constrained settings, consumption & pattern of

use can be surveyed over years by Exit Interviews

High use of antibiotics in the community and for self-

limiting viral infections

AB choice inappropriate for acute uncomplicated RTIs

Stakeholders behavior for AB use a cause of concern

Inappropriate availability of AB esp. at primary care

Availability of ABs for children is poor at public sector

Cont..

Important conclusions from the various

studies (2)

Federal government run tertiary care and Municipal

corporation do not have EML

For Delhi state EML is not followed for distribution of

antibiotics for primary care

Availability of ABs in public sector is based on supply

Treatment guidelines are not available in any facility

Hospitals generally do not have treatment guidelines or

antibiotic policy for inpatients as well

Medical case sheet is not filled completely & properly

Interventions and policy options suggested

to improve rational use of antibiotics

National policies can influence rational use of ABs; infection

prevention and control measures can decrease use of ABs

Policy makers to urgently prepare and implement at national

and state level Antibiotic Policy and Antibiotic Stewardship

Program for both public and private sector

All public sector agencies to develop STGs & EML in an

evidence-based manner for various level of health care,

implement & adherance to guidelines

Proper quantification and order of antibiotics for public health

facilities and reliable delivery from suppliers

Interventions and policy options suggested

to improve rational use of antibiotics

Establish hospital antibiotic committee or infectious control

committee

Continuous surveillance of AB use in the community and

hospitals in public and private sector

Restricting use & regulations for AB use in agriculture, poultry,

and livestock; education of farmers and other stakeholders

Education and awareness programs for all stakeholders

Newer ABs should not be available without prescription; strict

implementation of law (schedule H1)

Efforts by researchers are only worthwhile if policy

makers invest in the interventions urgently

Next steps……. Globally

Inappropriate antibiotic use in the community? YES

Variation in health systems and stakeholders

Each country needs to

Measure, monitor antibiotic use

Factors responsible at all stakeholders

Committed program for intervention & monitor

Required political commitment and multidisciplinary

team

Conclusions

Antibiotics are indeed wonder drugs

Use antibiotics judiciously

Save the newer generations of antibiotics for next

generations and severely ill patients