Ijaz, MK, FDA’s Non-prescription Drugs Advisory Committee Meeting, Gaithersburg, MD, March 23,...

Ijaz, MK, FDA’s Non-prescription Drugs Advisory Committee Meeting, Gaithersburg, MD, March 23, 2004

HAND HYGIENE: VIRAL SURROGATES TO DEMONSTRATE EFFICACY OF TOPICALS

AGAINST VIRUSES

M. Khalid Ijaz, D.V.M., Ph.D.

Director and Vice PresidentDivision of Aerobiology, Protozoology and Virology

MICROBIOTEST, INC., Sterling, VA 20164

and

Affiliate Professor Department of Molecular and Microbiology

George Mason University, Fairfax, VA 22030


VIRUSES, PUBLIC HEALTH AND HAND HYGIENE: HISTORICAL PERSPECTIVE MAJOR FACTORS IN TESTING THE ANTIVIRAL ACTIVITY OF HANDWASH & HANDRUB AGENTS IN VIVO TESTING OF TOPICALS TESING OF HYGIENIC HANDWASH AGENTS AGAINST VIRUSES IN VIVO THE FINGERPAD METHOD AND DATA GENERATED AT MICROBIOTEST ISSUES, RECOMMENDATIONS AND CONCLUDING REMARKS ACKNOWLEDGEMENTS

OUTLINE


Major Etiological Agents of Infectious Diseases Identified since 1972*

Over the > 30 years, a number of emerging and re-emerging viruses has dominated the scientific literature.

In 70s, enteric (rotavirus, Norwalk), Ebola, Hantaan viruses

In 80s, retroviruses including HIV AIDS and hepatitis C

In 90s, Sin Nombre, HEV, HGV, HFV, Nipah & Hendra, West Nile viruses and Prion)

In 2000s, FMDV, avian influenza, SARS-HCoV

(Partly from Desselberger, 2000

FACTORS PREDISPOSING TO SPREAD OF NEW, EMERGING AND RE-EMERGING VIRAL DISEASES INCLUDE BUT NOT LIMITED TO GLOBAL TRAVEL AND MASS MOVEMENTS, HUMAN DEMOGRAPHICS AND BEHAVIOUR, VIRAL GENOME CHANGE AND ADAPTATION AND ANIMAL HUSBANDRY INTENSIFICATION ETC.


VIRUSES, PUBLIC HEALTH AND HAND HYGIENE:

HISTORICAL PERSPECTIVE

FOLLOWING HISTORICAL INTERVENTION TRIALS BY SEMMELWEIS

IN 1846 @ VIENA, A NUMBER OF INTERVENTION TRIALS HAVE

BEEN SHOWN TO REDUCE THE RISK OF INFECTION.

VIRUSES ARE IMPORTANT ETIOLOGIC AGENT FOR MORBIDTY AND

MORTALITY GLOBALLY.

NEW EMERGING AND RE-EMERGING VIRUSES ARE ON THE RISE

(WEST NILE, SARS-HCoV).

IN THE US 5% OF NOSOCOMIAL CASES DUE TO VIRUSES, ~32% IN

PEDIATRIC, of which RSV was most common

(Aitken and Jeffries, 2001)



HISTORICAL PERSPECTIVE (cont’d)

HANDS PLAY AN IMPORTANT ROLE IN THE SPREAD OF MANY VIRAL

INFECTIONS AND PROPER HAND WASHING BY CAREGIVERS,

FOOD HANDLERS FOR INTERRUPTION OF SPREAD OF VIRUSES

AND OTHER TYPES OF PATHOGENS IS UNIVERSALLY

RECOGNIZED

THIS HAS BEEN DEMONSTRATED IN INTERVENTION EXPERIMENTAL

AS WELL AS STUDIES CONDUCTED IN CLINICAL SETTINGS

(Black et al., 1981, Hendley & Gwaltney, 1988; Ward et al., 1991)

INFECTIOUS VIRUS HAVE BEEN RECOVERED FROM NATUALLY

CONTAMINATED HANDS. CASES IN POINT – HCV, RSV, RHINO-,

ROTAVIRUSES (Alfurayh et al., 2000; Hall & Douglas, 1981;

Keswick et al., 1983 and Hendley & Gwaltney, 1988)



HISTORICAL PERSPECTIVE (cont’d)

Although the FDA Center for Food Safety and Nutrition (CFSAN)

recognize the significance of viruses being disseminated by food

handlers and healthcare worker and role played by hands in this regard, the

Tentative Final Monograph (TFM) of FDA does not address viruses at all.

PROPER ANTISEPTICS PROCEDURES FOR USED DECONTAMINATION OF

HANDS CAN INTERRUPT SUCH DISSEMINATION


DO VIRUSES SURVIVE ON HANDS?DO VIRUSES SURVIVE ON HANDS?

Ijaz, MK, FDA’s Non-prescription Drugs Advisory Committee Meeting, Gaithersburg, MD,

March 23, 2004

0

10

20

30

40

50

60

70

80

90

Rhinovirus BVDV/HCV

Rhinovirus

BVDV/HCV

SURVIVAL OF SELECTED VIRUSES ON FINGERPADS OF ADULTS AFTER 20 MINUTES

% S

urv

ival


PREVENTIONIS PRIMARY!

Protect patients…protect healthcare personnel…

promote quality healthcare!


IN VIVO TESTING OF TOPICALSIN VIVO TESTING OF TOPICALS


TESTING OF HYGIENIC HANDWASHING AGENTS AGAINST VIRUSES IN VIVO

The Whole-Hand Method

The Fingertip Method

The Fingerpad Method

The Whole-Hand Method

The Fingertip Method

The Fingerpad Method


ASTM STANDARD FOR HAND ANTISEPTICSASTM STANDARD FOR HAND ANTISEPTICS

E2011-99 - METHOD FOR EVALUATION OF HANDWASHING

FORMULATIONS FOR VIRUS-ELIMINATING ACTIVITY USING THE ENTIRE

HAND

E1838-02 - METHOD FOR DETERMINING THE VIRUS-ELIMINATING

EFFECTIVENESS OF LIQUID HYGIENIC HANDWASH AND HANDRUB

AGENTS USING THE FINGERPADS OF ADULT VOLUNTEERS

E2011-99 - METHOD FOR EVALUATION OF HANDWASHING

FORMULATIONS FOR VIRUS-ELIMINATING ACTIVITY USING THE ENTIRE

HAND

E1838-02 - METHOD FOR DETERMINING THE VIRUS-ELIMINATING

EFFECTIVENESS OF LIQUID HYGIENIC HANDWASH AND HANDRUB

AGENTS USING THE FINGERPADS OF ADULT VOLUNTEERS


MAIN STEPS IN THE FINGERPAD METHOD MAIN STEPS IN THE FINGERPAD METHOD WITH IRB PERMISSION, SUBJECTS RECEIVE DETAILS ON STUDY & REQUESTED

WRITTEN CONSENT; JUST BEFORE TESTING, HANDS OF SUBJECT

SCREENED FOR ANY DAMAGE TO SKIN; MAIN STEPS IN TESTING ARE:

WITH IRB PERMISSION, SUBJECTS RECEIVE DETAILS ON STUDY & REQUESTED

WRITTEN CONSENT; JUST BEFORE TESTING, HANDS OF SUBJECT

SCREENED FOR ANY DAMAGE TO SKIN; MAIN STEPS IN TESTING ARE:

1. SUBJECT WASHES HANDS WITH UN-MEDICATED SOAP & WATER

1. SUBJECT WASHES HANDS WITH UN-MEDICATED SOAP & WATER

2. DRIES HANDS WELL WITH PAPER TOWEL

2. DRIES HANDS WELL WITH PAPER TOWEL 3. HANDS RUBBED WITH 70-

75% ETHANOL TILL DRY

3. HANDS RUBBED WITH 70-75% ETHANOL TILL DRY

Dr. Sattar – CREM, University of Ottawa


FINGERPAD METHOD (CONT’D.)FINGERPAD METHOD (CONT’D.)

4. THUMB- & FINGERPADS DEMARCATED WITH PLASTIC VIAL

4. THUMB- & FINGERPADS DEMARCATED WITH PLASTIC VIAL

5. TEN µL TEST MICROBE IN SOIL LOAD PLACED

5. TEN µL TEST MICROBE IN SOIL LOAD PLACED

6. THUMBPADS ELUTED IMMEDIATELY (INPUT CONTROL)

6. THUMBPADS ELUTED IMMEDIATELY (INPUT CONTROL)

9. WHEN INOCULUM DRIES, TWO FINGERPADS ELUTED (BASELINE)

9. WHEN INOCULUM DRIES, TWO FINGERPADS ELUTED (BASELINE)

7. THUMBPADS IMMEDIATELY DECONTAMINATED

7. THUMBPADS IMMEDIATELY DECONTAMINATED

8. INOCULUM ON FINGERPADS ALLOWED TO DRY

8. INOCULUM ON FINGERPADS ALLOWED TO DRY



FINGERPAD METHOD (CONT’D.)FINGERPAD METHOD (CONT’D.)10. FINGERPAD TREATED

WITH 1 mL OF TEST SUBSTANCE OR CONTROL

SOLUTION

10. FINGERPAD TREATED WITH 1 mL OF TEST

SUBSTANCE OR CONTROL SOLUTION

11. FINGERPAD ELUTED WITH 1 mL OF ELUENT WITH OR WITHOUT

WATER RINSE OR DRYING

11. FINGERPAD ELUTED WITH 1 mL OF ELUENT WITH OR WITHOUT

WATER RINSE OR DRYING

12. SKIN SURFACE SCRAPED ON INSIDE LIP OF VIAL TO

RECOVER MOST OF ELUATE

12. SKIN SURFACE SCRAPED ON INSIDE LIP OF VIAL TO

RECOVER MOST OF ELUATE

13. FINGERPADS DECONTAMINATED

13. FINGERPADS DECONTAMINATED 14. HANDS WASHED WITH

SOAP & WATER

14. HANDS WASHED WITH SOAP & WATER

15. HANDS DRIED WELL WITH PAPER TOWEL

15. HANDS DRIED WELL WITH PAPER TOWEL



ADVANTAGES OF THE FINGERPAD METHODADVANTAGES OF THE FINGERPAD METHOD

MEASURED VOLUME OF TEST INOCULUM PLACED ON A WELL

DEFINED AREA & DRIED

DRIED INOCULUM EXPOSED TO A KNOWN VOLUME OF TEST

FORMULATION FOR A DEFINED & SHORT CONTACT TIME

INFECTIOUS AGENT STAYS WHERE IT WAS PLACED

CONTROL & REFERENCE SOLUTION CAN BE INCLUDED IN

THE SAME TEST ALONG TEST FORMULATION

MEASURED VOLUME OF TEST INOCULUM PLACED ON A WELL

DEFINED AREA & DRIED

DRIED INOCULUM EXPOSED TO A KNOWN VOLUME OF TEST

FORMULATION FOR A DEFINED & SHORT CONTACT TIME

INFECTIOUS AGENT STAYS WHERE IT WAS PLACED

CONTROL & REFERENCE SOLUTION CAN BE INCLUDED IN

THE SAME TEST ALONG TEST FORMULATION


ADVANTAGES (CONT’D.)ADVANTAGES (CONT’D.)

CAN DISTINGUISH BETWEEN PATHOGEN LOSS DUE TO MECHANICAL REMOVAL, IN SITU INACTIVATION & POST-TREATMENT WATER RINSING & TOWEL OR AIR-DRYING

CAN BE USED WITH CONVENTIONAL OR HANDRUB FORMULATIONS

SUITABLE FOR WORK WITH ALL MAJOR CLASSES OF MICROORGANISMS

GIVES RESULTS COMPARABLE TO THOSE WITH THE WHOLE-HAND METHOD


ADVANTAGES (CONT’D.)ADVANTAGES (CONT’D.)

THE FINGERPAD METHOD HAS BEEN USED FOR EVALUATION OF VARIETY OF HAND WASH AGENTS BY A NUMBER OF DIFFERENT LABS HERE IN NORTH AMERICA INCLUDING EUROPE.

Woolwine and Gerberding (1995)

Steinmann et al., (1995)

Mbithi et al., (1993)

At MICROBIOTEST, WE HAVE TESTED AN ALCOHOL-BASED PRODUCT AGAINST RHINOVIRUS AND BVDV/HCV


ALCOHOL-BASED ANTISEPTICSALCOHOL-BASED ANTISEPTICS

MAJOR RELEVANCE IN HAND ANTISEPSIS

INCREASING ACCEPTANCE EVEN IN U.S. & CANADA

CONVENIENT, SAFE, FAST-ACTING & ENVIRONMENTALLY-FRIENDLY

FOR USE BETWEEN HANDWASHINGS

FORMULATIONS WITH >60% ALCOHOL BROAD-SPECTRUM

GERMICIDES, INCLUDING ACTIVITY AGAINST MANY

NON-ENVELOPED VIRUSES

HEPATITIS A, CALICI- & PARVOVIRUSES MAY BE RESISTANT

SOME CONCERNS WITH AIR QUALITY

MAJOR RELEVANCE IN HAND ANTISEPSIS

INCREASING ACCEPTANCE EVEN IN U.S. & CANADA

CONVENIENT, SAFE, FAST-ACTING & ENVIRONMENTALLY-FRIENDLY

FOR USE BETWEEN HANDWASHINGS

FORMULATIONS WITH >60% ALCOHOL BROAD-SPECTRUM

GERMICIDES, INCLUDING ACTIVITY AGAINST MANY

NON-ENVELOPED VIRUSES

HEPATITIS A, CALICI- & PARVOVIRUSES MAY BE RESISTANT

SOME CONCERNS WITH AIR QUALITY


FOR RHINOVIRUS 12 & FOR BVDV 6 SUBJECTS WERE USED. 10 uL OF EACH VIRAL INOCULA WAS PLACED ON EACH DIGIT & DRIED. EXPOSED TO 1 mL OF THE PRODUCT FOR 15 S. POST-EXPOSURE, ELUATE WERE ASSAYED FOR RESIDUALINFECTIOUS VIRUS AND LOG 10 REDUCTION WAS CALCULATED.

THE EFFECTIVENESS OF AN ALCOHAL-BASED HAND GEL AGAINST RHINOVIRUS AND BOVINE VIRAL DIARRHEA

VIRUS (SURROGATE FOR HEPATITIS C VIRUS)

VIRUSTESTED

REDUCTION VIRUS TITER

IN VITRO

BASELINE CONTROL

TEST PRODUCT

REDUCTION VIRUS TITER WITH TEST PRODUCT

P VALUE

Bovine viral

diarrhea virus

10 4.88

10 4.57 0.34

10 0.50

10 4.07

<0.001

Rhinovirus Type 14

10 4.00 10 3.750.48 10 0.50 10 3.25 <0.0005


TESING ANTI-VIRAL ACTIVITY OF HAND ANTISEPTICS:

POTENTIAL SURROGATE VIRUSES

VIRUSES ASSAY SKIN SAFETY SURVIVAL=======================================================================

Adenovirus Yes Yes Good

Bovine viral diarrhea virus/HCV Yes Yes Good

Feline calicivirus/Norwalk Yes Yes Good

Hepatitis A virus Yes Yes Very Good

Rhinovirus Yes Yes Good

Rotavirus Yes Yes Very Good

Respiratory syncytial virus Yes Yes Very Poor========================================================================

Ansari & Sattar, 2003; Ijaz et al., unpublished data


ISSUES TO BE RESOLVEDISSUES TO BE RESOLVED IS IN SITU PATHOGEN INACTIVATION NECESSARY?

SHOULD WE ACCOUNT FOR PATHOGEN REMOVAL WITH POST-

TREATMENT RINSE & DRYING?

WHAT SHOULD BE THE PERFORMANCE CRITERIA FOR HANDWASH &

HAND RUBS?

WOULD SURROGATES BE ACCEPTABLE?

IS RESIDUAL ANTI-VIRAL ACTIVITY NEEDED?

HARMONIZATION OF TEST METHODS

FDA MONOGRAPH?

CTFA/SDA CITIZEN’S PETITION TO FDA ON VIRUCIDAL ACTIVITY OF

HAND ANTISPETICS

MICROBIOTEST’s PROTOCOL TO TO FDA ON VIRUCIDAL ACTIVITY OF

HAND ANTISPETICS

ASTM organized a symposium in October, 2004

IS IN SITU PATHOGEN INACTIVATION NECESSARY?

SHOULD WE ACCOUNT FOR PATHOGEN REMOVAL WITH POST-

TREATMENT RINSE & DRYING?

WHAT SHOULD BE THE PERFORMANCE CRITERIA FOR HANDWASH &

HAND RUBS?

WOULD SURROGATES BE ACCEPTABLE?

IS RESIDUAL ANTI-VIRAL ACTIVITY NEEDED?

HARMONIZATION OF TEST METHODS

FDA MONOGRAPH?

CTFA/SDA CITIZEN’S PETITION TO FDA ON VIRUCIDAL ACTIVITY OF

HAND ANTISPETICS

MICROBIOTEST’s PROTOCOL TO TO FDA ON VIRUCIDAL ACTIVITY OF

HAND ANTISPETICS

ASTM organized a symposium in October, 2004


March 23, 2004

Hand Hygiene Guideline

Exposure to healthcare workers to variety of viral pathogens warranted a discussion of antiviral activity of hand antiseptic agents

Discussion of antiseptic agents included information about

in vitro evidence of antiviral activityresults of in vivo testing (finger pad method)

mimics conditions under which products will be used by healthcare workers

controls for differing survival of viruses on skin

Dr. Boyce, 2004


March 23, 2004

CONCLUSIONS HAND ANTISEPTIC AGENTS PLAY AN IMPORTANT ROLE IN INTERRUPTION OF VIRAL DISSEMINATION FROM SURAFCE-TO- HAND-TO-HAND AND FINGERTIPS TO MOUTH FROM THE ENVIRONMENT TO HUMAN POPULATIONS. GLP VIRUCIDAL METHODS FOR TESTING EFFICACY OF HAND ANTISEPTIC AGENTS ARE AVAILABLE. DATA GENERATED BY FINGERPAD METHOD HERE IN NORTH AMERICA AND EUROPE CONFIRMED THE VIRUCIDAL DATA GENERATED BY THE WHOLE-HAND METHOD.

SURVIVAL AND DISINFECTION STUDIES OF VIRUSES IN BLOOD AND CELL-ASSOCIATED VIRUSES UNDERWAY.


March 23, 2004

CONCLUSIONS CANADA HAS STARTED PRODUCT REGISTRATION.

WORLD HEALTH ORGANIZATION (WHO) IS IN THE PROCESS OF FINALIZING GUIDELINES

FDA SHOULD REVISIT ISSUE OF LABEL CLAIMS AGAINST VIRUSES FOR FORMULATIONS TO BE USED IN:

NOSOCOMIAL SETTINGS

FOOD HANDLING ESTABLISHMENTS

FDA’S CURRENT EXPERTISE ARE IN THE ANTI-VIRAL THERPEUTIC EVALUATION. FDA SHOULD SEEK EITHER OUTSIDE EXPTERISE OR HIRE SOMEONE TO LOOK INTO THIS MATTER

TOPICALS ARE MEANT TO BE USED FOR INTACT SKIN AND ONLY FOR PREVENTATIVE PURPOSES NOT FOR TREATMENT


LITERATURE FOR FURTHER READINGLITERATURE FOR FURTHER READINGAnsari S.A. & Sattar, S.A. (2002). The Need and Methods for Assessing the Activity of Topical Agents against Viruses. In Handbook of Topical

Antimicrobials: Industrial Applications in Consumer Products and Pharmaceuticals, D. Paulson (ed.), Marcel Dekker, New York, NY. Pages 411-445.

Ansari, S.A. et al. (1989). In vivo protocol for testing efficacy of hand-washing agents against viruses & bacteria: Expts. with rotavirus & Escherichia coli. Appl. Environ. Microbiol. 55 (12):3113-3118.

Ansari, S.A. et al. (1991). Potential role of hands in the spread of respiratory viral infections: Studies with human parainfluenzavirus 3 & rhinovirus 14. J. Clin. Microbiol. 29:2115-2119.

ASTM (2002). Standard Test Method for Determining the Virus-Eliminating Effectiveness of Liquid Hygienic Handwash and Handrub Agents Using the Fingerpads of Adult Volunteers (#E-1838-02).

Aitken, C and Jeffries, D. Nosocomial spread of viral diseases. Clin. Microbiol. Rev. 2001; 14: 528-546 Bidawid, S. et al. (2000). Contamination of foods by food handlers: experiments on hepatitis A virus transfer to food its interruption. Appl. Environ. Microbiol. 66: 2759-2763. Desselberger U. Emerging and re-emerging infectious diseases. J. Infect. 2000, 40:3-15.Ijaz, MK, AH Brunner, SA Sattar, and CM Johnson-Lussenburg. Survival characteristics of airborne human coronavirus 229E. Journal of Gen. Virology 66:2843-2748, 1985.Ijaz, MK, MI Sabara, PJ Frenchick, and LA Babiuk. Assessment of intestinal damage in rotavirus infected newborn mice by D-xylose absorption test. Journal of Virological Methods 18: 153-157, 1987.Ijaz, MK, D Dent, D Haines, and LA Babiuk. Development of a murine model to study the pathogenesis of rotavirus infection. Experimental and

Molecular Pathology 51:186-204, 1989. Sattar, SA, Ijaz, MK. Transmission of viral infections through airborne route. CRC Critical Reviews in Environmental Control 17: 89-131, 1987.Sattar SA, Tetro J, Springthorpe VS, Giulivi A. (2001). Preventing the spread of hepatitis B and C viruses: where are germicides relevant? Am J Infect Control 2001, 29:187-97.Sattar, SA and MK Ijaz. Airborne Viruses. In: Manual of Environmental Microbiology. P Wilkes and LD Stenzenbach (eds.) ASM press,

Washington, USA, p. 871-883,2002.Sattar, S.A. et al. (2002). Hygienic hand antiseptics: should they not have activity and label claims against viruses? Am. J. Infect. Control. 30:

355-372.Westwood, JCN and Sattar, SA. The minimal infectious dose. In: G Berg et al., eds. Viruses in Water. Washington, DC: American Public Health Association. 1976, pp.61-69.


Hand-Hygiene WebsitesHand-Hygiene Websites

Guideline for Hand Hygiene in Healthcare Settings – CDC, 2002

http://www.cdc.gov/handhygiene/materials.htm

Hand Hygiene in Retail & Food service Establishments, CFSAN, FDA, 2003

http://vm.cfsan.fda.gov/~comm/handhyg.html

MICROBIOTEST PROTOCOL submitted to FDA on June 26, 2003

http://www.fda.gov/ohrms/dockets/dailys/03/Aug03/081403/75N-0183H_emc-000001-01.pdf

Guideline for Hand Hygiene in Healthcare Settings – CDC, 2002

http://www.cdc.gov/handhygiene/materials.htm

Hand Hygiene in Retail & Food service Establishments, CFSAN, FDA, 2003

http://vm.cfsan.fda.gov/~comm/handhyg.html

MICROBIOTEST PROTOCOL submitted to FDA on June 26, 2003

http://www.fda.gov/ohrms/dockets/dailys/03/Aug03/081403/75N-0183H_emc-000001-01.pdf

Ijaz, 2000. Division of Biofilms, Protozoology and Virology


MICROBIOTEST, INC.

Donna B. SUCHMANN

ACKNOWLEDGMENTS

WWW. MICROBIOTEST.COM

CREM- UNIVERSITY OF OTTAWA

Dr. Syed A. SATTAR

ASTM – International

Dr. John MITCHELL

Ms. Kathy BAXTER

Mr. Dan SMITH

Yale University

Dr. John BOYCE

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