key: cord-0689209-c4i9e6fl
authors: Eggers, Maren; Eickmann, Markus; Zorn, Juergen
title: Rapid and Effective Virucidal Activity of Povidone-Iodine Products Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Modified Vaccinia Virus Ankara (MVA)
date: 2015-09-28
journal: Infect Dis Ther
DOI: 10.1007/s40121-015-0091-9
sha: 6394756d9759bedd7e0053f7b99a7df74da7a16a
doc_id: 689209
cord_uid: c4i9e6fl

INTRODUCTION: Since the first case of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection was reported in 2012, the virus has infected more than 1300 individuals in 26 countries, and caused more than 480 deaths. Human-to-human transmission requires close contact, and has typically occurred in the healthcare setting. Improved global awareness, together with improved hygiene practices in healthcare facilities, has been highlighted as key strategies in controlling the spread of MERS-CoV. This study tested the in vitro efficacy of three formulations of povidone iodine (PVP-I: 4% PVP-I skin cleanser, 7.5% PVP-I surgical scrub, and 1% PVP-I gargle/mouthwash) against a reference virus (Modified vaccinia virus Ankara, MVA) and MERS-CoV. METHODS: According to EN14476, a standard suspension test was used to assess virucidal activity against MVA and large volume plating was used for MERS-CoV. All products were tested under clean (0.3 g/L bovine serum albumin, BSA) and dirty conditions (3.0 g/L BSA + 3.0 mL/L erythrocytes), with application times of 15, 30, and 60 s for MVA, and 15 s for MERS-CoV. The products were tested undiluted, 1:10 and 1:100 diluted against MVA, and undiluted against MERS-CoV. RESULTS: A reduction in virus titer of ≥4 log(10) (corresponding to an inactivation of ≥99.99%) was regarded as evidence of virucidal activity. This was achieved versus MVA and MERS-CoV, under both clean and dirty conditions, within 15 s of application of each undiluted PVP-I product. CONCLUSION: These data indicate that PVP-I-based hand wash products for potentially contaminated skin, and PVP-I gargle/mouthwash for reduction of viral load in the oral cavity and the oropharynx, may help to support hygiene measures to prevent transmission of MERS-CoV. FUNDING: Mundipharma Research GmbH & Co. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40121-015-0091-9) contains supplementary material, which is available to authorized users.

Four of the six coronaviruses (CoVs) that have made the transition from mammalian/avian hosts to humans are endemic in the human population, and typically associated with mild, self-limiting respiratory illness [1] . However, the remaining two human CoVs cause severe respiratory syndromes and are associated with considerable mortality [1] . In 2003, the severe acute respiratory syndrome (SARS)-CoV caused a disease outbreak that claimed nearly 800 lives [2] , and for the second consecutive decade this century, a new human CoV has emerged. The Middle East Respiratory Syndrome (MERS)-CoV was first isolated from a 60-year-old man in Saudi Arabia in June 2012 [3] . Three years later, it has been responsible for the infection of more than 1300 individuals in 26 countries, and more than 480 related deaths [4] .

Of all the cases of MERS-CoV reported to date, three quarters have occurred within the source country of Saudi Arabia (Table 1) [4] . Infection in the index case followed recent travel to Saudi Arabia, Qatar, UAE and Bahrain [5] . An International Health Regulations Emergency Committee has highlighted five main factors contributing to the spread of MERS-CoV in the Republic of Korea [6] .

Briefly, these were (1) a lack of awareness among healthcare workers and the general public; (2) suboptimal infection prevention and control measures in hospitals; (3) crowded emergency rooms and multi-bed hospital rooms; (4) the practice of patients seeking care at multiple hospitals; (5) multiple visitors staying with infected patients in hospital rooms.

Overall, clinical experience with MERS-CoV indicates that its spread within the human population requires close contact; the majority of cases have resulted from human-to-human transmission in healthcare settings [7] . There is good potential for outbreaks to be contained, given suitable levels of awareness and hygiene.

The latest outbreak in Korea, however, is testament to the cost of neglecting these basic requirements. A recent study by our group demonstrated impressive, rapid virucidal activity of povidone iodine (PVP-I) against the Ebola virus (EBOV) [8] . PVP-I was also effective against the European reference virus (Modified vaccinia virus Ankara; MVA), which was determined to be a suitable surrogate test agent, facilitating the safe testing of the virucidal activity of antiseptic products against hazardous pathogens, including enveloped viruses such as EBOV [8] . PVP-I is a broad-spectrum antimicrobial, used globally in the medical field-including the Middle Eastas a disinfectant for skin, hands and mucosal surfaces as well as for wound treatment and eye applications [9] . 

Three PVP-I antiseptic products were tested in this study: 4% PVP-I skin cleanser, 7.5% PVP-I surgical scrub and 1% PVP-I gargle/mouthwash, each with the brand name Betadine, manufactured by Mundipharma (Limburg, Germany). This article does not contain any new studies with human or animal subjects performed by any of the authors.

Methodology for propagation of MVA was as described in [8] . Calculations of viral titer (in cases of no virus or low viral count) were as detailed in [8] . 

The titers of MERS-CoV present in the control samples ranged from 6.00 to 6.50 log 10 TCID 50 / mL under clean and dirty conditions. MERS-CoV viral titers were reduced between 4.30 and 4.97 log 10 TCID 50 /mL after 15 s (Table 2) , which corresponds to a reduction in A practical measure applicable to both of these issues is the implementation of effective hand hygiene practice. Standard hand hygiene includes either washing hands with soap and water or the use of an alcohol-based hand rub [16] . Randomized, controlled trial data are available to support the effectiveness of PVP-I and alcohol hand rubs over plain soap hand wash for hand decontamination, based on post-hygiene colony-forming unit count [17] .

In the context of virucidal activity, PVP-I has demonstrated superiority over ethanol-based sanitizers in inactivating murine norovirus on a modified finger pad test [18] . In an evaluation of the effectiveness of nine different hand sanitizers against feline calicivirus (a surrogate for norovirus), antiseptics containing 10% PVP-I achieved a greater viral reduction rate than any of the alcohol-based sanitizers, non-alcoholic sanitizers or antimicrobial soaps [19] . PVP-I has demonstrated virucidal activity against a range of enveloped and non-enveloped viruses. Perhaps most relevant in the context of the MERS-CoV is the evidence for effective inactivation of the SARS-CoV to below detectable levels within 2 min of exposure [20] .

Effective hand hygiene is crucial in minimizing viral transmission from the contaminated hands of an infected individual, either through direct person-to-person contact, or indirectly via contamination of surfaces. However, respiratory viruses are also subject to airborne (particles B5 lm in size) or droplet ([5 lm) transmission, in which infected material is released by the infected individual breathing, coughing or sneezing [21] . Gargling represents an effective personal hygiene measure against airborne/droplet transmission, as it can reduce the microbe count at the pharynx [22] . Together with hand washing and mask use, it has been proposed that gargling is one of the three major personal hygiene protection measures against common airborne and droplet-transmitted infections [22] . Specialists advise that the criteria for selecting mouthwashes should include effectiveness of the antiseptic agent in killing pathogens [22] . highly cytotoxic in cell culture [27] . 

Identification of new respiratory viruses in the new millennium

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Middle East respiratory syndrome coronavirus (MERS-CoV) Summary of Current Situation, Literature Update and Risk Assessment

Emergencies preparedness, response. Summary and risk assessment of current situation in Republic of Korea and China

World Health Organization (WHO). WHO Statement on the 9th Meeting of the IHR Emergency Committee Regarding MERS-CoV

Frequently Asked Questions on Middle East Respiratory Syndrome cornonavirus

Povidone-iodine hand wash and hand rub products demonstrated excellent in vitro virucidal efficacy against Ebola virus and Modified vaccinia virus Ankara, the new European test virus for enveloped viruses

The use of povidone-iodine and hydrogen peroxide mixture as an adjunct to non-surgical treatment of slight to moderate chronic periodontitis

Quantitative suspension test for the evaluation of virucidal activity in the medical area. Test method and requirements (Phase 2/Step 1)

The method of 'right and wrong cases' ('constant stimuli') without Gauss's formulae

Beitrag zur Kollektiven Behandlung Pharmakologischer Reihenversuche

Essential Medicines and Health Products: Ebola vaccines, therapies, and diagnostics

Centers for Disease Control and Prevention. Middle East Respiratory Syndrome (MERS): Prevention and Treatment

State of knowledge and data gaps of Middle East respiratory syndrome coronavirus (MERS-CoV) in humans

Infection prevention and control during health care for probable or confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Interim guidance

Comparing hand hygiene measures in a neonatal ICU: a randomized crossover trial

Comparison of virucidal activity of alcohol-based hand sanitizers versus antimicrobial hand soaps in vitro and in vivo

In-vivo efficacy of hand sanitisers against feline calicivirus: a surrogate for norovirus

Inactivation of SARS coronavirus by means of povidone-iodine, physical conditions and chemical reagents

Respiratory virus RNA is detectable in airborne and droplet particles

Press release: 10 years after SARS-improper hand washing in the majority of HK people coupled with a 25% drop in cold & flu sick leave for reducing risk of spreading of germs doctor urges to regain strict personal hygiene habits

Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques

Washington: CDC-NIH

The effect of residual moisture in lyophilized smallpox vaccine on its stability at different temperatures

Leitlinie der Deutschen Vereinigung zur Bekämpfung der Viruskrankheiten (DVV) e.V. und des Robert Koch-Instituts (RKI) zur Prüfung von chemischen Desinfektionsmitteln auf Wirksamkeit gegen Viren in der Humanmedizin

Log 10 reduction factors in viral clearance studies