# RKS: ALLERGY TO PRESCRIBING ANTIVIRALS FOR A VIRUS!

- ANTIBACTERIALS RULE IN FIGHTING 'A' VIRUS😠

1st April 2022

WHY ANTIVIRALS SHUNNED IN CORONAVIRUS?

- The Baffling Mindset's Possibilities

Dear Reader,

It has been captured that over 200 million doses of azithromycin and doxycycline antibiotics were sold in India in a particular quarter (2020) of COVID-19 period before the 2nd wave. Strange and surprising why antibiotics - meant for bacterial infections, are being advocated for fighting a virus??

The story is similar for most other unregulated and semi-regulated markets wherein the medical professionals are at complete liberty to decide on their whims and fancies the best in management for their otherwise gullible patients.

In the African continent countries also, such widespread use of antibiotics, primarily meant for bacterial infection, has now been criticized for advocating in a viral infection such as COVID-19; an article elaborating this concern has also been recently published:

Adebisi YA, Jimoh ND, Ogunkola IO, Uwizeyimana T, Olayemi AH, Ukor NA & Lucero-Prisno III DE. The Use of Antibiotics in COVID-19 Management: A Rapid Review of National Treatment Guidelines in 10 African Countries. Tropical Medicine and Health 2021; 49: Article number 51; https://doi.org/10.1186/s41182-021-00344-w.

Not only has the SARS-CoV-2 virus been the biggest bouncer disease in recent decades, the treatment delivered seems to be a goggly by the healthcare providers. Let us analyze if such goggly can take wickets or will remain as wide balls.

MICROBES

Microbes are microscopic bugs detectable with a microscope, being too small to be seen with the naked eye, and are chiefly classified as :

Protozoa: <50 microns in size
Fungi: 5-10 microns in size
Bacteria: 1-5 microns in size
Virus: 0.02-0.4 microns in size

There need to be, and there are specific drugs for killing these microbes if they cause infection - then labeled as pathogen. The appropriate terminologies that need to be known are:

Antiprotozoals - fight against protozoa such as causing dysentery
Antifungals - fight against fungi such as causing mucormycosis (a COVID-19 complication)
Antibacterials - fight against bacteria that may additionally invade in COVID-19 pneumonia
Antivirals - fight against viruses such as novel coronavirus (SARS-CoV-2)

A generalized term additionally used is 'antimicrobials' meaning an agent that could destroy any of the above-mentioned pathogen be it a bacteria or a virus or any other. However, when the word 'antibiotic' is used it means a synthetic drug to SPECIFICALLY kill bacteria or reduce their multiplication.

ANTIBIOTICS & ANTIVIRALS

The most favored antibiotics of the medical fraternity for COVID-19 symptoms, especially for non-hospitalized mild-to-moderate cases, have been azithromycin, doxycycline, cefixime and co-amoxiclav - a fixed dose combination (FDC) of amoxicillin + clavulanic acid. A quick glance at the pharmacology of these antibiotics reveal facts - startling in face of their overuse / misuse or abuse in COVID-19 sufferers.

The above being a gospel truth, it would be a crime to not consider an anti-viral in the management of a confirmed COVID-19 patient knowing fully well that the culprit is a virus and not a bacterium.

COVID-19 - BACTERIA AS IMPLICATED PATHOGENS??

Seeing the alarming usage of antibiotics, primarily meant for bacterial infections, for COVID-19, there has been recent spurt in data revealing their true value. (Adebisi YA et al. Tropical Medicine and Health 2021; 49: Article number 51; https://doi.org/10.1186/s41182-021-00344-w)

Chedid M, Waked R, Haddad E, Chetata N, Saliba G & Choucair J. Antibiotics in Treatment of COVID-19 Complications: A Review of Frequency, Indications, and Efficacy. J Infect Public Health 2021; 14(5): 570-576.

Mean rate of antibiotic use in COVID-19 management is 74.0% and only 17.6% of patients had secondary infections as per close to 3000 patients evaluated in near 20 studies.

Moolla MS, Reddy K, Fwemba I, Nyasulu PS, Taljaard JJ, Parker A et al. Bacterial infection, Antibiotic Use and COVID-19: Lessons from the Intensive Care Unit. SAMJ 2021; 111(4).

Bacterial co-infection is rare at the time of intensive care unit admission with COVID-19.

Lansbury L, Lim B, Baskaran V & Lim WS. Co-infections in People with COVID-19: A Systematic Review and Meta-analysis. J Inf Secur 2020; 81(2): 266-275.

Meta-analysis (pooled study - most authentic indicator) revealed that only 7.0% of hospitalized COVID-19 patients had a bacterial co-infection.

He S, Liu W, Jiang M et al. Clinical Characteristics of COVID-19 Patients with Clinically Diagnosed Bacterial Co-infection: A Multi-center Study. PLoS One 2021; 16(4): e0249668.

Only 86 out of 905 (9.5%) confirmed COVID-19 patients were clinically diagnosed with bacterial co-infection in a recent study.

Getahun H, Smith I, Trivedi K, Paulin S & Balkhy HH. Tackling Antimicrobial Resistance in the COVID-19 Pandemic. Bull World Health Organ 2020; 98(7): 442-442A.

Only a few COVID-19 patients would need antibiotics for possible bacterial pneumonia and other superimposed/co-infections.

But the reality is opposite! Most COVID-19 confirmed patients receive ONLY antibiotics & ZERO antivirals to kill the culprit SARS-CoV-2 virus!

ANTIBIOTICS USAGE IN INDIA FOR COVID-19

THE EVIDENCE

There has been demonstrated spurt in antibiotic sales of antibiotics in India in parallel to rise in COVID-19 cases.

Antibiotics are definitely required in hospitalized patients having pneumonia but neither azithromycin nor doxycycline are prescribed in such Intensive Care Unit (ICU) situations. Thus, the bulk of such pills meant for swallowing (oral consumption) are prescribed by the treating general practitioner or physician in cases visiting the consultation as outpatients.

THE BELIEVED REASONING

There is no reason why antibacterials are prescribed in confirmed COVID-19 cases. However, it can be safely assumed that there were no real serious viral infections ever prevalent in the last half century or so in outdoor patients, and there were never any specific definitive antiviral available either for viral colds and diarrheas - the two most common non-bacterial affections encountered in day-to-day practice.

The medical practitioner had been abusing antibiotics for common cold and viral diarrheas but there has never been any implications since these have traditionally been self-limiting illnesses in adults. The changing scenario does not reflect in the mindset of the doctors. Write 'antibiotics for any and every infection' has been the motto since time immemorial and the same outlook continues.

The fall-out effect has been reserving antivirals when patient's symptoms and health starts deteriorating in infection with the deadly SARS-CoV-2. At such times it becomes too late to curtail the infection and the COVID-19 patient invariably lands up in hospital or even possibly in the ICU!

ICMR - FUELS THE FIRE

The Indian Council of Medical Research (ICMR) has become a very popular body in the eyes of even the layman - let alone the doctors. It would be worthwhile to dig into their recommendations - in collaboration with All India Institute of Medical Sciences (AIIMS) (Delhi, India) for antibiotics and antivirals for COVID-19 management.

Treatment Guidance advisory by ICMR: 22nd April 2021
Treatment Guidance advisory by ICMR: 17th May 2021
Treatment Guidance advisory by ICMR: 23rd September 2021
Treatment Guidance advisory by ICMR: 14th January 2022

Mild Infection: Ivermectin or Hydroxychloroquine (HCQ) / Ivermectin / Nil / Nil
Moderate Infection: Nil for all 4 advisories
Severe Infection: Remdesivir in all 4 advisories

This implies that in severe cases the critical patient's life presumably depends on only injectable approved antiviral, remdesivir - besides other ICU supportive measures. But, surprisingly, an antiviral is not favored for milder cases - only when the patient deteriorates is he / she to be advocated a drug to kill virus seemingly!

THE MoHFW CONFUSES

Parallel to the ICMR, the Ministry of Health & Family Welfare (MoHFW) also releases guidelines for clinical treatment of COVID in collaboration with the Drugs Controller General of India (DCGI) who functions under the Central Drugs Standard Control Organisation (CDSCO). The ICMR & MoHFW (except initially) have never recommended an antiviral excepting remdesivir in severe cases thus far but the state MoH [Maharashtra (India)] has been wisely advocating usage of antivirals since the start of COVID-19 onslaught.

Clinical Management of COVID-19 Guideline by MoH: 17th March 2020

Presence of Comorbidity / High Risk Group / Moderate & Severe Infection: Oral antivirals

Clinical Management of COVID-19 Guideline by MoH: 31st March 2020

Mild / Moderate Infection: Nil

Severe Infection: Azithromycin with HCQ

Clinical Management of COVID-19 Guideline by MoH: 13th June 2020

Mild Infection: HCQ

Moderate / Severe Infection: Remdesivir; Antibiotics if only secondary bacterial infection

Clinical Management of COVID-19 Guideline by MoH: 27th June 2020

Mild Infection: Nil
Moderate Infection: Remdesivir; Antibiotics if only secondary bacterial infection

Clinical Management of COVID-19 Guideline by MoH: 24th May 2021

Mild Infection: Ivermectin or HCQ

Moderate Infection: Remdesivir; Antibiotics if only secondary bacterial infection

Severe Infection: Remdesivir

Not to be outdone by the MoH in the center, the states of India also released their own dictates in the treatment of infection with SARS-CoV-2!

Clinical Management of COVID-19 Guideline by Maharashtra State in India: 22nd July 2020

Mild Infection: Favipiravir or HCQ + Cefixime or Co-Amoxiclav (if secondary bacterial infection)

Moderate Infection: Favipiravir or Remdesivir or HCQ / Doxycycline + Ivermectin & Injectable antibiotics for bacterial pathogens in pneumonia

Severe Infection: Remdesivir or HCQ & Injectable antibiotics for bacterial pathogens in pneumonia

In fact, a total of 4 states released their own treatment guidelines for managing patients with COVID-19 infection.

Oral antivirals, not primarily indicative for novel coronavirus, were initially recommended by the MoHFW in India as per the earliest guidelines of March 2020. Thereafter when oral antivirals, specifically clinically proven in SARS-CoV-2 infection, were approved by the DCGI for COVID-19 the same were shunned and overlooked in the subsequent guidelines by MoHFW.

Seemingly, the MoH in State of Maharashtra was wiser in recommending an antiviral in the mild stage of this disease itself - unlike their counterpart in center!

THE DIPLOMATIC WHO DODGES

WHO Recommendation - 2nd September 2020: Corticosteroids for only severe COVID-19.
WHO Recommendation - 20th November 2020: Remdesivir could be used selectively for severe COVID-19.
WHO Recommendation - 17th December 2020: Not to recommend lopinavir or ritonavir (antivirals) as well as HCQ for COVID-19.
WHO Recommendation - 31st March 2021: Not to recommend ivermectin for COVID-19.
WHO Recommendation - 6th July 2021: Recommend IL-6 blockers (tocilizumab & sarlilumab) for severe COVID-19.
WHO Recommendation - 24th September 2021: Monoclonal antibodies (mAbs) (casirivimab + imdevimab cocktail injection) mild-to-moderate COVID-19, AND in severe / critical cases if do not possess natural anti-SARS-CoV-2 spike protein antibodies.
WHO Recommendation - 7th December 2021: Not to recommend convalescent plasma therapy for COVID-19.
WHO Recommendations - 14th January 2022: Recommend JAK (Janus Kinase) inhibitors (baricitinib, ruxolitinib, tofacitinib) for severe COVID-19. Also new recommendation for mAbs (sotrovimab) for mild-to-moderate disease.

Near 50% of the WHO (World Health Organization) meetings for discussing COVID-19 treatment was to remove an agent from the therapeutic armamentarium rather than fortify it! The sum total of all WHO recommendations is to manage SEVERE COVID-19 patients with corticosteroids, IL-6 blockers and JAK inhibitors whilst mild or moderate cases with mAbs. Pindrop silence regarding status of newer approved antivirals in various countries (over continents) even after their availability for over a year for treating COVID-19!

ORAL ANTIVIRALS APPROVED FOR COVID-19

Besides the popular and now famous remdesivir whose injections have been in constant demand, irrespective of controversies surrounding its usage and recommendations, there have been tablets / capsules of antivirals also approved.

Remdesivir Injection: DCGI Approved - 1st June 2020
Favipiravir Tablets: DCGI Approved - 19th June 2020
Molnupiravir Capsules: DCGI Approved - 28th December 2021

It has been over one and half years that favipiravir has been approved by the highest regulatory authority, DCGI, in India and over 3 months since the next one i.e. molnupiravir has also been given the green signal. However, neither ICMR nor the MoHFW in India advocate these antivirals' usage making a mockery of the approval system in the country.

It needs to be acknowledged that these two very same antivirals have also been approved across the globe in various countries spanning continents.

Molnupiravir seems to be turning the tide in favor of acceptance of an oral tablet / capsule for mild and moderate COVID-19 disease treatment. It is sincerely hoped that the ICMR & MoH wake up and include such oral antivirals in their recommendations. It is also prayed that the medical professionals make an attempt to treat a virus infection such as COVID-19 with an antiviral rather than advocating useless antibiotics meant for bacterial infection.😠

OMICRON - CANNOT TO BE TAKEN 'LIGHTLY'

CASE FATALITY RATE - NOT THE BEST CRITERIA

Case Fatality Rate (CFR), also called case fatality risk or case fatality ratio is the proportion of people who die from a specified disease among all individuals diagnosed with the disease over a certain period of time and expressed as a percentage.

The COVID-19 waves in India:

1st Wave: April 2020 to January 2021 - cases: 11.11 million (mn); deaths: 3.56 mn (1.9% of households reported deaths); CFR: 1.435%
2nd Wave: February 2021 to June 2021 - cases: 26.73 mn; deaths: 5.77 mn (6% of households reported deaths); CFR: 0.845%
3rd Wave: December 2021 and ongoing - cases (expected): 42.55 mn (on basis of R0 being 2.69 instead of 1.69 in 2nd wave); deaths over 5 mn; CFR: 0.5%

It is expected that approximately over 5 mn may die during this Omicron tsunami presuming the 3rd wave ends by February 2022. This number is equivalent to the 2nd wave even though the Omicron variant is supposedly a more milder variety of SARS-CoV-2 and inspite of the lower CFR. The hospitalization rates will be less but more hospital beds will be occupied in view of the twice the number of patients falling victim to COVID-19 in this third wave.

HOSPITALIZATION - A GUIDING TREATMENT PRINCIPLE??

Omicron variant does not apparently affect the lungs as much as the other Delta and original Wuhan virus. This has been reflected in lesser oxygen support required during the 3rd wave in hospitalized patients - 23.4% as compared to 74% and 63% in the 2nd wave and 1st waves respectively. This is because the Omicron variant does not infect the cells deep within the lungs unlike the Delta subtype of SARS-CoV-2. Thus, instead of pneumonia there is commonly bronchitis diagnosed and the risk of dreaded acute respiratory distress syndrome (ARDS) is lesser in those infected by the Omicron virus during the 3rd wave.

Omicron variant has filled up U.S. and other countries' hospitals with more COVID-19 patients than any other surge of the pandemic. One of the reasons for hospitalization is Omicron can cause the underlying illness to flare up - for example, in patients with diabetes, infection with this SARS-CoV-2 variant can lead to development of life threatening diabetic ketoacidosis. Also, just as the earlier SARS-CoV-2 variants causing COVID-19 impacted the heart, kidney and other organs, the same damage is the likely by Omicron variant.

NUMBER OF DEATHS - A GUIDING CRITERIA

In-hospital mortality has fallen from about 12% during the Delta-predominant 2nd wave to 7% in 3rd wave spurred by Omicron. However, in term of absolute numbers the deaths are more since the number of patients admitted are twice more.

The reasons for a large number of deaths are:

More proportion of the population is affected by the third wave - could be double. This is reflected by the daily positivity rate of 16.16% in the 3rd wave as of end-January 2022 vs. 12.7% reported in 1st wave and 6% in the 2nd wave. A daily positive rate means the number of people tested for COVID-19 and confirmed as positive each day (a daily positive rate between 3-12% confirms appropriate testing of numbers being done).

The more lethal Delta variant constitutes approximately 70% of the COVID-19 positive cases in India during the 3rd wave.

Omicron-related deaths are more in those with multiple comorbidities like hypertension, heart disease [coronary heart / artery disease (CHD / CAD)], diabetes, hypothyroidism (low thyroid hormones status), etc. There were more cases in those between 20 to 40 years of age during the 1st and 2nd waves. During the 3rd wave 84% deaths reported are in the senior citizen - 86% of whom had a history of underlying disorder - comorbidity.

60% of deaths in the third wave are in those partially vaccinated, or unvaccinated individuals.

In the US also, Omicron is claiming an average of 2,200 lives each day – higher than the Delta variant, which peaked during the 2nd wave to 2,078. "Nothing about this has been mild for us at all," says Dr Bell as he walks across the ICU in the University of Virginia (U.S.). "We're still working just as hard to try to keep people alive with omicron as we were with delta."

CHOOSE ANTIVIRALS OVER ANTIBIOTICS

Countries such as India, Ghana, Kenya, Liberia, Botswana, Uganda, Nigeria, South Africa, Zimbabwe, Ethiopia, Rwanda and many others recommend various antibiotics such as azithromycin, doxycycline, cefixime, cefpodoxime, ceftriaxone, co-amoxiclav, ciprofloxacin, feropenem, meropenem for management of COVID-19. This is worrisome since the pathogen is a virus and only a few patients would have bacterial co-infection.

The following table provides the comparative value of some most commonly advocated antibiotics and compares the same with corresponding antivirals approved for COVID-19.

Even WHO does not encourage the use of broad-spectrum antibiotics for COVID-19 especially those on the Watch and Reserve List for fear of fostering resistance. Then why is it that something so obvious has been disregarded? There needs to be an insight in this matter.

NATIONAL TASK FORCE - INDIA

There is in India a constituted a National Task Force (NTF) for COVID-19. This body has conducted 154 meetings from March 2020 till January 2022. Of these only in 2 dozen meetings were treatment-related options discussed and there was only 1 meeting each for favipiravir and molnupiravir thus implying a step-motherly treatment to reviewing antivirals - in view several meetings held for recommending zinc, ivermectin, etc. for COVID-19.

In the NTF there are 24 members, including representatives of the MoH. Amongst these the split is:

4 Government representatives: NON-DOCTORS
4 Public Health Specialists
3 Epidemiologists
2 Microbiologists
2 Virologists
2 Cardiologists
2 Pulmonologists
2 Consulting Physician
2 Pediatricians
1 Pharmacologist

Thus, the treatment guidelines which are evolved periodically are by 4 qualified 'relevant' clinicians who are knowledgeable to treat such infections in adults. Amongst these, 3 are dedicated institutional heads or associated with ICMR's functioning - hence possibly one practicing clinician - a general physician, has been the true guide for the released Guidances on the COVID-19 Treatment Protocols compilation.

Thus, is the omission of antivirals the outcome of this scenario? And most practicing doctors following such nationally released guidelines and the 'Mediclaim' insurance companies have taken these as pretext to dishonour claim is any treatment other than mentioned in official released protocols is prescribed.

Never has a general practitioner in India possibly advocated an antiviral for common viral infection in outpatients except for oseltamivir when swine flu first showed its fangs in 2009. Hence, there is never a mindset to write antivirals tablets or capsules in day-to-day practice nor do the various treatment protocols released by ICMR or MoH advocate these antiviral pills - except Maharashtra State (India) guidelines.

TAKE HOME MESSAGE

This Omicron variant of the coronavirus is causing cluster infections not only in hospitals or offices but also in closed environments of homes and within extended families. Due to the high transmissibility, entire families are getting the infection with the virus within a very short period of time. Much before the first infected person starts showing symptoms, the virus is passing on to the rest in the family.

The death due to current variant has the same pattern as with the others implicated in the 1st and 2nd waves of COVID-19 . The lungs fail - get more stiff due to fibrosis and then the kidneys fail. Then the heart starts feeling the stress and the ultimate outcome is multi-organ system failure to which the patients succumb during the illness. Yet surprisingly, disappointingly and alarmingly the tackling of the 3rd COVID-19 wave is only management of symptoms based on the presentation of mild symptoms related to the Omicron variant infection, rather than address the causative virus - unless the patient is hospitalized. This means, for those unlucky, if the virus progresses its attention to the lungs and other organs and the disease takes a turn for the worst thereby resulting in hospitalization the treatment then only tries to kill the destructive invader! Till then the SARS-CoV-2 is free to enjoy a field day.

It would be prudent and orderly to readdress the use of antivirals for COVID-19. The regulators and the Governments should leave no stone unturned to promote prescribing specific antivirals for eliminating SARS-CoV-2 right in the beginning stage of infection rather than current scenario of wait-n-watch being in vogue - may possibly save many COVID-19 suffers from unnecessarily embracing the grave!

The motto of layman and the motive of government is to get on with life and living and lifestyle inspite of the coronavirus. This is a necessity and medically attainable now since pills for SARS-CoV-2 available. We take an antibiotic for sore throat or a pain-killer for backache and carry on with our activities and duties rather than sit at home and brood. Similarly, if affected by COVID-19 take a molnupiravir or some similar to kill the virus and get well rather than suffer and risk crying over spilled milk!

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser

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Dr R K Sanghavi