Antiviral Chemotherapy

• Antiviral chemotherapeutics target viruses.
• Antibiotics are ineffective against viruses because viruses do not grow or metabolize like cells and lack membranes and cell walls.
• Most antiviral drugs are synthetic, or "human-made."

Primary Modes of Action

• Antiviral drugs have four primary modes of action.
• They can inhibit attachment.
• They can disrupt genomic replication, including the use of "nukes".
• They can inhibit viral enzymes, including non-nukes.
• They generate antiviral proteins called interferons.

Drugs That Block Viral Attachment

• Amantadine (Symmetrel) is used most often for influenza.
• Vidarabine (Vira-A) treats herpes zoster and simplex.
• Enfuvirtide (Fuzeon) treats HIV, and was introduced in 2003.

Base Analogues

• Azidothymidine (AZT) uses a "nonsense" nucleic acid to stop replication.
• AZT is a nucleoside reverse transcriptase inhibitor (NRTI, nuke) used for retroviruses.
• Acyclovir (Zovirax) is used in ointment form to treat genital herpes and chicken pox.

Pre-Exposure Prophylaxis (PrEP)

• PrEP involves daily medication for those at high risk of contracting HIV.
• PrEP includes a combination of two nucleoside reverse transcriptase inhibitors (NRTIs, 'nukes').
• Truvada (tenofovir + emtricitibine) acts similarly to AZT.
• PrEP results in a 90% reduction rate in sexually-transmitted HIV.

Drugs That Inhibit Viral Enzymes

• Protease inhibitors, such as saquinavir (Invirase), inhibit the enzyme that processes HIV proteins.

• Reverse transcriptase inhibitors, such as nevirapine (Viramune), inhibit the enzyme that converts viral RNA to DNA (non-nuke).

• Neuraminidase inhibitors like oseltamivir (Tamiflu) inhibit spike enzymes that allow penetration and exit from a cell.

Treatments for SARS-CoV-2

• Several monoclonal antibody treatments are approved, including Bamlanivimab, Casirivimab, Imdevimab, and Sotrovimab.
• Treatments have been sporadic in Canada.
• They are used in highest-risk groups for severe outcomes if given early (within 10 days of infection).
• Mutations in variants may reduce effectiveness.
• Monoclonal antibody treatments are not a replacement for vaccination.
• Remdesivir (Veklury) is an RNA chain terminator, preventing reproduction of viral RNA genomes.
• It was originally ineffective against Ebola and HepC, but is now approved in Canada and the US for severe SARS CoV 2 infection.
• Paxlovid (nirmatrelvir; ritonavir) is a combination drug.
• Nirmatrelvir inhibits SARS CoV 2 protease, which creates functional SARS proteins, and ritonavir slows the metabolism of protease inhibitors.
• It is the first oral and at-home prescription treatment for SARS CoV 2.
• Paxlovid treats mild to moderate cases in high-risk groups for serious illness (18 and older).
• Molnupiravir (Lagevrio) is investigational.
• It incorporates into new RNA strands and can shift configuration between C and U bases, hypermutating the virus to death.
• Health Canada is investigating molnupiravir due to concerns over mutations leading to birth defects.

Interferons

• Interferons include 20 different proteins.

• Interferons include a, b, and g categories.

• Interferon g forms from tumor cells.

• Interferons a and b mobilize natural killer cells and come from virally infected cells.

• Interferons stimulate AVP production.

• AVPs stop viral protein synthesis by binding viral mRNA, blocking protein production.

• INF-a is now approved for use in hep B and C, genital warts, and HIV, and is being assessed for SARS COV 2.

Developing a Drug

• Developing drugs requires laboratory testing (in vitro)
• It requires animal testing (in vivo)
• It requires clinical trials
• Clinical trials have three phases that each increase in: the number of subjects, statistical significance, and stringency of test.

Phase I, II and III drug testing

• Phase I testing involves 20-100 healthy subjects.

• Phase I testing tests varied doses and monitors side effects and bioavailability.

• Phase II testing involves approximately 500 patients with a disease.

• Phase II testing continues to monitor side effects with different doses of medication and compares a new drug to controlled drugs.

• Phase III testing involves several thousand patients with disease.

• Phase III testing tests a drug against established methods.

• Phase III is triple blinded.

• Phase III establishes statistics on "efficacy" and "safety".

• Clinical trials take from 7 to 15 years and just 1 in 1,000 drugs make it to humans.

• Further, just 1 in 5,000 drugs make it through trials.

Superbugs

• Superbugs are bacteria that have become resistant to most antibiotics.
• Antibiotic resistance is a global health and development threat.
• The WHO has declared antimicrobial resistance (AMR) is one of the top 10 global public health threats for humanity.
• Misuse and overuse of antimicrobials are the main drivers for development of drug-resistant pathogens.
• A lack of clean water and sanitation and inadequate infection prevention promotes the spread of microbes that can be resistant to antimicrobial treatment.

How Bacteria Resist Antibiotics

• Destruction of the drug by an enzyme called penicillinase.
• Prevention of membrane penetration.
• Alteration of the target site.
• Rapid efflux of the drug before it can act.
• What contributes to resistance is the misuse of antibiotics.
• Overprescription of medications occurs.
• 150 million prescriptions are issued in North America annually.
• 112% of all prescriptions written for the common cold.
• Self-medication and incomplete antibiotic regimens contribute to resistance.

Major Superbugs

• The three major superbugs include: MRSA, VRE, and Clostridium difficile.
• MRSA (methicillin-resistant Staphylococcus aureus).
• Approximately 1 in 3 people (2.5 billion) carry S. aureus.
• Approximately 2% of people carry MRSA.
• The carrier rate seems higher in nurses, at approximately 5%.
• MRSA infections are sporadic or epidemic.
• MRSA spreads by direct contact.
• Death rate due to drug resistance of MRSA is unclear.
• So far, vancomycin has been effective.
• Clostridium difficile (C. difficile) is gram +ve. sporeforming bacillus.
• Difficile is a major cause of colitis or major inflammation of the colon
• Difficile spread by Fecal - oral route.
• Difficile is usually nosocomial (in hospitals) in North America.
• In Quebec, there were 7,000 cases in 4 years, a 4x increase, causing 600 deaths.
• Difficult is treated with vancomycin and antiprotozoal medications such as metronidazole.
• Difficult can also be treated with fecal transplants.
• Fecal transplants are a promising treatment for chronic, recurring C. difficile.
• VRE (vancomycin resistant Enterococcus): gram +ve cocci.
• It is part of normal flora.
• Developed by overuse of vancomycin.
• The VRE spread by Fecal - oral route.
• Prevalence remains low in Canada (