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Transcript
CHAPTER 8
Antiviral Antimicrobics and Resistance
I. GENERAL CONSIDERATIONS
Events in the cell unique to viral replication are the target
DNA polymerase is often inhibited
II. SELECTED ANTIVIRAL AGENTS
A. Inhibitors of Attachment
1. Antibody can bind to extracellular virus and prevent attachment
2. Antibody is useful in prophylaxis, but has been minimally effective in treatment.
B. Inhibitors of Cell Penetration and Uncoating
1. Amantadine and rimantadine are symmetrical amines, or acyclics, that inhibit
early steps in replication
2. Effective only against influenza A viruses, but sharply rising resistance rates now
preclude their routine use.
a. Pharmacology and Toxicity
1. Rimantadine is metabolized by the liver
2. Amantadine is excreted by the kidney
C. Neuraminidase Inhibitors
1. Oseltamivir and zanamivir are antivirals that selectively inhibit the neuraminidase
of influenza A and B viruses
2. Neuraminidase inhibitors are effective in treatment and prophylaxis of influenza
A and B viruses
D. Inhibitors of Nucleic Acid Synthesis
a. Idoxuridine and Trifluorothymidine
1. Idoxuridine and trifluorothymidine block DNA synthesis
b. Acyclovir
1. Acyclovir is effective against herpesviruses that induce thymidine kinase
2. Inhibits viral DNA polymerase and terminates viral DNA chain growth
i. Pharmacology and Toxicity
1. Oral form has low bioavailability but achieves concentrations in blood
that inhibit HSV and to a lesser extent varicella-zoster virus (VZV)
2. Intravenous acyclovir is used for serious HSV
ii. Treatment and Prophylaxis
1. Effective against herpes and zoster
c. Valacyclovir, Famciclovir, and Penciclovir
1. Valacyclovir is a prodrug of acyclovir that is better absorbed and once
absorbed, it becomes acyclovir
2. After absorption Famciclovir is converted to penciclovir which is a
competitive inhibitor of a guanosine triphosphate
d. Ganciclovir
1. Ganciclovir does not require viral thymidine kinase for phosphorylation
2. Neutropenia and thrombocytopenia limit use
i. Clinical Use
1. Indicated for the treatment of active CMV infection in
immunocompromised patients, but other herpesviruses are also
susceptible
ii. Resistance
1. After several months of continuous ganciclovir therapy for treatment of
CMV, between 5 and 10% of AIDS patients excrete resistant strains of
CMV
2. In virtually all isolates, there is a mutation in the phosphorylating gene,
and in a lesser number there may also be a mutation in the viral DNA
E. Inhibitor of Viral RNA Synthesis: Ribavirin
1. Ribavirin has several modes of action
2. Ribavirin is active against respiratory syncytial virus, Lassa fever virus, and
hepatitis C
F. Inhibitors of HIV
a. Nucleoside Reverse Transcriptase Inhibitors
i. Azidothymidine (AZT)
1. A nucleoside analog of thymidine
2. HIV reverse transcriptase is more than 100 times more sensitive
to AZT than is host cell DNA polymerase
3. The first useful treatment for HIV infection but now is
recommended for use only in combination with other inhibitors of
HIV replication
4. Resistance is associated with one or more mutations in the HIV
reverse transcriptase gene
ii. Didanosine (ddI, dideoxyinosine) and zalcitabine (ddC,
dideoxycytidine)
1. Nucleoside analogs that inhibit HIV replication
2. Serious adverse effects include peripheral neuropathy and
pancreatitis
3. Used only in combination with one or two other anti-HIV drugs
iii. Stavudine (D4T)
1. Interferes with viral reverse transcriptase and also terminates the
growth of the chain of viral nucleic acid.
2. Dose reduction is required for impaired renal function
iiii. Lamivudine (3TC)
1. 3TC suppresses development of AZT resistance
b. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
1. Compounds that are not nucleoside analogs but bind to essentially the
same site on reverse transcriptase also inhibit HIV reverse transcriptase
2. Nevirapine, delavirdine, and efavirenz, have been evaluated alone or in
combination with nucleosides
3. NNRTIs are often active against AZT-resistant strains
4. Rapid development of drug resistance occurs when NNRTIs are used
alone
c. Protease Inhibitors
1. Protease inhibitors block viral-encoded proteases
2. Saquinavir, ritonavir, indinavir, and nelfinavir are potent protease
inhibitors
3. Used in combination with other anti-HIV drugs
d. Inhibitor of viral entry – Maraviroc
e. Inhibitor of viral fusion – Enfuvirtide
f. Inhibitor of viral integration - Raltegravir
G. Nucleotide Analogs: Cidofovir
1. Mimic monophosphorylated nucleotides by having a phosphonate group
attached to the molecule
2. Cidofovir inhibits viral DNA polymerase
3. Resistance can develop with mutations in the viral DNA polymerase
4. Cidofovir is approved for CMV retinitis, and disseminated adenovirus
infections.
H. Other Antiviral Agents
a. Foscarnet
1. A pyrophosphate analog that inhibits viral DNA polymerase by
blocking the pyrophosphate-binding site of the viral DNA polymerase
2. Used to treat patients with ganciclovir-resistant CMV and acyclovirresistant HSV
b. Interferons
1. Recombinant DNA techniques allow large-scale production
2. Interferons inhibit viral protein synthesis
3. Interferon alpha is combined with ribavirin to treat chronic hepatitis C
c. Fomivirsen
1. A synthetic oligonucleotide, complementary to and presumably
inhibiting a coding sequence in CMV
2. Approved for the local (intravitreal) therapy of CMV retinitis in patients
who have failed other therapies
III. ANTIVIRAL RESISTANCE
A. Genetic alterations
1. Rate of viral replication. Higher rates of replication are associated with higher
rates of spontaneous mutations.
2. Selective pressure of the drug. The selective pressure increases the probability
of mutations to the point that virus replication is substantially reduced.
3. Rate of viral mutations. In general, single-stranded RNA viruses (eg, HIV,
influenza) have more rapid rates of mutation than double-stranded DNA viruses
(eg, herpesviruses).
4. Rates of mutation in differing viral genes. For example, within the
herpesviruses, the genes for phosphorylating nucleosides (eg, UL97) are more
susceptible to mutation than the viral DNA polymerase.
B. Detection of Resistance
1. Phenotypic resistance is detected by in vitro methods such as tissue culture
2. Genotypic methods are molecular detection of mutation by sequencing the viral
gene or by restriction enzyme patterns.
3. Viral quantitation such as an increase in patient's viral burden despite treatment
suggests development of resistant mutants