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PHARMACOLOGICAL
APPROACHES TO TREAT
VIRAL, PARASITIC AND
FUNGAL ORGANISMS
Jassin M. Jouria, MD
Dr. Jassin M. Jouria is a medical doctor, professor of
academic medicine, and medical author. He graduated
from Ross University School of Medicine and has
completed his clinical clerkship training in various
teaching hospitals throughout New York, including
King’s County Hospital Center and Brookdale Medical
Center, among others. Dr. Jouria has passed all USMLE
medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has
developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria
has also served on multiple levels in the academic field including faculty member and Department
Chair. Dr. Jouria continues to serves as a Subject Matter Expert for several continuing education
organizations covering multiple basic medical sciences. He has also developed several continuing
medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has
been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to
develop an e-module training series for trauma patient management. Dr. Jouria is currently
authoring an academic textbook on Human Anatomy & Physiology.
ABSTRACT
Antibiotic therapy, as part of a medical plan and lifesaving measure is a primary
focus in terms of the general principles that clinicians must understand when
selecting a course of pharmacology treatment for an infectious disease. This
course is part two of a 2-part series on pathogens and antimicrobial therapy with
a focus on general issues affecting antibiotic selection, the types of pathogens
and diseases treated, and on specific antibiotics’ indication, administration and
potential adverse effects. Antibiotic misuse and resistance is discussed.
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Policy Statement
This activity has been planned and implemented in accordance with the policies of
NurseCe4Less.com and the continuing nursing education requirements of the
American Nurses Credentialing Center's Commission on Accreditation for
registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity,
transparency, and best practice in clinical education for all continuing nursing
education (CNE) activities.
Continuing Education Credit Designation
This educational activity is credited for 5 hours. Nurses may only claim credit
commensurate with the credit awarded for completion of this course activity.
Pharmacology content is 5 hours.
Statement of Learning Need
The health literature has identified the inappropriate use of antimicrobial agents,
as well as the evolving pathogenicity of varied types of organisms and rising
problem of antimicrobial resistance. This is a critical learning topic for health
clinicians, especially in the field of infectious disease as decisions are made to
treat and educate patients to prevent and address an infectious disease process.
Course Purpose
To provide clinicians with knowledge of issues in antibiotic pharmacology and
related preventive and life saving measures.
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Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses and Medical
Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,
Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Please take time to complete a self-assessment of knowledge, on page 4,
sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge learned will be
provided at the end of the course.
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1. The efficacy of an antiviral agent depends on its ability
a.
b.
c.
d.
to be selectively toxic against the virus.
to overcome the viral resistance strategy.
to be effective against replicating and latent viruses.
All of the above.
2. True or False: Most antiviral agents available are only effective against
replicating viruses.
a. True
b. False
3. Anti-viral agents, known as immunomodulating agents,
a. interfere with the host cell receptor or co-receptor.
b. act directly by inhibiting viral replication at the cellular level.
c. augment or modify the host immune system to eradicate the infecting
virus.
d. inhibit attachment of viral specific glycoproteins to host cells.
4. _________________ is not recommended for immunosuppressed
patients because it causes vaccine-induced infection.
a.
b.
c.
d.
Salk polio vaccine
Oral polio vaccine
Zidovudine
Azidothymidine
5. Complications such as arthritis and arthralgia are reported among
women after vaccination with
a.
b.
c.
d.
live-attenuated measles vaccine.
killed measles vaccine.
rubella vaccine.
the 17D vaccine.
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Introduction
More recently, the development of new chemotherapeutic agents and vaccines
has assisted in proper management of certain diseases. A potent antiviral,
antiparasitic and antifungal agent should be effective to treat most studied
organisms. Specifically, an antiviral agent should be effective against both
replicating and latent viruses; it can be used for the treatment of overt viral
diseases, or in suppressive, preemptive and prophylactic therapy. It is important
to understand the mechanism of pharmacological agents used to treat pathogens
in order to guide the choice of drug in infectious disease management.
Antiviral Therapy
Antiviral agents are drugs used in the treatment of viral infections. They inhibit
certain major steps in viral replications, specific enzymes and structures that are
important in the viral growth and multiplication. Unlike antibacterial drugs, only
limited types of antiviral agent are available for the treatment of specific viral
infections. More recently, the development of new chemotherapeutic agents and
vaccines has assisted in proper medical management of these diseases. The
efficacy of an antiviral agent depends on the ability to be selectively toxic against
the virus and to overcome viral resistance.37,38,40-44
Because viruses are obligate intracellular organisms that depend on the host
synthetic machinery for replication, an antiviral agent must exhibit selective
toxicity against the target virus. It is therefore important to understand the
mechanism of actions of this drug, and the side effect and resistance pattern
associated with these agents. A primary focus of this course is to discuss various
types, uses and approaches to the development of the antiviral agent. In
addition, there will be a detailed study about the acquired resistance pattern of
viruses to antiviral drugs and available vaccines.
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Presently, only few viral infections have effective drugs of treatment. These
include human immunodeficiency virus, (HIV), respiratory syncytial virus (RSV),
varicella zoster virus (VZV), cytomegalovirus (CMV), hepatitis B virus (HBV),
hepatitis C virus (HCV), human papillomavirus (HPV), etc. The development of
antiviral agents over the years has been a challenge due to the difficulties in
establishing the right diagnosis, isolation and studying viruses. However, in recent
years, with the advancement in molecular technique, discovery of highly sensitive
and specific viral quantitative method, more antiviral agents are available for the
treatment of these diseases.
Viruses are obligate intracellular organism that depends on the host cellular
machinery for viral replications. During replication, the virus attaches itself to a
host cell, and after a successful entry, it uncoats by releasing nucleic acid into the
host cell. The released nucleic acid is transcripted to make new copies, which are
later translated into viral proteins, and assembled into infective virions. Antiviral
agents can target one or more of these stages. A potent antiviral agent should be
effective against both replicating and latent viruses. It can be used for the
treatment of overt viral diseases, or in suppressive, preemptive and prophylactic
therapy. The efficacy of an antiviral agent depends on the ability to be selectively
toxic against the virus, and overcome the viral resistance strategy. It is therefore
important to understand the mechanism of the antiviral agent in order to guide
the choice of drug in disease management.
Mechanism of Action
Mechanism of action of antiviral agent involves inhibition of virus-specific steps in
viral replication. These include:

Attachment to the cell

Penetration
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
Uncoating of nucleic acid

Transcription and translation of early (regulatory) proteins

Nucleic acid synthesis

Synthesis of late (structural) proteins

Assembly of mature virions

Viral release
In addition, since a virus depends mainly on the host cell metabolic activities,
potent antiviral agents should inhibit only virus-specific functions without
affecting the host. Therefore, the most antiviral agent has limited spectrum of
activity. Most compounds with in vitro antiviral effects are not suitable as an
antiviral agent because they are harmful to the host. Ordinarily, antiviral agents
should be effective for latent and replicating virus; however, most antiviral agents
available are only effective against replicating viruses.
Types and Uses
Based on the antiviral activity of the agents against viral infections, they can be
classified into two broad categories:
 Antiviral agents - act directly by inhibiting viral replication at the cellular
level.
 Immunomodulating agents - augment or modify the host immune system to
eradicate the infecting virus.
Antiviral agents may also be classified based on the virus, they act against (i.e.,
anti-HIV drugs include nevirapine, delaviradine, etc.). Some may be effective
against one or more viral diseases (i.e., Foscarnet in the treatment of both CMV
and HIV infection and lamivudine, which is effective against HBV and HIV
treatment).
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Generally, antiviral agents are categorized based on their antiviral active site in
viral replication. It is therefore important to understand the various stages
involved in the replication in order to know the mechanism of the drug action.
Fusion Inhibitors
These drugs prevent viral attachment or fusion by either interfering with the host
cell receptor or co-receptor. Maraviroc, an allosteic inhibitor interferes with HIV-I
attachment with CCR5 chemokine receptor. They also inhibit attachment of viral
specific glycoproteins to host cells.
Oseltamavir, peramivir, and zanamavir are neuraminidase inhibitors used for the
treatment of Influenza A and B virus. A recent study reported the inhibitory effect
of new compounds such as N-carboxamide. N-carboxamide acts on Influenza A
and B haemaglutinin to prevent binding of the virus. Enfurvirtide inhibits gp41mediated fusion of HIV-1 with the host cell.
Nucleic Acid Inhibitor
These antiviral agents inhibit synthesis of nucleic acid in different ways and most
of the available antiviral agents belong to this group. Some are nucleoside or
nucleotide analogue, synthetic compound or their derivatives.
Nucleoside analogues act against DNA polymerase. They are nucleosides with a
modified base or sugar. They are selective against virus-infected cells where
phosphorylation to the monophosphate, diphosphate or triphosphate forms by
cellular or viral kinase enzymes. The phosphorylated drug competes with the viral
nucleoside, and is incorporated into the viral genome causing termination of the
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growing chain or extensive misreading in the genome. This can lead to mutation
and transcription inactivation.
Anti-Herpesvirus Drugs
Guanosine Analogue
Acyclovir is used in the treatment of herpes simplex virus. It requires
phosphorylation by viral encodedthymidine kinase enzyme present only
herpesvirus-infected cell to acyclovir monophosphate. It acts as a DNA chain
terminator by competing with deoxyguanosine triphosphate as a substrate of DNA
polymerase. The drug is highly selective for cells with active viral replication. HSV
virus that lacks thymidine kinase are resistant to acyclovir.
Valacyclovir is a prodrug of acyclovir. It is effective in the treatment of HSV-1,
HSV-2, VZV, and CMV. It is rapidly metabolized in the gastrointestinal tract into
acyclovir and Valine by hydrolase enzyme. The mechanism of action is similar to
acyclovir.
Ganciclovir is a derivative of guanosine but with an additional hydroxyl methyl
group is used in the treatment of CMV. The mechanism of action is similar to
acyclovir. Famicyclovir, a prodrug of pencicyclovir is active against HSV-1, HSV-2
and VZV. Pritelivir acts on HSV-2 by inhibiting the helicase-primase enzyme.
Thymidine Analogue
Idoxuridine is effective against VZV, HSV and vaccinia virus. It inhibits the
biosynthesis of thymidine necessary for DNA synthesis causing mutation and
incomplete transcription. It is phosphorylated to the active form by both viral and
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cellular kinase. It has a potent antiviral activity when administered parenterally,
but with sufficient host toxicity.
Trifluridine is a halogenated thymidine analogue with similar mechanism of action
as idoxuridine. It is active against idoxuridine-resistant herpesvirus. Other
nucleoside analogues are vidarabine and trifluorothmidine.
Anti-HIV Drug
Azidothymidine or Zidovudine (pyrimidine analogue) is the first drug developed
for HIV treatment. It is phosprylated by cellular thymidine kinase to the
triphosphate form before inhibiting reverse transcriptase enzymes. It is also
effective against other retroviruses. It synergizes well when combined with other
compounds such as didanosine, zalzitabine, nevirapine, lamivudine, etc.
Zalcitabine is another pyrimidine analogue phosphorylated by cellular enzyme. It
has similar mechanism of action as Zidovudine.
Didanosine (purine analogue) is inhibitory against HIV-reverse transcriptase by
acting as a chain terminator. It is phosphorylated into the active form by creatine
kinase or phosphoribosyl pyrophosphate synthase enzyme. It is a good anti-HIV
agent when combined with other HAART (highly active antiretroviral therapy)
drugs.
Stavudine (thymidine Analogue) is used in combination with other drugs for the
treatment of HIV. The mechanism of action is similar with Zidovudine.
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Lamivudine (cytidine analogue) is effective in the treatment of HIV and HBV. It
directly inhibits viral transcriptase after phosphorylation by the cellular kinase to
its active form. It has a toxic effect on the host.
Anti-HBV Drugs
Entecavir (guanosine analogue) is active against HBV replication by terminating
viral DNA synthesis, inhibiting transcription of viral genomic mRNA and
preventing HBV reverse transcriptase priming. Entecavir selectively binds viral
DNA polymerase with little or no effect on the host polymerase. It is
phosphorylated by cellular kinase enzyme to its active form.
Telbivudine is a thymidine analogue, which is active against HBV and other
hepadnaviruses. It terminates viral DNA chain elongation by inhibiting
anticomplement strand of DNA. Phosphorylation to the active form is also by
cellular kinases. It has no genotoxicity effect.
Other nucleoside analogue inhibitors of HBV include zalcitabine, emtricitabine
lamivudine, abacavir and clevudine.
Drugs for Other Viruses
Ribavirin is a nucleoside analogue with antiviral activity against RSV and HCV. Its
potency in the management of Hemorrhagic and Lassa fever has also been
documented. The mechanism of action is poorly understood, but it is known to be
inhibitory to monophosphate dehydrogenase enzyme that is important in viral
DNA synthesis. Sofosbuvir is a new nucleoside drug approved for the treatment of
HCV.
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Non-nucleoside Analogue Drugs
The non-nucleoside analogue drugs directly bind viral enzymes such as reverse
transcriptase and noncompetitive inhibitor of the viral polymerase.
Foscarnet is an inorganic phosphate analogue, active against herpesvirus,
hepadnavirus and HIV. It blocks the pyrophosphate-binding site on the viral DNA
polymerase enzymes. It has nephrotoxicity effect and highly effective in the
treatment of acyclovir or gancicylovir resistant HSV and CMV.
Cidofovir is a monophosphorylated nucleotide analogue that does not require viral
enzymes for phosphorylation. It is activated by cellular kinase phosphorylation to
directly inhibit viral DNA polymerase and cause termination of the growing DNA
chain. It has antiviral activity against EBV, HHV, VZV, HHV, adenovirus and
polyomavirus. It is nephrotoxic.
Nevirapine, efavirence and delaviradine are other nonnucleoside analogue agents
used in the treatment of HIV. Other drugs such as amenamevir and pritelivir are
new drugs in clinical trials, which are proven to have antiviral activity against
Herpesvirus and HIV.
Protein Translational Inhibitors21,22,37,40
Interferons
Interferons are glycoproteins induced in response to infection and primarily
known for their antiviral and immunoregulatory activities. Interferons enhance
activation of macrophages, natural killer cells and other immune cells in the body.
They also stimulate the production of cytokines. With DNA recombinant
technology, different classes of interferon can be synthesized.
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Therapeutic Uses:
Interferon is used in the treatment of chronically active HBV infection. It inhibits
HBV-DNA polymerase with marked clearance of serum HBeAg when administered
to the infected patient. A significant response was observed when one of the
pegylated forms (PEG-IFN-α2) is used for patent with A and B genotype.
Chronic HCV infections are treated with IFNs to inhibit the disease progression to
cirrhosis, liver failure or hepatocellular carcinoma. The pegylated forms can be
used in combination therapy with ribavirin or other antiviral agents. Interferons
are also useful for the treatment of other viral diseases such as human papilloma
virus.
Immunomodulator
These agents stimulate activation of dendritic cells, pro-inflammatory cytokines
and macrophages. Imiquimod is an example of these agents used in the
treatment of perianal genital warts. Pegylated-IFN acts as an immunomodulator
in the treatment of HBV.
Integrase Inhibitor
Integrase inhibitory agent targets the enzyme integrase involved in the insertion
of viral DNA into the cellular genetic component. These antiviral agents have a
high affinity for protein binding and therefore have some toxicity towards the
host. Available integrase inhibitors in HIV-1 and 2 treatment include, raltegravir,
elvitegravir, indinavir and dolutegravir.
Specific Protease inhibitor
Protease enzymes are involved in viral replication by cleaving the polypeptide in
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reverse transcriptase released. These drugs inhibit proteolytic cleavage of these
polypeptide precursors that are vital for viral protein synthesis. Protease
inhibitors of HIV-1/HIV-2 virus are ritonavir, saquinavir, nelifinavir, among others
The Development Of Antiviral Agents
The central focus in the global prevention of diseases is through the development
of vaccines. Advancement in molecular techniques has assisted in overcoming
challenges posed through traditional method of producing vaccine by a passage in
egg, animals and even human. Techniques such as micro array technology,
nanotechnology, DNA sequencing, and gene therapy have increased research
interest in synthesizing a vaccine for common, emerging and re-emerging viral
diseases. Cloning of genomic DNA to mimic the virulent strain of the virus is
possible with the use of better enzyme and plasmid. Antigenic site involved in
neutralization is marked through selecting monoclonal antibodies, which allows
proper assessment of the viral surface proteins.1-3,35,87
The global interest in the development of vaccines is increasing every day with
about 15 newly discovered, unlicensed vaccines awaiting approval since human
papilloma virus-like particle (VLP) in 2006. Genomics, proteomics and related
technologies can be applied to the development of vaccines for emerging and reemerging viruses. With these promising inventions, the lists of new vaccines for
more such viral diseases will multiply in the future.
Aim of Vaccination
Vaccination is important to prevent and control transmission of diseases either
locally or globally. The significant success recorded with vaccination is
encouraging with the recent declaration of 10 countries (India, Nigeria, etc.) as
poliovirus free by the World Health Organization (WHO). Eradication of measles
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has also received a strong boost since 2000 although with few setbacks due to
the outbreak.34
Development of vaccines has other therapeutic importance, in addition to the
primary effect. The HPV vaccine was licensed, not because of its ability to inhibit
HBV transmission, but as cervical neoplastic preventing. Vaccines also reduce the
disease burden on the host. The VZV vaccine prevents continuous infection of the
virus wild type strain, but does not eradicate the disease and therefore reduces
the symptoms (herpes zoster) of the virus.
Vaccine Development
Initially, few methods were adopted for developing vaccine from viruses. One of
these methods is used in the production of inactivated vaccines. They contain
killed virus with intact antigen inactivated by chemical agents such as beta
propio-lactone, formaldehyde and formalin. They confer immunity against viruses
that are virulent, oncogenic or cause recurrent infections. Most often, they are
usually administered with adjuvants such as alum to increase their
immunogenicity. Inactivated vaccine confers short-lived immunity. Examples
include Salk Polio Vaccine (SPV), hepatitis A vaccine, influenza vaccine and rabies
vaccine. Salk polio vaccine or inactivated polio vaccine contains three strains of
polio-virus.34
In addition, other techniques were used to synthesize live-attenuated vaccines.
These vaccines are derived from genetically engineered viruses from which the
virulent gene is either removed or weakened. They mimic wild type strain and are
able to replicate in the host without causing any disease. They are heat labile and
induce immunity by stimulating both humoral and cellular response. Live
attenuated vaccine generates Th1 and Th2 T-cell response that confers long-term
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immunity. It is not suitable for vaccination of immunosuppressed patients as it
can revert into a virulent form. Examples include the vaccines for rubella, oral
polio, yellow fever, measles, mumps and influenza.33-36
A subunit vaccine is a recombinant vaccine developed by cloning and purification
of the immunogenic protein of a viral particle. They elicit immune response and
are considered safe for vaccination. Example is the recombinant HBV vaccine,
purified from the HBV carrier blood sample.
The DNA vaccine is an antigen-encoding plasmid that is capable of inducing in
vivo expression of the protein when administered to a subject. The introduction of
the antigen-encoding DNA along with major histocompatibility complex class 1
induces virus-specific immune response. They are heat stable and induce long
lasting immunity without a booster dose. No DNA vaccine is available for human
use, but the experiment in animal models indicates that it could be adapted for
therapeutic purpose.
Vaccine for Viral Diseases
The efficacy of a vaccine depends on the ability to initiate an immune response
(either cellular or humoral) that will prevent transmission of a pathogen. As
stated earlier, there are 15 approved vaccines for human management with more
others undergoing clinical trials. Sometimes, using adjuvants enhances vaccine
immunogenicity. Many adjuvants are available, but only aluminium and/or
phospholipid A is used for human.87
Vaccine for RNA Viruses34-36,57,58,75,77
Polio Virus Vaccine:
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The polio vaccine is of two types - the Salk and Oral polio vaccine. The Salk
vaccine contains three poliovirus strains grown in monkey kidney culture and
attenuated by formalin treatment. It stimulates serum immunoglobulin (IgG, IgM
and IgA) and is very effective in preventing systemic invasion of the virus. It does
not produce mucosal IgA, and therefore has no intestinal resistance to infection.
When the recipients are exposed to the wild strain, they become infected and
shed the virus in stool, without any disease.
The oral polio vaccine also contains three poliovirus strains attenuated by serial
passages in human diploid or monkey kidney culture. It stimulates mucosal IgA
and serum antibodies. It prevents gut infection and dissemination of the virus
into the blood. It can revert into the wild type and cause vaccine-induced
infection. It is not recommended for immunosuppressed patients.
Influenza Virus Vaccine:
Available influenza vaccines are live-attenuated, inactivated and subunit vaccines.
Live-attenuated vaccine is synthesized with the avian recombinant virus. These
vaccines are used to prevent avian influenza infection.
Identifying, modifying and purifying the antigenic part of the influenza virus
particles lead to the development of the subunit or split vaccine. It is easily
tolerated and less immunogenic than the wild type; whereas, inactivated vaccine
is made with virus grown in embryonated egg. It contains strains of influenza A
and B viruses inactivated by formalin. It produces short-term immunity.
Yellow Fever Virus:
There are two types of the yellow fever virus; the 17D and the French neurotropic
virus. The 17D vaccine, the first yellow fever vaccine is a live-attenuated vaccine
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produced by passaging 17 strain of yellow fever virus in chicken embryo. It
stimulates protective immunity in 95% of the recipient. It has long lasting effect.
The French Neurotropic yellow fever vaccine was synthesized in the mouse brain.
Because of the side effect, it is no longer produced.
Measles Virus:
Two types of measles vaccines are produced. The live-attenuated measles vaccine
is prepared from Edmonson or Schwartz strain of measles virus in chicken embryo
cell. It produces seroconversion in 90-95% and confers a long-term immunity on
the recipient. It rarely causes meningitis or encephalitis.
The killed measles vaccine is the formalin-inactivated type. It has short-lived
protection. It is no more in circulation because it reverted into the wild type when
administered to children causing atypical measles symptoms.
Rubella Virus:
Rubella vaccine is synthesized after serial passage in human diploid cells. It
stimulates IgA production in mucosal layer and confers long lasting immunity in
the recipient. It can be administered in combination with measles and mumps
vaccines. Complications such as arthritis and arthralgia are reported among
women after immunization with the rubella vaccine.
Rabies Vaccine:
Rabies vaccines used for active immunization are the nervous tissue, duck
embryo and tissue culture vaccine.
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The nervous tissue vaccine or simple vaccine, is prepared in the brain of sheep or
goats, and inactivated with phenol. It is used for post-exposure immunization.
The vaccine induces a good immune response, but carries neurological
complications. It is no longer available.
The duck embryo vaccine is a freeze-dried vaccine prepared in duck eggs and
inactivated with beta propiolactone. It has no neurological complications. The
vaccine is no more available because it is not very effective.
The tissue culture vaccine consists of human diploid cell and rhesus monkey
diploid cell culture vaccine. It is effective, safe and available for preventing rabies
infection.
HIV Vaccine:
Several strategies have been adopted to synthesize vaccines for preventing HIV
infections with mixed outcomes. However, some potential vaccines such as
subunit gp120, recombinant poxvirus-plasmid and DNA-primed recombinantadenovirus serotype 5 (rad5) were under trials to determine their immunogenicity
level.
Subunit-monomeric gp120 vaccine was synthesized by modifying the envelope
glycoprotein gp120 on the cell surface of the HIV virus, including alum adjuvant.
The clinical trial failed to yield efficient results as the vaccine showed no
immunogenicity against the primary wild type of the virus.
Recombinant poxvirus vector-vaccine concept involves using recombinantpoxvirus vectors to express HIV envelope and structural glycoprotein and boosted
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with subunit envelope. The trial outcome was promising as low level of
immunogenicity was observed.
The DNA primed vaccines incorporate recombinant-adenovirus serotype 5 to elicit
CD8+ that prevent infection by the virus. The vaccine was less effective in in vitro
method, but with promising prospects when the analogue of the vaccine was tried
in a nonhuman primate model.
Mumps Vaccine:
Mumps vaccine is produced in the chick embryo. It also confers long-term
immunity.
DNA Virus Vaccine
HBV Vaccine:
The first HBV vaccine was made from HBsAg particle in the plasma of infected
and inactivated with formalin. The current vaccine is a subunit vaccine that is
produced by cloning the S gene of HBV in yeast. The cloned gene is purified and
genetically engineered into a vaccine. The vaccine induces a long-lasting
immunity.
Varicella-zoster Virus:
A live-attenuated VZV vaccine has proven to be effective in preventing the virus
transmission. It can be administered to children, elderly and immunosuppressed
patients. The vaccine induces immunity and can be used as a prophylactic agent.
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Approaches To New Antiviral Drug Development
Discovery of antiviral drugs with new technique has evolved over the years from
conventional egg or animal culture to advanced molecular method, which aid viral
gene analysis. Specialized technique such as DNA sequencing, pharmacological
modelling and chromatography has advanced the production of the drug. Proper
understanding of important stages of viral replication through molecular
techniques has also assisted in improving the potency of the antiviral drugs,
promoted mutational analysis of viral drugs and development of vaccines to
prevent the viral diseases. Many factors hinder the development of antiviral
drugs. These include viral resistance, reduced efficacy, solubility, side effects and
bioavailability of the drugs due to shelf life of the constituting compounds. The
novel mechanism for the development of antiviral drugs is the same with all the
viruses. The following are the approach to the design of the antiviral
agents.21,22,43,44,90
Traditional Approach
Generally, the methodological process of antiviral production involves basic
requirement steps before the antiviral agent can be presented for approval.
Firstly, the list of current compounds against the viral agents and their
mechanism of action are assessed. This provides a template for the synthesis of
the new compound with a predefined, specific target site. The efficacy of the new
compound is then tested using different methods involving cell culture, animal
model and molecular techniques. After the in vitro techniques, the effect or
toxicity of the potential agents on the host cell is then determined.
Cell-based Antiviral Assay
This method provides a platform to screen large compound libraries for antiviral
activity. Cell-based assay is one of the best and most reliable and accurate
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techniques for cell testing because live cells are used for the experiment to
determine the cytopathic effect (CPE) of the antiviral drug. It has been efficiently
used for the development of antiviral agent against different diseases such as
Kaposi’s sarcoma-associated herpesvirus (KSHF), Epstein-Barr virus, influenza
virus, herpes virus, respiratory syncytial virus (RSV), etc. Different cell culture
systems are available which can be adapted for the assay based on the biology of
the virus (i.e., Primary, secondary and continuous cell line).
Biochemical Assay
Various biochemical assay techniques are available to determine the antiviral
activity of a compound. Phenotypic assay is used to measure the susceptibility of
a virus to particular drugs. Determining the concentration of the drug that will
inhibit the viral replication of the recombinant virus by 50% and 90% will achieve
this. The efficacy of the compound is then compared with the wild type. Genotypic
assay involves the studying of the genetic constitution of a virus, which influences
its susceptibility and resistance to a particular compound. This involves molecular
methods such as polymerase chain reaction (PCR), hybridization and sequencing
technique.
New Technology
Bioinformatics
The dynamic nature of the research in biology has recently been increasing the
discovery of new ideas, which help in antiviral drug development. Resources
available through bioinformatics can assist in the identification of a potential drug
with antiviral property. Recently, bioinformatics was used in predicting short
inference RNAs (siRNA) as a potential antiviral agent against dengue virus.
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Computational methods are also adapted into bioinformatics for analysis,
manipulation and storing scientific data in the database, which are accessible for
researchers. These new tools are in genomes study of viruses in predicting the
arrangement of genes, coding strength and role of the viral proteins. Information
about the biological importance and chemical properties of a compound in the
database can assist in the development of new antiviral drugs.
Genomics and Proteomics
Genomics and proteomics are important techniques that help in the study of the
viral genomes and translated protein, which are important in the viral replication.
Genomic sequencing assists in understanding the gene arrangement and studying
the mutational pattern of the virus through evolution. Genomics is very important
in molecular modelling and small molecule docking where the amino acid
components of the genes are analyzed to predict the expressed protein under
disease condition. With genomics, the NS5B of HCV polymerase enzymes has
been studied extensively to know its role in the viral resistance to some antiviral
agents.
Viral proteome consists of all proteins which a virus expresses, reflecting the
transcripted RNA as well as the post-translating reactions that are involved. Also,
factors that influence translation of protein are characterized by the application of
proteomics. Proteomics promises to be an effective tool in the discovery of new
drugs because it differentiates and identifies various genetic products of the virus.
It can also assist in analyzing the impact of biochemical processes such as
glycosylation, proteolysis, phosphorylation, hydrolysis, etc., on viral replication.
X-ray Cyrstallography
X-ray crystallography is an important tool for the three-dimensional analysis of a
drug target. This analysis determines the association between small compounds
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and their target protein; this process may manipulate the compound chemically
into an intended result. In 2006, two compounds with antiviral inhibitory property
attached to NS3 protease were prepared after x-ray crystallographic technique.
RNA Interference Technique
This section discusses RNA interference (RNAi), which is a distinct, conservative
genetic mechanism involving the control of gene expression. RNAi maintains
genomic structure and prevent host cell from viral infections. It is stimulated by
smaller, double stranded RNA (dsRNA), and it is involved in both transcription and
translational processes.
Recently, RNAi has become an important tool for analyzing gene function and
designing drug. It is used to produce drugs, which are used as a prophylaxis and
in the treatment of infectious diseases, including HIV, influenza virus, human
papilloma virus (HPV) and viral hepatitis (B and C).
Chemical Genetics
This is an emerging field that promises to be an effective tool in the development
of new antiviral drugs. Genes are classified into groups while new compounds are
designated into families based on their chemical properties. Combining genotype
and chemotype analysis will help to locate potential molecular targets, enzymes
and reactions that are suitable for antiviral actions. This idea will help to
understand the mechanism of action of the new compounds with a known
phenotype expressed by the virus and any mutations in the viral replication. The
effect of drug toxicity on the cellular response are better understood through this
technique, which may facilitate scientific decisions on the new compounds in
clinical trials.
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Approach to Drug Formulation
Because viruses are obligate intracellular microorganisms, the viral replication
takes place in the host cell and therefore, many cells are affected or damaged
during this process. The efficacy of antiviral agents depends largely on systemic
absorption of the drug and the ability to reach the target site. The development of
a novel drug delivery system (NDDS) has helped to circumvent many challenges
associated with the treatment of many viral infections particularly oral and
parenteral administered drugs. These challenges include, reduced bioavailability,
low solubility, short half-life, and toxicity associated with the drugs.
Conventional Formulations
Depending on the viral infection, many antiviral agents are formulated for use for
proper treatment of the diseases. Some of these drugs are available in oral,
topical and parenteral forms. Other drugs can also be formulated in two or more
forms, such as:
Oral Antiviral Drugs:
Oral drugs are formulated for easy absorption in the gastrointestinal tract and
usually reach peak serum concentrations or levels within a few hours of
administrations. Examples of orally available drugs and their antiviral actions
include:
 Acyclovir, famicyclovir, pencicyclovir are drugs available in oral form for the
treatment of herpes virus such as CMV, HSV-1 and 2, and VZV.
 Oseltamavir and rimantidineare administered orally for the treatment of
influenza virus A and B infections.
 For HBV infection treatment, available oral drugs include, adefovir,
cidofovir, lamivudine and telbivudine
 Oral anti-HIV drugs are zalcitabine, stavudine, abacavir, emtricitabine,
efavirence, and tenofovir.
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 Some drugs are orally inhaled for effective treatment. Zanamavir for
Influenza virus A and B treatment.
Parenteral Antiviral Drugs:
Parenteral administration of antiviral drugs is important because some drugs are
poorly absorbed in the gastrointestinal tract when taken orally or have a short
half-life. Parenteral formulations include:
 Cidofovir, acyclovir and gancicyclovir are given intraveneously for effective
treatment of herpes virus particularly HSV.
 Interferon, administered intramuscular for the treatment of HBV and HCV
infections.
Topical Antiviral Drugs:
Many antiviral agents are administered topically. Vidarabine, idoxuridine, and
acyclovir are antiviral drugs used in the treatment of HSV.
New Drug Delivery System
The new approach is designed for administering drugs in the treatment of viral
infections. These methods are used to prevent various problems associated with
conventional methods of drug delivery.
Transdermal Drug Delivery:
Transdermal drug delivery otherwise known as topical drug delivery system
involves the administration of drugs through the skin. The method has several
advantages when compared with conventional methods. It increases
bioavailability of drugs by preventing early liver metabolism and by being
painless, improving patient compliance, and curtailing use of hypodermic
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injections; additionally, it is non-invasive and can be self-administered. Various
systems are adopted to ensure delivery of the antiviral agent through the skin
barrier. These include iontophoresis, nanoparticle system, colloidal system and
microemulsion system.
Microemulsion System:
Microemulsion is a homogenous process involving the use of surfactant and/or
cosurfactant to disperse oil and water in a regulated stable heat condition. Poorly
absorbed antiviral agents such as ritonavir, penciclovir, and acyclovir have been
maintained in the gastrointestinal tract to increase their bioavailability using this
technique.
Iontophoresis System:
Iontophoresis involves the delivery of antiviral drugs through the skin barrier by
electrical driving force. Charged drugs are transferred by electrophoresis, while
lowly charged and uncharged ones are delivered by the electroosmotic flow of
water stimulated by the drive of mobile cations against the skin anions such as
keratin. This method can be used to administer drugs through ocular, buccal and
nasal routes.
Liposome System:
Liposomes are natural, non-toxic, bilayered, nanosizedlipids, which are employed
for drug delivery. Recent study experimented the delivery of nevirapine, which is
formulated on liposomes derived from egg phospholipids using thin film hydration
technique. This technique exhibits an excellent degree of drug delivery to the
target site with the absence of any systemic side effect.
Increased in vitro antiviral activity of adefovirdiproxil was observed when
prepared using solid lipid nanoparticles. Also, atazanavir showed a promising
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brain permeability prospect when formulated using this technique. Topical gel
preparation of idoxuridine tested for the treatment of HSV-1 and HSV-2 showed
an increased therapeutic value when compared with the plain types.
Other Techniques:
Other techniques such as ethosomes and microsphere system are newer
modifications, which could be adapted for topical drug delivery system. For
example, a study reported topical application of acyclovir formulated using
polymeric microsphere to increase the drug concentration at the target site.
Ocular Drug Delivery
This is a technique design to deliver drugs to the tissue of the eyes. Different
layers of the eyes pose barriers to antiviral agents from reaching of the target
site irrespective of the routes of administration (topical, parenteral or oral). New
techniques are designed to overcome these challenges with the development of
better methods such as transporter-mediated system, colloidal dosage system
(which include liposomes, nanoparticles, microemulsion and nanoemulsion)
microneedle, ultrasound and ionotropic systems.
Transporter-Mediated System:
Transporters are protein attached to the cell membrane, which is involved in the
regulation of active transport of nutrient in the cell. These transporters bind and
transport specific ligands in the drug compounds. In ocular drug delivery, efflux
and influx transporters play major role in the system. A prodrug of acyclovir and
gancicyclovir was formulated to improve ocular bioavailability of these drugs by
targeting the peptide transporters in the eyes. These drugs exhibited higher
therapeutic efficacy in the treatment of HSV, with less cytoxicity than
trifluorothymidine drug, which is the gold standard for the disease treatment.
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Colloidal Dosage System:
The Colloidal dosage system allows proper concentration of antiviral agent at the
target site, reduces continuous administration, circumvents the blood-ocular
barrier, prevents gastrointestinal side effect and increases bioavailability of the
antiviral drugs. Gancicyclovir liposomal formulation was shown to be more
distributed and permeable in the cornea than the free solution of the drug.
Ultrasound, Microneedle and Other Techniques:
These techniques are noninvasive method designed to release drug at the
intraocular regions of the eye, particularly the disease affecting the posterior
segment. The drugs are coated on the solid particles, which then diffuse following
the administration with subsequent removal of the particle. Various methods
(such as Ocusert, OcufitSR, Minidisc) are designed with this mechanism of action.
A fabricated ocular insert of acyclovir consisting of hydroxylpropyl methylcellulose
and cellulose acetate phthalate has increased absorption in the cornea. The use of
ultrasound and ionotropic technique for ophthalmic drug delivery has been
adopted enhanced treatment of eye infections, with further prospects in viral
treatment.
Acquired Drug Resistance
Despite successful antiviral therapy, resistance to the drug is a serious concern in
the management of infected patients, particularly the immunocompromised
where prolonged drug treatment, virus multiplication and other host factors
promote drug resistance. Genetic mutation is common in some viruses (i.e., an
influenza virus that undergoes antigenic drift and shift), which often result in
resistance to the antiviral drugs. In addition, weakened immune system due to
drugs, malnutrition or other debilitating diseases such as cancer could contribute
to this problem. Different patterns of drug resistance have been observed in viral
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infections such as cytomegalovirus, herpesvirus, influenza virus, hepatitis B and C
virus and HIV.21,22,40-44,90
Viral Infections and Drug Resistance
Antiviral drug resistance is defined as a reduced susceptibility of a virus to
antiviral agents in a laboratory culture system. This is evaluated by estimating
the concentration of drugs required to inhibit viral growth by 50% (IC50) or
(IC90). This in vitro expression of the resistant characteristics of the virus is
known as phenotype, which is influenced by mutations in the viral genome. This
may result into a change in the target enzymes, reduced drug concentration in
the cell, and evasion of host immune cells.
Repeated viral replications of some viruses increase the risk of assembly of
genetic variants in untreated patients. For example, in viruses such as HIV and
influenza virus, mutations in the polymerase enzyme involved in the viral
replication are commonly observed. The presence of mixed variants of a virus in a
patient is called viral quasispecies, the population of which is represented by the
“fittest virus.” The fittest virus in a mixed variant is the virus that exhibits drug
resistant properties.
Hepatitis C Virus
Genetic mutation is common in HCV replication and a recent study involving the
serial passages of the virus revealed replacement in amino acid residue of the
viral protein. The drugs of choice for the treatment of HCV infections are
boceprevir, simeprevir, telaprevir, ribavirin and interferon.
Interferon is an antiviral agent used for treatment of several viral infections
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including HCV. However, interferon administration is sometimes less effective and
often withdrawn due to side effects and HCV resistance to the drug. Interferon
resistance is difficult to predict and understand compared to other antiviral
agents, occurrence of which depends on the change or mutation in the specific
amino acid residue in the HCV core protein. The amino acid residue change
involves interferon sensitivity determining region (ISDR) of the viral protein.
In addition, HCV is also resistant to ribavirin drug. Amino acid change or
substitution in a specific region called ribavirin resistance determining region
(IRRDR) determines the sensitivity of HCV to ribavirin. HCV resistance to such as
boceprevir, telaprevir and sofosbuvir has been reported. Previous studies reported
a resistant pattern to nucleotide and protease inhibitors due to mutation in NS5B
position of the virus.
Hepatitis B Virus
Most Hepatitis B virus (HBV) drugs target DNA polymerase enzymes, which are
very important in the viral replication. Mutation of this enzyme often results in the
resistance pattern observed commonly among the HBV-resistant drugs. The
reverse transcriptase regions of the viral polymerase gene are mutated in the
resistant strains of the HBV. The effect of this mutation due to genetic change,
which confer resistance to drugs were established in a molecular study that
involved the interaction of the wild-type and the mutant strains of HBV with
thymidine tryphosphate compound. For example, high-level lamivudine resistance
is due to an amino acid change in the polymerase gene. Other amino acid points
on the polymerase gene are involved in the virus resistance to other drugs:
tenofovir at N236T, entecavir in L180M, telbivudine in L180M. Resistance to other
anti-HBV drugs includes adefovir (due to amino acid change in N236T and
A181V/T and tenofovir (M204V).
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Human Immunodeficiency Virus
An increase in the development of drugs in the treatment of human
immunodeficiency virus (HIV) drug has consequently affected the susceptibility of
some of these antiviral agents against the virus. This in part is due to the host
factor, patient non-compliance, and viral mutations. The mutation in genes of
enzymes (reverse transcriptase and protease gene) involved in viral replication,
which confer significant drug resistance, was reported in HIV infected patients.
There are different drugs used in the treatment of HIV infections. These include
lamivudine, zidovudine, enfuvirtide, maraviroc, and efavirence. HIV-1 strains that
are less susceptible to maraviroc and enfurvitide drugs have been observed due
to an amino acid change in the gp160 and gp40 of the virus respectively. This
results into a failed regimen in the recipients of these drugs. Other drugs such as
efavirence and nevirapine are used when resistance to maraviroc is observed. In
addition, the first approved drug for the treatment of HIV was Zidovudine.
Recently, it has been shown that HIV-2 is less susceptible to zidovudine
treatment.
Influenza Virus
The influenza virus is a major cause of influenza disease and poses a serious
health problem globally due to frequent mutation commonly observed in the
virus. The viral resistance to drugs is due to genetic changes in the virus antigen
leading to antigenic drift and shift. Therefore, only few effective drugs are
available for the treatment of the infection.
Frequent exposure to amantadine and rimantidine result into the viral resistance
to the drug. This is due to a point mutation in the RNA of the M2 ion channel in
the viral cell membrane.
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Influenza virus resistance to oseltamivir and zanamivir has been reported. This
may be due to a mutation on the hemagglutinin glycoprotein on the virus cell
membrane or specific enzymes involved in the viral attachment to the host cell.
Specific serotypes (H1N1 strain) showed resistance to oseltamvir.
Herpes Virus
The primary target of the drugs used for herpes virus infections is thymidine
kinase or DNA polymerase. Herpes virus resistance to drugs is rare in healthy
adults. However, more than 8% of immunosuppressed patient averagely develop
resistance to the drug. Resistance to acyclovir is due to the mutation of the
thymidine kinase gene, which altered the activity of the enzyme. The pattern of
mutation of the thymidine gene differs between the HSV and VZV, although the
significance of the viral resistance is milder in HSV. In addition, resistance in other
drugs, which include, pencicyclovir, famcyclovir and valacyclovir share the same
mechanism as acycylovir but at a different mutation point.
Cytomegalovirus (CMV) drug resistance, particularly with gancicylovir has been
extensively studied. Most of the drug resistant mechanism observed in the virus
is due to point mutation at different parts of the thymidine kinase gene resulting
in the impairment in the activity of the enzymes. Mutations in the viral DNA
polymerase also confer resistance to drugs such as Foscarnet, gancicyclovir, and
cidofuvir.
Investigation of Antiviral Resistance
Viral resistance is investigated by phenotypic and genotypic assay. Phenotypic
assay involves an in vitro susceptibility testing of an antiviral agent caused by
known or unknown viral mutations and associated interaction. This method is
effective in testing viruses that can be grown or cultured in the laboratory. It is
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time consuming and laborious. Various techniques used in this assay include, cell
culture, fluorometry, high-performance liquid chromatography (HPLC), etc.
Genotypic assay investigates mutations in the viral genome that are related to
reduced drug susceptibility to antiviral drug. Different molecular methods such as
real time PCR (polymerase chain reaction), gene sequencing, microarray, etc., can
be used to study viral genome. The phenotypic test may be complimentary to the
genotypic assay, however, there may be variations in these two assays.
Antiparasitic Agents
Parasitic infections are a substantial cause of human mortality affecting more
than 2 billion people worldwide. The highest incidence is in developing countries
where they are a leading cause of morbidity and mortality. Hence, these
pathologies have a high social and economic impact, which is reflected in the 0.5
billion U.S. dollars spent annually on the anti-parasitic drug market. The major
problem with drug development is that to develop a new anti-parasitic drug an
average of 300 million U.S. dollars is spent, which limits the progress in creating
alternative drugs. In fact, the disparity between the investment in new drugs
versus the global disease burden is astonishing: in 2000 it represented only 0.1%
of the investment in research, while tropical diseases accounted for 5% of the
global disease burden. An immediate solution for the shortage in new therapeutic
agents is the combination of existing drugs. This opens the possibility of reducing
toxicity, treatment regimens and the acquisition of resistance. Examples of this
practice are the treatment of African trypanosomiasis with eflornithine and
melarsoprol and schistosomiasis with praziquantel and oxamniquine.48-50,59-74
Protozoan Infections
Protozoa are eukaryotes that can be pathogenic to humans and are characterized
as intestinal or systemic. Protozoan parasites cause diseases, such as, Malaria,
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Sleeping Sickness, Chagas disease, Leishmaniasis, Babeasis, Toxoplasmosis,
Giardiasis, Amoebiasis, and Cryptosporidiosis. All of these diseases will be
described in more detail below. Protozoa infections are classified according to the
means of infection, enteric (Balantidium, Giardia, Entamoeba, Cryptosporidium,
Toxoplasma, Cyclospora, Microsporidia), sexual (Trichomonas), arthropod
(Babesia, Plasmodium, Leishmania, Trypanosoma), or others (Naegleria,
Acanthamoeba, Toxoplasma).
Malaria is the most prevalent systemic protozoan infection, infecting 300 million
people annually and killing approximately one million of those. Malaria is caused
by several species of parasites that use mosquitoes as a vector for infection. The
species causing disease in humans are Plasmodium falciparum, Plasmodium
vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. These
parasites infect red blood cells, causing hemolytic anemia. The highest incidence
is seen in Asia, Oceania, sub-Saharan Africa, and Latin America.
Malaria can manifest as an uncomplicated disease, causing myalgia, fever, cough,
anemia, thrombocytopenia, and diarrhea. Or it can present as severe malaria with
parasitemia greater than 5%, leading to intolerance of oral medications,
respiratory, renal failure, distress, altered mental status or seizures, and
metabolic acidosis or hypoglycemia.
Human African trypanosomiasis, or sleeping sickness, is also caused by a
protozoan, Trypanosoma brucei. The transmission to human hosts is done by
tsetse flies that are endemic only to Africa. The disease is caused by two
subspecies, T. bruceirhodesiense, most common in eastern and southern Africa
that leads to fast onset acute disease, and T. bruceigambiense, present mostly in
Central and West Africa that causes a slow onset chronic disease. T. Brucei can
cross the blood brain barrier which difficult treatment. The initial symptoms are
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hepatosplenomegaly, lymphadenopathy, fever and rash. With the progression of
disease the pathology is characterized by chronic meningoencephalitis with
listlessness, headaches, neuromuscular dysfunction, and disordered sleep.
Another pathogenic protozoan is Trypanosoma cruzi, the causative agent of
American trypanosomiasis or Chagas disease. This parasite is transmitted by
triatomine insects and is endemic only in Latin America. The first manifestation of
acute disease is an erythematous, indurated skin lesion at the site of the bite and
regional lymphadenopathy. Then, it can evolve to diffuse lymphadenopathy, fever,
hepato-splenomegaly, and in rare cases myocarditis and meningoencephalitis. In
the case of chronic Chagas disease it causes chronic heart failure,
cardiomyopathy, arrhythmia, and gastrointestinal tract disturbances.
Leishmania has 21 species that are known to cause disease in humans and infects
about 2 million people each year. This parasite is transmitted primarily by
sandflies of the genus Lutzomyiain the New World (Leishmania braziliensis,
Leishmania mexicana, and Leishmania panamensis), and of the genus
Phlebotomus in the Old World (Leishmania major, Leishmania tropica, or
Leishmania aethiopica). There are three main clinical manifestations; cutaneous
leishmaniasis, visceral leishmaniasis, and mucocutaneous leishmaniasis.
Cutaneous leishmaniasis is a self-limiting disease characterized by nodular skin
lesions that ulcerate, and occurs mostly in Afghanistan, Brazil, Pakistan, Syria,
Iran, Saudi Arabia, Peru, and Algeria. Visceral leishmaniasis is asymptomatic in
most cases, is more frequent in East Africa and India, and is caused
predominantly by Leishmania donovani. Mucocutaneous leishmaniasis develops
from cutaneous leishmaniasis caused by New World Leishmania species and leads
to ulcerative lesions in the nose, mouth, and pharynx.
Babesia is another protozoan parasite that infects humans, particularly the
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species B. microti and B. divergens. These parasites are transmitted by tick bites
in Europe, New England, American Midwest, and New York. Babeosis is in most
cases asymptomatic but can cause symptoms in immunocompromised patients,
such as fulminant hemolytic anemia or febrile illness.
Toxoplasmosis is caused by Toxoplasma gondii, a protozoan parasite and infects
95% of the human population in some areas. Although, it normally does not
cause symptoms in adults, in rare cases it leads to eye problems (chorioretinitis),
tenderness in the lymph nodes and muscle-aches. In immunocompromised
patients it can cause seizures and poor coordination. In pregnancy, toxoplasmosis
is more dangerous, affecting 200,000 women annually, and causing congenital
defects or miscarriage.
Giardia lamblia causes a zoonotic disease known as giardiasis, and is the most
common intestinal parasitic infection, causing symptoms yearly in around 280
million people. The most common transmission route is the consumption of
contaminated water and most infections cause gastrointestinal disturbances such
as diarrhea, bloating, flatulence, weight loss and abdominal cramps.
Entamoebahistolytica is a parasitic protozoan infecting 50 million people by the
fecal-oral route. Amebiasis is most common in tropical regions and usually
infected individuals do not develop symptoms. It can cause amebic dysentery
characterized by diarrhea and abdominal pain.
Cryptosporidiosis is caused by the protozoan parasites Cryptosporidium
parvumand Cryptosporidium hominis that can be found worldwide. In
immunocompetent hosts it is usually a self-limited disease causing only diarrhea.
In immunocompromised patients the diarrhea is particularly severe and can be
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fatal.
Cyclosporiasis is an infection transmitted by the consumption of water and
vegetables contaminated with the protozoan Cyclosporacayetanensis. This
disease is found worldwide, and causes watery diarrhea, abdominal cramps,
anorexia, and fatigue. A similar condition to cyclosporiasis, isosporiasis is caused
by Isospora belli in tropical and subtropical regions.
Amoebic Infections
Most pathogenic amoebic agents rarely cause infection in humans and are
ubiquitous in the environment worldwide, found in soil and fresh water. Naegleria
fowleri is the causative agent of primary amebic meningoencephalitis, which is a
rare and fatal condition. It causes symptoms such as altered taste or smell,
vomiting, fever, and later confusion, coma, and death. The infection route is via
the nasopharynx through contact with fresh water. Acanthamoeba Species cause
amebic keratitis, through contact lenses and ocular trauma, or disseminated
infection and granulomatous amebic encephalitis in immunocompromised
patients. Balamuthiamandrillaris causes subacute or chronic meningoencephalitis
with symptoms including fever, headache, skin lesions, vomiting, seizures,
cerebral mass lesions, and neurologic deficits.
Cestode Infections
Helminthes do not reproduce in humans but can induce eosinophilic responses in
the human host, after tissue invasion. Helminthes are categorized as trematodes,
cestodes, or nematodes. Cestodes are tapeworms that cause disease in the
gastrointestinal lumen. Taeniasaginata is found worldwide, and has higher
prevalence in Africa, Latin America, Central Asia, and Middle East. The infection
route is consumption of undercooked beef and presents with abdominal cramps
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and malaise. Taeniasolium is found in free-range pork meat, from sub-Saharan
Africa, Latin America, and Asia. It can cause cysticercosis in which larval cysts
infect subcutaneous tissue or skeletal muscle. It is usually asymptomatic, but it
can affect the central nervous system causing seizures, hydrocephalus, or chronic
meningitis.
Hymenolepsis nana, or dwarf tapeworm, is found worldwide and transmitted via
the fecal-oral route. It can cause abdominal discomfort and diarrhea.
Diphyllobothriumlatum infection can result in diarrhea, weakness, and dizziness
after eating raw or undercooked fish due to decreased vitamin B12 absorption.
Echinococcusspecies, Echinococcusgranulosus and Echinococcusmultilocularis are
the causative agents of cystic and alveolar echinococcosis, respectively. The
infection by Echinococcusgranulosus is caused by contact with infected dogs or
consumption of contaminated food or water. The disease is endemic to South
America, the Mediterranean littoral, East Africa, Eastern Europe, Central Asia, the
Middle East, China, and Russia. The parasites form cysts in the liver or lungs and
if these cysts rupture they can lead to anaphylaxis. Infection with
Echinococcusmultilocularis is less common and also characterized by formation of
cysts in the liver.
Trematode Infections
Trematode infections cause clinical infections in humans and occur worldwide. The
most prevalent trematode infection is schistosomiasis that affects 200 million
people globally. Mainly, Schistosomamansoni, Schistosomajaponicum and
Schistosomahaematobium cause this disease. The route of transmission is skin
contact with infected water that can develop into chronic hepatic or intestinal
disease, genitourinary disease or Katayama fever. These conditions are
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characterized by fever, cough, hematuria, myalgia, abdominal pain, eosinophilia,
and hepato-splenomegaly. In children, it can cause growth retardation and
anemia. Fasciola hepatica causes fascioliasis in sheep raising areas worldwide.
Infection occurs after eating infected vegetables. When larvae enter the liver the
host suffers from symptoms such as abdominal pain, eosinophilia, develop
intermittent biliary obstruction, weight loss, and fever.
Clonorchissinensis, OpisthorchisFelineus, and Opisthorchisviverrinicause
Clonorchiasis and Opisthorchiasis in humans are endemic to East Asia, Russia and
Southeast Asia, respectively. Eating undercooked freshwater fish is the primary
route of infection. The deposition of eggs by the adult worms in the biliary system
causes symptoms such as abdominal pain, fever, eosinophilia, and hepatomegaly,
which can lead to ascending cholangitis, cholangiocarcinoma, biliary pigment
stones, and pancreatitis.
Paragonimuswestermani in East and Southeast Asia causes Paragonimiasis. It
affects mainly the lungs causing chest pain, eosinophilia, fever, and cough. Eating
undercooked crayfish or crabs causes the infection. Trematodes such as
Fasciolopsisbuski, Metagonimusyokogawai, Heterophyesheterophyes, and
Echinostoma species can also infect the gastrointestinal tract causing mostly
asymptomatic infection.
Nematode Infections
Human infection by nematode parasites can be classified as intestinal or extraintestinal. Intestinal nematodes are soil-transmitted helminthes and include
Ascarislumbricoides, Ancylostomaduodenale, Trichuristrichiura, and
Necatoramericanus. These nematodes infect each an estimated number of 1
billion people, especially in tropical areas with poor sanitation. The adult worms
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can cause symptoms such as diarrhea, mild abdominal pain, nausea, appendicitis,
biliary or intestinal obstruction, and intestinal perforation. In children infection
can impair cognitive development and growth.
Enterobiusvermicularis is the causative agent of enterobiasis, and infection with
global distribution. The transmission in families is common via fecal-oral
contamination. It can lead to severe perianal pruritis. Strongyloidiasis is caused
by Strongyloidesstercoralis a soil nematode that infects humans through the skin
and is endemic to the tropics and subtropics. This parasite completes its life cycle
within the human host and can lead to acute or chronic infection. Acute infection
can cause rash, cough and eosinophilia or abdominal diarrhea, pain, polymicrobial
sepsis, meningitis or bronchopneumonia, by dissemination in
immunocompromised patients. In chronic infections nausea, eosinophilia,
abdominal pain, and diarrhea can occur in rare cases.
Extra-intestinal nematodes can cause trichinellosis, toxocariasis, filariasis,
onchocerciasis, loaiasis and other more rare conditions. Trichinellosis causative
agents are parasites of the Trichinella genus present in undercooked meat. The
disease is characterized by fever, diarrhea, myositis, conjunctivitis, periorbital
edema, and eosinophilia, but it can also cause myocarditis or encephalitis in rare
cases. Toxocaracanis and Toxocaracati are nematodes that cause the zoonotic
disease toxocariasis. It can present as a larva migrans syndrome causing fever,
cough, wheezing eosinophilia and often hepatomegaly.
Filariasis is caused by Wuchereriabancrofti and Brugia species, leading to
eosinophilia, fever, lymphedema, adenolymphangitis, and hydrocele. It can also
present as tropical pulmonary eosinophilia, with nocturnal asthma, fever, cough,
and weight loss. Onchocerciasis or river blindness is caused by Onchocerca
volvulus infection. The infection vector is Simulium blackflies present in equatorial
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Africa, Latin America and the Arabian Peninsula. Infection symptoms include
subcutaneous nodules, dermatitis, chorioretinitis, keratitis, and blindness.
Loaiasis is caused by Loa loa parasites and is transmitted by Chrysops flies in
Central and West Africa. The subcutaneous migration of worms causes
eosinophilia, Calabar swellings, urticaria, proteinuria, hematuria, and encephalitis.
Dog and cat hookworms, Angiostrongyluscantonensis, Baylisascarisprocyonis,
Gnathostomaspinigerum and Capillaria philippinensis, cause other similar
conditions.
Types of Parasites
Parasites are organisms that live in a host that it feeds from or fulfill needs for
reproduction. The three main classes of parasites are helminthes, ectoparasites
and protozoa. All parasites are capable of causing disease if they find the right
conditions, for example an immunocompromised host. The life of the parasite
inside the human host can go undetected for life or cause immediately dangerous
symptoms that jeopardize the host’s health. Parasitic infections are a global
health burden, with special incidence in underdeveloped countries. The tropical
and subtropical regions are particularly suited for parasites to live in the
environment, soil and water. Therefore, in these regions the means of infection
are abundant.
The parasitic diseases found in these temperate climates are termed neglected
tropical diseases since they are largely overlooked and little attention is given to
their treatment or to the research of new medications. Of these diseases the most
deadly worldwide is malaria that causes around 660,000 deaths per year, having
the highest incidence in sub-Saharan Africa. There are also other neglected
tropical diseases such as onchocerciasis and lymphatic filariasis that have high
mortality rates. Neglected tropical diseases infect an estimated one billion people
taking a huge toll in endemic areas especially in children. Hence, it is essential to
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know the treatments available for the treatment of these diseases.
The choice of treatment in parasitic infections depends always on the state of the
patient, the type of organism and risk of complications and side effects. Antiparasitic drugs can be classified according to the type of infection they treat. The
main class of anti-parasitic drugs is antihelmintics that kill all parasitic worms and
these can be separated into subtypes that target the different parasitic types.
They can be antinematodes, anticestodes, antitrematodes, antiamoebics, or
antiprotozoals. Most medications for mild diseases are administered orally since it
is the most convenient administration method. Intravenous therapy is usually
applied in situations where severe disease is caused by systemic infection or if it
affects certain organs such as the brain.
Most intestinal parasites are treated with luminal agents that are not easily
absorbed and therefore can act better in killing the parasites inside the intestine.
The clinician has to always take into account that most parasites can acquire
resistance to medications and therefore some cases have to be treated with
combined drug therapies. When a medication is not effective or not recommended
for a certain patient there are second line treatments that can be applied. The
information about the most common therapies for parasitic infections is described
below.
Antinematodes
Nematodes also known as roundworms are a diverse animal phylum inhabiting
nearly every ecosystem on Earth. The number of nematode species has been
estimated in 1 million and about half of those are parasitic. The parasitic
nematodes that affect humans are ascarids, filarias, hookworms, pinworms and
whipworms. These intestinal nematodes cause the diseases, ascariasis, filariasis,
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hookworm disease and trichuriasis.
Antinematodal drugs include piperazine, imidazothiazoles and
tetrahydropyrimidines, benzimidazole and pro-benzimidazoles, macrocyclic
lactones, organophosphorus compounds and salicylanilides. Mebendazole
and pyrantelpamoateare used for most nematode infections, while
thiabendazole, diethylcarbamazine and ivermectin are used only in specific cases.
These drugs can be divided in two main classes, depending on their mechanism of
action, those that act on biochemical processes of the worms and act more slowly
and those that disrupt ion influx by opening membrane ion channels killing worms
more rapidly. The ones that act biochemically affect a wide array of cellular
mechanisms such as β-tubulin formation (thiabendazole, flubendazole,
mebendazole, albendazole, and oxibendazole), chitinase activity (closantel),
lipooxygenase activity (diethylcarbamazine), alterations in glucose uptake and
metabolism and inhibition of glutathione reductase (melarsomine), pyruvate:
ferredoxinoxidoreductasefuntion (nitazoxanide), and isothiocyanate-ATP and
cholinesterase activity (nitroscanate and amoscanate).
The faster acting drugs affect ion chanells of the celular membrane being
classified as, cholinergic agonists (imidazothiazole, tetrahydropyrimidines,
quaternary/tertiary amines, pyridines, and amino-acetonitrile derivatives),
cholinergic antagonists (derquantel and phenothiazine), glutamate-gated chloride
channels allosteric modulators (avermectins and milbemycins), γ-aminobutyric
acid agonists (piperazine), and potassium channel activators (emodepside).
For intestinal nematodes causing ascariasis a single oral dose of Mebendazole,
Albendazole or Ivermectin is usually effective. Mebendazole is effective in many
tapeworm infections and acts by binding to tubulin. Ivermectin acts by tonic
paralysis of peripheral musculature and is ineffective in cestodes and trematodes.
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When this treatment does not work, mebendazole-ivermectin combination
therapy can be used. This treatment has mild side effects such as hepatitis,
nausea, diarrhea, or dizziness. Pyrantelpamoate is an alternative, acting as an
acetylcholine receptor agonist. It can cause vomiting, abdominal pain, nausea,
and diarrhea. Extraintestinal nematodes such as the infections trichinellosis,
toxocariasis, filariasis, Angiostrongyluscantonensis, Baylisascarisprocyonis,
Gnathostomaspinigerum, Capillariaphilippinensis or cutaneous larva migrans are
treated with albendazole or mebendazole, conjugated with corticosteroids.
Alternative treatments include mebendazole, thiabendazole, ivermectin, or
piperazinediethylcarbamazine. For onchocerciasis, ivermectin is the first line of
treatment but does not kill adult worms. To treat for adult worms, suramin is
used but presents high toxicity. Diethylcarbamazine is the recommended
treatment for loiasis, and cannot be administered in the case of onchocerciasis
because it causes blindness. It also has some side effects such as, arthralgia,
nausea, fever and asthma.
Anticestodes
Cestodes are also known as flat worms and all species are parasitic, having a
typical life cycle consisting of living as adults in the digestive tracts of
vertebrates, and in the bodies of distinct species as juveniles. In the case of
humans, infection occurs from the environment, Hymenolepis or
Echinococcus species, or by eating undercooked meat such as beef (T. saginata),
pork (Taeniasolium), and fish (Diphyllobothrium species). Most cestode infections
do not cause symptoms and go by undetected. Therefore in endemic regions
preventive therapy in regular intervals is advisable. In some non-endemic regions
there could be intentional cestodal infection for weight loss purposes.
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The drugs used to treat cestode infections can have several mechanisms of
action, such as, binding to tubulin acting of the GABA receptor or Glutamategated chloride channel, or blocking neuromuscular transmission at
the neuromuscular junction. Anticestodal medications include albendazole,
albendazolesulfoxide, dichlorophen, niclosamide and quinacrine. The treatment
for intestinal tapeworms is praziquanteland for extraintestinal cestodes
benzimidazoles are used. Praziquantel is an oral pyrazinoisoquinolone derivative
that acts by damaging the tegument of parasites, which leads to paralysis. The
side effects for this drug are dizziness, vomiting, diarrhea, headache, abdominal
pain, and hepatitis.
Alternative treatments are niclosamide and nitazoxanide. Niclosamideacts by
uncoupling oxidative phosphorylation and can lead to nausea and abdominal pain.
With Taeniasolium infection praziquantel is used to prevent cysticercosis and
corticosteroids are administered to decrease inflammation. If the disease presents
with intraparenchymal or subarachnoid cysts a combination of albendazole and
corticosteroids is used. This treatment can cause rash, nausea, abdominal pain,
leukopenia, alopecia, and hepatitis.
Ocular cysts have to be removed surgically before treatment. Higher doses and
longer treatment periods with praziquantel are necessary to treat Dwarf
Tapeworm infection. Echinococcosisis treated surgically or by albendazole therapy
depending on the cyst stage.
Antitrematodes
Trematodes are parasitichelminthes known as flatworms or flukes. Most
trematodes have a life cycle that includes a primary vertebrate host, where the
flukes sexually reproduce, and an intermediate molluschost, for asexual
reproduction. The endemic flatworm regions are Asia, Latin and South America,
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Africa, and the Middle East. Trematodes can be divided in two groups depending
on the system they infect, blood flukes including Schistosoma, and tissue flukes
that infect the lungs, bile ducts or other tissues, for example Fasciola hepatica.
Trematode infection can be life threatening to the host, for example,
schistossomiasis can cause recurrent pyogenic cholangitis, and intestinal flukes
such as fascioliasis can lead to intercurrent bacterial infections.
Praziquantel is the preferred treatment for trematodes and acts by increasing the
permeability of cellular membranes to calcium ions. The most common side
effects are headache, abdominal pain, nausea, vomiting, dizziness, malaise,
rash, pruritus and eosinophilia. It is not effective against fascioliasis, in which the
preferred treatment is triclabendazole that inhibits microtubule formation, or
alternatively bithionol. In the case of schistosomiasis, praziquantelis poorly
effectivein treating early infection since it does not killeggs or immature worms.
Artesunatecan treat these early cases.
In clonorchiasis and opisthorchiasisalbendazole, tribendimidine, triclabendazole or
bithionol can be used as an alternative. All of the drugs used to treat trematode
infections are administered orally.
Antiamoebics
In the case of gastrointestinal amebiasis the parasites enter through the mouth,
travel across the digestive system, and fix in the large intestine. There are some
harmless strains that do not cause damage (Entamoebadispar) and pathogenic
strains that can cause symptoms (E. histolytica). These amoebas cause severe
disease when they invade the epithelial barrier of the intestine, causing amoebic
dysentery that leads to intestinal ulcers, diarrhea, increased mucus production
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and bleeding. To kill the parasitic amoebas in the intestinal luminal drugs such as
iodoquinol, paromomycin and diloxanidefuroate are used.
In more severe cases, amoebas can enter the bloodstream and travel to the liver
or brain, where they form abscesses. These pathologies are usually treated with
nitroimidazole drugs (metronidazole and tinidazole) that can kill amoebas in the
intestine wall, blood, and liver. These tissue amebicides are rapidly absorbed and
therefore they have to be coupled with a luminal agent to eliminate amoebas in
the intestine.
Amoebic infections treatment relies on metronidazole, tinidazole, amphotericin,
pentamidine, azoles, sulfonamides, and possibly flucytosine. For the treatment of
amoebic colitis caused by Entamoebahistolytica metronidazole is the drug of
choice. However this drug can be insuficcient for thetreatment of invasive
amoebiasis because it does not eliminate intestinal parasite cysts. As an
alternative, tinidazole has been described to be more effective at preventing
relapses of the disease while having fewer side effects due to the shorter
treatment course. Tinidazole is a derivative of 2-methylimidazole part of the
nitroimidazole antibiotics family. This drug has similar side effects to
metronidazole such as nausea, fatigue, bitter taste, itchiness, headache, and
dizziness.
The treatment of Naegleriafowleri infection is very difficult and most patients die.
Most of the known cases of survival to infection have received intravenous
amphotericin, sometimes in combination with other drugs such as, fluconazole,
miconazole, ornidazole, sulfisoxazole, rifampin, and chloramphenicol. When
infection of the brain is confirmed intrathecaladministration of amphotericin can
be considered. Amphotericin B can only be used as a last resort treatment for
primary amoebic meningoencephalitis since it has potentially lethal side effects.
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The adverse effects include high fever, hypotension, nausea, dyspnea, shaking
chills, anorexia, vomiting, headache, tachypnea, and drowsiness.
Granulomatous amebic encephalitis caused by Acanthamoeba species usually in
immunocompromised patients can be treated with pentamidine, azoles,
sulfonamides, and flucytosine. In the case of amebic keratitis, a visionthreatening infection, topical chlorhexidine or polyhexamethylenebiguanide are
effective. For treatment to be successful, early diagnosis is essential, and
medication has to be complemented with surgical intervention. A combined
regimen of propamidine, miconazole nitrate, and neomycin has also been shown
to be effective. In more severe cases were the vision is permanently damaged a
corneal transplant is required.
Balamuthiamandrillaris infection causes meningoencephalitis that should be
treated with combination therapy including a macrolide combined with
flucytosine, sulfadiazine, pentamidine, fluconazole; or albendazole combined with
itraconazole or fluconazole, and miltefosine.
Antiprotozoals
Antimalarial drugs can be taken prophylactically prior to entering an endemic area
at the seasons in which the anopheles mosquito is more active. Antimalarial drugs
can be classified according to the stage of the parasite life cycle that they affect.
Treatment of malaria has to take into account the type of pathology and the
resistance to treatments. Once the parasite is inside erythrocytes it starts the
asexual stage, where it has to degrade hemoglobin to acquire essential amino
acids from which the parasite constructs its own protein. Therefore this stage is a
good target to eliminate Plasmodium species.
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For uncomplicated P. Falciparum malaria treatment, chloroquine is the
recommended therapy. This drug is cheap and has been extensively used for
many years in the treatment or prevention of malaria. It has many advantages
such as, a very high volume of distribution, and disadvantages such as, retinal
toxicity. There is widespread chloroquine-resistance in P. falciparum, but this
drugcan still be used mostly as a preventive therapy for Plasmodium vivax, P.
ovale, and P. malariae.
It acts on heme metabolism and can cause vomiting, nausea, headache, pruritis,
and blurred vision. If there is chloroquine resistance, artemether-lumefantrine,
atovaquone-proguanil, or oral quinine plus doxycycline are the recommended
therapies. Artemether-lumefantrine is an oral combination treatment, which is
effective against all erythrocytic stages of malaria by interfering with
hememetabolism. Side effects include vomiting, nausea, headache, and dizziness.
Therapy with atovaquone-proguanil is an oral, fixed dose combined treatment,
and acts by inhibiting electron transport in parasites’ mitochondria and the
dihydrofolatereductase step in purine synthesis. Side effects are nausea,
abdominal pain, vomiting, and hepatitis. A quinine plus doxycycline therapy relies
on toxic heme, and inhibition of the parasite’s apicoplast genome, respectively.
The side-effects are vomiting, nausea, abdominal pain, candidiasis, highfrequency hearing loss, tinnitus, and dizziness. For uncomplicated malaria caused
by P. vivax and P. ovale combined treatment of chloroquine and primaquine is
preferred. When in chloroquine resistant areas, mefloquine, atovaquoneproguanil, or quinine-doxycycline can be used. To prevent relapse, primaquine
administration is also necessary. Other Plasmodium species can be eliminated
with chloroquine.
The treatment of severe malaria relies on parenteralmedications, such as
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intravenous quinine, artesunate, and quinidine. Parenteral quinine has adverse
effects such as, hypoglycemia, infusion-related hypotension, and cinchonism.
Artesunate is more effective, acts more rapidly, and has fewer sideeffects than
quinine. The mechanism of action is inhibition of the essential membrane
glutathione S-transferase of Plasmodium falciparum, exported protein 1. It can be
combined with doxycycline, atovaquone-proguanil, mefloquine, or clindamycin.
The side effects are similar to artemether but it can also cause neutropenia.
Quinidine gluconate has the same mechanism of action as quinine and side
effects are hypotension, torsades de pointes, QT prolongation, and hypoglycemia.
After improvement patients can transition to oral medications such as
doxycycline, tetracycline, or clindamycin, which can be used in combination with
quinine and quinidine treatments. Due to the acquisition of resistancemechanisms
it is not advisable to use artemisinins unless in combination therapy. Chloroquine
resistance is present worldwide. Mefloquine cannot be used in South America,
Southeast Asia, and equatorial Africa.
Treatment of African Trypanosomiasis is difficult after the parasite causes
neurological symptoms and, if left untreated, it is always fatal. When detected
early it can be treated with intramuscular injection ofsuramin that can cause
allergic and toxic side effects such as hypotension, hepatitis, nephrotoxicity,
peripheral neuropathy, nausea and vomiting. Suramin causes urticaria in 90% of
patients and adrenal cortical damage in more than 50%, which can result in
lifelong dependency on corticosteroids. Pentamidine, given by intravenous
infusion or by intramuscular injection, is used to treat first stage Trypanosomiasis
and is generally well tolerated, but can cause side effect such as diarrhea,
hypoglycemia, nausea, injection site pain and vomiting. The mechanism of its
anti-protozoal action relies on the uptake by purine receptors of Trypanosoma
bruceigambiense that leads to accumulation of the drug and eventually kills the
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parasite by inhibiting enzymes and interacting with DNA. In more severe disease,
treatment involves intravenous eflornithine alone or in combination with
nifurtimox.
Eflornithine acts by irreversibly binding to the active site of ornithine
decarboxylase, preventing the natural substrate to access the enzyme. These can
lead to abdominal pain, vomiting, nausea, anorexia, insomnia, peripheral
neuropathy, and hepatitis. Melarsoprol is also administered intravenously only to
treat severe T.bruceirhodesiensedue to serious side effects similar to arsenic
poisoning, such as thrombocytopenia, nephrotoxicity, hepatitis, peripheral
neuropathy, myocardial damage, and reactive encephalopathy. The mechanism of
action depends on the metabolization to melarsen oxide, an arsen-oxide that
binds irreversibly to sulfhydryl groups causing the inactivation of enzymes,
particularly trypanothionereductase.
American trypanosomiasis is treated by oral administration of the
nitroheterocyclic compounds benznidazole or nifurtimox. These treatments’
mechanisms of action are not well understood and they cause side effects, such
as insomnia, nausea, vomiting, peripheral neuropathy, dermatitis, anorexia, and
myeloid-suppression. The treatment kills the parasite in the acute phase of
disease, but can only be used to manage signs and symptoms in chronic stages.
This disease can evolve to chronic if left untreated, causing serious heart and
digestive problems.
In leishmaniasis the treatment has to be adapted to the form of the disease.
Previously, treatment was administered in all cases, but nowadays it is only
applied is cases were the benefit trumps risk. Visceral, severe cutaneous and
mucocutaneous leishmaniasis have high associated morbidity and therefore are
always treated with pentavalent antimony compounds. Visceral leishmaniasis is
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treated with intravenous administration of liposomal amphotericin that act by
forming pores in cell membranes. Amphotericin side effects are lessened in the
liposomal formulation and can be nephrotoxicity, fever, electrolyte loss, and
rigors. Miltefosine is also used, via the oral route, causing apoptosis-like cell
death of the parasites. Adverse effects are vomiting, nausea, vertigo, renal
insufficiency, hepatitis, diarrhea, and teratogenicity.
Sodium stibogluconate is a pentavalent antimonial agent, administered via
intravenous or intramuscular injection, with limited use due to resistance. The
mechanism of action is inhibition of parasitic enzymes, and it causes side-effects,
including pancreatitis, anorexia, hepatitis, vomiting, myalgia, QT prolongation,
cytopenia, and arrhythmia. The other intramuscular drug used is paromomycin,
which inhibits mitochondrial respiration and metabolism. It induces
nephrotoxicity, ototoxicity, and hepatotoxicity. Cutaneous leishmaniasis can be
treated with the same agents, but the first line of treatment is usually antimonial
agents or a combination therapy of allopurinolor pentoxifylline plus antimonial
agents. Since response rates are variable mucocutaneous leishmaniasis is usually
treated with antimonial therapy, but combination treatments are more effective.
Babeosis treatment of asymptomatic patients is only done if it persists for more
than three months. For patients that have asplenia, have a fever of unknown
origin or have mild illness oral medications are recommended to prevent future
problems and transmission through blood donation. Atovaquone and azithromycin
combined oral therapy is effective in mild to moderate illness, and preferable to
oral quinine plus intravenous clindamycin that are currently used only for severe
disease in order to avoid acute renal failure.
Atovaquone is an analog of ubiquinone, with antipneumocystic activity, and
azithromycin is an azalide, that acts by decreasing the production of protein. The
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side effects of atovaquone are headache, fever, upper respiratory infections,
dizziness, myalgia, nausea, abdominal pain, vomiting, diarrhea, loss of appetite,
cough, and itching. Azithromycin adverse effects are upset stomach, nausea,
diarrhea, vomiting, abdominal pain, hearing changes, eye problems, and muscle
weakness. Assisted ventilation might be necessary if patients develop respiratory
distress.
Toxoplasmosis does not require treatment in nonpregnant, immunocompetent
individuals unless it affects the eyes. Immunocompromised patients can be
treated with an oral administered combination therapy of pyrimethamine and
sulfadiazine with folinic acid. These drugs act by inhibiting dihydrofolatereductase
and impairing nucleic acid synthesis. The adverse effects are abdominal pain,
rash, myelosuppression, crystal-induced nephropathy, and headaches.
Trimethoprim-sulfamethoxazole is available for oral or intravenous administration,
and is used only for toxoplasmicchorioretinitis and encephalitis. It causes side
effects such as vomiting, urticaria, rash, nausea, hyperkalemia,
myelosuppression, renal insufficiency, and hepatitis. Combination treatment of
pyrimethamine plus clindamycin, orally or intravenously, is also a good alternative
in cases of sulfamethoxazole allergy. Alternative therapies include clarithromycin,
atovaquone, azithromycin, and dapsone. In pregnant women spiramycin that acts
by inhibiting protein synthesis is recommended. It is well-tolerated causing only
abdominal pain and diarrhea. If fetal transmission occurs, the treatment of choice
is pyrimethamine-sulfadiazine plus folinic acid and the treatment is continued
after birth.
Intestinal protozoan infections require different treatment. For giardiasis a single
oral dose of tinidazole is usually sufficient. It acts by being metabolized into toxic
radicals that damage the DNA of the parasite. It has side effects that include
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abdominal discomfort, dysgeusia, nausea, and alcohol-induced disulfiram-like
reactions, and in more rare instances, seizures, peripheral neuropathy, and
neutropenia occur. Metronidazole, is lower in efficacy, has a similar mechanism of
action and side effects, when compared to tinidazole. The treatment can also use
an oral nitrothiazolyl-salicylamide, nitazoxanide, which inhibits
pyruvate/ferredoxinoxidoreductase. The adverse effects are nausea and vomiting.
In the case of amebiasis, asymptomatic patients are treated with oral
administration of paromomycin or iodoquinol to prevent invasive disease and
transmission. These drugs kill the cystic phase of the parasites and can cause
abdominal cramps, diarrhea and nausea due to poor absorption. Diloxanidecan
also be used but has more side effects, anorexia, headache, dizziness, vomiting,
nausea, diarrhea, abdominal cramps, pruritus andurticaria. In the case of
symptomatic infection,such as amebic liver abscess, a luminal agent has to be
combined with a tissueamebicide. The recommended drugs are metronidazole or
tinidazole that can cause abdominal discomfort, dysgeusia, nausea, seizures,
peripheral neuropathy, and neutropenia.
Cryptoporidosis can be treated in immunocompromised patients with oral
administration of paromomycin, macrolides, nitazoxanide, or rifamycins.
Cyclosporiasis and isosporiasis are treated using the oral medications
Trimethaprine-Sulfamethaxozol, because traditional drugs for protozoan infections
are usually not effective.
Infections by Dientamoebafragilis, Blastocystishominis or Trichomonasvaginalis
can be treated with iodoquinol, metronidazole, paromomycin, or tetracyclines. In
the case of Trichomonasvaginalisthe treatment is asingle dose of tinidazole or
alternatively metronidazole, to prevent infection the sexual partners should also
be treated. A combination therapy of high-dose tinidazole with doxycycline or
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ampicillin, or an intravaginal paromomycin administration has also shown to be
effective. These medications cannot be given to pregnant women.
Administration of Anti-parasitic Drugs
Anti-parasitics are drugs that are used to treat parasitic infections by killing or
inhibiting the growth of parasitic organisms. Chemotherapy is the primary mean
of treatment for parasitic infection since vaccination is not available. An ideal antiparasitic drug has a broad spectrum in eliminating the several stages of parasite
development, is safe to use (high therapeutic index, no drug interactions and
non-toxic), and is effective and cheap at one dose form that is easy to administer.
The most common route of administration for anti-parasitic medications is the
oral route. The administration method is an important factor when choosing the
medication since intravenous medications implies risks for the patients such as
infection. It also has to be administered by a trained clinician, which limits the
patient to be dislocated to the hospital. In developing countries access to health
care facilities is difficult, and clinicians should take that into consideration.
Oral Medication
Oral administration of medications is usually preferred to treat infections, in which
a topical agent cannot be used, since it the less invasive method of
administration. A medication is termed oral when it is taken through the mouth.
These medications have usually a systemic effect, entering the bloodstream after
absorption in the mucosal surfaces. Oral administration can be in alternative to
swallowed; buccal, absorbed in the cheek, sublabial, absorbed under the lip, or
sublingual, absorbed under the tongue. Oral medications can be presented in
tablets, capsules, sustained-release tablets and capsules, powders or granules,
drops and liquid medications or syrups. Therefore, before prescribing or
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administering an intravenous drug verifies if there is an oral formulation that can
be used alternatively.
For uncomplicated malaria, only oral anti-parasitic medications that are used
including atovaquone-proguanil (250 mg/100 mg, 4 tablets, every day for 3
days), artemether-lumefantrine (4 tablets, 20 mg/120 mg, at first time, 8 h later,
twice a day for 2 days), quinine (625 mg 3 times a day for 7 days), doxycycline
(100 mg twice a day), tetracycline (250 mg orally 4 times a day), clindamycin (67 mg /kg 3 times a day for 7 days), mefloquine (750 mg loading dose followed by
500 mg 6-12 h after initial dose), chloroquine (1000 mg followed by 500 mg at
6 h, 24 h, and 48 h), hydroxychloroquine (800 mg followed by 400 mg at 6 h, 24
h, and 48 h).
Chloroquine, when administered to children 14 years of age or below, has to be
limited to a dose of 600 mg per week. Artemether-lumefantrine and atovaquoneproguanil are generally not indicated for use in pregnant women because the in
pregnant women are unknown. Doxycycline and tetracycline are not indicated for
pregnant women.
For the treatment of Chagas disease the oral medications benznidazole (2.5-3.5
mg/kg twice a day for 60 days) and nifurtimox (2-3 mg/kg every 6-8 h for 90
days) are used. These medications are only effective in the treatment of the
acute phase of Chagas disease, when disease reaches the chronic phase,
medications are not effective in curing the disease but can help slow its
progression.
In cutaneous leishmaniases besides the intravenous and intramuscular
medications mentioned below the following oral drugs can be used, miltefosine
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(2.5 mg/kg/day (maximum 150 mg/d) for 28 days) and fluconazole (200 mg
once a day for 6 weeks).
Babesiosis is usually treated with atovaquone (750 mg twice a day) plus
azithromycin (500 mg for 1 day, then 250 mg once a day for 7-10 days).
The first line of treatment for Toxoplasmosis is a combination of three oral
therapies: pyrimethamine (200 mg once followed by 50 mg (if <60 kg) or 75 mg
(if >60 kg) once a day), plus sulfadiazine (1 g/kg (if <60 kg) or 1.5 g/kg (if >60
kg) 4 times a day), plus folinic acid (10-25 mg once a day).
In the case of intestinal/genitourinary protozoa such as giardiasis and
trichomoniasis the drugs used are tinidazole (2 g once), metronidazole (250 mg 3
times a day for 5-7 days), or nitazoxanide (500 mg twice a day for 3 days). For
the treatment of Trichomonasvaginalisif asingle-dose of metronidazole is not
sufficient, administration of 500 mg twice daily for 7 days is advisable, and if this
does not lead to improvements, it is recommended to increase treatment dose to
2 g of metronidazole or tinidazole daily for 5 days.
For the treatment of an asymptomatic carrier of amebiasis caused by
Entamoebahistolytica infection the oral administration of paromomycin (8-12
mg/kg 3 times a day for 7 days), iodoquinol (650 mg 3 times a day for 20 days),
or diloxanide (500 mg 3 times a day for 10 days) is recommended. On the other
hand, if it causes amebic colitis or disseminated disease administration of
metronidazole (500-750 mg orally 3 times a day for 10 days) or tinidazole (2 g
orally once a day for 3 days), followed by one of the previously mentioned
luminal agents is advisable. For amebic liver abscess there should be used a
combined administration of metronidazole (400 mg three times a day for 10
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days) or tinidazole (2g once a day for 6 days), with diloxanidefuroate (500 mg
three times a day for 10 days) or other luminal agent.
For cryptosporidiosis, oral nitazoxanide (500 mg orally twice a day for 3 days) is
recommended. For cyclosporiasis and isosporiasis, the treatment is oral TMP-SMX
(1 DS tablet orally twice a day for 7-10 days) or for AIDS-associated disease 4
times a day for 10 days.
When the treatment of intestinal tapeworm infections caused by Taeniasaginata,
Taeniasolium, Hymenolepsis nana, or Diphyllobothriumlatum, is necessary
praziquantel (5-10 mg/kg once), niclosamide (2 g once), or nitazoxanide (500 mg
twice a day for 3 days) are used. Cysticercosis and infection
Echinococcusgranulosus or by trematodes are also treated with praziquantel.
Cysticercosis can also be treated with albendazole (400 mg twice a day for 2-4
weeks) combined with corticosteroids.
Nematodal infections such as ascariasis, trichuriasis, hookworm, enterobiasis and
strongyloidiasis, are treated usually with albendazole (400 mg once),
mebendazole (500 mg once or 100 mg orallytwice a day for 3 days), ivermectin
(150-200 mg/kg once) or pyrantelpamoate (11 mg/kg, maximum 1 g for 3 days).
Topical Medication
A topical medication is applied to the surface of a particular site in the body. The
treatment options include creams, foams, gels, lotions, and ointments. The
objective of topical medications is to treat a limited area of the body without the
systemic application of the drug. Topical medications can have systemic effects
after being absorbed in through the site of application. This treatment is the more
appropriate in some cases since it can achieve high concentrations at the site of
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the infection. These medications can also be applied by inhalation, on the eyes or
ears.
Topical anti-parasitic therapy is used only in the treatment of Acanthamoeba
keratitis in which a combination of topical chlorhexidine and
polyhexamethylenebiguanide to 0.02% are used to administer hourly after
corneal debridement for 3 days, and every 3 hours after this period, for a
minimum period of 3 to 4 weeks. The combination therapy is essential since cysts
are resistant to therapy and this way the drugs act on both the trophozoites and
cysts.
Intravenous Therapy
Intravenous therapy consists in the infusion of liquid medications into a
vein. These medications have to be administered by a clinician. This route of
administration has some advantages such as fast action and complete
bioavailability. The disadvantages are various and include, pain, infection,
phlebitis, fluid infiltration or extravasation, fluid overload, hypothermia,
electrolyte imbalance and embolism. The administration is done using
instruments such as hypodermic needles, peripheral cannulas or central lines.
For severe malaria, intravenous anti-parasitic medications are used including
artesunate (2.4 mg/kg at 0 h, 12 h, 24 h, and 48 h, then once per day if
necessary), and quinidine (loading dose of 10 mg/kg over 1-2 h followed by 0.02
mg/kg/min continuous infusion for 24 h). Artesunate is a semi-synthetic
derivative of artemisinin that is also used in oral formulation to treat
uncomplicated malaria. It can be administered during pregnancy. Quinidine when
administered orally has a half-life of six to eight hours, and it is eliminated in the
liver by the cytochrome P450 system.
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African trypanosomias is is also treated with intravenous therapies that include,
for early stage intramuscular pentamidine (4 mg/kg/d for 7-10 d) and suramin
(100-200 mg followed by 1 g on days 1, 3, 7, 14, and 21), and for late stage
disease eflornithine (100 mg/kg every 6 h for 14 days) and melarsoprol (2.2
mg/kg/d for 10 days). Suramin cannot be administered to HIV patients since it
has been associated with high mortality. Melarsopol is diluted at 3.6% in
propylene glycol for intravenous injection, and half-life is less than 1 hour, but its
active metabolite reaches maximum levels in plasma in about 15 minutes and has
a half-life of 3.9 hours.
For visceral and mucocutaneous leishmaniasis, intravenous and intramuscular
medications are preferred to include, liposomal amphotericin (3 mg/kg IV once a
day on days 1 to 5, 14, and 21), sodium stibogluconate (20 mg/kg once a day for
28 days) or paromomycin (15 mg/kg/d IM for 21 days). For the treatment of
infection caused by the free-living amebae Naegleriafowleri, therapy should
include amphotericin B administered intravenously or intrathecally. Combination
with systemic oral therapy is also essential and can include azoles, rifampin, or
other antimicrobial agents. Amphotericin B treatment (0.7 to 1 mg/kg per day IV
to complete a 35 mg/kg total dose over 3 to 4 months) should not be
administered at doses greater than 1.5 mg/kg.
Usually intravenous medications are only used as a second line therapy or in
more severe cases. Administration by this route is more demanding for the health
care system, for the patient and for the clinician. Therefore, if there is an
alternative drug in oral or topical formulation it should be preferred as a first line
treatment.
Antifungal Agents
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Antifungals are drugs specifically used to treat fungal and other related infections.
In this section, this medication group will be discussed as well as its classification
according to the condition for which they are used for and their chemical
composition. Moreover, the mechanisms of action of antifungals are described in
detail and the most common side effects and adverse reactions related to their
use. Furthermore, interactions of the drugs with other medications or food and
substances are also covered.80-88
Understanding the use and classification of antifungal medications require
knowing the organism for which they are used against. The characteristics of
these organisms are the symptoms, infection from them brings about and other
conditions that result from these infections.
Understanding Fungal Infections
A fungal infection is brought about by the presence of fungi or an increased in the
number of these organisms in the hosts’ body. These organisms may be already
present within the host as a form of normal flora such as Candida or may be
introduced into the body of the host via several portals of entry into the body.
These organisms are simple unicellular or multicellular bodies that normally carry
out their reproductive processes through the use of spores.
Fungi are also protected from their outside environment by thick cell walls that is
highly different from the plasma membrane of common bacterial organisms. This
makes the common antibacterial agent ineffective against fungal infections
because their cell walls are structurally tougher than that of a bacterium. In
addition, most fungal organisms are not easily removed at the skin once they get
deposited into its spaces, rendering bathing and soaping ineffective in completely
removing them from the skin.
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Infection caused by fungal organisms is more difficult to treat, especially if they
are not diagnosed early and the infection has already started to spread or when
the immune system of the affected individual is already low. Moreover, most
fungal infections found on the skin cause discomfort on the part of the patient
and also results in the presence of rashes and other disruptions on the surface of
the affected skin area. Persistent scratching because of the pruritic effect of these
infections lead to micro abrasions in the skin, allowing for the fungi to go into the
deeper layers of the skin and cause a more serious infection.
How Antifungal Medications Differ from Other Agents
Antifungal medications are a group of drugs that have a differentiated action from
that of antibacterial agents. The formulation of these medications has been
necessary because of the ineffectiveness of other agents to treat fungal
infections. However, because fungal organisms do not evolve, much as viruses or
bacteria, the advancement or formulation of these drugs is also lagging behind
antivirals or antibacterial medications.
One of the main differences between fungi and bacteria is the nature of being
prokaryotic. Since bacteria are mostly prokaryotic, medications intended to treat
bacterial agents have to be formulated to be able to target structural and
metabolic components of these cells, which are not highly varied from the human
host. In contrast, fungi are mostly eukaryotic agents, and most of the substances
needed to negate the effects of fungal infections among the human host can also
harm the cells inherent to the host.
Naturally, fungi are multicellular organisms and have a rate of growth slower than
most infectious agents. This nature and characteristic of fungi make it more
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difficult to treat them as compared with bacterial agents, requiring more studies
and tests to be done with medications under the process of formulation before
they are deemed suitable for use among human hosts. However, even in the face
of these factors, antifungal agents, especially those that are widely used in the
market today, have gone through numerous advancements and reformulation as
a means to improve their efficacy and safety for use.
Classes of Antifungal Medications
Antifungal medications are classified according to their chemical composition. This
system of classification makes it easier for a health clinician to choose among
these drug classifications the best medication to be prescribed for a patient
depending on the symptoms presented and the diagnosis of fungal infections.
There are four major classes of antifungals included in this subsection. These
include polyenes, azoles (which include imidazole, triazole and thiazoles),
allylamines and echinocandins.
Polyenes
Polyenes are one class of antifungal drugs that is named aptly because of the
presence of double bonds that are alternately conjugated with each other. These
bonds make part and parcel of the structure of the medication around the
macrolide ring. The main constituent of these polyene antifungal agents is from
Streptomyces organisms. These medications work primarily by interacting with
substances called sterols in the cell membranes of the fungi. Example of these
sterols includes cholesterol and ergosterol.
Once an interaction between the antifungal and sterols has been established,
channels are formed inside the cellular membranes, causing the contents of these
cells to leak outside. This leakage then disables the cell to carry out its normal
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metabolic process, causing it to slowly die. Common examples of polyenes include
amphotericin B, nystatin and pimaricin. These medications and their actions are
discussed in detail below.
Amphotericin B
Probably the most well known antifungal medication of the polyene group is
amphotericin B. This medication is used mainly to treat mycoses that are life
threatening or those infections that are not essentially responsive to other
agents. It is also used to treat other mycotic infection, although dermatohytoses
are not normally treated using this agent. The drug was first introduced in 1956,
and since then, it was being touted as one antifungal medication to represent
itself as a gold standard for treatment and efficacy. This is because amphotericin
B has a broad-spectrum effect, targeting not only the most resilient of fungal
organisms, but also includes relief of infection from yeasts and molds.
Some of the organisms with which this drug is found to be highly effective against
include Coccidiodesimmitis, Blastomycesdermatidis, Histoplasmacapsulatum and
Paracoccicoidesbrasilensis. It is worth to note that these organisms are mostly
dimorphic and not normally responsive to other medications. Opportunistic
mycotic infections are also being treated using amphotericin B. Examples of these
infections include Candida infections and other zygomycetes, Cryptococcus and
Aspergillus. One of the reasons for the wide prescription of these medications
among patients with mycotic infections is that there are lower rates of drug
resistance to amphotericin B reported. However, there are small percentages of
patients with infections caused by Pseudallescheriaboydii and other rate mycotic
infections that have turned out to be resistant to amphotericin B. This drug is
normally prescribed to be administered to patients via the intravenous route.
During administration, especially via the intravenous route, patients are reported
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to complain of pain at the inflammation site, chill and some even turn out to
manifest signs and symptoms of phlebitis. These conditions may range from very
mild to severe, depending on individual responses of patients. Some cases of
renal failure have also been reported, because of the influence of the drug to the
tubuloglomerular feedback. However, administering sodium chloride, while the
patient receives amphotericin B is minimizing the risk.
Nystatin
Nystatin is the first agent of the antifungal group to be formulated, refined and
deemed as fit for use among human patients. It is still in wide use today, and has
been one of the primary proponents during the formulation of other polyene
medications developed over the years. It is also a broad-spectrum antibiotic
agent. However, because the innate capacity of the human immune system to
negate its toxic effects upon fungal agents, it is relegated mostly to be used
topically. Although administration of this drug may be done via other routes, it
would take higher doses and longer treatment times before a noticeable
therapeutic effect is seen. Nystatin is most effective in treating yeast infections
brought about by Candida.
Pimaricin
Natamycin, most commonly known as pimaricin, is a polyene agent that is used
as a treatment for patients with mycotic infections of the eye. It is used topically,
especially among patients with infections brought about by molds or yeasts.
Azoles
Azoles are antifungal agents that are recognized clinically because of their
efficacy in treating stubborn and recurrent fungal infections. These substances
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are usually represented in laboratory illustrations as having organic rings
consisting of five members. These rings contain two to three molecules and are
thought to be helpful in inhibiting the cytochrome P450-dependent enzymes
inside the fungi. These enzymes are primarily involved in the biosynthesis of the
sterol cellular membranes. Common examples of azole medications are
imidazoles and triazoles.
These medications, despite their proven positive effects on the treatment of
fungal infections among their patients have also been reported to have certain
side effects. However, these side effects are not as common or as life threatening
as those normally seen among patients receiving amphotericin B. Side effects of
these medications and other antifungal drugs will be discussed in the succeeding
subsections of this lesson.
Imidazoles
Imidazoles are mostly known for three most common antifungal drugs available
both with and without prescription. These drugs include miconazole, clotrimazole
and ketoconazole. Among these three drugs, ketoconazole is more widely known
because of its relative availability even with the absence of prescription.
The first azole medication that has been formulated for oral administration is
ketoconazole. This has made the drug more versatile and popular in the medical
world because of this. Infections to which ketoconazole are limited among
patients who are not essentially immunocompromised, such as B dermatitidis and
H capsulatum. However, the drug is also proven to be effective against various
mycotic infections such as cutaneous mycoses. Infections treated with
ketoconazole include dermatophyte Infections, such as cutaneous candidiasis and
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Pityriasisversicolor. However, these medications are not usually indicated for
infections caused by aspergillosis or due to the increased proliferation of yeasts.
Triazoles
Two of the most common triazoles that are widely used and prescribed today are
fluconazole and itraconazole. These two medications have slowly taken over the
central role amphotericin B has in managing and treating certain mycotic
infections. In fact, fluconazole has been popular for use among patients with
candida infections as well as those with cryptococcal infections. Moreover, the
drug is also used among those with confirmed coccidioidomycosis. This
medication’s usual route of administration is through the oral or intravenous
route.
Itraconazole, on the other hand, is used as a mainstay drug for treatment against
certain forms of aspergillosis. It is also used among patients with confirmed
diagnosis of coccidioidomycosis, blastomycosis, histoplasmosis and sporotrichosis.
Most patients receiving medications from this group have it administered orally
since the possibility of these drugs being given intravenously is still under study
for safety and efficacy. If these studies turn out with beneficial effects, then there
is a higher chance that more patients are to be prescribed these medications
since the bioavailability of these drugs would have already been given a solution.
Thiazole
This azole is the one of the variants of the azole group of medicine. It is mostly
used as a topical antifungal ointment, especially for the dermatomycoses. Its
action is very well established in vitro as well as in vivo, especially against the
Aspergillus flavus and Aspergillus ochraceus. Unlike other azoles, the thiazole
directly attacks the cell membrane of the fungus and destroys them. It shows the
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antifungal activity, irrespective of the growth of the fungus. It has also shown the
fungicidal and fungistatic activity in the non-growing fungus (inactive). It is a
very promising drug for the future.
Echinocandins
Another class of antifungal medications is the echinocandins. These are
lipopeptides that are water-soluble and acts by inhibiting glucan synthase. The
main mechanism of action by which these drugs combat fungal infections lie in
their ability to target the cellular wall of these fungi without causing resistance
from it. The entire process makes is easier for these agents to fight against fungal
infections. Echinocandins are usually prescribed for patients with infections
caused by Candida and Aspergillus.
Allylamines
This class of antifungal medications is normally used to treat local
dermatophytoses and is used both orally and topically. The main mechanism of
action for which these drugs exert its effect is seen in its capacity to inhibit the
effect of squaleneepoxidase upon the cells. This enzyme is highly essential in the
formation of ergosterol, a sterol that is usually present in the cell membrane of
fungi. Because the presence of squaleneepoxidase prevents the formation of
ergosterol, cells usually weaken because their cell walls get disrupted. This leads
to eventual cellular death.
Others (5- Flourocytosine)
The 5-flourocytosines are antifungal medications that are also antimetabolite
drugs in terms of formulation. These medications are usually a result of
incorporating several substances with fluoride, and an analog of cytosine. These
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drugs work by inhibition of the synthesis of RNA and DNA, thereby stopping
cellular replication and proliferation among those with fungal infections. This
process is achieved through the conversion of the intracytoplasmic materials in 5fluouracil. The result of this process is the creation of nucleotides, which help on
the inhibition of DNA synthesis.
Because these medications are antimetabolites in nature, there is a high
possibility of the development of drug resistance among patients. This makes it
necessary for these medications to be used in concomitance with other agents
such as amphotericin B. This is especially true in the treatment of mycotic
infections, fungal meningitis, and even tenacious strains of Candida infections.
How Antifungals Work
The manner that antifungal medications work is based primarily on the structure
of the fungal cell. It has been established in the previous sections that the cell
membrane of the fungal cell is different from most common infectious organisms.
In fact the fungal cell wall has stark similarities with most mammalian cells,
making it susceptible to less pathogens than other cells. Because of this reason,
medications that are intended to fight off fungal infections can be grouped
together depending on their mechanism of action, or which part of the fungi they
best act upon to prevent infection.
Pharmacodynamics
Bioavailability of most antifungal agents still remained a question until the early
1990s despite their wide use. This is because most of these drugs were
administered either orally or via the intravenous route. This is mostly performed
among patients with extensive fungal infections and with whom treatment needs
to be instituted right away or else serious complications may occur. Continuous
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clinical trials have resulted in most azole drugs to be administered safely orally.
However, the dosages, frequency and factors that influence the absorption of
most orally administered antifungal medications vary from person-to-person and
upon the drug itself.
Among the orally administered antifungal agents, the most readily absorbed in
the bloodstream is fluconazole. It has one of the highest levels of bioavailability of
90%. This rate levels with the intravenous administration of the drug. Moreover,
the absorption rate of this drug is not affected by food intake or gastric acidity
and other disease states. However, the same cannot be said true of the other
drug in this category as most of their absorption rates vary depending on how
they are formulated and administered. Furthermore, the bioavailability of these
substances are also affected by gastric acidity and food intake, thereby making it
impossible to administer this medication concomitantly with other agents such as
proton pump inhibitors and H2 receptor antagonists.
Itraconazole, on the other hand, may only be administered after food intake to
ensure optimal absorption of the drug from the bloodstream. Conversely, the
administration of this specific drug is also not affected by antacid intake. And
lastly, voriconazole’s bioavailability is further enhanced with food intake while
posaconazole needs to be taken after a high-fat meal to optimize absorption.
Another factor that needs to be fully understood in the administration of
antifungal agents and treatment of fungal infections is the manner in which the
drug is distributed in the body of the patient. This is because despite the
expected systemic effects of orally administered drugs, its effects may not be as
optimal in other sequestered areas of the body. Factors that are essential to be
considered in administering antifungal agents and their rate of distribution include
their route of administration, mode of elimination from the body, molecular size
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and protein binding capacity.
In terms of the site of administration, it is worth to note that most fungal
infections affecting the central nervous system (CNS) are linked with alarmingly
high rates of mortality and morbidity. This is because most of these infections of
the CNS spread faster than others and most agents used to treat CNS infections
cannot successfully cross the blood-brain barrier. The inability of these agents to
do so is relative to its large molecular size.
Among the antifungal agents able to cross the blood-brain barrier, voriconazole,
fluconazole and flucytosine have been found to achieve at least 50% success in
tests done. This has been given much importance since the prediction of efficacy
of the therapeutic effects of these medications through the CSF means it has
higher chances of success in other areas of the body. However, tests have proven
to be unreliable when it comes to the efficacy tests with amphotericin B because
of its inability to be detected in CSF. But despite this, the drug is one of the
essential treatment components among patients with fungal meningitis infections.
The above-mentioned data reveals that above and beyond the detectable level of
CSF concentrations, tissue concentrations may also be used as a basis for the
distribution of antifungal agents and their relative efficacy. The therapeutic
response of the brain tissues to the effect of echinocandins against some
infections has proven this. However, it is also worth to remember that apart from
CNS problems, other organs of the body, such as the eyes may also prove to be
one area where antifungal agents may have difficulty in distribution and therefore
have lower levels of efficacy as compared with the other sites.
In the prescription of antifungal agents, it is important to also consider how to
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best optimize its prescription in treating the pathogenic fungal infection of the
patient. Moreover, other factors such as the host, and the interaction of the
human host with the fungal agent and the environment work to cause the
infection and affect the action of the medications prescribed for these patients.
Special consideration and attention needs to be given to these factors since most
literatures do not fully describe these in detail as compared to the more
commonly recognized agents. Because of limited knowledge of these antifungal
agents, extensive in vitro and animal testing has been done to learn more about
their perceived efficacy and impact in the treatment of the most common fungal
infections. Among these agents that have gone through extensive testings are
echinocandins, polyenes and azole agents.
Pharmacokinetic actions of these agents have been revealed and described
through post-study reports. These reports were the products of the exposure of
the different mycotic organisms and infections to different substances thought to
be effective in combatting them. The process was a rather tedious one, with one
agent tested after another to determine its efficacy in treatment. Animal model
testing done on candidiasis treatment revealed that echinocandins and polyenes
are effective against this specific organism. However, this level of efficacy may be
achieved when the peak drug concentrations have reached twice the level of the
infecting pathogen. These studies reveal that as the drugs’ dosage increase and
the length of time the peak levels are maintained within the bloodstream, the
efficacy of the drug increases and the rate of relief of infection improves.
Specifically, such clinical trials also revealed that humans could benefit from
complementing administration of different medications to combat fungal
infections.
The pharmacokinetics of antifungal agents and its interactions with its host has
also been correlated with the potential for toxicities. A few compounds have been
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named to be responsible for this. For example, flucytosine and increased serum
concentrations of this drug have been linked to bone marrow suppression.
Another example would be the hepatotoxic effects exerted upon the patient by
higher doses of variconazole. Despite these identified pharmacodynamics of the
most commonly used antifungal agents, there is still a need to be vigilant about
the administration and use of these agents on the part of the prescribing clinician
and ample monitoring and evaluation done upon the person receiving these
agents. Moreover, ensuring that blood concentration levels of these drugs remain
in their safe ranges would help prevent any possible toxic and life-threatening
effects.
Individual Pharmacodynamics of Antifungal Agents
Azole and polyene group antifungals are known to have direct effects upon the
production and action of ergosterols. This sterol is a common component of the
cell membrane of most fungi. The azole group of medications exerts their effect
by preventing the production of 14 alpha-demythelase. This is an enzyme
dependent on the fungal cytochrome 450. By this, azoles are able to diminish the
defenses of the fungal cells by depleting its membrane and significantly affecting
ergosterol stores. When these stores are diminished, the membranes surrounding
the cell become impaired, allowing toxic substances to permeate the cells and
eventually cause arrest cellular growth. As more and more toxic substances come
inside the cell, the cell eventually dies. The process may be longer as compared
to other drugs, but it helps to effectively stop further growth and infection due to
fungal invasion.
The above-mentioned effect of azoles upon fungal cells is also responsible for the
presence of drug-to-drug interactions, increasing the chances of cellular
resistance to the effects of triazoles. However, in cellular molecules that were
byproducts of ketoconazoles, this effect extends to affect certain kinds of molds.
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Allylamines and other drugs in this category, however, help fend off fungal
infections through the inhibition of squalenemonoxygenase, which results in the
inhibition of the biosynthesis of ergosterols. Squalenemonoxygenase is an
essential enzyme that is responsible for the synthesis of ergosterol through the
conversion of squalene-to-squalene epoxide, the precursor to the formation of
lanosterol. Despite the similarity on how the substance affects ergosterol
production, allylamines do not exert the same influence that drugs such as azoles
have. However, allylamines have a special interaction with drugs such as rifampin,
which results in an enhanced metabolism of terbinafine among humans. This
metabolism usually results in the increased concentration of terbinafine on the
integumentary organs and lower concentration of the drug in the bloodstream.
Because of this concentration variance, the drug was normally prescribed as a
treatment for patients with skin and other cutaneous infections.
Among the polyene group, amphotericin B is probably the best known. The drug’s
pharmacologic action centers on its capacity to target the cell membrane of the
fungi. It does it by directly creating a bond with ergosterol. This bonding results
in the creation of intercalacted sections of the cellular membranes. Once
intercalated, the cellular membrane becomes more prone to leakages because
pores are formed that allow cellular contents to get deposited in them and slowly
leak from them. Moreover, amphotericin B has been found to have a higher
affinity with the fungal cellular membranes rich in ergosterol compared to those
that are high in cholesterol. Despite this, however, the drug is seen to have the
tendency to be accumulating its concentrations in organs such as the kidneys.
The rising concentration of the drug is one of the reasons why the drug has been
found to increase the risk of nephrotoxicity among those with long-term therapy,
leading to limitations on its prescription. Furthermore, the continued use of the
drug increases the possibility of inflammatory symptoms to occur such as fever
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and chills. These symptoms are normally seen when the drug is administered by
IV infusion. Because of its higher risk for nephrotoxicity and apparent
effectiveness in treating a wide range of infections, the drug is formulated into
two to best treat most conditions and to prevent the possibility of drug resistance
among patients who are taking it on a long-term basis.
Echinocandins, another group of antifungals, have a different mechanism of
action as compared with others. In fact, the drug is the only group that targets
the fungal cell wall directly. This it does by inhibition of the synthesis of glucan
polymers. These polymers are highly important in the structural cross-links
formed along the cell walls in fungal organisms found to be pathogenic in nature.
The drug binds with the enzymes responsible for the synthesis of glucans,
resulting the cell walls to be depleted of glucans. This depletion makes the cell
highly susceptible to osmotic cellular lysis and arrest the further spread of rapidly
growing cells. This process determines the class of echinocandin antifungals,
which are considered to he highly effective treatment for conditions such as
Candida. It is also considered to be fungistatic against other species of fungi,
such as Aspergillus.
Lastly, there are two groups of antifungal agents identified to be selective in
targeting the cellular growth and development of fungi similar to how common
cancer chemotherapeutic agents act. These medications are usually used in
conjunction with other agents since their efficacy as monotherapy is limited.
These medications include 5-flucytosine and 5-fluorouracil. Among these two,
flucytosine is more commonly known, because it directly inhibits and influences
RNA coding among fungal cells. This is carried out by converting to enzymes to
form 5-flourouracil and exert its influence, however, because of the antagonistic
effects of the normal bacterial flora of the intestines upon the drug, nausea,
vomiting and other symptoms of gastrointestinal upset are more pronounced
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among patients receiving the drug. In some cases, it can also cause bone marrow
depression, especially if taken on a long-term basis or in high doses. The primary
action of flucytosine is against yeast infections, but it needs to be administered as
part of adjuvant therapy to ensure that cellular resistance to it will be minimized
and mutations of possible resistant cells be controlled.
Adverse Affects of Antifungals
Intake of medications has the tendency and the possibility to cause both positive
and negative effects upon patients receiving them. This is also true among those
who are on antifungal therapy. Therapeutic effects of the drug are considered to
be positive and in this group of medications, that comes in the relief of fungal
infections. However, as the drug works to relieve patients of their infections, there
are also unexpected and rather unavoidable occurrences or side effects that exist
as part of the therapy. Drug side effects sometimes, when the drug being given
as part of therapy, indicate that the drug is actually working.
When the negative effects of drug therapy go beyond the tolerable and
considered normal occurrence, they are termed as adverse reactions. These
adverse reactions are bothersome symptoms felt and seen among patients who
are taking certain medications and are a cause for concern among physicians and
other heath clinicians. In some cases, stopping treatment using the offending
drug causes the symptoms to go away, but in the worst cases, these can threaten
the life of the patient and require extensive medical attention. In this section,
these effects of antifungal medications are to be discussed as well as the series of
interactions the drug may have with other substances.
Toxicity is one common occurrence among broad-spectrum drugs such as
amphotericin B. This is because the drug is toxic among a number of other cells
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apart from fungi. One of the primary adverse effects amphotericin B is well known
for is the development of nephrotoxicity among patients taking the drug. Apart
from this it is also known to produce Hypokalemia, Hypomagnesemia and Bone
marrow suppression. The bone-marrow suppression is primarily presented as
anemia.
Heptotoxicity is very uncommon with the use of Amphotericin B. The nephrotoxic
effects can start by affecting the urinary function of the patient, and as the
condition does not get addressed as soon as it should be, some patients suffer
from renal failure. Amphotericin B is also known to have acute infusion-related
effects. These symptoms can include the presence of either of the following:
 Pulmonary toxicity, which may be manifested by dyspnea, chest pains and
severe episodes of hypoxia. In some patients pulmonary toxicity may also
lead in the production of mucus along the airway.
 Abdominal pain
 Leg pain
 Flank pain
 Facial flushing
 Urticaria
The usual group of antifungal agents, especially fluconazole is antifungal with the
least number of reported cases of toxicity. However, despite the absence of more
life-threatening adverse reactions, the drug has been linked to incidences of
alopecia, anaphylaxis, hepatic necrosis, and Stevens-Johnson syndrome. If taken
for during the 1st trimester of pregnancy, congenital fetal anomalies can occur.
Most of the side effects are reversible as soon as therapy is stopped.
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Other azole agents have also been linked to episodes of nausea and diarrhea as
the usual side effects, which are managed by supportive therapy. However,
itraconazole has been found to bring about hypertension, edema and hypokalemia
among older patients prescribed with the drug. It also produces an allergic rash,
hepatitis, and hallucinations. It also has a negative inotropic effect, responsible
for reduced effectively of cardiac contractions and increased risk of congestive
heart failure.
Voriconazole, another azole agent, has been pointed out to cause phototoxicity
and other visual disturbances. These disturbances are described by most patients
are appearance of colorful wavy lines or flashes of bright lights. Despite these
findings, the condition is usually found to be transient and relieved once therapy
is halted. If shifting medications is not entirely possible, then lower doses are
normally administered since the effects are more pronounced among those taking
larger doses of the drug. Furthermore, skin irritation and rashes are also seen
among patients taking this drug, although these too are transient and disappear
gradually once therapy is stopped.
Posaconazole, another azole, has been reported in most literatures to be
responsible for causing renal toxicities among patients prescribed to take it.
Because of its hepatotoxic effects, patients who are prescribed to take
posaconazole are prescribed to undergo liver function tests. It is also known to
produce prolonged QT interval.
Echinocandins, the antifungal drug group is recognized for the capacity to cause
fewer side effects and adverse reactions such hepatitis and rash. These reactions
are thought mostly to be histamine-related, and usually relieved by decreasing
the infusion rate and treating histamine reactions with medications such as
diphenhydramine.
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Drug-to-Drug Interactions
The administration of a medication, especially as part of concomitant or adjuvant
therapy should be considered prior to administering them upon a patient. This is
also one of the primary considerations when administering antifungal medications
and one of the bases why therapy should be continued, shifted or stopped
altogether.
Antifungal medications can be responsible for altering the efficacy and safety of
other drugs, and they do this through several possible processes. The most
common among these mechanisms are the presence of additives in the drug
formulations that increases the toxicity of antifungals. The nephrotoxic effects of
amphotericin B best exemplify this. The level of toxicity brought about by
amphotericin B can be amplified or may amplify the nephrotoxic effects of other
agents such as aminoglycosides and other cyclosporine agents.
Another area in which interactions of drugs upon each other exerts a relative
effect is the inhibition of the effects of certain medications due to its metabolism
and interaction with other substances. For example, azole antifungal agents are
known to inhibit certain enzymes responsible for the production of ergosterol.
This key information needs to be carefully considered and factored in when
planning care and medication administration among patients receiving substances
that may enhance or antagonize the effects of azoles.
It is also essential to keep this information in mind among patients who are
prescribed to receive azoles but are on hormone therapies. These are the drugs
that are CYP3A4 inhibitors. That is the main mechanism of the drug-drug
interaction. Fluconazole has much less incidence of the drug-to-drug interaction.
However, fluconazole sometimes elevates serum levels of calcium channel
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blockers and known to interact with the medicines such as cyclosporine, warfarin
kind of oral anticoagulants, tacrolimus, rifabutin, phenytoin, some sulfonylurea
drugs such as tolbutamide and zidovudine. Rifampin can lower
the fluconazole blood levels.
Some medicines such as rifampin, phenytoin, rifabutin, didanosine
and carbamazepine are known to decrease the blood itraconazole
levels. Itraconazole also inhibits the metabolic degradation of other drugs,
elevating blood levels with the potentially serious consequences. Fatal cardiac
arrhythmias can occur, if the itraconazole is used along with the medicine, such
as cisapride, or some antihistamines, such as terfenadine, astemizole and
occasionally loratadine.
Rhabdomyolysis has also been linked with itraconazole-induced elevations in
serum levels of statins or cyclosporine. Serum levels of some drugs such as
digoxin, tacrolimus, oral anticoagulants, sulfonylureas may be raised, when these
drugs are used concomitantly with the itraconazole. Posaconazol drug interaction
can occur with the medicines such as statins, rifabutin, rifampin, various
immune-suppressants, and barbiturates.
Caspofungin and micafungin, two other substrates and by-products of antifungal
therapies are also reported to have interactions with the CYP450 enzyme system
that is responsible for the production of ergosterol. Caspofungin and its efficacy
and concentrations are affected by administration of medications such as
phenytoin and rifampin. Micafungin, on the other hand interacts with nifedipine
and sirolimus. When such interactions occur, the levels of the drug are elevated
significantly, thereby increasing its potential for toxicity. Moreover, caspofungin
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has been seen to have hepatotoxic effects, especially when given concomitantly
with cyclosporine.
Allergic Reactions
Drug and food interactions are extremely common with the azole group of the
antifungal medications. Other groups of antifungal medicines also produce allergic
reaction, but of mild category. Below, the each antifungal medicine mentioned
with the various allergic reactions it produces, when used as a part of the
treatment.
Amphotericin B:
Acute toxicity is seen in the Ambhotricin B therapy and give rise to symptoms like
fever, chill and nausea during the infusion. Acute during pulmonary events are
known to take place during the treatment of the Ambhotricin B therapy. The
patient typically describes symptoms such as dyspnea, chest pain, chest
tightness, bronchospasm, cyanosis, coughing, and hemoptysis.
Flucytosin:
It is not much known to produce severe allergic reactions upon administration of
the drug. It may produce cutaneous allergic reactions such as rash, urticaria,
pruritus, photosensitivity, toxic epidermal necrolysis, etc. Severe allergic reaction
to this drug can produce sudden ventricular dysfunction, dyspnoea and can lead
to cardiac arrest.
Itraconazole:
It can cause adverse allergic reactions such as hyperkalemia with AST/ALT
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(alanine aminotransferase) elevation and rash. Intravenous use of the
itraconazole can lead to chemical phlebitis and give rise to cutaneous reaction.
The clotrimazole group of medicines is known to cause cutaneous reaction such
as severe blistering eruptions and maculopapular eruptions.
Variconazole:
This medicine is known to cause immediate reaction in the patient following the
30 minutes to 1 hour of the administration of the drug. The patient typically
complaints of color changes, blurred vision, photophobia and photopsias.
Echinocandin:
Echinocandin is known to be very low in its toxicity. It rarely produces any allergic
reaction or the anaphylaxis. Occasionally produces a rash and hepatitis.
Summary
Infectious diseases are the one of the major reasons for the morbidity and the
mortality in the world. According to the World Health Organization, it is the third
highest reason for the fatality due to medical reasons. The pathogens, which are
responsible for the various kinds of the infectious diseases, are also emerging day
by day. Currently, the main focus is on the antimicrobial pharmacological
therapies, due to its higher efficacy in the treatment of various microbial
infections. Broad-spectrum antibiotics are the more widely used antibiotics to
treat the majority of infections. While in specific cases, antibiotic therapy is based
on the specific drug sensitivity of each individual type of pathogen. Increasing
antibiotic resistance is of high concern in the field of pharmacology, which is the
major driving force for the newer emerging antibiotic components.
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Antifungal medicines are a very different kind of antimicrobial agents with the
effect on the cell membrane of the growing fungus. Although antifungal agents
are known to cause a lot of allergic reaction and the adverse effects, the use of
antifungal medicine is absolutely warranted in the immunocompromised patients
such as HIV/AIDS. Due to an increasing incidence of antifungal agent related
allergies, these medicines should be used after patch testing for possible allergy.
Parasitic infections are a substantial cause of human mortality affecting more
than 2 billion people worldwide. Parasitics infection can become difficult to treat
because of the increasing resistance to the medications. In such cases,
combination drug therapy is recommended.
Viruses have proven themselves the most fatal microorganisms, because of the
newer merging strains day by day. Viral diseases like AIDS, swine flu, avian flu,
etc., have very high incidence rates and are a major cause of death worldwide.
Antiviral therapy inhibits certain major steps in viral replications, specific enzymes
and structures that are important to viral growth and multiplication. Unlike
antibacterial drugs, only limited types of antiviral agent are available for the
treatment of specific viral infections. Due to advancement in pharmacodynamics,
the invention of newer vaccines to treat various infectious diseases is emerging.
Many viral diseases have no specific or proven antiviral medication, but there is
hope for improved vaccines in the near future.
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1. The efficacy of an antiviral agent depends on its ability
a.
b.
c.
d.
to be selectively toxic against the virus.
to overcome the viral resistance strategy.
to be effective against replicating and latent viruses.
All of the above
2. True or False: Most antiviral agents available are only effective against
replicating viruses.
a. True
b. False
3. Anti-viral agents, known as immunomodulating agents,
a. interfere with the host cell receptor or co-receptor.
b. act directly by inhibiting viral replication at the cellular level.
c. augment or modify the host immune system to eradicate the infecting
virus.
d. inhibit attachment of viral specific glycoproteins to host cells.
4. _________________ is not recommended for immunosuppressed
patients because it causes vaccine-induced infection.
a.
b.
c.
d.
Salk polio vaccine
Oral polio vaccine
Zidovudine
Azidothymidine
5. Complications such as arthritis and arthralgia are reported among
women after vaccination with
a.
b.
c.
d.
live-attenuated measles vaccine.
killed measles vaccine.
rubella vaccine.
the 17D vaccine.
6. Maraviroc, an allosteic inhibitor,
a.
b.
c.
d.
augments the host immune system.
interferes with HIV-I attachment with CCR5 chemokine receptor.
modifies the host immune system.
is contraindicated for HIV-I infection.
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7. The ___________ vaccine is effective, safe and available for
preventing rabies infection.
a.
b.
c.
d.
tissue culture
duck embryo
nervous tissue
simple
8. A live-attenuated varicella-zoster virus (VZV) vaccine has proven
effective
a.
b.
c.
d.
only as a prophylactic agent.
but may not be administered to immunosuppressed patients.
after infection but not as a prophylactic agent.
when administered to children, elderly and immunosuppressed patients.
9. Many factors hinder the development of antiviral drugs, including
a.
b.
c.
d.
viral resistance.
reduced efficacy.
bioavailability of the drugs due to shelf life of its compounds.
All of the above
10. True or False: Cell-based assay is one of the best and most reliable
and accurate technique for cell testing.
a. True
b. False
11. _______________ is used to measure the susceptibility of a virus to
particular drugs.
a.
b.
c.
d.
Genotypic assay
Polymerase chain reaction (PCR)
Phenotypic assay
Genetic constitution
12. Which of the following is important in understanding the gene
arrangement and studying the mutational pattern of the virus
through evolution?
a.
b.
c.
d.
Proteomics
Genomics
Phenotypic assay
Bioinformatics
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13. An important tool is X-ray crystallography for antiviral compound
development because
a.
b.
c.
d.
it
it
it
it
provides a three-dimensional analysis of a drug target.
manipulates the compound chemically.
identifies various genetic products of a virus.
analyzes the impact of biochemical processes.
14. The efficacy of antiviral agents depends largely on
a.
b.
c.
d.
systemic drug absorption and reaching the target site.
the cytopathic effect (CPE) of the virus.
reduced bioavailability of the drug.
low solubility of the agent.
15. Oral administration of antiviral agents such as ritonavir, penciclovir,
and acyclovir are formulated
a.
b.
c.
d.
for poor absorption in the gastrointestinal tract.
to have a short half-life.
to reach peak serum concentration within hours.
for easy absorption in the gastrointestinal tract.
16. True or False: Because viruses are NOT intracellular
microorganisms, the viral replication takes place in the host cell.
a. True
b. False
17. Transdermal drug delivery has the advantage of
a.
b.
c.
d.
ocular bioavailability.
low solubility of the agent.
increased bioavailability.
being impermeable.
18. ______________ may play major role to overcome ocular barriers to
antiviral agents.
a.
b.
c.
d.
Liposomes
Iontophoresis
Microemulsion
Efflux and influx transporters
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19. The use of ______________ techniques for ophthalmic drug delivery
has been adopted for treatment of eye infections.
a.
b.
c.
d.
microemulsion
ethosomes
microsphere system
ultrasound and ionotropic
20. True or False: The presence of mixed variants of a virus in a patient
is called viral quasispecies.
a. True
b. False
21. When treating Hepatitis C virus (HCV) with the antiviral agent
interferon,
a.
b.
c.
d.
amino acid residue changes do not impact the drug’s efficacy.
interferon is predictably effective in treating HCV.
interferon remains effective even when HCV mutates.
interferon is often withdrawn due to HCV resistance to the drug.
22. True or False: Host Interferon resistance is predictable and easier to
understand compared to other antiviral agents.
a. True
b. False
23. Mutation of ______________ often results in the resistance pattern
observed commonly among the HBV-resistant drugs.
a.
b.
c.
d.
protease genes
wild-type strains of HBV
DNA polymerase enzymes
the RNA of the M2 ion channel
24. Herpes virus drug resistance is
a.
b.
c.
d.
rare in healthy adults.
common for even healthy adults.
below 8% even with immunosuppressed patients.
due to mutation of glycoprotein on the virus cell membrane.
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25. Influenza virus resistance to oseltamivir and zanamivir has been
reported, possibly due to
a. susceptibility of some antiviral agents against the virus.
b. a mutation of specific enzymes involved in viral replication.
c. a mutation of specific enzymes involved in viral attachment to the host
cell.
d. use by immunosuppressed patients.
26. Cytomegalovirus (CMV) drug resistance is mostly due
a.
b.
c.
d.
to
to
to
to
point mutation of the thymidine kinase gene.
reverse mutation.
increased bioavailability.
viral attachment to the host cell.
27. Viral resistance is broadly investigated by
a.
b.
c.
d.
phenotypic assay.
phenotypic and genotypic assay.
genotypic assay.
None of the above
28. Various techniques used in phenotypic assay include
a.
b.
c.
d.
real time polymerase chain reaction (PCR).
high-performance liquid chromatography (HPLC).
gene sequencing.
microarray.
29. ______________ investigates mutations in the viral genome.
a.
b.
c.
d.
High-performance liquid chromatography
Cell culture
Fluorometry
Genotypic assay
30. True or False: Phenotypic assay involves an in vitro susceptibility
testing of antiviral agents.
a. True
b. False
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31. _______________ is effective in testing viruses that can be grown
or cultured in the laboratory.
a.
b.
c.
d.
Genotypic assay
Gene sequencing
Phenotypic assay
Microarray
32. How are protozoa infections classified?
a.
b.
c.
d.
By
By
By
By
disease symptoms.
parasitic species.
global region.
means of infection, e.g., sexual transmission, insect bites.
33. __________ is the most prevalent systemic protozoan infection.
a.
b.
c.
d.
Amoebiasis
Sleeping Sickness
Chagas disease
Malaria
34. What disease is caused by Trypanosoma brucei?
a.
b.
c.
d.
American trypanosomiasis
Leishmania
Sleeping sickness
Leishmania tropica
35. ___________________, caused by a protozoan parasite, is more
dangerous in pregnant women, causing congenital defects or
miscarriage.
a.
b.
c.
d.
Cytomegalovirus
Toxoplasmosis
Giardiasis
Hemolytic anemia
36. What is the most common transmission route for Giardia lamblia?
a.
b.
c.
d.
contaminated water
tick bites
sandflies
mosquitos
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37. ___________ is most common in tropical regions and infected
individuals usually do not develop symptoms.
a.
b.
c.
d.
Amebiasis
Giardiasis
Cytomegalovirus
Chagas disease
38. True or False: Most pathogenic amoebic agents often cause infection
in humans.
a. True
b. False
39. The following is true of Cryptosporidiosis:
a.
b.
c.
d.
In healthy patients, it usually only causes diarrhea.
In immunocompromised patients, the diarrhea can be fatal.
It can be found worldwide.
All of the above
40. Naegleria fowleri is the causative agent of primary amebic
meningoencephalitis,
a.
b.
c.
d.
which is a rare and fatal condition.
transmitted by vegetables contaminated with the protozoan.
transmitted by infected fowl.
which is usually asymptomatic.
41. Cestodes are __________ that cause disease in the gastrointestinal
lumen.
a.
b.
c.
d.
nematodes
amoebic agents
tapeworms
ticks
42. Diphyllobothriumlatum infection can result in diarrhea, weakness,
and dizziness
a.
b.
c.
d.
after drinking contaminated water.
after eating raw or undercooked pork.
after eating raw or undercooked fish.
transmitted by contaminated vegetables.
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43. ________________________ is less common and also characterized
by the formation of cysts in the liver.
a.
b.
c.
d.
Echinococcusspecies
Echinococcusgranulosus
Diphyllobothriumlatum
Echinococcusmultilocularis
44. Trematode infections
a.
b.
c.
d.
cause schistosomiasis, which affects 200 million people globally.
are specific to Asia and Africa.
cause clinical infections in livestock only.
are contracted through tainted pork.
45. In children, ____________________ can cause growth retardation
and anemia.
a.
b.
c.
d.
echinococcosis
schistosomiasis
echinococcusmultilocularis
diphyllobothriumlatum
46. Paragonimiasis affects mainly the
a.
b.
c.
d.
gastrointestinal tract causing cramping and diarrhea.
gastrointestinal tract causing mostly asymptomatic infection.
lungs causing chest pain, eosinophilia, fever, and cough.
gastrointestinal lumen.
47. Once a parasite finds a home inside a human host,
a.
b.
c.
d.
the patient will be asymptomatic during the parasite’s life cycle.
the patient will experience nausea, cramping, and vomiting.
the patient will show symptoms immediately.
it can go undetected for life.
48. The parasitic diseases found in tropical or subtropical regions
a.
b.
c.
d.
are “neglected tropical diseases” since they are largely overlooked.
are given little attention or research for new medications.
include malaria, which kills 660,000 people annually.
All of the above
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49. Intravenous therapy is usually applied in situations
a.
b.
c.
d.
where
where
where
where
an organ such as the brain is infected.
mild disease is caused by infection.
the parasite is undetected in the host.
the patient suffers gastrointestinal infection.
50. True or False: Neglected tropical diseases infect an estimated one
billion people taking a huge toll in endemic areas especially in
children.
a. True
b. False
51. Most intestinal parasites are treated with luminal agents
a.
b.
c.
d.
that are easily absorbed.
that are not easily absorbed.
that most parasites cannot acquire resistance to.
None of the above
52. _____________ may only be administered after food intake to
ensure optimal absorption of the drug from the bloodstream.
a.
b.
c.
d.
Voriconazole
Itraconazole
Posaconazole
Terbinafine
53. For intestinal nematodes causing ascariasis a single oral dose of
______________ is usually effective.
a.
b.
c.
d.
Mebendazole
Albendazole
Ivermectin
All of the above
54. One of the primary adverse effects of amphotericin B is
a.
b.
c.
d.
Heptotoxicity.
irreversible amenia.
the development of nephrotoxicity.
phototoxicity.
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55. _____________ is the only group of antifungals that targets the
fungal cell wall directly.
a.
b.
c.
d.
Echinocandins
Allylamines
The azole group
Triazoles
56. Among the orally administered antifungal agents, the most readily
absorbed in the bloodstream is
a.
b.
c.
d.
itraconazole.
fluconazole.
voriconazole.
posaconazole.
57. The following is/are true of the structure of the fungal cell:
a.
b.
c.
d.
the fungal cell is similar to most common infectious organisms.
the fungal cell wall has stark similarities with most mammalian cells.
the fungal cell susceptible to more pathogens than other cells.
All of the above
58. True or False: Antifungal medications can be responsible for altering
the efficacy and safety of other drugs.
a. True
b. False
59. Agents used to treat fungal infections of the central nervous system
are not effective because
a.
b.
c.
d.
infections of the CNS spread slower than others.
these agents have large, relative molecular size.
most agents cannot successfully cross the blood-brain barrier.
the agents are unable to detect the fungal infection.
60. In the prescription of antifungal agents, it is important to also
consider
a.
b.
c.
d.
the condition of the host.
the interaction of the human host with the fungal agent.
the human host and the host’s environment.
All of the above
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CORRECT ANSWERS:
1. The efficacy of an antiviral agent depends on its ability
a.
b.
c.
d.
to be selectively toxic against the virus.
to overcome the viral resistance strategy.
to be effective against replicating and latent viruses.
All of the above [correct answer]
“The efficacy of an antiviral agent depends on the ability to be selectively
toxic against the virus, and overcome the viral resistance strategy…. A
potent antiviral agent should be effective against both replicating and
latent viruses.”
2. True or False: Most antiviral agents available are only effective against
replicating viruses.
a. True
“Ordinarily, antiviral agents should be effective for latent and replicating
virus; however, most antiviral agents available are only effective against
replicating viruses.”
3. Anti-viral agents, known as immunomodulating agents,
c. augment or modify the host immune system to eradicate the infecting
virus.
“Immunomodulating agents - augment or modify the host immune
system to eradicate the infecting virus.”
4. _________________ is not recommended for immunosuppressed
patients because it causes vaccine-induced infection.
b. Oral polio vaccine
“The Oral polio vaccine … can revert into the wild type and cause vaccineinduced infection. It is not recommended for immunosuppressed
patients.”
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5. Complications such as arthritis and arthralgia are reported among
women after vaccination with
c. rubella vaccine.
“Rubella vaccine … can be administered in combination with measles and
mumps vaccines. Complications such as arthritis and arthralgia are
reported among women after vaccination with the rubella vaccine.”
6. Maraviroc, an allosteic inhibitor,
b. interferes with HIV-I attachment with CCR5 chemokine receptor.
“Maraviroc, an allosteic inhibitor interfere with HIV-I attachment with
CCR5 chemokine receptor.”
7. The ___________ vaccine is effective, safe and available for
preventing rabies infection.
a. tissue culture
“The tissue culture vaccine consists of human diploid cell and rhesus
monkey diploid cell culture vaccine. It is effective, safe and available for
preventing rabies infection.”
8. A live-attenuated varicella-zoster virus (VZV) vaccine has proven
effective
d. when administered to children, elderly and immunosuppressed
patients.
“A live-attenuated VZV vaccine has proven to be effective in preventing
the virus transmission. It can be administered to children, elderly and
immunosuppressed patients.”
9. Many factors hinder the development of antiviral drugs, including
a.
b.
c.
d.
viral resistance.
reduced efficacy.
bioavailability of the drugs due to shelf life of its compounds.
All of the above.
“Many factors hinder the development of antiviral drugs. These include
viral resistance, reduced efficacy, solubility, side effects and bioavailability
of the drugs due to shelf life of the constituting compounds.”
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10. True or False: Cell-based assay is one of the best and most reliable
and accurate technique for cell testing.
a. True
“Cell-based assay is one of the best and most reliable and accurate
techniques for cell testing because live cells are used for the experiment
to determine the cytopathic effect (CPE) of the antiviral drug.”
11. _______________ is used to measure the susceptibility of a virus to
particular drugs.
c. assay
“Phenotypic assay is used to measure the susceptibility of a virus to
particular drugs.”
12. Which of the following is important in understanding the gene
arrangement and studying the mutational pattern of the virus
through evolution?
b. Genomics
“Genomic sequencing assists in understanding the gene arrangement and
studying the mutational pattern of the virus through evolution.”
13. An important tool is X-ray crystallography for antiviral compound
development because
a. it provides a three-dimensional analysis of a drug target.
“X-ray crystallography is an important tool for the three-dimensional
analysis of a drug target. This analysis determines the association
between small compounds and their target protein; this process may
manipulate the compound chemically into an intended result.”
14. The efficacy of antiviral agents depends largely on
a. systemic drug absorption and reaching the target site.
“The efficacy of antiviral agents depends largely on systemic absorption of
the drug and the ability to reach the target site.”
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15. Oral administration of antiviral agents such as ritonavir, penciclovir,
and acyclovir are formulated
a. for poor absorption in the gastrointestinal tract.
“Oral drugs are formulated for easy absorption in the gastrointestinal tract
and usually reach peak serum concentrations or levels within a few hours
of administrations. Poorly absorbed antiviral agents such as ritonavir,
penciclovir, and acyclovir have been maintained in the gastrointestinal
tract to increase their bioavailability using this technique.”
16. True or False: Because viruses are NOT intracellular
microorganisms, the viral replication takes place in the host cell.
b. False
“Because viruses are obligate intracellular microorganisms, the viral
replication takes place in the host cell and therefore, many cells are
affected or damaged during this process.”
17. Transdermal drug delivery has the advantage of
c. increased bioavailability.
“Transdermal drug delivery otherwise known as topical drug delivery
system involves the administration of drugs through the skin. The method
has several advantages when compared with conventional methods. It
increases bioavailability of drugs by preventing early liver metabolism,
painless, improve patient compliance, curtail use of hypodermic
injections, non-invasive and can be self-administered.”
18. ______________ may play major role to overcome ocular barriers to
antiviral agents.
d. Efflux and influx transporters
“Transporters are protein attached to the cell membrane, which is
involved in the regulation of active transport of nutrient in the cell. These
transporters bind and transport specific ligands in the drug compounds. In
ocular drug delivery, efflux and influx transporters play major role in the
system.”
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19. The use of ______________ techniques for ophthalmic drug delivery
has been adopted for treatment of eye infections.
d. ultrasound and ionotropic
“The use of ultrasound and ionotropic technique for ophthalmic drug
delivery has been adopted enhanced treatment of eye infections, with
further prospects in viral treatment.”
20. True or False: The presence of mixed variants of a virus in a patient
is called viral quasispecies.
a. True
“The presence of mixed variants of a virus in a patient is called viral
quasispecies, the population of which is represented by the ‘fittest virus.’”
21. When treating Hepatitis C virus (HCV) with the antiviral agent
interferon,
d. interferon is often withdrawn due to HCV resistance to the drug.
“Interferon is an antiviral agent used for treatment of several viral
infections including HCV. However, interferon administration is sometimes
less effective and often withdrawn due to side effects and HCV resistance
to the drug.”
22. True or False: Host Interferon resistance is predictable and easier to
understand compared to other antiviral agents.
d. False
“Interferon resistance is difficult to predict and understand compared to
other antiviral agents, occurrence of which depends on the change or
mutation in the specific amino acid residue in the HCV core protein.”
23. Mutation of ______________ often results in the resistance pattern
observed commonly among the HBV-resistant drugs.
c. DNA polymerase enzymes
“Most Hepatitis B virus (HBV) drugs target DNA polymerase enzymes,
which are very important in the viral replication. Mutation of this enzyme
often results in the resistance pattern observed commonly among the
HBV-resistant drugs.”
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24. Herpes virus drug resistance is
a. rare in healthy adults.
“Herpes virus drug resistance is rare in healthy adults.”
25. Influenza virus resistance to oseltamivir and zanamivir has been
reported, possibly due to
c. a mutation of specific enzymes involved in viral attachment to the host
cell.
“Influenza virus resistance to oseltamivir and zanamivir has been
reported. This may be due to a mutation on the hemagglutinin
glycoprotein on the virus cell membrane or specific enzymes involved in
the viral attachment to the host cell.”
26. Cytomegalovirus (CMV) drug resistance is mostly due
a. to point mutation of the thymidine kinase gene.
“Cytomegalovirus (CMV) drug resistance, particularly with gancicylovir
has been extensively studied.149 Most of the drug resistant mechanism
observed in the virus is due to point mutation at different parts of the
thymidine kinase gene resulting in the impairment in the activity of the
enzymes. Mutations in the viral DNA polymerase also confer resistance to
drugs such as Foscarnet, gancicyclovir, and cidofuvir.”
27. Viral resistance is broadly investigated by
b. phenotypic and genotypic assay.
“Viral resistance is investigated by phenotypic and genotypic assay.”
28. Various techniques used in phenotypic assay include
b. high-performance liquid chromatography (HPLC).
“Phenotypic assay involves an in vitro susceptibility testing of an antiviral
agent caused by known or unknown viral mutations and associated
interaction.… Various techniques used in this assay include, cell culture,
fluorometry, high-performance liquid chromatography (HPLC), etc.”
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29. ______________ investigates mutations in the viral genome.
d. Genotypic assay
“Genotypic assay investigates mutations in the viral genome that are
related to reduced drug susceptibility to antiviral drug.”
30. True or False: Phenotypic assay involves an in vitro susceptibility
testing of antiviral agents.
a. True
“Phenotypic assay involves an in vitro susceptibility testing of an antiviral
agent caused by known or unknown viral mutations and associated
interaction.”
31. _______________ is effective in testing viruses that can be grown
or cultured in the laboratory.
c. Phenotypic assay
“This method is effective in testing viruses that can be grown or cultured
in the laboratory.”
32. How are protozoa infections classified?
d. By means of infection, e.g., sexual transmission, insect bites.
“Protozoa infections are classified according to the means of infection,
enteric (Balantidium, Giardia, Entamoeba, Cryptosporidium, Toxoplasma,
Cyclospora, Microsporidia), sexual (Trichomonas), arthropod (Babesia,
Plasmodium, Leishmania, Trypanosoma), or others (Naegleria,
Acanthamoeba, Toxoplasma).”
33. __________ is the most prevalent systemic protozoan infection.
d. Malaria
“Malaria is the most prevalent systemic protozoan infection, infecting 300
million people annually and killing approximately one million of those.”
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34. What disease is caused by Trypanosoma brucei?
c. Sleeping sickness
“Human African trypanosomiasis, or sleeping sickness, is also caused by a
protozoan, Trypanosoma brucei.”
35. ___________________, caused by a protozoan parasite, is more
dangerous in pregnant women, causing congenital defects or
miscarriage.
b. Toxoplasmosis
“Toxoplasmosis is caused by Toxoplasma gondii, a protozoan parasite and
infects 95% of the human population in some areas…. In pregnancy
toxoplasmosis is more dangerous, affecting 200,000 women annually, and
causing congenital defects or miscarriage.”
36. What is the most common transmission route for Giardia lamblia?
a. contaminated water
“Giardia lamblia causes a zoonotic disease known as giardiasis, and is the
most common intestinal parasitic infection, causing symptoms yearly in
around 280 million people. The most common transmission route is the
consumption of contaminated water….”
37. ___________ is most common in tropical regions and infected
individuals usually do not develop symptoms.
a. Amebiasis
“Amebiasis is most common in tropical regions and usually infected
individuals do not develop symptoms.”
38. True or False: Most pathogenic amoebic agents often cause infection
in humans.
b. False
“Most pathogenic amoebic agents rarely cause infection in humans and
are ubiquitous in the environment worldwide, found in soil and fresh
water.”
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39. The following is true of Cryptosporidiosis:
a.
b.
c.
d.
In healthy patients, it usually only causes diarrhea.
In immunocompromised patients, the diarrhea can be fatal.
It can be found worldwide.
All of the above [correct answer]
“Cryptosporidiosis is caused by the protozoan parasites Cryptosporidium
parvumand Cryptosporidium hominis that can be found worldwide. In
immunocompetent hosts it is usually a self-limited disease causing only
diarrhea. In immunocompromised patients the diarrhea is particularly
severe and can be fatal.”
40. Naegleria fowleri is the causative agent of primary amebic
meningoencephalitis,
a. which is a rare and fatal condition.
“Naegleria fowleri is the causative agent of primary amebic
meningoencephalitis, which is a rare and fatal condition.”
41. Cestodes are __________ that cause disease in the gastrointestinal
lumen.
c. tapeworms
“Cestodes are tapeworms that cause disease in the gastrointestinal
lumen.”
42. Diphyllobothriumlatum infection can result in diarrhea, weakness,
and dizziness
c. after eating raw or undercooked fish.
“Diphyllobothriumlatum infection can result in diarrhea, weakness, and
dizziness after eating raw or undercooked fish due to decreased vitamin
B12 absorption.”
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43. ________________________ is less common and also characterized
by the formation of cysts in the liver.
d. Echinococcusmultilocularis
“Infection with Echinococcusmultilocularis is less common and also
characterized by formation of cysts in the liver.”
44. Trematode infections
a. cause schistosomiasis, which affects 200 million people globally.
“Trematode infections cause clinical infections in humans and occur
worldwide. The most prevalent trematode infection is schistosomiasis that
affects 200 million people globally.”
45. In children, ____________________ can cause growth retardation
and anemia.
b. schistosomiasis
“In children, [schistosomiasis] can cause growth retardation and anemia.”
46. Paragonimiasis affects mainly the
c. lungs causing chest pain, eosinophilia, fever, and cough.
“Paragonimiasis is caused by Paragonimuswestermani in East and
Southeast Asia. It affects mainly the lungs causing chest pain,
eosinophilia, fever, and cough. Infection is caused by eating undercooked
crayfish or crabs.”
47. Once a parasite finds a home inside a human host,
d. it can go undetected for life.
“The life of the parasite inside the human host can go undetected for life
or cause immediately dangerous symptoms that jeopardize the host’s
health.”
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48. The parasitic diseases found in tropical or subtropical regions
a.
b.
c.
d.
are “neglected tropical diseases” since they are largely overlooked.
are given little attention or research for new medications.
include malaria, which kills 660,000 people annually.
All of the above [correct answer]
“The parasitic diseases found in these temperate climates are termed
neglected tropical diseases since they are largely overlooked and little
attention is given to their treatment or to the research of new
medications. Of these diseases the most deadly worldwide is malaria that
causes around 660,000 deaths per year, having the highest incidence in
sub-Saharan Africa.”
49. Intravenous therapy is usually applied in situations
a. where an organ such as the brain is infected.
“Intravenous therapy is usually applied in situations where severe disease
is caused by systemic infection or if it affects certain organs such as the
brain.”
50. True or False: Neglected tropical diseases infect an estimated one
billion people taking a huge toll in endemic areas especially in
children.
a. True
“Neglected tropical diseases infect an estimated one billion people taking
a huge toll in endemic areas especially in children.”
51. Most intestinal parasites are treated with luminal agents
b. that are not easily absorbed.
“Most intestinal parasites are treated with luminal agents that are not
easily absorbed and therefore can act better in killing the parasites inside
the intestine.”
52. _____________ may only be administered after food intake to
ensure optimal absorption of the drug from the bloodstream.
b. Itraconazole
“Itraconazole, on the other hand, may only be administered after food
intake to ensure optimal absorption of the drug from the bloodstream.”
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53. For intestinal nematodes causing ascariasis a single oral dose of
______________ is usually effective.
a.
b.
c.
d.
Mebendazole
Albendazole
Ivermectin
All of the above [correct answer]
“For intestinal nematodes causing ascariasis a single oral dose of
Mebendazole, Albendazole or Ivermectin is usually effective.”
54. One of the primary adverse effects of amphotericin B is
c. the development of nephrotoxicity.
“One of the primary adverse effects amphotericin B is well-known for is
the development of nephrotoxicity among patients taking the drug.”
55. _____________ is the only group of antifungals that targets the
fungal cell wall directly.
a. Echinocandins
“Echinocandins, another group of antifungals, have a different mechanism
of action as compared with others. In fact, the drug is the only group that
targets the fungal cell wall directly.”
56. Among the orally administered antifungal agents, the most readily
absorbed in the bloodstream is
b. fluconazole.
“Among the orally administered antifungal agents, the most readily
absorbed in the bloodstream is fluconazole.”
57. The following is/are true of the structure of the fungal cell:
b. the fungal cell wall has stark similarities with most mammalian cells.
“The manner in which antifungal medications work is based primarily on
the structure of the fungal cell. It has been established in the previous
sections that the cell membrane of the fungal cell is different from most
common infectious organisms. In fact the fungal cell wall has stark
similarities with most mammalian cells, making it susceptible to less
pathogens than other cells.”
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58. True or False: Antifungal medications can be responsible for altering
the efficacy and safety of other drugs.
a. True
“Antifungal medications can be responsible for altering the efficacy and
safety of other drugs, and they do this through several possible
processes.”
59. Agents used to treat fungal infections of the central nervous system
are not effective because
c. most agents cannot successfully cross the blood-brain barrier.
“In terms of the site of administration, it is worth to note that most fungal
infections affecting the central nervous system (“CNS”) are linked with
alarmingly high rates of mortality and morbidity. This is because most of
these infections of the CNS spread faster than others and most agents
used to treat CNS infections cannot successfully cross the blood-brain
barrier.”
60. In the prescription of antifungal agents, it is important to also
consider
a.
b.
c.
d.
the condition of the host.
the interaction of the human host with the fungal agent.
the human host and the host’s environment.
All of the above [correct answer]
“In the prescription of antifungal agents, it is important to also consider
how to best optimize its prescription in treating the pathogenic fungal
infection of the patient. Moreover, other factors such as the host, and the
interaction of the human host with the fungal agent and the environment
work to cause the infection and affect the action of the medications
prescribed for these patients.”
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