pharmacological approaches to treat viral, …focus in terms of the general principles that...

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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. to be selectively toxic against the virus. b. to overcome the viral resistance strategy. c. to be effective against replicating and latent viruses. d. 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. Salk polio vaccine b. Oral polio vaccine c. Zidovudine d. Azidothymidine

5. Complications such as arthritis and arthralgia are reported among

women after vaccination with

a. live-attenuated measles vaccine. b. killed measles vaccine. c. rubella vaccine. d. 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 gp41-

mediated 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 re-

emerging 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 recombinant-

adenovirus 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 recombinant-

poxvirus 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.


25

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.


26

• 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


27

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


28

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.


29

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


30

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


31

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).


32

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.


33

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


34

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,


35

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


36

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.


37

Babesia is another protozoan parasite that infects humans, particularly the

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.


38

In immunocompromised patients the diarrhea is particularly severe and can be

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


39

route is consumption of undercooked beef and presents with abdominal cramps

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


40

disease, genitourinary disease or Katayama fever. These conditions are

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 extra-

intestinal. Intestinal nematodes are soil-transmitted helminthes and include

Ascarislumbricoides, Ancylostomaduodenale, Trichuristrichiura, and

Necatoramericanus. These nematodes infect each an estimated number of 1


41

billion people, especially in tropical areas with poor sanitation. The adult worms

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


42

volvulus infection. The infection vector is Simulium blackflies present in equatorial

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


43

taking a huge toll in endemic areas especially in children. Hence, it is essential to

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. Anti-

parasitic 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


44

whipworms. These intestinal nematodes cause the diseases, ascariasis, filariasis,

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


45

paralysis of peripheral musculature and is ineffective in cestodes and trematodes.

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.


46

The drugs used to treat cestode infections can have several mechanisms of

action, such as, binding to tubulin acting of the GABA receptor or Glutamate-

gated 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,


47

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


48

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.


49

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 vision-

threatening 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.


50

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, high-

frequency 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, atovaquone-

proguanil, 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


51

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


52

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


53

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


54

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


55

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


56

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

anti-parasitic 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,


57

drops and liquid medications or syrups. Therefore, before prescribing or

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 (6-

7 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 atovaquone-

proguanil 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


58

medications mentioned below the following oral drugs can be used, miltefosine

(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


59

combined administration of metronidazole (400 mg three times a day for 10

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


60

appropriate in some cases since it can achieve high concentrations at the site of

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


61

liver by the cytochrome P450 system.

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.


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Antifungal Agents

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


63

removing them from the skin.

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


64

most infectious agents. This nature and characteristic of fungi make it more

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


65

cells to leak outside. This leakage then disables the cell to carry out its normal

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.


66

During administration, especially via the intravenous route, patients are reported

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


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efficacy in treating stubborn and recurrent fungal infections. These substances

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


68

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


69

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


70

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 5-

fluouracil. 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


73

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


74

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.


75

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


76

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


77

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


78

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.


79

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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85


a. to be selectively toxic against the virus. b. to overcome the viral resistance strategy. c. to be effective against replicating and latent viruses. d. All of the above



a. True b. False


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. Salk polio vaccine b. Oral polio vaccine c. Zidovudine d. Azidothymidine

5. Complications such as arthritis and arthralgia are reported among

women after vaccination with

a. live-attenuated measles vaccine. b. killed measles vaccine. c. rubella vaccine. d. the 17D vaccine.

6. Maraviroc, an allosteic inhibitor,

a. augments the host immune system. b. interferes with HIV-I attachment with CCR5 chemokine receptor. c. modifies the host immune system. d. is contraindicated for HIV-I infection.


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7. The ___________ vaccine is effective, safe and available for preventing rabies infection.

a. tissue culture b. duck embryo c. nervous tissue d. simple

8. A live-attenuated varicella-zoster virus (VZV) vaccine has proven

effective

a. only as a prophylactic agent. b. but may not be administered to immunosuppressed patients. c. after infection but not as a prophylactic agent. d. when administered to children, elderly and immunosuppressed patients.

9. Many factors hinder the development of antiviral drugs, including

a. viral resistance. b. reduced efficacy. c. bioavailability of the drugs due to shelf life of its compounds. d. 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. Genotypic assay b. Polymerase chain reaction (PCR) c. Phenotypic assay d. 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. Proteomics b. Genomics c. Phenotypic assay d. Bioinformatics


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13. An important tool is X-ray crystallography for antiviral compound development because

a. it provides a three-dimensional analysis of a drug target. b. it manipulates the compound chemically. c. it identifies various genetic products of a virus. d. it analyzes the impact of biochemical processes.

14. The efficacy of antiviral agents depends largely on

a. systemic drug absorption and reaching the target site. b. the cytopathic effect (CPE) of the virus. c. reduced bioavailability of the drug. d. low solubility of the agent.

15. Oral administration of antiviral agents such as ritonavir, penciclovir,

and acyclovir are formulated

a. for poor absorption in the gastrointestinal tract. b. to have a short half-life. c. to reach peak serum concentration within hours. d. 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. ocular bioavailability. b. low solubility of the agent. c. increased bioavailability. d. being impermeable.

18. ______________ may play major role to overcome ocular barriers to

antiviral agents.

a. Liposomes b. Iontophoresis c. Microemulsion d. 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. microemulsion b. ethosomes c. microsphere system d. 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. amino acid residue changes do not impact the drug’s efficacy. b. interferon is predictably effective in treating HCV. c. interferon remains effective even when HCV mutates. d. 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. protease genes b. wild-type strains of HBV c. DNA polymerase enzymes d. the RNA of the M2 ion channel

24. Herpes virus drug resistance is

a. rare in healthy adults. b. common for even healthy adults. c. below 8% even with immunosuppressed patients. d. 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. to point mutation of the thymidine kinase gene. b. to reverse mutation. c. to increased bioavailability. d. to viral attachment to the host cell.

27. Viral resistance is broadly investigated by

a. phenotypic assay. b. phenotypic and genotypic assay. c. genotypic assay. d. None of the above

28. Various techniques used in phenotypic assay include

a. real time polymerase chain reaction (PCR). b. high-performance liquid chromatography (HPLC). c. gene sequencing. d. microarray.

29. ______________ investigates mutations in the viral genome.

a. High-performance liquid chromatography b. Cell culture c. Fluorometry d. 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. Genotypic assay b. Gene sequencing c. Phenotypic assay d. Microarray

32. How are protozoa infections classified?

a. By disease symptoms. b. By parasitic species. c. By global region. d. By means of infection, e.g., sexual transmission, insect bites.

33. __________ is the most prevalent systemic protozoan infection.

a. Amoebiasis b. Sleeping Sickness c. Chagas disease d. Malaria

34. What disease is caused by Trypanosoma brucei?

a. American trypanosomiasis b. Leishmania c. Sleeping sickness d. Leishmania tropica

35. ___________________, caused by a protozoan parasite, is more

dangerous in pregnant women, causing congenital defects or miscarriage.

a. Cytomegalovirus b. Toxoplasmosis c. Giardiasis d. Hemolytic anemia

36. What is the most common transmission route for Giardia lamblia?

a. contaminated water b. tick bites c. sandflies d. mosquitos


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37. ___________ is most common in tropical regions and infected individuals usually do not develop symptoms.

a. Amebiasis b. Giardiasis c. Cytomegalovirus d. 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. In healthy patients, it usually only causes diarrhea. b. In immunocompromised patients, the diarrhea can be fatal. c. It can be found worldwide. d. All of the above

40. Naegleria fowleri is the causative agent of primary amebic

meningoencephalitis,

a. which is a rare and fatal condition. b. transmitted by vegetables contaminated with the protozoan. c. transmitted by infected fowl. d. which is usually asymptomatic.

41. Cestodes are __________ that cause disease in the gastrointestinal

lumen.

a. nematodes b. amoebic agents c. tapeworms d. ticks

42. Diphyllobothriumlatum infection can result in diarrhea, weakness,

and dizziness

a. after drinking contaminated water. b. after eating raw or undercooked pork. c. after eating raw or undercooked fish. d. transmitted by contaminated vegetables.


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43. ________________________ is less common and also characterized by the formation of cysts in the liver.

a. Echinococcusspecies b. Echinococcusgranulosus c. Diphyllobothriumlatum d. Echinococcusmultilocularis

44. Trematode infections

a. cause schistosomiasis, which affects 200 million people globally. b. are specific to Asia and Africa. c. cause clinical infections in livestock only. d. are contracted through tainted pork.

45. In children, ____________________ can cause growth retardation

and anemia.

a. echinococcosis b. schistosomiasis c. echinococcusmultilocularis d. diphyllobothriumlatum

46. Paragonimiasis affects mainly the

a. gastrointestinal tract causing cramping and diarrhea. b. gastrointestinal tract causing mostly asymptomatic infection. c. lungs causing chest pain, eosinophilia, fever, and cough. d. gastrointestinal lumen.

47. Once a parasite finds a home inside a human host,

a. the patient will be asymptomatic during the parasite’s life cycle. b. the patient will experience nausea, cramping, and vomiting. c. the patient will show symptoms immediately. d. it can go undetected for life.

48. The parasitic diseases found in tropical or subtropical regions

a. are “neglected tropical diseases” since they are largely overlooked. b. are given little attention or research for new medications. c. include malaria, which kills 660,000 people annually. d. All of the above


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49. Intravenous therapy is usually applied in situations

a. where an organ such as the brain is infected. b. where mild disease is caused by infection. c. where the parasite is undetected in the host. d. where 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. that are easily absorbed. b. that are not easily absorbed. c. that most parasites cannot acquire resistance to. d. None of the above

52. _____________ may only be administered after food intake to

ensure optimal absorption of the drug from the bloodstream.

a. Voriconazole b. Itraconazole c. Posaconazole d. Terbinafine

53. For intestinal nematodes causing ascariasis a single oral dose of

______________ is usually effective.

a. Mebendazole b. Albendazole c. Ivermectin d. All of the above

54. One of the primary adverse effects of amphotericin B is

a. Heptotoxicity. b. irreversible amenia. c. the development of nephrotoxicity. d. phototoxicity.


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55. _____________ is the only group of antifungals that targets the fungal cell wall directly.

a. Echinocandins b. Allylamines c. The azole group d. Triazoles

56. Among the orally administered antifungal agents, the most readily

absorbed in the bloodstream is

a. itraconazole. b. fluconazole. c. voriconazole. d. posaconazole.

57. The following is/are true of the structure of the fungal cell:

a. the fungal cell is similar to most common infectious organisms. b. the fungal cell wall has stark similarities with most mammalian cells. c. the fungal cell susceptible to more pathogens than other cells. d. 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. infections of the CNS spread slower than others. b. these agents have large, relative molecular size. c. most agents cannot successfully cross the blood-brain barrier. d. the agents are unable to detect the fungal infection.

60. In the prescription of antifungal agents, it is important to also

consider

a. the condition of the host. b. the interaction of the human host with the fungal agent. c. the human host and the host’s environment. d. All of the above


95

CORRECT ANSWERS:


a. to be selectively toxic against the virus. b. to overcome the viral resistance strategy. c. to be effective against replicating and latent viruses. d. 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.”



a. True “Ordinarily, antiviral agents should be effective for latent and replicating virus; however, most antiviral agents available are only effective against replicating viruses.”


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 vaccine-induced infection. It is not recommended for immunosuppressed patients.”


96

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. viral resistance. b. reduced efficacy. c. bioavailability of the drugs due to shelf life of its compounds. d. 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.”


103

39. The following is true of Cryptosporidiosis:

a. In healthy patients, it usually only causes diarrhea. b. In immunocompromised patients, the diarrhea can be fatal. c. It can be found worldwide. d. 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. are “neglected tropical diseases” since they are largely overlooked. b. are given little attention or research for new medications. c. include malaria, which kills 660,000 people annually. d. 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. Mebendazole b. Albendazole c. Ivermectin d. 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. the condition of the host. b. the interaction of the human host with the fungal agent. c. the human host and the host’s environment. d. 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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References Section

The reference section of in-text citations include published works intended as helpful material for additional reading. 1. Alberts B, Johnson A, Lewis J, et al. New York, Molecular Biology of the Cell,

4th edition, Garland Science; 2002. 2. Liise-anne Pirofski and Arturo Casadevall. BMC Biology 2012, 10:6

http://www.biomedcentral.com/1741-7007/10/6 3. Nikolaos, I, et al (2010). Dynamics of infectious disease transmission by

inhalable respiratory droplets. J R Soc Interface. 2010 Se 6:7(50):1355-1366.

4. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cho H, Uehara T, Bernhardt TG.Cell. 2014 Dec 4;159(6):1300-11.

5. Antibiotics that target protein synthesis. McCoy LS, Xie Y, Tor Y.Wiley Interdiscip Rev RNA. 2011 Mar-Apr;2(2):209-32.

6. Prospective multicentre feasibility study of a quality of care indicator for intravenous to oral switch therapy with highly bioavailable antibiotics. Buyle FM, Metz-Gercek S, et al. Antibiotic Strategy International-ABS Quality Indicators Team.J Antimicrob Chemother. 2012 Aug;67(8):2043-6.

7. Antibiotic dosing in cirrhosis. Halilovic J, Heintz BH.Am J Health Syst Pharm. 2014 Oct 1;71(19): 1621-34. Review.

8. β-lactam antibiotic concentrations during continuous renal replacement therapy. Beumier M, Casu GS, et al. Crit Care. 2014 May 22; 18(3): R105.

9. Catheter-related Corynebacterium bacteremia: should the catheter be removed and vancomycin administered? Ghide S, Jiang Y, et al. Eur J Clin Microbiol Infect Dis. 2010 Feb;29(2):153-6. Epub 2009 Dec 17.

10. Metronidazole treatment for acute phase amoebic liver abscess in patients co-infected with HIV. Ohnishi K, Uchiyama-Nakamura F. Int J STD AIDS. 2012 Aug; 23(8): e1-3.

11. Combined preoperative mechanical bowel preparation with oral antibiotics significantly reduces surgical site infection, anastomotic leak, and ileus after colorectal surgery. Kiran RP, Murray AC, et al. Surg. 2015 Sep; 262(3): 416-25; discussion 423-5.

12. The role of microbiological monitoring and drug history in the effectiveness of antibiotic prophylaxis and antibiotic treatment of infectious complications after reconstructive surgeries. Bogomolova ns, Kuznetsova sm, et al. 2015 mar-apr; 60(2): 20-6.

13. Surbhi Leekha, Christine L. Terrell, Randall S. Edson. General Principles of Antimicrobial Therapy, Mayo Clin Proc. 2011 Feb; 86(2): 156–167

14. Jacquolyn G. Black, Microbiology Principles and Exploration 4/E. http://www.srspharma.com/narrow-spectrum-antibiotics.htm

15. Verstraeten N, Knapen W, Fauvart M, Michiels J. A Historical Perspective on Bacterial Persistence. Methods Mol Biol. 2016;1333:3-13.


109

16. Cho H, Uehara T, Bernhardt TG. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell. 2014 Dec 4;159(6):1300-11.

17. Badari MS, Elgendy SG, Mohamed AS, Hassan AT. Immunomodulatory Effects of Levofloxacin on Patients with Pneumonia in Assiut University Hospitals. Egypt J Immunol. 2015; 22(1):79-85.

18. Breilh D, Texier-Maugein J, Allaouchiche B, Saux MC, Boselli E. Carbapenems. J Chemother. 2013 Feb;25(1):1-17.

19. van Zuuren EJ, Fedorowicz Z. Interventions for rosacea: abridged updated Cochrane systematic review including GRADE assessments. Br J Dermatol. 2015 Sep;173(3):651-62. Epub 2015 Aug 30. Review.

20. Schifano JM, Edifor R, Sharp JD; et al. Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site. Proceedings of the National Academy of Sciences of the United States of America.2013 May; 110: 8501–6.

21. Susan M. Turley. Fourth edition, chapter 4. Routes of administration and the drug cycle. Understanding pharmacology for health professionals. Page 47-63. 2010. Pearson Education, Inc. http://www.boomer.org/c/p4/c07/c07.pdf, 2015

22. Aschenbrenner Diane S., Venable Samantha J. Drug Administration. Drug Therapy in Nursing. 209, 29- 30. http://study.com/academy/lesson/routes-of-drug-administration-oral-topical-inhalation-injection.html, 2015

23. http://textbookofbacteriology.net/antimicrobial.html, 2015 24. http://www.nhs.uk/conditions/Antibiotics-

penicillins/Pages/Introduction.aspx, 2015 25. Gonzalez-Estrada, A; Radojicic, C (May 2015). Penicillin allergy: A practical

guide for clinicians. Cleveland Clinic journal of medicine 82 (5): 295–300. 26. Prayle A1, Watson A, Fortnum H, Smyth A. Side effects of aminoglycosides

on the kidney, ear and balance in cystic fibrosis. Thorax. 2010 Jul;65(7):654-8.

27. Torres MJ, Blanca M (2010). "The complex clinical picture of beta-lactam hypersensitivity: penicillins, cephalosporins, monobactams, carbapenems, and clavams". Med. Clin. North Am. 94 (4): 805–20, xii.

28. Slimings C, Riley TV (2014). "Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis". J. Antimicrob. Chemother. 69(4): 881–91.

29. Qiuxang T, Ya Z, Jian L et al. Structure of the CCR5 chemokine receptor-HIV entry inhibitor Maraviroc complex. Science, 2013; 341:6152.

30. Evelien V, Fusun G, Zafer C et al. Novel inhibitors of influenza virus fusion-Activity relationship and interaction with viral hemaglutinin. J Virol. 2010; 84(9): 4277-4288.

31. Birkman A. Helicase-primase inhibitor pritelivir for HSV-2 infection. New England journal of Medicine. 2014; 370: 201-210.

32. Christiane MH, Augustine G, Sheik HK et al. Ribavirin for Lassa fever postexposure prophylaxis. Emerg Infect Dis. 2010; 16(12): 2009-2011.

33. Chono K, Katsumata K, Suzuki H, Shiraki K et al. Synergistic activity of


110

amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2013; 97: 154–160.

34. World Health Organization. WHO removes Nigeria from polio endemic list. Press release. September 2015.

35. Stéphane V, Mira J, Shaun K. et al. Controlling measles using supplemental immunization activities: A mathematical model to inform optimal policy. Vaccine. 2015; 33(10): 1291–1296.

36. Betáková T, Švancarová P. Role and application of RNA interference in replication of influenza viruses. ActaVirologica. 2013; 57(2): 97–104.

37. Motavaf M, Safari S, Alavian SM. Therapeutic potential of RNA interference: a new molecular approach to antiviral treatment for hepatitis C. Journal of Viral Hepatitis. 2012; 19(11):757–765.

38. Deshpande PB, Dandagi P, Udupa N, Goal SV, Jain SS, Vasanth SG. Controlled release polymeric ocular delivery of acyclovir. Pharm Dev Technol. 2010; 15:369–78.

39. Boom-joon K. Hepatitis B mutation in relation to liver disease progression of Korean patient. World J Gastroenterol, 2014; 20(2) 460-467.

40. Perales C, Beach NM, Sheldon J, Domingo E: Molecular basis of interferon resistance in hepatitis C virus. CurrOpinVirol. 2014, 8:38-44.

41. Gotte M: Resistance to nucleotide analogue inhibitors of hepatitis C virus NS5B: Mechanisms and clinical relevance. Curr Opin Virol 2014, 8:104-108.

42. Kieffer TL, George S: Resistance to hepatitis C virus protease inhibitors. Curr Opin Virol. 2014, 8:16-21.

43. Vadlapudi, A.D., Vadlapatla, R.K., and Mitra, A.K. Current and emerging antivirals for the treatment of cytomegalovirus (CMV) retinitis: an update on recent patents. Recent Pat. Antiinfect. Drug Discov. 7:8–18, 2012.

44. Zachary, K. (2016). Pharmacology of antiviral drugs for influenza. UpToDate. Retrieved online at https://www.uptodate.com/contents/pharmacology-of-antiviral-drugs-for-influenza?source=search_result&search=antiviral%20agents&selectedTitle=5~150.

45. Horn D, Duraisingh MT. Antiparasitic chemotherapy – from genomes to mechanisms. Annu Rev Pharmacol Toxicol. 2014:71-94. doi:10.1146/annurev-pharmtox-011613-135915.

46. Who. WHO | Malaria. Available at: http://www.who.int/mediacentre/factsheets/fs094/en/index.html

47. Mugnier MR, Cross GAM, Papavasiliou FN. The in vivo dynamics of antigenic variation in Trypanosoma brucei. Science. 2015;347(6229):1470-1473. doi:10.1126/science.aaa4502.

48. Jones JL, Parise ME, Fiore AE. Neglected parasitic infections in the United States: toxoplasmosis. Am J Trop Med Hyg. 2014;90(5):794-799. doi:10.4269/ajtmh.13-0722.

49. Esch KJ, Petersen CA. Transmission and epidemiology of zoonotic protozoal diseases of companion animals. Clin Microbiol Rev. 2013;26(1):58-85. doi:10.1128/CMR.00067-12.


111

50. Dufour AC, Olivo-Marin J-C, Guillen N. Amoeboid movement in protozoan pathogens. Semin Cell Dev Biol. 2015. doi:10.1016/j.semcdb.2015.10.010.

51. Legua P, Seas C. Cystoisospora and cyclospora. Curr Opin Infect Dis. 2013;26(5):479-483. doi:10.1097/01.qco.0000433320.90241.60.

52. Grace E, Asbill S, Virga K. Naegleria fowleri: Pathogenesis, Diagnosis, and Treatment Options. Antimicrob Agents Chemother. 2015;59(11):6677-6681. doi:10.1128/AAC.01293-15.

53. Wang Y, Feng X, Jiang L. Current advances in diagnostic methods of Acanthamoeba keratitis. Chin Med J (Engl). 2014;127(17):3165-3170.

54. Lorenzo-Morales J, et al (2013). Is Balamuthia mandrillaris a public health concern worldwide? Trends Parasitol. 2013;29(10):483-488. doi:10.1016/j.pt.2013.07.009.

55. Silva C V, Costa-Cruz JM. A glance at Taenia saginata infection, diagnosis, vaccine, biological control and treatment. Infect Disord Drug Targets. 2010;10(5):313-321.

56. Thompson RCA. Neglected zoonotic helminths: Hymenolepis nana, Echinococcus canadensis and Ancylostoma ceylanicum. Clin Microbiol Infect. 2015;21(5):426-432. doi:10.1016/j.cmi.2015.01.004.

57. Hibberd, P., and Hirsch, M. (2016). Seasonal influenza vaccination in adults. UpToDate. Retrieved online at https://www.uptodate.com/contents/seasonal-influenza-vaccination-in-adults?source=search_result&search=influenza%20virus%20vaccine&selectedTitle=1~150

58. Monath, T. (2016). Yellow Fever, UpToDate. https://www.uptodate.com/contents/yellow-fever?source=search_result&search=yellow%20fever%20virus&selectedTitle=1~150.

59. Colley DG, Bustinduy AL, Secor WE, King CH. Human schistosomiasis. Lancet (London, England). 2014;383(9936):2253-2264. doi:10.1016/S0140-6736(13)61949-2.

60. Nyindo M, Lukambagire A-H. Fascioliasis: An Ongoing Zoonotic Trematode Infection. Biomed Res Int. 2015;2015:786195. doi:10.1155/2015/786195.

61. Petney TN, Andrews RH, Saijuntha W, Wenz-Mucke A, Sithithaworn P. The zoonotic, fish-borne liver flukes Clonorchis sinensis, Opisthorchis felineus and Opisthorchis viverrini. Int J Parasitol. 2013;43(12-13):1031-1046. doi:10.1016/j.ijpara.2013.07.007.

62. Blair D. Paragonimiasis. Adv Exp Med Biol. 2014;766:115-152. doi:10.1007/978-1-4939-0915-5_5.

63. Das AK. Hepatic and biliary ascariasis. J Glob Infect Dis. 2014;6(2):65-72. doi:10.4103/0974-777X.132042.

64. Vleeschouwers W, Hofman P, Gillardin JP, Meert V, Van Slycke S. Appendicitis-like clinical image elicited by Enterobius vermicularis: case report and review of the literature. Acta Chir Belg. 2013;113(2):139-142.

65. Toledo R, Munoz-Antoli C, Esteban J-G. Strongyloidiasis with emphasis on human infections and its different clinical forms. Adv Parasitol.


112

2015;88:165-241. doi:10.1016/bs.apar.2015.02.005. 66. Kappagoda S, Singh U, Blackburn BG. Antiparasitic therapy. Mayo Clin Proc.

2011;86(6):561-83. doi:10.4065/mcp.2011.0203. 67. Robertson AP, Buxton SK, Puttachary S, et al. Antinematodal Drugs – Modes

of Action and Resistance: And Worms Will Not Come to Thee (Shakespeare: Cymbeline: IV, ii). In: Parasitic Helminths. Wiley-VCH Verlag GmbH & Co. KGaA; 2012:233-249. doi:10.1002/9783527652969.ch14.

68. Bahmani M, Rafieian-Kopaei M, Hassanzadazar H, Saki K, Karamati SA, Delfan B. A review on most important herbal and synthetic antihelmintic drugs. Asian Pac J Trop Med. 2014;7S1:S29-33. doi:10.1016/S1995-7645(14)60200-5.

69. Brunetti E, Kern P, Vuitton DA. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop. 2010;114(1):1-16. doi:10.1016/j.actatropica.2009.11.001.

70. Martinez DY, Seas C, Bravo F, et al. Successful treatment of Balamuthia mandrillaris amoebic infection with extensive neurological and cutaneous involvement. Clin Infect Dis. 2010;51(2):e7-11. doi:10.1086/653609.

71. World Health Organization. Guidelines for the Treatment of Malaria. 2015, 3rd Ed Geneva. 2015.

72. Dondorp AM, Fanello CI, Hendriksen ICE, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet (London, England). 2010;376(9753):1647-1657. doi:10.1016/S0140-6736(10)61924-1.

73. Kennedy PG. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol. 2013;12(2):186-194. doi:10.1016/S1474-4422(12)70296-X.

74. Van Griensven J, Boelaert M. Combination therapy for visceral leishmaniasis. Lancet (London, England). 2011;377(9764):443-444. doi:10.1016/S0140-6736(10)62237-4.

75. Collinet-Adler S, Ward HD. Cryptosporidiosis: environmental, therapeutic, and preventive challenges. Eur J Clin Microbiol Infect Dis. 2010;29(8):927-935. doi:10.1007/s10096-010-0960-9.

76. Institute for Quality and Efficiency in Health Care. Using medication_ Oral medications. Natl Libr Med - PubMed Heal. 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072625/.

77. Hibberd, P. (2016). Immunizations in HIV-infected patients. UpToDate. Retrieved online at https://www.uptodate.com/contents/immunizations-in-hiv-infected-patients?source=search_result&search=HIV%20vaccine&selectedTitle=1~129.

78. Chandrasekar P, Management of invasive fungal infections: a role for polyenes, The journal of antimicrobial chemotherapy, 2011 Mar;66(3):457-65. doi: 10.1093/jac/dkq479.

79. Loyes A, Thangaraj H, Easterbrook P, Ford N, Roy M, Chiller T, Govender N ... Bicanic T. (2013) Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect. Dis., 13(7),


113

pp. 629-637. 80. Cuenca-Estrella M, Verweij PE, Arendrup MC et al. ESCMID guideline for the

diagnosis and management of Candida diseases 2012: diagnostic procedures. ClinMicrobiol Infect 2012; 18 (Suppl 7): 9–18.

81. Alastruey-Izquierdo A, Mellado E, Pelaez T et al. Population-based survey of filamentous fungi and antifungal resistance in Spain (FILPOP Study). Antimicrob Agents Chemother 2013; 57: 3380–3387.

82. Jesús F. Aparicio, Eva G. Barreales, Tamara D. Payero, Cláudia M. Vicente, Antonio de Pedro, Javier Santos-Aberturas. (2015) Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation. Applied Microbiology and Biotechnology.

83. Rotta I, Sanchez A, Gonçalves PR, Otuki MF, Correr CJ. Efficacy and safety of topical antifungals in the treatment of dermatomycosis: a systematic review. Br J Dermatol. 2012; 166(5): 927–933

84. Jeans AR, Howard SJ, Al-Nakeeb Z Et al. Pharmacodynamics of voriconazole in a dynamic in vitro model of invasive pulmonary aspergillosis: implications for in vitro susceptibility breakpoints. J Infect Dis 2012; 206: 442–452.

85. Sanjay G. Revankar, Jack D. Sobel, Antifungal drugs, Merc’s manual (professional version), 2014.

86. Vale-Silva L, Ischer F, Leibundgut-Landmann S, Sanglard D. Gain-of-function mutations in PDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells. Infect Immun 2013; 81: 1709–1720.

87. Tang, M. M., Corti, M. A. M., Stirnimann, R., Pelivani, N., Yawalkar, N., Borradori, L. and Simon, Dec. 2012, Severe cutaneous allergic reactions following topical antifungal therapy. Contact Dermatitis, 68: 56–57. doi: 10.1111/j.1600-0536.2012.02151.x

88. Leroux-Roels, Geert, et al. (2011). Understanding Modern Vaccines: Perspectives in Vaccinology. Chapter 5: Science Direct. Elseviere; Volume 1, Issue 1. Retrieved online at http://www.sciencedirect.com/science/article/pii/S2210762211000064.

89. Modlin, J.F., et al. (2016). Poliovirus vaccination. UpToDate. Retrieved online at https://www.uptodate.com/contents/poliovirus-vaccination?source=search_result&search=oral%20polio%20vaccine&selectedTitle=5~87.

90. Sax, P. (2016). Clinical trials of HIV antiretroviral therapy: Integrase inhibitors. UpToDate. Retrieved online at https://www.uptodate.com/contents/clinical-trials-of-hiv-antiretroviral-therapy-integrase-inhibitors?source=search_result&search=wild-type&selectedTitle=2~7.

91. Kozal, M. (2016). Drug resistance testing in the clinical management of HIV infection. UpToDate. Retrieved online at https://www.uptodate.com/contents/drug-resistance-testing-in-the-clinical-management-of-hiv-infection?source=search_result&search=viral%20drug%20resistance&selectedTitle=2~150.


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