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Home , Amenamevir, Dichlorophen, Flubendazole, Nitroscanate, Nucleic acid inhibitor, Oxibendazole

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 therapy with a focus on general issues affecting selection, the types of pathogens and diseases treated, and on specific ’ indication, administration and potential adverse effects. Antibiotic misuse and resistance is discussed.

1 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

2 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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 -induced .

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.

4 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com Introduction

More recently, the development of new chemotherapeutic agents and has assisted in proper management of certain diseases. A potent antiviral, and 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 . 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.

5 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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), 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

6 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com • 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., in the treatment of both CMV and HIV infection and , which is effective against HBV and HIV treatment).

7 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

8 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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. acts on HSV-2 by inhibiting the helicase-primase enzyme.

Thymidine Analogue

Idoxuridine is effective against VZV, HSV and 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

9 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 . It is active against idoxuridine-resistant herpesvirus. Other nucleoside analogues are and trifluorothmidine.

Anti-HIV Drug

Azidothymidine or Zidovudine ( 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 phosphorylated by cellular enzyme. It has similar mechanism of action as Zidovudine.

Didanosine ( 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.

10 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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. 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 inhibitors of HBV include zalcitabine, emtricitabine lamivudine, abacavir and .

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.

11 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 can be synthesized.

12 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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, failure or hepatocellular carcinoma. The pegylated forms can be used in combination therapy with 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. 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 13 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 14 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

15 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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:

16 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 17 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

18 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com The nervous tissue vaccine or simple vaccine, is prepared in the brain of sheep or goats, and inactivated with . 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 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

19 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

20 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com Approaches To New 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 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

21 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

22 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 23 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

24 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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, , , lamivudine and • Oral anti-HIV drugs are zalcitabine, stavudine, abacavir, emtricitabine, efavirence, and tenofovir.

25 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com • 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 and by being painless, improving patient compliance, and curtailing use of hypodermic

26 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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, , 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 27 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

28 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 29 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

30 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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).

31 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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. 32 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 33 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 with and .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, 34 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 . Or it can present as severe malaria with parasitemia greater than 5%, leading to intolerance of oral , respiratory, renal failure, distress, altered mental status or , 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 35 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com hepatosplenomegaly, lymphadenopathy, fever and rash. With the progression of disease the pathology is characterized by chronic meningoencephalitis with listlessness, , 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.

36 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 , 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.

37 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 . 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, , 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 38 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 in which larval cysts infect subcutaneous tissue or . It is usually asymptomatic, but it can affect the central 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 after eating raw or undercooked fish due to decreased B12 absorption.

Echinococcusspecies, Echinococcusgranulosus and Echinococcusmultilocularis are the causative agents of cystic and alveolar , 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

39 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com disease, genitourinary disease or Katayama fever. These conditions are characterized by fever, cough, hematuria, myalgia, abdominal pain, , and hepato-splenomegaly. In children, it can cause growth retardation and anemia. 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 and 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 . 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 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

40 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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, , 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 41 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 , 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 42 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 . 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 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

43 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com whipworms. These intestinal nematodes cause the diseases, ascariasis, filariasis, disease and trichuriasis.

Antinematodal drugs include , imidazothiazoles and tetrahydropyrimidines, and pro-, macrocyclic lactones, organophosphorus compounds and . and pyrantelpamoateare used for most nematode infections, while thiabendazole, and 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, , mebendazole, , and ), 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 ( 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 ( and ), γ-aminobutyric acid agonists (piperazine), and potassium channel activators ().

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 44 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 .

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, 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 ( 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. 45 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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, , 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,

46 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com Africa, and the Middle East. Trematodes can be divided in two groups depending on the system they infect, blood flukes including , 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 that inhibits microtubule formation, or alternatively . 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, , 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 47 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 drugs ( and ) 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 . 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, , 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. 48 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com The adverse effects include high fever, , 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, , 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.

49 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com For uncomplicated P. Falciparum malaria treatment, 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, -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 50 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

51 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 compounds. Visceral leishmaniasis is 52 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 53 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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- 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 . 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 54 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 . 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 55 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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. 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, 56 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

57 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 58 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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 59 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 60 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com liver by the 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.

61 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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 62 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 63 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 , triazole and ), 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 64 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

65 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

66 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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

67 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 directly attacks the cell membrane of the fungus and destroys them. It shows the 68 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 drugs in terms of formulation. These medications are usually a result of incorporating several substances with fluoride, and an analog of . These

69 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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 70 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 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 71 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

72 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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 of antifungal agents and its interactions with its host has also been correlated with the potential for toxicities. A few compounds have been

73 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com named to be responsible for this. For example, flucytosine and increased serum concentrations of this drug have been linked to 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. 74 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

75 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

76 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

77 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

78 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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. 79 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

80 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com blockers and known to interact with the medicines such as cyclosporine, warfarin kind of oral , tacrolimus, , , some sulfonylurea drugs such as tolbutamide and zidovudine. Rifampin can lower the fluconazole blood levels.

Some medicines such as rifampin, phenytoin, rifabutin, didanosine and 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 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

81 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

82 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com (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.

83 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement.

84 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

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.

85 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

86 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

87 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

88 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

89 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

90 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

91 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

92 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.

93 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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

94 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com CORRECT ANSWERS:

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 [correct answer]

“The efficacy of an antiviral agent depends on the ability to be selectively toxic against the virus, and overcome the viral resistance strategy…. A potent antiviral agent should be effective against both replicating and latent viruses.”

2. True or False: Most antiviral agents available are only effective against replicating viruses.

a. True

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

3. Anti-viral agents, known as immunomodulating agents,

c. augment or modify the host immune system to eradicate the infecting virus.

“Immunomodulating agents - augment or modify the host immune system to eradicate the infecting virus.”

4. ______is not recommended for immunosuppressed patients because it causes vaccine-induced infection.

b. Oral polio vaccine

“The Oral polio vaccine … can revert into the wild type and cause vaccine- induced infection. It is not recommended for immunosuppressed patients.”

95 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

96 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

97 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

98 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

99 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

100 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

101 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

102 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

103 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.”

104 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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.” 105 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com

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.” 106 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com

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.”

107 Nursece4Less.com Nursece4Less.com Nursece4Less.com Nursece4Less.com 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. 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