Antimicrobial Therapies 4 (Antiviral Drugs / Antiprotozoal Drugs / Anthelmintic Drugs)

Question 1

Antiviral Drugs

Answer 1

Viruses are intracellular parasites

The do not have a cell wall or cell membrane and do not carry out metabolic processes

They use much of the metabolic processes of the host—very few drugs are selective enough to prevent viral replication without injuring the infected individual

Treating viral illness is further complicated by the fact that symptoms appear late in the course of illness—after the virus has replicated—so drugs that prevent replication
are not helpful

Viral URIs that can be treated are Influenza A,
influenza B, and RSV

Flu vaccine is more effective than trying to treat the patient after they are infected

Antivirals can be helpful when the patient
cannot be immunized OR when there is an
outbreak

Question 2

Neuraminidase Inhibitors

Answer 2

Oseltamivir—Tamiflu prototype drug
Zanamivir—Relenza

Effective against flu A and B; they do not interfere with immune response to the flu vaccines

Given prior to exposure, these agents prevent infections and when given 24-48 hours after the symptoms occur, they modestly decrease the intensity and duration of the illness

MOA
• Flu viruses use a certain neuraminidase that it slotted into the host cell membrane to release newly formed viruses; this enzyme is critical for the virus to live
• These drugs selectively inhibit neuraminidase—this prevents new virions from being made and prevents the virus from spreading

Pharmacokinetics
• Oseltamivir is dosed orally as a prodrug that is hydrolyzed by the liver into active form
• Zanamivir is not active orally and is given via inhalation
• Both are eliminated unchanged in the urine

ADEs
• GI discomfort and nausea
• Symptoms are lessened if taken with food
• Irritation of the respiratory tract from Zanamivir—use with caution in those with
asthma or COPD—because it can cause
bronchospasm

Resistance
• Mutations of the neuraminidase enzyme
have been identified in adults with either of the neuraminidase inhibitors
• These mutants are usually less infective and less virulent than the wild type
influenza

Question 3

Amantadine Antivirals

Answer 3

Amantadine—Symmetrel [prototype]
Rimantadine—Lumazine
Spectrum is only Influenza A
Due to resistance—Amantadine is not recommended in the US

Question 4

Ribavirin

Answer 4

Virazole; synthetic guanosine analog

Effective against a broad spectrum of RNA
and DNA viruses

Used in treatment of immunosuppressed
children with RSV

Also effective in chronic Hepatitis C infections when used with other direct acting antivirals [DAAs]

MOA
Inhibits replication of RNA and DNA viruses

Pharmacokinetics
• Effective orally and by inhalation
• Aerosol is used to treat RSV
• Absorption is increased if the oral drug is taken with a fatty meal
• Drugs and metabolites are eliminated in the urine

ADEs
• Ribavirin—dose dependent transient amnesia, elevated bilirubin
• Aerosol can be safer, but respiratory function in babies can deteriorate quickly after aerosol treatment is started—close monitoring is mandatory
• Ribavirin is contraindicated in pregnancy

Question 5

Treating Hepatic
Viral Infections

Answer 5

Chronic Hep B can be treated with Peginterferon-α-2a injected SQ weekly

Oral therapy for chronic Hep B can be with Lamivudine, Adefovir and Tenofovir

Chronic Hep C is treated with a combination of direct acting antivirals
[DAAs]—based on the genotype of the virus that patient has

Ribavirin can be added to the DDAs
to boost the viral response

Pegylated interferon is no longer
commonly used for chronic Hep C

Question 6

Treating Hepatis B—Interferons

Answer 6

Naturally occurring inducible glycoproteins that interfere with virus to infect the host cells

Interferons are synthesized by recombinant DNA technology—α [alpha], ß [beta] and γ [gamma]

In pegylated formulations—polyethylene glycol has been attached to interferon-α to increase the size of the molecule, and lengthens duration of action and reduces clearance

MOA
• Incompletely understood
• Involves the induction of host cell enzymes
that inhibit viral RNA translation—leading
to the breakdown of viral RNA

Uses
• Peginterferon alfa-2a is approved for chronic Hep B
• Also indicated for treatment of Hep C in
combination with other drugs [but no longer
common]

ADEs
• Flu like sx—fever, chills, myalgias, arthralgias, Gi distress
• Fatigue and mental depression is common
• Dose limiting BM toxicity, severe fatigue, weight loss, somnolence, thyroiditis often
curbs the use of this agent
• HF has been reported

Question 7

Hepatitis B—Lamivudine

Answer 7

Epivir-HBV is a cytosine analog is an inhibitor of both Hep B and HIV reverse transcriptase

Must be phosphorylated by host enzymes to active form

Competitively inhibits Hep B RNA-dependent DNA polymerase

Intracellular half-life of the triphosphate is much longer than its ½ life

Rate of HBV resistance is high after long term use—therefore it is no longer 1st line in treating chronic Hep B

Question 8

Hepatitis
B—
Adenovir

Answer 8

Hepsera is a nucleotide analog that is phosphorylated by cellular kinases to adefovir diphosphate, which is incorporated into viral DNA

This causes termination of chain elongation and prevents replication of Hep B virus

Given once daily; renally excreted via glomerular filtration and tubular secretion

Stopping the drug may result in an exacerbation of Hep B

Nephrotoxicity can occur with chronic use

Use with caution in those with CKD

No longer 1st line in treatment of Hep B—as it has lower efficacy than other agents

Question 9

Hepatitis B— Entecavir

Answer 9

Baraclude is a guanosine nucleoside
analog for the treatment of Hep B

After intracellular phosphorylation to
triphosphate, it competes with natural
substrate, deoxyguanosine triphosphate,
for viral reverse transcriptase

Effective against lamivudine-resistant
strains of Hep B; it is dosed once a day

Excreted unchanged in the urine;
adjustments are needed in those with
CKD

Avoid use of other agents with renal
toxicity

Question 10

Treatment of Hepatitis C

Answer 10

Once Hep C is inside the cell, a viral genome is released from the nucleocapsid and a Hep C viral polyprotein is translated using the internal ribosome entry site

Core NS3 and NS5a proteins form the replication complex on fat drops and
serve as a scaffold for RNA polymerase to reproduce the viral genome—which is then packed in an envelope of glycoproteins before noncytolytic secretion of mature virions

DAAs– target NS3/NS4A protease, NS5B polymerase and NS5A involved in
Hep C replication

Question 11

Treatment of Hepatitis C

Answer 11

NS3/NS4A Protease Inhibitors

Viral NS3/NS4A serine protease needed to process single polyprotein encoded by Hep C RNA into active proteins

Without these serine proteins, RNA replication does not occur and the Hep C life cycle is stalled
 Paritaprevir + Ritonavir boost
 Grazoprevir
 Voxilaprevir
 Glecaprevir

ADEs—rash, itching, nausea, fatigue, anemia

NS5B Polymerase Inhibitors

NS5B is only RNA polymerase responsible for
Hep V replication and is processed with other Hep C proteins into an individual polypeptide by the viral NS3/NS4A serine protease; these drugs inhibit NS5B

Sofosbuvir
Dasabuvir
ADEs—few; well tolerated

NS5A Replication Complex Inhibitors

NS5A is a viral protein necessary for Hep B
RNA replication and assembly

This protein forms a membranous web
[along with NS4B]—and this web is the
platform for virus replication

Ledipasvir
Ombitasvir
Elbasvir
Velpatasvir
Pribrentasvir
Daclatasvir

Many drug interactions due to their
metabolism by CYP 450 and p-glycoprotein inhibition

Ribavirin

Approved for the treatment of chronic Hep C when used in combination with standard pegylated interferon or with DDAs

Guanosine analogue, improves viral clearance, decreases relapses rates and improves rates of SVR

Adding Ribavirin to a DDA backed regimen is based on Hep C genotype, cirrhosis status, presence of mutation and treatment history

MOA is unknown

This drug is given BID with food, and it is weight based

Question 12

Treating Herpes Virus Infections

Answer 12

Acyclovir
Zovirax is the prototype antiherpetic drug

It covers HSV1, HSV2, VZV and some
strains of Epstein-Barr virus

DOC in treating HSV encephalitis

Most common use is for genital herpes

Used to prevent disease to seropositive
patients before BMT and post-cardiac
transplant patients

MOA
• Guanosine analog; monophosphorylated in the cell the HSV-encoded enzymes
• Monophosphate analog is converted to triphosphate with competes as a substrate
for viral DNA and incorporates in the viral DNA, causing the DNA chain to terminate

Pharmacokinetics
• Iv, oral, topical routes
• Topical form has questionable efficacy
• Distributes well throughout the body,
including CSF
• Partially metabolized to an inactive product
• Excretion is via the urine from glomerular
filtration and tubular secretion
• The drug accumulates in those with CKD
• The valyl ester, Valacyclovir, has better
bioavailability—it is rapidly hydrolyzed to
Acyclovir and achieves level comparable
to giving IV Acyclovir

ADEs
• Depends on route of administration
• Local irritation from topical use
• Headache, diarrhea, nausea and vomiting can be seen with oral dosing
• Transient renal dysfunction can be seen with high doses or in a dehydrated patient
getting the drug IV

Resistance
• Altered or deficient thymidine kinase and DNA polymerases found in some resistance—especially in the immunocompromised
• Cross resistance to other agents in the family does occur

Question 13

Cidofovir

Answer 13

Vistide—indicated for CMV retinitis in patients with AIDS

Nucleotide analog of cytosine—inhibits viral
DNA synthesis

Slow elimination of the active intracellular
metabolite allows prolonged dosing intervals

Given IV—causes renal toxicity;
contraindicated in those with pre-existing renal problems and in those on other nephrotoxic drugs

Neutropenia and metabolic acidosis occur

Oral Probenecid and IV NS are given with
Cidofovir to mute the nephrotoxic effect

With the introduction of HAART, the
incidence of CMV in the immunosuppressed patient has declined as has the use of this drug

Question 14

Foscarnet

Answer 14

It is a pyrophosphate derivative, and does not need activation by viral or cell kinases

Used for CMV retinitis in the immunosuppressed and or Acyclovir resistant HSV

Works by reversibly inhibiting viral
DNA and RNA polymerases

Mutation of the polymerase structure is
responsible for resistance

Poorly absorbed after oral dose; must be
given IV

Must be given frequently to avoid
relapse when plasma levels fall

Dispersed throughout the body, >10 %
enters the bone matrix, where it slowly
disperses

Parent drug is eliminated by glomerular filtration and tubular excretion

ADEs—nephrotoxicity, anemia, nausea, fever; low Ca++ and Mg+ because of chelation; low K+, phosphate abnormalities, seizures, arrhythmias

Question 15

Ganciclovir

Answer 15

Cytovene—analog of Acyclovir that has
greater activity for CMV; used in the
treatment of CMV retinitis in the
immunosuppressed and to prevent CMV in
the transplant patient

MOA
• Activated through conversion to the nucleoside triphosphate by viral and cell
enzymes
• Nucleotide inhibits viral DNA polymerase
and can be incorporated into the DNA
causing chain termination

Pharmacokinetics
• Given IV and distributes throughout the body and CSF
• Excretion into urine through glomerular filtration and tubular secretion
• Accumulates in those with CKD
• Valganciclovir, an oral agents—is the valyl ester of Ganciclovir
• Valganciclovir [Valcyte] has high oral bioavailability; it hydrolyses rapidly in the liver and intestine after oral dose and obtains high levels of Ganciclovir

ADEs
• Severe dose dependent neutropenia
• Carcinogenic and teratogenic
• BB warning for use in pregnancy

Resistance
• Resistant strains of CMV have been seen with low levels of Ganciclovir triphosphate

Question 16

Penciclovir
and
Famciclovir

Answer 16

Penciclovir [Denivir]— acyclic guanosine
nucleotide derivative active against HSV-1,
HSV-2, VZV

Given topically; monophosphorylated
by viral thymidine kinase and enzymes
from nucleoside triphosphate that
inhibits HSV DNA polymerase

Intracellular ½ life longer than Acyclovir

Minimally absorbed after topical use; well
tolerated

Famciclovir [Famvir]— cyclic analog of 2’-
deoxyguaosine is a prodrug that is
metabolized to the active Peniciclovir

Antiviral spectrum is similar to that of
Ganciclovir, and it is approved to treat acute
Herpes Zoster, genital HSV infection, and
recurrent Herpes labialis

Effective orally; ADEs are headache and nausea

Question 17

Trifluridine

Answer 17

Viroptic—fluorinated pyrimidine nucleoside
analog that is structurally similar to thymidine

Once converted to triphosphate, inhibits the
incorporation of thymidine triphosphate into viral DNA and leads to synthesis of defective DNA that causes the virus to stop replicating

Active against HSV-1, HSV-2, vaccinia

Indicated to treat HSV keratoconjunctivitis
and recurrent epithelial keratitis

Too toxic to use systemically; use is
restricted to ophthalmic drops

Short ½ mandates frequent
administration

ADEs—transient irritation of eye;
eyelid edema

Question 18

Antiprotozoal Drugs

Answer 18

Parasites common in underdeveloped tropical and subtropical countries where sanitary conditions, hygiene and control of vectors [of transmission] are not adequate

Because of world travel—these diseases are NOT confined to specific geographical areas

Protozoal parasites have metabolic processes closer to that of the human than to prokaryotic bacterial pathogens

Many of these agents have serious toxic effects—especially in cells with high metabolic activity

Most of these agents are NOT proven to be safe in pregnancy

Treating Parasites

Luminal agents—affect the amoeba in the lumen of the bowel

Systemic agents—effective against the amoeba in the intestinal wall and liver

Mixed agents—work in both the lumen and
systemic forms of amebiasis—although luminal concentrations are too low to be used alone

Question 19

Mixed
Amebicides

Answer 19

Metronidazole [Flagyl]—prototype drug

Nitroimidazole that is DOC to treat amebic infections

Can also be used to treat Giardia lamblia, Trichomonas vaginalis, anaerobic cocci, anaerobic Gram
– bacilli [Bacteroides], anaerobic
Gram + bacilli [Clostridium difficile]

MOA
• Amoebas possess electron transport proteins; the nitro group of Flagyl is able to
serve as an electron acceptor, and forms
reduced cytotoxic compounds that cause
the death of Entamoeba histolytica

Pharmacokinetics
• Completely and rapidly absorbed after oral dose
• For amebiasis, it is usually given with a luminal amebicide, such as Iodoquinol [Yodoxin] or Paromomycin—combination
therapy increases cure rates to >90%
• Distributes well throughout tissues and fluids; levels found in vaginal, seminal, saliva, breast milk and CSF
• Metabolized by hepatic oxidation and then glucoronidated
• Giving with inducers of CYP 450, such as Phenobarbital, enhances metabolism; inhibitors, such as Cimetidine,
prolongs the ½ life
• Accumulates in those with liver disease
• Parent drug an metabolites are excreted in the urine

ADEs
• Nausea
• Vomiting
• Epigastric distress
• Abdominal cramps
• Metallic taste
• Oral yeast
• Neurotoxicity—dizziness, vertigo paresthesias
• If taken with alcohol, a Disulfiram-like reaction can occur

Question 20

Tinidazole [Tindamax]

Answer 20

2nd generation nitroimidazole—similar to
Metronidazole in coverage, ADEs, and drug interactions

Used to treat amebiasis, amebic liver abscess, giardiasis and trichomoniasis

Is as effective as Flagyl, but more expensive

Alcohol should be avoided when using this agent

Question 21

Luminal
Amebicides

Answer 21

After treatment of invasive intestinal or extraintestinal amebic disease is complete—a luminal agent, Iodoquinol [Yodoxin],
Diloxanide furoate or Paromomycin—should be used to treat the asymptomatic colonized
state

Iodoquinol

• Yodoxin
• Halogenated 8-hydroxyquinolone
• Amoebicidal against E. histolytica
• Effective against luminal trophozoite and cysts
• ADEs—rash, diarrhea, dose-related peripheral neuropathy, optic neuritis [rare]

Paromomycin

• Aminoglycoside antibiotic, only effective against luminal forms of E. histolytica—it is not significantly absorbed from the GI tract
• Directly amoebicidal; exerts its effect by decreasing the population of intestinal flora
• ADEs—GI distress, diarrhea

Question 22

Systemic Amebicides

Used for treating extraintestinal amebiasis, such as liver abscess and intestinal
wall infections

Answer 22

Chloroquine

• Aralen
• Used with Flagyl to treat liver abscess
• Kills trophozoites in liver abscesses, but not useful in luminal amebiasis
• After therapy, patient should be given a luminal amebicide
• Also effective to treat malaria

Dehydroemetine

• Alternative to treat amebiasis
• Inhibits synthesis by blocking chain elongation
• Given IM
• Use of this agent is limited—it is a ipecac
alkaloid—with toxicity—it has largely been
replaced by Metronidazole
• ADEs—pain at injection site; nausea,
arrhythmias, HF, neuromuscular weakness,
dizziness, rash

Question 23

Commonly Used Options for Parasites

Answer 23

Asymptomatic cyst carriers
-Iodoquinol OR Paromomycin

Diarrhea / dysentery
Extraintestinal
-Metronidazole + Iodoquinol OR
Paromomycin

Amebic Liver Abscess
-Metronidazole [or Tinidazole] +
Iodoquinol [or Paromomycin]

Question 24

Treating
Malaria

Answer 24

Transmitted to humans via the bite of the female Anophelesmosquito

Presentation is headache, fatigue, fever, chills and sweats

P. falciparum is the most dangerous and primary cause of severe malaria—causing fulminating disease with high fever,
many parasites in the blood and organ system failure; this pathogen can cause capillary obstruction, cerebral malaria,
and death within days without treatment

P. vivax, P. malariae and P. ovale can cause a
milder form of the disease, but P. vivax and P. ovale can remain dormant in the liver
[hypnozoite stage] which can cause relapse
months or years later

P. knowlesi is an uncommon form—seem in
Asia—can cause severe human cases

Resistance to antiprotozoal drugs, especially P. falciparum, currently make treating this disease challenging

Question 25

Treating Malaria

Answer 25

Primaquine
8 aminoquinoline oral agent that
eradicates primary liver forms of
Plasmodium and the hypnozoites of
recurring malarias [P. vivax; P. ovale]—this
is the only agent that prevents relapse of
the these strains of the protozoa in the
liver

The sexual [gametocytic] form of all
plasmodia are destroyed in the blood or
are prevented from maturing later in the
mosquito, interrupting transmission

This drug does NOT work on the blood
from of malaria, and as a result—cannot
be used as monotherapy

MOA
• Metabolites act as oxidants that disrupt the
metabolic processed of the plasmodia
mitochondria
• Metabolites are responsible for
schizonticidal action as well as hemolysis and
methemoglobinemia [toxicities seen]

Pharmacokinetics
• Well absorbed after oral dose
• Not concentrated in the tissues
• Rapidly oxidized
• Which compound causes the schizonticidal activity has not be identified
• Minimally excreted in the urine

ADEs
• Drug induced hemolytic anemia in those with G6PD deficiency
• Large doses can cause GI distress
• Occasional methemoglobinemia
• Should not be used during pregnancy
• All species can develop resistance to Primaquine

Question 26

Chloroquine

Answer 26

Aralen is a synthetic 4-aminoquinolone—backbone of malarial therapy—but is now limited due to P. falciparum
resistance—which is present in all malaria endemic areas except some parts of Central America

Less effective against P. vivax

Used to prophylax against malaria in travelers going to Chloroquine sensitive areas

Can be used to treat extra intestinal amebiasis

MOA
• Binds to heme, prevents its polymerization to hemozoin
• Increased pH and accumulation of heme causes oxidative damage to the phospholipid membranes, leading to lysis of the parasites and the RBC

Pharmacokinetics
• Rapidly and completely absorbed after oral dose
• Very large volume of distribution, concentrates in RBCs, liver, spleen, kidney, lung, melanin containing tissues and WBCs
• It hangs around in the RBCs
• Drug also penetrates the CNS and crosses the placenta
• Dealkylated by the liver mixed-function oxidase system
• Parent drug and metabolites are excreted mainly in the urine

ADEs
• At low doses—used in prophylaxis—very few
• At higher treatment doses—GI upset, itching, headaches, blurred vision
• Dilated eye exam should be done routinely
with prolonged use—due to toxicity to the
retina
• Discoloration of nail beds and mucous
membranes can occur with chronic use
• Use with caution in those with liver dysfunction, severe GI problems or neurologic disease
• Patients with psoriasis or porphyria should NOT take this drug—as it can provoke an acute attach
• Can prolong QTc interval, so using it in patients on other drugs that prolong the QT interval should be avoided

Question 27

Atovaquone-
Proguanil

Answer 27

Malarone—combination agent for
Chloroquine resistant strains of P. falciparum—used in the prevention and treatment of malaria for travelers from outside malaria-endemic areas

Not routinely used in endemic areas due to the likelihood for emergence of high-level resistance

Atovaquone is a hydroxynaphthoquinone with inhibits mitochondrial processes

Cycloguanil, the active triazine metabolite of proguanil, inhibits plasmodial dihydrofolate reductase—preventing DNA synthesis

Atovaquone can also treat Babesia sp. and Pneumocystis jirovecii

Proguanil is metabolized via CYP 450 2C19—known to exhibit a genetic polymorphism causing poor metabolism of the drug in
some individuals

Take with food or milk to facilitate absorption

ADEs—nausea, vomiting, abdominal pain, headache, diarrhea, anorexia and dizziness

Question 28

Mefloquine

Answer 28

Lariam—4-methanolquinolone—structurally
like quinine

Effective agent to prevent all plasmodia,
and for treatment when used in
combination with an artemisinin derivative
for infections from MDR forms of P.
falciparum

MOA is unknown; widely distributed to
tissues

Long ½ life—20 days; because of
enterohepatic recirculation and its
concentration in various tissues

Primarily excreted via the bile into the feces

ADEs—at high doses—nausea, vomiting,
dizziness, hallucinations and depression

Because of the potential for neuropsychiatric
reactions, this drug is usually reserved for
treating malaria when other agents cannot be used

EKG abnormalities and cardiac arrest can
occur if Lariam taken with Quinine and
Quinidine

Question 29

Quinine

Answer 29

Alkaloid isolated from the ark of the
Cinchona tree

Interferes with heme polymerization,
causing death of the RBC form of the
plasmodial parasite

Reserved for severe infections and
Chloroquine resistant malaria

Usually given with Doxycycline, Tetracycline
or Clindamycin

TAKEN ORALLY, WELL
DISTRIBUTED THROUGHOUT THE BODY

ADES—CINCHONISM— NAUSEA, VOMITING,
TINNITUS AND VERTIGO

ADES ARE REVERSIBLE AND ARE NOT REASONS TO SUSPEND TREATMENT

SUSPEND TREATMENT IF
HEMOLYSIS OCCURS

Question 30

Artemisinin

Answer 30

Derived from sweet wormwood plant
1st line for MDR P. falciparum malaria

Giving with another antimalarial is recommended to prevent resistance

One orally available regimen is Artemisinin + Lumefantrine [used successfully in uncomplicated disease]—Brand name Coartem

Artesunate + Sulfadoxine-pyrimethamine, Mefloquine, Clindamycin or others—the
antimalarial action of Artemisinin derivatives involves the production of free radicals
from cleavage of the drug’s endoperoxide bridge by heme iron in the parasite food
vacuole

Oral, rectal, IM and IV formulas are available

Short ½ life prevents use of these drugs for prevention

ADEs—nausea, vomiting, diarrhea, rash has occurred

High doses can prolong the QTc interval

Question 31

Pyrimethamine
[Daraprim]

Answer 31

Daraprim—inhibits plasmodial
dihydrofolate reductase needed to synthesize tetrahydrofolate—which is
needed to make nucleic acids

It is a blood schizonticide and a strong sporonticide

Not used alone to treat malaria

Fixed dosed combinations with Sulfadoxine

Resistance to this combo has developed—so usually given with other agents—Artemisinin
derivativesPyrimethamine + Sulfadoxine used to treat Toxoplasma gondii

If megaloblastic anemia occurs with this
agent during treatment—it can be
reversed with Leucovorin

Question 32

Treating Trypanosomiasis

Answer 32

African sleeping sickness
[Trypanosomiasis] and American Chagas Disease
[Trypanosomiasis] are 2 chronic and eventually fatal disease from
Trypanosoma

Pentamidine
[Pentam or Nebupent]

Active against many protozoa—African
trypanosomiasis from T. brucei gambiense—it is used to treat early stage disease without
CNS involvement

Can also treat or prevent Pneumocystis jirovecii and can be used to treat Leishmaniasis

MOA
• T. brucei concentrates the drug by an energy-dependent high affinity uptake system—resistance occurs if the protozoa
cannot concentrate the drug
• MOA not fully understood—drug interferes with parasite synthesis of RNA, DNA, phospholipids and proteins

Pharmacokinetics
• Given IM or IV to treat Trypanosomiasis and
pneumonia from P. jirovecii
• For prevention of P. jirovecii pneumonia—pentamidine is given via nebulizer
• Drug distributes widely and is concentrated in liver, kidney, adrenals, spleen and lungs
• It does not enter the CSF— cannot be used for late stage Trypanosomiasis
• Drug is not metabolized; excreted very slowly in the urine

ADEs
• Renal dysfunction, reversible when stopped
• Hyperkalemia; low BP, pancreatitis; ventricular arrhythmias; elevated BS

Suramin
Used in early stage African
trypanosomiasis from T. brucei
rhodesiense

Very reactive and inhibits many
enzymes, especially those involved
in metabolism—which seems to be
action that kills the trypanocite

Given IV

Germanin binds to plasma proteins and does not penetrate the blood-brain barrier

Long ½ life [>40 days], excreted unchanged in the urine

ADEs—rare, but nausea, vomiting, shock and loss of consciousness can be seen

Other ADEs—acute urticaria, blepharitis, paresthesias, photophobia, hyperesthesia of the hands and feet; renal
insufficiency, but is reversible when drug is stopped
Test dose should be given, as acute hypersensitivity has been seen

Melarsoprol

Trivalent arsenic compound

Only agent available to treat late
stage African trypanosome infections
and those with CNS involvement from
T. brucei rhodesiense

Drug reacts with enzymes in the organism and the host

Given by slow IV; can be irritating to
surrounding tissues

DOC for CNS infections that have occurred
rapidly as the trypanocidal
concentrations in the CSF are quite adequate

Human readily oxidizes the drug to a nontoxic pentavalent arsenic compound

Very short ½ life and is rapidly excreted in the urine

Its use is limited by CNS toxicities—reactive
encephalopathy, which is fatal in 10 percent

Hypersensitivity reactions, febrile reactions can follow injection

Other ADEs—peripheral neuropathy, HTN, liver toxicity, albuminuria

Hemolysis can occur in those with G6PD
deficiency

Question 33

Treating Trypanosomiasis

Answer 33

Eflornithine

Irreversible inhibitor of ornithine decarboxylase; inhibiting this enzyme stops polymerases in the parasite and causes cell division to cease

IV form is DOC for late stage African trypanosomiasis from T. brucei gambiense

Topical Eflornithine [Vaniqa] is used to treat unwanted facial hair in woman

Short ½ life requires IV dose to be given frequently

Less toxic than Melarsoprol, but can cause anemia, seizures, and temporary hearing loss

Question 34

Nifurtimox

Answer 34

Used to treat T. cruzi [Chagas Disease]—although its use in chronic stage disease has shown variable results

Can be used with Eflornithine to treat late stage T. brucei gambiense

Undergoes reduction and generates O2 radicals—superoxide and H2O2—that are toxic to the parasite

Given orally; extensively metabolized

ADEs—common with chronic administration
[especially in older patients]—anaphylaxis,
dermatitis, GI distress—severe enough to
cause weight loss; peripheral neuropathy,
dizziness and headache

Question 35

Benznidazole

Answer 35

Nitroimidazole derivative with MOA
similar to Nifurtimox—but better tolerated
for treating Chagas Disease
ADEs—dermatitis, peripheral neuropathy, insomnia, anorexia

Question 36

Treating Leishmaniasis

Answer 36

Protozoal infection from many species of genus Leishmaniasis

3 manifestations—cutaneous, mucocutaneous and visceral [in this presentation, the parasite is in the liver, spleen and blood, if not treated, it is fatal]

Transmitted b the bite of the infected sandflies

For the visceral form—treatment options include IV Amphotericin B, pentavalent antimonials—Na+ Stibogluconate or Meglumine antimoniate + Pentamidine and
Paromomycin

Miltefosine—only oral agent for visceral disease

Choice of drug depends on species of parasite, host factors and local resistance patterns

Sodium Stibogluconate

Pentavalent antimonial is a prodrug which is
reduced to active trivalent antimonial
compound

MOA is not fully understood

Minimal absorption; excreted in the urine

ADEs—injection site pain, pancreatitis,
elevated LFTs, arthralgias, myalgias, GI
distress, cardiac arrhythmias

Miltefosine

1st oral agent for visceral Leishmaniasis

Can also be used for cutaneous and
mucocutaneous forms

MOA is unknown, but it is thought to interfere with phospholipids and sterols in the parasite membrane

ADEs—nausea, vomiting, teratogenic; do not use in pregnant women

Question 37

Treating
Toxoplasmosis

Answer 37

One of the most common infections
in humans—caused by T. gondii

Transmitted to humans from eating
inadequately cooked infected meat
or accidently ingesting oocysts from
cat feces

Infected pregnant woman can
transmit T. gondii to her fetus

Treatment of choice—Sulfadiazine + Pyrimethamine
Leucovorin given to prevent folate deficiency

If rash occurs, immediately stop Pyrimethamine—because hypersensitivity to this agent can be severe

Other treatment options:
Pyrimethamine + Clindamycin Trimethoprim/Sulfamethoxazole
[Bactrim DS]

Trimethoprim/Sulfamethoxazole used to prevent Toxoplasmosis and P. jirovecii in the immunosuppressed

Question 38

Treating Giardiasis

Answer 38

•Binucleate trophozoite [4 flagella]
•Four nucleate cyst [drug-resistant]

Giardia lamblia commonly diagnosed
intestinal parasite

Two life cycles

Ingestion occurs from fecally contaminated water or food

Trophozoites exist in the small
intestine

Cysts are formed and pass out in feces

Many infections are asymptomatic, but those that have symptoms have diarrhea— and it can be very severe, and very serious in those
immunosuppressed or frail

DOC is Metronidazole orally for 5 days

Alternative therapy is a single dose of
Tinidazole [Tindamax]—just as effective as
Flagyl, but the cost of the 2 gram once time
dose is $144-$288 compared to $15 for
Metronidazole 5 day course

Nitazoxanide, a nitrothiazole derivative,
also approve to treat giardiasis
This agent also used to treat
Cryptosporidiosis from C. parvum

For Giardiasis, Nitazoxanide is given orally for 3 days

Albendazole can also treat Giardiasis
Paromomycin is used for the
pregnant patient

Question 39

Anthelmintic Drugs

Answer 39

Overview—Yes, it is Treating Worms

Nematodes, trematodes and cestodes are 3
major groups of worms

Anthelmintic drugs aim for metabolic targets
that present in parasite but are absent or
different than those of the human

Nematodes are long roundworms that cause
infections in the intestine, blood and tissues

Mebendazole [Emverm]

Synthetic benzimidazole; 1st line for whipworms [Trichuris trichiura], pinworms [Enterobius vermicularis], hookworms
[Necator americanus; Ancylostoma duodenale] and roundworms [Ascaris lumbricoides]

Mebendazole [and all benzimidazoles], act by binding to parasite ß-tubulin and preventing polymerization in the parasite

Affected worms are expelled in the feces

Do not use in pregnant patient

In certain mass prevention/treatment
scenarios this drug and Albendazole can be
given in 2nd or 3rd trimester

Question 40

Pyrantel pamoate

Answer 40

Effective in roundworms, pinworms
and hookworms

Poorly absorbed after oral dose

Acts as a depolarizing, neuromuscular blocking drug

The worms are paralyzed and expulsed in the feces

ADEs– nausea, vomiting and diarrhea.

Thiabendazole
Synthetic benzimidazole
Potent broad spectrum anthelmintic
Use limited to topical treatment of cutaneous larva migrans
Has many toxic effects, so not used often

Question 41

Ivermectin [Stromectal]

Answer 41

DOC to treat cutaneous Larva migrans,
Strongyloidiasis and Onchocerciasis

Also used to treat pediculosis [lice] and scabies

Targets glutamate gated Cl- channel receptors—causing paralysis and death of the worm

Orally dosed—does not readily cross blood-brain barrier

Do not use in pregnancy

Killing the larvae I n onchocerciasis can cause a Maxxotti reaction—fever, headache, dizziness, somnolence, low BP—severity depends on the parasite load
Antihistamines and steroids can reduce the
symptoms

Diethylcarbamazine

DOC for infection with
Wuchereria bancrofti, Brugia
malayi or Brugia timori
Kills the larvae and has action
against the worms
Rapidly absorbed oral dose
with food; excreted in the
urine
 ADEs—fever, nausea,
vomiting, arthralgia,
headache

Question 42

Drugs to
Treat
Nematodes

Answer 42

In countries where filariasis is endemic combination of drugs can be used annually as preventative therapy Diethylcarbamazine + Albendazole or Ivermectin + Albendazole

Those suspected of having onchocerciasis should not be given Diethylcarbamazine—it can accelerate night blindness and cause a severe Mazzotti reaction

Drugs to Treat Trematodes

Flukes—leaf shaped flatworms that
are characterized by the tissues they
infect—liver, lung, blood, etc.

Praziquantal [Biltricide]

Praziquantel is DOC for all forms of
Schistosomiasis, other trematode infections and cestode infections, such as taeniasis

Causes contracture and paralysis of parasites by increasing the permeability of cell wall membrane to Ca++

Rapid absorption after oral dose—should be taken with food

Extensively metabolized and inactive
metabolites are excreted in urine
ADEs—dizziness, malaise, headache, GI upset
Dexamethasone, Phenytoin, Rifampin,
Carbamazepine increase metabolism of this
drug; Cimetidine causes increased drug levels
Contraindicated for ocular cysticercosis [killing
the organism in the eye can call cause
irreversible damage]

Question 43

Drugs Used
to Treat
Cestodes

Answer 43

True tapeworms

Worms with a flat segmented body and attach to the host’s intestine

Tapeworms lack a mouth and a digestive tract

Niclosamide
Alternative to Praziquantel to treat taeniasis,
diphyllobothriasis and other cestodes

Inhibits mitochondrial phosphorylation of ADP in the parasite—killing the cestode, but not the ova Laxative is given before the dose to purge the bowel of all dead segments and to enhance digestion and liberation of the ovaETOH should be avoided for 24 hours

This agent is no longer available in US, but used successfully worldwide

Question 44

Albendazole

Answer 44

Albenza
-Inhibits synthesis of glucose uptake in
nematodes and is effective against most
nematodes
-Primary action in treating cestodes, such as
cysticercosis and hydatid disease [larvae of
Echinococcus granulosis]

This agent is effective in treating
Microsporidiosis

Drug is erratically absorbed after oral dosing

High fat meal increases absorption

Undergoes extensive 1st pass metabolism
Active sulfoxide and its metabolites are excreted in the bile
If used 1-3 days for nematodes, ADEs are mild—headache and nausea
Treatment long term—90 days—for hydatid disease has the risk of liver toxicity and agranulocytosis or pancytopenia [rare]
Medical therapy for neurocysticercosis is associated with inflammation of the CNS from the dying parasites—headache, vomiting, fever and seizures