Antimicrobial part 4 Flashcards
Antiviral Drugs
♦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
Treating Viral Respiratory Infections
♦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
Neuraminidase Inhibitors examples
Oseltamivir—Tamiflu prototype drug
Zanamivir—Relenza
Neuraminidase Inhibitors
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
Neuraminidase Inhibitors: 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
Neuraminidase Inhibitors: 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
Neuraminidase Inhibitors: 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
Neuraminidase Inhibitors: 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
Amantadine Antivirals examples
♦Amantadine—Symmetrel [prototype]
♦Rimantadine—Lumazine
♦Spectrum is only Influenza A
♦Due to resistance—Amantadine is not recommended in the US
Ribavirin
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]
Ribavirin: MOA
• Inhibits replication of RNA and DNA viruses
Ribavirin: 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
Ribavirin: 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
Treating Hepatic Viral Infections
vMany different types of viral hepatitis—Hep B [DNA
virus] and Hep C [RNA virus] are the most
common cause of chronic Hep, cirrhosis and hepatocellular cancer
♦In 2019, we only have therapy for these two viral
hepatitis viruses
How is chronic Hep B treated
♦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
How is chronic hep C 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
Treating Hepatis B—Interferons
-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
Hepatitis B—Interferons: MOA
• Incompletely understood
• Involves the induction of host cell enzymes that inhibit viral RNA translation—leading to the breakdown of
viral RNAs
Hepatitis B—Interferons: 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]
Hepatitis B—Interferons: 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
Hepatitis B—Lamivudine
♦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
Hepatitis B—Adenovir
♦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 replicationof 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
Hepatitis B—Entecavir
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
Treatment of Hepatitis C
♦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
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
NS3/NS4A Protease Inhibitors examples
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
NS5B Polymerase Inhibitors examples
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 pglycoprotein inhibition
Ribavirin Pearls
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
Options for Hepatitis C
♦Elbasvir/grazoprevir [Zepatier]
♦Glecaprevir/pibrentasvir [Mavyret]
♦Paritaprevirritonavir/ombitasvir [Technivie]
♦Pariaprevier/rtionavir/ombitasvir+dasabuvir [Viekira park,
Viekira XR]
♦Sofosbuvir + daclatasvir [Sovaldi + Daklinza]
♦Sofosbuvir/ledipasvir [Harvoni]
♦Sofosbuvir/velpatasvir [Epclusa]
♦Sofasbuvir/velpatasvir/voxilaprevir [Vosevi]
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
Acyclovir: 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
Acyclovir: 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
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
Acyclovir: 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
Cidofovir
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
Foscarnet
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
ADEs—nephrotoxicity, anemia, nausea, fever; low Ca++ and Mg+ because of chelation; low K+, phosphate abnormalities, seizures, arrhythmias
Parent drug is eliminated
by glomerular filtration and
tubular excretion
Ganciclovir
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
Ganciclovir: 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
Ganciclovir: 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
Ganciclovir: ADEs
• Severe dose dependent neutropenia • Carcinogenic and teratogenic • BB warning for use in pregnancy
Ganciclovir: Resistance
• Resistant strains of CMV have been seen with low levels of Ganciclovir triphosphate
Penciclovir and Famciclovir
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
Trifluridine
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 HSV1, 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
Acyclovir
slide 42
MOA:
Virsuses or diseases affected:
Amantadine
MOA:
Virsuses or diseases affected:
Cidofovir
MOA:
Virsuses or diseases affected:
Famciclovir
MOA:
Virsuses or diseases affected:
Forcarnet
MOA:
Virsuses or diseases affected:
Ganciclovir
MOA:
Virsuses or diseases affected:
Interferon-α
MOA:
Virsuses or diseases affected:
Lamivudine
MOA:
Virsuses or diseases affected:
Oseltamivir
MOA:
Virsuses or diseases affected:
Penciclovir
MOA:
Virsuses or diseases affected:
Ribavirin
MOA:
Virsuses or diseases affected:
Rimantadine
MOA:
Virsuses or diseases affected:
Valacyclovir
MOA:
Virsuses or diseases affected:
Zanamivir
MOA:
Virsuses or diseases affected:
Treating Parasites…
Amebiasis is an intestinal infection from Entamoeba histolytica This pathogen is endemic in developing countries; transmitted by fecal-oral route from ingesting contaminated food or water Many that are infected have no symptoms, but some can have symptoms
Diagnosis is made by
isolating amoeba in the
feces
Because of the chance of invasive disease and being a potential source of infection—therapy is indicated for symptomatic patients and asymptomatic carriers
Drugs are classified as
luminal, systemic, mixed
amebicides according to
their site of action
Treating Parasites: Luminal agents
Luminal agents—affect the amoeba in the lumen
of the bowel
Treating Parasites: Systemic agents
Systemic agents—against the amoeba
in the intestinal wall and liver
Treating Parasites: Mixed agents
—work in both the lumen and
systemic forms of amebiasis—although luminal
concentrations are too low to be used alone
Mixed
Amebicides
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]
Metronidazole: 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
Metronidazole: 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
Metronidazole: 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
Tinidazole
Tindamax
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
Luminal Amebicides
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
Luminal Amebicides examples
Iodoquinol
Paromomycin
Iodoquinol
• Yodoxin • Halogenated 8- hydroxyquinolone • Amoebicidal against E. histolytica • Effective against luminal trophozoite and cysts • ADEs—rash, diarrhea, doserelated 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
Systemic Amebicides
Used for treating extraintestinal amebiasis, such as liver abscess and intestinal
wall infections
Systemic Amebicides examples
Chloroquine
Dehydroemetine
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
What drug would you give for asymptomatic cyst carriers
Iodoquinol OR Paromomycin
What drug would you give for diarrhea/dysentery or extraintestinal
Metronidazole + Iodoquinol OR
Paromomycin
What drug would you give for amebic liver abscess
Metronidazole [or Tinidazole] +
Iodoquinol [or Paromomycin]
Treating Malaria cause by:
Acute infection caused by 5 species of Plasmodium P. Falciparum P. vivax P. malariae P. ovale P. knowlesi
Treating Malaria
Transmitted to humans via the bite of the female Anopheles
mosquito
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
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
Primaquine: 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]
Primaquine: 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
Primaquine: 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
Chloroquine
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
Chloroquine: 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
Chloroquine: 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 mixedfunction oxidase system • Parent drug and metabolites are excreted mainly in the urine
Chloroquine: 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 p
AtovaquoneProguanil
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
Mefloquine
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
Quinine
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
Artemisinin
Derived from sweet wormwood plant
1 st 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 + Sulfadoxinepyrimethamine, 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
Pyrimethamine
[Daraprim]
Daraprim—inhibits plasmodial
dihydrofolate reductase needed to
synthesize tetrahydrofolate—which is
needed to make nucleic acids
It is a blood schizonticide and astrong sporonticide
Not used alone to treat malaria
Fixed dosed
combinations wit
Sulfadoxine
Resistance to this combo has developed—so usually given with other agents—Artemisinin derivatives
Pyrimethamine +
Sulfadoxine used to
treat Toxoplasma
gondii
If megaloblastic anemia occurs with this agent during treatment—it can be reversed with Leucovorin
Treating Trypanosomiasis
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
Pentamidine: MOA
• T. brucei concentrates the drug by an energydependent 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
Pentamidine: 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
Pentamidine: 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 manyenzymes, 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
Melarsopro
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
Other ADEs—peripheral
neuropathy, HTN, liver
toxicity, albuminuria
Hypersensitivity
reactions, febrile
reactions can follow
injection
Hemolysis can occur in
those with G6PD
deficiency
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
Nifurtimox
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
Benznidazole
Nitroimidazole derivative with MOA similar to Nifurtimox— but better tolerated for treating Chagas Disease
ADEs—dermatitis,
peripheral
neuropathy, insomnia,
anorexia
Treating Leishmaniasis
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
Not absorbed orally, so must be given IV; distributed into the extravascular compartment
Minimal absorption;
excreted in the urine
ADEs—injection site pain, pancreatitis, elevated LFTs, arthralgias, myalgias, GI distress, cardiac arrhythmias
Resistance has been
seen to this drug
Miltefosine
1 st 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
Treating
Toxoplasmosis
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 for toxoplasmosis
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
↓
Pyrimethamine + Clindamycin Trimethoprim/Sulfameth
↓
Trimethoprim/Sulfamethoxazole used to prevent
Toxoplasmosis and P. jirovecii in the immunosuppressed
Treating Giardiasis
Giardia lamblia
commonly diagnosed
intestinal parasite
Two life cycles
•Binucleate trophozoite [4 flagella]
•Four nucleate cyst [drug-resistant] 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
For Giardiasis, Nitazoxanide is given orally for 3 days Albendazole can also treat Giardiasis Paromomycin is used for the pregnant patient
Anthelmintic Drugs
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
Treating Nematodes
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]
Treating
Nematodes
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)
Drugs to treat Nematodes
Pyrantel pamoate
Thiabendazole
Ivermectin [Stromectal]
Diethylcarbamazine
Pyrantel pamoate
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
Ivermectin [Stromectal]
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
In countries where filariasis is endemic combination of
drugs can be used annually as preventative therapy
such as
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]
Drugs to
Treat
Trematodes
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
Praziquantal [Biltricide]
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]
Drugs Used
to Treat
Cestodes
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 ova
ETOH should be avoided for 24 hours
This agent is no longer available in US, but used
successfully worldwide
Albendazole
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
