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8/12/2019 3 Mycobacterium Fungus Parasite Handout
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Mycobacterium
Fungal
Parasitic infections
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Objectives
• Prescribe appropriate medications used to
treat mycoplasma, fungi, yeast, protozoa,
parasites
• Recognize side effects, toxicities, interactions,
contraindications
• Define specific issues related to the use of
these medications
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MYCOBACTERIUMTUBERCULOSIS, LEPROSY, AVIUM
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TUBERCULOSIS
TB, MTB, XTB
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Symptoms of TB
• Two stages
– Latent
• Present, no symptoms
–
Shown by skin test• Not infectious
• May treat to avoid active disease
– Active
•Symptoms
– Sputum test or Xray confirms
• Spreads by coughing, sneezing, breathing
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Medications used to treat TB
• Always Tx with combinations of medications –
at least 4
• Choice depends on status of infection
– TB
– MTB
– XTB
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First line medications – for plain TB,
NOT for MTB or XTB
• Isoniazid
• Rifampin
•
Ethambutol• Streptomycin
• Pyrazinamide
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Second line medications
• When resistance to first line
• In HIV or microbial resistance
– Ofloxacin
–Ciprofloxacin
– Ethionamide
– Aminosalicylic acid
– Cycloserine
–Amikacin inj
– Kanamycin inj
– Capreomycin inj
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Overview of mechanisms
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Detailed look at first line medications
• Non-drug resistant TB only
• Use all 4 for at least 6-9 months
– Isoniazid
– Rifampin
– Pyrazinamide
– Ethambutol
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Isoniazid/Nydrazid
• First line medication (with other 3)
• Related to nicotinic acid
•
Bacteriocidal in dividing infections• Effective against most mycobacterium
• Resistance is developing
–Always use in combination to avoid developmentof resistance
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Mechanism of action- isoniazid
• Specific for mycolic acids
– Inhibitor of lipid synthesis
– Inhibitor of nucleic acid synthesis
– Inhibitor of cell wall synthesis
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Pharmacokinetics- isoniazid
• Lipid soluble
– Penetrates encased organisms
• Liver metabolism
– Genetic variability
• Urinary excretion
•
Oral or parenteral – Do not take with Aluminum containing antacids
orally (forms complex – becomes ineffective)
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Toxicity/side effects/interaction
isoniazid
• Minimize toxicity with prophylactic pyridoxine
• Rash, fever, jaundice and peripheral neuritis
– Black box warning- liver toxicity
• Hypersensitivity
• Inhibits metabolism of phenytoin
–
Particularly in slow acetylators• Age related hepatic dysfunction
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Rifampin/Rifadin
• Produced by streptomyces mediterranei
• Fairly broad spectrum
•
Always used in combination to avoidresistance
• Inhibits RNA polymerase of mycobacteria
–
Prevents formation of RNA
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Toxicity/ side effects/interaction-
rifampin
• Rash, fever
• Nausea and vomiting
•
Jaundice and hepatitis• Induces microsomal enzymes
– Decreases half life of – Coumadin, digoxin, quinidine, ketoconazole, propranolol,
corticosteroids, theophylline, contraceptives...
– Methadone- can precipitate withdrawal
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Ethambutol/Myambutol
• May inhibit arabinosyl transferase
– Inhibits production of mycoplasmic cell wall
– Inhibits actively growing TB
• Dose according to weight
– May decrease the dose after 60 days
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Side effects- ethambutol
• May cause irreversible blindness
– Monthly eye exams recommended
• Liver toxicity
– Require frequent LFTs
• Not recommended for children under 13
•
Excreted into milk• Pregnancy category C
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Interactions- ethambutol
• Do not take at the same time as aluminum
containing antacids
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Streptomycin
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• Black box warning neurotoxicity
• Side effects
– Ototoxicity
– Dermatitis
• Contraindications
– Renal compromised
• Interactions – Ototoxicity is potentiated by concomitant use of
diuretics
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Pyrazinamide
• Disrupts the membrane potential of the
myobacteria
• Used in children
• Pregnancy C
• Secreted into milk
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Side effects- pyrazinamide
• Hepatotoxicity, gout
• May alter results of urine dipstick test – so use
BUN, Creatinine
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MDR TB
• Resistant to isoniazid and rifampin
• May still treat with ethambutol and
pyrazinamide
• Add second line medications
• Treat at least 2 years
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Bedaquiline/Sirturo
• Recently Approved for MDRTB
• Taken orally
•
Metabolized by CYP3A• Ethnic differences
– Lower AUC seen in Black populations
• Up to 34%
– Does not appear to interfere with efficacy
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Side effects/interactions
bedaquiline
• Side effects
– Joint pain
– Nausea
– LFT increase – QT prolongation
– Death
•
Interactions CYP3A inhibitors
• Preg B
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Current International guidelines
non-resistant TB
• The initial phase should consist of two-fourmonths of isoniazid, rifampicin, pyrazinamide,and ethambutol.
• Isoniazid and ethambutol given for six months
is an alternative continuation phase regimenthat may be used when adherence cannot beassessed, but it is associated with a higherrate of failure and relapse, especially inpatients with HIV infection.
• Patients with tuberculosis and HIV infectionshould also receive co-trimoxazole asprophylaxis for other infections.
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MDR TB, XDR TB
• MDR – multi-drug resistant
– Resistant to at least isoniazid and rifampicin
– Requires 2 years treatment
–Add second line medication
• XDR-TB Extremely Drug Resistant
– Resistant to any fluoroquinolone, and at least one of three
injectable second-line drugs (capreomycin, kanamycin, and
amikacin),
WHO Global Task Force on XDR-TB October 2006
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XDR treatment
• One possible treatment regimen includes:
– Capreomycin
– Moxifloxacin
– Ethionamide
– Terixidone
– Pyrazinamide
– Clofazimine
– Aminosalisylic acid
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Research into treatment of XDR
• Meropenem + clavulanate
• Effective in vitro
• Science 2009, 323: 12151218
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Chemoprophylaxis of TB
• Patient has been exposed
• Has positive TB test, but no symptoms
• May have a history of TB
•
Includes those from at risk populations – eg: from Latin America, Asia, Africa…
• Household contact of TB patients
• Persons whose smear or culture results remain
positive after three months of therapy withantitubercular meds
• Treat for up to 9 months
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MYCOBACTERIUM AVIUM
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Mycobacterium avium
• Usually only seen severe immune
compromised patients (AIDS, steroids)
– Generally lung disease
• Rifabutin
• Macrolide antibiotics
• Quinolones
• Clofazimine
• Amikacin
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HANSON’S DISEASE
Leprosy
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Hanson’s disease
• 6 million worldwide
• Drugs currently used include combinations of
– Sulfones (including dapsone)
– Rifampin
– Clofazimine
– Thalidomide
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Hanson’s Dz - Recommended
treatment
• 2 years with first line
– Dapsone
– Clofazimine
• Rifampin
• May also require (particularly in HIV patient)
– Rifabutin
– Macrolides (clarithromycin, azithromycin)
– Fluoroquinolones
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Research
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Clofazimine/Lamprene
• Thought to inhibit RNA synthesis
• Also has anti-inflammatory properties
• Side effects
– May develop red discolorations on rough skin
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Thalidomide
• Highly teratogenic – never give to preg or
likely preg
• Useful in erythema nodosum leprosum
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TREATMENT OF FUNGALINFECTIONS
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Examples of anti-fungal medications
• Nystatin
• Terbinafine
• Griseofulvin
• Ketoconazole
• Fluconazole
•Clotrimazole
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Types of infections
• Candida• Dermatophytes
– Tricophyton
– Epidermophyton
– Microsporon• Tinnea ringworm
• Outer layer of the skin
• Common nosocomial infections
• Topical vs systemic treatments
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Fungi/yeast
Candida sp. (vulvovaginitis)C. Albicans
C. Glabrata (resistant strains)
Saccharomyces cerivisiae (hard to treat vaginitis)
Malessazia furfurPityrosporum orbiculare (tinnea versicolor)
Coccidiodes nimitis (Valley fever)
Cryptococcus neroformans (opportunistic meningitis)
Pneumocystis carinii (pneumonia in HIV)
PCP histoplasmosis (uncommon in AZ)
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Skin and soft tissue
• Candida – intertrigo
• Tinea (dermatophytes)
– Corporis
– Capitis
– Cruris
– Barbae
– Manum
– Versicolor (M.furfur, P.orbiculare, P.ovale)
• Onychomycosis (candida, dermatophytes, other)
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• Candida intertrigo
• Tinea pedis
• Candida onychomycosis
• Tinea capitus with keroin
• Tinea corporis
•
Tinea versicolor
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MEDICATIONS
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Examples of antifungal medications
• Gentian violet
• Nystatin
• Azoles
– Clotrimazole
– Tioconazole
• Terbinafine
• Griseofulvin• Many others
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Anti-fungals
• Nystatin (mycostatin) (swished around in the mouthfor thrush) – Yeast
• Griseofulvin – blocks cell division (not for pregnant) –
Dermatophytes• Terbinafine (Lamisil)
– Dermatophytes, candida, sporotrichosis
• Azole/triazole –
Broad spectrum, used in topical and systemic infections – Aspergillosis, crytococcus..
– Often used to prevent or treat fungus in AIDs patient
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Azole/triazole
Ketoconazole (Nizoral)
Fluconazole (Diflucan) systemic antifungal for AIDSpts – overused – doesn’t work as well now
Itraconazole (Sporanox)Poorly absorbed, requires acid
Voriconazole (Vfend)
Broadest spectrum, moderately well absorbed, some renal
excretionFor aspergellosis (FDA appr) and other off label
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Azoles, imidazoles, triazoles
• Inhibits microsomal enzymes
• Inhibits sterol biosynthesis in fungal
membranes
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Ketoconazole/Nizoral®
• Available OTC – Also available orally
– Don’t take with antihistamines like cimetidine
– Require GI acid for absorption, don’t take withantacids
• Reduces activity when taken with inducers ofcP450s like phenytoin and rifampin
•
Competes with CYP3A4, raises cyclosporineconcentrations – Potentially fatal with terfenadine and coumadin
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Ketoconazole side effects
• Nausea, anorexia, vomiting
• Allergy and hair loss
• Inhibits steroid biosynthesis
• Causes endocrine problems,
– Menstrual irregularities
– Gynecomastia
– Decreased libido and azoospermia
– Decrease testosterone, decrease cortisol synthesis
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Terbinafine /Lamisil
• Topical and oral
• Care with kidney and liver dysfunction (lower dose)
• Side effects
–
GI (AND, abdominal pain), rash, HA, dygeusia, anosmia,hepatotoxicity
• Preg B, not recommended during nursing
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Griseofulvin
• Dermaphytes – Ringworm
• Inhibits fungal mitosis through disruption of microtubules
• Side effects –
CNS (HA, dizziness, confusion), rash incl hives andphotosensitivity, GI (ANVD), granulocytosis and hepatotoxic longterm (use 6-9 months in nail fungus)
– Check CBC and LFT before, during and after treatment
• Both men and women should wait 1-6 months beforeattempting a pregnancy after termination of treatment
• Induces microsomal enzymes – Interacts with warfarin
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Amphotericin B/Fungizone
• Macrolide antibiotic• Colloid solution, Can be given iv
• Some resistance
•
Side effects – Fever and chills
– Respiratory problems, hypotension
• CI cardiac or pulmonary disease
•Mechanism – Ergosterol binding
– Pokes holes in fungal membrane
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Flucytosine
• Antimetabolic, pyrimidine analog
• Some resistance developing
• Can cause bone marrow depression
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Micafungin sodium
• New antifungal
• Approved for prophylaxis duringhematopoietic stem cell transplant (ppl’s bone
marrow killed off when getting bone marrow transplant)• Approved for esophageal candidiasis
• Interaction with nifedipine, increasesconcentration of nifedipine
• Side effects reported include hypersensitivity,renal and hepatic dysfunction, and hemolysis
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Posaconazole/Noxafil
• Effective against aspergillus and candida whenfluconazole and itraconazole don’t work
• Used for prophylaxis of invasive aspergillus andcandida in 13 years and older due to
immunocompromise• Adverse effects include hepatic toxicity
• Inhibits CYP3A4, caution with terfenadine,astemizole, cisapride, pimozide, halofantrine or
quinidine, may cause QT prolongation and torsades• Do not administer with ergot alkaloids
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NAFTIN (naftifine hydrochloride)
• Topical antifungal
– Effective for tineas
– Not for use in eyes, mouth or intravaginal
• Mechanisms
– Squalene 2, 3-epoxidase inhibitor
• Adverse effects
– Skin irritation
• Preg B
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PROTOZOA
Malaria
TrypanosomesLeishmaniasis
Giardiasis
Helminthiasis
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Medications used to treat parasites
• Chloroquin
• Metronidazole
• Piperazine
• Artemisinin
• Mebendazole, albendazole
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M l i
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Malaria
Plasmodium falciparumArtemisinin
Extract of wormwood shrub
Do not use alone
Chloroquine, primaquine, mefloquine
Atkovaquone/proguanil
Artesunate
Quinine, quinidine
Sulfonamides and tetracyclines
Used in combinations
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M l i t t t
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Malaria treatments
• Quinine wormwood
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L f t i / th (C t )
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Lumefantrin/aremether (Coartem)
• Currently works in chloroquine resistant
malaria
• Not for prevention
• CYP3A4 substrate
• Prolongs the QT interval
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S tibilit
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Susceptibility
• By region and species
– Middle East usu. Susceptible to chloroquine
– Sub-Saharan African usu. Resistant to chloroquine
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RTS S
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RTS,S
• Malaria kills ~900,000 each year
• Vaccine candidate, recombinant or
plasmodium with hepB surface angiten
• Reduced clinical malaria by 35%
• Effectiveness drops over time, but prevents
65 cases of malaria for every 100 children
vaccinated• Olotu A., Fegan G., Wambua J., et al. N Engl J Med 2013; 368:1111-1120
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Parasitic
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Parasitic
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Protozoa
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Protozoa
• Trypanosomiasis
• Leishmaniasis
• Amebiasis
• Giardiasis
• Trichomoniasis
• Toxopolasmosis
•Cryptorsporidiosis
• Pneumocystosis
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Antiparasitics
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(pediatric use okay)
• Metronidazole – basic good for parasites – Not in first trimester of pregnancy
• Paromomycin (Humatin)
– Can use in pregnancy
– Non-absorbed, good for lumenal ameoba
• Miscellaneous
– Nitazoxanide (Alinia)
• Cryptospridium parva (diarrhea)
– Pentamidine, suramin, nifurtimox, eflornithine, prizaquantel,
benzidazole• Tinidazole/Fasigyn
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Metronidazole
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Metronidazole
• Interferes with electron transport
• Drug of choice in giardiasis
• Also useful in bacterial infections
• Side effects include
– Headache, nausea, dysgeusia
– Some neurotoxicity
– Profound vomiting if take with alcohol
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Helminths
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Helminths
• Enterobius vermicularis (pinworm)• Ascaris lumbricoides (roundworm)
– Nematodes
• Ancylostoma duodenale (hookworm)
– Causes anemia
• Trichauris trichuria (whipworm)
• flukes
–Trematodes
• Tapeworms
– Cestodes
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Hookworm Pinworm
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Hookworm Pinworm
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Anthelminthics
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(pediatric use okay)
• Pyrantel/Antiminth – Pinworm only
• Mebendazole/Vermox
– Hookworm and roundworm – Single 100 mg dose for pinworm
– 100 mg bid for 3 days for other worms
• Albendazole/Albenza
– Hookworm and roundworm – Single 400 mg dose for most worms
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Antihelminthic drugs
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Antihelminthic drugs
• Benzimidazoles
• Diethylcarbamazine
• Ivermectin
• Piperazine
• Praziquantel
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Benzimidazoles
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Benzimidazoles
• Useful in GI tract
• Binds microtubules
• Includes mebendazole (Vermox)
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Piperazine/Vermizine
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Piperazine/Vermizine
• Causes flaccid paralysis
• Blocks acetylcholine binding
• Allow expulsion
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Praziquantal/Biltricide
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Praziquantal/Biltricide
• Causes spastic paralysis
• Higher dose activates host mechanisms
• Used for schistosomiasis and liver flukes
• Also for trematodes and cestodes
• Causes abdominal discomfort
•
Considered safe in children over 4
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Antiparasitics/anthelminthics-side
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effects
•Paromomycin – GI (ANVD,cramps), HA, dizziness, rash/itch
• Nitazoxanide
– Low dose, minimal side effect
• some GI, HA, increase LFTs
• Pyrantel
– Stays in lumen, minimal side effects, HA, GI