3 Mycobacterium Fungus Parasite Handout

8/12/2019 3 Mycobacterium Fungus Parasite Handout

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Mycobacterium

Fungal

Parasitic infections



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

Southwest College of NaturopathicMedicine

2



MYCOBACTERIUMTUBERCULOSIS, LEPROSY, AVIUM


4



TUBERCULOSIS

TB, MTB, XTB


5



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


6



Medications used to treat TB

• Always Tx with combinations of medications –

at least 4

• Choice depends on status of infection

– TB

– MTB

– XTB


7



First line medications – for plain TB,

NOT for MTB or XTB

• Isoniazid

• Rifampin

•

Ethambutol• Streptomycin

• Pyrazinamide


8



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


9



Overview of mechanisms


10



Detailed look at first line medications

• Non-drug resistant TB only

• Use all 4 for at least 6-9 months

– Isoniazid

– Rifampin

– Pyrazinamide

– Ethambutol


11



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


12



Mechanism of action- isoniazid

• Specific for mycolic acids

– Inhibitor of lipid synthesis

– Inhibitor of nucleic acid synthesis

– Inhibitor of cell wall synthesis


13



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)


14



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


16



Rifampin/Rifadin

• Produced by streptomyces mediterranei

• Fairly broad spectrum

•

Always used in combination to avoidresistance

• Inhibits RNA polymerase of mycobacteria

–

Prevents formation of RNA


17



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


19



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


20



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


21



Interactions- ethambutol

• Do not take at the same time as aluminum

containing antacids


22



Streptomycin


23

• Black box warning neurotoxicity

• Side effects

– Ototoxicity

– Dermatitis

• Contraindications

– Renal compromised

• Interactions – Ototoxicity is potentiated by concomitant use of

diuretics



Pyrazinamide

• Disrupts the membrane potential of the

myobacteria

• Used in children

• Pregnancy C

• Secreted into milk


24



Side effects- pyrazinamide

• Hepatotoxicity, gout

• May alter results of urine dipstick test – so use

BUN, Creatinine


25



MDR TB

• Resistant to isoniazid and rifampin

• May still treat with ethambutol and

pyrazinamide

• Add second line medications

• Treat at least 2 years


26



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


27



Side effects/interactions

bedaquiline

• Side effects

– Joint pain

– Nausea

– LFT increase – QT prolongation

– Death

•

Interactions CYP3A inhibitors

• Preg B


30



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.


31



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


32



XDR treatment

• One possible treatment regimen includes:

– Capreomycin

– Moxifloxacin

– Ethionamide

– Terixidone

– Pyrazinamide

– Clofazimine

– Aminosalisylic acid


33



Research into treatment of XDR

• Meropenem + clavulanate

• Effective in vitro

• Science 2009, 323: 12151218


34



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


35



MYCOBACTERIUM AVIUM


36



Mycobacterium avium

• Usually only seen severe immune

compromised patients (AIDS, steroids)

– Generally lung disease

• Rifabutin

• Macrolide antibiotics

• Quinolones

• Clofazimine

• Amikacin


37



HANSON’S DISEASE

Leprosy


38



Hanson’s disease

• 6 million worldwide

• Drugs currently used include combinations of

– Sulfones (including dapsone)

– Rifampin

– Clofazimine

– Thalidomide


39



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


40



Research


41



Clofazimine/Lamprene

• Thought to inhibit RNA synthesis

• Also has anti-inflammatory properties

• Side effects

– May develop red discolorations on rough skin


43



Thalidomide

• Highly teratogenic – never give to preg or

likely preg

• Useful in erythema nodosum leprosum

Southwest College of NaturopathicMedicine 44



TREATMENT OF FUNGALINFECTIONS




Examples of anti-fungal medications

• Nystatin

• Terbinafine

• Griseofulvin

• Ketoconazole

• Fluconazole

•Clotrimazole




Types of infections

• Candida• Dermatophytes

– Tricophyton

– Epidermophyton

– Microsporon• Tinnea ringworm

• Outer layer of the skin

• Common nosocomial infections

• Topical vs systemic treatments




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)




Skin and soft tissue

• Candida – intertrigo

• Tinea (dermatophytes)

– Corporis

– Capitis

– Cruris

– Barbae

– Manum

– Versicolor (M.furfur, P.orbiculare, P.ovale)

• Onychomycosis (candida, dermatophytes, other)




• Candida intertrigo

• Tinea pedis

• Candida onychomycosis

• Tinea capitus with keroin

• Tinea corporis

•

Tinea versicolor




MEDICATIONS




Examples of antifungal medications

• Gentian violet

• Nystatin

• Azoles

– Clotrimazole

– Tioconazole

• Terbinafine

• Griseofulvin• Many others




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

Southwest College of Naturopathic

Medicine 55



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


Medicine 56



Azoles, imidazoles, triazoles

• Inhibits microsomal enzymes

• Inhibits sterol biosynthesis in fungal

membranes


Medicine 57



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


Medicine 59



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


Medicine 60



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


Medicine 62



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


Medicine 63



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


Medicine 65



Flucytosine

• Antimetabolic, pyrimidine analog

• Some resistance developing

• Can cause bone marrow depression


Medicine 66

i f i di



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

67

P l /N fil



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

68



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


Medicine 69



PROTOZOA

Malaria

TrypanosomesLeishmaniasis

Giardiasis

Helminthiasis


Medicine 70



Medications used to treat parasites

• Chloroquin

• Metronidazole

• Piperazine

• Artemisinin

• Mebendazole, albendazole


Medicine 71

M l i



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

72

M l i t t t



Malaria treatments

• Quinine wormwood

73



L f t i / th (C t )



Lumefantrin/aremether (Coartem)

• Currently works in chloroquine resistant

malaria

• Not for prevention

• CYP3A4 substrate

• Prolongs the QT interval

76

S tibilit



Susceptibility

• By region and species

– Middle East usu. Susceptible to chloroquine

– Sub-Saharan African usu. Resistant to chloroquine

77

RTS S



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

78

Parasitic



Parasitic

79

Protozoa



Protozoa

• Trypanosomiasis

• Leishmaniasis

• Amebiasis

• Giardiasis

• Trichomoniasis

• Toxopolasmosis

•Cryptorsporidiosis

• Pneumocystosis

80



Antiparasitics



(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

82

Metronidazole



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

83



Helminths



Helminths

• Enterobius vermicularis (pinworm)• Ascaris lumbricoides (roundworm)

– Nematodes

• Ancylostoma duodenale (hookworm)

– Causes anemia

• Trichauris trichuria (whipworm)

• flukes

–Trematodes

• Tapeworms

– Cestodes

85

Hookworm Pinworm



Hookworm Pinworm

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Anthelminthics



(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

87

Antihelminthic drugs



Antihelminthic drugs

• Benzimidazoles

• Diethylcarbamazine

• Ivermectin

• Piperazine

• Praziquantel

88

Benzimidazoles



Benzimidazoles

• Useful in GI tract

• Binds microtubules

• Includes mebendazole (Vermox)

89



Piperazine/Vermizine



Piperazine/Vermizine

• Causes flaccid paralysis

• Blocks acetylcholine binding

• Allow expulsion

91

Praziquantal/Biltricide



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

92

Antiparasitics/anthelminthics-side



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

3 Mycobacterium Fungus Parasite Handout

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