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

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Infectious diseases
Mycobacterium
Tuberculosis
MDR TB
XTB
Mycobacterium avium
Hansens disease
Fungi and yeast
Protozoa
Malaria
Trypanosomes
Leishmaniasis
Giardiasis
Helminthiasis
Pinworm
Roundworm
Hookworm
Whipworm
Flukes
Tapeworm

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MYCOBACTERIUM
TUBERCULOSIS, 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 development
of 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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Genetic polymorphism
Fast vs slow acetylators
Fast acetylation
Autosomal dominant
Heterozygous or homozygous
Inuit and Japanese
Slow acetylation
Renal function is more important
Scandinavians, Jews and North African Caucasians

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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 avoid
resistance
Inhibits RNA polymerase of mycobacteria
Prevents formation of RNA
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Pharmacokinetics- rifampin
Oral
Lipid soluble, widely distributed
Orange-red urine, feces, saliva, tears, sweat

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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

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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Bedaquiline dosing
Recommended dosage 24 weeks
Weeks 1-2: 400 mg (4 tablets of 100 mg) once
daily with food
Weeks 3-24: 200 mg (2 tablets of 100 mg) 3
times per week with food (with at least 48
hours between doses) for a total dose of 600
mg per week.
Swallow tablet whole with water.
Avoid alcohol use during treatment.
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Bedaquline black box warning
WARNING
An increased risk of death was seen in the
SIRTURO treatment group (9/79, 11.4%)
compared to the placebo treatment group
(2/81, 2.5%) in one placebo-controlled trial.
Only use SIRTURO when an effective treatment
regimen cannot otherwise be provided.
QT prolongation can occur with SIRTURO. Use
with drugs that prolong the QT interval may
cause additive QT prolongation.
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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-four
months of isoniazid, rifampicin, pyrazinamide,
and ethambutol.
Isoniazid and ethambutol given for six months
is an alternative continuation phase regimen
that may be used when adherence cannot be
assessed, but it is associated with a higher
rate of failure and relapse, especially in
patients with HIV infection.
Patients with tuberculosis and HIV infection
should also receive co-trimoxazole as
prophylaxis 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 with
antitubercular 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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HANSONS DISEASE
Leprosy
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Hansons disease
6 million worldwide
Drugs currently used include combinations of
Sulfones (including dapsone)
Rifampin
Clofazimine
Thalidomide

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Hansons 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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Sulfones
Dapsone
Like the sulfonamides (problem for ppl with sulfa
drug allergies)
Oral
Side effects include hemolysis and blood problems
Worse in patients with genetic deficiency in NADH
dependent methemoglobin reductase

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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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Mycobacterium in tattoo ink
N Engl J Med 2012; 367:1020-1024
Relatively common
Result of an outbreak in late 2011 in
Rochester NY
persistent, raised, erythematous rash in the
tattoo area
M. chelonae infection
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TREATMENT OF FUNGAL
INFECTIONS
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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 furfur
Pityrosporum 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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Treatment of skin fungal infections
Candida
Topical nystatin or azoles, refer if dont respond
Tinea (dermatophytes)
Topical terbinafine or azole for up to 4 weeks, griseofulvin
2-8 weeks, prefer itraconazole or fluconazole among azoles
Tinea versicolor (over large body part)
Topical terbinafine or azoles, systemic azole (daily for 7
days, or large single dose, flucon 400, repeat in one week
Onychomycosis
Systemic necessary
Griseo 6-9 months, terbinafine 25-500 up to 6 months
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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 mouth
for 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 AIDS
pts overused doesnt work as well now
Itraconazole (Sporanox)
Poorly absorbed, requires acid
Voriconazole (Vfend)
Broadest spectrum, moderately well absorbed, some renal
excretion
For 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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Azole side effects
All may cause GI, CNS, rash, hepatotoxicity,
significant drug interactions.
Ketoconazole worst side effects in humans (prevents
endogenous production of hormones)
Fluconazole
Itraconazole
N, rash, VD, HA, fatigue, edema, HT, decrease libido
Voriconazole
Visual changes (30%), N, rash, fever, V HA tachycardia, BP
changes

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Ketoconazole/Nizoral
Available OTC
Also available orally
Dont take with antihistamines like cimetidine
Require GI acid for absorption, dont take with
antacids
Reduces activity when taken with inducers of
cP450s like phenytoin and rifampin
Competes with CYP3A4, raises cyclosporine
concentrations
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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Fluconazole /Diflucan
Oral, systemic
Lipid soluble, found in secretions and CSF
Renal excretion, Caution in renal dysfunction
Increases plasma concentration of phenytoin
and warfarin, rifabutin and zidovudine
Useful in candidiasis and other fungi
Used chronically in HIV with coccidiomycosis
Causes nausea and vomiting with high dose
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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 and
photosensitivity, GI (ANVD), granulocytosis and hepatotoxic long
term (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 before
attempting a pregnancy after termination of treatment
Induces microsomal enzymes
Interacts with warfarin
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Nystatin
Considered a topical, stays in gut when
swallowed
Polyene macrolide antibiotic
Not absorbed
Used in thrush and nail fungus
Side effects
GI (ANVD, abdominal pain), rash, hypersensitivity
possible


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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 during
hematopoietic stem cell transplant (ppls bone
marrow killed off when getting bone marrow transplant)
Approved for esophageal candidiasis
Interaction with nifedipine, increases
concentration of nifedipine
Side effects reported include hypersensitivity,
renal and hepatic dysfunction, and hemolysis
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Posaconazole/Noxafil
Effective against aspergillus and candida when
fluconazole and itraconazole dont work
Used for prophylaxis of invasive aspergillus and
candida 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
Trypanosomes
Leishmaniasis
Giardiasis
Helminthiasis
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Medications used to treat parasites
Chloroquin
Metronidazole
Piperazine
Artemisinin
Mebendazole, albendazole

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Malaria
Plasmodium falciparum
Artemisinin
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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Malaria treatments
Quinine wormwood
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Chloroquine
Generally considered of low toxicity
Concentrated in liver
Useful in amebiasis
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Atovaquone/Mepron
Lipophilic, oral but poorly absorbed
Interferes with electron transport in parasites
Few side effects, rash, fever, vomiting
Not for use in children, older patients,
pregnancy and lactation
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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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Susceptibility
By region and species
Middle East usu. Susceptible to chloroquine
Sub-Saharan African usu. Resistant to chloroquine
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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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Protozoa
Trypanosomiasis
Leishmaniasis
Amebiasis
Giardiasis
Trichomoniasis
Toxopolasmosis
Cryptorsporidiosis
Pneumocystosis
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Protozoa
Giardia lamblia (diarrhea)
E.histolytica (GI, HIV associated)
Trichomoniasis vaginalis (vaginitis)
Toxoplasmosis gondii
Cryptosporidium parvum (diarrhea, HIV
associated)
Outbreaks in municipal water supplies
Microsporidium (diarrhea, HIV associated)

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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
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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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Tindamax
Tinidazole/Fasigyn
Approved for treatment of
Trichomonas vaginalis
Giardia duodenalis
Entamoeba histolytica
Not for use in pregnancy or nursing (dont resume
nursing for 72 hours following last dose)
Disulfiram like reaction, watch for neurological
reactions (dizziness, ataxia..)
GI symptoms common, including dysgeusia
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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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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

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Antihelminthic drugs
Benzimidazoles
Diethylcarbamazine
Ivermectin
Piperazine
Praziquantel
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Benzimidazoles
Useful in GI tract
Binds microtubules
Includes mebendazole (Vermox)
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Ivermectin
Nematodes and insects
Paralyzes muscles
May activate glutamate gated Cl channel
Oral
Causes CNS effects only at high doses
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Piperazine/Vermizine
Causes flaccid paralysis
Blocks acetylcholine binding
Allow expulsion

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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
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
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