Mycobacterium tuberculosis

Mycobacterium leprae

Mycobacteria
intrinsically resistant to most antibiotics  they grow slowly compared with
other bacteria  Antibiotics ineffective

can also be dormant and thus completely resistant to many drugs or killed only
very slowly

The lipid-rich mycobacterial cell wall is impermeable to many agents

Mycobacterial species are intracellular pathogens, and organisms residing within

macrophages are inaccessible to drugs that penetrate these cells poorly
DRUGS USED IN TUBERCULOSIS
 Isoniazid penetrates into macrophages and is active
ISONIAZID against both extracellular and intracellular organisms.

Isoniazid inhibits synthesis of mycolic acids, which are essential

components of mycobacterial cell walls.

Adverse Reactions
Fever and skin rashes

Isoniazid-induced hepatitis

Peripheral neuropathy Isoniazid promotes

excretion of pyridoxine, and this toxicity is readily reversed
by administration of pyridoxine in a dosage as low as 10 mg/d.

pyridoxine deficiency  memory loss, psychosis, and seizuresanemia, tinnitus,

and gastrointestinal discomfort.
 Rifapentine Rifabutin
RIFAMPIN
RIFAMYCINS
Inhibits DNA-dependent RNA
polymerase, thereby blocking Bactericidal activity against susceptible bacteria and
production of RNA mycobacteria
• resistance rapidly emerges when used as a single drug in the
treatment of active infection

Toxicity: Rash, nephritis, thrombocytopenia, cholestasis,

flu-like syndrome with intermittent dosing
ETHAMBUTOL
Inhibits mycobacterial arabinosyl
transferases, which are involved in the
polymerization reaction of arabinoglycan 
an essential component of the mycobacterial
cell wall
Bacteriostatic activity against susceptible
mycobacteria

Toxicity: Retrobulbar neuritis

PYRAZINAMIDE
Not fully understood
• pyrazinamide is converted to the
active pyrazinoic acid under acidic
conditions of macrophage lysosomes

Bacteriostatic activity against susceptible

strains of M tuberculosis
“Sterilizing” agent used during first 2 months of therapy
• allows total duration of therapy to be shortened to 6 months

Toxicity: Hepatoxicity, hyperuricemia

STREPTOMYCIN
Prevents bacterial protein synthesis by
binding to the S12 ribosomal subunit

Bactericidal activity against susceptible

mycobacteria
Used in tuberculosis when an injectable drug is
needed or desirable and in treatment of drug-
resistant strains

Toxicity: Nephrotoxicity, ototoxicity

Antifungal
Agents
POLYENE MACROLIDE Amphotericin B

PYRIMIDINE ANALOG Flucytosine

AZOLES Ketoconazole
Itraconazole
Fluconazole

ECHINOCANDINS Caspofungin
Micafungin

ALLYLAMINE Terbinafine
POLYENE MACROLIDE

produced by Streptomyces nodosus

Amphotericin B binds to ergosterol and alters the
permeability of the cell

Forms pores in fungal membranes (which contain ergosterol) Loss of intracellular contents through pores is
but not in mammalian (cholesterol-containing) membranes fungicidal

Localized and systemic Infusion-Related Toxicity

• Candidemia • Oral but not absorbed effective only
• Cryptococcus on fungi within the lumen of the tract toxicity
• Histoplasma • IV for systemic use
• Blastomyces • intrathecal for fungal meningitis
• Coccidioides • topical for ocular and bladder infection
Cumulative Toxicity
• Aspergillus
PYRIMIDINE ANALOG

Flucytosine is a water-soluble pyrimidine

analog related to the chemotherapeutic agent fluorouracil
(5-FU)

Interferes with DNA and RNA synthesis selectively in fungi

Cryptococcus and chromoblastomycosis infections

Toxicity: Myelosup-pression
AZOLES

The imidazoles consist of ketoconazole, miconazole, and clotrimazole

The triazoles include itraconazole, fluconazole, voriconazole, and posaconazole.

Blocks fungal P450 enzymes and interferes with ergosterol synthesis

The selective toxicity of azole drugs results from their greater affinity for fungal than for human
cytochrome P450 enzymes

Imidazoles exhibit a lesserdegree of selectivity than the triazoles, accounting for their higher
incidence of drug interactions and side effects.
KETOCONAZOLE
Ketoconazole was the first oral azole introduced into clinical use

It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome

P450 enzymes  As a result, systemic ketoconazole has fallen out of clinical use in the USA

ITRACONAZOLE
Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100–400 mg/d

It does not affect mammalian steroid synthesis, and its effects on the metabolism of other hepatically
cleared medications are much less than those of ketoconazole

Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis.

FLUCONAZOLE
Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration

oral bioavailability is high

Drug interactions are also less common because fluconazole has the least effect of all the azoles
on hepatic microsomal enzymes

Fluconazole is the azole of choice in the treatment and secondary prophylaxis of cryptococcal
meningitis
Fluconazole is the agent most commonly used for the treatment of mucocutaneous candidiasis

Fluconazole displays no activity against aspergillus or other filamentous fungi.

Antifungal topical
miconazole clotrimazole ketoconazole

Oral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to nystatin
Miconazole &clotrimazole cream, both agents are useful for dermatophytic infections, including tinea corporis,
tinea pedis, and tinea cruris

Topical and shampoo forms of ketoconazole are also available and useful in the treatment
Of seborrheic dermatitis and pityriasisversicolor
Antifungal topical
Nystatin is a polyene macrolide much like amphotericin B

It is too toxic for parenteral administration and is only used topically

Nystatin is currently available in creams, ointments, suppositories, and other forms for
application to skin and mucous membranes

it is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract  has little
toxicity

Nystatin is active against most Candida Sp

indications : oropharyngeal thrush, vaginal candidiasis, and intertriginous candida infections.

ECHINOCANDINS Caspofungin anidulafungin
IV only Micafungin
Blocks glucan synthase 
Prevents synthesis of fungal cell
wall
Toxicity:
Minor gastrointestinal effects,
flushing
• Interactions:
Increases cyclosporine
Fungicidal Candida sp also levels (avoid combination

used in aspergillosis
ALLYLAMINE Terbinafine

Inhibits epoxidation of squalene in fungi

Reduces ergosterol  prevents synthesis of
fungal cell membrane

Mucocutaneous fungal infections

Gastrointestinal upset, headache,

hepatoxicity