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282 Antibacterial Drugs

Drugs for Treating Mycobacterial Infections

In the past 100 years, advances in hygiene have led to a drastic decline in tubercular diseases in central Europe. Infection with

Mycobacterium tuberculosis could be diagnosed increasingly earlier and in most cases be cured by a systematic long-term therapy (6–12 months) with effective chemotherapeutics. Worldwide, however, tuberculosis has remained one of the most threatening diseases. In developing countries, long-term combination therapy is scarcely realizable. Therapeutic success is thwarted by a lack of adequate (medical) infrastructure and financial resources, and insuf cient compliance of patients; as a result, millions of persons die annually of tuberculosis infections. The insuf cient treatment entails an additional bad consequence: more and more mycobacterial strains develop resistance and cannot be adequately treated. Patients suffering from immune deficiency are affected more severely by infections with M. tuberculosis.

Antitubercular drugs (1)

Drugs of choice are isoniazid, rifampin, and ethambutol, along with streptomycin and pyrazinamide. Less well tolerated, secondline agents include p-aminosalicylic acid, cycloserine, viomycin, kanamycin, amikacin, capreomycin, and ethionamide.

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. In the bacterium it is converted to isonicotinic acid, which is membrane impermeable and hence likely to accumulate intracellularly. Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation. Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin B6 (pyridoxine), and liver damage.

Rifampin. Source, antibacterial activity, and routes of administration are described on p.276. Although mostly well tolerated, this drug may cause several adverse effects

including hepatic damage, hypersensitivity with flulike symptoms, disconcerting but harmless red/orange discoloration of body fluids, and enzyme induction (failure of oral contraceptives). Concerning rifabutin, see

p.276.

Pyrazinamide exerts a bactericidal action

byan unknown mechanism. Itisgiven orally. Pyrazinamide may impair liver function; hyperuricemia results from inhibition of renal urate elimination.

Streptomycin must be given i.v. like other aminoglycoside antibiotics (p.280). It damages the inner ear and the labyrinth. Its nephrotoxicity is comparatively minor

Ethambutol. The cause of ethambutol’s specific antitubercular action is unknown. It is given orally. It is generally well tolerated, but may cause dose-dependent reversible disturbances of vision (red/green blindness, visual field defects).

Antileprotic drugs (2)

Rifampin is frequently given in combination with one or both of the following twoagents.

Dapsone is a sulfone that, like sulfonamides, inhibits dihydrofolate synthesis (p.274). It is bactericidal against susceptible strains of M. leprae. Dapsone is given orally. The most frequent adverse effect is methemoglobinemia with accelerated erythrocyte degradation (hemolysis).

Clofazimine is a dye with bactericidal activity against M. leprae and anti-inflamma- tory properties. It is given orally but is incompletely absorbed. Because of its high lipophilicity, it accumulates in adipose and other tissues and leaves the body only rather slowly (t½ ~ 70 days). Red-brown skin pigmentation is an unwanted effect, particularly in fair-skinned patients.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Drugs for Treating Mycobacterial Infections

283

A. Drugs used to treat infections with mycobacteria (1. tuberculosis, 2. leprosy)

 

 

 

Combination therapy

 

 

Reduced risk of

 

Reduction of dose and of

 

 

bacterial resistance

 

risk of adverse reactions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Isoniazid

 

 

Pyrazinamide

ONH NH2

C

 

 

O

 

 

 

N C

 

 

 

NH2

N

Mycobacterium

N

CNS damage

tuberculosis

 

and peripheral

 

 

Liver damage

neuropathy

O

OH

 

(Vit. B6 administration)

 

C

 

Liver damage

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

Ethambutol

 

 

 

 

 

 

 

 

 

Isonicotinic acid

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

CH3

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

C

 

 

CH2

 

 

CH2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

HO CH2

CH

 

 

HC CH2

OH

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

HN

(CH2)2

NH

 

 

 

 

 

 

 

Nicotinic acid

Optic nerve damage

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Rifampicin

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H3C

CH3

 

 

 

 

 

 

 

 

 

 

 

 

H3C

OH

 

 

 

 

 

 

 

 

 

 

1.

H3CCOO

 

OH

O

CH3

 

 

 

 

 

 

 

 

H3C

CH3OH

OH

 

 

 

 

 

 

 

 

 

 

H3CO

O

 

 

NH

N

N N CH3

 

 

 

2.

 

 

 

 

CH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

O

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Liver damage

 

 

 

 

 

 

 

 

 

 

 

O

and enzyme induction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H2N

 

C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

 

 

 

p-Aminobenzoic acid

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Folate

Dapsone

 

 

 

 

 

 

 

 

 

 

 

 

synthesis

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

H2N

 

S

 

NH2

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Mycobacterium

 

Hemolysis

 

 

 

 

 

 

 

 

 

 

 

leprae

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Streptomycin

an aminoglycoside antibiotic

H2N

C

NH

 

 

 

NH

 

 

HO

 

OH

 

 

 

 

NH2

HO

 

N

C

NH

 

O

H

 

 

 

 

HN

CH3

O

 

 

 

O

 

OH

 

 

 

H3C

C

OH

O

 

H

OH

 

 

 

OCH2OH

Vestibular and cochlear ototoxicity

Clofazimine

Cl

CH3

NN CH

CH3

NNH

Cl

Skin discoloration

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

284 Antifungal Drugs

Drugs Used in the Treatment of Fungal Infections

Infections due to fungi are usually confined to the skin or mucous membranes: local or superficial mycosis. However, in immune deficiency states, internal organs may also be affected: systemic or deep mycosis.

Mycoses are most commonly due to dermatophytes, which affect the skin, hair, and nails following external infection, and to Candida albicans, a yeast organism normally found on body surfaces, which may cause infections of mucous membranes, less frequently of the skin or internal organs when natural defenses are impaired (immunosuppression, or damage of microflora by broadspectrum antibiotics).

Imidazole derivatives inhibit synthesis of ergosterol, an integral constituent of cytoplasmic membranes of fungal cells. Fungi stop growing (fungistatic effect) or die (fungicidal effect). The spectrum of affected fungi is very broad. Because they are poorly absorbed and poorly tolerated systemically, most imidazoles are suitable only for topical use (clotrimazole, econazole, oxiconazole and other azoles). Fluconazole and itroconazole are newer orally effective triazole derivatives. Owing to its hydroxyl group, fluconazole is suf ciently water-soluble to allow formulation as an injectable solution. Both substances are slowly eliminated (plasma t½ ~ 30 hours). The topically active allyl amine naftidine and the morpholine amorolfine also inhibit ergosterol synthesis, albeit at a different step. Both are for topical use.

The polyene antibiotics amphotericin B and nystatin are of bacterial origin. They insert themselves into fungal cell membranes (probably next to ergosterol molecules) and cause formation of hydrophilic channels. Amphotericin B is active against most organisms responsible for systemic mycoses. Because polyene antimycotics are nonabsorbable, it must be given by infusion, which is, however, poorly tolerated (chills, fever, CNS disturbances, impaired renal function, and

phlebitis at the infusion site). Applied topically to skin or mucous membranes, amphotericin B is useful in the treatment of candidal mycosis. Because of the low rate of enteral absorption, oral administration in intestinal candidiasis can be considered a topical treatment. Likewise, nystatin is only used topically (e.g., oral cavity, gastrointestinal tract) against candidiasis.

Flucytosine is converted in candidal fungi to 5-fluorouracil by the action of a specific fungal cytosine deaminase. As an antimetabolite, this compound disrupts DNA and RNA synthesis (p.300), resulting in a fungicidal effect. Given orally, flucytosine is rapidly absorbed. It is often combined with amphotericin B to allow dose reduction of the latter.

Caspofungin is a cyclic polypeptide that inhibits synthesis of the fungal cell wall. It can be used in systemic mycoses due to aspergillus fungi when amphotericin B or itroconazole cannot be employed. It is given by infusion and causes various adverse effects.

Griseofulvin originates from molds and has activity only against dermatophytes. It presumably acts as a spindle poison to inhibit fungal mitosis. Although targeted against local mycoses, griseofulvin must be used systemically. It is incorporated into newly-formed keratin. “Impregnated” in this manner, keratin becomes unsuitable as a fungal nutrient. The time required for the eradication of dermatophytes corresponds to the renewal period of skin, hair, or nails. Griseofulvin may cause uncharacteristic adverse effects. Because of its cumbersome application, this antimycotic is becoming obsolete.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Drugs Used in the Treatment of Fungal Infections

285

A.Antifungal drugs

Cell wall

Cytoplasmic membrane

Ergosterol

Synthesis

Mitotic spindle

 

DNA/RNA

 

 

metabolism

 

 

OH

 

OH

N

F

N

 

 

 

HO

N

HO

N

5-Fluorouracil

Uracil

cell

 

Cytosine

 

Fungal

 

deaminase

 

 

 

 

 

NH 2

 

NH 2

 

N

F

N

 

 

HO

N

HO

N

Flucytosine

 

Caspofungin

Inhibition of

 

cell wall synthesis

Azoles

 

 

 

 

 

Imidazoles topical,

 

 

 

 

e.g., clotrimazole

 

 

 

 

N

C

 

 

 

 

N

 

 

 

 

 

Cl

 

 

 

 

Triazoles systemic,

 

 

 

 

e.g., fluconazole

 

OH

 

 

 

N

 

 

N

 

CH2

C

CH2

 

N

N

 

N

 

 

F

N

 

 

 

 

 

 

 

 

F

 

 

Griseofulvin

 

 

 

 

Mold fungi

Incorporation into growing skin, hair, nails “Impregnation effect”

Polyene Antibiotics

Streptomyces bacteria

Amphotericin B

Nystatin

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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