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ANTIBIOTICS 3

(YEAR 1 TERM 2) (Session 2014-2015)

by

Professor

Dr. Naeem Hasan Khan

17.04.2015

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MACROLIDE ANTIBIOTICS

Are a group of antibiotics with a macrocyclic lactone structure to which one or more “deoxy sugars “ are attached.

ERYTHROMYCIN

Binds irreversibly to a site of the bacterial ribosome thus inhibiting protein synthesis.

Bacteriostatic but acts as bacteriocidal in higher doses.

Administration: • Erythromycin base is destroyed by gastric acid, thus enteric coated

tablets or esterified forms of the antibiotics are administered. • I.V. is associated with high incidence of thrombophlebitis.17/4/2015

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Conti.,

Distribution :• Erythromycin is well distributed to all body fluids, except CSF.• Diffuses in the prostatic fluid• Concentrate in liver.

Elimination :• Erythromycin is extensively metabolized.• Inhibit the oxidation of many drugs through interaction with

cytochrome 450.• Interferes with the metabolise of theophylline and

carbamazepin.

Excretion :• Primarily concentrated and excreted in bile.• Inactive metabolites are excreted in urine.17/4/2015

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Conti.,

Antibacterial spectrum of erythromycin:

Straphylococcus aureus. Streptococcus pyogenes. Streptococcus pneumoniae. Corynebacterium diphtheriae. Morexella cattarhalis. Neisseria gonorrhoeae. Mycoplasma pneumoniae. Chlamydia trachomatis. Chalamydia psittaci.

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Uses : It is a drug of choice for urogenital infections occuring during pregnancy. Is very effective in atypical pneumonia. Is classical drug to use in syphilis when patient is allergic to penicillins. Effective against many of same organisms as penicillin. It may be used in patients with penicillin allergy. Resistance to erythromycin is becoming a serious problem.

Adverse effects of erythromycin :• Epigastric distress.• Cholestatic jaundice.• Ototoxicity.

Contraindication : in hepatic dysfunction.

Interactions : with digoxin and food, interferes with the absorption of erythromycin.17/4/2015

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AZITHROMYCIN

• Binds irreversibly to a site of the bacterial ribosome thus inhibiting protein synthesis.

• Interfere tranpeptidation.• Bacteriostatic but acts as bacteriocidal in higher doses.

Antibacterial spectrum of Azithromycin:

Chlamydia trachomatis. Chalamydia psittaci. Bordetella pertussis. Campylobacter influenzae. Legionella pneumophila.

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Administration :• Azithromycin is stable towards stomach acid.• Adequately absorbed upon oral administration.• I.V. is associated with much less (1%) incidence of

thrombophlebitis as compared to erythromycin.

Distribution of Azithromycin :• Concentrate in liver.• Widely distributed in tissues.• Serum levels of azithromycin is low.• Concentrated in neutrophils and fibroblasts.• Longest half-life.

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Conti.,

Elimination of Azithromycin :• As that of erythromycin.

Excretion :• Extensively metabolized and excreted through bile.

Uses:• More active in respiratory infections than erythromycin.• Less active against streptococci and straphylococci than erythromycin.• Preferred therapy in urithritis, endocervical and rectal infections.• Is alternative to tetracyclines.• Is a drug of choice in “legionellosis” disease.

Adverse effects of Azithromycin:• Same as for erythromycin.• Cross resistance occurs with erythromycin.

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CLARITHROMYCIN

• This antibiotic has the spectrum of antibacterial activity similar to that of erythromycin.

• It is effective against “Haemophilus influenzae”.

• A drug of choice, in combination with other drugs in eradicating “Halicobacter pylori”

(bacteria in stomach responsible for production of high HCL acid, leading to peptic ulcer).

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Administration andFate of some ofmacrolideantibiotics

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Some properties of macrolide antibiotics

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AMINOGLYCOSIDES

Aminoglycoside (with 2 amino sugars joined by a glycosidic linkage) antibiotics

had been the mainstays for the treatment of serious infections due to aerobic Gram-negative bacilli.

However, their use is associated with serious toxicities, they have been replaced by safer antibiotics, such as, third and fourth generations of cephalosporins, Carbapenems and Flouroquinolones.

All members of this group inhibit the bacterial protein synthesis. They acts inside the cell by binding to the ribosome. They are bactericidal All members of this class resemble one another in therapeutic,

pharmacokinetic and toxic properties. 17/4/2015

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Pharmacokinetics : All aminoglycosides are water soluble and do nor cross

readily cell membrane. Poor absorption through intestinal tract. Administered I.V. or I.M. Distribute mainly to extra cellular fluid. Less transfer to CSF. As a single daily dose is the current practice.

Elimination : All of them are eliminated unchanged mainly by glomerular

filtration and attain high level in urine.

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Administration and fate of Aminoglycosides

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Antibacterial spectrum of Aminoglycosides : Staphylococci. Aerobic Gram-negative bacteria (All Enterobacteriaceae). Bacterial resistance of aminoglycosides is increasing due to

variable problems.

Uses :• Gram-negative bacillary infections (septicaemia, renal, pelvic

and abdominal sepsis).• Bacterial endocarditis.• Tuberculosis and plague.• Topical use.

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Adverse activity of Aminoglycosides :

Aminoglycoside toxicity is a risk at high doses or longer duration.

Ototoxicity. Nephrotoxocity. Neuromuscular blockade. Rashes. bone marrow depression. Haemolytic anaemia.

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GENTAMYCIN

is a bactericidal antibiotic that works by irreversibly binding the 30S subunit of the bacterial ribosome, interrupting protein synthesis. This mechanism of action is similar to other aminoglycosides.

Used against infections, particularly those caused by Gram-negative organisms.

However, Gentamicin is not used for Neisseria gonorrhoeae and N. meningitidis.

Gentamicin is also ototoxic and nephrotoxic ( with this toxicity remaining a major problem in clinical use).

Gentamicin is one of the few heat-stable antibiotics that remain active even after autoclaving.

Patients with cyctic fibrosis eliminate Gentamycin rapidly. When applied to eyes, give effective corneal concentration.17/4/2015

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STREPTOMYCIN Streptomycin is a bacterial protein synthesis inhibitor, binds to

the small subunit of the bacterial ribosome. Superseded as a first line choice for tuberculosis against

Mycobacterium tuberculosis and Staphylococcus aureus. Infective endocarditis caused by enterococcus when the

organism is not sensitive to Gentamycin.  Plague has historically been treated with it as the first-line

treatment. In veterinary medicine, streptomycin is the first-line antibiotic

for use against Gram-negative bacteria in large animals. It is commonly combined with procaine penicillin for I.M. route. Traditionally is given by I.M. but may also be administered by

I.V. route. Side effects are tinitus, vertigo, nephrotoxicity, fetal toxicity,

neuromuscular paralysis, and ataxia. Streptomycin is also used as a pesticide.

Adverse effects of this medicine are ototoxicity, nephrotoxicity, fetal auditory toxicity, and neuromuscular paralysis.

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AMIKACIN

• Acts by binding to the bacterial ribosomalsubunit,causing the bacterium unable to synthesizeproteins

• Is expensive.• Amikacin is most often used for treating severe, hospital-acquired

infections with resistant Gram-negative bacteria.• Amikacin may be combined with a β-lactam antibiotic.• Is usually used as a last-resort medication against multidrug-resistant

bacteria. • Administered by I.V. or I.M. routes or via nebulization. • Side-effects of amikacin are similar to those of other aminoglycosides.

Effective against : Pseudomonas aeruginosa , Pseudomonas aeruginosa Serratia marcescens and Serratia marcescens

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NEOMYCIN

Principally used for topically for skin, eye and ear infections. Neomycin is not absorbed from the gastrointestinal tract. Similar to other aminoglycosides, neomycin has excellent activity

against Gram-negative and Gram-positive bacteria. It is relatively toxic to humans, and many people have allergic

reactions to it (hypersensitivity). neomycin is known for its ability to bind to duplex RNA with high

affinity.

Spectrum:• Enterobacter cloacae.• Escherichia coli.• Proteus vulgaris.

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TETRACYCLINES

• The first member of the group discovered was Chlortetracycline derived from a golden-colored, fungus-like, soil-dwelling bacterium named ”Streptomyces aureofaciens.”

• Oxytetracycline was discovered shortly afterwards from “Streptomyces rimosus.”

• Later on Tetracycline was developed and so on…............• Tetracycline antibiotics (as a group) are protein synthesis

inhibitors, inhibiting the binding of aminoacyl- t RNA to the mRNA-ribosome complex.

• Tetracyclines have been found to inhibit metalloproteinases. • Tetracycline inhibits cell growth by inhibiting translation. • Translation is the process in which cellular ribosome create protein.

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CLASSIFICATION OF TETRACYCLINES

• Naturally occurring Tetracycline. Chlortetracycline. Oxytetracycline. Demeclocycline.

• Semi-synthetic Momcycline. Lymecycline. Meclocycline. Methacycline. Minocycline. Rolitetracycline.

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• Short acting (half life is 6-8 hours) Tetracycline. Chlortetracycline. Oxytetracycline.

• Intermediate acting (half life is about 12 hours) Demeclocycline. Methacycline.

• Long acting (half life is +16 hours) Doxycycline. Minocycline.17/4/2015

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TETRACYCLINES

Mechanism action of Tetracyclines: Tetracycline antibiotics (as a group) are protein synthesis

inhibitors, inhibiting the binding of aminoacyl- t RNA to the mRNA-ribosome complex. By this mechanism bacterial protein synthesis is inhibited.

Antibacterial spectrum : Tetracyclines are broad spectrum bacteriostatic antibiotics. Effective against Gram-negative and Gram–positive bacteria.

Resistance:The most commonly encountered, naturally occuring resistance factor confers an inability of the organism to accumulate the drug, thus producing resistance.17/4/2015

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PHARMACOKINETICS OF TETRACYCLINES

Absorption :

Most tetracyclines are adequately, yet incompletely absorbed after oral ingestion.

However, taking these drugs with dairy foods in the diet, decreases the absorption due to formation of non-absorbable chelates of the tetracyclines with calcium ions.

These chelates are also formed with iron, magnesium and aluminium ant-acids.

Doxycycline and Minocycline are almost totally absorbed by oral route.

Currently Doxycycline is preferred for parenteral administration and Minocycline is available I.V. as well.

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• Administration and fate of Tetracyclines.

• In tetracycline preparations, stability must be considered in order to avoid formation of toxic epi-anhydrotetracyclines.(Fanconi’s syndrome)

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IMPORTANCE OF DOXYCYCLINE

A single dose of 200 mg can prevent development of tick bite disease.

(TICKS are external parasites living on the blood of mammals, birds, reptiles and amphibians, e.g. castor bean tick). Best used against Mycoplasma pneumoniae (skin lesion, headache, fever followed by encephalo-meningitis). In the treatment of cholera. In sexually transmitted diseases. Of choice in “rocky mountain spotted fever.”

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Distribution: Tetracyclines concentrate in the liver, kidneys, spleen and skin. They bind to tissues undergoing calcification. Penetration in the body fluids is adequate. All Tetracyclines enter CSF with the exception of Minocycline. Minocycline is not effective in C.N.S. infections. All Tetracyclines cross the placental barrier and concentrate in

fetal bones and teeth.

Elimination: They are metabolized and conjugated to form soluble

glucuronides. Are secreted in bile. Tetracyclines are also excreted in breast milk.

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Conti.,

Adverse effects: Gastric discomfort (Nausea, vomiting, dizziness). Phototoxicity. Effects the calcified tissues. Fatal hepatotoxicity. Intracranial hypertension. Superinfection (overgrowth of Candida in vagina).

Contraindications of Tetracyclines: In patients with renal problems (high urea ) except Doxycycline. Should not be administered in pregnancy, breast feeding and

children under 10 years of age ( permanent yellow-gray staining ). In myasthenia gravis.

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CHLORAMPHENICOL

• Chlroamphenicol is active against a wide range of Gram-positive and Gram-negative organisms. Because of its severe toxicity, its use is restricted to life-threatening infections for which no alternatives exist.

Mechanism of action: The drug binds to the bacterial 50S ribosomal subunit and

inhibits protein synthesis in higher circulating chloramphenicol levels, producing bone marrow toxicity.

Inhibits cytochrome P450 system.

Antimicrobial spectrum of chloramphenicol: Is a broad spectrum antibiotic (bacteriostatic or bactericidal) Is active against bacteria and other microorganisms. Has excellent activity against anaerobes.17/4/2015

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Inhibition of the cytochrome P450 system by chloamphenicol

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Mechanism action of Chloramphenicol

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Administration and fateof Chloramphenicol

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Resistance : Is conferred that codes acetyl coenzyme A tranferase. When there is inability of drug to penetrate the organism.

Pharmacokinetics: May be administered I.V. or orally. Completely absorbed by oral route (lipophilic nature). Widely distributed in body fluids. Enters CSF. Metabolized in liver and excreted through renal tubules. It is also secreted into breast milk.

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Adverse effects of Chloramphenicol: G.I.T. upset and overgrowth of Candida albicans. Anaemias (haemolytic and aplastic). Gray baby syndrome. This occurs in neonates because they

have decreased ability to excrete the drug. This leads to poor feeding, depressed respiration, cardiovascular collapse, cyanosis (gray baby) and death.

Very high doses in adults may cause the above toxicity.

Interactions: Blocks the metabolism of warfarin, phenytoin, tolbutamide

and chlorpropamide.

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THANKS FOR BEING ATTENTIVE17/4/2015