Dr Khulood AlsarafDr Khulood AlsarafDr Khulood AlsarafDr Khulood Alsaraf

Tetracyclines Tetracyclines are :-

Tetracycline, Demeclocycline, Doxycycline & Minocycline

-All Tetracyclines have a similar mechanism of action

-They have different chemical structures &are produced by different species of streptomyces

-Structural analogues of these comp. have been synthesized to improve pharmacokinetic properties & antimicrobial activity.

-Tetracyclines bind to 30S ribosome & there by prevent binding of aminoacyl transfer RNA [ tRNA ] to the A site [ acceptor site ] on the 50S ribosomal unit.

-Tetracyclines affect both eukaryotic & prokaryotic cells but are selectively toxic for bac. because they readily penetrate microbial memb. & accumulate in the cytoplasm through an energy – dependent Tetracycline transport system that is absent from mammalian cells. -Resistance is related largely to changes in cell permeability and a resultant decreased accumulation of drug due to increased efflux from the cell by an energy-dependent mechanism.

.

Tetracyclines have broad spectrum activity & are effective against both gm-ve & gm+ve bacteria, including Rickettsia, Coxiella, Mycoplama pneumonia, Chlamydia spp. and some spirochetes.

Significant differences in serum half – life allow the grouping of the Tetracyclines into subclasses :-1- short acting [Tetracycline]

2- Intermediate acting [ Demeclocycline ]

3- Long acting [ Minocycline & Doxycycline ]

Clinical uses

The selection of an agent, therefore is based on tolerance, ease of administration and cost.The restriction of their use in pregnancy and in patients under the age of 8 years applies to all preparations.1-Doxycycline, with its longer half-life and lack of nephrotoxicity, is a popular choice for patients with pre-existing renal disease or those who are at risk of developing renal insufficiency. [ The lack of nephrotoxicity is related mainly to biliary excretion, which is the primary route of doxycycline elimination.]2-Doxycycline is a potential first-line agent in the prophylaxis of anthrax after exposure.3-Doxycycline is the drug of choice for primary stage of Lyme disease in adults and children older than 8 years.

4-Minocycline is an effective alternative to rifampin for eradication of meningococci.5-The tetracyclines are still the drugs of choice for treatment of cholera, diseases caused by Rickettsia and coxilla, the chlamydial diseases (trachoma and lymphogranuloma) and non-specific urethritis.6-They are also effective in the treatment of brucellosis, and infection caused by Mycoplasma spp.7-Tetracyclines are clinically effective in the treatment of acne because of their antioxidant effect.8-In mild to moderate attacks of pelvic inflammatory disease as a result of the drug’s action on anaerobic bacteria and Chlamydia.

Adverse effects

1- gastric disturbances 2- fatal hepatotoxicity 3- photosensitivity 4- dizziness, nausea, vomiting occur as vestibular problems with mioncycline 5- effect on calcified tissues deposition in the bone occur during calcification in growing children, this causes discoloration & hyperplasia of the teeth. 6- superinfection over growth of candida or resistant staph. [ in the intestine] may occur.

C.I 1- in renally – impaired patients [ except doxycycline ] 2- in pregnant women 3- breast – feeding women 4- in children under 8 years of age

GlycylcyclinesTigecycline Have very broad antibacterial spectrumEffective against S.aureus including methecillin-resistance, vancomycin-resistance strains, streptococci, pencillin-susceptible and resistance strains, entericocci, gm+ve rods, anaerobes both gm+ve and gm-ve, chlamydia sp., proteus sp., and p aeruginosa.Given by IV injection only, rapidly distributed into body tissues, metabolized by liver and eliminated primarily via biliary/fecal excretion.It is FDA-approved for treatment of skin infection, intra- abdominal infections, and community-acquired pneumonia.Main adverse effects include:1- nausea, vomiting and diarrhea2- hypersensitivity reactions (drug fever, skin rash)3- readily bound to calcium deposited in newly formed bone or teeth in young children causing discoloration and enamel dysplasia.4- impaired hepatic function5- renal tubular acidosis and other renal injury.

Macrolides/ Ketolides-They consist of a large lactone ring to which sugar are attached.

-Macrolides include :-Erythromycin, Clarithromycin, Azithromycin, & Telithromycin.

-Macrolides bind to the 50S ribosomal subunit of bacteria but not to the 80S mammalian ribosome, this accounts for its selective toxicity

-Binding to the ribosome occurs at a site near peptidyl transferase, with a resultant inhibition of translocation, peptide bond formation & release of oligopeptidyl tRNA .

-They are effective against a no. of organisms, including Mycoplama spp., H. influenzae, Strep., Staph. & Gonococci.

-Clarithromycin is very effective against H. influenzae, & Mycobacterium avium – intracellulare.

-Azithromycin is superior against Neisseria, H. influenzae but less active against mycobacterial species.

- Clarithromycin & Azithromycin are among the drug of choice in treating disseminated Mycobacterium avium complex.T1/2 of Erythromycin 1-4 hrs

T1/2 of Clarithromycin 3-7 hrs

T1/2 of Azithromycin approaches 68 hrs

Clinical uses1-Treatment of mycoplasma pneumonia infections2-Eradication of corynebacterium diphtheriae ( from pharyngeal carrier)3-Chlamydial infections4-For campylobacter enteritis and chlamydial conjunctivitis and prevention of secondary pneumonia in neonates.5-Staphylococcus are generally susceptible to erythromycin, so it is suitable alternative drug for the penicillin-hypersensitive individual.6-It is a second-line drug for the treatment of gonorrhea and syphilis.7-Clarithromycin→ has activity against toxoplasma gondi and mycobacterium avium-intracellulare.8-The prolonged half-life and protein binding and the use of a single one-time dose of azithromycin appear to be extremely beneficial in the treatment of sexually transmitted disease.9-Infection with ureaplasma.

Adverse effect

The incidence of S.E is very low

1- mild GI upset with nausea diarrhea & abdominal pain 2- general hypersensitivity [ rash, fever, eosinophilia ] 3- cholestatic hepatitis

C.I In patient with hepatic dysfunction, bec. The drug accumulated in the liver

Ketolides Telithromycin: approved for limited clinical use.•It is active in vitro against streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Mycoplasma sp.,and H pylori.•Many macrolide-resistant strains are susceptible to ketolides.•Orally effective.•In the USA, telithromycin is now indicated only for treatment of community-acquired bacterial pneumonia.