(Tetracyclines & Linezolid) Laith Mohammed Abbas Al-Huseini Antimicrobials Protein Synthesis Inhibitors (Tetracyclines & Linezolid) Laith Mohammed Abbas Al-Huseini M.B.Ch.B., M.Sc, M.Res, Ph.D Department of Pharmacology and Therapeutics

Introduction A number of antibiotics exert their antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis. Bacterial ribosomes are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits). In general, selectivity for bacterial ribosomes minimizes potential adverse consequences encountered with the disruption of protein synthesis in mammalian host cells. However, high concentrations of drugs such as chloramphenicol or the tetracyclines may cause toxic effects as a result of interaction with mitochondrial mammalian ribosomes, since the structure of mitochondrial ribosomes more closely resembles bacterial ribosomes.

Tetracyclines Class of antibiotics having a nucleus four fused cyclic rings with a system of conjugated double bonds. Derived from a golden-coloured, fungus-like, soil-dwelling bacterium named Streptomyces aureofaciens Substitutions on these rings alter the individual pharmacokinetics and spectrum of antimicrobial activity.

Mechanism of Action Tetracyclines enter susceptible organisms via passive diffusion and by an energy-dependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane. Tetracyclines concentrate intracellularly in susceptible organisms. The drugs bind reversibly to the 30S subunit of the bacterial ribosome. This action prevents binding of tRNA to the mRNA–ribosome complex, thereby inhibiting bacterial protein synthesis.

Spectrum of Antibacterial Activity Tetracyclines are active against many gram-positive and gram-negative bacteria, including mycobacteria and anaerobes. Rickettsiae, chlamydiae, protozoa, spirochetes and mycoplasmas are also sensetive. The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline, all of which are poor substrates for the efflux pump, if that is the mechanism of resistance.

Classification Tetracycline Chlortetracycline Oxytetracycline Demeclocycline Methacycline Doxycycline Minocycline Short-acting (6-8 hours) Intermediate-acting (12 hours) Long-acting (16-18 hours)

Pharmacokinetics Absorption: oral administration is approximately 30% for chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–100% for doxycycline and minocycline. Distribution: The tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and skin. Moreover, they bind to tissues undergoing calcification (for example, teeth and bones) or to tumors that have a high calcium content.

Pharmacokinetics Only minocycline and doxycycline achieve therapeutic levels in the cerebrospinal fluid (CSF). All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition. Elimination: Tetracycline and doxycycline are not hepatically metabolized. Tetracycline is primarily eliminated unchanged in the urine, whereas minocycline undergoes hepatic metabolism and is eliminated to a lesser extent via the kidney. In renally compromised patients, doxycycline is preferred, as it is primarily eliminated via the bile into the feces.

Therapeutic Uses Empirical therapy: Tetracyclines are often employed when the nature and sensitivity of the infecting organism cannot be reasonably guessed. First choice in: (a) Venereal diseases (b) Atypical pneumonia (c) Cholera (d) Brucellosis (e) Plague (f) Relapsing fever (g) Rickettsial infections Second choice in: Tetanus, anthrax, actinomycosis and Listeria infections. Gonorrhoea Syphilis Leptospirosis pneumonia due to Chlamydia pneumoniae. Chancroid and tularemia.

Therapeutic Uses 4. Other situations in which tetracyclines may be used are: Urinary tract infections: Odd cases in which the organism has been found sensitive. (b) Community-acquired pneumonia, when a more selective antibiotic cannot be used. (c) Amoebiasis: along with other amoebicides for chronic intestinal amoebiasis. (d) As adjuvant to quinine or artesunate for chloroquine-resistant P. falciparum malaria. (e) Acne vulgaris: prolonged therapy with low doses may be used in severe cases.

Adverse Effects 1.Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa and is often responsible for noncompliance with tetracyclines. Esophagitis may be minimized through co-administration with food (other than dairy products) or fluids and the use of capsules rather than tablets. 2. Effects on calcified tissues: Deposition in the bone and primary dentition occurs during the calcification process in growing children. This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth. The use of tetracyclines is limited in pediatrics. 3. Hepatotoxicity: Rarely hepatotoxicity may occur with high doses, particularly in pregnant women and those with preexisting hepatic dysfunction or renal impairment.

4. Phototoxicity: Severe sunburn may occur in patients receiving a tetracycline who are exposed to sun or ultraviolet rays. This toxicity is encountered with any tetracycline, but more frequently with tetracycline and demeclocycline. Patients should be advised to wear adequate sun protection. 5. Vestibular dysfunction: Dizziness, vertigo, and tinnitus may occur particularly with minocycline, which concentrates in the endolymph of the ear and affects function. Doxycycline may also cause vestibular dysfunction. 6. Pseudotumor cerebri: Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. 7. Contraindications: The tetracyclines should not be used in pregnant or breast-feeding women or in children less than 8 years of age.

Resistance Three mechanisms of resistance: (1) impaired influx or increased efflux by an active transport protein pump. (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome. (3) enzymatic inactivation.

Minocycline Demeclocycline 200 mg orally daily for 5 days, can eradicate the meningococcal carrier state, but because of side effects and resistance of many meningococcal strains, ciprofloxacin or rifampin is preferred. Demeclocycline Inhibits the action of antidiuretic hormone in the renal tubule and has been used in the treatment of inappropriate secretion of antidiuretic hormone or similar peptides by certain tumors.

Tigecycline It is the first member of a new class of synthetic tetracycline analogues (glycyl-cyclines), has several unique features. Its spectrum is very broad includes methicillin resistant staphylococci (MRSA), multidrug-resistant streptococci, vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase–producing gram-negative bacteria. Many tetracycline-resistant strains are susceptible to tigecycline because it is not affected by the common resistance determinants. Formulated for i.v. administration only (poorly absorbed from GIT), is given as a 100 mg loading dose, then 50 mg every 12 hours.

As with all tetracyclines, tissue and intracellular penetration is excellent. Elimination is primarily biliary, and no dosage adjustment is needed for patients with renal insufficiency. Approved for treatment of skin and skin-structure infection, intra-abdominal infections, and communityacquired pneumonia. Not effective for urinary tract infections. The most common side effect is nausea and occasionally vomiting. Others are epigastric distress, diarrhoea, skin reactions, photosensitiviy injection site complications and superinfections.

Linezolid A synthetic oxazolidinone developed to combat resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus, VRE, and penicillin-resistant streptococci. Binds to the bacterial 23S ribosomal RNA of the 50S subunit, thereby inhibiting the formation of the 70S initiation complex. Its antibacterial action directed primarily against Gr+ve organisms, such as staphylococci, streptococci, and enterococci, as well as Corynebacterium species and Listeria monocytogenes.

Moderately active against Mycobacterium tuberculosis and may be used against drug-resistant strains. Generally is bacteriostatic. However, it is bactericidal against streptococci. Resistance primarily occurs via reduced binding at the target site. Cross-resistance with other protein synthesis inhibitors does not occur. Completely absorbed after oral administration, widely distributed throughout the body. The drug is excreted both by renal and non-renal routes.

The most common adverse effects are gastrointestinal upset, nausea, diarrhea, headache, and rash. Possesses nonselective monoamine oxidase activity and may lead to serotonin syndrome if given concomitantly with large quantities of tyramine-containing foods. Irreversible peripheral neuropathies and optic neuritis have been associated with greater than 28 days of use