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65 Cards in this Set
- Front
- Back
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What does Chloramphenicol, tetracyclines, macrolides, clindamycin, streptogramins & linezolid all have in common
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Selectively inhibit bacterial protein synthesis. Bacteria have 70S ribosomes, mammalian cells have 80S ribosomes. Differences form the basis for the selective toxicity of these drugs against microorganisms.
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With the exception of tetracyclines, the binding sites for these drugs (Chloramphenicol, macrolides, clindamycin, streptogramins & linezolid are on the
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50S ribosomal subunit.
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How do Chloramphenicol, macrolides, telithromycin, and clindamycin prevent protein synthesis
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block transpeptidation
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Tetracyclines bind to the
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30S ribosomal subunit
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Are tetracyclines bactericidal or bacteriostatic?
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Bacteriostatic
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Drug causes teeth discoloration
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Tetracycline
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What is the specific action of tetracycline on the 30S subunit?
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It blocks the binding of aminoacyl-tRNA to the acceptor site on the mRNA -ribosome complex
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What is the most important method of resistance to tetracycline?
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The most important of these are production of an efflux pump and ribosomal protection
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How does tigecycline escape the methods of resistance to tetracyclines?
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1. Tigecycline is not a suspect to the efflux pumps 2. Ribosomal protection is not protective against tigecycline due to steric hinderance of a bulkly substituent
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Tetracycline absorption is _____ by dairy products , food and antacids,
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impaired
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How does tetracycline manage to enter into growing bones and teeth?
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It chelates with calcium
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What tetracycline inhibits the action of ADH in the renal tubule?
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Demeclocycline
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What disease is demeclocycline used to treat?
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Inappropriate secretion of ADH
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What is the indication for minocycline usage?
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It can eradicate the meninogococcal carrier state
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What resistant strains are now susceptible to Tigecycline?
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The methicillin- resistant, Vanco- intermediate, and Vanco- resistant strains of Staph aureus and coagulase- negative staphylococci; PCN resistant strept; Vanc resist Enterococi; Multi-drug resistant Acinetobacter
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Which organisms are intrinsically resistant to Tigeccycline?
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Proteus and P. aeruginosa
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Tetracyclines should be avoided in children under the age of ___
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eight
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What occurs when tetracycline is deposited in fetal teeth
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It can lead to fluorescence, discoloration, and enamel dysplasia
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What occurs when tetracycline is deposited in fetal bone ?
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It may cause deformity or growth inhibition
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When tetracycline are given with diuretics, it may produce ____-
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nitrogen retention
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Name the infections in which tetracyclines are considered the drug of choice?
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Mycoplasma pneumoniae, chlamydiae, rickettsiae, and some spirochetes
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What is the mechanism of action of tetracycline
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Decreases protein synthesis by inhibiting 30S ribosome
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Streptogramins are
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bactericidal for most susceptible organisms
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Linezolid is mainly
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bacteriostatic. The drug binds to a unique site on the 50S ribosome, inhibiting initiation
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Tetracyclines have little effect on mammalian protein synthesis because an active efflux mechanism prevents
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their intracellular accumulation
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Chloramphenicol
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No other antimicrobials have been discovered in this chemical class. Effective orally & parenterally & widely distributed readily crossing the placental and blood-brain barriers
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Chloramphenical's antimicrobial activity:
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Wide spectrum of antimicrobial activity and is usually bacteriostatic. Some strains of H. influenzae, Neisseria meningitidis, and Bacteroides are highly susceptible and for these organisms chloramphenicol may be bactericidal. Not active against Chlamydia species. Resistance to chloramphenicol is plasmid-mediated
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Clinical uses of Chloramphenicol
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Because of its toxicity, chloramphenicol has very few uses as a systemic drug. It is a backup drug for severe infections caused by Salmonella species and for the treatment of pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons. Sometimes used for rickettsiel diseases and for infections caused by anaerobes such as Bacteroides fragilis. Commonly used as a topical.
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Toxicity of chloramphenicol
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1) GI disturbances - these conditions may occur from direct irritation and from superinfections, especially candidiasis. 2) bone marrow - inhibition of red cell maturation leads to a decrease in circulating erythrocytes. Dose-dependent and reversible. Aplastic anemia is rare reaction which is usually irreversible and may be fatal.3) gray baby syndrome: infants & characterized by decreased RBCs, cyanosis and cardiovascular collapse. Neonates are deficient in hepatic glucoronosyltransferase and are sensitive to chloramphenicol.
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Clindamycin provides prophylaxis against ___
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against endocarditis during dental procedures in individual with valvular heart disease
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Drug interactions of chloramphenicol
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Chloramphenicol inhibits hepatic drug-metabolizing enzymes, thus increasing the elimination half-lives of drug including phenytoin, tolbutamide and warfarin
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Drug that causes gray baby syndrome and aplastic anemia
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Chloramphenicol
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Tetracyclines
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Broad-spectrum bacteriostatic antibiotics
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Oral absorption is variable of the tetracyclines and may be impaired by foods and multivalent cations:
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Ca++, Fe++, aluminum, Mg++
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Pharmocokinetics of tetracyclines
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Wide tissue distribution and cross placental barrier. Undergo enterohepatic cycline.
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Antibacterial activity of tetracyclines
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Activity against gram-positive and gram-negative bacteria, species of Rickettsia, Chlamydia, Mycoplasma and some protozoa. However resistance is widespread. Resistance mechanisms include efflux pump development and the formation of ribosomal protection proteins that interfere with tetracycline binding.
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Clinical uses of tetracyclines.
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treatment of infections caused by Mycoplasma pneumoniae (in adults), chlamydiae, rickettsiae, vibrios, and some spirochetes. Doxycycline is currently an alternative to macrolides in the initial treatment of community-acquired pneumonia. Also used as alternative drugs in treatment of syphilis. Also, respiratory infection, prophylaxis against infection in chronic bronchitis, treatment of leptospirosis and treatment of acne. Specific tetracyclines are used in the treatment of GI ulcers caused by H. pylori.
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Tigecycline (a tetracycline)
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derivative of minocycline include a broad spectrum of action that includes organisms resistant to standard tetracyclines. antimicrobial activity includes gram positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains), beta-lactamase-producing gram negative bacteria, anaerobes, chlamydiae and mycobacteria. Only for IV
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Toxicity of tetracyclines
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GI: mild nausea and diarrhea to severe, possibly life-threatening enterocolitis. Disturbances in the normal flora may lead to candidiasis (oral and vaginal) and bacterial superinfections with S aureus or Clostridium difficile.
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Fetal exposure to tetracyclines
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may lead to tooth enamel dysplasia and irregularities in bone growth. Benefits of tetracyclines may outweigh the risk. Treatment of younger children may cause enamel dysplasia and crown deformation when permanent teeth appear.
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Hepatic and renal toxicity of tetracyclines
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high doses of tetracyclines, may lead to hepatic necrosis. Though not directly nephrotoxic, tetracyclines may exacerbate preexisting renal dysfunction.
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Tetracyclines, especially demeclocycline, may cause enhanced skin sensitivity to
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UV light
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The macrolide antibiotics
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erythromycin, azithromycin and clarithromycin.
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Macrolides (erythromycin, azithromycin and clarithromycin) has activity against
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many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram positive cocci and some gram negative organisms. The spectra of activity of azithromycin and clarithromycin are similar but include greater activity against species of Chlamydia, Mycobacterium avium complex and Toxoplasma.
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Antibacterial activity of macrolides
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Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram positive cocci and some gram negative organisms. The spectra of activity of azithromycin and clarithromycin are similar but include greater activity against species of Chlamydia, Mycobacterium avium complex and Toxoplasma. Azithromycin is also effective in gonorrhea, as an alternative to ceftriazone and in syphilis, as an alternative to penicillin G.
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Resistance to the macrolides in gram positive organisms involves
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efflux pump mechanisms and the change of the ribosomal binding site. Cross-resistance between individual macrolides is complete.
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Clinical uses - Erythromycin (macrolide)
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Erythromycin is effective in the treatment of infections caused by M pneumoniae, Corynebacterium, Campylobacter jejuni, Chlamydia trachomatis, Chlamydophila pneumoniae, Legionella pneumophila, Ureaplasma urealticum and Bordetella pertussis. The drug is also active against gram positive cocci (but not penicillin-resistant Streptococcus pneumoniae (PRSP) strains) and beta-lactamase-producing staphylococci (but not methicillin-resistant S aureus (MRSA) strains).
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Clinical uses - Azithromycin (macrolide)
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Azithromycin has a similar spectrum of activity but is more active against H influenzae, Moraxella catarrhalis and Neisseria.
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Clinical uses - Clarithromycin
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almost the same spectrum of antimicrobial activity and clinical uses as erythromycin. The drug is also used for prophylaxis against and treatment of M avium complex and as a component of drug regimens for ulcers caused by H pylori
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Toxicity of macrolides
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GI irritation (common), skin rashes and eosinophilia. Erythromycin inhibits several forms of hepatic cytochrome P450 and can increase the plasma levels of many drugs, including anticoagulants, carbamazepine, cisapride, digoxin and theophylline.
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Which tetracyclines are associated with vestibular reactions?
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Doxycycline and Minocycline
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Drug notorious for causing pseudomembranous colitis
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Clindamycin
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What is the specific action of erythromycin on its subunit?
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After it binds to the 50S ribosomal RNA, it blocks the aminoacyl translocation reaction and formation of initiation complexes
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What is the mechanism of action of erythromycin?
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Inhibition of protein synthesis at the 50s subunit of ribosome
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What are the most mechanism of resistance to erythromycin?
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Efflux and methylase production (this modifies the 50 S binding site)
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Inhibitors of CYP450
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Cimetidine, ketoconazole, erythromycin, isoniazid and grapefruit
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What is MLS- type B resistance?
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Macrolide-Lincosamide (clindamycin)-streptogramin cross resistance due to constitutive methylase production because they share the same binding site
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What is the drug of choice for Legionnaires' disease
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Erythromycin
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Telithromycin
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Some macrolide-resistant strains are susceptible to telithromycin because it binds more tightly to ribosomes and is a poor substrate for bacterial efflux pumps that mediate resistance.
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Clindamycin
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Gram negative aerobes are intrinsically resistant because of poor penetration of clindamycin through the outer membrane. Cross-resistance between clindamycin and macrolides is common. Eliminated by biliary and renal excretion.
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Main use of clindamycin is in the treatment of
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severe infections caused by certain anaerobes such as Bacteroides. Clindamycin has been used as a backup drug against gram positive cocci and is recommended for prophylaxis of endocarditis in valvular disease patients who are allergic to penicillin.
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Streptogramins
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Quinupristin-dalfopristin, a combination of 2 streptogramins, is bactericidal and has a duration of antibacterial activity longer than the half-lives of the 2 compounds. Antibacterial activity includes penicillin-resistant pneumococci, methicillin-resistant (MRSA) and vancomycin-resistant staphylococci (VRSA) and resistant E faectium;
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Streptogramins are potent inhibitors of
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CYP3A4 and increase plasma levels of many drugs
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Linezolid
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Linezolid is active against drug-resistant gram positive cocci, including strains resistant to penicillins (MRSA, PRSP) and vancomycin (VRE). The drug is also active against L monocytogenes and corynebacteria. Linezolid binds to a unique site located on the 23S ribosomal RNA of the 50S ribosomal subunit, and there is curently no cross-resistance. Linezolid should be reserved for treatment of infections caused by multidrug-resistant gram positive bacteria.
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linezolid is metabolized
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in the liver. thrombocytopenia and neutropenia occur, most commonly in immunosuppressed patients. Linezolid has been implicated in the serotonin syndrome when used in patients taking selective serotonin reuptake inhibitors.
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