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Section 3 Macrolides, Lincomycins &Vancomycins Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected] Part A Macrolides • Erythromycin (红霉素) • Clarithromycin (克拉霉素) • Azithromycin (阿奇霉素) • Telithromycin(泰利霉素) 14 member rings 14 member rings 15 member rings General properties of Macrolides 1. Antimicrobial spectrum: • G+ organisms • G- cocci: Streptococcus pyogenes and pneumoniae • Mycoplasma pneumoniae(肺支原体) and Legionnella (军团菌)etc. 2. Antimicrobial activity: • bactericidal and bacteriostatic, depending on the concentration. • more active at alkaline 3. Mechanism of action: subunit macrolide 4. Mechanism of resistance: • modification of the ribosomal binding site • production of esterase that hydrolyze macrolides. • reduced permeability of cell membrane or active efflux system is involved. • Cross-resistance is complete between erythromycin and the other macrolides. General properties of Macrolides 4. ADME 1) Absorption: Stearate and ester of erythromycin are fairly acid-resistant and somewhat batter absorbed. Food interferes with absorption. General properties of Macrolides 4. ADME 2) Distribution: does not cross BBB. 3) Elimination: it is concentrated in the liver, where some is unactived, while some is excreted in active form in the bile. General properties of Macrolides 5.Clinical Uses: 1) Mycoplasma (支原体) infections. 2) Legionnaire’s disease (军团菌病). 3) Chlamydia infections (衣原体感染). 4) Streptococcus (链球菌) infections. 5) Diphtheria (白喉), chincough (百日咳). 6) toxoplasmosis(弓形虫病). General properties of Macrolides 6.Adverse response: 1) GI Effects: nausea, vomiting, abdominal cramps(痉挛)… 2) Liver Toxicity: Cholestatic hepatitis (胆汁淤积性肝炎). 3) Cardiotoxic effects 4) Auditory impairment (Ototoxicity) Hypersensitivity reactions Superinfections General properties of Macrolides 7. Drug interactions • Erythromycin metabolites can inhibit cytochrome P450 enzyme. Macrolides • Erythromycin (红霉素) • Clarithromycin (克拉霉素) • Azithromycin (阿奇霉素) • Telithromycin(泰利霉素) Part B Lincomycin & Clindamycin • Lincomycin (林可霉素) • Clindamycin (克林霉素) Lincomycin & Clindamycin Antimicrobial properties • resemble erythromycin in antibacterial spectrum, activity, mechanism and resistance. Mechanism of action: ①Chloramphenicol ②Macrolides, Clindamycin ③Tetracyclines Lincomycin & Clindamycin Pharmacokinetics • about 90% protein-bound • excretion via the liver,bile, and urine • penetrate well into most tissue, including bone, but not CSF. Lincomycin & Clindamycin Clinical Uses • • • • severe anaerobic infection aerobic G+ cocci infection combination with pyrimethamine (乙胺嘧啶) for AIDS-related toxoplasmosis(弓形体病) combination with primaquine (伯氨喹) for AIDS-related pneumocystis carinii pneumonia(肺囊虫性肺炎). Lincomycin & Clindamycin Adverse response: 1) GI effects: Antibiotic-associated colitis (pseudomembranous colitis 伪膜性结肠炎). 2) allergic reaction 3) impaired liver function Vancomycins Vancomycin (万古霉素) Norvancomycin (去甲万古霉素) Teicoplanin (替考拉宁,太古霉素) Vancomycins Antibacterial activity bactericidal for G+ bacteria ( especially G+ ococci, including MRSA & MRSE) Vancomycins • Antibacterial Mechanism Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide. • Resistance occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser. Fig. Antibacterial Mechanism of Vancomycins Vancomycins • ADME • Oral administration (poorly absorbed). • Intravenous administration, is excreted by glomerular filtration (accumulates when renal function is impaired). • Widely distributed in the body, including CSF when the meninges is inflamed. Vancomycins • Clinical Uses 1) severe infection caused by MRSA etc. 2) alternative for b-lactam 3) enterococcal or staphyococcal endocarditis (combination with gentamicin). 4) pseudomembranous colitis Pseudomembranous enterocolitis Pseudomembranous colitis. Endoscopic en face view of colon wall demonstrating several pseudomembranes (arrows). Hurley and Ngueyn Arch Intern Med. 2002;162:2177-2184. Pseudomembranous enterocolitis Normal Focal ulceration can be seen at the tips of the mucosa. The exudate of fibrin and inflammatory tissue. Vancomycins • Adverse Reactions 1) Hypersensitive reaction (e.g. red man syndrome) 2) Ototoxicity 3) Nephrotoxicity 4) Gl effects, etc. Section 4 Aminoglycosides & polymyxins Part A Aminoglycosides Overview • History and Source : the research made by Waksman and coworks within 19391943 • Clinical Applications: for the treatment of aerobic G- bacterial infections and tuberculosis • Two classes: crude product and semisynthetic derivative Aminoglycosides General properties 1. Antimicrobial activity: i) rapidly bactericidal to resting bacterium ii) broad-spectrum iii) more active at alkaline General properties 1. Antimicrobial activity: iv) concentration-dependent activity v) the duration of post antibiotic effect (PAE) is concentration- dependent (10 hours). vi) first exposure effect (FEE) Peak Concentration Blood Concentration Bacterial growth is inhibited long after concentration below the MIC MIC Time (h) General properties 2. Antimicrobial spectrum: • aerobic G- bacilli and cocci • aerobic G+ organisms • Streptomycin and kanamycin are also active against Mycobacterium tuberculosis General properties 3. Mechanism of action: • inhibit protein synthesis • act as Ionic- sorbent, act directly on permeability of the cell membrane of bacterium. Mechanism of action - inhibit protein synthesis •Blocks the initiation of protein synthesis Mechanism of action - inhibit protein synthesis •Blocks the initiation of protein synthesis Mechanism of action - inhibit protein synthesis Mechanism of action - inhibit protein synthesis Mechanism of action - inhibit protein synthesis •Incorporation of incorrect amino acid Mechanism of action - inhibit protein synthesis •Blocks further translocation and elicits premature terminations Mechanism of action - inhibit protein synthesis •disrupt the normal cycle of ribosomal, make the ribosomal exhausted Mechanism of action - inhibit protein synthesis i) Interfering with the initiation complex of peptide formation. ii) Inducing misreading of mRNA, which causes the incorporation of incorrect amino acid into peptide, resulting nonfunctional or toxic protein. Mechanism of action - inhibit protein synthesis iii) causing breakup of polysomes into nonfunctional monosomes. iv) disrupt the normal cycle of ribosomal, make the ribosomal exhausted. Mechanism of resistance produces enzymes Altered ribosomal subunit Changes of Porins Active efflux system Mechanism of Resistance i) The microorganism produces a transferase enzyme or enzymes that inactivate the aminoglycoside by adenylyation, acetylation, or phosphorylation. ii) Impaired entry of aminoglycoside into the cell. iii) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of mutation. General properties ADME i) Absorption: not absorbed after po, but rapidly absorbed after IM, peak time 0.5-2h. ii) Distribution: Binding to plasma protein is minimal, do not enter cell, nor do they cross BBB,but they cross the placenta, reach high concentrations in secretions and body fluids. Tissue level is low expect in the cortex of kidney. General properties ADME iii) Elimination: excreted mainly by glomerular filtration. If renal function is impaired, accumulation occurs with a increase in those toxic effects which are dose related. T1/2=2-3h General properties Clinical Uses • be mostly used against aerobic G- bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with b-lactam antibiotic or fluoroqunolones (氟喹诺酮类) • against aerobic G+ bacteria and in sepsis, be almost always used in combination with penicillins or vancomycin • against Mycobacterium tuberculosis General properties Adverse reactions i) Ototoxicity • involves progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ in the ear (irreversible!! ). Ototoxicity (cochlea) • Kanamycin(1.6%)> Amikacin> Sisomicin> Gentamicin> Tobramycin(0.4%) Ototoxicity (vestibular organ) • Kanamycin(4.7%)> Streptomycin> Sisomicin> Gentamicin> Tobramycin(0.4%) General properties Adverse reactions ii) Nephrotoxicity • consists of damage to the kidney tubules and be reversed if stop using. • Amikacin < Streptomycin or Tobramycin< Gentamicin < Kanamycin <Neomycin Nephrotoxicity & Ototoxicity Blue, high frequency Red, low frequency General properties Adverse reactions iii) Neuromuscular blockade (paralysis) • generally occurred after intra-pleural or intraperitoneal instillation of large doses of an aminoglycosides • Tobramycin < Gentamicin < Kanamycin or Amikacin <Streptomycin <Neomycin • Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity. General properties Adverse reactions iv) Allergic reaction • skin rashes fever, eosinophiliay (嗜酸粒 细胞增多症), anaphylactic shock, etc. Aminoglycosides agents • • • • • • Streptomycin (链霉素) Gentamicin (庆大霉素) Tobramycin(妥布霉素) Amikacin(阿米卡星) Netilmicin(奈替米星) Neomycin(新霉素) Aminoglycosides agents • • • • • • • • • Kanamycin(卡那霉素) Arbekacin (阿贝卡星) Dibekacin (地贝卡星) Micronomicin(小诺米星) Sisomicin(西索米星) Etilmicin(依替米星) Isepamicin(异帕米星) Astromicin (阿司米星,福提霉素) Spectinomycin (大观霉素),etc. Streptomycin 1. ADME i) Absorption: IM ii) Distribution: mainly at extracellular fluid, crosses the BBB and achieves therapeutic concentrations with inflamed menings. iii) Excretion: 90%, kidney age↑→ T1/2↑ Streptomycin 2.Clinical uses i) plague(鼠疫) and tularemia(兔热病): combination with an oral tetracycline. ii) tuberculosis: as first-line agent iii) bacterial endocarditis: (enterococcal 肠球菌, viridans streptococcal 草绿色链 球菌, etc.), streptomycin and penicillin produce a synergistic bactericidal. Streptomycin 3. Adverse reactions i) Allergic reaction skin rashes, fever, anaphylactic shock ii) Ototoxicity (cochlea > vestibular organ) iii) Neuromuscular blockade (paralysis) iv) Nephrotoxicity Gentamicin 1. ADME Gentamicin can accumulate in cortex of the kidney . 2.Clinical use : ii) important agent (first choice) for serious G bacillary infections (sepsis, pneumonia, etc.), because of its low cost and reliable activity. Gentamicin 2.Clinical Uses : ii) infection induced by enterococcal, viridans streptococcal, staphylococcal etc. Gentamicin is used concurrently with other antibiotics (e.g. b-lactams) iii) prevent the infection induced by operation Gentamicin 2.Clinical Uses : iv) local application: for treatment of infected burn, wounds,or skin lesions and the prevention of intravenous catheter infections, etc. Gentamicin 3. Adverse reactions i) Ototoxicity (vestibular organ > cochlea) ii) Nephrotoxicity iii) Nausea and vomiting etc. Tobramycin 1. antimicrobial activity & pharmacokinetics: very similar to those of getamicin. 2. Adverse reactions: Ototoxicity and Nephrotoxicity (may be less than dose gentamicin). Amikacin 1.Antibacterial activity: The spectrum of antimicrobial activity of amikacin is the broadest in the group. Amikacin 2.Clinical uses : • Treatment of G-bacillary infections which resistance to gentamicin and tobramycin. • Most strains resistance to amikacin found is also resistance to other aminoglycosides. • combination with b-lactams, produce a synergistic bactericidal. Amikacin 3. Adverse reactions i) Ototoxicity (cochlea > vestibular organ) ii) Nephrotoxicity (may be less than gentamicin or Tobramycin). iii) Neuromuscular blockade (paralysis), rarely iv) skin rashes, fever, nausea and vomiting etc. Netilmicin i) similar to gentamicin & tobramycin in its pharmacokinetic properties. ii) broad spectrum, against aerobic Gbacilli. iii) tolerance to many aminoglycosides - inactivating enzymes. iv) less toxic Part B Polymyxins 1. Polymyxin A,B,C,D,E 2.Notice: because of the extreme toxicity, they are now rarely used. 3. Antibacterial activity: they are restricted to G- bacilli (Narrow spectrum) 4.Mechanism of action: they interact with phospholipids and penetrate into and disrupt the structure of cell membranes. Lipopoly -saccharide Outer membrane Peptidoglycan Cytoplasmic membrane polymyxins Part B Polymyxins 4. Clinical uses: infection of Pseudomonas aeruginosa (铜绿假单胞 菌属) and other G- bacilli, local application. Resisitance rarely happened. Part B Polymyxins 5. Adverse reaction(25%): i) Nephrotoxicity (22.2%) ii) Neurotoxicity: Neuromuscular blockade (paralysis) iii) Allergic reaction iv) others: hepatotoxicity Section 5 Tetracyclines & Chloramphenicol Part A Tetracyclines Part A Tetracyclines Two classes: • crude product Tetracycline(四环素) Cholortetracycline (金霉素) Oxytetracycline (土霉素) • semisynthetic derivative Doxycycline(多西环素) Minocycline(米诺环素) General properties of Tetracyclines Antimicrobial activity: • bacteriostatic • bactericidal (high concentration) • Minocycline > Doxycycline > Tetracycline General properties of Tetracyclines “broad-spectrum” antibiotic • Rickattsiae (立克次体) • a number of aerobic and anaerobic G+ & G- bacteria • Chlamydia (衣原体) • Coxiella burnetii (螺旋体) • Mycoplasma pneumoniae (支原体) • Plasmodium (疟原虫) • not active against fungi, virus. General properties of Tetracyclines Mechanism of action: Bind to 30S subunit of ribosome, preventing access of aminoacyl tRNA to acceptor (A) site on the mRNA-ribosome complex General properties of Tetracyclines Mechanism of action: ①Chloramphenicol ②Macrolides, Clindamycin ③Tetracyclines General properties of Tetracyclines Resistance Mechanism: (1) Decreased intracellular accumulation due to either impaired influx or increased efflux by a active transport protein pump. (2) Ribosome protection that interfere with the tetracycline binding to the ribosome. (3) Enzyme inactivation of tetracycline. General properties of Tetracyclines ADME : (1) Absorption are impaired by food (except doxycycline and minocycline). (2) Distributed widely to tissue and body fluid except for CSF. • across the placenta and are also excreted in the milk. • tetracyclines are bound to- and damage- growing bones and teeth (chelation with calcium). (3) Excreted mainly in bile and urine. General properties of Tetracyclines Clinical Uses (1) Rickettsial(立克次体) infections. (2) Mycoplasma(支原体) infections. (3) Chlamydia(衣原体) infection. (4) Leptospira(螺旋体) infection. (5) Bacterial infection. General properties of Tetracyclines Adverse reactions (1) Gastrointestinal effects. (2) Superinfections. (3) Deposition of the drugs in growing teeth and bones. (4) Hepatic toxicity and renal toxicity. (5) Photosensitivity. (6) Vestibular toxicity (minocycline). Brown discoloration of teeth due to tetracycline exposure. Tetracyclines agents • Tetracycline (四环素) • Doxycycline (多西环素) • Minocycline (米诺环素) Part B Chloramphenicol Chemical structure p 1246 p776pharm Chloramphenicol 1. Antimicrobial activity: (1) a wide antimicrobial spectrum. (2) primarily bacteriostatic , may be bactericidal to certain species. Chloramphenicol 2. Mechanism of action Acts primarily by binding reversibly to the 50 S ribosomal subunit (near the site of action of macrolides and clindamycin, which it inhibits competitively). Mechanism of action: ①Chloramphenicol ②Macrolides, Clindamycin ③Tetracyclines Chloramphenicol 2. Mechanism of Resistance (1) a plasmid-encoded acetyltransferase that inactives the drugs (2) low permeability of bacterial cell membrane Chloramphenicol 3. Adverse reactions (1)Hematological Toxicity: • dose-related toxic effect anemia, leukopenia, thrombocytopenia • idiosyncratic response aplastic anemia(再障), fatal pancytopenia. (2) Gray baby syndrome. (3) hypersensitivty reaction, etc. 4. Drugs interactions inhibits Cy P450 enzyme mediated metabolism of warfarin, phenytoin, etc. Chloramphenicol 5.Clinical uses (1) Bacterial meningitis. (2) Typhoid fever(伤寒) and other types of systemic Salmonella infections. (3) Eye bacterial infection. (4) Anaerobic infection. (5) Rickettsial disease and brucellosis, etc. Thanks !