Macrolides, Lincomycins &Vancomycins Section 3 Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University

Erythromycin ( 红霉素 )Erythromycin ( 红霉素 ) Clarithromycin ( 克拉霉素 )Clarithromycin ( 克拉霉素 ) Azithromycin ( 阿奇霉素 )Azithromycin ( 阿奇霉素 ) Telithromycin( 泰利霉素 )Telithromycin( 泰利霉素 ) Part A Macrolides

14 member rings 15 member rings 14 member rings

1. Antimicrobial spectrum ： G + organismsG + organisms G - cocci:Streptococcus pyogenes and pneumoniaeG - cocci: Streptococcus pyogenes and pneumoniae pneumoniae( 肺支原体 ) and Legionnella ( 军团菌 )etcMycoplasma pneumoniae( 肺支原体 ) and Legionnella ( 军团菌 )etc. 2. Antimicrobial activity: bactericidal and bacteriostatic,bactericidal and bacteriostatic, depending on the concentration. depending on the concentration. more active at alkalinemore active at alkaline General properties of Macrolides

3. Mechanism of action: macrolide subunit

4. Mechanism of resistance: modification of the ribosomal binding sitemodification of the ribosomal binding site production of esterase that hydrolyze macrolides.production of esterase that hydrolyze macrolides. reduced permeability of cell membrane orreduced permeability of cell membrane or active effluxsystem is involved. active efflux system is involved. Cross-resistance is complete betweenCross-resistance is complete between erythromycin and the other macrolides. erythromycin and the other macrolides.

4. ADME 1) Absorption: Stearate and ester of erythromycin are fairly acid-resistant and somewhat batter absorbed. Food interferes with 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. 1) Mycoplasma ( 支原体 ) infections. 2) Legionnaire’s disease ( 军团菌病 ). 2) Legionnaire’s disease ( 军团菌病 ). 3) Chlamydia infections ( 衣原体感染 ). 3) Chlamydia infections ( 衣原体感染 ). 4) Streptococcus ( 链球菌 ) infections. 4) Streptococcus ( 链球菌 ) infections. 5) Diphtheria ( 白喉 ), chincough ( 百日咳 ). 5) Diphtheria ( 白喉 ), chincough ( 百日咳 ). 6) toxoplasmosis( 弓形虫病 ). 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 ). ( 胆汁淤积性肝炎 ). 3) Cardiotoxic effects 4) Auditory impairment (Ototoxicity) Hypersensitivity reactions Hypersensitivity reactions Superinfections Superinfections General properties of Macrolides

7. Drug interactions Erythromycin metabolites can inhibit cytochrome P450 enzyme.Erythromycin metabolites can inhibit cytochrome P450 enzyme. General properties of Macrolides

Erythromycin ( 红霉素 )Erythromycin ( 红霉素 ) Clarithromycin ( 克拉霉素 )Clarithromycin ( 克拉霉素 ) Azithromycin ( 阿奇霉素 )Azithromycin ( 阿奇霉素 ) Telithromycin( 泰利霉素 )Telithromycin( 泰利霉素 ) Macrolides

Lincomycin ( 林可霉素 )Lincomycin ( 林可霉素 ) Clindamycin ( 克林霉素 )Clindamycin ( 克林霉素 ) Part B Lincomycin & Clindamycin

Antimicrobial properties resemble erythromycin in antibacterial spectrum, activity, mechanism and resistance.resemble erythromycin in antibacterial spectrum, activity, mechanism and resistance. Lincomycin & Clindamycin

 Mechanism of action: ① Chloramphenicol ② Macrolides, Clindamycin ③ Tetracyclines

Pharmacokinetics Pharmacokinetics about 90% protein-boundabout 90% protein-bound excretion via the liver,bile, and urineexcretion via the liver,bile, and urine penetrate well into most tissue, including bone, but not CSF.penetrate well into most tissue, including bone, but not CSF. Lincomycin & Clindamycin

Clinical Uses severe anaerobic infectionsevere anaerobic infection aerobic G + cocci infectionaerobic G + cocci infection combination with pyrimethamine ( 乙胺嘧啶 ) for AIDS-related toxoplasmosis （弓形体病）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）. 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 Lincomycin & Clindamycin

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 bactericidal for G + bacteria ( especially G + ococci, including MRSA & MRSE) ( especially G + ococci, including MRSA & MRSE) Vancomycins

Antibacterial MechanismAntibacterial Mechanism Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan penta- peptide. Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan penta- peptide. ResistanceResistance occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser. occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser. Vancomycins

Fig. Antibacterial Mechanism of Vancomycins

ADMEADME Oral administration (poorly absorbed).Oral administration (poorly absorbed). Intravenous administration, is excreted by glomerular filtration (accumulates when renal function is impaired).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.Widely distributed in the body, including CSF when the meninges is inflamed. Vancomycins

Clinical UsesClinical Uses 1) severe infection caused by MRSA etc. 2) alternative for  -lactam 3) enterococcal or staphyococcal endocarditis (combination with gentamicin). 4) pseudomembranous colitis Vancomycins

Pseudomembranous enterocolitis Hurley and Ngueyn Arch Intern Med. 2002;162: Pseudomembranous colitis. Endoscopic en face view of colon wall demonstrating several pseudomembranes (arrows).

Focal ulceration can be seen at the tips of the mucosa. The exudate of fibrin and inflammatory tissue. Pseudomembranous enterocolitis Normal

Adverse ReactionsAdverse Reactions 1) Hypersensitive reaction (e.g. red man syndrome) (e.g. red man syndrome) 2) Ototoxicity 3) Nephrotoxicity 4) Gl effects, etc. Vancomycins

Aminoglycosides & polymyxins Section 4

History and Source : the research made by Waksman and coworks within History and Source : the research made by Waksman and coworks within Clinical Applications: for the treatment of aerobic G - bacterial infections and tuberculosis Clinical Applications: for the treatment of aerobic G - bacterial infections and tuberculosis Two classes: crude product and semisynthetic derivativeTwo classes: crude product and semisynthetic derivative Overview Part A Aminoglycosides

Aminoglycosides

1. Antimicrobial activity: i) rapidly bactericidal to resting bacterium i) rapidly bactericidal to resting bacterium ii) broad-spectrum 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) General properties Blood Concentration MIC Peak Concentration Time (h) Bacterial growth is inhibited long after concentration below the MIC

2. Antimicrobial spectrum ： aerobicG - bacilli and cocci aerobic G - bacilli and cocci aerobic G + organisms aerobic G + organisms Streptomycin and kanamycin are also active against Mycobacterium tuberculosis Streptomycin and kanamycin are also active against Mycobacterium tuberculosis General properties

3. Mechanism of action: inhibit protein synthesisinhibit protein synthesis act as Ionic- sorbent, act directly on permeability of the cell membrane of bacterium.act as Ionic- sorbent, act directly on permeability of the cell membrane of bacterium. General properties

Blocks the initiation of protein synthesis Blocks the initiation of protein synthesis Mechanism of action -inhibit protein synthesis Mechanism of action - inhibit protein synthesis

Blocks the initiation of protein synthesis Blocks the initiation of protein synthesis

Mechanism of action -inhibit protein synthesis Mechanism of action - inhibit protein synthesis

Incorporation of incorrect amino acid Incorporation of incorrect amino acid Mechanism of action -inhibit protein synthesis Mechanism of action - inhibit protein synthesis

Blocks further translocation and Blocks further translocation and elicits premature terminations elicits premature terminations

disrupt the normal cycle of ribosomal, disrupt the normal cycle of ribosomal, make the ribosomal exhausted make the ribosomal exhausted Mechanism of action -inhibit protein synthesis 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 Mechanism of action - inhibit protein synthesis

iii) causing breakup of polysomes into nonfunctional monosomes. nonfunctional monosomes. iv) disrupt the normal cycle of ribosomal, make the ribosomal ribosomal, make the ribosomal exhausted. exhausted. Mechanism of action -inhibit protein synthesis Mechanism of action - inhibit protein synthesis

Mechanism of resistance produces enzymes Altered ribosomal subunit Changes of Porins Active efflux system

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. Mechanism of Resistance

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. T 1/2 =2-3h T 1/2 =2-3h General properties

Clinical Uses be mostly used against aerobicG- bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with  -lactam antibiotic or fluoroqunolones ( 氟喹诺酮类 )be mostly used against aerobic G- bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with  -lactam antibiotic or fluoroqunolones ( 氟喹诺酮类 ) against aerobicG+ bacteria and in sepsis, be almost always used in combination with penicillins or vancomycinagainst aerobic G+ bacteria and in sepsis, be almost always used in combination with penicillins or vancomycin against Mycobacterium tuberculosisagainst 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!! ).involves progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ in the ear (irreversible!! ). Ototoxicity (cochlea) Ototoxicity (cochlea) Amikacin> Gentamicin> Tobramycin(0.4%)Kanamycin(1.6%)> Amikacin> Sisomicin> Gentamicin> Tobramycin(0.4%) Ototoxicity (vestibular organ) Ototoxicity (vestibular organ) > Gentamicin> Tobramycin(0.4%)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.consists of damage to the kidney tubules and be reversed if stop using. Amikacin < Tobramycin< Gentamicin <Amikacin < Streptomycin or Tobramycin< Gentamicin < Kanamycin <Neomycin General properties

Blue, high frequency Red, low frequency Nephrotoxicity Ototoxicity & Ototoxicity

Adverse reactions iii) Neuromuscular blockade (paralysis) generally occurred after intra-pleural or intra- peritoneal instillation of large doses of an aminoglycosidesgenerally occurred after intra-pleural or intra- peritoneal instillation of large doses of an aminoglycosides Tobramycin < Gentamicin < Amikacin <Tobramycin < Gentamicin < Kanamycin or Amikacin <Streptomycin <Neomycin Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity.Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity. General properties

Adverse reactions Adverse reactions iv) Allergic reaction skin rashes fever, eosinophiliay ( 嗜酸粒 细胞增多症）, anaphylactic shock, etc.skin rashes fever, eosinophiliay ( 嗜酸粒 细胞增多症）, anaphylactic shock, etc. General properties

Streptomycin （链霉素） Streptomycin （链霉素） Gentamicin （庆大霉素） Gentamicin （庆大霉素） Tobramycin （妥布霉素） Tobramycin （妥布霉素） Amikacin （阿米卡星） Amikacin （阿米卡星） Netilmicin （奈替米星） Netilmicin （奈替米星） Neomycin （新霉素） Neomycin （新霉素） Aminoglycosides 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. Aminoglycosides Aminoglycosides agents

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 ↑ → T 1/2 ↑ age ↑ → T 1/2 ↑ 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 Streptomycin

1. ADME Gentamicin can accumulate in cortex of the kidney. 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.  -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. Gentamicin

1. antimicrobial activity & pharmacokinetics: very similar to those of getamicin. 2. Adverse reactions: Ototoxicity and Nephrotoxicity (may be less than dose gentamicin). Tobramycin

1.Antibacterial activity: The spectrum of antimicrobial activity of amikacin is the broadest in the group. 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.Treatment of G-bacillary infections which resistance to gentamicin and tobramycin. Most strains resistance to amikacin found is also resistance to other aminoglycosides.Most strains resistance to amikacin found is also resistance to other aminoglycosides. combination with  -lactams, produce a synergistic bactericidal.combination with  -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. Amikacin

i) similar to gentamicin & tobramycin in its pharmacokinetic properties. ii) broad spectrum, against aerobic G- bacilli. iii) tolerance to many aminoglycosides - inactivating enzymes. iv) less toxic Netilmicin

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. 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

etracyclines & Chloramphenicol Tetracyclines & Chloramphenicol Section 5

Part A etracyclines Part A Tetracyclines

 Two classes: crude productcrude product Tetracycline( 四环素 ) Tetracycline( 四环素 ) Cholortetracycline ( 金霉素 ) Cholortetracycline ( 金霉素 ) Oxytetracycline ( 土霉素 ) Oxytetracycline ( 土霉素 ) semisynthetic derivativesemisynthetic derivative Doxycycline( 多西环素 ) Doxycycline( 多西环素 ) Minocycline( 米诺环素 ) Minocycline( 米诺环素 ) Part A etracyclines Part A Tetracyclines

 Antimicrobial activity: bacteriostaticbacteriostatic bactericidal (high concentration)bactericidal (high concentration) Minocycline > Doxycycline > TetracyclineMinocycline > Doxycycline > Tetracycline General properties of Tetracyclines

 “broad-spectrum” antibiotic Rickattsiae ( 立克次体 )Rickattsiae ( 立克次体 ) a number of aerobic and anaerobic G + & G - bacteriaa number of aerobic and anaerobic G + & G - bacteria Chlamydia ( 衣原体 )Chlamydia ( 衣原体 ) Coxiella burnetii ( 螺旋体 )Coxiella burnetii ( 螺旋体 ) Mycoplasma pneumoniae ( 支原体 )Mycoplasma pneumoniae ( 支原体 ) Plasmodium ( 疟原虫 )Plasmodium ( 疟原虫 ) not active against fungi, virus.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: ① Chloramphenicol ② Macrolides, Clindamycin ③ Tetracyclines

 Resistance Mechanism: (1) Decreased intracellular accumulation due to either impaired influx or increased efflux by a active transport protein pump. (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.across the placenta and are also excreted in the milk. tetracyclines are bound to- and damage- growing bones and teeth (chelation with calcium).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). General properties of Tetracyclines

Brown discoloration of teeth due to tetracycline exposure.

Tetracycline ( 四环素 )Tetracycline ( 四环素 ) Doxycycline ( 多西环素 )Doxycycline ( 多西环素 ) Minocycline ( 米诺环素 )Minocycline ( 米诺环素 ) Tetracyclines agents

Part B Chloramphenicol p 1246 p 1246p776pharm Chemical structure

1. Antimicrobial activity: (1) a wide antimicrobial spectrum. (1) a wide antimicrobial spectrum. (2) primarily bacteriostatic, may be bactericidal to certain species. (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). Acts primarily by binding reversibly to the 50 S ribosomal subunit (near the site of action of macrolides and clindamycin, which it inhibits competitively). Chloramphenicol

 Mechanism of action: ① Chloramphenicol ② Macrolides, Clindamycin ③ Tetracyclines

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 dose-related toxic effect anemia, leukopenia, thrombocytopenia anemia, leukopenia, thrombocytopenia idiosyncratic response idiosyncratic response aplastic anemia( 再障 ), fatal pancytopenia. 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. 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. systemic Salmonella infections. (3) Eye bacterial infection. (4) Anaerobic infection. (5) Rickettsial disease and brucellosis, etc. Chloramphenicol

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