Part 3 Macrolides, Lincomycins &Vancomycins Chemotherapeutic drugs Wei-wei Hu, PhD [email protected].

Part 3

Macrolides, Lincomycins &Vancomycins

Chemotherapeutic drugs

Wei-wei Hu, PhD

[email protected]

Macrolides Macrolides （大环内酯类）（大环内酯类）

• First generation: - Erythromycin( 红霉素 ) - Medecamycin( 麦迪霉素 ) - Spiramycin( 螺旋霉素 )• Second generation: - Clarithromycin( 克拉霉素 ) - Azithromycin( 阿奇霉素 ) - Acetylmedecamycin( 乙酰麦迪霉素 )• Third generation: - Telithromycin( 替利霉素 )

Macrolides Macrolides （大环内酯（大环内酯类）类）

General properties of Macrolides

1.Chemistry: contain a macrocyclic lactone ring (usually containing 14 to 16 atoms) to which deoxy sugars are attached.

2.Antimicrobial activity:

bactericidal or bacteriostatic, depending on the concentration, high activity in alkaline condition.

3. Antimicrobial spectrum ： G+ organisms:

- cocci: streptococcus pyogenes, hemolytic streptococcus and streptococcus pneumoniae （化脓性、溶血性和肺炎链球菌） , staphylococcus (produce β-lactamase or MRSA 耐甲氧西林的金葡菌 )

- bacilli: diphtheria （白喉） , bacillus anthraci （炭疽），破伤风杆菌

G- organisms:

- cocci: meningococcus ( 脑膜炎奈瑟菌 ) ， N. gonorrhoeae ( 淋病奈瑟菌 )

- bacilli:legionella pneumophila （军团菌） , bordertella pertussis （百日咳杆菌） , haemophilus influenzae （流感嗜血杆菌）（对大肠埃希菌、变形杆菌无效）

Other ： - mycoplasma pneumoniae （肺炎支原体）

- chlamydia （衣原体） - rickettsia （立克次体） - spirochetes （螺旋体）


4. Mechanism of action:


1. Preventing the peptidyl transfer2. Blocking translocation of peptidyl tRNA from A site to P site3. Inhibiting the formation of functional 70s ribosome

5. ADME of Macrolides:

(1)Absorption: • Erythromycin is destroyed by stomach acid and must

be administrated with enteric coating. • Stearates ( 硬脂酸 ) and ester ( 酯化 ) are fairly acid-

resistant and somewhat better absorbed.• Clarithromycin and Azithromycin are stable to acid.• Food interferes with absorption (except

Clarithromycin).

General properties of macrolides

5. ADME of macrolides:

(2)Distribution: Erythromycin diffuses readily

into most tissues, including prostatic fluid

and placenta, BBB impenetrable.

(3) Metabolism and Elimination: most

metabolized in the liver, excreted in the bile ； clarithromycin and its metabolite excreted in

urine.


6.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) Diphtheria （白喉）(5) Pertussis （百日咳）(6) Streptococcus （链球菌） , staphylococous

（金葡菌） infections


7.Adverse response:

(1) GI effects: nausea, vomiting, abdominal

cramps, etc.

(2) Liver toxicity: Cholestatic hepatitis

（胆汁淤积性肝炎） .

(3) Auditory impairment.

(4) Allergic reaction

(5) Superinfections


8. Resistance mechanism:

(1) modification of the ribosomal binding site

(2) production of esterase that hydrolyze

macrolides

(3) reduced permeability of cell membrane or

active efflux

(4) Ribosome mutation (base mutation of 23s rRNA

or ribosome protein mutation)

***Cross-resistance is complete between

erythromycin and the other macrolides.


9. Drug interaction

• Erythromycin metabolites can inhibit

cytochrome P450 enzyme.


• Erythromycin ( 红霉素 ) : chlamydia ( 支原体 ) and chlamydial ( 衣原体 ) infections, community-acquired pneumonia, penicillin substitute for staphylococcal, streptococcal or pneumococcal infection. Cause obvious GI reactions and liver toxicity.

• Clarithromycin ( 克拉霉素 ) : highest activity, its metabolite has activity.

• Azithromycin ( 阿奇霉素 ): penetrates into most tissues well and released slowly from tissues, permits once daily dosing. High activity against mycoplasma ( 支原体 ) and chlamydia( 衣原体 ). Has PAE.

• Telithromycin ( 泰利霉素 ): 酮内酯类抗生素， good absorption and penetration, high binding to ribosome, low efflux, effective to MLSB resistant bacteria.

Macrolides

• resemble erythromycin in antibacterial spectrum, activity,

mechanism and resistance.

bactericidal or bacteriostatic, depending on the concentration,

G+ coccus, G- coccus, anaerobebut not mycobacteria pneumoniae ( 肺炎衣原体 ), virus,

fungi, and resistant to aerobic G- bacilli, enterococcus, Clostridium difficile ( 难辨梭状芽孢杆菌 )

Lincomycin & Clindamycin

Pharmacokinetics

• p.o., ~ 90% protein-bound (Clindamycin)• penetrate well into most tissue, including

bone, but not CSF (except toxoplasmic

encephalitis).• Metabolized in liver and excreted via, bile,

and urine


Clinical Uses

• severe anaerobic infection • aerobic G+ cocci infection ( 金葡菌骨髓炎 )• combination with pyrimethamine ( 乙氨嘧啶 ) for

AIDS-related toxoplasmosis ( 弓形体病 ) & with

primaquine ( 伯氨喹 ) for pneumocystis carinii

pneumonia ( 卡氏肺囊虫肺炎 ).


Adverse response:

(1)Gastrointestinal effects:• nausea, vomiting, abdominal pain, diarrhea

• antibiotic-associated colitis is caused by toxigenic C difficile

(pseudomembranous colitis, 难辨梭状芽孢杆菌引起的伪膜性结肠炎 ).

--Superinfection( 二重感染 ) ： an infection following a previous

infection, especially when caused by microorganisms that are resistant or have

become resistant to the antibiotics used earlier

(2)allergic reaction

(3)impaired liver function (occasionally)

Lincomycin & ClindamycinLincomycin & Clindamycin

Vancomycins

- Vancomycin- Norvancomycin- Teicoplanin

Antibacterial activity (Narrow spectrum)

bactericidal for G+ bacteria (especially G+ ococci, including MRSA & MRSE 耐甲氧西林表皮葡萄球菌 ), Clostridium difficile ( 难辨羧杆菌 ), Bacterooides fragilis ( 脆弱拟杆菌 , 去甲万古 )

• Antibacterial Mechanism

Inhibiting cell wall synthesis by binding to

the D-Ala-D-Ala terminus of nascent

peptidoglycan pentapeptide.

Vancomycins

Fig. Antibacterial Mechanism of Vancomycins

• Resistance

- vancomycin-resistant enterococci mechanism:

occurred because of the alteration of D-Ala-D-Ala.

- vancomycin-resistant staphylococous auteus

mechanism:

* cell wall thickening

* change of the component of cell wall

* change of PBP

Vancomycins

ADME• Oral administration (poorly

absorbed ， pseudomembranous colitis).

• Intravenous administration, widely distributed in the body,

including CSF when the meninges is inflamed.

• excreted by glomerular filtration (accumulates when renal

function is impaired).

Vancomycins

Clinical Uses

1) severe infection caused by MRSA etc.

2) alternative for β-lactams

3) enterococcal ( 肠球菌 ) or staphyococcal ( 链球菌 )

endocarditis( 心内膜炎 ) (combination with gentamicin).

4) pseudomembranous colitis

***Overuse should be avoided, in view of limited options for

treatment of resistant gram positive infections.

Vancomycins

Adverse Reactions

1) Hypersensitive reaction

(e.g. red man syndrome)

2) Ototoxicity

3) Nephrotoxicity

4) Gl effects, phlebitis etc.

Vancomycins

Chemotherapeutic drugs

Part 4

Aminoglycosides & Polymyxins

AminoglycosidesAminoglycosides 氨基糖苷类抗生素

History• 1944 Streptomycin ( 链霉素 based on the

research made by Waksman and coworkers within 1939-1943)

• 1957 kanamycin 卡那霉素• 1964 gentamicin 庆大霉素• 1967 tobramycin 妥布霉素• Amikacin & netilmicin 阿米卡星和奈替米星

(semisynthetic)

Aminoglycosides

Nobel Prize

• Streptomycin 链霉素• Neomycin 新霉素• Kanamycin 卡那霉素• Tobramycin 妥布霉素

• Gentamicin 庆大霉素• Micronomicin 小诺米

星 • Sisomicin 西索米星• Astromicin 阿司米星

• Amikacin 阿米卡星，丁胺卡那霉素

• Netilmicin 奈替米星• B kanamycin 卡那霉素 B

• Arbekacin 阿贝卡星

• Dibekacin 地贝卡星

• Etilmicin 依替米星 • Isepamicin 异帕米星

Aminoglycosides

1. Antimicrobial activity:

i) rapidly bactericidal to resting bacterium

ii)broad-spectrum ： G- bacilli ， G+ organisms (including MRSA - netilmicin) , TB , less acitive to G-

cocci, and ineffective for anaerobic strains.

iii) clinical applications: for the treatment of aerobic G- bacilli infections and tuberculosis

iv) unabsorbable in GI tract

v) more active in alkaline environment

Aminoglycosides

1. Antimicrobial activity:vi) concentration-dependent activity vii) the duration of post antibiotic effect (PAE)

is concentration- dependent (10 hours).viii) first exposure effect (FEE)

Blood Concentration

MIC

Peak Concentration

Time (h)

Bacterial growth is inhibited long after concentration below the MIC

AminoglycosidesAminoglycosides

2. Mechanisms of action:

(1) act as ionic- sorbent, act directly on permeability of the cell membrane of bacterium.

General properties

Aminoglycosides

i) Interfering with the initiation complex of peptide

formation (30S or 70S).

ii) Inducing misreading of mRNA, which causes the

incorporation of incorrect amino acid into peptide,

resulting nonfunctional or toxic protein. iii) causing breakup of polysomes into nonfunctional

monosomes.iv) disrupt the normal cycle of ribosomal, make the

ribosomal exhausted.

2.Mechanism of action

(2) inhibit the whole process of protein synthesis

Aminoglycosides

i) The microorganism produces a transferase enzyme

that inactivate the aminoglycoside by adenylation,

acetylation, or phosphorylation.

ii) The receptor protein on the 30S ribosomal subunit

may be deleted or altered as a result of mutation.

iii) Impaired entry of aminoglycoside into the cell.

iv) Increased efflux

3. Mechanism of Resistance3. Mechanism of Resistance

Aminoglycosides

Diagrammatic representation of transfer and transfer reduction of aminoglycoside across the bacterial cell wall.• If it is modified by acetylation, adenylation, or phosphorylation, the drug will not bind to ribosomes and will leave the bacterial cell.

4. ADMEi) Absorption: not absorbed by oral, but rapidly absorbed after i.m.

ii) Distribution: minimal binding to plasma protein; high

concentrations in secretions and body fluids; unable to cross

cell membrane and BBB, able to cross the placenta. Tissue level

is low except in the cortex of kidney and endolymph and

perilymph of inner ear.

iii) Metabolism and Elimination: excreted mainly by glomerular

filtration. Accumulation occurs in renal failure with dose-related

toxic effects.

Aminoglycosides

5. Clinical Uses

• mostly used against infection induced by aerobic G- bacilli .

• G- bacilli induced severe infection, such as sepsis( 败血症 ),

pneumonia and meningitis, almost always used in combination

with-lactam antibiotics and fluoroquinolones.

• G+ cocci severe infection:combined with vancomycin, β-

lactamase- resistant penicillins

• TB (streptomycin and Kanamycin) and atypical mycobacteria

分枝杆菌 (Amikacin)

Aminoglycosides

7. Adverse reactions

i) Ototoxicity （耳毒性） Caused by progressive destruction of vestibular

and cochlear sensory cells (hearing loss irreversible!!).

Cochlear toxicity: tinnitus （耳鸣） and high frequency hearing

loss Kanamycin>Amikacin>Sisomicin>Gentamicin>Tobramycin

Vestibular toxicity: vertigo, ataxia and loss of balance

Kanamycin>Streptomycin>Sisomicin>Gentamicin>Tobramycin

Aminoglycosides


ii) Nephrotoxicity

consists of damage to the kidney tubules

but reversible

Neomycin> Kanamycin>Gentamicin>Streptomycin or Tobramycin>Amikacin

Aminoglycosides


iii) Neuromuscular blockade (paralysis)

• generally occurred after intra-pleural or intra-peritoneal instillation of large doses of aminoglycosides

• Treatment: Calcium salt or inhibitor of cholinesterase (neostigmine) .

Neomycin>Streptomycin>Amikacin or Kanamycin> Gentamicin>Tobramycin

Aminoglycosides

7. Adverse reactionsiv) Allergic reaction

skin rashes, fever, angioneurotic edema, anaphylactic shock, etc.

Aminoglycosides

1. ADME

i) Absorption: im

ii) Distribution: mainly at extracellular fluid, can cross the BBB when meninges is inflamed.

iii) Excretion: 90% from kidney

2.Clinical uses

i) plague 鼠疫 and tularemia 土拉菌病 ( 兔热病 ): combination with an oral tetracycline.

ii) tuberculosis: as a first-line agent

iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptomycin and penicillin produce a synergistic bactericidal effect.

Streptomycin


i) Allergic reaction

skin rashes, fever, anaphylactic shock

ii) Ototoxicity: disturbance of vestibular function, deafness of newborn

iii) Neuromuscular blockade (paralysis) ： avoided in Myasthenia Gravis, avoided combining with anesthetics, scoline

iv) Nephrotoxicity

Streptomycin

1. ADME

Gentamicin can accumulate in cortex of the kidney .

2.Clinical use :

i) serious G- bacillary infections (sepsis, pneumonia, etc.).

ii) infection induced by enterococcus, viridans streptococcus, staphylococcus etc. (in combination with other antibiotics, e.g. -lactams)

iii) prevent the infection induced by operation (e.g., gastrointestinal operation )

iv) local application or intrathecal administration (rarely use)

Gentamicin

1. Features1. Features• The antimicrobial activity and pharmacokinetic The antimicrobial activity and pharmacokinetic

properties of tobramycin are very similar to those of properties of tobramycin are very similar to those of getamicin.getamicin.

2. Adverse reactions 2. Adverse reactions • Ototoxicity Ototoxicity less toxic to cochlear and vestibularless toxic to cochlear and vestibular• Nephrotoxicity Nephrotoxicity less renal tubular damageless renal tubular damage

TobramycinTobramycin

1.Antibacterial activity: the broadest in the group.

- effective against G- bacilli and staphylococcus aureus

- ineffective to other G+ cocci

- tolerance to modifying enzyme of enteric G- bacilli and pseudomonas

2.Clinical uses :

- treatment of G- bacillary infections which are resistant to gentamicin and tobramycin.

- most strains resistant to amikacin found also resistant to other aminoglycosides.

- combination with -lactams, produce a synergistic bactericidal effect.

Amikacin

1. Broad spectrum, especially strong effect against

aerobic G- bacilli. Effective against MRSA and

strains resistant to other aminoglycosides.

2. Tolerant to many aminoglycosides- inactivating enzymes.

3. Less toxic

Netilmicin

Polymyxins 多粘菌素

1.Notice: because of the extreme toxicity, they are now rarely used.

2.Antibacterial activity: narrow spectrum (G- bacilli), slow active, bactericidal.

Not active to G+ organisms, G- coccus, Bacterooides fragilis( 脆弱杆菌） , proteusbacillus vulgaris （变形杆菌） , serratia plymuthica （沙雷菌属）

卫生部在 10 月 9 印发了《产 NDM － 1 泛耐药肠杆菌科细菌感染诊疗指南（试行版）》 : 轻、中度感染：敏感药物单用即可，如氨基糖苷类、喹诺酮类、磷霉素等，也可以联合用药，如氨基糖苷类联合环丙沙星、环丙沙星联合磷霉素等。无效患者可以选用替加环素、多粘菌素。

Polymyxins

3. Mechanism of action: they interact with phospholipids (are surface-active) and penetrate into and disrupt the structure of cell membranes.

4. Clinical uses: substitute of β-lactams and aminoglycosides, to treat infection of pseudomonas aeruginosa ( 铜绿假单胞菌属） and other G- bacilli, local application.

Mechanism of Mechanism of PolymyxinsPolymyxins actionaction

Polymyxins

6. Adverse reaction:

(1) Nephrotoxicity (22%)

(2) Neurotoxicity

(3) Allergic reaction

(4) other reactions

Part 5

Tetracyclines & Chloramphenicol四环素和氯霉素

Part A Tetracyclines

http://upload.wikimedia.org/wikipedia/commons/8/8e/Tetracycline_structure.svg

Divided into:

• Crude products (Naturally occurring)

- Tetracycline ( 四环素 )

- Chlortetracycline ( 金霉素 )

- Oxytetracycline( 土霉素 )

- Demeclocycline( 地美环素 )

• Semisynthetic derivatives

- Doxycycline( 多西环素 )

- Minocycline( 米诺环素 )

- Meclocycline( 甲氯环素 )

- Lymecycline( 赖甲环素 )

- Methacycline( 美他环素 )

- Rolitetracycline( 吡甲四环素 )

- tigecycline ( 替加环素 ) (glycylcyline, 2005 approved)

Tetracyclines


(1) Bacteriostatic

(2) Bactericidal (at high concentration )

(3) Minocycline>Doxycycline>Tetracycline

Tetracyclines

2. Antimicrobial spectrum: (1)Broad spectrum: active against a wide range of

aerobic and anaerobic gram-positive and gram-negative bacteria.

(2)Effective against Rickettsia ( 立克次体 ), spirochetes ( 螺旋体 ), Mycoplasma pneumoniae ( 肺炎支原体 ), Chlamydia ( 衣原体 ), and Plasmodium ( 疟原虫 ).

(3) Ineffective against fungi ( eg. candida albicans 白色念珠菌 ), virus.

Tetracyclines

3. Mechanism of action: (1) Enter bacteria by passive diffusion through

porins or active transport by an energy-dependent system.

(2) Inhibit protein synthesis in susceptible microorganisms (blocking combination of tRNA with 30S subunit).

(3) Increase the permeability of the cell membrane

Tetracyclines

Tetracyclines, Chloramphenicol, Macrolides

4. 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.

Tetracyclines

5. ADME of Tetracyclines:(1) Absorption largely differ from each other after oral

administration (doxycycline and minocycline 95-100%). Absorption are impaired by food (except doxycycline and minocycline).

(2) Distributed widely to tissue and body fluid except for CSF (minocycline exclusive).

(3) Excreted mainly in bile and urine.

Tetracyclines

5. ADME of Tetracyclines:

(4) Able to penetrate the placenta and are also excreted in the milk.

(5) As a result of chelation with calcium, tetracyclines are bound to- and damage- growing bones and teeth.

Tetracyclines

6.Clinical Uses

(1)Rickettsial ( 立克次体 ) infections: Rickettsia Conorii ( 伤寒 ).

(2)Mycoplasma ( 支原体 ) infections: M. pneumonia and M.urealyticum ( 肺炎支原体 / 溶脲支原体 ).

(3)Chlamydia( 衣原体 ) infection ： Chlamydia psittaci, pneumonia, rachomatis ( 鹦鹉热 / 肺炎 / 沙眼衣原体 ).

(4)Leptospira ( 螺旋体 ) infection ： Borrelia burgdorferi, recurrentis, treponema pallidum ( 伯氏疏 / 回归热 / 梅毒螺旋体 ) infection.

(5)Bacterial infection: Calymmatobacterium granulomatis, Vibrio cholerae, brucellosis ( 肉芽肿鞘杆菌 / 霍乱弧菌 / 布鲁菌 ) infection.

Tetracyclines

7. 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( 光敏反应 ).(6)Vestibular toxicity.

Tetracyclines

8. Drug interaction

antacids containing aluminum, calcium, or magnesium, and iron-containing preparations

Impaire the absorption of tetracyclines

anticoagulant therapy Because tetracyclines have been shown to depress plasma prothrombin activity

bacteriostatic drugs interfere with the bactericidal action of penicillin

Tetracyclines

Part B Chloramphenicol ( 氯霉素 )

p 1246 p 1246

p776pharm p776pharm

Chemical structureChemical structure


(1) Possesses a wide antimicrobial spectrum

G- > G+, rickettsia ( 立克次体 ), spirochetes ( 螺旋体 ), pneumoniae ( 肺炎支原体 )

but not chlamydia ( 衣原体 ), mycobacteria, virus, fungi

(2) Primarily bacteriostatic, bactericidal to certain species.

Chloramphenicol

2. Mechanism of action

Inhibit protein synthesis in susceptible bacteria, and to a lesser extent, in mammalian cell (because mitochondrial ribosomes resemble bacterial ribosomes, both are 70 S).

Acts primarily by binding reversibly to the 50 S ribosomal subunit (near the site of action of macrolides and clindamycin).

Chloramphenicol

Tetracyclines, Chloramphenicol, Macrolides

2. Mechanism of Resistance

(1) Usually caused by a plasmid-encoded acetyltransferaes that inactivates the drugs.

(2) The permeability of bacterial cell membrane is changed.

Chloramphenicol

3. ADME of Tetracyclines:

(1) p.o. or i.v.

(2) Distributed widely to tissue and body fluid including CSF, placenta, milk （ inhibit the bacteria in cells ） .

(3) Metabolized by liver and excreted by kidney.

Chloramphenicol

4.Clinical uses with caution

(1) Bacterial meningitis or intracerebral abscess( 脑脓肿 ).

(2) Typhoid fever( 伤寒 ) and other types of

systemic Salmonella infections.

(3) Eye bacterial infection.

(4) Anaerobic infection.

(5) Rickettsial disease and brucellosis ( 布鲁菌病 ), etc.

Chloramphenicol


(1)Hematological Toxicity:

by dose-related toxic effect on bone marrow: anemia( 贫血 ), leukopenia( 白细胞减少症 ) and or thrombocytopenia ( 血小板减少症 )

by idiosyncratic response: aplastic anemia( 再生障碍性贫血 ), leading in many cases to fatal pancytopenia( 全血细胞减少症 ).

Chloramphenicol

5. Adverse reactions(2) Toxicity for newborn infants: - Gray baby syndrome ( 灰婴综合征 ).(3)Other reactions: - GI reactions - hypersensitivity reaction - neuritis (sight impairment) - CNS side effects

Chloramphenicol

6. Drugs interactions

- Inhibiting hepatic P450 enzyme, thus prolonging the half-life time of drugs that metabolized by this system, e.g. warfarin, phenytoin, tolbutamide, etc.

- Rifampicin, phenytoin and pentobarbital accelerate its metabolism.

- If have to combined with penicillin, chloramphenicol should be dosed later.

- Antagonistic to lincomycins and macrolides.

Chloramphenicol

Part 3 Macrolides, Lincomycins &Vancomycins Chemotherapeutic drugs Wei-wei Hu, PhD [email protected].

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Transcript of Part 3 Macrolides, Lincomycins &Vancomycins Chemotherapeutic drugs Wei-wei Hu, PhD [email protected].