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β-Lactam antibio tics

Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

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Page 1: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

β-Lactam antibiotics

Page 2: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Classification

PenicillinsCephalosporinsOther β-Lactam drugs

Cephamycins (头霉素类)Carbapenems (碳青霉烯类)Oxacephalosporins (氧头孢烯类)β-Lactamase inhibitors ( β- 内酰胺酶抑制剂)Monolactums (单环 β- 内酰胺类)

Page 3: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Mechanism of action

Inhibiton of bacterial cell wall synthesis

Target: PBPs(penicillin-binding proteins)

Cell-wall autolytic enzyme

Page 4: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Mechanism of resistanceInactivation of drug by β-lactamase

Trapping mechanism

Modification of PBPs

Impared penetration of drug to target PBPs

Absence of autolysins

Page 5: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

PenicillinsHistory

Basic structure: 6-APA

ClassificationNatural penicillins

Semisynthesized penicillins

Page 6: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Penicillin G

ChemistryAntimicrobial activity

• Gram-positive cocciStreptococci ,pneumococci , staphylcocci

•Gram-positive rodsB.anthracis, diphtheriae, clostridium teran

i

Page 7: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Penicillin G

•Gram-negative cocciMeningococci, diplococcus gonorrhoeae

•Spirochetetreponema pallidum leptospirrosis

Page 8: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

PharmacokineticsAbsorptionDistributionmetabolismExcretion

90% tubular secretion10% glomerular filtration

Page 9: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Clinical usesFirst choice for the following infections

Infection caused by streptococci, pneumococci, meningococci etc

Infection caused by spirochetes

Infection caused by gram-positive rods

Page 10: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Adverse reactionsAllergic reactions

Common: urticaria, fever,angioneurotic edema,eosinophlia, hemolytic anemiaSevere: anaphylactic shock

Herxheimer reaction

Page 11: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Allergic reactions Reason:degraded products of penicillin

Prevention: History of allergic reactions Skin test Epinephrine

Adverse reactions

Page 12: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Synthesized penicillinsAcid-resistant penicillinsPenicillinase-resistant penicillinsExtended-spectrum penicillinsExtended-spectrum penicillins against P.aeruginosaPenicillins against gram-negative bacteria

Page 13: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Acid-resistant penicillinsDrugs: penicillin V,phenethicillin

Character Orally effective, not resist β-Lactamase Lower potency than penicillin G

• Clinical uses: moderate infections

• Adverse reactions: allergic reaction

Page 14: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Penicillinase-resistant penicillins

Drugs:oxacillin, cloxacillin, dicloxacillin

Clinical use

Infection caused by penicillin-resistant staphylococci

Page 15: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Extended-spectrum penicillins

Ampicillin, amoxycillin, pivampicillin

Oral effective, susceptible to β-Lactamase

Broad spectrum: G+ G-

Clinical uses: infection caused by gram-negative rods

Page 16: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Extended-spectrum Penicillins against P.aeruginosa

Carbenicillin,sulbencillin, ticarcillin,

furbencillin, piperacillin, mezlocillin

• Character: more activity on P.aeruginosa

• Usually in combination with aminoglycosides

Page 17: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Penicillins against gram-negative bacteria

Mecillinam, pivmecillinam, temocillin

Narrow-spectrum:mainly on G- rods

β-Lactamase resistant

Treatment of infections caused by G- rods

Page 18: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

CephalosporinsChemistry: 7-ACA

Classification: four generationsFirst-generation cephalosporinsSecond- generation cephalosporinsThird-generation cephalosporinsFourth- generation cephalosporins

Page 19: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

First-generation cephalosporins

Cephazolin, cephalothin,cefradine,cefalexinCommon characters:Activity on gram-positive bacteria: first>secon

d>third Activity on gram-negative bacteria: first<secon

d<thirdStability to β-Lactamase produced by gram-neg

ative rods: first<second<thirdRenal toxicity: first>second>third

Page 20: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

First-generation cephalosporins

Clinical uses

•Penicillin-resistant staphylococcal infection

•Minor to moderate infections caused by sensitive bacteria

Page 21: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Second-generation cephalosporins

Cefamandole, cefuroxime,cefaclor

Common characters More stable to β-Lactamase More active on gram-negative bacteria Less active on gram-positive bacteria Less renal toxicity

Page 22: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Second-generation cephalosporins

Effective on anaerobesNo effect on P.aeruginosa

Clinical uses• Gram-negative bacteria infections

• Anaerobic infections

Page 23: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Third-generation cephalosporins

Ceftriaxone, ceftazidimeCommon characters• Much more active on gram-negative bacteria

• Stable to extended β-Lactamase produced by gram-negative bacteria

• Effective on anaerobes and P.aeruginosa

• No renal toxicity

• Penetrating body fluids and tissues well

Page 24: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Third-generation cephalosporins

Clinical uses

a wide variety of serious infections caused by organisms that are resistant to most other drugs

Page 25: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Fourth- generation cephalosporins

Cefpirome,cefepime, cefclidinCharacter:• Enhanced antimicrobial activity

• Stable to ESBLs

• More activity on gram-positive cocci

• Clinical uses:• infections caused by organisms that are resis

tant to third-generation cephalosporins

Page 26: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Other β-Lactam drugs

Page 27: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

Cephamycins

CefoxitinSimilar to third-generation cephalosporinsMore activity on anaerobesUsed to treat mixed anaerobic and aerobic infections

Page 28: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

CarbapenemsThe most important antimicrobial agents in 1990’s

Wide spectrum and high activity

Resistant to mostβ-Lactamase(including ESBLs and cephalosporinase)

Page 29: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

CarbapenemsThienamycin

Imipenem

Imipenem-cilastatin:tienam

Meropenem

Panipenem

Page 30: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

OxacephalosporinLatamoxef, flomoxef

Higher activity on anaerobes (especially Bacteroids fragilis)than third-generation cephalosporins

Well resitant to β-Lactamase

Page 31: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

β-Lactamase inhibitors

Clavulanic acid

Sulbactam

tazobactam

Page 32: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

β-Lactamase inhibitors

Weak antimicrobial action

Protect β-lactams from inactivation by β-lactamase

Synergism

Page 33: Β-Lactam antibiotics. Classification Penicillins Cephalosporins Other β-Lactam drugs Cephamycins (头霉素类) Carbapenems (碳青霉烯类) Oxacephalosporins (氧头孢烯类)

MonobactamsAztreonam, carumonamNo effect on gram-positive bacteria and anaerobesHigh activity on gram-negative bacteriaPenicillin-allergic patients tolerate wellLow toxcity