Transcript β-Lactam antibiotics

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（ β-内酰胺酶抑制剂）
Monolactums（单环β-内酰胺类）
Mechanism of action
Inhibiton of bacterial cell wall
synthesis
Target: PBPs(penicillin-binding
proteins)
Cell-wall autolytic enzyme
Mechanism of resistance
Inactivation of drug by β-lactamase
Trapping mechanism
Modification of PBPs
Impared penetration of drug to target
PBPs
Absence of autolysins
Penicillins
History
Basic structure: 6-APA
Classification
Natural penicillins
Semisynthesized penicillins
Penicillin G
Chemistry
Antimicrobial activity
• Gram-positive cocci
 Streptococci ,pneumococci ,
staphylcocci
• Gram-positive rods
 B.anthracis, diphtheriae, clostridium
terani
Penicillin G
• Gram-negative cocci
Meningococci, diplococcus
gonorrhoeae
• Spirochete
treponema pallidum
leptospirrosis
Pharmacokinetics
Absorption
Distribution
metabolism
Excretion
90% tubular secretion
10% glomerular filtration
Clinical uses
First choice for the following infections
Infection caused by streptococci,
pneumococci, meningococci etc
Infection caused by spirochetes
Infection caused by gram-positive
rods
Adverse reactions
Allergic reactions
Common: urticaria,
fever,angioneurotic
edema,eosinophlia, hemolytic
anemia
Severe: anaphylactic shock
Herxheimer reaction
Adverse reactions
Allergic reactions
 Reason:degraded products of penicillin
 Prevention:
 History of allergic reactions
 Skin test
 Epinephrine
Synthesized penicillins
Acid-resistant penicillins
Penicillinase-resistant penicillins
Extended-spectrum penicillins
Extended-spectrum penicillins against
P.aeruginosa
Penicillins against gram-negative
bacteria
Acid-resistant penicillins
Drugs: penicillin V,phenethicillin
Character
 Orally effective, not resist β-Lactamase
 Lower potency than penicillin G
• Clinical uses: moderate infections
• Adverse reactions: allergic reaction
Penicillinase-resistant penicillins
Drugs:oxacillin, cloxacillin,
dicloxacillin
Clinical use
Infection caused by penicillinresistant staphylococci
Extended-spectrum penicillins
Ampicillin, amoxycillin, pivampicillin
Oral effective, susceptible to β-Lactamase
Broad spectrum: G+ GClinical uses: infection caused by
gram-negative rods
Extended-spectrum Penicillins
against P.aeruginosa
•
•
Carbenicillin,sulbencillin, ticarcillin,
furbencillin, piperacillin, mezlocillin
Character: more activity on P.aeruginosa
Usually in combination with
aminoglycosides
Penicillins against gramnegative bacteria
Mecillinam, pivmecillinam, temocillin
Narrow-spectrum:mainly on G- rods
β-Lactamase resistant
Treatment of infections caused by Grods
Cephalosporins
Chemistry: 7-ACA
Classification: four generations
First-generation cephalosporins
Second- generation cephalosporins
Third-generation cephalosporins
Fourth- generation cephalosporins
First-generation cephalosporins
Cephazolin, cephalothin,cefradine,cefalexin
Common characters:
 Activity on
gram-positive bacteria:
first>second>third
 Activity on gram-negative bacteria:
first<second<third
 Stability to β-Lactamase produced by gramnegative rods: first<second<third
 Renal toxicity: first>second>third
First-generation cephalosporins
Clinical uses
•Penicillin-resistant
staphylococcal infection
•Minor to moderate infections
caused by sensitive bacteria
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
Second-generation
cephalosporins
Effective on anaerobes
No effect on P.aeruginosa
Clinical uses
• Gram-negative bacteria infections
• Anaerobic infections
Third-generation cephalosporins
Ceftriaxone, ceftazidime
Common 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
Third-generation cephalosporins
Clinical uses
a wide variety of serious
infections caused by organisms
that are resistant to most other
drugs
Fourth- generation
cephalosporins
Cefpirome,cefepime, cefclidin
Character:
•
• Enhanced antimicrobial activity
• Stable to ESBLs
• More activity on gram-positive cocci
Clinical uses:
• infections caused by organisms that are
resistant to third-generation cephalosporins
Other β-Lactam drugs
Cephamycins
Cefoxitin
Similar to third-generation
cephalosporins
More activity on anaerobes
Used to treat mixed anaerobic and
aerobic infections
Carbapenems
The most important antimicrobial
agents in 1990’s
Wide spectrum and high activity
Resistant to mostβLactamase(including ESBLs and
cephalosporinase)
Carbapenems
Thienamycin
Imipenem
Imipenem-cilastatin:tienam
Meropenem
Panipenem
Oxacephalosporin
Latamoxef, flomoxef
Higher activity on anaerobes
(especially Bacteroids fragilis)than
third-generation cephalosporins
Well resitant to β-Lactamase
β-Lactamase inhibitors
Clavulanic acid
Sulbactam
tazobactam
β-Lactamase inhibitors
Weak antimicrobial action
Protect β-lactams from inactivation by
β-lactamase
Synergism
Monobactams
Aztreonam, carumonam
No effect on gram-positive bacteria
and anaerobes
High activity on gram-negative
bacteria
Penicillin-allergic patients tolerate well
Low toxcity