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

Allergic reactions  Reason :degraded products of penicillin  Prevention:  History of allergic reactions  Skin test  Epinephrine Adverse reactions

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 penicillin- resistant staphylococci

Extended-spectrum penicillins Ampicillin, amoxycillin, pivampicillin Oral effective, susceptible to β-Lactamase Broad spectrum: G + G - Clinical 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 gram- negative bacteria Mecillinam, pivmecillinam, temocillin Narrow-spectrum:mainly on G - rods β-Lactamase resistant Treatment of infections caused by G - rods

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 gram- negative 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 mostβ- Lactamase(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