1. Beta lactam antibiotics & Other cell wall synthesis inhibitors
Pawitra Pulbutr
M.Sc. In Pharm (Pharmacology)

2. วัตถุประสงค์เชิงพฤติกรรม
เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, กลไกการดื้อยา, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ที่เกิดจากการใช้ยา, การนำไปใช้ประโยชน์ทางคลินิก รวมทั้งข้อดีและข้อเสียของยาต้านแบคทีเรียในกลุ่มดังต่อไปนี้
Beta-lactam antibiotics ได้แก่ Penicillins, Cephalosporins, Monobactam, Carbapenam รวมทั้ง beta-lactamase inhibitors
Cell wall synthesis inhibitors อื่นๆได้แก่ vancomycin, bacitracin, cycloserine, fosfomycin

3. Bacterial cell wall Peptidoglycan of gram positive is more thicker
PBP = penicillin binding protein
essential for peptidoglycan synthesis… transpeptidase activity
site of beta lactam drugs binding ....Target of drug action

4. Peptidoglycan synthesis
D-Ala-D-Ala 1 2 3 4 5
PBPs action
Transpeptidase
Peptidoglycan synthesis

5. Beta lactam compounds Beta lactam ring Penicillins Cephalosporins
Monobactam
Carbapenem

6. Mechanism of action Bind with PBPs covalently
Beta lactam antibiotics = D-Ala-D-Ala like structure
Inhibit transpeptidase activity***
Inhibit peptidoglycan synthesis
Inhibit cell wall synthesis
Cell lysis & death
Bactericidal
Active on active growing bacteria only***

7. Classification of Penicillins
Benzylpenicillin and congeners
Penicillin G (Benzylpenicillin) … IV/ IM
Penicillin V (Phenoxymethylpenicillin)
Beta lactamase resistant penicillins
Nafcillin, Methicillin … IV
Isoxazolyl pen … Cloxacillin, Dicloxacillin, Flucloxacillin
Broad spectrum penicillins
Aminopenicillin … Ampicillin, Bacampicillin, Pivampicillin, Amoxycillin
Extended spectrum penicillins
Carboxypenicillin … Carbenicillin, Ticarcillin …IV
Ureidopenicillin … Piperacillin, Mezlocillin, Azlocillin …IV

8. Absorption after oral administration Resistance to Penicillinase
Non-proprietary name
Major properties
Absorption after oral administration
Resistance to Penicillinase
Useful antimicrobial spectrum
Penicillin G
Variable (poor) No
Streptococcal species**
Enterococci**, Listeria, Neisseria meningitidis, many anaerobes (not Bacteroides fragilis)***, spirochetes, Actinomyces, Erysipelothrix spp., Pasteurella multocida***
Penicllin V
Good
Methicillin
Nafcillin
Cloxacillin
Oxacillin
Dicloxacillin
Poor (not orally)
Variable
Yes
Indicated only for non-methicillin resistant strain of Staphylococcus aureus and Staphylococcus epidermidis. Compared to other penicillins, these penicillinase resistant penicillins lack activity against Listeria monocytogenes and Enterococcus spp.

9. Ampicillin
Amoxycillin
Good
Excellent No
Extends spectrum of penicillin to include sensitive strains of Enterobacteriaceae***, Escherichia coli, Proteus mirabilis, Salmonella, Shigella, Haemophilus influenzae***, and Helicobacter pylori.
Superior to penicillin for treatment of Listeria monocytogenes and sensitive enterococci. Amoxycillin most active of all oral beta-lactams against penicillin resistant S. pneumoniae (PRSP)
Carbenicillin
Carbenicillin indanyl
Poor (not orally)
Less active than ampicillin against Streptococcus species, Enterococcus faecalis, Klebsiella and Listeria monocytogenes. Activity against Pseudomonas aeruginosa is inferior to that of mezlocillin and piperacillin
Ticarcillin
Poor (not given orally)
Mezlocillin
Poor (not orally)
Extends spectrum of ampicillin to include Pseudomonas aeruginosa****, Enterobacteriaceae***, Bacteroides species***
Piperacillin

10. Cephalosporins beta lactam ring containing penicillin-like
broader spectrum
More resist beta-lactamase
7-cephalosporanic acid
Cephamycin, Moxalactam… cephalosporin-like
Classified into 4 generations
***All cephalosporins lack activity against Enterococci, Listeria monocytogenes, Legionella spp., MRSA, Acinetobacter

11. Generation
Useful
First
Streptococci* (Not PRSP), Staphylococcus aureus**(Not MRSA)
Some gram negative E.coli, Klebsiella, Proteus
Second
More gm negative…Escherichia coli, Klebsiella, Proteus, Haemophilus influenzae, Moraxella catarrhalis. Not as active against gram positive organisms as first generation agents… (Not to PRSP)
Cephamycins (cefoxitin, cefotetan) Inferior activity against S. aureus compared to cefuroxime but with added activity against Bacteroides fragilis and other Bacteroides
Third
Enterobacteriaceae#, Pseudomonas aeruginosa, Serratia, Neisseria gonorrhea, activity for S. aureus, S. pneumoniae and Streptococcus pyogenes*** comparable to first generation agents. Activity against Bacteroides spp. Inferior to that of cefoxitin and cefotetan
Fourth
Comparable to third generation but more resistant to some beta-lactamase (Esp. Enterobacter)
@All cephalosporins lack activity against Enterococci, Listeria monocytogenes, Legionella spp., MRSA, Acinetobacter

12. Monobactam Aztreonam (Azactam®) Effective to gram negative only***
Effective to P.aeruginosa, Serratia, other gm negative
Not effective to gram positive / anaerobes
Resistance to Ambler class B*** (Metallo--lactamase)
Not to ESBL (destroy monobactam & 3rd ceph.)
Spectrum … like aminoglycosides
No cross hypersensitivity with penicillins***
ADRs … skin rash, increase aminotransferase
Clinical uses… P. aeruginosa infection

13. Carbapenem
Imipenem (Tienam®), Meropenem (Meronem®), Ertapenem (Invanz®)
Broad spectrum***… gram positive, negative, anaerobes
Well tolerate to beta-lactamase enzyme (Except…metallo- beta lactamase; Ambler class B)
Not effective to MRSA, Clostridium difficile, Enterococcus faecium***
Drug of choice for Enterobacter infection***
Imipenem destroy by renal dehydropeptidase
Imipenem + Cilastatin (dehydropeptidase inhibitors) >>> Tienam®
Imipenem IV g q 6-8 hr
Meropenem IV 1 g q 8 hr

14. Other cell wall synthesis inhibitors
Vancomycin
Bacitracin
Cycloserine
Fosfomycin

15. Peptidoglycan synthesis
D-Ala-D-Ala 1 2 3 4 5
PBPs action
Peptidoglycan synthesis

16. Cell wall synthesis inhibitors
Beta lactam antibiotics
Penicillins
Cephalosporins
Monobactam …. Aztreonam
Carbapenem … Imipenem , Meropenem, Ertapenem
Beta-lactamase inhibitors
Vancomycin
Bacitracin
Cycloserine
Fosfomycin

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