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

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

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

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

Beta lactam compounds Beta lactam ring Penicillins Cephalosporins Monobactam Carbapenem

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***

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

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.

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

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

Generation Useful Spectrum@ 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

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

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 0.25-1 g q 6-8 hr Meropenem IV 1 g q 8 hr

Other cell wall synthesis inhibitors Vancomycin Bacitracin Cycloserine Fosfomycin

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

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

THE END