Transcript not orally - e

Beta lactam antibiotics
& Other cell wall
synthesis inhibitors
Pawitra Pulbutr
M.Sc. In Pharm
(Pharmacology)
วัตถุประสงค์เชิงพฤติกรรม
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เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, กลไกการดื้อยา, เภสัชจลนศาสตร์,
อาการไม่พงึ ประสงค์ท่เี กิดจากการใช้ยา, การนาไปใช้ประโยชน์ทางคลินิก
รวมทัง้ ข้อดีและข้อเสียของยาต้านแบคทีเรียในกลุม่ ดังต่อไปนี้
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Beta-lactam antibiotics ได้แก่ Penicillins,
Cephalosporins, Monobactam, Carbapenam
รวมทัง้ beta-lactamase inhibitors
Cell wall synthesis inhibitors อืน่ ๆได้แก่ 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
D-Ala-D-Ala
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2
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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
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Benzylpenicillin and congeners
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Beta lactamase resistant penicillins
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Nafcillin, Methicillin … IV
Isoxazolyl pen … Cloxacillin, Dicloxacillin,
Flucloxacillin
Broad spectrum penicillins
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Penicillin G (Benzylpenicillin) … IV/ IM
Penicillin V (Phenoxymethylpenicillin)
Aminopenicillin … Ampicillin, Bacampicillin,
Pivampicillin, Amoxycillin
Extended spectrum penicillins
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Carboxypenicillin … Carbenicillin, Ticarcillin …IV
Ureidopenicillin … Piperacillin, Mezlocillin,
Azlocillin …IV
Nonproprietary
name
Major properties
Absorption
after oral
administration
Resistance
to
Penicillinase
Penicillin G
Variable
(poor)
No
Penicllin V
Good
No
Methicillin
Nafcillin
Poor (not
orally)
Variable
Yes
Cloxacillin
Oxacillin
Dicloxacillin
Good
Useful antimicrobial spectrum
Streptococcal species**
Enterococci**, Listeria, Neisseria
meningitidis, many anaerobes (not
Bacteroides fragilis)***,
spirochetes, Actinomyces,
Erysipelothrix spp., Pasteurella
multocida***
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)
Good
No
Ticarcillin
Poor (not given
orally)
No
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
Mezlocillin
Poor (not orally)
No
Piperacillin
Poor (not given
orally)
No
Extends spectrum of ampicillin to
include Pseudomonas aeruginosa****,
Enterobacteriaceae***, Bacteroides
species***
Cephalosporins
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beta lactam ring containing
penicillin-like
broader spectrum
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More resist beta-lactamase
7-cephalosporanic acid
Cephamycin, Moxalactam… cephalosporinlike
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
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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
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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
D-Ala-D-Ala
1
2
3
4
5
PBPs action
Peptidoglycan synthesis
Cell wall synthesis inhibitors
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Beta lactam antibiotics
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Penicillins
Cephalosporins
Monobactam …. Aztreonam
Carbapenem … Imipenem , Meropenem,
Ertapenem
Beta-lactamase inhibitors
Vancomycin
Bacitracin
Cycloserine
Fosfomycin