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1. Pharmacology 3 (PHL417)

2.  Bacterial cell wall is composed of a peptidoglycan
polymer that is composed of glycan units joined by
peptide cross links.
 Cell wall inhibitors prevent cell wall synthesis, thus
require actively proliferating microorganisms and have
no effect on non-dividing bacteria and on organisms
lacking this structure (mycobacteria, fungi,
protozoa,…etc).
 Cell Wall inhibitors include:
1. Penicillins
2. Cephalosporins
3. Carbapenems
4. Monobactams
5. b-lactamase inhibitor/antibiotic combinations
6. Others (Bacitracin– Telavancin – Vancomycin)

3. Bacterial cell wall of gram-
positive bacteria
NAM=N-acetylmuramic acid;
NAG=N-acetylglucosamine;
PEP=cross-linking peptide.
PBP
(Penicillin-binding protein)
1.PBP
(PBP is a wall synthesis
enzyme)
2.PBP
(PBP is transpeptidase
enzyme)
Blockade of cell wall
synthesis
Morphologic changes
 Formation of crosslinks
essential for membrane integrity
 Autolysins  destruct
current cell wall
P

4. Antibacterial spectrum determinants:
1. Ability of antibiotic to cross the peptidoglycan cell wall
2. Susceptibility to PBP which is determined by:
 Size of b-lactam AB
 Charge &hydrophobicity of the AB
 LPS (in G –VE) is a barrier for water-soluble penicillins
 “Porins” are water filled channels in the LPS layer allowing
restrictive transmembrane entry of some penicillins e.g.:
Pseudomonas aeruginosa

5. 1. Natural penicillins
 Include penicillin V, penicillin G, and ampicillin
 Ampicillin is semisynthetic (replace R-group)
 Spectrum:
G+ve cocci  Streptococcus pneumoniae
G-ve cocci  Neisseria gonorrhoeae
G+ve bacilli  Bacillus anthracis
Spirochetes  Treponema Pallidum (Syphilis)
 They are susceptible to inactivation by bacterial b-
lactamases

6. 2. Antistaphylococcal penicillins
 Include methicillin, oxacillin, and dicloxacillin
 All are penicillinase-resistant penicillins (use): MSSA
 Causes toxic nephritis, so not used clinically.
 Now used to identify MRSA
 They have no activity against G –ve infections

7. 3. Extended-spectrum penicillins
 Include ampicillin, and amoxicillin
 Same spectrum as penicillin G, but
more effective against G-ve bacilli
(extended spectrum)
 Used in respiratory infections
 Amoxicillin used prophylactically in
dental surgeries for patients with
abnormal heart valves
 Resistance (due to plasmid-mediated
peicillinases e.g.: Escherichia coli)
 Combination with b-lactamase inhibitor
extends their spectrum

8. 4. Antipseudomonal penicillins
 Include carbenicillin, ticarcillin and
piperacillin (most potent)
 Active against G-ve bacilli except
Klebsiella due to its constitutive
penicillinase
 Formulation with clavulanic acid or
tazobactam extends their spectrum

9. 5. Penicillins and aminoglycosides
 b-lactams + aminoglycosides  synergism ….. Why?
Because cell wall synthesis inhibitors alter the
permeability of bacterial cells, these drugs can facilitate
the entry of other antibiotics (such as aminoglycosides)
that might not ordinarily gain access to intracellular
target sites.
 b-lactams + aminoglycosides   mixed in infusions
….. Why?
Because on prolonged contact, the positively charged
aminoglycosides form an inactive complex with the
negatively charged penicillins.

11. b-lactamase


1. b-lactamase activity
 Could be constitutive (associated
with m.o. chromosomes)
 Could be acquired by plasmid
transfer
2. Decreased permeability
 Due to presence of an efflux
pump
3. Altered PBPs
 Acquired by plasmid transfer
 Modified PBPs have low affinity
for the b-lactam ring
 It explains MRSA resistance

12. 1. Hypersensitivity
 Penicilloic acid (metabolite) [hapten]  react
with tissue proteins immune reaction (5%)
 Maculopapular rash to angioedema (swelling
of lips, tongue and periorbital area) or
anaphylaxis
 Cross antigenicity among different b-lactams
is present
2. Diarrhea
 Due to disruption of normal balance of
intestinal microorganisms
 Most common with penicillins that are not
completely absorbed
 Pseudomembranous colitis can also occur

13. 3. Nephritis
All penicillins, but particularly methicillin,
have the potential to cause acute interstitial
nephritis
4. Neurotoxicity
 Penicillins are damaging to neuronal tissue 
seizures
 Epileptic patients are at risk and will require
dosage adjustments especially if
accompanied by renal dysfunction

14. 5. Hematologic toxicities
 Ticarcillin, piperacillin & naficillin  
coagulation
 Important concern in patients receiving
anticoagulant therapy
 Cytopenia (especially when treatment > 2 wks
 Eosinophilia might occur
6. Cation toxicity
 Penicillins are administered as Na+ or K+ salts
  Na+  hypokalemia
 Avoided by using the most potent AB ( dose
of drug and its cation)

15.  The cephalosporins are β-lactam antibiotics that
are closely related both structurally and
functionally to the penicillins.
 Cephalosporins have the same mode of action as
penicillins, and they are affected by the same
resistance mechanisms.
 However, they tend to be more resistant than
the penicillins to certain β-lactamases.
 They are classified according to their spectrum and
resistance to penicillinase into 4 generations.

16. 4th Generation3rd Generation2nd Generation1st Generation
++++++++G(+ve)
++++PEcK
G(-ve)
-++-HEN
P. aeruginosa
Serratia
marcescens
------Other strains
Cefepime
Cefdinir
Cefotaxime
Ceftriaxone
Cefuroxime Na
Cefuroxime axetil
Cefazolin
Cephalexin
Members
Administered
parenterally only
Associated with
collateral damage
“induction &
spread of
resistance”
------Notes

17.  Mechanisms of bacterial resistance to the
cephalosporins the same as those described for the
penicillins.
 Although they are not susceptible to hydrolysis
by staphylococcal penicillinase, cephalosporins
may be susceptible to Extended-Spectrum β-
Lactamases (ESBLs).
 E. coli and K. pneumoniae are associated with
ESBLs.

18. Hypersensitivity
 3-5% of patients allergic to penicillins show
cross sensitivity to cephalosporins.
 Cross sensitivity is determined by similarity
in the side chain, not the β-lactam
structure.
 The rate of highest allergic cross
sensitivity is between penicillin and first
generation cephalosporins.

19.  These are beta lactam antibiotics with structures related to
but quite different than penicillins.
 Members:
Imipenem – meropenem
 Imipenem + cilastatin “tienam®”  to protect it from
metabokism by renal dehydropeptidase.
Antibacterial spectrum:
 Gram(+) cocci/bacilli – Gram(-) cocci/bacilli – Anaerobes
 Imipenem  resists hydrolysis by b-lactamases, plays role in
empiric therapy …..why?
Gram (+)/(-)/anaerobes/P. aeruginosa

20. Adverse effects:
 Imipenem/cilastatin  NVD
 Eosinophilia and neutropenia are less than other b-lactams
  dose imipenem  seizures (less likely with meropenem)

21.  It has a unique b-lactam ring that is not fused to other rings.
 Members: Aztreonam “Azactan®”
 Spectrum: Gram positive/anaerobes  NO action
Enterobacteriaceae (P. aeruginosa)  (+ve)
 This narrow spectrum prevents its use in empiric therapies.
 It is resistant to the action of most β-lactamases, with the
exception of the extended-spectrum β-lactamases
(ESBLs).
 It is administered either IV or IM and can accumulate in
patients with renal failure.
 Aztreonam is relatively nontoxic, but it may cause phlebitis,
skin rash, and occasionally, abnormal liver function tests.
 It shows little cross-reactivity with antibodies induced by
other β-lactams  safe alternative for treating patients are
allergic and unable to tolerate penicillins and/or
cephalosporins.

22.  Members: Clavulanic acid –
sulbactam – tazobactam
 They contain a β-lactam ring, but
by themselves, do not have
significant antibacterial activity.
 Instead, they bind to and
inactivate β-lactamases 
protecting the antibiotics that are
normally substrates for these
enzymes.

23.  It is a tricyclic glycopeptide.
 Important because of its effectiveness against multiple
drug-resistant organisms, such as MRSA and
enterococci.
 Concerns arouse about emergence of resistance to
vancomycin (vancomycin resistant enterococci –VRE-
and  MIC of MRSA)

24.  Active against:
Gram +ve cocci/bacilli
MRSA
MRSE (MR Staphylococcus epidermis)
 Vancomycin (I.V.)  used in patients with prosthetic
heart valves or those undergoing implantation with
the device especially in hospitals where MRSA &
MRSE is a problem.
 Vancomycin + aminoglycosides  ttt of
Enterococcal carditis.

25.  Poorly absorbed orally, so used IV.
 Oral route  ttt of AB-associated
colitis (C.difficile)
 Inflammation of meninges allows
penetration.
 Vancomycin + ceftriaxone 
synergistic in meningitis
 90-100% excreted by glomerular
filtration (with minimal metabolism).
 Dose adjustment is essential in
patients with renal failure.

26.  Rapid infusion   histamine  flushing
“red man syndrome”.
 Treatment of infusion reaction:
1.  Infusion rate
2.  Infusion volume
3. Pre-treatment with antihistamine
 Ototoxicity (in renal failure)  due to
vancomycin accumulation
 Nephrotoxicity (additive when used with
aminoglycosides)

27.  It is a cyclic lipopeptide antibiotic.
 Mechanism of action:
Binds to cytoplasmic membrane  depolarization   DNA, RNA,
and protein synthesis  bactericidal (dose dependant).
 Antibacterial spectrum:
 Indicated for ttt of complicated skin infections due to S.
aureus.
 It’s inactivated by pulmonary surfactants (so not used in
ttt of pneumonia).

28.  It is a semi-synthetic lipoglycopeptide antibiotic that is
a synthetic derivative of vancomycin.
 Mechanism of action:
Like vancomycin ( cell wall) + daptomycin ( cell membrane)
 Antibacterial spectrum:
 MRSA, Gram (+) strep/staph.
 Not effective against VRE

29.  Adverse effects:
 Prolongs QTc interval
 Interfers with coagulation
monitoring tests  blood
samples monitoring coagulation
should be collected as close to
the next dose of telavancin as
possible.

30.  Cyclic peptide mixture, active against G+ve.
 Mechanism of action:
Inhibit cell wall formation by interfering with peptidoglycan
transfer to the developing cell wall.
Due to systemic toxicity, it is limited to topical use.
Uses:
Alone or in combination with polymyxin or neomycin in treatment of
mixed skin infections.
Side effects:
Nephrotoxicity.

31.  Are amphipathic (containing lipophilic and lipophobic
groups).
 Effective against G-ve bacteria, including
pseudomonas.
 It disrupt bacterial cell membrane through interaction
with phospholipid components.
Uses:
Polymixin-B used topically for external otitis and corneal ulcers.
Side effects:
Nephrotoxicity & neurotoxicity.