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Cell wall synthesis inhibitors

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الكلية كلية الطب     القسم  الادوية     المرحلة 3
أستاذ المادة انتصار جواد حمد المختار       21/06/2018 13:50:52

Antimicrobial drugs
Dr. Entisar Al-Mukhtar

Cell wall synthesis inhibitors They include 1) ?-lactam ABs (penicillins, cephalosporins, monobactams & carbapenems). 2) vancomycin 3) daptomycin. All have little or no effect on bacteria that are not growing and dividing.
Cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links (note: mammalian cells do not possess cell wall).
Peptidoglycan is strong enough to resist the high internal osmotic pressure. The peptidoglycan synthesis represent a target for many antibacterial drugs like: Cycloserine, Vancomycin, Bacitracin and ?-lactam ABs (penicillins, cephalosporins, monobactams and carbapenems ). ?-lactams ABs inhibit the final transpeptidation by forming covalent bonds with penicillin–binding proteins that have transpeptidase activities, thus preventing the formation of cross links

Penicillins:
- Classified as -lactam drugs because of their unique four-membered lactam ring.
- Most widely effective and the least toxic, but increased resistance limit their use.
- They differ from each other in R substituent attached to the 6 aminopenicillanic acid residue.
- The nature of this side chain affects antimicrobial spectrum, stability to acid of stomach, cross-hypersensitivity & susceptibility to bacterial degradative enzymes (? -lactamases).

Classification of Penicillins
Natural penicillins Antistaphylococcal penicillins (?-lactamase resistant)
Extended Spectrum Penicillins Antipseudomonal penicillins
Penicillin G
Penicillin V
Methicillin Nafcillin Oxacillin Cloxacillin Dicloxacillin Flucloxacillin
Ampicillin Amoxicillin Pivampicillin Hetacillin Bacampicillin Metampicillin Talampicillin Epicillin
Carbenicillin Ticarcillin
Piperacillin
Temocillin

Mechanism of action
Penicillins interfere with the last step of bacterial peptidoglycan synthesis (transpeptidation or cross-linkage). Thus, cell lysis occurs, either through osmotic pressure or activation of autolysins.
Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan, they are inactive against MOs devoid of peptidoglycan, such as mycobacteria, protozoa, fungi, and viruses.

1. Penicillin-Binding Proteins (PBPs):
Penicillins inhibit PBPs the enzymes involved in the cross-linking of the peptidoglycan layer of the cell wall. Alterations in some of these PBPs result in bacterial resistance e.g, methicillin-resistant Staph. Aureus (MRSA). [Note: The main defence of bacteria against penicillins is to produce ?-lactam enzymes which open & inactivates ?-lactam ring.]
2. Production of autolysins:
Many bacteria, particularly G + cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Thus, the antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis & destruction of the existing cell wall by autolysins.
Antibacterial spectrum
The ability to cross the peptidoglycan cell wall to reach PBPs affects the antibacterial spectrum.
Size, charge & hydrophobicity of ? -lactam ABs can determine the susceptibility of PBPs to these ABs. In general, G + MOs have cell walls that are easily traversed by penicillins &, therefore, in the absence of resistance, they are susceptible to these drugs.
The G - MOs have an outer lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins.


However, G - bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry. [Pseudomonas aeruginosa lacks porins, thus are resistant to many AM agents.]
1. Natural penicillins: (penicillin G and V)
Obtained from fermentations of Penicillium chrysogenum fungus. Amoxicillin & ampicillin (also known as aminopenicillins) are semisynthetic penicillins.
Preparations of natural pencillins
Names Method of administration Notes
Penicillin G (benzyl penicillin)
IV or IM
every 6hr Crystalline Penicillin
Used in severe infections. Produced as a salt of potassium or sodium.
Penicillin V (phenoxymethylpenicillin)
Orally more acid-stable, spectrum like penicillin G, but less active against G-bacteria.
Not used for bacteremia due to poor oral absorption
benzathine penicillin G IM (depot) Benzathine is a stabilizer that causes slower release over 2-4 weeks. Used as single dose monthly in rheumatic fever prophylaxis
Procaine benzylpenicillin, IM (depot) every 12 hr a stable salt liberate benzylpenicillin slowly over 12-24 hr.)


Penicillin G (benzyl-penicillin)
• Effective against:
? G + cocci (S. Pneumonia, S. Pyogenes & S. viridans)
? G – cocci (N. gonorrhoeae & N. meningitidis)
? G + bacilli (Bacillus anthracis & Corynebacterium diphtheriae)
? Spirochetes (Treponema pallidum & Treponema pertenue "yaws").




Uses: drug of choice for
1. Meningococcal meningitis (N. meningitidis)
2. Anthrax (Bacillus anthracis)
3. Tetanus (Clostridium tetani)
4. Gas gangrene (Clostridium perfringens)
5. Diphtheria (Corynebacterium diphtheriae)
6. Syphilis (Treponema pallidum),
7. Leptospirosis (Leptospira species)
8. Actinomycosis (Actinomyces israelii)
9. Lyme disease (Borrelia burgdoreri) in children.
• Benzyl penicillin is less effective for endocarditis due to enterococcus faecalis & it should be combined with an AG, usually gentamicin
• Susceptible to inactivation by ?-lactamases (penicillinases).
• Silver nitrate eye drops prevent gonococcal ophthalmia in newborns (note: the Penicillinase-producing strains are treated by ceftriaxone, with azithromycin or spectinomycin as a backup).

2. Antistaphylococcal penicillins (?-lactamase-resistant penicillins):
( Methicillin, Nafcillin, Oxacillin, Cloxacillin & Dicloxacillin )
• Restricted use for penicillinase-producing staphylococci, including methicillin-sensitive S. aureus (MSSA). [Note: Because of its toxicity (interstitial nephritis) methicillin is used only in laboratory tests to identify S. aureus resistant strains].
• MRSA is currently a source of serious community and nosocomial (hospital-acquired) infections and is resistant to most ?-lactam ABs], MRSA is usually susceptible to vancomycin.
• They have minimal-no activity against G - infections.

3. Extended-spectrum penicillins: ( Ampicillin and amoxicillin )
• spectrum similar to pencillin G but are more effective against G - bacilli (E. coli, H. in¬uenzae, P. mirabilis & Salmonella typhi).
• Amoxicillin is a structural analogue of ampicillin but differ in that:
1. its better absorbed from gut (especially after food)
2. has higher bioavailability (double plasma concentration)
3. diarrhea is less frequent

Uses
? Respiratory infections.
? Infections with susceptible G - bacilli (above)
? Ampicillin (± gentamicin) is the drug of choice for the G + bacillus ( L. monocytogenes and susceptible enterococcal species ).
? Amoxicillin is used prophylactically by dentists for prevention of bacterial endocarditis in patients with abnormal heart valves.
• Resistance is a major clinical problem due to plasmid-mediated penicillinases. [Note: E. coli and H. influenzae are frequently resistant.]
• The combination of amoxicillin + clavulanic acid (? -lactamase inhibitor) as Co-Amoxiclav (Augmentin) or ampicillin + sulbactam (? -lactamase inhibitor) protect them from enzymatic hydrolysis, e.g, without ?-lactamase inhibitor, MSSA is resistant to ampicillin and amoxicillin.
Side Effects
a. Both can cause diarrhea (C. difficilile).
b. Ampicillin can cause macular rashes (especially in patients with renal failure & those who take allopurinol).
c. Cholestatic jaundice (with Co-Amoxiclav & clavulanic acid may be responsible)

4. Antipseudomonal penicillins: ( Piperacillin and Ticarcillin )
• Effective against P. aeruginosa & other G – bacilli ( Enterobacter, E. coli, P. mirabilis, Proteus (indole positive) & H. inf¬uenzae), but not against Klebsiella (in which penicillinase is constitutive).
• given parenterally only.
• Piperacillin is more potent.
• Combination of ( Ticarcillin + clavulanic acid ) or ( Piperacillin + tazobactam ), extends spectrum to include penicillinase-producing MOs (e.g, most Enterobacteriaceae and Bacteroides species).





Notes:
1. The ?-lactam ABs can enhance antimicrobial activity (synergistic effect) of AGs. Because they facilitate the entry of other ABs (such as AGs) that might not ordinarily gain access to intracellular target sites.

2. Penicillin & AG combination should never be placed in the same infusion fluid, since AGs (positive charge) form an inactive complex with penicillins (negative charge).
Resistance
1. Natural resistance occurs in MOs that either lack a peptidoglycan cell wall (e.g., Mycoplasma) or their cell walls are impermeable to the drugs.
2. Acquired resistance occurs by transfer of resistant plasmid & the organism may become resistant to several ABs.
By obtaining resistance plasmids, bacteria may acquire one or more of the following properties:
1. ?-Lactamases activity:
• a major cause of penicillins resistance which hydrolyzes the cyclic amide bond of the ?-lactam ring.
• ?-Lactamases are either constitutive, or more commonly, are acquired by the transfer of plasmids.
• Some of the ?-lactam ABs resist ?-lactamases [Note: in certain MOs ?-lactamases may be induced by ?-lactam ABs (e.g., 2nd and 3rd generation cephalosporins).]
• G + MOs secrete ?-lactamases extracellularly, whereas G - bacteria inactivate ?-lactam drugs in the periplasmic space between the inner & outer membranes.
2. Decreased permeability to the drug:
• Prevents the drug from reaching the target PBPs.
• The presence of an efflux pump can also reduce the amount of intracellular drug (e.g., K. pneumoniae).
3. Altered PBPs:
• Modified PBPs have a lower affinity for ? -lactam ABs e.g, MRSA.


Pharmacokinetics Administration:
• The combination of (ampicillin + sulbactam), (ticarcillin + clavulanic acid) & (piperacillin + tazobactam), also the antistaphylococcal penicillins nafcillin and oxacillin must be administered IV or IM.
• The (Ampicillin + sulbactam) combination available parenterally only.
• Phenoxymethylpenicillin, amoxicillin & dicloxacillin are given orally only
• Others are given orally, IV, or IM.
• [Note: combination of (amoxicillin + clavulanic acid) is available only in an oral formulation in the USA].
• Procaine pen. G and benzathine pen. G are administered IM as depot forms.
• Intrathecal administration of benzylpenicillin can cause convulsion
Absorption:
• Most penicillins are incompletely absorbed from GIT & they reach the intestine in sufficient amounts to affect the intestinal flora.
• Amoxicillin is almost completely absorbed thus, it is not appropriate treatment for shigella- or salmonella derived enteritis (as therapeutically effective levels do not reach the organisms in the intestinal crypts).
• All penicillinase-resistant penicillins should be taken on an empty stomach (food ? gastric emptying time & drugs are destroyed by stomach acid).
Distribution:
• The ?-lactam ABs distribute well throughout the body.
• All penicillins cross the placenta (but with no teratogenic effects). However, penetration to bone or CSF is insufficient unless these sites are inflamed.
• Insufficient penetration into infected prostate.
Metabolism: Host metabolism of ?-lactam ABs is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function.
Excretion:
• Primary through renal tubular secretion, with renal insufficiency penicillins doses should be adjusted (except nafcillin & oxacillin which are metabolized in the liver).
• Probenecid can usefully blocks penicillins tubular secretion (by competing on transport mechanism).
• Penicillins are excreted in breast milk.

Adverse reactions
1. Hypersensitivity: a most important adverse effect that is caused by penicilloic acid a penicillin metabolite that serves as a hapten. It occurs in 5% patients & is ranging from rashes to angioedema and anaphylaxis. Cross-allergic reactions occur among ? -lactam ABs.
2. Diarrhea: occurs due to alteration in normal intestinal flora that may progress to C. difficile–associated diarrhea & pseudomembranous colitis.
3. Nephritis: All penicillins, particularly methicillin can cause acute interstitial nephritis. [Note: Methicillin is therefore no longer used clinically.]
4. Neurotoxicity: pencillins are neuronal tissue irritant and can provoke seizures if injected intrathecally or very high blood levels are reached. Epileptic patients are particularly at risk (penicillins can cause GABAergic inhibition).
5. Hematologic toxicities: ?ed coagulation with ? doses of piperacillin, ticarcillin & nafcillin, and to some extent penicillin G.


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