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ANTIBIOTICS
Cell Wall Synthesis Inhibitors
Beta-lactam antibiotics:
Drugs with structure containing a beta-lactam ring; include the penicillins and cephalosporins.
This ring must be intact for antimicrobial action.
Beta-lactamases:
Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the lactam ring of certain
penicillins and cephalosporins.
Penicillin- binding proteins:
Bacterial cytoplasmic membrane proteins that acts as the initial receptors for penicillins and
other beta-lactam antibiotics.
Peptidoglycan ,Murein:
Chain of polysaccharides and polypeptides that are Cross-linked to form the bacterial cell wall.
Selective Toxicity:
More toxic to the invader (bacteria) than to the host ; a property of useful antimicrobial drugs.
Transpeptidases:
Bacterial enzymes involved in the cross-linking of linear peptidoglycan chains, the final step in
cell wall synthesis.
# Penicillins and cephalosporins are the major antibiotics that
inhibit bacterial cell wall synthesis.
# Vancomycin, fosfomycin, and bacitracin also inhibit cell wall synthesis but for various reasons
are not nearly as important as the beta-lactam drugs.
# The selective toxicity of the these drugs is mainly due to specific action on the synthesis of a
cellular structure that is unique to the microorganism.
Penicillins
A- Classification:
it has 4 – membrane lactam ring , first drug in this group was pencillin G . there are many types of pencillins
available like
pencillin include following subtypes :-
=narrow spectrum p like benzyle pencillin , phenoxymethyl pencillin , phenethicilin .
=antistaphylococal p (B-lactamase resistance)like cloxacillin , flucloxacillin , methicillin .
=braod spectrum p like ampicillin , amoxycillin, bacapicillin , talampicillin, pivampicillin , mezlocillin .
=anti-pseudomonal p include :-
-carboxypencillin (carbencillin , carpicillin, ticarcillin , temocillin ).
-ureidopencillin(azlocillin, piperacillin ).
B- Pharmacokinetics:
# Pencill. Vary in their resistance to gastric acid and therefore vary in their oral bioavailability.
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# They are usually excreted unchanged in the urine via glomerular filtration and tubular
secretion.
# Ampicillin and nafcillin are excreted partly in the bile.
# Procaine and benzathine forms of penicillin G are administrated im
# Most penicillins cross the blood-brain barrier only when the meninges are inflammed.
C-Mechanismof Action and Resistance:
# Beta-lactam antibiotics are bactericidal drugs.
# They act to inhibit cell wall synthesis by the following steps:
(1)binding of the drug to specific receptors PBPs.
(2)inhibition of transpeptidase enzymes.
(3)activation of autolytic enzymes that cause lesions in the bacterial cell wall.
# Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial activity.
# The formation of beta-lactamases (penicillinases) by most
staph. and many gram-negative organisms is thus a major mechanism of bacterial resistance.
# Inhibitors of these bacterial enzymes (eg. Clavulanic acid, sulbactam, tazobactam) are
sometimes used in combination with penicillins to prevent their inactivation.
D. Clinical uses:
1. Narrow spectrum, penicillinase- susceptible agents:
(penicillin G)
- Streptococci. - Meningococci.
- Gram positive bacilli. - Spirochetes.
2- Very narrow spectrum, penicillinase- resistant drugs:
- includes methicillin, nafcillin & oxacillin.
- used in the treatment of staphylococcal infections.
- MRSA(Methicillin resis tant staph.) are resistant to members of this subgroup.
3- Wider spectrum, penicillinase-susceptable drugs:
a. Ampicillin and amoxicillin:
- Their indications similar to penicillin G as well as infections due to enterococci, Listeria
monocytogenes, E. coli, Proteus merabilis, Haemophilus influenzae , & Moraxella catarrhalis ,
though resistant strains occur.
- When used in combination with inhibitors of penicillinases ( clavulanic acid, etc.) their
antibacterial activity is enhanced.
b- Piperacillin and ticarcillin:
- Have activity against several G- rods including pseudomonas, enterobacter and in some cases
Klebsiella spp.
E. Toxicity:
1. Allergy: include urticaria, severe pruritus, fever, joint
swelling, haemolytic anemia, nephritis, & anaphylaxis.
- Methicillin causes nephritis more than others.
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- Nafcillin is associated with neutropnia.
2. Gastrointestinal disturbances:
- Nausea and diarrhea may occur with oral penicillins, especially with ampicillin which has been
implicated in pseudo- membranous colitis.
- Gastrointestinal upsets may be caused by direct irritation or by overgrowth of gram- positive
organisms or yeasts.
CEPHALOSPORINS:
A. Classification:
- Derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure.
- They are designated first-, second-, third-, or forth generation drugs according to the order of
their introduction Into clinical use.
B. Pharmacokinetics:
- several are available for oral use but most administered parentrally.
- The major elimination is by renal excretion via active tubular secretion, some may undergo
hepatic metabolism.
- Cefoperazone and ceftriaxone are excreted mainly in the bile.
-Most 1st &2nd generation do not enter the CSF fluid even when the meninges are inflammed.
C.Mechanism of Action and Resistance:
- They bind to PBPs on bacterial cell membrane to inhibit cell wall synthesis by mechanism
similar to those of the penicillins.
- Cephalosporins are batericidal against susceptible organisms.
- Less susceptible to staph. Penicillinases.
- Some bacteria are resistant through the production of other beta-lactamases.
- Resistance may resulted from decrease in membrane permeability and fromchanges in PBPs.
- Methicillin resistant staph. are also resistant to most cephalosporins.
D. Clinical Uses:
1. First generation drugs:
- Cefazolin (parentral) & Cephalexin (oral) are examples of this subgroups.
- They are active against G+ cocci, including Staph. & Strept., E. coli @ K. pneumoniae.
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- Clinical uses include treatment of infections caused by these organisms and surgical
prophylaxis in selected conditions.
- Have minimal activity against gram-negative cocci, enterococci, methicillin-resistant Staph, &
most G-rods.
2. Second-generation drugs:
- Less active against G+ organisms than the 1st generation
drugs but have an extended G- coverage.
- Clinical uses include infections caused by Bacteroids fragilis (Cefotetan, cefoxitin) and by H.
fluenzae or Morexella catarrhalis (cefuroxime, cefaclor).
3. Third Generation Drugs:
(Cefoperazone, Cefotaxime)
- increased activity against G- organisms resistant to other beta-lactam drugs and ability to
penetrate the blood – brain barrier (excpet cefoperazone & cefixime).
- Most are active against enterobacter, providencia, Serratia marcescens and beta- lactamase
producing strains of H. influenzae and Neisseria.
- Individual drugs also have activity against pseudomonas (cefazidime) & B. fragilis
(ceftizixime).
- Drugs in this subclass should usually be reserved for treatment of serious infections eg.(
bacterial meningitis).
- Ceftriaxone (parenteral) & cefixime (oral), currently drugs of choice in gonorrhea, are
exceptions.
- Likewise, in acute otitis media, a single injection of ceftriaxone is an effective as 10-days
course of treatment with amoxicillin or cefaclor.
4. Fourth-generation drugs:
- Cefipime is more resistant to beta-lactamases produced by G- organisms, including enterbacter,
haemophilus, and neisseria.
- Cefipime combines the G+ activity of the 1st generation agents with the wider gram-negative
spectrumof the 3
rd
generation cephalosporins.
E. Toxicity:
1. Allergy:
- Cephalosporin cause a range of allergic reactions from skin rashes to anaphylactic shock. They
occur less frequently with cephalosporin than with penicillins.
- Complete cross hypersensitivity between different cephalosporins should be assumed.
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- Cross- reactivity between penicillins and cephalosporins is incomplete (5-10 %).
- Patients with a history of anaphylaxis to penicillins should not be treated with cephalosporins.
2. Other adverse effects:
- They may cause pain at intramuscular injection sites and phlebitis after iv administration.
- Increase the nephrotoxicity when combined with aminoglycosides.
- Drugs containing a methylthiotetrazole group (cefoperazone, cefotetan, moxalactam) cause
hypoprothrombineamia and may cause disulfiramlike reactions with ethanol.
- Moxalactam also decreases platelet function and may cause severe bleeding.
Other Beta-lactam Drugs
A. Aztreonam:
- is a monobactam that is resistant to beta-lactamases produced by certain G- rods, including
klebsiella, pseudomonas, and serratia.
- has no activity against G+ bacteria or anaerobes.
- It is an inhibitor of cell wall synthesis and synergistic with aminoglycosides.
- Administered iv and is eliminated via renal tubular secretion so its t ½ is prolonged in renal
failure.
- Adverse effect include gasterointestinal upset with possible superinfection, vertigo and
headache, & rare hepatotoxicity.
- Though skin rash may occur, there is no cross allergenicity with penicillins.
B. Imipenem and meropenem:
- They are carbapenems ( chemically different from penicillins but retaining the beta-lactam ring
structure) with low susceptibility for beta-lactamases.
- The drug have wide activity against G+ cocci ( including some penicillin resistant
pneumococci), G- rods, & anaerobes.
- It is administered parenterally and is especially useful for infections caused by organisms
resistant to other antibiotics. It is currently the drug of choice for infection due to enterobacter.
- Imipenem is rapidly inactivated by renal dehydropeptidase I and is administered in fixed
combination with cilastatin, an inhibitor of this enzyme.
- Cilastatin increases the plasma t ½ of imipenem and inhibits the formation of a potentially
nephrotoxic metabolite.
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- Adverse effect of Imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very
high plasma levels, CNS toxicity( confusion,
encephalopathy, seizures).
- There is partial cross- allerginicity with the penicillins.
- Meropenem is similar to imipenem except that it is not metabolized by renal dehydropeptidase
and is less likely to cause seizures.
C. Beta-lactamase Inhibitors:
- Clavulanic acid, sulbactam, and tozabactam are used in fixed combinations with certain
hydrolyzable penicillins.
- They are most active against plasmid encoded betalactamases such as those produced by
gonococci, streptococci , E coli, and H influenzae.
- They are not good inhibitors of inducible chromosomal beta- lactamases formed by
enterobacter and pseudomonas.
OTHER INHIBITORS OF CELL
WALL SYNTHESIS
A. Vancomycin:
- It is a bactericidal glycoprotein that binds to the D- Ala D-Ala terminal of the nascent
peptidoglycan pentapeptide side chain and inhibits transglycosylation.
- This action prevents elongation of the peptidoglycan chain and interferes with cross- linking.
- Resistance involves a decrease affinity of vancomycin for the binding site due to the
replacement of the terminal D-Ala by D-lactate.
- Vancomycin has a narrow spectrum of activity and is used for serious infections caused by
drug-resistant gram-positive, including methicillin resistant staphylococci ( MRSA ), penicillin
resistant pneumococci, and c. difficile.
- Vancomycin resistant enterococci have emerged recently, a potentially serious clinical problem
since such organisms usually exhibit multiple drug resistance.
- Likewise, strains of MRSA have been reported with intermediate resistance to vancomycin,
leading to treatment failures.
- Vancomycin is not absorbed from the GI tract and may be given orally for bacterial
enterocolitis.
- When given parenterally, vancomycin penetrate most tissues and is eliminated unchanged in
the urine.
- Dosage modification is mandatory in patients with renal impairment.
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- Toxic effects of vancomycin include chills, fever , phlebitis, ototoxicity.
- Rapid iv infusion may cause diffuse flushing (“ red man syndrome”).
B. Fosfomycin:
- It is an antimetabolite inhibitor of cytosolic enolpyrovate transferase.
- This action prevents the formation of N- acetylmuramic acid , an essential precursor molecule
for peptidoglycanchain formation.
- Resistance to fosfomycin occurs via decreased intracellular accumulation of the drug.
- Fosfomycin is excreted by the kidney, with urinary levels exceeding the (MICs) for many
urinary tract pathogens.
- In a single dose , the drug is less effective than a 7- day course of treatment with
fluoroquinolones.
- With multiple dosing, resistance emerges rapidly and diarrhea is common.
- Fosfomycin may be synergistic with beta- lactam andquinolone antibiotics in specific
infections.
C. Bacitracin:
- It is a peptide antibiotic that interfer with a late stage in cell wall synthesis in G+ organisms.
- Have a marked nephrotoxicity so it is limited to topical use.
D. Cycloserine:
- Is an antimetabolite that blocks the incorporation of D- Ala into the pentapeptide side chain of
the peptidoglycan.
- Potential neurotoxic ( tremors, seizures, Psychosis), cycloserine is only used to treat
tuberculosis caused by organisms resistant to first-line anti-tuberculosis drugs.
E- Daptomycin :
Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against
vancomycin-resistant strains of enterococci and staphylococci. The drug is eliminated via the
kidney. Creatine phosphokinase should be monitored since daptomycin may cause myopathy.