Beta Lactam
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Transcript of Beta Lactam
Penicillins
Alexander Fleming
Between 1962 and 2000, no major classes of antibiotics were introduced
Fischbach MA and Walsh CT Science 2009
Microbial Sources of Antibiotics
9
Administration of Antibiotics
Spectrum of Activity
Drug Mechanisms of Action
The Beta-Lactam Antibiotics
• Cell wall active agents– Prevent the final step in the synthesis of the
bacterial cell wall
• Range from very narrow spectrum to very broad spectrum
β-Lactams
β-lactam ring
• Penicillin (over 50 compounds)– Share 4-sided ring (b lactam ring)
• Natural penicillins• Narrow range of action• Susceptible to penicillinase (b lactamase)
How do they work?
1. The β-lactam binds to Penicillin Binding Protein (PBP)
2. PBP is unable to crosslink peptidoglycan chains
3. The bacteria is unable to synthesize a stable cell wall
4. The bacteria is lysed
N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), are two derivatives of glucose that form the polysaccharide chains that make up the backbone of peptidoglycan in the bacterial cell wall.
“Penicillin binding protein”
Peptidoglycan Synthesis
1. Precursors are cross-linked by PBP & then added to cell wall2. Penicillin enters the cell through porins & binds to PBP3. Binding results in release of lysins , which breaks down preformed cell wall4. After Penicillin binds to PBP, PBP can no longer synthesize protines essential for
integrity of cell wall.
Penicillinase (b Lactamase)
Classification– Natural penicillins
• Penicillin G,• Penicillin V• Benzathine Penicillin• Procaine Penicillin
– Semi-synthetic penicillins• Ampicillin, Oxacillin
• Structure– Thiazolidine ring– Beta-lactam ring– Variable side chain (R group)
• Bicyclic : (A) thiazolidine ring (B) β-lactam ring
N
S CH3
CH3
COOHO
ROCHN αThiazolidinering
ß-lactam ring
Acyl side-chainß
1
23
4
5
Examples
R=CH2
R=OCH2
BENZYL PENICILLIN (Penicillin G)
PHENOXYMETHYL PENICILLIN(Penicillin V)
Procaine Penicillin G
• a longer-acting, intramuscular alternative to benzyl penicillin, given 12 hourly.
Benzathine Penicillin G• longest acting• used almost exclusively in the prevention of
streptococcal pharyngitis (hence the prevention of rheumatic fever) and in the treatment of syphilis
Ist penicillin:• Penicillin G-active against G+ve and some G-ve
bacteria and Non-toxic• But not effective against wide range of bacteria• Ineffective on oral administration; only given by
Injection• Sensitive to β-lactamases (degradation)• Allergic reactions in some
Semi-synthetic method
• Fermentation gave 6-Aminopenicillanic acid (6-APA) which was treated synthetically with acid chlorides to give Penicillin analogues
N
S CH3
CH3
COOHO
RCOCl
NH2
N
S CH3
CH3
COOHO
RCOHN
Methicillin :
• First semi-synthetic Penicillin, resistant to penicillinase• Has 2 methoxy groups in ortho position on aromatic
ring in the side chain, which shield the lactam ring
• BUT: Only 1/50 th activity as Penicillin G against G+; inactive against G-
N
S CH3
CH3
COOHO
RCOHN
R Penicillin
C6H5O(CH)CH2CH3-
OMe
OMe
OCH2CH3
Propicillin
Methicillin
Nafcillin
Figure 20.6
The PENICILLINSNarrow spectrum penicillins
Penicillin G Penicillin V
Broad Spectrum Penicillins (Aminopenicillins) Amoxicillin Ampicillin Bacampicillin
Penicillinase-resistant Penicillins (Anti-staphyloccocal penicillins) Cloxacillin Nafcillin Methicillin Dicloxacillin Oxacillin
Extended-Spectrum penicillins (Anti-pseudomonal penicillins) Carbenicillin Mezlocillin Piperacillin Ticarcillin
Beta-lactamase inhibitors Clavulanic acid Sulbactam Tazobactam
The R group is responsible for the
activity of the drug, and cleavage of the beta-lactam ring will render the
drug inactive.
Chemical structure of penicillins
Therapeutic Indications of penicillins:• The penicillins are indicated for the
treatment of streptococcal infections• Syphilis• Tetanus
Adverse Effects of Penicillins
GI system effects- the major adverse effects of penicillin therapy involve the GIT.
Nausea, vomiting, diarrhea, abdominal pain, glossitis, stomatitis, gastritis, sore mouth and furry tongue.
The reason for some of these effects (superinfection) is associated with the loss of bacterial flora.
Adverse Effects of Penicillins
• Hypersensitivity reactions- rashes, pruritus, fever and urticaria
• These indicate mild allergic reaction. Wheezing and diarrhea may also occur.
• Anaphylaxis can also happen leading to shock or death. It occurs in 5-10% of those receiving penicillins.
• Pain and inflammation on injection sites
• The Cephalosporins have gradually replaced Penicillins in daily practice.
• The main advantage is the rarity of Anaphylactic reactions.
• Like the Penicillins, Cephalosporins are bactericidal and disrupt the synthesis of the Peptidoglycan layer of bacterial cell walls, important for bacterial cell wall structural integrity.
• Cephalosporins
Other Inhibitors of Cell Wall Synthesis
Figure 20.9
Cephalosporin• Cephalosporium acremonium (mold)• Widely administered today
– Diverse group (natural and semisynthetic)• Structure
– similar to penicillin except • Main ring is different• Two sites for R groups
THE CEPHALOSPORINS• Cephalosporins are sometimes grouped into
‘generations’ depending on their antimicrobial properties
• Each newer generation of cephalosporins has significantly greater Gram negative antimicrobial properties than the preceding generation.
• Unfortunately this is accompanied by a decreased efficacy against Gram positive bacteria.
First Generation cephalosporins
Second generation cephalosporins
Third Generation cephalosporins
Fourth generation cephalosporins: have true broad-spectrum activity
THE CEPHALOSPORINS
• First Generation cephalosporins- are largely effective against the same gram-positive organisms affected by penicillin.
• Second generation cephalosporins- are effective against those strains as well as Haemophilus influenza, Entreobacter aerogenes and Nesseria sp. These drugs are less effective against gram positive bacteria
THE CEPHALOSPORINS
• Third Generation cephalosporins- are relatively weak against gram-positive bacteria but more potent against gram-negative bacteria, to include Serratia marcescens.
• Fourth generation cephalosporins- developed to fight against the resistant gram-negative bacteria. The first drug is cefepime.
First generation cephalosporins cefadroxil Cefazolin Cephalexin Cephalotin Cephapirin Cephadrine
Second Generation cephalosporins Cefaclor Cefamandole Cefonizind Cefotetan Cefoxitin Cefmetazole Cefprozil Cefuroxime
Third Generation Cephalosporins Cefnidir Cefixime Cefoperazone Cefotaxime Cefpodoxime Ceftazidime Moxalactam
Fourth Generation Cephalosporins Cefepime Cefpirome Cefquinome
The different R groups allow for versatility and improved effectiveness.
Classification
• Cephalosporins– 1st Generation
• Cephalexin, Cefazolin– 2nd Generation
• Cefoxitin, Cefuroxime, Cefotetan– 3rd Generation
• Cefotaxime, Ceftriaxone, Ceftazidime– 4th Generation
• Cefepime
Gram-negative cell Gram-positive cell
Outer membrane
PeptidoglycanPeptidoglycan
PenicillinBinding proteins(PBPs)
Inner (cytoplasmic) membrane
Cephalosporin• The mechanism of action
– The cephalosporins are primarily BACTERICIDAL.
– They interfere with the cell-wall building ability of bacteria when they divide.
– They prevent the bacteria from biosynthesizing the framework of their cell wall.
– The weakened cell wall will swell and burst causing cell death.
Cephalosporin• Pharmacokinetics
– Only a few cephalosporins are administered orally, most are administered parenterally.
– Their half-lives are short and they are excreted mainly in the urine.
• Contraindications and Precautions– The drugs are contraindicated in patients
with known allergies to cephalosporins and penicillins.
Cephalosporin
Adverse Effects• GI system- Nausea, vomiting, diarrhea,
anorexia, abdominal pain and flatulence are common effects.
• CNS – headache, dizziness, lethargy and paresthesias have been reported.
• Renal system- nephrotoxicity in individuals with pre-existing renal disease
• Hypersensitivity
Cephalosporin
Drug-Drug interactions• ALCOHOL- many patients experience a
disulfiram-like reactions when taken with some specific cephalosporins ( cefamandole, cefoperazone or moxalactam).
• The patient may experience flushing, headache, nausea, vomiting and muscular cramps. This may occur even up to 72 hours of cephalosporin discontinuance.
Resistance to Penicillin and its derivatives is caused by a specific enzyme: many gram-negative bacteria
produce penicillinase (b-lactamase)
β-Lactamase Inhibitors
• How do you evade a β-lactamase?1. Use a non-β-lactam agent2. Steric Inhibition
Penicillins with large side chains Cephalosporins
3. β-lactam + β-lactamase inhibitors Not all β-lactamases are inhibitable (!)
Combined antibiotic therapy
Combining different antibiotics can sometimes aid in treatment of infections.
Obviously this type of therapy only prevails when chemicals are compatible and act at different sites or within different pathways.
Inhibition of the “Resistance” Enzyme
Augmentin: Clavulanic acid + Amoxycillin.
•By combining the b-lactam antibiotic with an inhibitor of the b-lactamase (clavulanic acid) produced by the microbe, overcomes this mode of resistance and allows the antibiotic to become effective again.
Augmentin
Clavulanic acid
Inhibitor
Augmentin is amoxycillin + clavulanic acid
• Augmentin is effective against susceptible bacteria causing infections of the middle ear (otitis media), tonsillitis, throat infections(pharyngitis), laryngitis, bronchitis, sinusitis, and pneumonia. It is also used in treating urinary tract infections, and skin infections.
• DOSING: Augmentin should be taken on a full stomach to reduce stomach upset. No more than one tablet should be taken at a time since the extra clavulanic acid can cause stomach upset.
• Recommended adult doses are 500 mg every 8-12 hours, 250 mg every 8 hours, 875 mg every 12 hours
– Sulbactam (ampicillin/sulbactam: Unasyn)– Tazobactam (piperacillin/tazobactam: Zosyn)
Sulbactam• Unasyn (Amp/Sulbactam)• Spectrum: Amp + most anaerobes + many enteric Gm
(-) rods, OSSA• DoC: for GNR mixed infection – E.coli, Proteus,
anaerobes when Pseudomonas is not implicated– Diabetic foot (once Pseudomonas ruled out)– Wound infections
• Sulbactam alone is very active against Acinetobacter spp.
Tazobactam
• Zosyn (Pip/Tazo)• THE most broad-spectrum penicillin• Tazobactam may improve the activity of
piperacillin vs. gram-negative rods, including anaerobes
• 4.5g IV q8h = 3.375g IV q6h• 4.5g IV q6h for Pseudomonas