Introduction to Beta Lactam Antibiotics
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Transcript of Introduction to Beta Lactam Antibiotics
Dr. Vishaal Bhat
Melaka Manipal Medical College
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
Most widely produced and used antibacterial drugs in the world since 1941.
-Lactams are divided into several classes based on their structure and function.
Often named by their origin, but all classes have a common -Lactam ring structure.
(inhibitors of cell wall synthesis)
The major subdivisions are:
(a) penicillins whose official names
usually include or end in cillin(b) cephalosporins which are
recognized by the inclusion
of cef or ceph in their official names.
(c) carbapenems (e.g. meropenem,
(d) monobactams (e.g. aztreonam)
(e) beta-lactamase inhibitors (e.g.
clavulanic acid, sulbactam).
I. PENICILLINSA. FLEMING(18811955)Penicillin G- P. notatum
1928- Alexander Fleming discovers a mold which inhibits the growth of staphylococcus bacteria
1940- penicillin is isolated and tested on mice by researchers at Oxford
1941- penicillin mass produced by fermentation for use by US soldiers in WWII
1950s- 6-APA is discovered and semi-synthetic penicillins are developed.
1960s to today- novel -lactams/ -lactamase inhibitors are discovered and modified from the natural products of bacteria
Penicillins Natural penicillins
PenG, PenVK, Benzathine Pen, Procaine Pen
Oxacillin, Dicloxacillin, Methicillin, Nafcillin
How do they work?
1. The -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
Mechanism of Action
Bacteria have many methods with which to combat the effects of -lactam type drugs.
Intrinsic defenses such as efflux pumps can remove the -lactams from the cell.
-Lactamases are enzymes which hydrolyze the amide bond of the -lactam ring, rendering the drug useless.
Bacteria may acquire resistance through mutation at the genes which control production of PBPs, altering the active site and binding affinity for the -lactam .
The -lactams are time-dependent killers The effect is directly proportional to the amount of TIME the
concentration of the antibiotic at the site of infection is ABOVE the MIC of the organism.
The -lactams are BACTERICIDAL (at therapeutically attainable levels)
Absorption,distribution & metabolism
Oral absorption of most penicillins is poor
Exception: penicillin v
Food interferes with absorption
To increase GI absorption: give ester form: BacampicillinCarbenicillin
Relatively insoluble in lipid
Hence, have poor penetration into cells and BBB
Inflammation ( eg. Meningitis ) permits entrance into CSF
Absorp., metabolism ( cont. )
Protein binding differs :Ampicillin and penicillin G 20% boundNafcillin, oxacillin, 90% boundcloxacillin , dicloxacillin
Metabolism and excretion
Not metabolized in humanExcreted mostly unchanged in urine( except. Nafcillin,oxacillin, cloxacillin, dicloxacillin )Probenecid blocks their secretionHalf-life 30-60 min ( increased in renal failure)
Used i.m ,slow i.v or infusionHighest activity against Gram-positive organisms but susceptible to Beta-lactamase.
Gram-positive aerobic cocci Staph. aureus- not producing penicillinase, S.pneumoniae ( group A ), S.pyogenes
Gram-negative aerobic cocci- N.meningitides, N. gonorrhea-no longer of choice
Gram- positive bacilli: Bacillus anthracis Spirochetes: T. pallidum drug of choice Anaerobes
Clostridium spp but inactive against B.fragilis Actinomycetes israelii (actinomycosis)
Developed to prolong duration of penicillin G in the blood
1. Penicillin G procaine
Duration 12- 24 hr
It is given i.m and not i.v( risk of procaine toxicity)
Seldom used now ( increased frequency of penicillinase producing N. gonorrhea
Repository penicillins ( cont.)
2. Penicillin G benzathine (i.m)
Duration 3- 4 weeks
Painful at the injection site ( limits its use )
2. Rheumatic fever prophylaxis( inhibits
group A beta- hemolytic streptococci)
3. Streptococcal pharyngitis
Disadvantages of penicillin G
A. Destroyed by gastric HCL
B. Inactivated by penicillinase
C. Narrow spectrum of activity
Acid resistant penicillins
Phenoxy- methyl penicillin ( penicillin v), p.o.
( spectrum of activity is similar to penicillin G )
Group A Streptococcal pharyngitis
Prophylaxis against group A streptococci in pts with history of rheumatic heart disease.
Readily hydrolyzed by beta-lactamase
Lower activity against G+ compared to Penicllin G
Are the choice for infections caused by penicillinaseproducing S. aureus.
However, MRSA & ORSA has emerged.
Not effective against G- aerobes( E.coli, klebsiella, N.gonorrhea or pseudomonas spp.)
Less active than penicillin on anaerobes.
High protein and food binders
Extended- spectrum penicillins
a) Ampicillin, Ampicillin- sulbactam, Bacampicillin, Amoxicillin, Amoxicillin- clavulanic acid.
Less active than penicillin G against G+ cocci. Active against G- organisms.
UsesH. Influenza infections ( otitis media, sinusitis, chronic
bronchitis, pneumonia, bacterial meningitis ).
E. Coli infections ( Urinary & biliary infections ).
Samonella infections ( typhoid fever )
Shigella infections ( ampicillin )
Gonococcal infections ( alternative for penicillin in the treatment of gonorrhea )
Prophlaxis of infective endocarditis
DisadvantagesAmoxicillin & ampicillin alone are readily destroyed by Staph.
Antipseudomonal penicillins ( cont )
Ticarcillin-clavulanic acid, piperacillin,piperacillin-tazobactam ( Tazocin )
Pseud. aeruginosa. For pseud. septicemia, they should be given together with an aminoglycoside
( eg. Gentamicin ).
Ticarcillin and piperacillin alone are readily destroyed by S. penicillinase. High dose may lead to hypernatraemia due to sodium content.
Adverse effects of penicillins
1.Hypersensitivity reactions ( occur in 1-10% of pts; fatality occur in 0.002%)
( immediate, accelerated & late allergic rxns) ** Cross-reactions
Stevens- Johnson syndrome
2. Super infections
4. May cause convulsions after high doses by i.v or in renal failure
-Lactamases were first discovered in 1940 and originally named penicillinases.
These enzymes hydrolyze the -lactam ring, deactivating the drug, but are not covalently bound to the drug as PBPs are.
Especially prevalent in Gram (-) bacteria.
Three classes (A,C,D) catalyze the reaction using a serine residue, the B class of metallo- -lactamases catalyze the reaction using zinc.
How do you evade a -lactamase?1. Use a non--lactam agent
2. Steric Inhibition
Penicillins with large side chains
3. -lactam + -lactamase inhibitors
Not all -lactamases are inhibitable (!)
There are currently three clinically available -lactamase inhibitors which are combined with -lactams; all are produced through fermentation.
These molecules bind irreversibly to -lactamases but do not have good activity against PBPs. The rings are modified to break open after acylating the enzyme.