Download Mechanism of action

Beta-Lactam antibiotics & Other Cell Wall
Synthesis Inhibitors
Beta-Lactam antibiotics
• Clinically useful families of beta-lactam compounds
include the
– Penicillins
– Cephalosporins
– Monobactams
– Carbapenems
Introduction
The penicillins constitute one of the most
important groups of antibiotics
– widely used
– have unique advantages
– choice for a large number of infectious diseases
History
• The penicillins were the first antibiotics discovered as
natural products from the mold Penicillium
• 1928 - Alexander Fleming
– Bread mold (Penicillin notatum) growing on petri dish
• 1939 - Florey, Chain, and Associates
– Began work on isolating and synthesis large amounts of
Penicillin
• Late 1940 - available for general use in US
Structure
• Penicillins as well as cephalosporins are called
beta-lactam antibiotics and are characterized by
three fundamental structural requirements:
– Thiazolidine ring (A)
– Β-Lactam ring
– Side chain (R)
Classification
• Narrow-spectrum penicillinase-suseptible agents (penicillin
G and Penicillin V) –
– gram positive and gram negative cocci, non-beta-lactamaseproducing anaerobes
• Very narrow spectrum penicillinase-resistant
– nafcillin, methicillin, cloxacilline, oxacillin
– resistant to staphylococcal beta-lactamases, active to
staphylococci and streptococci
Classification
• Extended-spectrum penicillins (ampicillin,
amoxicillin)
– Gram negative organisms, but are destroyed by betalactamases
• Mezlocillin, azlocillin, piperacillin, carbenicillin,
ticarcillin
– Pseudomonas, kelebsiella and gram-negative
microorganism
Mechanisms of Drug Actions
• All penicillin derivatives produce their bacteriocidal
effects by:
– Binding to specific enzymes (penicillin Binding Protein
[PBP])
– Inhibition of the transpeptidation reaction and cell wall
synthesis
– Activation of autolytic enzyme in microorganism
Mechanisms of Drug Actions
• The cell walls of bacteria are essential for their normal
growth and development.
• Peptidoglycan is a heteropolymeric component of the cell
wall that provides rigid mechanical stability by virtue of its
highly cross-linked latticework structure
– two alternating amino sugars (N-acetylglucosamine and Nacetylmuramic acid) that are cross-linked by peptide chains.
(NAG-NAM).
Mechanisms of Drug Actions
• Binding to PBPs results in:
– Inhibition of transpeptidase: transpeptidase catalyzes
the cross-linking of the pentaglycine bridge with the
fourth residue (D-Ala) of the pentapeptide. The fifth
reside (also D-Ala) is released during this reaction.
Spheroblasts are formed
– Structural irregularities: binding to PBPs may result in
abnormal elongation, abnormal shape, cell wall defects
Transpeptididase
Comparison of the structure and composition of gram-positive and
gram-negative cell walls
Pharmacokinetics
• Oral Administration of Penicillin G.
– About one-third of an orally administered dose of penicillin G is
absorbed from the intestinal tract under favorable conditions
• Food may interfere with enteric absorption of all penicillins,
Gastric juice at pH 2 rapidly destroys the antibiotic Ingestion
– should be administered at least 30 minutes before a meal or 2
hours after
Pharmacokinetics
• Oral Administration of Penicillin V.
– It is more stable in an acidic medium, and therefore is better
absorbed from the gastrointestinal tract
• On an equivalent oral-dose basis, penicillin V (K+ salt PENVEE K, V-CILLIN K, others) yields plasma concentrations
two to five times greater than those provided by penicillin
G.
Parenteral Administration of Penicillin G
• After intramuscular injection, peak concentrations in plasma are
reached within 15 to 30 minutes. This value declines rapidly, since the
half-life of penicillin G is 30 minutes.
• Repository preparations of penicillin G are employed.
– penicillin G procaine (maintained for as long as 4 to 5 days)
– penicillin G benzathine. (duration of antimicrobial activity in the plasma is about 26
day)
• Intrathecal administration is inadvisable particularly with
benzylpenicillin as it can cause convulsions.
Distribution
• Penicillin G is distributed widely throughout the body
– Volume of distribution is about 0.35 liters/kg
– 60% of the penicillin G in plasma is reversibly bound to
albumin
• Penicillin does not readily enter the CSF when the
meninges are normal
Excretion
• Penicillin G is rapidly eliminated from the body, mainly by:
– the kidney
– in small part in the bile and by other routes
• Approximately 10% of the drug is eliminated by glomerular
filtration and 90% by tubular secretion.
– Probenecid markedly decreases the tubular secretion of the
penicillins
• Clearance values are considerably lower in neonates and
infants, because of incomplete development of renal function
Unitage of Penicillin
• 1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g
• 1.0 milligram of pure penicillin G sodium thus equals
1667 units
• 1.0 mg of pure penicillin G potassium represents 1595
units
• The dosage and the antibacterial potency of the
semisynthetic penicillins are expressed in terms of
weight.
Mechanisms of Bacterial Resistance to
Penicillins
• Resistance to penicillins and other beta lactams is due to one
of general mechanisms:
– Inactivation of the antibiotic by beta lactamase
– Modification of target PBPs
– Imparied penetration of drug to target PBPs
– The presence of an efflux pump
– Production of biofilms
• There are more than 300 different types of beta lactamase enzymes.
The process is genetically controlled commonly with plasmids.
• beta-lactamase production is particularly important in Staphylococci,
Neisseria gonorrhoeae, Hemophilus
Adverse effects
• Hypersensitivity Reactions
– rash, urticaria, fever, bronchospasm, vasculitis, serum sickness,
exfoliative dermatitis and anaphylaxis
• Penicillins and their breakdown products act as haptens after
covalent reaction with proteins
– The most abundant breakdown product is the penicilloyl (major) moiety
• Very high doses of penicillin G can cause seizures in kidney
failure
• These are cross-reactions between various types of penicillins.
Management of the Patient
Potentially Allergic to Penicillin
Adverse effects
• Evaluation of the patient‘s history
• Desensitization occasionally is recommended
for patients who are allergic to penicillin and
who must receive the drug
Adverse effects cont
•
•
•
•
•
•
Convulsions and encephalopathy can occur, especially
at higher doses and especially if administered
intrathecally (NOT advised).
Interstitial nephritis (Methicillin)
Coomb's positive hemolytic anemia
Neutropenia (especially the b-lactamase -resistant
penicillins)
Decreased platelet aggregation (carbenicillin and
ticarcillin)
Hypernatremia and hypokalemia (carbenicillin)
Drug-drug Interactions
•
Penicillins bind to and inactivate aminoglycosides. This is
a form of chemical antagonism.
•
When an aminoglycoside and a penicillin are
administered, the infusions should be staggered by about
1 to 2 hours.
Cephalosporins
• Mechanism of Action: Cephalosporins are composed of a dihydrothiazine
ring and a b-lactam ring. The mechanism of action is identical to
penicillins
• Mechanism of Resistance: Same as penicillins
• Cephalosporins are less susceptible to Staphylococcus beta-lactamase;
Methicillin-resistant Staphylococcus is resistant to most cephalosporins.
• Classification: The cephalosporins are classified as first, second, third
generation or forth generation cephalosporins. This classification is
dependent on the antimicrobial activity.
Cephalosporins
First Generation
Second Generation
Third Generation
Fourth Generation
Cefadroxil *
Cefaclor *
Cefdinir
Cefepime
Cefazolin
Cefamandole
Cefoperazone
Cefpirome
Cephalexin *
Cefonicid
Cefotaxime
Cefclidine
Cephalothin
Ceforanide
Ceftazidime
Cephaprin
Cefotetan
Ceftibuten
Cephradine *
Cefoxitin
Ceftizoxime
Ceftriaxone
Cefuroxime
* Oral Agent
Cefixime
Cefozopran
First generation cephalosporins
•
•
•
•
•
•
Cephalothin, cefazolin, cephalexin
Gram positive cocci (Streptococcus, pneumococcus but not or
methicillin-resistant Staphylococcus)
Gram negative organisms (Escherichia coli, Klebsiella pneumoniae,
and the indole negative Proteus mirabilis)
Anaerobic cocci (Peptococcus and Peptostreptococcus, but NOT
Bacteroides fragilis).
They are ineffective against Pseudomonas aeruginosa, Enterobacter,
and indole-positive Proteus species.
These drugs do not cross the blood-brain barrier.
Second generation cephalosporins
cefuroxime, cefamandole, cefoxitin, cefaclor, cefotetan
•
The spectrum is extended to more Gram negative bacteria
Enterobacter species, Klebsiella species, and indole-positive
Proteus species.
Cefamandole, cefuroxime, cefonicid, ceforanide, and cefaclor
–
•
– Haemophilus influenza (meningitis)
• cefoxitin, cefmetazole, and cefotetan
– Bacteroid Fragilis
• These drugs do not achieve adequate levels in the
CSF.
Third generation cephalosporins
• less active than first-generation agents against gram-positive
cocci
• more active against the Enterobacteriaceae, including blactamase-producing strains
• cross the blood-brain barrier
• The spectrum is extended to include: Enterobacter, Pseudomonas
(ceftazidime and cefoperazone only), Serratia, b-lactamase
producing Haemophillus influenza and Neisseria species.
– Only ceftizoxime and moxalactam retain good activity against
Bacteroides fragilis.
Fourth generation
• cefepime, cefpirome, cefclidine, cefozopran
• more resistant to some betalactamases
• active against P aeruginosa, Enterobacteriaceae ,
S aureus , and S pneumoniae ,Haemophilus and
Neisseria sp
• Penetrate well into CSF
• Good activity against gr+ and gr- bacteria
Cephalosporins Active Against
Methicillin-Resistant Staphylococci
• Ceftobiprole, ceftaroline
– methicillin-resistance in staphylococci
– activity against enterococci and broad gram-negative
spectrum
– powerful antipseudomonal characteristics and appears
to be less susceptible to development of resistance
Pharmacokinetics
• Some cephalosporins may be given orally but most are
given parenterally (IM or IV).
• They are widely distributed in the body like penicillins.
• Some such as cefuroxime (2nd genereation), cefoperazone,
cefotaxime,, ceftriaxone, and ceftazidime (third generation)
also cross the blood-brain barrier and are drugs of choice
for meningitis due to Gram-negative intestinal bacteria.
Pharmacokinetics
• Almost all are primly eliminated via the kidneys and
are actively secreted by the renal tubules.
Cefoperazone and ceftriaxone are eliminated
through the biliary tract.
Adverse effects
• Hypersensitivity
• Nephrotoxicity (cephaloridine) and intolerance to alcohol
(disulfiram like reaction)
– cefamandole, cefotetan, moxalactam, cefoperazone
• Diarrhea may occur with oral forms (cefoperazone)
• During treatment with such drugs, these resistant organisms
as well as fungi, often proliferate and may induce
superinfection.
• Hypoprothrombinemia, Thrombocytopenia, Platelet
dysfunction.
– Administration of vitamin K (10mg) twice a week can prevent this.
THERAPEUTIC USES
• A cephalosporin with or without an aminoglycoside is firstline treatment of Klebsiella.
• First generation cephalosporins are used for surgical
prophylaxis of wound infection.
• Third generation cephalosporins are used to treat
meningitis due to pneumococci, meningococci, and
Haemophillus influenza.
• Ceftriaxone is the drug of choice for treating betalactamase producing Neisseria gonorrhea.
Carbapenems
• Doripenem, ertapenem, imipenem, meropenem
– structurally similar to the penicillins. These drugs were developed to
deal with beta-lactamase producing Gram-negative organisms,
which were resistant to broad spectrum and extended spectrum
penicillins.
– Carbapenems are derived from Streptomyces
Imipenem
Mechanism of action
•
–
binds to PBP, disrupts cell wall synethesis and is bactericidal
Antimicrobial spectrum
•
–
–
–
It is a broad-spectrum antibiotic
gram-negative rods, including P aeruginosa, gram-positive
organisms, and anaerobes
Enterococcus faecium, methicillin-resistant strains of
staphylococci, Clostridium difficile are resistant.
Imipenem
• Metabolism:
– hydrolyzed by dehydropeptidase,
– it is always administered with cilastatin, an inhibitor of
dipeptidase.
• Side efects: Individuals who are allergic to the penicillins
may demonstrate cross-reactivity with imipenem.
– Imipemem may produce nausea and vomiting.
– Seizures have been reported with high doses, particularly in
patients with renal failure.
Meropenem, Doripenem
• It is similar to imipenem.
• It is not degraded by dehydropeptidase, thus no
cilastatin is needed.
• Excessive levels in kidney failure can cause
seizures with imipenem but not with meropenem.
• They have slightly greater activity against gramnegative aerobes and slightly less activity against
gram-positives
Ertapenem
• longer serum t1/2 that allows once-daily dosing
• inferior activity against P. aeruginosa
• activity against gram-positive organisms,
Enterobacteriaceae and anaerobes
• May use in intra-abdominal and pelvic infections.
Monobactam
•
Aztreonam: This drug is a monocyclic beta-lactam (a monobactam)
•
Mechanism of action: Aztreonam interacts with penicillin binding
proteins and induces the formation of long filamentous bacteria.
•
Antimicrobial spectrum
resembles the spectrum of the aminoglycosides.
–
•
•
•
Gram positive and anaerobic bacteria are resistant.
Susceptible organisms include: Enterobacteriaceae, Pseudomonas, Hemophillus
and Neisseria. Aztreonam is resistant to the beta-lactamase produced by gram
negative organisms.
Side effects: Generally, the drug is well tolerated. Patients who are
allergic to penicillins do not exhibit cross-reactions with aztreonam.
Beta-Lactamase Inhibitors
•
Clavulanic Acid, Sulbactam and tazobactam
•
•
Mechanism of action:
They are potent inhibitors of many bacterial beta-lactamases
and can protect hydrolyzable penicillins from inactivation by
these enzymes.
They are included in combination with amoxacillin
(Augmentum) or with ticaricillin. In particular, clavulanic acid
is an irreversible, "suicide" inhibitor of beta-lactamase.
•
Beta-Lactamase Inhibitors
• They are available only in fixed combinations with
specific penicillins:
• Ampicillin + sulbactam
• Amoxicillin + clavulanic acid
• Ticarcillin + clavulanate potassium
• Piperacillin + tazobactam sodium
Vancomycin
• Mechanism of Action:
– inhibits cell wall synthesis by interfering with second
stage of synthesis of peptidoglycan (inhibit
transglycosilation by binding to the D-Ala-D-Ala
terminus)
– no cross resistance with penicillin
– may also have effect of inhibiting synthesis of RNA
Vancomycin
• Antimicrobial Activity
– excellent activity against gram-positive aerobes
(especially staphylococci, streptococci, and enterococci)
– Vancomycin+gentamicin
• Enterococcus faecium , enterococcus fecalis
• Pharmacokinetics
– poorly absorbed from GI tract
– penetrates well into most areas in body except CNS
– not removed by hemodialysis
Vancomycin
• Side Effects:
– ototoxicity is most common serious side effect (is
usually permanent)
– nephrotoxicity rarely seen, higher incidence with
concomitant use of aminoglycosides
– "red man syndrome" (histamine release )
Vancomycin
• Clinical Applications
– Sepsis, endocarditis (+gentamicin)
– Drug of choice for MRSA, coagulase-negative
staphylococci, and Corynebacterium jeikeium;
– Alternate drug in staphylococcal, streptococcal, and
enterococcal infections (penicillin allergic patients)
– Clostridium difficile colitis (orally) and this regimen is
much more expensive than metronidazole
Teicoplanin
• Teicoplanin is a glycopeptide antibiotic
• It is like vancomycin in mechanism of action,
spectrum of activity, and renal elimination.
• T1/2 >vancomycin
• i.m administration
• MECHANISMS OF ACTION
• Teicoplanin inhibits cell-wall synthesis by binding to
the D-Ala-D-Ala terminus of cell wall precursor (
bactericidal)
DALBAVANCIN
• mechanism of action same as vancomycin
• It has improved activity against many gram-positive
bacteria including methicillin-resistant and
vancomycin-intermediate S aureus
• It is not active against most strains of vancomycinresistant enterococci
• Dalbavancin has an extremely long half-life of 6–11
days
TELAVANCIN
• Like vancomycin, telavancin inhibits cell wall
synthesis by binding to the D-Ala-D-Ala terminus
• disruption of membrane potential and increases
membrane permeability
• it is active versus gram-positive bacteria, including
strains with reduced susceptibility to vancomycin
Fosfomycin trometamol
• Mechanism of Action:
– Blocks very early step in bacterial cell wall synthesis
– It inactivates enzyme enolpyruvyl transferase
– Blocking the addition of phosphoenolpyruvate to UDPN-acetylglucosamine
– Reduces bacterial adherence to epithelial cells
– bactericide
Fosfomycin
• Antimicrobial Activity
– E. coli (less effective than TMP-SMX and
fluoroquinolones)
– Enterococcus faecalis
– activity against other aerobic gram-negative rods not
clearly known
– Safe for use in pregnancy
Fosfomycin
• Pharmacokinetic: long half life
• Side Effects: diarrhea (10%), headache (10%), and
vaginitis (8%)
• Clinical Applications
– acute uncomplicated urinary tract infection in adults
caused by either E. coli or Enterococcus faecalis
Daptomycin
• Mechanism of Action
– Daptomycin (Cubicin) is in a novel antibiotic class
known as a cyclic lipopeptides (bactericide)
– bind to the cell membrane via calcium-dependent
insertion of its lipid tail
– depolarize cell membrane with potassium efflux and
rapid cell death
• Antimicrobial Activity
– extremely good activity against gram-positive pathogens (anaerbic,aerobic),
including MRSA
– active against vancomycin-resistant strains of enterococci and S aureus
Daptomycin
• Pharmacokinetic: long half life allows for once daily
dosing; available in IV form only
• Side Effects: few adverse effects; elevation in CPK in
about 3%, nephrotoxicity with aminoglycoside
• Clinical Applications: complicated skin and soft
tissue infections (MRSA); under investigation for
endocarditis; VSEF*, not indicated for pneumonia
(did not perform well in pneumonia trials)
*vancomycin susceptible E. faecalis
BACITRACIN
• The bacitracins are a mixed group of polypeptide
antibiotics. The major constituent is bacitracin A.
• inhibits cell wall formation
– Interfer dephosphorylation in cycling of the lipid carrier
that transfers peptidoglycan subunits to the growing cell
wall
BACITRACIN
•
•
•
•
gram-positive & gram-negative cocci and bacilli
Neisseria
H.influenzae, and Treponema pallidum
Dosage forms
– ophthalmic and dermatologic ointments
– the antibiotic also is available as a powder for the
preparation of topical solutions
CYCLOSERINE
• Cycloserine is a structural analog of D-alanine
• inhibit alanine racemase
• inhibits the incorporation of D-alanine into
peptidoglycan pentapeptide
• inhibits many gram-positive and gram-negative
organisms
• treat tuberculosis caused by strains of
Mycobacterium tuberculosis resistant to first-line
agents
CYCLOSERINE
• Adverse effects
– headaches, tremors, acute psychosis, and convulsions