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Beta Lactam Antibiotics
Presentation by:
Saurav Chandra Sarma
Int. Ph.D NCU 3rd Sem.
Outline
1
• What is Antibiotic???
• Bacterial cell structure
2
• Beta-lactam Antibiotics and it’s mode of action
• Resistance to Beta lactam Antibiotics
• Examples
3
• Beta-lactamases and its classification
• Proposal
• Conclusion.!!!
Antibiotics and it’s Classification
Antibiotics
•An antibiotic is an agent that either kills or inhibits the
growth of a microorganism.
•Excludes substances that kill bacteria but that are not
produced by microorganisms such as Gastric juices &
Hydrogen Peroxide.
•Also excludes synthetic antibacterial compound such as
sulfonamides.
•Penicillin is the first natural antibiotic discovered by
Alexander Fleming in 1928.
Classification of Antibiotics
Based on mode
of Action
Bacteriostatic Bactericidal
Based on their
spectrum of
action
Broad-spectrum
Narrow
Spectrum
Source: Google Images
Types of Antibiotics
(Based on their mode of action)
Bacteriostatic Antibiotics
• Tetracyclines
• Spectinomycin
• Sulphonamides
• Macrolides
• Chloramphenicol
• Trimethoprim
Bactericidal Antibiotics
• Penicillins
• Cephalosporins
• Fluoroquinolones
(Ciprofloxacin)
• Glycopeptides (Vancomycin)
• Monobactams
• Carbapenems
Types of Antibiotics
(Based on their structural similarities)
Antibiotics: Mode of Action
•Inhibitors of DNA synthesis
•Inhibitors of bacterial protein synthesis
•Inhibitors of bacterial cell wall synthesis
•Interference with metabolism
•Impairment of nucleic acids
Antibiotic Targets
Sourcs: Microbiology: A Clinical Approach
Bacterial Cell structure
Gram positive vs. Gram negative
bacteria
Source: Google Images
Cell Wall
Source: Google Images
Structure of Peptidoglycan layer
•Peptidoglycan is a carbohydrate composed of alternating
units of NAMA and NAGA.
•The NAMA units have a peptide side chain which can be
cross linked from the L-Lys residue to the terminal D-Ala-D-
Ala link on a neighboring NAMA unit.
Source: Google Images
Transpeptidase Enzyme
•The cross linking reaction is catalyzed
by a class of transpeptidases known as
penicillin binding proteins
•A critical part of the process is the
recognition of the D-Ala-D-Ala
sequence of the NAMA peptide side
chain by the PBP. Interfering with this
recognition disrupts the cell wall
synthesis.
•β-lactams mimic the structure of the
D-Ala-D-Ala link and bind to the active
site of PBPs, disrupting the cross-
linking process.
Source: Google Images
Transpeptidation mechanism
Source: Google Images
Transpeptidation mechanism
Source: Google Images
Beta–lactam Drugs
Beta-Lactam Antibiotics
β-lactam ring
•Contains a beta-lactam ring in their molecular structures.
•Nitrogen is attached to the beta carbon relative to the
carbonyl ring and hence the name.
Classification
•Penicillins
•Cephalosporins
•Other β-Lactam drugs
--Cephamycins
--Carbapenems
--Oxacephalosporins
--β-Lactamase inhibitors
--Monolactams
Beta-Lactam Structure
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
Mechanism of β-Lactam Drugs
• The amide of the β-lactam ring is unusually
reactive due to ring strain and a conformational
arrangement which does not allow the lone pair of
the nitrogen to interact with the double bond of
the carbonyl.
• β-Lactams acylate the hydroxyl group on the serine
residue of PBP active site in an irreversible manner.
• This reaction is further aided by the oxyanion hole,
which stabilizes the tetrahedral intermediate and
thereby reduces the transition state energy.
Discovery of Penicillin(First beta-
lactam drug)
•Discovered in 1928.
• While working in his lab, trying to kill a deadly bacteria,he noticed a
blue mold growing on the dish
•Learned that it was the mold Penicillum Notatum.
•Penicillin is found in this mold.
•Noticed that the bacteria around the mold was dissolving.
Source: Google Images
How it is was Developed
• For 9 years, nobody could purify the Penicillum Notatum
to get the pure penicillin.
Finally, in 1938, a team of Oxford University Scientists,
headed by Howard Florey and Ernst B. Chain helped to
develop penicillin.
Source: Google Images
Beta Lactam Antibiotics
Mechanism of β-Lactam Drugs
• The amide of the β-lactam ring is unusually
reactive due to ring strain and a conformational
arrangement which does not allow the lone pair of
the nitrogen to interact with the double bond of
the carbonyl.
• β-Lactams acylate the hydroxyl group on the serine
residue of PBP active site in an irreversible manner.
• This reaction is further aided by the oxyanion hole,
which stabilizes the tetrahedral intermediate and
thereby reduces the transition state energy.
Mechanism of β-Lactam Drugs
The hydroxyl attacks the amide and forms a
tetrahedral intermediate.
Mechanism of β-Lactam Drugs
The tetrahedral intermediate collapses, the amide
bond is broken, and the nitrogen is reduced.
Mechanism of β-Lactam Drugs
The PBP is now covalently bound by the drug and
cannot perform the cross linking action.
Penicillin
Natural Penicillin
Penicillin V (Phenoxymethylpenicillin)
EFFECTIVE AGAINST:
• Gram positive + Less effective
against Gram negative bacteria
TREATMENT FOR:
• Tonsillitis
• Anthrax
• Rheumatic fever
• Streptococcal skin infections
CHARACTERISTICS:
• Narrow spectrum
• Should be given orally
• Prone to beta-lactamase
Penicillin V (Phenoxymethylpenicillin)
EFFECTIVE AGAINST:
• Gram positive + Less effective
against Gram negative bacteria
TREATMENT FOR:
• Tonsillitis
• Anthrax
• Rheumatic fever
• Streptococcal skin infections
CHARACTERISTICS:
• Narrow spectrum
• Should be given orally
• Prone to beta-lactamase
Amino-Penicillin
Ampicillin R=Ph
Amoxicillin R= Ph-OH
Ampicillin
EFFECTIVE AGAINST:
• Gram positive + Gram negative
bacteria
TREATMENT FOR:
• Ear infection
• Sinusitis
• Urinary tract infections
• Meningitis
CHARACTERISTICS:
• Broad spectrum
• Can be given orally and
parenterally
• Prone to beta-lactamase
Ampicillin
Sulbactam
+
ll
Unasyn
Amoxicillin
EFFECTIVE AGAINST:
• Gram positive + Gram negative
bacteria
TREATMENT FOR:
• Skin infection
• Sinusitis
• Urinary tract infections
• Streptococcal pharyngitis
CHARACTERISTICS:
• Broad spectrum
• Can be given orally and parenterally
• Prone to beta-lactamase
SIDE-EFFECTS:
• Rash, diarrhea, vomiting, nausea,
edema, stomatitis, and easy
fatigue.
Amoxicillin
Clavulanic Acid
+
ll
Augmentin
Anti-Staphylococcal Penicillin
Methicillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT FOR:
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Interstitial nephritis
Oxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT AGAINST:
• penicillin-resistant Staphylococcus
aureus
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Hypersensitivity and local reactions
• In high doses, renal, hepatic, or
nervous system effects can occur
Nafcillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT AGAINST:
• Staphylococcal infections
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Allergic reactions
• Nausea and vomiting
• Abdominal pain
Cloxacillin
EFFECTIVE AGAINST:
• Staphylococci that produce
beta-lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction
Dicloxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria +
Staphylococci that produce beta-
lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction
• Diarrhoea, nausea, rash, urticaria
pain and inflammation at
injection site
Flucloxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria +
Staphylococci that produce beta-
lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction
• Diarrhoea, nausea, rash, urticaria
pain and inflammation at
injection site
Anti-Pseudomonal Penicillin
Piperacillin
EFFECTIVE AGAINST:
• Gram positive +Gram negative
CHARACTERISTICS:
• Extended Spectrum
• Should be given
by intravenous or intramuscular injection
SIDE-EFFECT:
• Hypersensitivity
• Gastrointestinal
• Renal
• Nervous system
*Piperacillin+Tazobactam=Zosyn
Carbenicillin
EFFECTIVE AGAINST:
• Gram negative + Limited Gram
positive
TREATMENT FOR:
• Urinary tract infections
CHARACTERISTICS:
• Highly soluble in water and acid-
labile
SIDE-EFFECT:
• High doses can cause bleeding
• Hypokalemia
Ticarcillin
EFFECTIVE AGAINST:
• Mainly gram negative bacteria
particularly Pseudomonas aeruginosa
TREATMENT FOR:
• Stenotrophomonas maltophilia
infections
CHARACTERISTICS:
SIDE-EFFECT:
• Diarrhoea
• Bleeding
• Fever
• Fainting
Cephalosporin
Beta Lactam Antibiotics
These has been conventionally classified into four
generations based on Generation system
• This is based on chronological sequence of development,
but more importantly ,takes into consideration the overall
antibacterial spectrum as well as potency.
• First-generation cephalosporins are predominantly active
against Gram-positive bacteria, and successive generations
have increased activity against Gram-negative bacteria
(albeit often with reduced activity against Gram-positive
organisms).
First Generation Cephalosporins
Cefalothin Cefalexin
Cefadroxil Cefazolin
Second Generation Cephalosporins
Cefuroxime(Oral) Cefotetan
Third Generation Cephalosporins
Cefotaxime Ceftriaxone
Ceftazidime
Fourth Generation Cephalosporins
Cefepime
Carbapenem
What are carbapenems
• Carbapenems are a class of beta-lactam
antibiotics with a broad spectrum of
antibacterial activity. They have a structure
that renders them highly resistant to beta-
lactamases. Carbapenem antibiotics were
originally developed from thienamycin, a
naturally-derived product of Streptomyces
cattleya.
57Dr.T.V.Rao MD
Carbapenems common uses
• Imipenem
– Broad spectrum, covers Gram-positive, Gram-negative
(including ESBL-producing strains), Pseudomonas and
anaerobes
• Meropenem
– Less seizure-inducing potential, can be used to treat CNS
infections
• Ertapenem
– Lacks activity vs. Acinetobacter and Pseudomonas
– Has limited activity against penicillin-resistant
pneumococci
58Dr.T.V.Rao MD
Imipenem
EFFECTIVE AGAINST:
• Aerobic and anaerobic, Gram
positive and gram negative
bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamase
enzymes
SIDE-EFFECT:
• Seizuregenic at high doses
Meropenem
EFFECTIVE AGAINST:
• Aerobic and anaerobic, Gram
positive and gram negative
bacteria
CHARACTERISTICS:
• Ultra Broad Spectrum
• Intravenous
• Resistant to beta-lactamase
enzymes
SIDE-EFFECT:
• Diarrhoea
• Vomiting
• headache
Ertapenem
EFFECTIVE AGAINST:
• Gram positive and gram negative
bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamase
enzymes
• Not active against MRSA
SIDE-EFFECT:
• Convulsions
• Seizures
• headache
Monobactam
Aztreonam
EFFECTIVE AGAINST:
• Gram positive +Gram
negative+Anaerobic bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamase
enzymes
• Not active against MRSA
SIDE-EFFECT:
• Diarrhoea
• Nausea
• Vomiting
BETA-LACTAMASE INHIBITORS
• Resemble β-lactam antibiotic structure
• Bind to β-lactamase and protect the antibiotic from destruction
• Most successful when they bind the β-lactamase irreversibly
• Three important in medicine:
» Clavulanic Acid
» Sulbactam
» Tazobactam
Beta–lactam Resistance
Resistance-The Global Battle.!!!
What is Resistance?
•Drug resistance refers to unresponsiveness of a microorganism
to an antimicrobial agent.
•Drug resistance are of two types:
---Natural Resistance
---Acquired Resistance
Natural Resistance:
•Some microbes have always been resistant to certain anti-microbial agent.
•They lack the metabolic process or the target side thai is affected by
particular drug.
E.g: Gram negative bacilli are normally unaffected by Penicillin G.
M. tuberculosis is insensitive to Tetracyclines.
•This type of resistance does not pose significant clinical problem.
Acquired Resistance:
•It is the development of resistance by an organism which was sensiive before
due to the use of antimicrobial agent over a period of time.
•This can happen with any microbe and is a major clinical problem.
However, the development of resistance is dependent on the microorganism
as well as the drug.
Porins
Altered penicillin binding proteins
b-lactamases
MECHANISMS OF RESISTANCE
MECHANISMS FOR ACQUIRING
RESISTANCE
69
CHALLENGES OF b-LACTAMASES
1940 : Introduction of penicillins
1940 : First description of b-lactamases published
1944 : Strains of staphylococcus aureus producing
b-lactamase
1960s : Clinical use of expanded spectrum penicillins
- such as ampicillin and carbenicillin
1970s : plasmid mediated b-lactamases assumed prominence in
enterobacteriaceae and gram-negative bacteria
1980-90 : Development of broad-spectrum cephalosporins, cephamycins,
monobactams and carbapenems
1990 : Increased resistance among gram-negative bacteria with inducible
chromosomally-mediated b lactamases
JAC (1993); suppl A: 1-8
Beta–lactamases
Beta-Lactamase Enzyme
Functional
Classification
Group 1
(Cephalosporinases*)
Group 2
(Penicillinases,
Cephalosporinases)
Group 3
(Metalloenzymes*)
Group 4
(Penicillinases*)
* Not inhibited by Clavulanic Acid
Beta-Lactamase Enzyme
Molecular
Classification
Serine Based
Class A Class C Class D
Metallo
B-lactamases
Class B
Beta-Lactamase Enzyme
Molecular
Classification
Serine Based
Class A Class C Class D
Metallo
B-lactamases
Class B
ESBLs are enzymes that mediate resistance to
extended-spectrum (third generation)
cephalosporins (e.g., ceftazidime, cefotaxime,
and ceftriaxone) and monobactams (e.g.,
aztreonam) but do not affect cephamycins
(e.g., cefoxitin and Cefotetan) or carbapenems
(e.g., meropenem or imipenem).
Extended spectra Beta-Lactamase
(ESBL)
WHY SHOULD WE DETECT THESE ENZYMES?
• The presence of an ESBL-producing organism in a clinical infection can
result in treatment failure if one of the above classes of drugs is used.
• ESBLs can be difficult to detect because they have different levels of
activity against various cephalosporins. Thus, the choice of which
antimicrobial agents to test is critical. For example, one enzyme may
actively hydrolyze ceftazidime, resulting in ceftazidime minimum
inhibitory concentrations (MICs) of 256 µg/ml, but have poor activity on
cefotaxime, producing MICs of only 4 µg/ml.
• If an ESBL is detected, all penicillin's, cephalosporins, and aztreonam
should be reported as resistant, even if in vitro test results indicate
susceptibility
RISK FACTORS FOR ESBL INFECTION
• Length of hospital stay
• Severity of illness
• Time in the ICU
• Intubation and mechanical ventilation
• Urinary or arterial catheterization
• Previous exposure to antibiotics
Metallo Beta-lactamase
• Resistant against broad spectrum of beta-lactam antibiotics
• These include the antibiotics of the carbapenem family.
• This class of β-lactamases is characterized by the ability to
hydrolyze carbapenems and by its resistance to the
commercially available β-lactamase inhibitors but susceptibility
to inhibition by metal ion chelators.
• The most common bacteria that make this enzyme are Gram
negative such as Escherichia coli and Klebsiella pneumoniae ,
Pseudomonas aeroginosa.
BETA-LACTAMASE INHIBITORS
• Resemble β-lactam antibiotic structure
• Bind to β-lactamase and protect the antibiotic from destruction
• Most successful when they bind the β-lactamase irreversibly
• Three important in medicine:
» Clavulanic Acid
» Sulbactam
» Tazobactam
Beta Lactam Antibiotics

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Beta Lactam Antibiotics

  • 1. Beta Lactam Antibiotics Presentation by: Saurav Chandra Sarma Int. Ph.D NCU 3rd Sem.
  • 2. Outline 1 • What is Antibiotic??? • Bacterial cell structure 2 • Beta-lactam Antibiotics and it’s mode of action • Resistance to Beta lactam Antibiotics • Examples 3 • Beta-lactamases and its classification • Proposal • Conclusion.!!!
  • 3. Antibiotics and it’s Classification
  • 4. Antibiotics •An antibiotic is an agent that either kills or inhibits the growth of a microorganism. •Excludes substances that kill bacteria but that are not produced by microorganisms such as Gastric juices & Hydrogen Peroxide. •Also excludes synthetic antibacterial compound such as sulfonamides. •Penicillin is the first natural antibiotic discovered by Alexander Fleming in 1928.
  • 5. Classification of Antibiotics Based on mode of Action Bacteriostatic Bactericidal Based on their spectrum of action Broad-spectrum Narrow Spectrum
  • 7. Types of Antibiotics (Based on their mode of action) Bacteriostatic Antibiotics • Tetracyclines • Spectinomycin • Sulphonamides • Macrolides • Chloramphenicol • Trimethoprim Bactericidal Antibiotics • Penicillins • Cephalosporins • Fluoroquinolones (Ciprofloxacin) • Glycopeptides (Vancomycin) • Monobactams • Carbapenems
  • 8. Types of Antibiotics (Based on their structural similarities)
  • 9. Antibiotics: Mode of Action •Inhibitors of DNA synthesis •Inhibitors of bacterial protein synthesis •Inhibitors of bacterial cell wall synthesis •Interference with metabolism •Impairment of nucleic acids
  • 12. Gram positive vs. Gram negative bacteria Source: Google Images
  • 14. Structure of Peptidoglycan layer •Peptidoglycan is a carbohydrate composed of alternating units of NAMA and NAGA. •The NAMA units have a peptide side chain which can be cross linked from the L-Lys residue to the terminal D-Ala-D- Ala link on a neighboring NAMA unit. Source: Google Images
  • 15. Transpeptidase Enzyme •The cross linking reaction is catalyzed by a class of transpeptidases known as penicillin binding proteins •A critical part of the process is the recognition of the D-Ala-D-Ala sequence of the NAMA peptide side chain by the PBP. Interfering with this recognition disrupts the cell wall synthesis. •β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross- linking process. Source: Google Images
  • 19. Beta-Lactam Antibiotics β-lactam ring •Contains a beta-lactam ring in their molecular structures. •Nitrogen is attached to the beta carbon relative to the carbonyl ring and hence the name.
  • 22. 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
  • 23. Mechanism of β-Lactam Drugs • The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl. • β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner. • This reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy.
  • 24. Discovery of Penicillin(First beta- lactam drug) •Discovered in 1928. • While working in his lab, trying to kill a deadly bacteria,he noticed a blue mold growing on the dish •Learned that it was the mold Penicillum Notatum. •Penicillin is found in this mold. •Noticed that the bacteria around the mold was dissolving. Source: Google Images
  • 25. How it is was Developed • For 9 years, nobody could purify the Penicillum Notatum to get the pure penicillin. Finally, in 1938, a team of Oxford University Scientists, headed by Howard Florey and Ernst B. Chain helped to develop penicillin. Source: Google Images
  • 27. Mechanism of β-Lactam Drugs • The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl. • β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner. • This reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy.
  • 28. Mechanism of β-Lactam Drugs The hydroxyl attacks the amide and forms a tetrahedral intermediate.
  • 29. Mechanism of β-Lactam Drugs The tetrahedral intermediate collapses, the amide bond is broken, and the nitrogen is reduced.
  • 30. Mechanism of β-Lactam Drugs The PBP is now covalently bound by the drug and cannot perform the cross linking action.
  • 33. Penicillin V (Phenoxymethylpenicillin) EFFECTIVE AGAINST: • Gram positive + Less effective against Gram negative bacteria TREATMENT FOR: • Tonsillitis • Anthrax • Rheumatic fever • Streptococcal skin infections CHARACTERISTICS: • Narrow spectrum • Should be given orally • Prone to beta-lactamase
  • 34. Penicillin V (Phenoxymethylpenicillin) EFFECTIVE AGAINST: • Gram positive + Less effective against Gram negative bacteria TREATMENT FOR: • Tonsillitis • Anthrax • Rheumatic fever • Streptococcal skin infections CHARACTERISTICS: • Narrow spectrum • Should be given orally • Prone to beta-lactamase
  • 36. Ampicillin EFFECTIVE AGAINST: • Gram positive + Gram negative bacteria TREATMENT FOR: • Ear infection • Sinusitis • Urinary tract infections • Meningitis CHARACTERISTICS: • Broad spectrum • Can be given orally and parenterally • Prone to beta-lactamase Ampicillin Sulbactam + ll Unasyn
  • 37. Amoxicillin EFFECTIVE AGAINST: • Gram positive + Gram negative bacteria TREATMENT FOR: • Skin infection • Sinusitis • Urinary tract infections • Streptococcal pharyngitis CHARACTERISTICS: • Broad spectrum • Can be given orally and parenterally • Prone to beta-lactamase SIDE-EFFECTS: • Rash, diarrhea, vomiting, nausea, edema, stomatitis, and easy fatigue. Amoxicillin Clavulanic Acid + ll Augmentin
  • 39. Methicillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT FOR: CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Interstitial nephritis
  • 40. Oxacillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT AGAINST: • penicillin-resistant Staphylococcus aureus CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Hypersensitivity and local reactions • In high doses, renal, hepatic, or nervous system effects can occur
  • 41. Nafcillin EFFECTIVE AGAINST: • Gram positive bacteria TREATMENT AGAINST: • Staphylococcal infections CHARACTERISTICS: • Very narrow Spectrum • Should be given parenterally SIDE-EFFECT: • Allergic reactions • Nausea and vomiting • Abdominal pain
  • 42. Cloxacillin EFFECTIVE AGAINST: • Staphylococci that produce beta-lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction
  • 43. Dicloxacillin EFFECTIVE AGAINST: • Gram positive bacteria + Staphylococci that produce beta- lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction • Diarrhoea, nausea, rash, urticaria pain and inflammation at injection site
  • 44. Flucloxacillin EFFECTIVE AGAINST: • Gram positive bacteria + Staphylococci that produce beta- lactamase CHARACTERISTICS: • Very narrow Spectrum • Should be given orally SIDE-EFFECT: • Allergic reaction • Diarrhoea, nausea, rash, urticaria pain and inflammation at injection site
  • 46. Piperacillin EFFECTIVE AGAINST: • Gram positive +Gram negative CHARACTERISTICS: • Extended Spectrum • Should be given by intravenous or intramuscular injection SIDE-EFFECT: • Hypersensitivity • Gastrointestinal • Renal • Nervous system *Piperacillin+Tazobactam=Zosyn
  • 47. Carbenicillin EFFECTIVE AGAINST: • Gram negative + Limited Gram positive TREATMENT FOR: • Urinary tract infections CHARACTERISTICS: • Highly soluble in water and acid- labile SIDE-EFFECT: • High doses can cause bleeding • Hypokalemia
  • 48. Ticarcillin EFFECTIVE AGAINST: • Mainly gram negative bacteria particularly Pseudomonas aeruginosa TREATMENT FOR: • Stenotrophomonas maltophilia infections CHARACTERISTICS: SIDE-EFFECT: • Diarrhoea • Bleeding • Fever • Fainting
  • 51. These has been conventionally classified into four generations based on Generation system • This is based on chronological sequence of development, but more importantly ,takes into consideration the overall antibacterial spectrum as well as potency. • First-generation cephalosporins are predominantly active against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).
  • 52. First Generation Cephalosporins Cefalothin Cefalexin Cefadroxil Cefazolin
  • 57. What are carbapenems • Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to beta- lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya. 57Dr.T.V.Rao MD
  • 58. Carbapenems common uses • Imipenem – Broad spectrum, covers Gram-positive, Gram-negative (including ESBL-producing strains), Pseudomonas and anaerobes • Meropenem – Less seizure-inducing potential, can be used to treat CNS infections • Ertapenem – Lacks activity vs. Acinetobacter and Pseudomonas – Has limited activity against penicillin-resistant pneumococci 58Dr.T.V.Rao MD
  • 59. Imipenem EFFECTIVE AGAINST: • Aerobic and anaerobic, Gram positive and gram negative bacteria CHARACTERISTICS: • Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes SIDE-EFFECT: • Seizuregenic at high doses
  • 60. Meropenem EFFECTIVE AGAINST: • Aerobic and anaerobic, Gram positive and gram negative bacteria CHARACTERISTICS: • Ultra Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes SIDE-EFFECT: • Diarrhoea • Vomiting • headache
  • 61. Ertapenem EFFECTIVE AGAINST: • Gram positive and gram negative bacteria CHARACTERISTICS: • Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes • Not active against MRSA SIDE-EFFECT: • Convulsions • Seizures • headache
  • 63. Aztreonam EFFECTIVE AGAINST: • Gram positive +Gram negative+Anaerobic bacteria CHARACTERISTICS: • Broad Spectrum • Intravenous • Resistant to beta-lactamase enzymes • Not active against MRSA SIDE-EFFECT: • Diarrhoea • Nausea • Vomiting
  • 64. BETA-LACTAMASE INHIBITORS • Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction • Most successful when they bind the β-lactamase irreversibly • Three important in medicine: » Clavulanic Acid » Sulbactam » Tazobactam
  • 66. Resistance-The Global Battle.!!! What is Resistance? •Drug resistance refers to unresponsiveness of a microorganism to an antimicrobial agent. •Drug resistance are of two types: ---Natural Resistance ---Acquired Resistance
  • 67. Natural Resistance: •Some microbes have always been resistant to certain anti-microbial agent. •They lack the metabolic process or the target side thai is affected by particular drug. E.g: Gram negative bacilli are normally unaffected by Penicillin G. M. tuberculosis is insensitive to Tetracyclines. •This type of resistance does not pose significant clinical problem. Acquired Resistance: •It is the development of resistance by an organism which was sensiive before due to the use of antimicrobial agent over a period of time. •This can happen with any microbe and is a major clinical problem. However, the development of resistance is dependent on the microorganism as well as the drug.
  • 68. Porins Altered penicillin binding proteins b-lactamases MECHANISMS OF RESISTANCE
  • 70. CHALLENGES OF b-LACTAMASES 1940 : Introduction of penicillins 1940 : First description of b-lactamases published 1944 : Strains of staphylococcus aureus producing b-lactamase 1960s : Clinical use of expanded spectrum penicillins - such as ampicillin and carbenicillin 1970s : plasmid mediated b-lactamases assumed prominence in enterobacteriaceae and gram-negative bacteria 1980-90 : Development of broad-spectrum cephalosporins, cephamycins, monobactams and carbapenems 1990 : Increased resistance among gram-negative bacteria with inducible chromosomally-mediated b lactamases JAC (1993); suppl A: 1-8
  • 72. Beta-Lactamase Enzyme Functional Classification Group 1 (Cephalosporinases*) Group 2 (Penicillinases, Cephalosporinases) Group 3 (Metalloenzymes*) Group 4 (Penicillinases*) * Not inhibited by Clavulanic Acid
  • 73. Beta-Lactamase Enzyme Molecular Classification Serine Based Class A Class C Class D Metallo B-lactamases Class B
  • 74. Beta-Lactamase Enzyme Molecular Classification Serine Based Class A Class C Class D Metallo B-lactamases Class B
  • 75. ESBLs are enzymes that mediate resistance to extended-spectrum (third generation) cephalosporins (e.g., ceftazidime, cefotaxime, and ceftriaxone) and monobactams (e.g., aztreonam) but do not affect cephamycins (e.g., cefoxitin and Cefotetan) or carbapenems (e.g., meropenem or imipenem). Extended spectra Beta-Lactamase (ESBL)
  • 76. WHY SHOULD WE DETECT THESE ENZYMES? • The presence of an ESBL-producing organism in a clinical infection can result in treatment failure if one of the above classes of drugs is used. • ESBLs can be difficult to detect because they have different levels of activity against various cephalosporins. Thus, the choice of which antimicrobial agents to test is critical. For example, one enzyme may actively hydrolyze ceftazidime, resulting in ceftazidime minimum inhibitory concentrations (MICs) of 256 µg/ml, but have poor activity on cefotaxime, producing MICs of only 4 µg/ml. • If an ESBL is detected, all penicillin's, cephalosporins, and aztreonam should be reported as resistant, even if in vitro test results indicate susceptibility
  • 77. RISK FACTORS FOR ESBL INFECTION • Length of hospital stay • Severity of illness • Time in the ICU • Intubation and mechanical ventilation • Urinary or arterial catheterization • Previous exposure to antibiotics
  • 78. Metallo Beta-lactamase • Resistant against broad spectrum of beta-lactam antibiotics • These include the antibiotics of the carbapenem family. • This class of β-lactamases is characterized by the ability to hydrolyze carbapenems and by its resistance to the commercially available β-lactamase inhibitors but susceptibility to inhibition by metal ion chelators. • The most common bacteria that make this enzyme are Gram negative such as Escherichia coli and Klebsiella pneumoniae , Pseudomonas aeroginosa.
  • 79. BETA-LACTAMASE INHIBITORS • Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction • Most successful when they bind the β-lactamase irreversibly • Three important in medicine: » Clavulanic Acid » Sulbactam » Tazobactam

Hinweis der Redaktion

  1. Adding the oxygen decreases the nucleophilicity of the carbonyl group, making penicillin V acid stable and orally viable
  2. Adding the oxygen decreases the nucleophilicity of the carbonyl group, making penicillin V acid stable and orally viable
  3. Ampicillin is active against Gram-(+) bacteria including Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus (but not methicillin-resistant strains), and some Enterococci Ampicillin is relatively non-toxic. Its most common side effects include rash, diarrhea, nausea and vomiting.[4] In very rare cases it causes severe side effects such as anaphylaxis and Clostridium difficile diarrhea.
  4. Side effects are similar to those for other β-lactam antibiotics, including nausea, vomiting, rashes, and antibiotic-associated colitis. Loose bowel movements (diarrhea) may also occur. Rarer side effects include mental changes, lightheadedness, insomnia, confusion, anxiety, sensitivity to lights and sounds, and unclear thinking.
  5. Dicloxacillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of theisoxazolyl group on the side chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamases.
  6. Dicloxacillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of theisoxazolyl group on the side chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamases.
  7. Ticarcillin's antibiotic properties arise from its ability to prevent cross-linking of peptidoglycan during cell wall synthesis, when the bacteria try to divide, causing cell death.
  8. Reistance by efflux mechanism
  9. Inactivated by ESBL(Extended Spectrum beta-lactamases