1. Principles of Antimicrobial Therapy

Report
Principles of Antimicrobial Therapy
Kaukab Azim MBBS, PhD
Learning Objectives
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Definition
Classification
Bacteriostatic & bactericidal
Mechanism of action of each Major class
Empiric drug therapy with help of gram stain and
with knowledge of common pathogens
• Out come of therapy, factors related to therapy
• Development and mechanism of resistance
• Various combinations; advantages &
disadvantages of combo therapy
Antibiotic
• A chemical substance produced by
various species of organisms that is
capable of killing or inhibiting the
growth of other microbes or cells
• Penicillium chrysogenum
vs
• Staphylococcus aureus
Classification
• Chemical classification
• Mechanism of action
• Bactericidal and bacteriostatic
• Broad & narrow spectrum
Classification of antibiotics
Cell wall
disruption
Cell membr
affecting
Protein
synthesis
Cellular
component
affecting
Penicillin
Cephalosporins
Vancomycin
Bacitracin
Polyene antifungals
Allylamines
Azole antifungals
50 S ribosomal subunit
Macrolides
Chloramphenicol
30 S ribosomal subunit
Tetracycline
Aminoglycosides
Rifampin
Quinolones
Antimetabolite
Trimethoprim
Sulfonamides
Antivirals
Acyclovir
Ribavirin, Zidovudine
Affecting nucleic
acids
Echinocandin
Mechanism of Action
• Target: Cell wall synthesis;
all β-lactam drugs
• Target: Protein synthesis;
macrolides, chloramphenicol,
tetracycline, aminoglycosides
• Target: RNA polymerase; rifampin
Mechanism of Action
• Affecting cellular components:
DNA gyrase inhibitors: Quinolones
• DHF reductase inhibitor: Trimethoprim
PABA: Sulfonamides
• Inhibit reverse transcriptase enzyme:
Zidovudine
• Cell wall permeability: Amphotericin B;
Polymyxin B
• Inhibitors of biosynthetic pathways:
Bacitracin
Bacteriostatic
Protein Synthesis Inhibitors (except
aminoglycosides)
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Tetracyclines
Macrolides
Clindamycin
Chloramphenicol
Linezolid
Sulphonamides
Bactericidal
 Agents affecting Cell wall synthesis
 Examples of bactericidal drugs
 Beta-lactam antibiotics
 Vancomycin
 Aminoglycosides
 Fluoroquinolones
Bactericidal antibiotics
• Bactericidal drugs are preferred in:
– Impaired host defense
– Infections with poor blood flow (endocarditis,
endovascular infections)
– Low WBC (<500)
– Cancer patients
– CSF penetration (meningitis)
Effect of bactericidal and bacteriostatic
on bacterial growth
Log
Narrow & Broad Spectrum
• Broad Spectrum: Drugs which affect both
gram-pos and gram-neg bacteria;
tetracycline, imipenem, 3rd generation
cephalosporins
• Narrow Spectrum: Drugs which have
activity against only gram-positive bacteria
i.e. antistaphylococcal penicillins and 1st
generation cephalosporins
Selecting a Therapeutic Regimen
1.
Confirm presence of infection:
(a). History (b) signs and symptoms
i.
Fever
ii. Pain, tenderness and inflammation
iii. Symptoms related to organ
iv. WBC count and ESR
(c) Identify predisposing factors
2. Before selecting Empiric therapy
get material for c/s or for microscopy
3. Consider the spectrum of activity; narrow vs broad
spectrum
4. Special conditions like sepsis or meningitis
Empiric therapy
• To start empiric therapy
• Know the microbiology of pathogens
• Know the common pathogens
responsible for common infections
Disease by staph. and strep. groups
• Staphylococcus: pneumonia, abscesses, infective endocarditis,
surgical wound infections, food poisoning
• Streptococci : pharyngitis, scarlet fever, rheumatic fever,
impetigo, acute glomerulonephritis
• Streptococcus : Neonatal septicemia and meningitis
• Streptococcus pneumoniae (diplococci): sinusitis, otitis media,
pneumonia, septicemia in aspleenic individual
• Enterococcus: UTI, biliary tract infection, subacute
endocarditis, pyelonephritis
-Empiric therapy for pharyngitis is
A.
B.
C.
D.
Ampicillin (kind of penicillin)
Terbinafine
Ivermectin
Chloroquine
Disease by gram negative cocci
Diplococci
1. Neisseria meningitidis:
Meningitis & meningococcemia
2. Neisseria gonorrhea:
Urethritis, endocervicitis, arthritis and
ophthalmia neonatum
3. Moraxella cattarhalis
Otitis media, bronchopneumonia in COPD,
bronchitis
Bacilli or Rods
Bacilli
Gram-pos
Bacillus anthracis
Bacillus cereus
Clostridium species
C. diphtheria
Gram-neg
P. aeruginosa
H. influenzae
B. purtusis
Brucella
Campylobacter
*Enterobacteriaceae
*Family consists of E. coli, Salmonella spp., Shigella spp.,
Klebsiella, V. cholera, Proteus spp.
Identification of the pathogen
Collection of infected material before beginning
antimicrobial therapy
1. Stains—Gram or acid-fast (which is already done)
2. Serology
3. Culture and sensitivity
4. Thin layer smears
Minimal inhibitory concentration (MIC) is the
lowest concentration of antimicrobial that prevents
visible growth of microbes
Other factors for selection of therapy
HOST FACTORS
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Allergy
Age
Pregnancy
Metabolic abnormalities
Organ dysfunction
Concomitant use of drugs
Comorbid disease states
Selecting a Drug: Drug Factors
a. Resistance to drug ( ceftazidime)
b. Pharmacokinetic & Pharmacodynamic factors
i. Concentration-dependent killing & post
antibiotic effect. e.g. Aminoglycosides,
Fluoroquinolones
ii. Time-dependent killing
e.g. β-lactum, vancomycin, macrolides,
linezolid
Post-Antibiotic Effect / Loading Dose
• The Post-Antibiotic Effect (PAE) shows the
capacity of an antimicrobial drug to inhibit the
growth of bacteria after removal of the drug
from the culture.
• The PAE provides additional time for the
immune system to remove bacteria that might
have survived antibiotic treatment before they
can eventually regrow after removal of the
drug.
Selecting a drug
 Tissue penetration
CSF, abscesses, diabetic foot infection
 Protein binding
 Toxicity:
chloramphenicol, vancomycin,
aminoglycosides, clindamycin
 Cost
Monitoring Therapeutic Response
• Clinical assessment
• Laboratory tests
• Assessment of therapeutic failure
a. Due to drug selection
b. Due to host factors
c. Due to resistance
Mechanisms Of Resistance
Resistance
Intrinsic
Mutation
Acquired
Transferred
Conjugation
Transformation
Transduction
Mechanisms for acquired resistance
• A mutation in a relevant gene occur as a random
selection under the pressure exerted by antibiotic;
trait can be passed vertically to daughter cells
• Transfer of an extrachromosomal DNA carrier
(plasmid), is the most common of acquired
resistance; Transfer can occur via
1. Transduction
2. Transformation
3. Conjugation
1. Transduction; occurs when bacteria-specific
viruses (bacteriophages) transfer DNA between
two closely related bacteria
2. Transformation; is a process where parts of DNA
are taken up by the bacteria from the external
environment. This DNA is normally present in
the external environment due to the death and
lysis of another bacterium.
3. Conjugation; occurs when there is direct cell-cell
contact between two bacteria and transfer of
small pieces of DNA called plasmids takes place
Cellular Resistance
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ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science
Creative Quarterly. Jan 07
Resistance in some antibiotics
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Β- lactams:
Hydrolysis , mutant PBP
Tetracycline:
Active eflux from the cell
Aminoglycosides:
Inactivation by enzymes
Sulfonamides:
Overproduction of target
Fluoroquinolones:
Mutant DNA gyrase
Bleomycin:
Binding by immunity prot.
Chloramphenicol:
Reduced uptake into cell
Vancomycin:
Reprograming of D-ala-D-ala
Quinupristin/ dalfopristin:Ribosomal methylation
Macrolides Erythromycin: RNA methylation, drug efflux
Preventing/Decreasing Resistance
a.
b.
c.
d.
e.
f.
Consult experts!
Control use of antibiotics
Rotate drugs
Use narrow spectrum drugs
Combination chemotherapy
Pharmacodynamics principles
Superinfections
1. New infection
2. Most common organisms
Enterobacteriaceae
Pseudomonas
Candida
3. Due to removal of inhibitory mechanisms
4.  Spectrum   alteration in normal flora
  risk of superinfection
Combination Therapy: Uses
1.
2.
3.
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Empirical therapy
Polymicrobial infections
Synergism desired
Prevent development of resistance
• Good combo is 2 bactericidal e.g. cell
wall inhibitor & aminoglycosides.
Synergism
• Synergism is usually defined as a four-fold or
greater DECREASE in the MIC(Minimum inhibitory
concentration) or MBC(Minimum bactericidal
concentration) of the individual antibiotics when
they are present together.
• E.g. Aminoglycoside with a cell wall synthesis
inhibitor (penicillin, cephalosporin, vancomycin).
• Probably due to increase entry of the AG into the
bacterium where it interacts with the ribosome
inhibiting protein synthesis.
• Synergism may result if one drug inhibits the
inactivation of the other. E.g. clavlanate has little
antibacterial activity but in irreversibly inhibits
ß-lactamase and is used in combination with
penicillins.
• Two drugs may act at different steps in a critical
metabolic pathway. E.g. trimthoprim and
sulfamethoxazole. Sulfonamides inhibit the
synthesis of folic acid and trimethoprim inhibits
the reduction of folate to tetrahydrofolate.
ANTAGONISM
• More likely to occur when a bactericidal drug (e.g.,
penicillin, aminoglycoside) is combined with a
primarily bacteriostatic drug (e.g. tetracycline).
• The explanation is that the bactericidal drugs
require the cells to be growing or actively
synthesizing protein and that the bacteriostatic
drugs prevent growth or protein synthesis and
thereby counter the effect of the bactericidal drug.
• The effect of the combination is not likely to be
less than the effect of the bacteriostatic agent
alone.
GOOD COMBINITION
• Two bactericidal e.g. cell wall inhibitor
& aminoglycosides
• Two bacteriostatic e.g. Quinupristin
and dalfopristin
Combination Tx: Disadvantages
1. Antagonism of antibacterial effect
2. Increased risk of toxicity
THE END

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