principles of antimicrobial therapy kaukab azim mbbs, phd
TRANSCRIPT
![Page 1: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/1.jpg)
Principles of Antimicrobial Therapy
Kaukab Azim MBBS, PhD
![Page 2: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/2.jpg)
Learning Objectives• 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
![Page 3: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/3.jpg)
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 chrysogenumvs
• Staphylococcus aureus
![Page 4: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/4.jpg)
Classification
• Chemical classification
• Mechanism of action
• Bactericidal and bacteriostatic
• Broad & narrow spectrum
![Page 5: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/5.jpg)
Classification of antibioticsCell wall disruption
Penicillin
Cephalosporins
Vancomycin Bacitracin
Echinocandin
Cell membraffecting
Polyene antifungals
Allylamines Azole antifungals
Protein synthesis
50 S ribosomal subunit
Macrolides Chloramphenicol
30 S ribosomal subunit
Tetracycline
Aminoglycosides
Cellular component affecting
Affecting nucleic acids
Rifampin Quinolones
Antimetabolite Trimethoprim
Sulfonamides
Antivirals Acyclovir Ribavirin, Zidovudine
![Page 6: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/6.jpg)
Mechanism of Action
• Target: Cell wall synthesis; all β-lactam drugs
• Target: Protein synthesis; macrolides, chloramphenicol, tetracycline, aminoglycosides
• Target: RNA polymerase; rifampin
![Page 7: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/7.jpg)
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
![Page 8: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/8.jpg)
BacteriostaticProtein Synthesis Inhibitors (except
aminoglycosides) – Tetracyclines – Macrolides – Clindamycin– Chloramphenicol– Linezolid – Sulphonamides
![Page 9: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/9.jpg)
Bactericidal Agents affecting Cell wall synthesis Examples of bactericidal drugs
Beta-lactam antibiotics Vancomycin Aminoglycosides Fluoroquinolones
![Page 10: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/10.jpg)
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)
![Page 11: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/11.jpg)
Effect of bactericidal and bacteriostatic on bacterial growth
Log
![Page 12: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/12.jpg)
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
![Page 13: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/13.jpg)
Selecting a Therapeutic Regimen
1. Confirm presence of infection: (a). History (b) signs and symptoms
i. Feverii. Pain, tenderness and inflammation iii. Symptoms related to organ iv. WBC count and ESR
(c) Identify predisposing factors2. Before selecting Empiric therapy
get material for c/s or for microscopy 3. Consider the spectrum of activity; narrow vs broad
spectrum4. Special conditions like sepsis or meningitis
![Page 14: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/14.jpg)
Empiric therapy
• To start empiric therapy
• Know the microbiology of pathogens
• Know the common pathogens responsible for common infections
![Page 15: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/15.jpg)
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
![Page 16: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/16.jpg)
-Empiric therapy for pharyngitis is
A. Ampicillin (kind of penicillin)B. TerbinafineC. IvermectinD. Chloroquine
![Page 17: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/17.jpg)
Disease by gram negative cocci Diplococci
1. Neisseria meningitidis:Meningitis & meningococcemia
2. Neisseria gonorrhea:Urethritis, endocervicitis, arthritis and ophthalmia neonatum
3. Moraxella cattarhalisOtitis media, bronchopneumonia in COPD, bronchitis
![Page 18: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/18.jpg)
Bacilli or RodsBacilli
Gram-pos Gram-negBacillus anthracis P. aeruginosaBacillus cereus H. influenzaeClostridium species B. purtusisC. diphtheria Brucella Campylobacter *Enterobacteriaceae
*Family consists of E. coli, Salmonella spp., Shigella spp., Klebsiella, V. cholera, Proteus spp.
![Page 19: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/19.jpg)
Identification of the pathogenCollection 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
![Page 20: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/20.jpg)
Other factors for selection of therapy
HOST FACTORS
• Allergy• Age• Pregnancy• Metabolic abnormalities• Organ dysfunction• Concomitant use of drugs• Comorbid disease states
![Page 21: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/21.jpg)
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 killinge.g. β-lactum, vancomycin, macrolides, linezolid
![Page 22: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/22.jpg)
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.
![Page 23: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/23.jpg)
Selecting a drug
Tissue penetration CSF, abscesses, diabetic foot infection
Protein binding
Toxicity:chloramphenicol, vancomycin, aminoglycosides, clindamycin
Cost
![Page 24: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/24.jpg)
Monitoring Therapeutic Response
• Clinical assessment• Laboratory tests• Assessment of therapeutic failure
a. Due to drug selectionb. Due to host factorsc. Due to resistance
![Page 25: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/25.jpg)
Mechanisms Of Resistance
ResistanceIntrinsic Acquired
Mutation Transferred
Conjugation Transformation Transduction
![Page 26: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/26.jpg)
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
![Page 27: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/27.jpg)
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
![Page 28: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/28.jpg)
Cellular Resistance
•
• • ATTACK OF THE SUPERBUGS:
ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly.
Jan 07
![Page 29: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/29.jpg)
Resistance in some antibiotics• 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
![Page 30: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/30.jpg)
![Page 31: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/31.jpg)
Preventing/Decreasing Resistance
a. Consult experts!b. Control use of antibioticsc. Rotate drugsd. Use narrow spectrum drugse. Combination chemotherapyf. Pharmacodynamics principles
![Page 32: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/32.jpg)
Superinfections
1. New infection2. Most common organisms
EnterobacteriaceaePseudomonasCandida
3. Due to removal of inhibitory mechanisms4. Spectrum alteration in normal flora
risk of superinfection
![Page 33: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/33.jpg)
Combination Therapy: Uses
1. Empirical therapy2. Polymicrobial infections3. Synergism desired• Prevent development of resistance
• Good combo is 2 bactericidal e.g. cell wall inhibitor & aminoglycosides.
![Page 34: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/34.jpg)
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.
![Page 35: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/35.jpg)
• 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.
![Page 36: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/36.jpg)
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.
![Page 37: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/37.jpg)
GOOD COMBINITION
• Two bactericidal e.g. cell wall inhibitor & aminoglycosides
• Two bacteriostatic e.g. Quinupristin and dalfopristin
![Page 38: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/38.jpg)
Combination Tx: Disadvantages
1. Antagonism of antibacterial effect2. Increased risk of toxicity
![Page 39: Principles of Antimicrobial Therapy Kaukab Azim MBBS, PhD](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649db65503460f94aa79df/html5/thumbnails/39.jpg)
THE END