General Principles of Antimicrobial Therapy - Best Care Always!
Principles of Antimicrobial Therapy
-
Upload
lana-hoover -
Category
Documents
-
view
44 -
download
0
description
Transcript of Principles of Antimicrobial Therapy
![Page 1: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/1.jpg)
Principles of Antimicrobial Therapy
Kaukab Azim MBBS, PhD
![Page 2: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/4.jpg)
Classification
• Chemical classification
• Mechanism of action
• Bactericidal and bacteriostatic
• Broad & narrow spectrum
![Page 5: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/8.jpg)
BacteriostaticProtein Synthesis Inhibitors (except
aminoglycosides) • Tetracyclines • Macrolides • Clindamycin• Chloramphenicol• Linezolid • Sulphonamides
![Page 9: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/9.jpg)
Bactericidal Agents affecting Cell wall synthesis Examples
Beta-lactam antibiotics Vancomycin Aminoglycosides Fluoroquinolones
![Page 10: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/11.jpg)
Effect of bactericidal and bacteriostatic on bacterial growth
Log
![Page 12: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/15.jpg)
Gram-positive and gram-negative
Gram-pos & gram-neg cocci GRAM POSITIVE COCCI
Chains / pairs Clusters
Staphylococcus Streptococcus AND Enterococci
![Page 16: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/16.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 gp. B: Neonatal septicemia and meningitis
• Streptococcus pneumoniae (diplococci): sinusitis, otitis media, pneumonia, septicemia in aspleenic individual
• Enterococcus: UTI, biliary tract infection, subacute endocarditis, pyelonephritis
![Page 17: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/19.jpg)
Identification of the pathogen
Collection of infected material before beginning antimicrobial therapy
1. Stains—Gram or acid-fast (which is already done)2. Serologies 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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/21.jpg)
Selecting a Drug: Drug Factors
a. Resistance to drug ( ceftazidime)b. Pharmacokinetic & Pharmacodynamic factors
i. Concentration-dependent killing & post antibiotic effecte.g. Aminoglycosides, Fluoroquinolones
ii. Time-dependent killinge.g. β-lactum, vancomycin,macrolides, linezolid
![Page 22: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/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](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/23.jpg)
Time (h)
Log 10
CFU
/mL
PAE
80 2 4 6
4 x MIC
3 x MIC2 x MICMICBroth
8
0
2
4
6
10
Concentration dependence & PAE
Wash
![Page 24: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/24.jpg)
Time (h)
Log 10
CFU
/mL
80 2 4 6
> 5 x MICMIC
8
0
2
4
6
10Time-Dependent Killing
Wash
![Page 25: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/25.jpg)
Duration-Based Drug Action
•
![Page 26: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/26.jpg)
Selecting a drug
Tissue penetration CSF, abscesses, diabetic foot infection
Protein binding
Toxicity:chloramphenicol, vancomycin, aminoglycosides, clindamycin
Cost
![Page 27: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/27.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 28: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/28.jpg)
Mechanisms Of Resistance
ResistanceIntrinsic Acquired
Mutation Transferred
Conjugation Transformation Transduction
![Page 29: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/29.jpg)
![Page 30: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/30.jpg)
Cellular Resistance
•
• • ATTACK OF THE SUPERBUGS:
ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly.
Jan 07
![Page 31: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/31.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
• Transduction
• Transformation
• Conjugation
![Page 32: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/32.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 of : RNA methylation, drug
Erythromycin efflux
![Page 33: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/33.jpg)
Preventing/Decreasing Resistance
a. Consult experts!b. Control use of antibioticsc. Rotate drugsd. Use narrow spectrum drugse. Combination chemotherapyf. Pharmacodynamic principles
![Page 34: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/34.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 35: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/35.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 36: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/36.jpg)
Combination Therapy: OutcomesLo
g 10 C
FU/m
LADDITIVE
Control
Drug B
Drug A
Drug A + B
0 12Time (h)
SYNERGISM
Time (h)0 12
Control
Drug B
Drug A
Drug A + B
![Page 37: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/37.jpg)
Combination Therapy: Outcomes
Log 10
CFU
/mL
ANTAGONISM
Time (h)0 12
Control
Drug B
Drug A
Drug A + B
![Page 38: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/38.jpg)
GOOD COMBINITION
• Two bactericidal e.g. cell wall inhibitor & aminoglycosides
• Two bacteriostatic e.g. Quinupristin and dalfopristin
![Page 39: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/39.jpg)
Combination Tx: Disadvantages
1. Antagonism of antibacterial effect
2. Increased risk of toxicity
![Page 40: Principles of Antimicrobial Therapy](https://reader038.fdocuments.us/reader038/viewer/2022102800/56813578550346895d9cdac4/html5/thumbnails/40.jpg)
THE END