Principles of Antimicrobial Therapy Flashcards
Use of chemicals agents against invading living organisms (cells)
Term is used for both treatment of cancer and treatment of infection
Chemotherapy
l A chemical substance capable of killing or inhibiting the growth microbes
May be naturally occurring or synthetic
Antimicrobia
A chemical substance produced by various species of organisms that is capable of killing or inhibiting the growth of other microbes or cells
Antibiotic
The ability of a drug to injure a target cell or organism without injuring other cells or organisms that are in intimate contact #choosy
Selective Toxicity
Targeting structural, physiological or metabolic difference between invading microbe and host cell
Paul Erlich(1906) “Inordertousechemotherapysuccessfully,wemustsearchforsubstancesthathaveanaffinityforthecellsofparasitesandapowerofkillingthemgreaterthanthedamagesuchsubstancescausetotheorganism(host)itself.Wemustlearntoaimwithchemicalsubstances.”
Selective Toxicity
Drugs which inactivate or destroy microbes –Antibacterial discussion is focused here
–Antiviral
–Antifungal
–Antiparasitics
Antimicrobials
Antimicrobial Targets
Cell wall
peptidoglycan
Cytoplasmicmembrane
Protein synthesis
Nucleic acid synthesis
What are drugs that inhibit CW synthesis?
- Cycloserine
- vancomycin
- bacitracin
- Fosfomycin
- Penicillins
- Cephalosporins
- Monobactams
- Carbapenems
Inhibitors of Folic Acid
Trimetroprim
Sulfonamides
inhibitors of DNA replication ( DNA gyrase)
Nalidixic Acid
Quinolones
inhibitors of DNA-Dependent RNA Polymerase
RifamPIN
Inhibitors of Protein Synthesis ( 50s Inhibitors)
Erythromycin
Chloramphenicol
Clindamycin
30s Inhibitors
Tetracycline
Spectinomycin
Streptomycin
Gentamycin
Tobramycin
Amikamycin
Nmemonics : GATTASS
Inhibits the Cell membranes
Polymyxins
Mechanism of Action
Target: Cell wall synthesis;_________
all β-lactam drugs
Target: Protein synthesis; ______________
macrolides, chloramphenicol,tetracycline, aminoglycosides
Target: RNA polymerase;
rifampin
“an R for R”
Mechanism of Action
Affecting cellular components: DNA gyraseinhibitors: _________
Quinolones
DHF reductase inhibitor: _______-
Trimethoprim
” Reductase : Tagabawas TTTTTT”
PABA: ____________
Sulfonamides
“P.S. “
Inhibit reverse transcriptase enzyme: ____________
Zidovudine
**” **mahilig sa baliktaran : ZOUIE”
Cell wall permeability:______________
Amphotericin B; PolymyxinB
“cell wall permeaBility: B
Inhibitors of biosynthetic pathways:____________-
Bacitracin
” Bayosynthetic:Bacitracin”
BacteriostaticDrugs
Protein Synthesis Inhibitors (except___________ )
–Tetracyclines
–Macrolides
–Clindamycin
–Chloramphenicol
–Linezolid
–Sulphonamides
** aminoglycosides**)
Bactericidal
Beta-lactamantibiotics
Vancomycin
Aminoglycosides
Fluoroquinolones
“FAVBulous napapatay lahat”
When to Use Bactericidal Drugs
Impaired host defense
Infections with poor blood flow (endocarditis, endovascular infections)
Low WBC (<500
)Cancer patients
CSF penetration (meningitis)
___________: Drugs which affect both Gram-pos and Gram-negbacteria;
Broad Spectrum
tetracycline, imipenem, 3rdgeneration cephalosporins
_____________: Drugs which have activity against only gram-positive bacteria
i.e. antistaphylococcalpenicillinsand 1stgeneration cephalosporins
Narrow Spectrum
____________ shows the capacity of an antimicrobial drug to inhibit the growth of bacteria after removal of the drug from the culture
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
Post-Antibiotic Effect PAE
When is antimicrobial therapy warranted for a given patient? Is an antimicrobial agent indicated on the basis of clinical findings? Or is it prudent to wait until such clinical findings become apparent? Have appropriate clinical specimens been obtained to establish a microbiologic diagnosis? What are the likely etiologic agents for the patient’s illness?
-use of antimicrobial before the pathogen responsible for a particular illness or the susceptibility to a particular antimicrobial agent is known
Presumptive therapy
Based on experience with a particular clinical entity Usual justification
hope that early intervention will improve the outcome
Empiric Antimicrobial Therapy
Approach to Empiric Therapy
Formulate clinical diagnosis of microbial infection history, PE
Obtain specimen for lab examination
Formulate microbiologic diagnosis
Determine necessity for empiric therapy
Is there a significant risk of serious morbidity if therapy is withheld until a specific pathogen is detected by the clinical laboratory?
Institute treatment
Laboratory Investigation in Diagnosis of Infectious Agents
Identification of the pathogen Collection of infected material before beginning antimicrobial therapy
Minimal inhibitory concentration (MIC)is the lowest concentration of antimicrobial that prevents visible growth of microbes
- Stains—Gram or acid-fast (which is already done)
- Serology
- Culture and sensitivity
- Thin layer smears
___________-is the lowest concentration of antimicrobial that prevents visible growth of microbes
Minimal inhibitory concentration (MIC)
Choosing an Antimicrobial
Three Things to Consider
Host
Organism
Drug
Host
Organism
Drug
Choosing an Antimicrobial
Identity the infecting organism –It must be possible to make a probability assessment of the most likely culprit(s)
Likely antimicrobial susceptibility pattern of the invading organisms must be estimated PD
The presence or absence of host factors that can modify the choice of antimicrobial agents PK
–History of previous adverse reactions -must be specific as to nature of reaction
–Age of patient
Host Factors
Concomitant disease states or the use of immunosuppressive medications
Prior adverse drug effects
Impaired elimination or detoxification of the drug
Age of the patient
Pregnancy status
Epidemiologic exposure
Pharmacologic Factors
Kinetics of absorption, distribution, and elimination Ability of the drug to be delivered to the site of infection
Potential toxicity of an agent
Pharmacokinetic or pharmacodynamicinteractions with other drugs
Determines not only the choice of the agent but also its dose and the route by which it should be administered –Ability to achieve effective concentration at sites of interest: e.g., CSF –Local factors that may modify drug efficacy
Site of Infection
Blood-Brain Barrier Penetrability
Excellentwithorwithoutinflammation
Sulfonamides
Chloramphenicol
Trimethroprim
Metronidazole
Rifampicin
Isoniazid
Fluconazole
Flucytosine
FFIRM CST
Blood-Brain Barrier Penetrability
Goodonlywithinflammation
Penicillins Cephalosporins:cefuroxime(2ndgen);
3rdgenparenteral(exceptcefoperazone);
4thgen Imipenem+cilastatin Meropenem Aztreonam Ciprofloxacin
Blood-Brain Barrier Penetrability
that is good with inflammation exception in 3rd gen parenteral
cefoperazone
Minimalornotgoodevenwithinflammation
Aminoglycosides
Tetracyclines
Lincosamides
Macrolides
“MALT”
No passag eeven with inflammation
Polymixins
1st and 2ndgen cephalosporins
AmphotericinB
Polymixins
1st and 2ndgen cephalosporins
AmphotericinB
The only 2nd gen cephalosporin that can penetrate the BBB that is good with inflamation
CEFUROXIME
Local Factors
Pus –Aminoglycosides and polymixins bind to (and are inactivated by) pus.
Beta-lactamases produced by such organisms as Bacteroides fragiliscan cause local inactivation of beta-lactamantibiotics at the site of mixed infection.
pH –Aminoglycosideshave low activity at low pH Presence of foreign body
Pus –_____________ bind to (and are inactivated by) pus.
Aminoglycosidesand polymixins
Beta-lactamases produced by such organisms as _____________ can cause local inactivation of beta-lactamantibiotics at the site of mixed infection.
Bacteroides fragilis
pH –_________________ low activity at low pH
Aminoglycosideshave
Immune competence
______________ competence necessary to eradicate microorganisms
Immune system
___________________- -increased problem in treatment of infection
–Need to kill infecting organism rather than just inhibit growth
–Often necessitates high dose prolonged therapy -increasing risk of toxicity and unwanted effects
Immune suppression
Resistance in Some Antibiotics
Hydrolysis , mutant PBP
Β-lactams
Resistance in Some Antibiotics
Active efluxfrom the cell
Tetracycline
Resistance in Some Antibiotics
Inactivation by enzymes
Aminoglycosides
Resistance
Overproduction of target
Sulfonamides
Resistance in Some Antibiotics
Mutant DNA gyrase
Fluoroquinolones
Resistance in Some Antibiotics
lReduced uptake into cell
Chloramphenico
Resistance in Some Antibiotics
Reprogramingof D-ala-D-ala
Vancomycin
Resistance in Some Antibiotics
Ribosomal methylation
Quinupristin/ dalfopristin
Resistance in Some Antibiotics
RNA methylation, drug efflux
Macrolides
Erythromycin
Combination Therapy:
Uses
- Empirical therapy
- Polymicrobialinfections
- Synergism desired To prevent development of resistance
A good combintaion: 2 bactericidal e.g. cell wall inhibitor & aminoglycosides
is usually defined as a four-fold or greater DECREASE in the MIC or MBC 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
Synergism Synergism may result if one drug inhibits the inactivation of the other –
E.g. ____________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
clavulanate
More likely to occur when a bactericidal drug (e.g., penicillin, aminoglycoside) is combined with a primarily bacteriostatic drug (e.g. tetracycline)
Antagonism
_____________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
Bactericidal drugs
Combination: Disadvantages
- Antagonism of antibacterial effect
- Increased risk of toxicity
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
Assessment of therapeutic failure
a. Due to drug selection
b. Due to host factors
c. Due to resistance
What are the ideal characteristics of an antimicrobial ?
- Selective toxicity
- low toxicity to the host
3, cidal > static
- narrow spectrum
Amonth the Bacteriostatic drugs this is NOT PURELY but only RELATIVELY STATIC. In INCREASE DOSAGE can become BACTERICIDAL
CHLORAMPHENICOL
What are the common causes of pneumonia and CNS?
NBSH
- N. meningitidis
- B. fragilis
- S. pneumoniae
- H. influenzae
