Chemotherapy I/II Flashcards
Receptor-Effector concept
specific bullets to kill bacteria
salvarsan
Selective toxicity of chemotherapy
need greater toxicity to parasite than host
What are two potential problems associated with chemotherapy
hypersensitivity and organ directed
How does chemotherapy work
lowers the microorganism load so that the host defense system can get rid of the foreign organisms from the body
Three adverse effects of antimicrobial therapy
overextensions of pharmacologic actions
organ directed toxicity
hypersensitivity reactions
What six drugs lead to hepatotoxicity?
tetracyclines
isoniazid
erythromycin estolate
clindamycin
sulfonamides
amphotericin B
Which five drugs lead to renal toxicity?
cephalosporins
vancomycin
aminoglycosides
sulfonamides
amphotericin B
Which three drugs are associated with ototoxicity?
aminoglycosides
vancomycin
minocycline (vestibular only)
Which two drugs are associated with visual toxicity?
ethambutol
isoniazid
Which two drugs (plus one class of drugs) leads to hemopoietic toxicity?
many antiviral agents
chloramphenicol
sulfonamides
What are some drug allergy symptoms? (4)
anaphylactic shock
skin rashes
immune induced blood dyscrasias
immune hemolytic anemias
Which two drugs are associated with hemolytic anemias?
sulfonamides
nitrofurantoin
Which three drugs are associated with photosensitivity?
tetracyclines
fluroquinolones
sulfonamides
** high risk for secondary infections
With chemotherapeutic agent which six things need to be considered with host, pathogen factor, and chemotherapeutic agent?
- metabolism of host
- toxicity of chemotherapeutic agent
- disease caused by pathogen factor
- host’s defense system
- resistance of host
- therapeutic effect on pathogen factor
- pathogen’s resistance against chemotherapeutic agent
What are the five general mechanisms of action on microorganisms?
- inhibit synthesis of cell wall
- damage outer membrane
- modify nucleic acid or DNA synthesis
- modify protein synthesis (at ribosomes)
- modify energy metabolism within the cytoplasm (at folate cycle)
Chemotherapy selects for
drug resistant stains
What two types of drug resistance are there?
natural and acquired
Mechanism for resistance:
pathogen or cell fails to:
absorb drug
Mechanism for resistance:
pathogen or cell
inactivates drug
Mechanism for resistance:
pathogen or cell
pumps drug out (MDR, p-glycoprotein)
Mechanism for resistance:
drug target is ______ thus resistant to drug
modified
Mechanism for resistance:
increased production of
target molecules
Mechanism for resistance:
altered metabolic pathway
bypasses drug target
How does multiple drug resistance occur?
transmitted by plasmids
Antimicrobial resistance is acquired by:
a mutation and passed ______ by selection to daughter cells
vertically
Antimicrobial resistance is acquired by ______ ____ of resistance determinants from a donor cell, often of another bacterial species.
horizontal transfer
Three examples of horizontal transfer
transduction (bacteriophages)
transformation (incorporation of free DNA)
conjugation (transfer of genes through sex pilus)
Transduction uses a __________ to incorporate donor DNA into recipient bacterium
bacteriophage
In transduction, what type of DNA will receipient bacterium have?
bacteriophage DNA and bacteria’s DNA
How does transformation work?
Bacterial cell lysed –> new bacteria picks up a bacterial chromosome from lysed cell and that bacterial chromosome gets incorporated into bacterial cell’s DNA
How does conjugation work?
Direct cell-to-cell contact.
2 bacterial cells - 1 has a mobile blasma and pilus. Pilus from donor cell attaches to recipient cel
Relaxosome connects donor cell to the transferosome of recipient cell. Now, the recipient cell has been injected with mobile plasmid.
What does horizontal transfer result in?
multiple drug resistance
What type of bacteria is particularly susceptible to horizontal transfer?
gram (-)
6 causes of antibiotic resistance?
over-prescribing of antibiotics
patients not finishing tx
over-use of antiobiotics in livestock and fish farming
lack of new antibiotics being developed
lack of hygiene and poor sanitation
poor infection control in hospitals and clinics
Penicillin-resistant strains of ______ account for 50% or more of isolates in some European countries and the proportion of such strains is rising in US
pneumococci
Worldwide emergency of _____ and _____ that produce b-actamase is major therapeutic problem
Haemophilus and gonococci
Methicillin-resistant strains of _________ are widely distributed among hospitals and are increasingly isolated from community-acquired infections.
S. aureus (MRSA)
There are now strains of ______, _____, and _____ that are resistant to all known drugs.
enterococci, pseudomonas, enterbacters
Epidemics of multiple drug-resistant strains of ________ have been reported in US.
M. tuberculosis
Antimicrobial agents are frequently used ____ the _____ responsible for the illness or susceptibility to a particular antimicrobial agent is known. This is called empirical antimicrobial therapy.
before the pathogen
Empirical antimicrobial therapy is based on
experience
Choice of antimicrobial agents depends on
host factors - immunocompromised, liver damage, kidney damage, age, dosing requirements, costs, etc.
In empirical antimicrobial therapy, you must obtain a culture before/after prescribing antibiotic.
BEFORE
then formulate dx.
change therapy if needed.
Example of narrow spectrum antimicrobial drug
isoniazid
Example of extended-spectrum antimicrobial drug
ampicillin
Example of broad-spectrum antimicrobial drug
tetracycline
What kind of spectrum is going to have the most adverse side effects?
broad spectrum
What kind of spectrum will treat the most infections
broad-spectrum
Broad spectrum antibiotics disrupt
natural flora everywhere
Empirical therapy timeline: mixed infection suspected
infected pt –> take specimens for identification and sensitivity testing –> empirical therapy - coverage by antibiotics effective against Gram-positive, gram-negative, and anaerobes –> receive culture report with sensitivities
IF only a gram negative infection, patient’s tx needs to be adjusted to only tx gram-negative infections.
Same with gram positive.
If mixed - continue therapy as initiated
bacteriocidal
cell death
bacteriostatis
growth inhibition
stops growth which allows immune system to take care of infection
Zone of clearance is the zone where
bacteria cannot grow.
Can you tell if antibiotic is cidal or static using agar?
No. Clearing just tells you if organism is sensitive to antibiotic
increased zone of clearance means
increased sensitivity
when to use bacteriocidal?
bactericidal - no remarkable difference between bacteriostatic and bactericidal concentrations
when to use bacteriostatic?
inhibitory concentrations are much lower than bactericidal
When you remove a bacteriostatis agents, what happens if you do not have a robust immune system?
starts growing again. while bacteriostatic agent is present, growth is halted but never dies off, therefore when agent is removed and immune system has not cleared the bacteria, it will begin growing again
What happens with bacteriocidal agent is removed?
No regrowth.
If immunocompromised, what type of agent should we use?
bacteriocidal agent
It is important to reach and maintain ____ ____ ___ in order to prevent the development of resistance. Maintenance of constant blood levels is more important in what kind of agent?
adequate blood levels
bacteriostatic than bactericidal agent
Concentration dependent killing
rate and extent of killing dependent upon drug concentration (aminoglucosides and quinolones)
Time dependent killing
killing is not increased with increasing concentrations above MBC (beta-lactams, vancomycin) but is dependent on time of exposure to antibiotic
What dictates how long to use an antibiotic?
time dependent killing
Concentration dependent killing must reach
certain concentration of drug to be bactericidal
What type of agents inhibit synthesis?
bactericidal - cell wall and DNA
What type of agents inhibit protein and metabolism
bacteriostatis
MIC
minimum inhibitor concentration - smallest concentration to keep cells from growing
MBC
minimum bactericidal concentration - smallest concentration to kil cells
PAE
postantibiotic effect
What is PAE?
persistent suppression of bacterial growth after limited exposure to an antimicrobial agent
exact mechanism i unknown
Clinical importance of PAE
don’t have to have dose given as often if PAE exists
Synergism
when inhibitory or killing effects of two or more antimicrobials used together are significantly greater than expected from their effects when used individually
2 + 2 = 7
Synergism mechanism
Blockade of sequential steps in metabolic sequence
TMP - SMX
Synergism mechanism
Inhibition of enzymatic inactivation
beta-lactamase inhibitors
Synergism mechanism
Enhancement of
antimicrobial agent uptake
Synergism: penicillin and aminoglycans together
Independently the cells are inhibited only (static)
Penicillin destroys cell walls so aminoglycans can gain entry – cell death occurs (cidal)
Antagonism
inhibition of bactericidal activity by bacteriostatis agents
2 antibiotics don’t work well together
Antagonism: induction of enzymatic inactivation: some gram-negative bacilli contain
inducible beta lactamases
drug-drug interactions that nullify effects
