Fina: Ch 10: Antimicrobial Treatment Flashcards
Origins of Antimicrobial therapy
naturally occurring antimicrobials:
-metabolic products of bacteria and fungi
-microbes produce antibiotics (their weapons) to reduce competition for nutrients and space
derived from:
-bacteria & molds
first systemic attempt to find specific antimicrobials occurred in early 1990s
Antibiotic
substance produced by microorganisms that in small amounts inhibits another microorganism
microbes produce antibiotics (their weapons) to reduce competition for nutrients and space
History of Chemotherapy
1910: Paul Erhlich “father of chemo” discovered that Salvarsan could treat syphilis
1935: Sulfa drugs were discovered
1928-1940: Alexander Flemming discovered antimicrobial action from the mold Penicillium, however many years passed before penicillin was purified and produced
Qualities of the ideal antimicrobial
selective toxicity solubility in bodily fluids toxicity not easily altered by bacteria non-allergenic stability resistance by microorganisms not easily required long shelf life reasonable cost
Selective toxicity
drug kills the pathogen without damaging the host
Stability
maintenance of a constant, therapeutic concentration in blood and tissue fluids
The action of microbial drugs
- inhibition of cell wall synthesis
- disruption of cell membrane function
- inhibition of protein synthesis
- inhibition of nucleic acid synthesis
- action as antimetabolites
Inhibition of cell wall synthesis
the cell wall is a good, selective target b/c eukaryotes dont have peptidoglycan
penicllin and cephalosporins inhibit the peptide crosslinks that hold the carb units together (similar to taking a blow torch and cutting links in a chain link fence)
Penicillin: Inhibition of cell wall synthesis
produced by the mold Penicillium chrysogenum
-a diverse group (1st, 2nd, 3rd generations)
-natural: penicillin G and V
-semisynthetic: ampicillin and Augmentin
-structure - beta-lactam ring
the R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive
Injury to the plasma membrane
change in permeability of plasma membrane causes loss of important metabolites from cell
- interact with membrane phospholipids
- distorts the cell surface
- leakage of proteins and nitrogen bases
Inhibition of protein synthesis
exploit difference in ribosomes:
- drugs specifically bind to 70S and not 80S because of specific shape of ribosomes
- erythromycin, streptomycin, tetracycline, chloramphenical
- some toxicity since mitchondria have 70S ribosomes
Inhibition of nucleic acid synthesis
inhibition of DNA replication
inhibition of transcription of RNA
-modes of action include:
-Quinolones: inhibits DNA unwinding enzymes
-Rifampicin: inhibits bacterial RNA polymerase
Inhibition of folic acid synthesis
Sulfonamides (sulfa drug) and trimethoprim
-competitive inhibition preventing the metabolism of DNA, RNA and amino acid
Biolfilm Effects on antibiotic treatment
Biofilms - unaffected by the same antimicrobials that work against them when they are free living
-penetration of the biofilm
-different phenotype is expressed by biofilm bacteria, giving them different antibiotic sensitivity
Strategies for treating biofilm infections:
-interrupting quorum sensing signals
-adding DNase to antibiotics helps with penetration
-impregnating devices with antibiotics
Bioavailability effects on antibiotic treatment
the chemical structure of a drug AND the mode of entry of a drug influence:
- concentration of drug in blood
- time of drug in blood
Actions of antimicrobial drugs: eukaryotic pathogens
treatment of eukaryotic pathogens is more difficult because they are more similar to human cells
- need to target the few differences between cells
- target sterols in cell membrane in fungi
- target protein gates in invertebrate nervous system
Actions of antimicrobial drugs: viral pathogens
treatment of viral pathogens is more difficult because they find protection inside the human cell
- limited drugs available
- difficult to maintain selective toxicity
- effective drugs: target viral replication cycle
- entry
- nucleic acid synthesis
- assembly/release
Drug-Host interaction
be cautious of toxicity to organs
some drugs can cause allergic reactions (especially penicillin and sulfa drugs)
many times, drugs will suppress or alter the normal microflora (good to take extra sources of live cultures lto replenish flora - like lactobaccillus acidophilus found in yogurt and milk)
need effective drugs: be mindful to use the best drug for the job
Tests to guide chemotherapy
Disk-diffusion method (Kirby-Bauer technique)
same as testing disinfectants
Zone of inhibition surrounding the discs is measured and compared w/a standard for each drug
E test - uses a strip that contains a gradient of antimicrobial chemical
Indicates the concentration of antimicrobial needed to inhibit growth
The future of chemotherapeutic agents
many disease have become resistant to antibiotics
chemicals produced by plants and animals are providing new antimicrobial agents
Therapeutic index
the ratio of the dose of the drug that is toxic to humans as compared to its minimum effective (therapeutic) dose
the smaller the ratio, the greater the potential for drug reactions
the drug with the highest therapeutic index has the widest margin of safety
the MIC and the therapeutic index
in vitro activity of a drug is not always correlated with the in vivo effect
Failure of antimicrobial agents is due to:
the inability of the drug to diffuse into that body compartment (brain, joints, skin)
resistant microbes in the infection that didnt make it into the sample collected for testing
an infection caused by more than one pathogen (mixed) some of which are resistant to the drug
How drug resistance develops
resistance to penicllin developed in bacteria as early as 1940
microbes become newly resistant to a drug after one of the following occurs:
-spontaneous mutations in critical chromosomal genes
-acquisition of entire new genes or sets of genes via horizontal transfer from another species
Chromosomal drug resistance
usually results from spontaneous random mutation
can be the result of phenotypic, rather than a genotypic change - slowing or stopping of metabolism so that the microbe cant be harmed by the antibiotic
Resistance thru horizontal transfer
Resistance (R) factors - plasmids containing antibiotic resistance genes (some have 6-7 resistance genes)
can be transferred thru conjugation, transformation or transduction
plasmids encoded w/drug resistance are naturally present in microbes before they have been exposed to an antibiotic
transposons that have duplicated and inserted genes for drug resistance into plasmids
Superbug!
Antibiotic resistant strain propagation
antimicrobial exposure causes pressure to select resistant strains
without antibiotics, selective pressure decreases and antibiotic resistance genes may be lost
can have intermicrobial transfer of plasmids containing resistance genes
clinical implications in the development of drug resistant Steph aureus – how do we treat S. aureus infections when they become completely resistant to our last line antibiotic, Vancomycin?
Synthetic advances in antibiotics (penicillins)
original penicillin was narrow spectrum and susceptible to microbial counterattacks
molecule has been altered and improved upon over the years
later penicillins overcome the limitations of the original molecule
beta-lactamase breaks the beta-lactam ring and renders penicillin inactive
The future of chemotherapeutic agents
some drugs are actually a combo of 2 drugs
can start with one antibiotic then if it is being degraded, a second one can be released
Superinfection
a second infection that occurs due to treatment of a first bacterial infection
antibiotics are taken for the first infection that selects for the second bacterial species
Chemotherapeutic drug
any chemical used in the treatment, relief or propholaxis of a disease
Antimicrobials
any microbial drug, regardless of its origin
Antibiotics
substance produced by microorganisms that in small amounts inhibits another microorganism
Semisynthetic drugs
drugs that are chemically modified in the lab after being isolated from natural sources
Synthetic drugs
drugs produced entirely by chemical reactions
Narrow spectrum
target a specific group
Broad spectrum
effective against more than one group of bacteria
3 factors to know before beginning antimicrobial therapy
- the nature of the microorganisms causing the infection
- the degree of the microorganisms susceptibility to various drugs
- the overall medical condition of the patient
5 mechanisms of drug resistance
- drug inactivation
- decreased permeability
- activation of drug pumps
- change in drug binding site
- use of alternative metabolic pathways
How does natural selection increase the under of resistant bacteria in a population treated with antibiotics?
if population is exposed to a drug, sensitive individuals are inhibited or destroyed, the resistant forms survive and proliferate
offspring will have these resistant genes
Probiotic
preparations of live microorganisms that are fed to humans and animals to improve the intestinal biota
Prebiotic
nutrients that encourage the growth of beneficial microbes in the intestine
