1.4 Flashcards
Antibiotics:
a class of chemotherapeutic agents
Chemotherapeutic agents are
chemical
compounds used to treat disease
Antimicrobials destroy
pathogenic microbes or
inhibit their growth within host
Antibiotics destroy or inhibit
bacteria
Most antibiotics are — products or their
derivatives
microbial
selective toxicity
– ability of drug to kill or inhibit pathogen while
damaging host as little as possible
therapeutic dose
– drug level required for clinical treatment
toxic dose
– drug level at which drug becomes too toxic for patient
i.e., produces side effects
therapeutic index
– ratio of toxic dose to therapeutic dose
Bacteriocidal antibiotics
– kill bacteria
Bacteriostatic antibiotics
– inhibit growth of bacteria
Broad-spectrum antibiotics
– attack many different bacteria (Gram + and Gram -)
Narrow-spectrum antibiotics
– attack only a few different bacteria
Determining the Level of
Antimicrobial Activity
• effectiveness expressed in two ways
– minimal inhibitory concentration (MIC)
– minimal bacteriocidal concentration (MBC)
– minimal inhibitory concentration (MIC)
• lowest concentration of drug that inhibits growth of pathogen
– minimal bacteriocidal concentration (MBC)
• lowest concentration of drug that kills pathogen
Dilution Susceptibility Tests
• involves inoculating media containing different
concentrations of drug
– broth or agar with lowest concentration showing no
growth is MIC
– if broth used, tubes showing no growth can be
subcultured into drug-free medium
• broth from which microbe cannot be recovered is MBC
Disk Diffusion Tests
• disks impregnated with specific drugs are
placed on agar plates inoculated with test
microbe
• drug diffuses from disk into agar,
establishing concentration gradient
• observe clear zones (no growth) around
disks
Kirby-Bauer method
• standardized method for carrying out disk
diffusion test
• sensitivity and resistance determined using tables
that relate zone diameter to degree of microbial
resistance
• table values plotted and used to determine if
concentration of drug reached in body will be
effective
Kirby-Bauer method (steps)
Inoculate plate evenly with bacteria whose susceptibility is being studied Place discs containing antibiotics or control solutions onto the plates Incubate a defined amount of time at a defined temperature Measure zone of inhibition
Measurement of Drug
Concentrations in the Blood
• concentration of drug at infection site must
be > — to be effective
MIC
microbiological, chemical, immunological,
enzymatic, or chromatographic assays can
be used to determine
concentration of
drug in blood
Factors Influencing the
Effectiveness of Antimicrobial
Drugs (3)
• ability of drug to reach site of infection
• ability of drug to reach concentrations in body
that exceed MIC of pathogen
• susceptibility of pathogen to drug
Ability of drug to reach site of
infection
• depends in part on mode of administration (3)
– oral
– topical
– parenteral routes
– oral
• some drugs destroyed by stomach acid
– parenteral routes
• nonoral routes of administration
drug can be excluded by (2)
blood clots or necrotic
tissue
Factors influencing ability of drug
to reach concentrations
exceeding MIC (4)
- amount administered
- route of administration
- speed of uptake
- rate of clearance (elimination) from body
Mechanism of Action of
Antimicrobial Agents
• can impact pathogen by targeting some
function necessary for its (2)
reproduction or
survival
Ideally, targeted function is very specific to
pathogen =
high therapeutic index.
– Not always possible
b-lactams (4)
penicillins
cephalosporins
carbapenems & monobactams
(+ b-lactamase inhibitors)
Glycopeptides (2)
vancomycin & teichoplanin
Polypeptides (2)
bacitracin & polymixins
Others (3)
cycloserine
isoniazid & ethionamide
ethambutol
- Disruption of bacterial cell wall (2)
– Peptidoglycan is unique to bacteria
– Most pathogens contain peptidoglycan
peptidoglycan repeat unit forms in
cytoplasm
• involves use of
uridine
diphosphate (UDP) as a carrier
repeat unit then transported across
membrane by
bactoprenol (“lipid”)
repeat unit attached to growing
peptidoglycan chain
cross-links formed by
transpeptidation
Transpeptidation creates crosslinks in
peptidoglycan
Transpeptidation is the exchange of one
peptide bond for another
b-lactam antibiotics inhibit —
transpeptidation
penicillin G
higher activity against most gram-positive bacteria, low agaist gram negative; destroyed by acid and penicillinase
penicillin V
more acid restraint than penicillin G
ampicillin
active against gram-positive and gram-negative bacteria; acid stable
carbenicillin
active against gram negative bacteria like pseudomonas and proteus; acid stable, not well absorbed by small inteastine
methicillin
penicillinase-resistant, but less active than penicillin G, acid liable
ticarcillin
similar to carbenicillin but more active against pseudomonas
first generation cephalosporin
cephalothin
second generation cephalosporin
cefoxitin
third generation cephalosporin
cefoperazone
ceftriaxone
Carbapenems and monobactams
Two newer classes of b-lactam antibiotics
b-lactamase inhibitors
Not antibiotics, but help b-lactam antibiotics by
preventing their degradation by b-lactamases
b-lactamases are enzymes produced by some bacteria that are
resistant to
b-lactam antibiotics
Examples of b-lactamase inhibitors: (3)
clavulanic acid, sulbactam, and tazobactam
Use in combination with b-lactam antibiotic
— was 1st combination
= amoxicillin + clavulanic acid
Augmentin
= amoxicillin + clavulanic acid
Vancomycin binds terminal D-Ala-D-Ala and sterically inhibits
addition of peptidoglycan subunits to the cell wall.
Vancomycin binding to existing peptidoglycan chains inhibits
the
transpeptidation reaction that crosslinks the chains.
vancomycin has been important for treatment of antibiotic resistant (2)
staphylococcal and
enterococcal infections
Vancomycin and teichoplanin are —
glycopeptides
bacitracins
Prevent recycling of lipid carrier
polymixins
Binds phospholipids and disrupts outer
and inner membranes of gram negative
bacteria (topical because of more
general mode of action = toxic)
Cycloserine
Second line treatment for
Mycobacterium tuberculosis
Cycloserine is a cyclic
analog of
alanine - Also crosses blood brain barrier and is an NMDA receptor agonist (with uses and side effects)
Isoniazid & Ethionamide
Inhibits Mycobacteria by
affecting synthesis of
mycolic
acid (abundant wax in the cell
wall)
Ethambutol
Inhibits Mycobacteria by
affecting attachment of
mycolic acid in the cell
wall
Oxazolidinones
linezolid
Binds 23S rRNA and
prevents formation of
70S initiation complex
Inhibition of protein synthesis
Tetracyclines
Bind 16S rRNA of 30S
subunit and prevent
binding of aa-tRNA to
A site
Inhibition of protein synthesis
Aminoglycosides
streptomycin
amikacin
gentamycin
tobramycin
Bind to 30S subunit and
distort A site, causing
translation misreading, which
inhibits protein synthesis
Inhibition of protein synthesis
Chloramphenicol
Lincosamides
Bind to 50S subunit and inhibit
peptidyltransferase activity
. Inhibition of protein synthesis
Macrolides
Erythromycin, azithromycin, clarithromycin
• Bind 23S rRNA in the 50S subunit
and block the translocation reaction
• also prevent formation of the 50S
subunit
Inhibition of nucleic acid synthesis
Quinolones
ciprofloxacin and other -floxacins
Interfere with type II topoisomerases
(DNA gyrase or topoisomerase IV) and
stabilize DNA double strand breaks
Inhibition of nucleic acid synthesis
Rifampin & Rifabutin
Rifampin
Bind to RNA polymerase and prevent
the initiation of transcription
Inhibition of nucleic acid synthesis
Metronidazole
• a prodrug with no inherent antimicrobial activity
• produces DNA-damaging radicals under anaerobic conditions
via enzymes functioning in anaerobes and microaerophiles
Antimetabolites (4)
Sulfonamides, trimethoprim, dapsone, and p-aminosalicylic
acid
Drug Resistance
Big problem for clinical treatment of —
Resistance can often be transmitted to other —
infections
bacteria
New mutations of bacterial genes that
encode the targets of —
antibiotics
Pre-existing resistance genes that are
transmitted from
one bacterium to another
Plasmids
- some can promote their own
transfer by
conjugation
Transducing bacteriophage
- can package non-phage DNA
= transfer by transduction
Bacterial chromosomal genes (2)
- mutations
- transfer by transformation
Transposons
- hop into other genetic elements
Integrons (2)
- segments of DNA containing
complete sets of genes - found on plasmids, transposons,
and bacterial chromosomes
Superinfection
development and spread of drug-resistant pathogens
caused by drug treatment, which destroys drug sensitive strains
Killing of normal flora removes
the
inhibitory effect of the normal flora (which produce antibacterial substances & compete for essential nutrients). This allows for uninhibited growth of potentially pathogenic bacteria & fungi
Common organisms in Superinfections include: (4)
Clostridium difficile (spore-forming agent of pseudomembranous colitis)
MDR (multi-drug-resistant) gram-negative rods
MRSA (methicillin-resistant Staphylococcus aureus)
Candida or other fungi
Preventing emergence of drug
resistance (3)
- give drug in high concentrations
- give two or more drugs at same time
- use drugs only when necessary
possible future solutions (2)
– continued development of new drugs
– use of bacteriophages to treat bacterial
disease
