Term
| Protein Synthesis Inhibitors - targets |
|
Definition
Target the bacterial ribosome.
Bacterial – 70S (50S/30S)
Mammalian – 80S (60S/40S)
High levels may interact with mammalian
ribosomes.
50S binders
Macrolides, Clindamycin, Chloramphenicol,
30S binders
Aminoglycosides, Tetracyclines |
|
|
Term
| Tetracyclines: uses, side effects, drug interactions |
|
Definition
Tetracycline, doxycycline, minocycline
Activity versus gram positive bacteria (not always
predictable), gram negative bacteria
Uses
E.g. chlamydia (STD) , acne, h. pylori, traveler's diarrhea
Side effects
GI upset, esophageal ulcers, photosensitivity
Hepatotoxicity – fatty infiltration of liver (high dose)
Effects on bones and teeth
Bind to calcium in developing bones and teeth – yellow or
brown discoloration – do not use in children < 8 years
Tetracyclines
Chelate with calcium, Fe supplements,
Magnesium laxatives, most antacids, oral
contraceptives |
|
|
Term
| Macrolides - Erythromycin: uses, forms, elimination, side effects. |
|
Definition
Antibacterial coverage similar to penicillin
Often used for those with penicillin allergy
Four forms
Base (unstable in stomach acid- is inactivated)
3 derivatives of the base
estolate, stearate, ethylsuccinate
these 3 need to be converted to the base
Different forms: dictates with/without food.
Without food – base and stearate
With or without – ethylsuccinate, estolate
IV formulations available
Kinetics
In general, poor absorption
Elimination
Hepatic
Inhibits CYP450
drug interactions!!!********
Side effects
Gastrointestinal
Others
-Is most commonly used for beta lactam allergies |
|
|
Term
| Other macrolides - Azithromycin, Clarithromycin |
|
Definition
Clarithromycin
CYP 450 drug interactions***
Azithromycin
Long t1/2
Loading dose 500 mg day 1, then 250 mg once daily
“Less CYP450 interactions”
Look up if unsure – these things change as new data comes out. |
|
|
Term
|
Definition
Anaerobic activity
Gram pos and neg anaerobes
Gram pos aerobes (NOT gram negative aerobes)
Clostridium difficile
One of the more notorious drugs that causes
c. difficile diarrhea.
C. difficile diarrhea – anaerobic gram positive rod
**** can be fatal
Treat by discontinuing drug, starting metronidazole as first
line and based on response can consider changing to
vancomycin if appropriate |
|
|
Term
| Aminoglycosides - uses, synergism, method of action. |
|
Definition
Binds the 30S subunit.
Only active against aerobes because
an oxygen dependent system is
required to transport the molecules
into the cell.
Synergism with cell wall inhibitors is
seen because they increase the
permeability of the cell. |
|
|
Term
| Aminoglycosides (gentamicin, tobramycin, amikacin)- spectrum, bacteriocidal or bacteriostatic? |
|
Definition
Bactericidal inhibitors of protein synthesis
Spectrum (often used in combination)
Aerobic gram negative rods & enteric
pathogens
Enterobacteriaceae (E.coli, Klebsiella pneumoniae, Serratia
marcescens, Proteus mirabilis) and Pseudomonas aeruginosa)
Inactive against most gram positives
Not effective versus anaerobes as AG
transport across the bacterial cell is O2
dependent |
|
|
Term
| Aminoglycosides - areas of poor penetration vs areas of excellent penetration, absorbtion/elimination |
|
Definition
Poor penetration
tissue
CSF
20% in bronchial secretions
abscess (additionally needs oxygen to
get inside the bacteria)
Excellent penetration
urine 25 -100x serum level
Absorption: IV only - not absorbed via GI
Elimination
Primarily by the kidneys
T1/2 : e.g. 2-3 hrs to 24-48 hrs with renal
impairment
Dose adjustment will be required
Therapeutic drug monitoring is performed!
Levels pre and post – pre most useful |
|
|
Term
| Aminoglycosides: Adverse effects, Drug interactions |
|
Definition
Adverse effects
Ototoxicity **
Loss of hearing (cochlear – high pitched), vestibular,
tinnitus (tinnitus=ringing of the ear, and is the first sign)
Nephrotoxicity **
More likely to occur when
therapy is continued for > 5 days
doses are higher
in elderly
in those with renal impairment
Increase in SCr, increase in trough concentration: Troughs is the concentration of the drug staying in the body which leads to the ototoxicity, needs to be monitored).
Uptake by tubular cells – acute tubular necrosis
Drug interactions
Penicillins
Ototoxins
Nephrotoxins or drugs that alter renal blood flow
Serum Drug monitoring
Occurs in many institutions
Once daily versus 3 times daily dosing affects
monitoring |
|
|
Term
| Sulfonamides and Trimethoprim: method of action, synergism |
|
Definition
Structural analog of para-aminobenzoic acid (PABA)
competitive inhibitors of reactions with PABA
Suppress growth by inhibiting synthesis of folic acid
Required for synthesis of RNA, DNA, and proteins
Interferes where PABA is combined with pteridine
to form dihydropteroic acid
Mammalian cells can take folate from the diet whereas
bacterial cells have to make it.
Both drugs used
together kill more
bacteria
Bacteria = e.coli |
|
|
Term
|
Definition
Biologically active form of folic acid = THFA
derived by the 2-step reduction of folate
involving dihydrofolate reductase.
THFA plays a key role in the transfer of 1-
carbon units (e.g. methyl) to the essential
substrates involved in the synthesis of DNA,
RNA, and proteins.
More specifically, THFA is involved with the
enzymatic reactions necessary to synthesis of
purine, thymidine, and amino acid.
Humans do not generate folate endogenously
because they cannot synthesize PABA, nor can
they conjugate the first glutamate. |
|
|
Term
| Trimethoprim & Sulfonamides (separately & specifically) what do they decrease? |
|
Definition
Folate analogue
Inhibits Dihydrofolate Reductase
(DHFR)
Suppresses tetrahydrofolic acid
production @ a different stage vs
sulfonamides (further down in the process).
Ultimately, suppresses synthesis of DNA, RNA and
proteins
Sulfonamides: They inhibit the Dihydropteroate sunthetase, which will decrease Dihydropteoic acid (higher up in the metabolic pathway). |
|
|
Term
| Sulfonamides and Trimethoprim: resistance and spectrum of activity |
|
Definition
Resistance
Bacteria can increase production of PABA
Bacteria can synthesize more dihydrofolate reductase
Spectrum of activity when combined
Gram positive cocci
Gram positive rods (listeria)
Gram negative rods
Nocardia
Protozoa – toxoplasmosis: (parasitic infection commonly seen in AIDS or immunocompromised patients).
Chlamydiae |
|
|
Term
| Sulfonamides and Trimethoprim: adverse effects |
|
Definition
ulfonamide
Hypersensitivity
Sulfonamide structure
Kernicterus - Newborns
Bilirubin deposited in brain
Bili – PN bound, doesn’t enter CNS
Sulfonamides- displace bili from
binding sites - can enter the CNS
Not supposed to use - 3
rd
trimester,
near term, new borns, breastfed
infants
Crystalluria
Less of a concern with the more
soluble newer agents
TMP
GI, rash
TMP - specific to bacterial
DHFR more than human
High doses, the effect on
mammalian cells:
hematologic
Megalobastic anemia (anemia with larger then normal RBC's),
thrombocytopenia (deficiency in platelets) and
neutropenia (deficiency in neutrophils) – in individuals
with a folic acid deficiency |
|
|
Term
| Sulfamethoxazole (SMZ) and TMP: other names, how supplied |
|
Definition
Other names: Bactrim, Septra, cotrimoxazole
Supplied
In a ratio of TMP:SMZ = 1:5
Single strength tabs = 80 mg TMP, 400 mg SMZ
Double strength tabs = 160 mg TMP, 800 mg SMZ
IV available – for some infections, dosed on the
trimethoprim portion |
|
|
Term
| Fluoroquinolones (the floxacins, quinolones): method of action, spectrum, elimination and adverse effects. |
|
Definition
Inhibit bacterial DNA gyrase & topoisomerase III– bactericidal
Enzyme that converts closed circular DNA into a
supercoiled configuration
Without supercoiling – replication does not occur
Spectrum – broad
Aerobic gram negative bacteria
Some gram positive bacteria
Anaerobic activity is poor
Majority are renally eliminated and therefore
require dose adjustment
Adverse effects
GI (N/V/D)
CNS effects – dizziness, headache, confusion
Rarely – tendon rupture (not rec in those < 18 years or
in preg women or those breastfeeding)
Hyper and hypoglycemia reactions - gatifloxacin |
|
|
Term
|
Definition
Drug interactions
Cationic compounds
Aluminum, magnesium, calcium containing
antacids, milk and dairy products, sucralfate
These are contained in antacids
Warfarin: prolonged
Other floxacins
Levofloxacin – better Fvalue (bioavailability) (~99%)
Gatifloxacin – pulled from market
Moxifloxacin |
|
|
Term
|
Definition
Linked to resistance issues with many other pathogens.
MRSA
Cdiff
Pseudomonas
E Coli |
|
|
Term
|
Definition
• Empiric therapy (only under duress)
• Identify the Infecting Organism and what
drugs are susceptible
– Culture and sensitivity |
|
|
Term
| Classification of Antimicrobial drugs |
|
Definition
Classification by susceptible organism (spectrum of activity)
• Classification by mechanism of action |
|
|
Term
| What can antimicrobials target? |
|
Definition
• Cell wall synthesis
• Cell membrane permeability
• Protein synthesis
• Synthesis of nucleic acids
• Metabolism
• Viral enzymes |
|
|
Term
| Classification of Penicillins |
|
Definition
Affinity for PBPs
• Resistance to penicillinase
• Ability to penetrate Gr –ve cell envelop
• Affect of stomach acid on bioavailability
• Pharmacokinetic properties |
|
|
Term
| How do penicillins weaken the cell wall |
|
Definition
Molecular targets of penicillins
– collectively called penicillin binding proteins
(PBP), binidng to this inhibits Transpeptidases (cross linking of the bacterial cell wall).
– binding needed for antimicrobial effect
– Only present during growth and division
• > 8 PBPs identified … these are just a few:
» Transpeptidases (penicillins inhibit these)
»Autolysins (penicillines activate autolysins): cause break down of the cell wall to permit growth and division.
» Other bacterial enzymes
Mechanism - weaken cell wall
OVERSIMPLIFICATION and not the only
mechanism as weakening of cell wall does not
always cause death
–Bacteria take in H2O
–Cells rupture
–Bactericidal |
|
|
Term
|
Definition
AUTOLYSINS cleave cell wall bonds
– Break down segments of the cell wall to
permit growth and division
• Exposure to penicillins activates autolytic
enzymes that degrade the bacteria.
» If these autolytic enzymes are not activated, e.g., in
certain strains of Staphylococcus aureus, the bacteria
are not killed and the strain is said to be tolerant.
• By activating these, penicillins promote
active destruction of the cell membrane |
|
|
Term
| Why penicillins don't directly hurt the host |
|
Definition
Selective toxicity
• Mammalian cells lack walls
• Target enzymes that affect wall integrity |
|
|
Term
| Mechanisms of resistance to Penicillin |
|
Definition
Three mechanisms account for clinically
significant bacterial resistance to penicillins, and
other β-lactam antibiotics as well:
(1) destruction of antibiotic by β-lactamase
(2) failure of antibiotic to penetrate the outer membrane
of gram-negative bacteria to reach PBP targets,
(3) low-affinity binding of antibiotic to target PBPs |
|
|
Term
| Beta lactamase inhibitors |
|
Definition
Have no antimicrobial activity when used
alone
• Combined with antimicrobials
– Clavulanic acid (combined with amoxicillin)
– Tazobactam (piperacillin)
– Sulbactam (ampicillin) |
|
|
Term
|
Definition
Methicillin Resistant Staph Aureus
• Resistant to penicillin/ beta lactam AB
• MOA: bacteria, through genetic mutation,
developed PBPs with a low affinity for beta
lactam antibiotics |
|
|
Term
|
Definition
Natural penicillins, penicillinase sensitive
– Penicillin G and Penicillin V
• Narrow-spectrum penicillins, penicillinase resistant
(antistaphylococcal penicillins)
– cloxacillin
• Aminopenicillins, penicillinase sensitive
– ampicillin, amoxicillin
• Extended-spectrum, penicillinase sensitive
• Beta lactamase inhibitor combinations
– amoxicillin-clavulanic acid, ticarcillin/Clavulanic acid
piperacillin/Tazobactam
Carboxy penicillins
Ticarcillin
Ureidopenicillins
Piperacillin |
|
|
Term
|
Definition
Most common allergy (0.4-7%)
• Immediate, accelerated or late
– Hives
– anaphalaxis
• Cross sensitivity
– Other penicillins
– Cephalosporins (1%) |
|
|
Term
| Cephalosproins- Bacteriocidal or Bacteriostatic? Structure? |
|
Definition
Same mechanism as penicillins
• Bactericidal
• Have a beta lactam ring and therefore can
be susceptible to beta lactamases |
|
|
Term
| Cephalosprins: classifications, general trends. |
|
Definition
Classified as 1
st
, 2
nd
, 3
rd
, 4
th
generation
cephalosporins
• In general from 1
st
to 4
th
generation:
– activity vs gram negative bacteria & anaerobes
– resistance to destruction by beta lactamases
– penetration into CSF |
|
|
Term
| Cephalosprins: Adverse effects |
|
Definition
• Adverse effects
– Hypersensitivity
• Cross reactivity with penicillins
• Others?
– Specific adverse effects to each agent… |
|
|
Term
| Vancomycin: Mechanism of action, spectrum |
|
Definition
Mechanism of Action
• Disrupts cell wall synthesis promoting lysis and death
• Spectrum
– Bactericidal vs most gram +ve bacteria
» except enterococcus - needs to be combined with an aminoglycoside for
synergy
– Reserved for severe infections, those resistant to clox or
penicillins (MSRA –drug of choice)
– 2
nd
line for c. diff diarrhea |
|
|
Term
| Vancomycin: Special notes |
|
Definition
Huge molecule - poor penetration into certain tissues
(e.g. CSF)
» Not dialyzable (unless high flux membrane)
• Given IV as not absorbed orally
» Oral – infections of intestine such as c. diff where it can act “locally”
• For prolonged treatment courses
– e.g. staph osteomyelitis – home IV programs
• Therapeutic drug monitoring
– Troughs (and peaks) |
|
|
Term
| Vancomycin: Adverse effects |
|
Definition
Ototoxicity:
» often irreversible, occurs RARELY, associated drug levels of > 60-80 micrograms/L
» caution with concurrent ototoxins (e.g. aminoglycosides, high dose IV
furosemide)
• Thrombophlebitis
• Hypersensitivity reactions (rare)
– Drug fever, allergic rash
• Infusion related effects (more common)
– “Red man syndrome” – related to histamine release
» Slow infusion time (usually given over an hour so prolong this)
» Pre-medicate – diphenhydramine (Benadryl)
• Nephrotoxicity
» Rare but caution with other drugs that cause nephrotoxicity |
|
|
Term
| Vancomycin: Elimination and levels are monitored |
|
Definition
• Renally eliminated
– Creatinine clearance (monitor renal function)
• Levels especially important in those with renal
dysfunction
– Peaks and troughs (Troughs are most useful)
– **RECORD TIMES: infusion start and stop, when the pre
and post level were drawn.***
• Depending on institution:
– pharmacokinetic monitoring (often by pharmacists)
» Protocols (tell when to draw levels, dosage adj. based on levels)
» Trough is almost always 30 minutes prior to next dose
» Peak 1 hour after a 1 hour infusion |
|
|
Term
| Mechanisms of Microbial Drug Resistance |
|
Definition
• Organisms can
• produce drug metabolizing enzymes
•E.g. penicillinases
• Reduce uptake of drugs/increase active export (efflux pump)
• Reduce antibiotic binding and action
• Synthesize compounds antagonistic to drug actions |
|
|
Term
| Steps to prevent AB resistance |
|
Definition
• Prevent Infection
• Vaccinate
• Get catheters out
• Diagnose and treat infection effectively
• Target pathogens
• Expert knowledge
• Use AB wisely
• Practice antimicrobial control
• Use local knowledge
• Tx infection – not contamination or colonization
• Prevent transmission
• Wash hands |
|
|
Term
| Influences on antimicrobial use (ADME) |
|
Definition
• Allergies
• Drug interactions
• ADME considerations (pharmcokinetic properties)
• A – e.g. with or without food, enteral feeds, chelation, gastric pH, GI
motility
• D - e.g. when drawing levels, tissue penetration
• Generally good to urine, kidney and other soft tissues
• Generally poor to eye (use intraocular), prostate , abscess,
endocarditis vegetation
• CNS penetration influenced by inflammation
• M – e.g. interactions
• E – e.g. organ dysfunction
• Side effects and adverse reactions |
|
|
Term
Pharmacodynamics
• Bacteriostatic v. Bactericidal |
|
Definition
Static
• Macrolides
• Tetracyclines
• Clindamycin
• Sulfonamides
• Cidal (important in neutropenia, meningitis, endocarditis)
• β-lactams
• Aminoglycosides
• Fluoroquinolones
• Vancomycin
• Metronidazole
• Exceptions – there’s always exceptions
• Sulfamethoxazole alone is static, BUT with Trimethoprim is cidal
• Nothing is cidal against enterococcus (double cover) |
|
|
Term
Concentration- v. Time-Dependent
killing |
|
Definition
Concentration-dependent:
• rate and extent of bacterial killing depend on extent
that peak drug concentration above MIC
• Aminoglycosides
• Fluoroquinolones
• Metronidazole
• Time-dependent: extent of kill depends on length
of time that active drug concentration is above the
MIC
• β-lactams
• Macrolides
Supports infrequent, high dosing
(ex. Once-daily AG dosing)
Supports frequent or continuous
dosing (ex. cloxacillin q4h) |
|
|
Term
| General issues with antimicrobial use |
|
Definition
• How is it administered
• Timing and interval
• IV
• Infusion related reactions
• Thrombophlebitis
• Compatibilities |
|
|
Term
| Combinations of antibiotics |
|
Definition
Additive or synergistic
• Trimethoprim added to sulfamethoxazole
• Penicillins and aminoglycosides |
|
|
