W1P2 Flashcards
Antibiotics
Derivative produced by the metabolism of microorganisms that possesses antibacterial activity at low concentrations and is not toxic to the host. Also includes molecules obtained by semi-synthesis
Antiseptics
Compounds used for the external treatment of wounds (19th century)
- Dakin’s solution (1915)
- Isopropyl alcohol
- Chlorhexidine
What are the two factors involving in choosing an antibiotic
Route of administration
Oral (po), IV, IM, topical
Dosage
May depend on weight, age (sexual maturation), body surface area
Route and dosage DEPENDS on WHAT you are trying to treat and WHERE in the body.
- Pharmacodynamics and pharmacokinetics
POPULATION Age (Neonate, child, elderly) - Restrictions on use in various ages Pregnancy - Restrictions (harm to fetus) Renal or liver dysfunction - Routes of elimination
Site of Infection
Empirical Treatment
Need to know which bacteria are usually involved in a particular clinical syndrome
- and you use an AB that you GUESS will work best
Need to know the prevalence of resistance to a particular antibiotic locally – hospital-level or community-level… changes over time
What are the common potential pathogens in our Nose and Sinus
S.pneumoniae, GAS, S.aureus, H.influenzae
What are the common potential pathogens in our Throat/Pharynx
GAS
What are the common potential pathogens in our Lungs/Bronchi
S.pneumoniae, H.influenzae, S.aureus,
Klebsiella spp/other Enterobacteriaceae
What are the common potential pathogens in our Middle Ear
S.pneumoniae
What are the common potential pathogens in our Intestines
Salmonella, Shigella, E.coli O157:H7
What are the common potential pathogens in our Urinary Tract
Enterobacteriaceae
Enterococcus
What are the common potential pathogens in our CNS
N.meningitidis, H.influenzae, S.pneumoniae, Listeria
What are the common potential pathogens in our Eye
Haemophilus, Moraxella, N.gonorrhoeae, S.aureus, S.pneumoniae
What are the common potential pathogens in our Blood
anything. anYtHiNg
What are the common potential pathogens in our Wouds
S.aureus, GAS
What are the common potential pathogens in our Bone and Joints
S.aureus, GAS, Kingella kingae
Pharmacokinetics
what the body does to the drug
Pharmacodynamics
what the drug does to the body (therapeutic/toxic effects)
What are the Important Drug Parameters
Absorption Distribution Half-life Protein binding Elimination
***Which Antibiotics have such good bioavailability that po= IV availability?
- What is the rate limiting step here?***
Clindamycin po = IV Fluoroquinolones po = IV Septra po = IV Tetracyclines po = IV Metronidazole po = IV Linezolid po = IV
rate-limiting step:
- GI tolerance
- GI absorption (e.g. patient is nauseated etc)
Pharmacokinetics: what are the two ways antibiotics work?
a. Time- dependent AB
- conc INdependent: really doesn’t matter HOW much you give***
b. Concentration- dependent AB
Examples of Time- dependent antibiotics
Beta Lactams:
- Penicillins
- Cephalosporins
- Carbapenems
Just remember THESE^
Other: Vancomycin Macrolides Clindamycin Tetracyclines Linezolid Quinipristin/dalfopristin
Concentration Dependent AB
Aminoglycosides
Fluoroquinolones
Metronidazole
Pharmacokinetics: Time-Dependent Activity
Activity of the antibiotic is dependent on the AMOUNT of time that is spent above the minimum inhibitory concentration (MIC) of the organism for that specific antibiotic at that specific place/tissue/organ.
Classic type of antibiotic class that uses this: Beta-lactams
***Pharmacokinetics
Concentration Dependent activity***
Activity of the antibiotic is dependent on the CONCENTRATION above the minimum inhibitory concentration (MIC) of the organism for that specific antibiotic at that specific place/tissue/organ.
Classic type of antibiotic class that uses this: aminoglycosides
What determines if the antimircrobial activity is Bacteriostatic vs Bactericidal?
Bacteriostatic vs. bactericidal: Depends on activity of antimicrobial Inhibition of cell wall synthesis or protein synthesis = cidal Changes in bacterial physiology = static Depends on drug concentration
What are the antimicrobial Classes
B- lactam AB [penicillins and their derivatives] Cephalosporins Carbapenems and Monobactams Glycopeptides Macrolides and Ketolides Aminoglycosides Fluoroquinolones Sulfonamides Tetracyclines and Tigecycline Lincosamides Metronidazole Rifamycins
Beta-Lactam Group
Penicillins
Cephalosporins
Carbepenems
Monobactam
- Penicillins and their Derivatives are..
- a part of which group?
- Mechanism of action
- Resistance
- what is their pharmacokinetics
Beta-Lactam group: All have a β-lactam ring in their molecular structure
Mechanism of action:
Inhibition of cell wall synthesis by binding to penicillin-binding proteins
Resistance:
Inactivation of antibiotic (penicillinase, or β-lactamase) (e.g. most MSSA)
Mutated penicillin-binding protein (e.g.. MRSA)
Decrease in penetration of antibiotics
SHEILD against resistance: β-lactamase inhibitors are added to penicillins to “mop-up” β-lactamase enzymes (irreversibly bind to them)
TIME-DEPENDENT KILLING
Penicillins
- What does it target
- resistance
While penicillin did/does well against gram-positive organisms including gram-positive anaerobes
Resistance:
S. aureus started to become resistant to it
- specifically those that developed Penicillinase (β-lactamase specific for penicillin)
Gram negative enterobacteriaceae started to become resistant
- β-lactamases
Emergence of new (and resistant) pathogens such as Pseudomonas spp became apparent
Obviously things needed to change… elevated AB were created to address resistant strains
What are new penicillins created for specific bacterial species?
S. aureus targeting designs
- Cloxacillin
- (Methicillin)
- Due to increased S. aureus activity = loss of anaerobic activity
- Aminopenicillines gives Expanded gram negative coverage (i.e. against E. coli)
- Ampicillin IV
- Amoxicillin (Amoxil) po
Expanded gram negative coverage (esp. Pseudomonas aeruginosa)
- Ticarcillin
- Piperacillin
Penicillins and B-lactamase inhibitors
This combination makes them resistant to β-lactamases
- side effect: Diarrhea, due to β-lactamase inhibitor
BROAD SPECTRUM
All combinations are active against:
- S. aureus
- Most gram-positive organisms including
- Enterococcus and Listeria spp
- Most gram-negative respiratory pathogens (Haemophilus and Moraxella spp)
- Most gram-negative enteric bacteria
- Most anaerobes (gram-positive and gram-negative)
Timentin and Pip/tazo
- Active against ALL above BUT ALSO Pseudomonas spp
General activity of Cephalosporins on gram positive vs gram negative
Cephalosporins effectiveness for gram +
Great in 1st gen, gets worse then 5th gen is good cause it acts against MRSA
They are inverse in their effectiveness against gram positive vs gram negative :
- Earlier gens: better at gram positive, nothing for gram negative
- Later gens: better at gram negative, worse for gram positives
- Generally are resistant to simple B lactamases
What are the Gram Negative EXCEPTIONS on the action of Cephalosporins
It has NO EFFECT on Campulobacter ssp
and
no effect on Pseudomonas EXCEPT Ceftazidime which works for pseudomonas in the 3rd and 4th generation ONLY
What are the Gram Positive EXCEPTIONS on the action of Cephalosporins
Cephalosporins don’t work against these gram +ve: ENTEROCOCCUS and LISTERIA … therefore need to use another Antibiotic
Carbapenems
BROAD SPECTRUM
Like BROAD SPECTRUM β-lactams/β-lactamase inhibitor combinations
- Gram-positives (MSSA), gram-negative, anaerobes
- Usually resistant to β-lactamases
Recent emergence of carbapenemases in gram-negative enteric rods
- Emerging problem
Adverse reactions All β-lactams
- Mild side effects
- Serious side effects
Mild side effects
- GI upset
- Diarrhea (β-lactamase inhibitors; cefixime/Suprax)
- Drug induced neutropenia
Serious side effects
- Seizures
ALL β-lactams lower seizure threshold**
Wide therapeutic window so pretty safe
Some lower the threshold more than others (e.g. imipenem)
- SO DON’T GIVE TO PEOPLE WITH MENINGITIS
- Anaphylaxis
If anaphylaxis with one penicillin, high risk of reacting to another penicillin – less risk with cephalosporins
3% cross-reactivity between penicillins and carbapenems
Pharmacological key points β-lactams
- Which cross the BBB
Which β-lactams cross the BBB appreciably?
Penicillin IV (high dose) Ampicillin IV (high dose) Third generation cephalosporins IV (high dose) Cefepime Carbapenems
Which β-lactams have activity against MSSA?
Cloxacillin po/IV (and methicillin)
β-lactam/β-lactamase combinations (po/IV)
1st and 2nd generation cephalosporins po/IV
- 3rd generation IV NOT that good – just OK
Cefepime
Carbapenems
Which β-lactams have activity against Pseudomonas spp?
Ticarcillin and Piperacillin (IV) Timentin and Pip/tazo (IV) Ceftazidime (IV) Cefepime (IV) Carbapenems (IV)
Which β-lactams have activity against anaerobes?
Penicillin (po/IV)
All β-lactam/β-lactamase combinations (po/IV)
Carbapenems (IV)
What are the 4 groups that beta lactams work against?
Staph aureus
E. coli
Pseudomonas
Anaerobes
Glycopeptides
- examples
Vancomycin
Teicoplanin
Vancomycin Action
TWO STEPS
- Chain linking and
- Cross bridging
“Inhibition of cell wall synthesis
Inhibit the the chain formation and the cross-linking of peptidoglycan”
Vancomycin’s antibacterial spectrum
Possesses ONLY Gram positive activity including anaerobic gram-positive
very good activity against clostridium difficile (oral treatment)
- Vanco is the most effective against gram positive HOWEVER it works SLOWER. so in emerg/severe cases, you want to pair it with say a beta-lactam* for faster action.
Vancomycin biological absorption
BBB penetration, mainly with inflammation
Need higher levels to penetrate BBB, bone and cartilage, heart tissue
Need higher levels when dealing with MRSA
measure peak levels of AB to make sure it is enough to cross barriers.
Adverse Reactions of Vancomycin
Nephrotoxicity
Usually with accumulation (high trough levels)
when co-administered with other nephrotoxic drugs
Therapeutic drug monitoring to prevent this
When administered over short period (1 hr) [given too fast]
- Histamine release (Red-(wo)man syndrome) :
Flushing
Hives
Even hypotension
What are examples of Macrolides?
Macrolides Erythromycin (IV/po) - Erythromycin estolate (po) Clarithromycin (po) - Biaxin Azithromycin (IV/po) - Zithromax
Macrolide spectrum of resistance
Essentially
Gram-positives:
S. pneumoniae (if S)
Group A Streptococcus (if S)
Gram-negatives:
Campylobacter spp
Bordetella pertussis
Atypical bacteria:
Mycoplasma spp, Chlamydia spp, Clamydophila spp
Non-tuberculous mycobacteria:
Clarithromycin, azithromycin
Do Macrolides cross BBB?
NO
so you can’t use them to treat meningitis
Biology of Viruses
Obligate intracellular parasites
Use host cell machinery to replicate
Contain nucleic acid core surrounded by a protein capsid (some with envelopes)
Attach to host cells by binding to receptors on host cell surface
Enter cell by endocytosis of membrane
Assemble new particles within host cell that are released during cell lysis or by budding
Latent Virus
i.e. Chicken pox when you are young can remain unproblematic
until you’re older and it re-activates, manifests as Shingles
What is Vertical Transmission
- Examples
In utero- from mother to baby
Fetus becomes infected in-utero in two different ways:
Maternal viremia and infection of placenta (e.g.: rubella, CMV, Parvovirus)
OR
Exposure to virus in birth canal (e.g.: HSV, HIV)
In arthropod borne diseases, what are examples of arthropods
ticks
mosquitos
What is the difference between aerosol vs droplet transmission
Aerosal: a suspension of fine solid particles or liquid droplets in air or another gas
Droplet Transmission: occurs when bacteria or viruses travel on relatively large respiratory droplets that people sneeze, cough, or exhale
Gastrointestinal Route of Viruses
- examples of GI viruses
Viruses shed in stool contaminate food or water subsequently ingested by a susceptible host (Fecal-oral spread)
Viruses must withstand GI tract (stomach acid, bile salts, proteolytic enzymes) Enteroviruses Hepatitis A Norovirus Rota virus
Examples of Transcutaneous Virus routes
Direct inoculation from insect bites, animal bites or from mechanical devices (needles)
Arboviruses (e.g.: dengue, West Nile)
CMV, Hepatitis B, HIV
Rabies
Arbovirus
Refers to VECTOR borne viruses, i.e. Mosquito viruses
Transmucosal Viral Route examples
i. e. sexual, genital or oral transmission
- CMV, Hepatitis B, HSV, HIV
