Transcript Antimicrobial Drugs - LSU School of Medicine

Antimicrobial Drugs
(the stuff Dr. Figueroa didn’t tell you about in MIP)
Jeffery A. Hobden, Ph.D.
Wonder Drugs
• Decreased morbidity
and mortality in US
after WWII from
infectious diseases
• Made practical some
areas of medicine
• Cancer chemotherapy
• Gut surgery
• Increased productivity
in agriculture
Antibiotics - Exploited
• In 2007, two antibiotics
were in the top 20 drugs
prescribed in the US
• Amoxicillin – 34,801,000
• Azithromycin – 23,782,000
• In 2000, 24 million pounds
of antibiotics were used in
agriculture (chickens, pigs,
cattle, etc) vs. 3 million
pounds used to treat sick
humans
• Unrestricted access
Top 20 Prescribed Drugs
Tainted Seafood
• Chinese seafood tested
between 10/06 and
05/07 were repeatedly
positive for
• Nitrofuran
• Malachite green
• Fluoroquinolones
• Shipments banned
from entering US
• Buy only local seafood!
Alabama officials hold a press conference –
“Drugs in your seafood are bad, M’Kay?
The Consequences
“That which does not kill us makes us
stronger.” - Friedrich Nietzsche
Can’t we just get more?
• Screening natural or
synthetic compounds
for antibacterial
activity
• Preclinical studies
(animals)
• Safety (what is safe for
animals may not be true for
humans)
• Efficacy (pharmacological
parameters are different in
animals)
Wait – there’s more…
• Clinical studies (humans)
• Phase 1 – short term studies in small number of healthy
humans or patients with target disease, to determine
metabolism and basic pharmacologic and toxicological
properties of antibiotic
• Phase 2 – first controlled clinical studies to assess the
effectiveness of the antibiotic and to determine short-term
side effects and risks.
• Phase 3 – expanded controlled and uncontrolled clinical
studies to gather data regarding benefit – risk relationship.
• Phase 4 – marketing!
Is it any wonder?
• Antibiotics are big
business for pharm
• Freebies
• Advertising
• Sponsorships
• Not as profitable as
drugs for erectile
dysfunction,
cholesterol control,
anxiety attacks, etc.
After MIP, what else is there
to know about antibiotics?
•What’s the origin of that antibiotic?
•What’s special about it’s chemistry?
•What happens to it after its in my
body?
•Will it kill or maim me if I take it?
Classification of Antibiotics
by Mechanism of Action
• Inhibition of cell
wall synthesis
• Beta-lactam drugs
• Penicillins
• Cephalosporins
• Carbapenems
• The others
• Cycloserine
• Vancomycin
• bacitracin
Classification of Antibiotics
by Mechanism of Action
• Disruption of
cell membranes
• Polymyxin
• Polyenes (antifungal agents)
Classification of Antibiotics
by Mechanism of Action
• Inhibition of protein synthesis
• Reversible inhibition (bacteristatic)
• Chloramphenicol
• The tetracyclines
• The macrolides (erythromycin)
• Clindamycin
• Streptogramins
• Linezolid
• Irreversible – the bactericidal aminoglycosides
Susceptibility and Resistance
• In vitro values are guides,
not rules
• In vivo, bug is resistant if
cidal concentrations are
toxic to the host
• Achievable serum
concentrations are what
determine susceptibility or
resistance to drug
• Low pH, high protein
concentrations, anoxia
• Pharmacological
parameters of drugs (serum
versus other bodily fluids)
Bacterial Mechanisms
of Resistance
• Prevent antibiotic
from reaching its
target
• Destroy or
inactivate antibiotic
before it reaches
target
• Alter target
Choosing the right antibiotic –
is it really needed?
• Nature of the illness – is it a bacterial
infection or something else?
• Presumptive diagnosis (based on
history and clinical symptoms) says
yes!
• Empiric therapy – broad spectrum drug
• Specific therapy – narrow spectrum
Choosing the right antibiotic –
pharmacokinetic considerations.
• Location of infection
• Some antibiotics may or may not reach
therapeutic concentrations in certain
bodily fluids (ex. CSF and urine)
• Degree to which antibiotic binds
serum proteins
• Excessive binding will affect passive
diffusion of antibiotic from serum to
tissue
Choosing the right antibiotic –
host factors.
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Status of host immune system (cidal vs. static)
Local environment of infected site (pus, foreign bodies, etc)
Age (organ function in newborns and elderly)
Inherited metabolic disorder
Pregnancy (fetal or neonatal development)
Choosing the right antibiotic –
host factors.
• drug allergies
• Rashes
• Anaphylaxis
• Co-morbid
conditions are
aggravated by some
antibiotics
• Seizures
• Blood disorders
SJS Syndrome
First up….
• The sulfonamides
• The quinolones
• The beta-lactams
• Penicillins
• Cephalosporins
• Carbapenems
Looking a-head….