Transcript Source of Drug

CHEMOTHERAPY
 Antimicrobial
 Antiviral
chemotherapy
 Antiparasitic
 Cancer
chemotherapy
Drugs
Chemotherapy
CHEMOTHERAPY
 Concepts
 Many
easy to understand.
distinct diseases so less
prototype drugs.
ANTIBIOTICS
 General
Principles
 Mechanism
of Action
 Pharmacokinetics/Therapeutic
 Adverse
effects
Uses
STUDY AIDS
 Objectives
 Summary
tables
STUDY AIDS
 Review
questions on web:
http://info.unmc.edu/scholarchemo1/
AntiBio/AntibioTestframe.htm
STUDY AIDS
 http://dev1.unmc.edu/JeopardyGame/A
ntibiotics.htm
 http://dev1.unmc.edu/JeopardyGame/A
ntibioticsDouble.htm
ANTIMICROBIAL
CHEMOTHERAPY
Selective
Toxicity
CHEMOTHERAPY
Allows
the normal hostdefense mechanisms to
gain control.
CLASSIFICATION OF
CHEMOTHERAPEUTIC
AGENTS
Control
Number of
bacteria
Bacteriostatic agent
Bactericidal agent
Time
BACTERIOSTATIC DRUGS
 Sulfonamides
 Erythromycin
 Tetracyclines
BACTERICIDAL DRUGS
 Trimethoprim
+Sulfamethoxazole
 Aminoglycosides
 β-lactams
Inhibit Protein Synthesis
Nucleic acid synthesis
Cell membrane
Permeability
T
XXXX
Cell Wall Synthesis
Antimetabolites
CHOICE OF THE
ANTIBIOTIC
 First
determine etiology of the
infection.
CHOICE OF THE
ANTIBIOTIC
 Sensitivity
pattern of the infecting
organism must be determined.

Consider pharmacokinetics and host
factors.
PHARMACOKINETIC
FACTORS
 Location
 Route
of Infection.
of Administration.
 Pattern
of excretion, metabolism, and
degree of protein binding.
HOST FACTORS
 Host

defense (Immunocompetence).
Local factors.
 Age.
 Genetic
 Drug
factors.
Allergy.
HOST FACTORS
 Renal
disease and liver disease.
 AIDS
 Pregnancy.
USES OF ANTIBIOTICS
 Empirical
antimicrobial therapybefore the pathogen is known.
 Infections
with known etiology.
MISUSES OF ANTIBIOTICS
 Treatment
of nonresponsive
infections.
 Therapy
of fever of unknown origin
Fever of short duration
Fever persisting for 2 or more weeks.
MISUSES OF ANTIBIOTICS
 Dosing
errors
Wrong frequency
Excessive or subtherapeutic doses
MISUSES OF ANTIBIOTICS
 Inappropriate
reliance on
chemotherapy alone (e.g.
abscesses).
MISUSES OF ANTIBIOTICS
 Lack
of adequate bacteriological
information.
• Absence of supporting data
• Agents selected by habit
• Doses are routine, rather than individualized
COMBINATION
CHEMOTHERAPY
 Separate
but simultaneous
administration.
Combination ChemotherapyAdvantages
 Treatment
of polymicrobial
infections.
 Prevent
or delay resistance.
 Synergy.
Combination ChemotherapyAdvantages
 Severe
infections of unknown
etiology-empirical therapy.
DISADVANTAGES
 Increased
risk of toxicity.
 Increased
likelihood of
superinfections.
 Increased
cost.
 Antagonism
of an antibacterial effect.
FIXED DOSE
COMBINATIONS
 Ratio
and dose of antibiotics are
determined based on in vitro studies.
 Encourages
inadequate treatment.
PROPHYLAXIS OF INFECTION
 This
should be used only in
circumstances in which efficacy has
been demonstrated and the benefits
outweigh the risks.
PROPHYLAXIS OF
INFECTION
 Effective
when a single drug is used
to prevent infection from a specific
microorganism.
 In
patients undergoing organ
transplantation or receiving cancer
chemotherapy.
PROPHYLAXIS OF INFECTION
 Primary
and 2ndary prevention of
opportunistic infections in AIDS
patients when CD4 counts are below
certain threshholds.
PROPHYLAXIS OF INFECTION
 To
prevent wound infections after
various surgical procedures.
Complications of Antimicrobial
Therapy
 Drug
Resistance
 Superinfections
 Toxicity
DRUG RESISTANCE
 Involves
a stable genetic change in
the bacteria.
DRUG RESISTANCE
 Mutation
and selection with passage
vertically.
 Horizontal
transfer from a donor cell
by transduction, transformation or
conjugation.
MUTATION-SELECTION
 Occurs
in many different genes.
 Random
events that confer a survival
advantage when a drug is present.
CHROMOSOMAL MUTATIONS
 Antibiotics
agents.
are acting as selecting
+ Antibiotic
Resistant Population
HORIZONTAL GENE TRANSFER
 Mobile
genetic elements (plasmids,
transposable elements, integrons,
gene cassettes).
 Transduction
 Transformation
CONJUGATION
Direct cell to cell contact through a sex
pilus or bridge
Very important for the spread of
resistance because multiple resistance
genes can be transferred
simultaneously.
Enzyme Inactivation
Altered Permeability
Mod. of target site
and reduced affinity
CROSS-RESISTANCE
e.g. sulfonamides, penicillins
PREVENTION OR DELAY OF
RESISTANCE
 Judicious
(appropriate) or careful
use of antibiotics
 Adequate
Dosage
 Combination
Chemotherapy
SUPERINFECTIONS
A
new infection appearing during the
chemotherapy of a primary one.
 Caused
by removing inhibitory
influence of the normal flora.
+ Antibiotic
(Broad spectrum)
Resistant pathogen
Secondary infection from
resistant organisms
TREATMENT OF THE
SUPERINFECTION
 Stop
present therapy.
 Culture
 Treat
infected area.
against the offending
microorganism.
TOXICITY
 Hypersensitivity
 Direct
Toxicity- GI
BACTERICIDAL AGENTS
 Drugs
whose killing action is time
dependent don’t show increased
killing above MBC; bactericidal
activity continues as long as the
serum concns. exceed MBC.
Gram
Gram _
+
Rickettsia
Gram
Gram
+
_
Amoeba
Drug Concentration on
microbial killing
 AUC:MIC
(area under the serum
concentration time curve: minimal
inhibitory concentration).
 Peak serum concentration:MIC
Appropriate Dose of
Antimicrobial Agent
 Principles
of pharmacokinetics and
pharmacodynamics are used to
determine this.
Appropriate Dose of Antimicrobial
Agent
 Pharmacodynamic
factors include
cidal vs static activity and
postantibiotic effects.
CIDAL VS STATIC
 For
primarily static agents inhibitory
drug concn’s are much lower than
cidal concn’s.
 Usually
cell wall active drugs are
cidal and protein synthesis inhibitors
are static.
CIDAL VS STATIC
 Some
agents that are considered to
be static may be cidal vs selected
organisms.
CIDAL VS STATIC
 Static
and cidal agents are equivalent
for immunocompetent hosts.
 Cidal
agents should be used when
host defenses are impaired.
CIDAL VS STATIC
 Bactericidal
agents can be divided
into 2 groups (1) concentration
dependent e.g. aminoglycosides and
quinolones and (2)time dependent
killing e.g. beta lactams and
vancomycin.
POSTANTIBIOTIC EFFECT
 Persistent
suppression of bacterial
regrowth after brief exposure.
 Mechanism
is likely multifactorial
and may vary with the specific
antimicrobial drug and organism
combination.
No. of Viable
bacteria/ml.
Postantibiotic effect
0
Drug added
4
8
Hours
Drug removed
POSTANTIBIOTIC EFFECT
 With
aminoglycosides it has allowed
once daily dosing and less
monitoring.