20 Principles of Pharmacology - Pharmacologic Principles of Antimicrobial Therapy
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Robert Rubin
HST-151 1
Pharmacologic Principles of Antimicrobial Therapy
I. Introduction
A. Successful antimicrobial therapy occurs when an effective concentration
of drug is delivered to the site of infection for a sufficient period of time.
Minimum effective concentrations are those needed to inhibit growth
(bacteriostatic concentration, MIC) or kill (bacteriocidal concentration,
MBC) the pathogen in question.
Bacteriocidal therapy required in the following conditions
a. Bacterial infection in the neutropenic host
b. Endocarditis (and other intravascular infections)
c. Meningitis and brain abscess
d. Staphylococcal (and probably other forms of) osteomylitis
e. Prosthetic device infection
B. Drug Absorption
1. The determinants of drug absorption are poorly understood and can only
be determined by clinical studies.
2. Must determine effects of food, gastric pH, and antacids on drug
absorption.
a. Food absorption usually decreases, may increase
b. Ketoconazole requires acid pH
c. Chelation of tetracyclines and fluoroquinolones by cations in
antacids may block absorption.
C. Drug Elimination
Three major routes of elimination:
1. Kidneys– renal elimination may occur either by glomerular filtration or
tubular secretion; in general, tubular secretion (seen with penicillins and
many cephalosporins) is more efficient than glomerular filtration, and
results in shorter serum half-lives. Probenicid blocks active secretion.
2. Hepatobiliary – if significant hepatobiliary elimination occurs, then
little dosage adjustment is needed in renal failure.
3. Metabolism – generally occurs in the liver, and can lead to drug
interactions, because of effects on liver enzyme systems.
,HST-151 2
D. Distribution of Antimicrobial Agents in Tissues
There are three major determinants of distribution of drugs between the
plasma (central compartment) and extravascular space (peripheral
compartment)
1. Nature of the Capillary Bed – In most tissues and organs the capillary
bed is fenestrated by small pores that permit the ready diffusion of
substances with molecular weights up to 1000 daltons (most antimicrobial
agents). A few locations in the body, termed specialized sites, have
unfenestrated capillaries. As drugs must pass through the endothelial cells
of the capillaries to reach extravascular space in these specialized sites, the
rate of diffusion is limited by the degree of lipid solubility of the drug.
a. The most clinically important specialized sites, are the central
nervous system, the retina and the prostate gland.
b. Such drugs as the β-lactams, aminoglycosides, most
tetracyclines and vancomycin are weakly lipid soluble and
penetrate specialized site poorly.
2. Degrees of Serum Binding – only free drug is available for diffusion
and is active. The major binding protein for most drugs is albumin.
3. Active Transport Pumps – The best studied of these pumps act on
organic anions and are located in the choroid plexus of the brain, the retina
and the proximal tubule of the kidney. These pump out β-lactam drugs
and are completely inhibited by probenicid.
E. Site of Infection –
The site of infection determines not only the choice of the agent, but also
its dose and the route by which it is administered.
1. In general, we wish to exceed to MIC.
2. Effects of subinhibitory concentrations
a. Alter the bacterial morphology and adherence properties
b. Decrease opsonic requirements
c. Enhance phagocytosis
d. Aid in intracellular killing
, HST-151 3
II. Penicillins
A. Structure
H
H N
N S
S Penicillinase O
O 2 1 O HN
N
O OH COOH
COOH
benzylpenicillin 1 Thiazolidine ring benzylpenicilloic acid
2 β-lactam ring
Three components: A thiazolidine ring, the β-lactam ring, and a side
chain. The side chain determines in large part to antibacterial spectrum and
pharmacologic properties of a particular penicillin.
B. Mechanism of Action – surprisingly incompletely understood.
1. Penicillin inhibits bacterial growth by interfering with the synthesis of
the bacterial cell wall after binding to penicillin binding proteins (many
of these are enzymes are involved in cell wall biosynthesis).
2. Although penicillins are bacteriocidal drugs, the mechanisms by which
they kill bacteria vary for different species. For pneumococcus and E.
coli, killing is by lysis resulting from deregulation of the autolytic enzyme
system (i.e., peptidoglycan hydrolases). Penicillin may also directly
enhance autolytic activity. In the case of streptococcus, penicillin induces
hydrolysis of cellular RNA.
3. Post-antibiotic effects are observed with gram-positive, but not gram
negative bacteria.
C. Spectrum of Activity
see appendix for details
generally active against cocci, many bacilli and anaerobes.
activity against enterobacteriaceae and pseudomonas seen with
aminopenicillins.
D. Resistance (see XII A for more details)
1. The most important mechanism of bacterial resistance to penicillin is
enzymatic hydrolysis of the β-lactam bond by β-lactamases.
a. S. aureus – plasmid encoded and inducible. This plasmid is
increasingly found in enterococcus.
b. In gram negatives, β-lactamases can be chromosomally or
plasmid mediated, constitutive or inducible, and active against only
certain β-lactams or broad spectrum.
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