Phrm306 antibiotics

Principles of Antimicrobial therapy
PHRM306
PHARMACOLOGY II

Principles of Antimicrobial Therapy
I. Overview:
 Antimicrobial therapy takes advantage of the
biochemical differences that exist between
microorganisms are human beings.
 Antimicrobial drugs are effective in the
treatment of infections because of their selective
toxicity.
 That is, they have the ability to injure kill an
invading microorganism without harming the
cells of the host.

II. Selection of Antimicrobial Agents
1. The organism’s identity
2. Its susceptibility to a particular agent
3. The site of the infection
4. Patient factors
5. The safety of the agent
6. The cost of the therapy

A. Identification of the infecting organism
• Characterization of the organism is central to selection
of the proper drug.
• A rapid assessment of the nature of the pathogen can
sometimes be made on the basis of the Gram stain,
which is particularly useful in identifying the presence
and morphologic features of microorganisms in body
fluids that are normally sterile.

B. Empiric therapy prior to identification of
the organism
1. The acutely ill patient with
infections of unknown origin
2. Selection a Drug

C. Determination of antimicrobial
susceptibility of infective organisms
1. Bacteriostatic drugs: Which arrest the growth
& replication of bacteria at serum levels
achievable in the patient.
Bactericidal agents: Which kills bacteria at
serum levels achievable in patients.
• Cholarmphenicol is static against gram
negative rods and is cidal against other
organisms such as S. pneumoniae

• 2. Minimum inhibitory concentration: Minimum
Inhibitory Concentration (MIC) is the lowest
concentration of antibiotics that inhibits bacterial
growth.
• To provide effective antimicrobial therapy, the
clinically obtainable antibiotic concentration in body
fluid should be greater then the MIC.
• 3. Minimum Bactericidal concentration: the
minimum bactericidal concentration (MBC) is the
lowest concentration of antimicrobial agent that
results in a 99.9 percent decline in colony count
after overnight broth dilution incubations.

D. Effect of the site of injection on
therapy
• The blood Brain Barrier: this barrier is formed by
the single layer of tail-like endothelial cells fused
by tight junctions that impede entry from the blood
to the brain of virtually all molecules, except those
that are small and lipophilic.
• The penetration and concentration of an
antibacterial agent in the CSF is particularly
influenced by the following:

1. Lipid soluble drug, such as quinolones and
metronidazole, have significant penetration into
the CNS.
• In contrast, β-lactum antibiotics, such as
penicillin, are ionized at physiologic PH and have
low solubility in lipids. They therefore have
limited penetration through the intact blood brain
barrier under normal circumstances.
2. Molecular Weight of the drug
3. Protein binding of the drug

E. Patient factors
1. Immune System
2. Renal Dysfunction: serum creatinine levels
are frequently used as an index of renal
function for adjustment of drug regimens.
3. Hepatic dysfunction
4. Poor perfusion
5. Age
6. Pregnancy
7. Lactation
F. Safety of the agent
G. Cost of the therapy

III. Route of Administration
• Some antibiotics, such as Vancomycin, the
aminoglycosides and amphotericin are so poorly
absorbed from gastrointestinal tract that adequate
serum levels can not be obtained by oral
administration.
• Parenteral administration is used for drugs that
are poorly absorbed from the gastrointestinal tract
and for the treatment of the patients with serious
infections.

IV. Determinants of Rational Dosing
• Two important pharmacodynamic
properties that have a significant influence
on the frequency dosing are:
1.Concentration-depending Killing
2.Post-antibiotic effect

V. Agents used bacterial infections
• Penicillin
• Cephalosporin's
• Tetracycline's
• Aminoglycosides
• Macrolides
• Fluoroquinolones
• Others

VI. Chemotherapeutic Spectra
A. Narrow-Spectrum antibiotics: Isoniazid is
active only against mycobacteria
B. Extended-Spectrum: Ampicillin acts against
gram positive and some gram negative
bacteria
C. Broad-Spectrum Antibiotics: Tetracycline and
chloramphenicol affect a wide variety of
microbial species

VII. Combinations of antimicrobial
drugs
• Treatment of tuberculosis
• Advantages of drug combinations: When
infection is of unknown origin. Beta lactums and
aminoglycosides show synergism
• Disadvantages of drug combinations: A number
of antibiotics act only when organisms are
multiplying. Thus co administration of an agent
that causes bacteriostasis plus a second agent
that is bactericidal may result in the first drug
interferring with the action of second.

VIII. Drug Resistance
A. Genetic alterations leading to drug resistance
1. Spontaneous mutations of DNA: Emergence of
rifampin-resistant Mycobacterial tuberculosis
when rifampin is used as a single antibitotic.
2. DNA transfer of drug resistance
B. Altered expression of proteins in drug-resistant
organisms
1. Modification of target site
2. Decreased accumulation
3. Enzymic Inactivation

IX. Prophylactic Antibiotics
X. Complications of Antibiotics Therapy
1.Hypersensitivity
2.Direct toxicity
3.Superinfections
XI. Sites of Antimicrobial Actions

Introduction
β-Lactam antibiotics are the most widely
produced and used antibacterial drugs in the
world, and have been ever since their initial
clinical trials in 1941.
β-Lactams are divided into several classes based
on their structure and function; and are often
named by their origin, but all classes have a
common β-Lactam ring structure.

Discovery of Penicillin
• First discovered in 1928 by British physician
Alexander Fleming
• Accidental discovery of a contaminated
bacterial culture
• Fungus Penicillium notatum killed the culture
of Staphylococcus aureus growing in the petri
dish

Zone of Inhibition
• Around the fungal colony is a
clear zone where no bacteria
are growing
• Zone of inhibition due to the
diffusion of a substance with
antibiotic properties from the
fungus

Penicillin Today
• Still the most widely used antibiotic
• Still the drug of choice to treat many bacterial
infections
• Scientists have continued to improve the yield
of the drug
• Present day strains of P. chrysogenum are
biochemical mutants that produce 10,000
times more penicillin than Fleming's original
isolate

Mechanism of Action
Target- Cell Wall Synthesis
The bacterial cell wall is a cross linked polymer
called peptidoglycan which allows a bacteria to
maintain its shape despite the internal turgor
pressure caused by osmotic pressure
differences.
If the peptidoglycan fails to crosslink the cell wall
will lose its strength which results in cell lysis.
All β-lactams disrupt the synthesis of the bacterial
cell wall by interfering with the transpeptidase
which catalyzes the cross linking process.

Peptidoglycan
Peptidoglycan is a carbohydrate composed of
alternating units of NAMA and NAGA.
The NAMA units have a peptide side chain which
can be cross linked from the L-Lys residue to the
terminal D-Ala-D-Ala link on a neighboring
NAMA unit.
This is done directly in Gram (-) bacteria and via a
pentaglycine bridge on the L-lysine residue in
Gram (+) bacteria.

Transpeptidase- PBP
The cross linking reaction is catalyzed by a class of
transpeptidases known as penicillin binding
proteins. A critical part of the process is the
recognition of the D-Ala-D-Ala sequence of the
NAMA peptide side chain by the PBP. Interfering
with this recognition disrupts the cell wall
synthesis. β-lactams mimic the structure of the
D-Ala-D-Ala link and bind to the active site of
PBPs, disrupting the cross-linking process.

Mechanism of β-Lactam Drugs
The amide of the β-lactam ring is unusually
reactive due to ring strain and a conformational
arrangement which does not allow the lone pair
of the nitrogen to interact with the double bond
of the carbonyl.
β-Lactams acylate the hydroxyl group on the
serine residue of PBP active site in an
irreversible manner.

The hydroxyl attacks the amide and forms a
tetrahedral intermediate.

The tetrahedral intermediate collapses, the amide
bond is broken, and the nitrogen is reduced.

The PBP is now covalently bound by the drug and
cannot perform the cross linking action.

Bacterial Resistance
Bacteria have many methods with which to combat the
effects of β-lactam type drugs.
• Intrinsic defenses such as efflux pumps can remove the
β-lactams from the cell.
• β-Lactamases are enzymes which hydrolyze the amide
bond of the β-lactam ring, rendering the drug useless.
• Bacteria may acquire resistance through mutation at
the genes which control production of PBPs, altering
the active site and binding affinity for the β-lactam .

Range of Activity
β-Lactams can easily penetrate Gram (+) bacteria, but the
outer cell membrane of Gram (-) bacteria prevents
diffusion of the drug. β-Lactams can be modified to
make use of import porins in the cell membrane.
β-Lactams also have difficulty penetrating human cell
membranes, making them ineffective against atypical
bacteria which inhabit human cells.
Any bacteria which lack peptidoglycan in their cell wall
will not be affected by β-lactams.

Toxicity
β-Lactams target PBPs exclusively, and because
human cell membranes do not have this type of
protein β-lactams are relatively non toxic
compared to other drugs which target common
structures such as ribosomes.
About 10% of the population is allergic
(sometimes severely) to some penicillin type β-
lactams.

Classes of β-Lactams
The classes of β-lactams are distinguished by the
variation in the ring adjoining the β-lactam ring
and the side chain at the α position.
Penicillin

Modification of β-Lactams
β-Lactam type antibiotics can be modified at various
positions to improve their ability to:
-be administered orally (survive acidic conditions)
-be tolerated by the patient (allergies)
-penetrate the outer membrane of Gram (-) bacteria
-prevent hydrolysis by β-lactamases
-acylate the PBPs of resistant species (there are many
different PBPs)

Penicillins- Natural
Natural penicillins are those which can be obtained
directly from the penicillium mold and do not
require further modification. Many species of
bacteria are now resistant to these penicillins.
Penicillin G
not orally active

Penicillin G in Acidic Conditions
Penicillin G could not be administered orally due
to the acidic conditions of the stomach.

Penicillin V
Penicillin V is produced when phenoxyacetic acid rather
than phenylacetic acid is introduced to the penicillium
culture. Adding the oxygen decreases the
nucleophilicity of the carbonyl group, making penicillin
V acid stable and orally viable.

Production
All commercially available β-lactams are initially
produced through the fermentation of bacteria.
Bacteria assemble the penicillin molecule from L-AAA, L-
valine, and L-cysteine in three steps using ACV (L-δ-(α-
aminoadipoyl)-L-cysteinyl-D-valine) synthase, IPN
(Isopenicillin N ) synthase, and acyltransferase.
Modern recombinant genetic techniques have allowed
the over expression of the genes which code for these
three enzymes, allowing much greater yields of
penicillin than in the past.

Penicillin Biosynthetic Pathway

Semi-Synthetic Penicillins
The acyl side chain of the penicillin molecule can be
cleaved using enzyme or chemical methods to produce
6-APA, which can further be used to produce semi-
synthetic penicillins or cephalosporins
75% of the penicillin produced is modified in this manner.

Penicillins- Antistaphylococcal
Penicillins which have bulky side groups can block
the β-Lactamases which hydrolyze the lactam
ring.

These lactamases are prevalent in S. aureus and S.
epidermidis, and render them resistant to Penicillin G
and V. This necessitated the development of semi-
synthetic penicillins through rational drug design.
Methicillin was the first penicillin developed with this
type of modification, and since then all bacteria which
are resistant to any type of penicillin are designated as
methicillin resistant. (MRSA- methicillin-resistant S.
aureus)

Methicillin is acid sensitive and has
been improved upon by adding
electron withdrawing groups, as was
done in penicillin V, resulting in
drugs such as oxacillin and nafcillin.
Due to the bulky side group, all of the
antistaphylococcal drugs have
difficulty penetrating the cell
membrane and are less effective
than other penicillins.
Oxacillin
Nafcillin

Penicillins- Aminopenicillins
In order to increase the range of activity, the penicillin
has been modified to have more hydrophilic groups,
allowing the drug to penetrate into Gram (-) bacteria
via the porins.
Ampicillin R=Ph
Amoxicillin R= Ph-OH

These penicillins have a wider range of activity than
natural or antistaphylococcal drugs, but without the
bulky side groups are once again susceptible to attack
by β-lactamases
The additional hydrophilic groups make penetration of
the gut wall difficult.

Due to the effectiveness of the aminopenicillins, a
second modification is made to the drug at the
carboxyl group.
Changing the carboxyl group to an ester allows
the drug to penetrate the gut wall where it is
later hydrolyzed into the more polar active form
by esterase enzymes.
This has greatly expanded the oral availability of
the aminopenicillin class.

Penicillins- Extended Spectrum
Extended spectrum penicillins are similar to the
aminopenicillins in structure but have either a
carboxyl group or urea group instead of the
amine

Penicillins- Extended Spectrum
Like the aminopenicillins the extended spectrum
drugs have an increased activity against Gram (-)
bacteria by way of the import porins.
These drugs also have difficulty penetrating the gut
wall and must be administered intravenously if
not available as a prodrug.
These are more effective than the aminopenicillins
and not as susceptible to β-lactamases

Cephalosporins
• Cephalosporins were discovered shortly after
penicillin entered into widespread product,
• First discovered in 1945 from a Cephalosporium
fungi
• but not developed till the 1960’s.

Chemical structure of cephalosporins
• Cephalosporins are similar to penicillins but
have a 6 member dihydrothiazine ring
instead of a 5 member thiazolidine ring.
• Derived from 7-aminocephalosporanic
acid. 7-aminocephalosporanic acid (7-ACA)
can be obtained from bacteria, but it is
easier to expand the ring system of 7-APA
because it is so widely produced.
• They suffer the “attack” of bacteria at their
beta-lactam ring.

Cephalosporins
Unlike penicillin, cephalosporins have two side chains
which can be easily modified. Cephalosporins are also
more difficult for β-lactamases to hydrolyze.

Mechanism of ActionMechanism of Action
N
O
HHH
NR
O
S
CO2H
O
C
Me
O
7
OH
Ser Enzyme
-CH3CO2
-
N
O
HHH
NR
O
S
CO2H
O
Ser
Enzyme
NoteNote
The acetoxy group acts as a good leaving group and aids the mechanismThe acetoxy group acts as a good leaving group and aids the mechanism

Cephalosporins,
Classification
Cephalosporins are divided into four
generations with original agents
being referred to as first-generation
cephalosporins, and the most recent
agents as fourth-generation
cephalosporins
In general, the spectrum of activity
of cephalosporins increases with
each generation because of
decreasing susceptibility to bacterial
β-lactamases

First-Generation Cephalosporins
Examples: cephradine, cephalexin, cephadroxil, cephapirin
They are active against most staphylococci, pneumococci, and all
streptococci, with the important exception of enterococci
Their activity against aerobic G-ve bacteria and against anaerobes
is limited
They act as penicillin G substitutes. They are resistant to β-
lactamase
They distribute widely throughout the body, but do not penetrate
well into the CSF (not used for meningitis)
They should not be given to patients with a history of immediate-
type hypersensitivity reactions to penicillins

Second-Generation
Cephalosporins
They have a broader bacteriologic
spectrum than do the first-generation
agents
They are more resistant to β-lactamase
than the first-generation drugs
For example, cefamandole, cefuroxime,
and cefaclor not only are more active
against G-ve enteric bacteria but are
active against both β-lactamase-negative
and -positive strains of H. influenzae
Excretion is primarily renal, and they
distribute widely. However, they do not
attain sufficient concentrations in the
CSF to warrant their use in the treatment
of bacterial meningitis

 Third-Generation Cephalosporins
 These agents retain much of the G+ve activity of the
first two generations, although their anti-
staphylococcal activity is reduced. They are
remarkably active against most G-ve enteric isolates
 Some third-generation cephalosporins (e.g.,
ceftazidime and cefoperazone) also are active against
most isolates of P. aeruginosa
 These antibiotics diffuse well into most tissues (e.g.,
cefotaxime and ceftriaxone
 Indications include suspected bacterial meningitis and
treatment of hospital-acquired multiple-resistant G-ve
aerobic infections and suspected infections in certain
compromised hosts
 Ceftriaxone is the drug of choice in treating infections
caused by N. gonorrhoeae in geographic areas with a
high incidence of penicillin-resistant isolates
Cephalosporins,
Classification

 Fourth-Generation Cephalosporins
 This generation of cephalosporins (such as cefepime, cefpirome) combines the anti-
staphylococcal activity (but only those that are methicillin-susceptible) of first-
generation agents with the G-ve spectrum (including Pseudomonas) of third-generation
cephalosporins
 This class of cephalosporins have increased stability against hydrolysis by β-
lactamases
Cephalosporins, Classification
 These drugs are usually administrated parenterally
 They demonstrated good penetration into CSF compared to cefotaxime
 They are highly active against common pediatric meningeal pathogens, including
Streptococcus pneumoniae. Their in vitro activity against penicillin-resistant
pneumococci is generally twice that of cefotaxime or ceftriaxone
 Fourth-generation agents are particularly useful for the empirical treatment of serious
infections in hospitalized patients when gram-positive microorganisms,
Enterobacteriaceae, and Pseudomonas all are potential etiologies

 Fifth-Generation Cephalosporins
 These are novel cephalosporins with activity against MRSA
 Example: Ceftaroline
 Ceftaroline, the active metabolite of a N-phosphono prodrug, ceftaroline fosamil,
has been recently approved by the US FDA for the treatment of acute bacterial
skin and skin structure infections and community-acquired bacterial pneumonia
 This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell
wall synthesis and has a high affinity for PBP2a, which is associated with
methicillin resistance
 Ceftaroline is consistently active against multidrug-resistant Streptococcus
pneumoniae and Staphylococcus aureus, including methicillin-resistant strains
Cephalosporins, Classification

Carbapenems
Carbapenems are a potent class of β-lactams which
attack a wide range of PBPs, have low toxicity, and are
much more resistant to β-lactamases than the
penicillins or cephalosporins.

Carbapenems
Thienamycin, discovered by Merck in the late
1970’s, is one of the most broad spectrum
antibiotics ever discovered.
It uses import porins unavailable to other β-
lactams to enter Gram (-) bacteria.
Due to its highly unstable nature this drug and its
derivatives are created through synthesis, not
bacterial fermentation.

Carbapenems
Thienamycin was slightly modified and marked as
Imipenem. Due to its rapid degradation by renal
peptidase it is administered with an inhibitor called
cilastatin under the name Primaxin. Imipenem may
cause seizures or sever allergic reactions.
Other modifications of Thienamycin have produced
superior carbapenems called Meropenem and
Ertapenem, which are not as easily degraded by renal
peptidase and do not have the side effects of
Imipenem.

Monobactams have a monocyclic β-lactam ring
and are resistant to β-lactamases.

 Aztreonam was isolated from Chromobacterium violaceum .
 Aztreonam is the first clinically useful monobactam.
 The antimicrobial activity of Aztreonam differs from those of
other β-lactam antibiotics and more closely resembles that of
an aminoglycosides in activity without the nephrotoxicity of
aminoglycosides.
Aztreonam

Clinical uses of aztreonam
Active against G- aerobes only
Alternative for penicillins ( piperacillin ) and
cephalosporins ( ceftazidime ) allergic pts for G-
infections
Safe alternative to aminoglycosides, esp. in elderly and
pts with renal impairements

β-Lactamases
β-Lactamases were first discovered in 1940 and
originally named penicillinases.
These enzymes hydrolyze the β-lactam ring,
deactivating the drug, but are not covalently
bound to the drug as PBPs are.
Especially prevalent in Gram (-) bacteria.
Three classes (A,C,D) catalyze the reaction using a
serine residue, the B class of metallo- β-
lactamases catalyze the reaction using zinc.

β-Lactamase Inhibitors
There are currently three clinically available β-lactamase
inhibitors which are combined with β-lactams; all are
produced through fermentation.
These molecules bind irreversibly to β-lactamases but do
not have good activity against PBPs. The rings are
modified to break open after acylating the enzyme.

β-Lactam/Inhibitor combinations
Aminopenicillins:
ampicillin-sulbactam = Unasyn
amoxicillin-clavulante = Augmentin
Extended-Spectrum Penicillins
piperacillin-tazobactam = Zosyn
ticarcillin-clavulanate = Timentin

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