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ANTIBIOTICS
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ANTIBIOTICS
• Agents (may be given iv/po/im) used to treat or
occasionally prevent infection ( known as
Prophylaxis), also known as antimicrobials
(includes antibacterial agents, antifungal agents,
anti-parasitic agents)
• NB: Samples from site of infection to be sent to
laboratory for identification and antibiotic
susceptibility profile- means appropriate
antibiotic may be selected
CONTENTS OF LECTURE
• Basis of Antimicrobial Action
• Site of Action
• Examples of Antibiotic Class, Site of
Activity, Spectrum of Activity, Toxicity,
Resistance to Antibiotic
• Antibiotic Policy, Audit, Surveillance
• Brief Outline of Antifungal/Antiviral
Therapy
ANTIBIOTICS
• Biologically produced by filamentous fungi
and bacteria of the actinomycete family.
• The key to their mode of Action is Selective
Toxicity: the ability to inhibit bacteria or
other microorganisms, without affecting the
host adversely- balance of toxicities
• Action: may be narrow spectrum or broad
spectrum
CHOICE OF ANTIBIOTIC
• Antibiotics should only be used if indicated
• Inappropriate use may be detrimental to the
patient e.g.non-treatment of infection, change of
normal flora, development of
pseudomembranous colitis
And detrimental to the wider community
encouraging the development of Resistance
The House of Lords select committee( Path to Least
Resistance) and SARI Report ( A Strategy for the
Control of Antimicrobial Resistance in Ireland )
Get Smart campaign in the U.S
CHOICE OF ANTIBIOTIC
IS DETERMINED BY:
Bacteria causing infection in that particular
patient, VERY IMPORTANT to SEND
SAMPLES FROM INFECTION SITES of
patient to Microbiology for gram stain and
culture and sensitivity profiles
Spectrum of Activity
HOST FACTORS:
Pharmacokinetics/Pharmacodynamics
Presence of Resistance
Four things
SARI REPORT APRIL 2001
RECOMMENDED STRATEGIES
• Recommended
Infrastructure
• Surveillance of
Antimicrobial
Resistance
• National Reference
Laboratories
• Monitoring Supply
and Use of
Antimicrobials
• Development of Guidance
for Appropriate Use of
Antibiotics
• Education in relation to
appropriate use of
Antibiotics
• Development of
Principles in relation to
Infection Control
• Future Research in the
Area
Better Prescribing
Complications Appropriate
ANTIBIOTICS
May be:
• Bacteriostatic – inhibits growth of
Bacteria, so acts by preventing bacteria
from multiplying and then hosts defences
deal with the small number of bacteria left
• Bactericidial – kills Bacteria, so eliminates
bacteria
HOW TO KILL A CELL
• Damage to CELL WALL or inhibition of
it`s synthesis
• Damage to cell membrane
• Alteration of cell proteins and/or nucleic
acids
• Enzyme Inhibition
• Inhibition of nucleic acid /protein
FOUR MAIN TARGETS OF
ANTIBIOTICS IN BACTERIA
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Cell Wall Synthesis
Protein Synthesis
Nucleic Acid Synthesis
Cell Membrane Function
EXAMPLES OF ANTIBIOTICS
WORKING AT TARGET SITES
• Cell Wall Synthesis: B-Lactams e.g.
Penicillins, Cephalosporins and
Glycopeptides e.g. Vancomycin
• Protein Synthesis: Aminoglycosides,
Erythromycin,Tetracyclines,
Chloramphenicol, Fusidic Acid
• Nucleic Acid Synthesis: Quinolones,
Rifampicin
• Cell Membrane Function: Polymyxin,
Amphotericin
3 MECHANISMS OF
RESISTANCE
• Alteration in Target Site: target enzyme
altered so that it has a lowered affinity for
the antibacterial (or additional target
enzyme may be synthesized)
• Altered Uptake: so decreasing amount of
drug reaches the target, may do this by
altering entry into the cell or pumping drug
out i.e Efflux Mechanism
MECHANISMS OF
RESISTANCE
• Production of enzymes which modify or
destroy the antibacterial agent (drug
inactivation) –very important e.g. Blactamases, aminogylcoside modifying
enzymes
• ALL TYPES OF RESISTANCE MAY BE
CHROMOSOMAL OR PLASMID OR
TRANSPOSON MEDIATED
For each Antibiotic consider
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Mechanism of Action
Spectrum of Activity
Toxicity
Resistance
Cell Wall Synthesis Inhibitors
CELL WALL SYNTHESIS
INHIBITOR ANTIBIOTICS
B-Lactam antibiotics
• Structure: large family of compounds all
containing the B-Lactam ring. The different
members are distinguished by the structure
of the ring attached to the B-Lactam ring.
• Examples: Penicillins, there is a five
member ring attached to the B-Lactam ring,
in Cephalosporins a six member ring .
Blactam ring
Mechanism of Action
• Peptidoglycan: a vital component of the
cell wall, unique to bacteria.
• B-Lactam antibiotics inhibit cell wall
synthesis by binding enzymes called
Penicillin Binding Proteins which are
responsible for the final stages of
peptidogylcan (cell wall) crosslinking or
formation, subunits acculmulate in the
cell Cell Lysis or Death
Spectrum of Activity
• Benzylpenicillin: mainly active against Gram
Positive organisms e.g. Streptococci and
Staphylococci
• Ureidopenicillins: active against certain gram
positive and gram negative organisms
• Cephalosporins: Broad spectrum of activity gram
negative and positive organisms
• Carbapenems : has a broad spectrum of activity
even against ESBL producing organisms
NEVER GIVE INTRATHECIALLY:B-Lactam antibiotics
TOXICITY
• Serious Allergy : to B-Lactam drugs in the
form of immediate hypersensitivity reaction
occurs in ~0.004-0.015% of treatment
courses
• Mild idiopathic reactions e.g. rash in up to
25% esp. with ampicillin
• 10-20% of those allergic crossreact with
cephalosporins
• In renal impaired patients Benzylpenicillin
can produce neurotoxicity in high doses
RESISTANCE TO BLACTAM
ANTIBIOTICS
• 3 Mechanisms
• Alteration in target site: MRSA produces an
additional PBP, which has lower affinity for BLactams and thus cell wall synthesis continues
even when other PBP`s are inhibited: Resistant to
all B-Lactam antibiotics
• Alteration in access to the target: Gram negative
bacteria display this , porin channels alter structure
and B-Latam antibiotic cannot get to their target
RESISTANCE TO B-LACTAM
ANTIBIOTICS
• Production of B-Lactamases: these
enzymes are produced by the bacteria and
catalyse the hydrolysis of the B-Lactam ring
, so that antibiotic is inactive, some
inactivate some e.g. ampicillin but not
others cloxacillin or meropenem
To overcome this mechanism of resistance ,
B-Lactamase inhibitors are added to the
antibiotic e.g. clavulanic acid added to
ampicillin = augmentin
CELL WALL SYNTHESIS
INHIBITORS
Glycopeptides
• Large molecules , e.g vancomycin,
teicoplanin
• Mechanism of Action: Act at an earlier
stage than Blactams , interfers with cell wall
synthesis by binding to D-ala-D-ala at the
end of the pentapeptide chains, part of
growing cell wall
Absortion/Excretion
• Must be given I.V. for systemic infections
as not absorbed from the intestinal tract
(useful property when treating C.difficile
diarrhoea, when need to treat the organism
in the bowel lumen)
• Excretion by the Kidneys
Spectrum Of Activity
• NB: Only active against GRAMPOSITIVE organisms
• Used to treat Staphylococci resistant to BLactam antibiotics e.g.MRSA or in patients
allergic to B-Lactam drugs
TOXICITY
• Redman Syndrome:
must be given slowly
over at least an hour
I/V
• Potentially Ototoxic
• Potentially
Nephrotoxic
• Important to assay
blood levels
RESISTANCE
• Resistance can occur especially in
enterococci i.e. Vancomycin resistant
enterococci (VRE)- may be chromosomal or
plasmid mediated
ANTIBIOTICS THAT INHIBIT
PROTEIN SYNTHESIS
AMINOGLYCOSIDES
Structure: Related molecules containing
either strepitidine(streptomycin) or 2deoxystreptamine (e.g. gentamicin)
Mechanism of Action: Aminoglycosides kill
and inhibit organisms by intering with the
binding of formylmethionyl- t RNA to the
ribosome, this prevents the formation of
initiation complexes from which protein
synthesis proceeds.
AMINOGLYSOCIDES
ABSORPTION/EXCRETION
• Cannot be given orally as it is not absorbed
from the gut , so must be given I/V OR I/M
• They do not penetrate well into tissues,
bone or cross the blood brain barrier
• They are excreted by the KIDNEYS
AMINOGLYSOCIDES-USES
• GRAM-NEGATIVE
SERIOUS INFECTION
esp. SEPTICAEMIA e.g.
Pseudomonas at dose 5-7
mg.kg per day once daily
dosing
• Syneristic activity with BLactam antibiotics against
Staphylococci and
Streptococci
• STREPTINOMYCIN
Used for mycobacterial
infections and B-Lactam
resistant N.gonorrhoeae
AMINOGLYSOCIDESTOXICITIES
• Potentially NEPHROTOXIC and
OTOTOXIC
• Small therapeutic range , therefore
ANTIBIOTIC ASSAY very important
especially if patient at risk or has renal
impairment
AMINOGLYSOCIDESRESISTANCE
2 Mechanisms
Most important is the production of
aminoglycoside-modifying enzymes- often
plasmid mediated and transferable between
bacteria, the aminoglycoside ia altered in
structure resulting in change of uptake of
antibiotic, this occurs by one-step mutation
The 2nd mechanism is alterations in cell
permeability of cell wall through porin
channels
PROTEIN SYNTHESIS
INHIBITORS-MACROLIDESetc
• Macrolides, Lincosamides, Streptogramins
• These group share overlapping sites on
ribosomes and resistance to macrolides
confers ressitance to the other two groups
• Examples: Macrolides-erythromycin and
Lincosamides-clindamycin
MACROLIDES
• STRUCTURE: Large cyclic molecules
which all contain a macrocyclic lactone ring
• Mechanism of Action: Erythromycin binds
to the 23S r RNA in the 50S subunit of the
ribosomes and blocks the translocation step
in protein synthesis, thereby preventing the
release of t RNA after peptide bond
formation
MACROLIDESABSORBTION/EXCRETION
• Can be administer orally and I/V
• Well distributed through the body, even for
intracellular organisms
• Drug is concentrated in th liver and excreted
in the bile, some also seen in the urine
• Uses: Active against gram-positive
organisms , alternative for Penicillin allergic
patients, also active against Legionella,
Campylobacter species and mycoplasmas,
chlamydiae and rickettsiae
MACROLIDES-TOXICITY
• Relatively non-toxic but may cause nausea
and vomiting after oral administration,
occasionally causes jaundice
MACROLIDES-RESISTANCE
• Due to alteration in the 23S r RNA target by
methylation of two adenine nucleotides in
the RNA.
• Resistance is plasmid mediated and
inducible ( i.e the presence of erythromycin
induces expression of resistance )
INHIBITORS OF NUCLEIC
ACID SYNTHESIS
• Inhibitors of Nucleic Acid Precursors:
Sulphonamides, Trimethoprim
• Inhibitors of DNA replication: Quinolones
• Inhibitor of RNA polymerase: rifampicin
Quinolone Antibiotics
• Examples: Nalidixic acid,
Ciprofloxacin
• Mechanism of Action:
Inhibit the activity of
DNA gyrase and thereby
prevent supercoiling of the
bacterial chromosome ,
this is specific to bacterial
cells and thos enot affect
mammalian cells
Quinolone Antibiotics
ABSORPTION etc
• Adminstered mostly
orally, well absorbed from
GI tract
• Excreted mostly in the
urine
• Well distributed
throughout the body
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Spectrum of Activity
Gram negative bacteria
Urinary tract infections
Chlamydiae, Rickettsiae
Legionella species
Atypical mycobacteria
Levofloxacin
/Moxifloxacin have
broader spectrum against
Gram positive organsisms
QUINOLONES TOXICITY
• Gastrointestinal disturbances most common
• Neurotoxicity and Photosensitivity less
common 1-2%
• In children possible toxic effects on
cartilage development
• Again may result in normal flora upset
QUINOLONE RESISTANCE
• Spontaneous Chromosomal Resistance
• 2 Forms
• Changes in the DNA gyrase subunit
structure of the bacteria resulting in lower
affinity for the drug
• Changes in cell wall permeability- if other
drugs enter by this route there may be cross
resistance
ANTIBIOTIC PROPHYLAXIS
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MICROBIAL FLORA
CHOICE OF ANTIBIOTIC
TIMING OF ADMINSTRATION
DURATION
SIDE EFFECTS
ANTIBIOTIC PROPHYLAXIS
• Patient of normal
• Patients undergoing
susceptibility exposed
certain Surgery e.g.
to specific pathogens
abdominal surgery
e.g. Neisseria
• Patients with increased
meningitidis causing
susceptibility to
meningitis.
infection e.g.
• Patients at risk of
Prosthetic heart valves
development of TB,
or post splenectomy
e.g. HIV patients
exposed to open TB
ANTIBIOTIC ASSAYS
• Assay when an antibiotic has a narrow therapeutic
index e.g Aminoglysocides
• Assay when normal route of excretion iis impaired
e.g. patient with renal impairment on vancomycin
• Assay in patients receiving prolonged therapy for
serious infection e.g. endocarditis
• Assay in Neonates with serious infection
• Assay if failure to respond to therapy
• Assay to check compliance
EXAMPLE OF ANTIBIOTIC
ASSAYS
• Aminoglysocides e.g.
gentamicin
• Glycopeptides e.g.
vancomycin
• Isoniazid : to ensure
compliance with
therapy especially in
substance abusers
• Aminoglycosides and
Glycopeptides : trough
level: taken immediately
before dose is given and
Peak : taken 1 hour post
dose
• Aminoglycosides: trough
correlates with toxicity
• Glycopeptides: Trough
correlates with adequate
therapetic level.
ANTIVIRAL THERAPY
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Prevention of viral infection
Virucides: e.g warts and cryotherapy
Antivirals: inhibit viral replication
Prevention of viral infections with the use
of standard precautions and vaccines e.g.
Hepatitis B
Immunoglobulin may be given in certain
cases to prevent infection such as rabies
NEWER ANTIFUNGAL AGENTS
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ITRACONAZOLE
LIPOSOMAL AMPHOTERICIN
VORICONAZOLE
DEVELOPING NEW AGENTS:
ANTIFUNGAL PEPTIDES SUCH AS
ECHINOCANDINS e.g. Capsofungin
HAART for HIV infection
• Highly Active Antiretroviral Therapy
• PROTEASE INHIBITORS e.g Saquinavir
• NUCLEOSIDE-REVERSE-TRANSCRIPTASE
INHIBITORS e.g ZDV, Didanosine (ddl), 3TC
• NON-NUCLEOSIDE REVERSETRANSCRIPTASE INHIBITORS e.g Nevirapine
• Recommended antiretroviral: 2 NRTI`s + PI or
NNRTI`s