Antimicrobial agents 2 wafaa

Dr.Wafaa Ezz
Elarab
Antimicrobial Drugs-2Antimicrobial Drugs-2

(according to Lippincott´s Pharmacology, 2009)(according to Lippincott´s Pharmacology, 2009)
Summary of antimicrobial agents affecting cell wallSummary of antimicrobial agents affecting cell wall
synthesissynthesis
Agents affecting
the cell wall b-lactamase
inhibitors
b-lactam antibiotics Other antibiotics
Penicillins Cephalosporins Carbapenems Monobactams
1st generation 2nd generation 3rd generation 4th generation
Bacitracin
Vancomycin
Daptomycin
Clavulanic acid
Sulbactam
Tazobactam
Amoxicillin
Ampicillin
Dicloxacillin
Indanyl carbenicillin
Methicillin
Nafcillin
Oxacillin
Penicillin G
Penicillin V
Piperacillin
Ticarcillin
Ertapenem
Imipenem/cilastatin*
Meropenem
Aztreonam
CefepimeCefadroxil
Cefazolin
Cephalexin
Cefaclor
Cefprozil
Cefuroxime
Cefoxitin
Cefdinir
Cefixime
Cefotaxime
Ceftazidime
Ceftibuten
Ceftizoxime
Ceftriaxone

B lactam antibioticsB lactam antibiotics

Classification:
– Narrow spectrum – penicillinase sensitive
– Narrow spectrum – penicillinase resistant
– Broad spectrum penicillins
– Extended-spectrum penicillins
• Penicillins

What's the difference between Broad
Spectrum and Extended Spectrum
antibiotics?
Broad spectrum antibiotics have activity against both gram positive and gram
negative bacteria. Examples would be tetracycline and chloramphenicol.
Extended spectrum antibiotics are antibiotics which have had chemical
modifications which increase their gram negative coverage. Cephalosporins are a
good example. 1st generation cephalosporins have no gram negative coverage.
Gram negative coverage progressivly increases as you go higher in generations.

Penicillins
 Large diverse group of compounds
 Could be synthesized in the laboratory
 more economical to obtain natural penicillin
through microbial fermentation and modify it to
semi-synthetic forms
 Penicillium chrysogenum – major source
 All consist of 3 parts
 thiazolidine ring
 beta-lactam ring
variable side chain dictates microbial activity
6

A- Narrow spectrum – penicillinase (= β-
lactamase) sensitive
• Benzylpenicillin (penicillin G)
Naturally occurring
Poor oral availability (sensitive to stomach acid)
=> given by injection
Active against gram-positive bacteria
• Phenoxymethylpenicillin (penicillin V)
is more acid-stable than benzylpenicillin, which allows
it to be given orally.

B- Narrow spectrum – penicillinase (= b-
lactamase) resistant
• Methicillin
Semisynthetic
Poor oral availability (only parenteral)
Active against Gram +ve bacteria
Mostly used for Staphylococcus aureus
However, MRSA & ORSA has emerged
• Oxacillin
Good oral availability
• Cloxacillin
• Dicloxacillin

C- Broad spectrum – penicillinase (= b-lactamase)
sensitive
( Aminopenicillins)
 Ampicillin
 Semisynthetic
 Good oral availability
 Active against Gram +ve and Gram -ve bacteria
 Active against Enterobacteria
 Amoxycillin
 Excellent oral availability

D- Extended spectrum – penicillinase (= b-lactamase)
sensitive
(= Carboxypenicillins)
 Carbenicillin
 Semisynthetic
 Poor oral availability
 Active against Gram +ve and Gram -ve bacteria
Including Pseudomonas aeruginosa
 Ticarcillin
 Mezlocillin
 Piperacillin

Adverse effects of penicillins
1.Hypersensitivity reactions ( occur in 1-10% of pts;
fatality occur in 0.002%)
2. Super infections: A condition in which a patient with a
infectious disease acquires a second infection.
3. Diarrhoea
4. May cause convulsions after high doses by i.v or in
renal failure

CephalosporinsCephalosporins
 Account for majority of all antibiotics
administered
 Isolated from Cephalosporium acremonium
mold
 Beta-lactam ring that can be altered
 Relatively broad-spectrum, resistant to most
penicillinases, & cause fewer allergic reactions
 Some are given orally, many must be
administered parenterally
13

Cephalosporins
 4 generations exist
 First generation – cephalothin, cefazolin – most
effective against gram-positive cocci
 Second generation – cefaclor, cefonacid – more
effective against gram-negative bacteria
 Third generation – cephalexin, cefotaxime –
broad-spectrum activity against enteric bacteria
with beta-lactamases
 Ceftriaxone – new semisynthetic extended-
spectrum drug for treating wide variety of
infections
14

Fourth generation – (mostly b-lactamase restistant)
Cefepime
Broadest antimicrobial spectrum (Gram +ve and
Gram –ve)
Used for MDR (multi drug resistant) bacteria
and mixed infections

Adverse effects of cephalosporin
1. Hypersensitivity reactions- most common
Anaphylaxis, bronchspasm, urticaria – rash
2. Nephrotoxicity ; esp. cephradine
3. Superinfections
4. Diarrhea: oral cephalosporins, cefoperazone,
ceftriaxone & moxalactam.
5. Cefamandole, moxalactam & cefoperazone may cause:
a) Bleeding disorders
b) Flushing, tachycardia, vomiting with alcohol
intake


naturally-derived product of Streptomyces cattleya

Their structure renders them highly resistant to beta-
lactamases

Same mechanism of action as penicillins
 Imipenem
 broad spectrum against aerobic and anaerobic
Gram +ve as well as Gram -ve bacteria.
 Hydrolysed in the mammalian kidney by a
dihydropeptidase enzyme, and so is given with a
dehydropeptidase inhibitor, cilastatin
 Active against Pseudomonas aeruginosa and the
Enterococcus species
• Meropenem
• Doripenem
• Carbapenem
Other beta-lactam antibioticsOther beta-lactam antibiotics


Unlike other beta-lactams, the monobactam contains a nucleus
with no fused ring attached

Same mechanism of action as penicillins
 Aztreonam

The only commercially available monobactam antibiotic

Aztreonam has strong activity against susceptible Gram -ve
bacteria, including Pseudomonas aeruginosa

It has no useful activity against Gram +ve bacteria or anaerobes

It is known to be effective against a wide range of bacteria
including Citrobacter, Enterobacter, E coli, Haemophilus,
Klebsiella, Proteus, and Serratia species
• Monobactams

Other inhibitors of cell wall synthesisOther inhibitors of cell wall synthesis
 1-1- GlycopeptideGlycopeptide
(Vancomycin)
Important "last line" against antibiotic
resistant S. aureus
2-2- Polypeptide antibioticsPolypeptide antibiotics
(Bacitracin)
Topical application
Against gram-positives

1- Vancomycin
Only effective against Gram-positive bacteria
Poor oral absorption
Used to be the “Magic bullet” for methicillin-resistant
staphylococci, but now staph are becoming V-resistant.
Dose-related ototoxocity:
Tinnitus and can progress to total deafness
 Bind to D-Ala-D-Ala terminus of peptidoglycan
polypeptide prevents further elongation and
cross-linking of peptidoglycan chain
Mechanism of action

2- Bacitracin
•Mixture of polypeptides From Bacillus
subtilis
•Serious nephrotoxicity => only topical use
vs gram (+) bacteria
mechanism of action
• Inhibits dephosphorylation that transfers
peptidoglycan subunits to the growing cell
wall

Other Inhibitors of Cell Wall SynthesisOther Inhibitors of Cell Wall Synthesis
 Antibiotics effective against
Mycobacteria:
interfere with mycolic acid
synthesis or incorporation
Isoniazid (INH)
Ethambutol

2. Antibiotics that Inhibit Protein
Synthesis
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(according to Lippincott´s(according to Lippincott´s
Pharmacology, 2009)Pharmacology, 2009)
PROTEIN SYNTHESIS INHIBITORSPROTEIN SYNTHESIS INHIBITORS
TETRACYCLINESTETRACYCLINES
AMINOGLYCOSIDESAMINOGLYCOSIDES
MACROLIDES/KETOLIDESMACROLIDES/KETOLIDES
CHLORAMPHENICOLCHLORAMPHENICOL
CLINDAMYCINCLINDAMYCIN
QUINUPRISTIN/DALFOPRISTINQUINUPRISTIN/DALFOPRISTIN
LINEZOLIDLINEZOLID
DemeclocyclineDemeclocycline
DoxycyclineDoxycycline
MinocyclineMinocycline
TetracyclineTetracycline
AmikacinAmikacin
GentamicinGentamicin
NeomycinNeomycin
NetilmicinNetilmicin
StreptomycinStreptomycin
TobramycinTobramycin
AzithromycinAzithromycin
ClarithromycinClarithromycin
ErythromycinErythromycin
TelithromycinTelithromycin

2. Inhibition of protein synthesis
Ribosomes are essential for translation of mRNA into
proteins
No translation  No protein synthesis
No protein synthesis  No growth
Acting at 30S ribosomes
Aminoglycosides √

Tetracyclines √
Acting at 50S ribosomes
Chloramphenicol √
Macrolides √
Clindamycin
Streptogramins
Oxazolidones

Antibacterial Medications thatAntibacterial Medications that
Inhibit Protein SynthesisInhibit Protein Synthesis
Target ribosomes of bacteria
Aminoglycosides: bind to 30S subunit causing it to
distort and malfunction; blocks initiation of translation
Tetracyclines: bind to 30S subunit blocking
attachment of tRNA.
Macrolides: bind 50S subunit and prevents protein
synthesis from continuing.

Protein Synthesis InhibitorsProtein Synthesis Inhibitors
 Mostly bacteriostatic
 Selectivity due to differences in prokaryotic and
eukaryotic ribosomes

Antimicrobials that Bind to the 30S
Ribosomal Subunit

AminoglycosidesAminoglycosides
(bactericidal)
 mechanism of action - Aminoglycosides inhibit
translation of the mRNA by irreversible binding and
change the shape of 30S subunit of the ribosome,
causes the misreading of the codons along the mRNA.
This misreading of the codons causes an error in
translation leading to improper protein expression
leading to bacterial cell death.

 Against many Gram- and some Gram+.
 Most important adverse side-effect: (ototoxicity) and
kidney damage.
 Resistance – several mechs: inactivation of the drug
by acetylation, or adenylation, to prevent drug access,
(streptomycin only).
 Synergy - The aminoglycosides synergize
with B-lactam antibiotics. The B-lactams
inhibit cell wall synthesis and thereby increase
the permeability of the aminoglycosides.

 Gentamicin – used for acute, life-thretening gram- infections.
Has synergism with pen and van and combo.
 Amikacin – used for bact that are gent-resistant.
 Netilmicin – less toxic than gentamicin.
 Neomycin – too toxic for parenteral use. Used for topically
for skin infections and orally for sterilizing bowel before
surgery.
 Streptomycin – active against Mycobacterium tuberculosis.
But bec of its ototoxicity, rifampicin replaces.
 Rifampicin – resistance develops quickly alone; so, with TB,
combine with isoniazid, ethambutol, and pyrazinamide for the
1st 2 mos of treatment, followed by another 4 mos with
rifampicin and isoniazid.

Tetracyclines (bacteriostatic)
tetracycline, minocycline and doxycycline
 Mode of action - The tetracyclines reversibly
bind to the 30S ribosome and inhibit binding
of aminoacyl-t-RNA to the acceptor site on
ribosome (mRNA).
 Spectrum of activity - Broad spectrum; Useful
against intracellular bacteria
 Adverse effects –
 Super infection: Destruction of normal
intestinal flora resulting in increased secondary
infections.
 staining and impairment of the structure of
bone and teeth.
 Photosensitivity so Patients should be kept
out of heavy sunlight when receiving
tetracyclines

TetracyclinesTetracyclines
 Penetration into cell requires an energy-dependent
transport not present in mammals.
 Stable chelate complexes are formed by the
tetracyclines with many metals, including calcium,
magnesium, and iron. Such chelates are usually very
insoluble in water (so Oral absorption impaired by
food
 Resistant organisms develop
1. an efflux pump and do not accumulate the drug.
2. Genes for tet-resistance transmitted by plasmids.

Antimicrobials that Bind to the 50SAntimicrobials that Bind to the 50S
Ribosomal SubunitRibosomal Subunit

• The most important members of the group are
erythromycin, clarithromycin, azithromycin, spiramycin
bacteriostatic
 Spectrum of activity – Narrow spectrum bacteriostatic mainly
against Gram-positive bacteria, Mycoplasma, Legionella
(intracellular bacterias) but not against the
Enterobacteriaceae.
 Macrolides are bacteriostatic for most bacteria but are cidal
for a few Gram-positive bacteria.
• Macrolides
• Erythromycin is acid labile but is given as an enterically
coated tablet.
• Macrolides are widely distributed in the body except to
the brain and cerebrospinal fluid.
• Few side effects (GI disturbances)

It binds at the P-site of the 50S ribosomal subunit. As a
result of which, during translation, the P-site is
occupied by the macrolide. When the t-RNA attached
with the peptide chain tries to move to the P-site, it
cannot go there due to the presence of the macrolide,
thus getting thrown away. This prevents the transfer of
the peptidyl tRNA from the A-site to the P-site and
blocks the protein synthesis due to the inhibition of the
translocation of the nascent peptide chain.
 Mechanism of action:

ChloramphenicolChloramphenicol
Lincomycin, Clindamycin (bacteriostatic)
 Mode of action - These antimicrobials bind to the
50S ribosome and inhibit (polypeptide bond
formation) peptidyl transferase activity.
 Spectrum of activity - Chloramphenicol - Broad
range;
Lincomycin and clindamycin - Restricted range
 Resistance - Common
 Adverse effects - Chloramphenicol is toxic (bone
marrow suppression) but is used in the treatment of
bacterial meningitis.

A bacteriostatic antibiotic which inhibits protein synthesis
by forming a stable complex with elongation factor EF-G,
guanosine diphosphate and the ribosome
Use: mainly against G+ve bacteria, treatment of
staphylococcal infections.
• Fucidic acid
• Elongation factors are a set of proteins that facilitate the events
of translational elongation, the steps in protein synthesis from the
formation of the first peptide bond to the formation of the last one.
Mechanism of action:

Inhibition of Protein Synthesis by Antibiotics
Figure 20.4

Antibacterial
Drugs that Inhibit
Protein Synthesis

Antimicrobial agents 2 wafaa

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