ANTIMIKROBIAL

DR.HUSNI SAMADIN

ANTIMICROBIAL CHEMOTHERAPY
CHEMOTHERAPEUTIC AGENTS
Cmpounds used in treatment of diseases
ANTIMICROBIAL AGENTS
Compounds used in treatment of microbial diseases
Categories of antimicrobial agents
Antibiotics : biologically produced by microbes
Synthetic
Semi-synthetic : other chemical groups are added to
a nucleus of antibiotic
http://ssmmid.org

Antibiotic/Antimicrobial

Antibiotic: Chemical produced

by a microorganism that kills or
inhibits the growth of another
microorganism

Antimicrobial agent: Chemical

that kills or inhibits the growth of
microorganisms

Antimicrobial Agents
Disinfectant: antimicrobial agent
used only on inanimate objects
:Chemotherapeutic agent
antimicrobial agent that can be
used internally

Disinfection
Pasteurization: destruction of all
disease-producing microorganisms
or reduction in spoilage
microorganisms
Sterilization: killing or removal of all
living organisms and their viruses

Characteristics of Antibacterial Agents

1.Selective Toxicity
Inhibit growth of bacteria without damage to host
Due to differences between bacterial and human cells
at four major sites:

Cell wall
Cell membrane
Ribosomes
Nucleic acids

http://ssmmid.org

Few antiviral agents

due to lack of
selective toxicity

Characteristics of Antibacterial Agents

2. Spectrum of Activity
Broad Spectrum:
Active against both gram-positive and gram-negative
bacteria e.g. tetracycline, quinolones.

Narrow spectrum:
Active against one or very few types of bacteria
Vancomycin for Staph. & Enterococci.

Metronidazoleantiprotozoal.

antiamoebic

http://ssmmid.org

and

Characteristics of Antibacterial Agents

3. Cidal vs Static
Bactericidal
Agents that kill bacteria
Are useful in life-threatening infections
Also useful in patients with low WBC count

Bacteristatic
Agents that inhibit but do not kill bacteria
Bacteria may grow again when drug is withdrawn
Host defences are needed to kill bacteria
In large doses may become bactericidal
http://ssmmid.org

ANTIMICROBIALS : MECHANISMS OF ACTION

1.Inhibition of cell wall synthesis
Penicillins, Cephalosporins
Vancomycin, Bacitracin

2.Injury to plasma membrane

Polymyxin B, Nystatin,
Amphotericin B, Azoles

Transcription

mRNA

Transalation

Proteins

Replication

Rifampicin
Quinolones

3. Inhibition of protein Synthesis

Erythomycin, tetracyclin

5. Inhibition of nucleic
acid synthesis

6. Uncertain site of action

Metronidazole, INH

Enzymatic
activity

4.Inhibition of enzymatic activity

Trimethoprim,
Sulphamethoxazole
http://ssmmid.org

Groups of Antimicrobial Agents

(Mechanisms of Action)

Inhibitors of cell wall synthesis

Inhibitors of cell membrane functions
Inhibitors of protein synthesis
Inhibitors of enzymatic activity
Inhibitors of nucleic acids synthesis
http://ssmmid.org

Site of action of inhibitors

of cell wall synthesis

Cell wall synthesis

Cross-linking of
peptidoglycan

NAG

Beta-lactams
Fosfomycin

NAMA

Transfer to
peptidoglycan

NAMA-pentapeptide
Amino
Acids

Lipid carrier
(membrane)

NAG

Vancomycin

Bacitracin

NAG = N-acetylglucosamine
NAMA = N-acetylmuramic acid

Dephosphorylation
of lipids

http://ssmmid.org

Inhibitors of cell wall synthesis

A: BETA LACTAMS

Have a beta-lactam ring in their molecule

Penicillins
Cephalosporins
Carbapenems
Monobactams

all are bactericidal

B: GLYCOPEPTIDES
Vancomycin & Teicoplanin

C: CYCLOSERINE & BACITRACIN

http://ssmmid.org

Inhibitors of cell wall synthesis

A: BETA LACTAMS

Penicillins
Act by inhibiting cross-linking of peptidoglycan by
binding with penicillin binding proteins (PBPs) on
the cytoplasmic mamebrane leads to :
cell lysis
ovoid cell
filament cell
Accoridng to type of PBPs
http://ssmmid.org

Action of penicillins on grampositive bacterial cell wall

Penicillin

Capsule

Peptidoglycan
layer

Phospholipid
Tcytoplasmic
membrane

PBP

PBP

Transport protein

Cell lysis

Results of
action of
penicillins

Ovoid cell
Filament

http://ssmmid.org

Inhibitors of cell wall synthesis

A: BETA LACTAMS

Penicillins e.g.

Penicillin G
Ampicillin, Amoxycillin
Carbenicillin, Piperacillin for pseudomonas
Methicillin for penicillinase-producing
S. aureus

http://ssmmid.org

Inhibitors of cell wall synthesis

A: BETA LACTAMS

Cephalosporins
Inhibit cross-linking of peptidoglycan
Majority are produced by molds of genus cephalosporium

Advantage over Penicillins

Broad range of activity
Less susceptibility to b-lactamases
Fewer hypersensitivity reactions

http://ssmmid.org

Inhibitors of cell wall synthesis

A: BETA LACTAMS

Cephalosporins
Generation Names
Use
Activity
First
Cephradine I.M/I.V & G+ve bacteria
Cephalexin
oral
Second
Cefactor I.M/ I.V & G+ve + G-ve
oral
Third
Cefotaxime I.M/I.V Mostly G-ve, G+ve
Ceftazidime
Marked resistance
to beta-lactamases
Fourth
Cefpirome I.M., I.V.
http://ssmmid.org

Inhibitors of cell wall synthesis

A: BETA LACTAMS
Carbapenems (imipenem, meropenem)
Broadest activity of the b-lactams G+ve, G-ve and
anaerobes
Marked resistance to b-lactamases

Monobactams
Selective activity against G-ve bacilli including
Pseudomonas
Resistant to most b-lactamases

http://ssmmid.org

Inhibitors of cell wall synthesis

Vancomycin, Cycloserine, bacitracin
Block the formation of precursors of peptidoglycan
Vancomycin - bactericidal against G+ve.
Drug of choice against MRSA
Cycloserine - second-line anti-TB drug
Bacitracin - for superficial skin infections

http://ssmmid.org

Inhibitors of Cell Membrane Functions

A. Antibacterials
A few drugs in this group
Due to structural similarity of bacterial and
human cell membranes
Polymyxins disrupt phospholips leakage of
cell contents.

http://ssmmid.org

Inhibitors of Cell Membrane Functions

B. Anti-fungals
1. Polyenes
Act by binding with ergosterol in cell membrane large
pores leakage of cell contents
Nystatin, amphotericin-B, candicidin, trichomycin
2. Imidazoles
Act by inhibiting ergosterol synthesis
Clotrimazole (Canesten) - Topical agents
Ketoconazole
Fluconazole
Systemic agents

Inhibitors of protein synthesis : sites of action

Growing polypeptide
Chloramphenicol
50S

Tetracycline
tRNA

Erythromycin

Transcription
DNA
mRNA
30S

Streptomycin
70S prokaryotic
ribosome

Direction of
ribosome travel

Inhibitors of Protein Synthesis

Selective toxicity is due to differences in ribosomes
In human cells 80S = 60S & 40 S subunits
Bacterial cells 70S = 50S & 30S subunits
A. Drugs that act on 30S subunit
1.Aminoglycosides Streptomycin
Gentamicin/Amikacin
Change shape of 30S portion & blocks initiation of translation
Are bactericidal
Are toxic for kidneys and ears
Poorly absorbed from GIT given by injections

Inhibitors of Protein Synthesis

A. Drugs that act on 30S subunit
2.Tetracyclines - Doxycycline
Minocycline
Block attachment of tRNA to mRNA-ribosome complex
Are bacteriostatic against G+ve & G-ve bacteria
mycoplasma, chlamydiae and rickettsiae
Cause staining of teeth in young children

Inhibitors of Protein Synthesis

Drugs that act on 50S subunit

1. Chloramphenicol
Inhibit formation of peptide bond
Bacteriostatic / Bactericidal
Causes bone marrow suppression aplastic anaemia

2. Macrolides
Erythromycin,Clarythromycin, Azithromycin
Prevent movement of ribosome along mRNA
Bacteriostatic
One of the least toxic drugs

Inhibitors of Nucleic acid synthesis

A. Inhibitors of mRNA synthesis

Rifampicin
Inhibits mRNA synthesis by affecting
DNA-dependent polymerase of bacterial
cell without affecting human cells
First-line anti-TB drug.

Inhibitors of Nucleic acid synthesis

B. Inhibitors of DNA synthesis
1. Quinolones (naldixic acid)
Inhibit DNA gyrase which maintains the supercoiling of
closed circular DNA
Are broad spectrum bactericidal

2.Fluroquinolones
Ciprofloxacin,Ofloxacin, Sparfloxacin
Are broader spectrum than quinolones
Damage growing bones so not given to pregnant
women and young children.

Inhibitors of Nucleic acid synthesis

B. Inhibitors of DNA synthesis (anti-metabolites)
3.Sulfonamides and
trimethoprim

Para-aminobenzoic
acid (PABA)
Sulfamethxazole

Compete with PABA to

stop synthesis of folic
acid which is needed for
purine synthesis. These
are used in combination

Dihydrofolic acid
Trimethoprim

Tetrahydrofolic acid

Purines and other

precursors

DNA

Uncertain mechanisms of action

Isoniazid (INH), Ethambutol, Pyrazinamide
Are first line anti-TB drugs

Metronidazole (Flagyl)
Probably inhibit DNA synthesis
Bactericidal against G-ve anaerobes and Protozoa
(Giardia and Trichomonas)

Chemoprophylaxis
Is the use of antimicrobial agents to prevent
infections as:
A. In normal persons exposed to pathogens
Rifampicin 600 mg twice daily during outbreaks
of meningitis.
Isoniazid (INH) to prevent TB in those recently
infected.
Tetracycline to prevent plaque

Chemoprophylaxis
B. In persons with high susceptibility to
infections
Opportunistic infections in immunosuppressed
persons like AIDS
Recurrent urinary tract infections (UTI )
Congenital and rheumatic heart diseases
C. Prior to Surgery
Tooth extraction to prevent endocarditis
Colorectal surgery to prevent peritonitis and
wound infections

Antimicrobial Resistance
Relative or complete lack of effect
of antimicrobial against a previously
susceptible microbe
Increase in MIC

Asal usul Resistensi

A. Non genetic.
1.

Mencegah akses

2. Menghilangkan agen antimkroba dari sel menggunakan

efflux pump
3. Inanktivasi agen anti mikroba melalui modifikasi dan
degradasi.
4. Modifikasi dari target antimikroba

B. Genetic.
5. Transfer gen.
6. Mutasi

Mekanisme resistensi terhadap antimikroba

1. Mencegah akses
2. Menghilangkan agen antimkroba dari sel
menggunakan efflux pump
3. Inanktivasi agen anti mikroba melalui
modifikasi dan degradasi.
4. Modifikasi dari target antimikroba

Mekanisme Resistensi Terhadap antimikroba

MEKANISME
RESISTENSI

Enzimatik

KHUSUS
SARANA UNTUK
MENCAPAI
RESISTEN

CONTOH

Penghancuran
cincin betalaktamase oleh
enzim. Dengan
Resistensi
cincin betastaphylococi
laktam hancur,
terhadap
antibiotik tidak
penisilin;
akan lagi memiliki Resistensi
kemampuan
Enterobacteriacea
untuk mengikat e terhadap
PBP (Penisilinpenicllins,

Perubahan
sasaran

Perubahan
pengikat
protein
penisilin
Perubahan
Mutasi untuk
PBPs asli atau
akuisisi PBPs
akan
menyebabkan
ketidakmampua
n antibiotik
untuk mengikat

Resistensi
terhadap
methicillin
staphylococc
i dan
oksasilin

Menurun nya
pembentukan
saluran Porin
Karena ini adalah di
mana beta-laktam
menyeberangi
membran luar untuk
Penurunan
mencapai PBP dari
serapan
bakteri Gram-negatif,
perubahan dalam
angka atau karakter
dari saluran ini dapat
mengurangi
penyerapan
Betalactam ..

Enterobacter
aerogenes ,
Klebsiella
pneumoniae dan
Pseudomonas
aeruginosa
terhadap
imipenem

Perubahan dalam
struktur molekul
komponen dinding sel
Perubahan prekursor menurun
sasaran
mengikat vankomisin
sehingga sintesis dinding
sel mampu untuk
melanjutkan.

Enzimatik
modifikasi

Enzim mengubah
Memodifikasi berbagai
situs pada molekul
aminoglikosida sehingga
kemampuan dari obat ini
untuk mengikat ribosom
dan sintesis protein
berhenti sangat berkurang
atau hilang sama sekali.

Resistensi terhadap
vankomisin
enterococci

Resistensi
beberapa bakteri
negatif Grampositif dan Gram
untuk
aminoglikosida

Penurunan
serapan

Perubahan
sasaran

Perubahan angka
atau karakter
saluran Porin (melalui
aminoglikosida yang
Perlawanan dari
melintasi membran
berbagai bakteri
luar untuk mencapai
Gram-negatif untuk
ribosom dari bakteri
aminoglikosida
gram negatif) sehingga
penyerapan
aminoglikosida
berkurang.
Modifikasi protein
ribosomal atau rRNA
16. Ini mengurangi
Resistensi
kemampuan
Mycobacterium spp
aminoglikosida untuk terhadap
berhasil mengikat dan streptomisin
menghambat sintesis

Penurunan
serapan

Perubahan pada
membran luar
mengurangi penyerapan
obat dan / atau aktivasi
pompa yang
menghilangkan kuinolon
sebelum konsentrasi
intraseluler cukup untuk
metabolisme DNA
menghambat.

Perlawanan Gram
negatif dan
staphylococci
(penghabisan
mekanisme saja)
untuk berbagai
kuinolon

Perubahan subunit
Gram negatif dan
girase DNA menurunkan
Gram positif
Perubahan kemampuan kuinolon
ketahanan
sasaran
untuk mengikat enzim ini
terhadap kuinolon
dan mengganggu proses
berbagai
DNA

Resistensi diperoleh melalui mutasi dan transfer gen horizontal

Mutasi adalah perubahan spontan dalam urutan DNA dalam gen
yang dapat menyebabkan perubahan dalam sifat yang kode untuk.
Setiap perubahan dalam pasangan basa tunggal dapat menyebabkan
perubahan yang sesuai pada satu atau lebih asam amino untuk yang
dikode, yang kemudian dapat mengubah enzim atau struktur sel
yang berakibat pada perubahan afinitas atau aktivitas antimikroba
yang efektif dari yang ditargetkan.
Dalam genom prokariotik, mutasi sering terjadi karena perubahan
dasar yang disebabkan oleh agen eksogen, kesalahan DNA
polimerase, penghapusan, insersi dan duplikasi

Transfer gen horizontal, atau proses swapping materi genetik

antara tetangga "kontemporer" bakteri, merupakan sarana
dimana resistensi dapat diperoleh. Banyak dari gen resistensi
antibiotik dilakukan pada plasmid, transposon atau integrons
yang dapat bertindak sebagai vektor yang mentransfer gen untuk
anggota lain dari spesies bakteri yang sama, serta bakteri di lain
genus atau spesies. Transfer gen horizontal dapat terjadi melalui
. tiga mekanisme utama: transformasi, transduksi atau konjugasi
Transformasi melibatkan pengambilan fragmen pendek DNA t
oleh bakteri alami . Transduksi melibatkan transfer DNA dari
satu bakteri ke lain melalui bakteriofag.. Konjugasi melibatkan
transfer DNA melalui pilus seksual dan membutuhkan sel-sel
kontak. Fragmen DNA yang mengandung gen resistensi dari
donor resisten, kemudian dapat membuat bakteri sebelumnya
rentan mengekspresikan perlawanan sebagai kode oleh gen
. resistensi baru diperoleh

?What Factors Promote Antimicrobial Resistance

Exposure to sub-optimal levels of antimicrobial
Exposure to microbes carrying resistance genes

Inappropriate Antimicrobiale use

Prescription not taken correctly
Antibiotics for viral infections
Antibiotics sold without medical supervision
Spread of resistant microbes in hospitals due
to lack of hygiene

Inappropriate Antimicrobial Use

Lack of quality control in manufacture or outdate
antimicrobial

Inadequate surveillance or defective susceptibility assay

Poverty or war

Use of antibiotics in foods

Proposals to CombatAntimicrobial Resistance

Speed development of new antibiotics
Track resistance data nationwide
Restrict antimicrobial use
Direct observed dosing (TB)

Proposals to Combat
Antimicrobial Resistance
Use more narrow spectrum
antibiotics
Use antimicrobial cocktails

.Effect of combinations of drug

Synergism occurs when the effect of
two drugs together is greater than the
.effect of either alone
Antagonism occurs when the effect of
two drugs together is less than the
.effect of either alone
Effects of Combinations of