ANTIMIKROBA

DAN UJI KEPEKAAN

dr. Evita Mayasari, MKes.
Medical Faculty, University of Sumatera Utara

OBAT ANTIMIKROBA
Obat yang digunakan untuk menghambat
pertumbuhan dan atau membunuh bakteri
penyebab infeksi yang dapat diberikan per oral,
parenteral atau lokal sebagai obat luar
luar..
Antibiotika bahan yang dihasilkan oleh biotik
biotik
atau
t mak
makhluk
hl k hidup
hid /mikroorganisme
hidup/
ik
i
seperti
ti
Bakteri,, Actinomycetes,
Bakteri
Actinomycetes, jamur.
jamur.

2
dr. Edhie Djohan Utama,
Utama, SpMK
SpMK..

ANTIMIKROBA
ANTIBIOTIKA
CHEMOTHERAPEUTIKA
ANTI FUNGUS
ANTI VIRUS
ANTISEPTIKA
DESINFEKTANSIA
dr. Edhie Djohan Utama,
Utama, SpMK
SpMK..

PENEMUAN AWAL ANTIMIKROBA

SALVARSAN : ditemukan pada awal tahun 1900
oleh Paul Ehrlich untuk pengobatan penyakit
Syphilis.(Noble Prize)
PRONTOSIL (Sulfonamide) Oleh Gerard Domagk
1927 dan penggunaannya tahun 1935 (Noble
Prize)
SULFADIAZINE 693 = Sulfanilamide oleh British
Team pimpinan A.J.Evans
A J Evans tahun 1938
PENICILLIN oleh Alexander Fle
Flemming tahun 1929
dan penggunaannya tahun 1940 (Noble Prize)
NYSTATIN : antifung
antifungal
al pertama dijumpai tahun
1949 oleh Elisabeth Hazen & Brown
STREPTOMYCIN oleh Selman Waksman tahun
1940 (Noble Prize)
4

MIKROORGANISME YANG MENGHASILKAN

ANTI
NTIMIKROBA
MIKROBA
Bakteri
Actinomycetes (2100) (Streptomyces
(Streptomyces))
(400) (Genus Bacillus)

Fungi (800) (Mold = Penicillium & Cephalosporium)

Cephalosporium)
Algae
Protozoa

dr. Edhie Djohan Utama, SpMK.

JENIS DAN CARA KERJA

ANTIMIKROBA

Menghambat sintes
sintesis
is dinding sel bakteri
Merusak p
permeabilitas membran
sitoplasma
si
toplasma
Menghambat sintes
sintesis
is protein
protein..
Menghambat sintesis
sintesis asam nu
nukkleat.
leat.

dr. Edhie Djohan Utama, SpMK.

PENICICLLIN (Mold = Penicillium

Penicillium))
PNC--G dan Penicillin V
PNC
Methicillin,, Oxacillin
Methicillin
Oxacillin,, Cloxacillin
Cloxacillin,, Dicloxacillin
Ampicillin & Amoxacillin,
Amoxacillin, Carbenicillin
Carbenicillin,, Ticarcillin
Ticarcillin,,
Piperacillin,, Mezlocillin
Piperacillin
CEPHALOSPORIN ((mold
mold
ld = Cephalosporium
C h l
Cephalosporium)
i )
Gen.I : Cefachlor,
Cefachlor, Cephalothin,
Cephalothin, Cephalexin
Gen.II : Cefuroxim,
Cefuroxim, Cefixime
Cefixime,, Cefoxitin
Gen.III : Cefotaxime,
Cefotaxime, Ceftriaxone,
Ceftriaxone, Cefoperazon
Gen.IV : Cefepime,
Cefepime, Cefpirom
CARBAPENEM : Imipenem & Meropenem
MONOBACTAM : Aztreonam
GLYCOPEPTIDE : Vancomycin dan Teichoplanin
CYCLOSERINE : secondd line
li anti
ti tbc
tb
BACITRACIN : Untuk infeksi kulit superfis
superfisial

PENICILLIN GROUP
Penicillins:: penicillin G ((Pfizerpen
Penicillins
Pfizerpen;; Bicillin;
Bicillin; Wycillin),
Wycillin),
penicillin V ((Betapen
Betapen;; PenPen-Vee K), methicillin (Staphcillin),
Staphcillin),
ampicillin (Omnipen
Omnipen;; Polycillin
Polycillin)),
Polycillin),
) oxacillin (Bactocill ),
)
amoxicillin (Amoxil
(Amoxil;; Biomox;
Biomox; Polymox),
Polymox), ticarcillin (Ticar),
Ticar),
carbenicillin (Geocillin),
Geocillin), piperacillin (Pipracil),
Pipracil), mezlocillin
(Mezlin
Mezlin),
), bacampicillin
p
(Spectrobid
Spectrobid),
p
), dicloxacillin (Dynapen
Dynapen),
y p ),
nafcillin (Nallpen;
Nallpen; Unipen).
Unipen).

Penicillins plus -lactamase inhibitors or compounds

pre enting antibiotic degradation on the kidneys:
preventing
kidneys
kidne s:
s:
amoxicillin + clavulanate (Augmentin
Augmentin),
),
ticarcillin + clavulanate (Timentin
Timentin),
),
ampicillin
i illi + sulbactam
lb t
(Unasyn
U
Unasyn),
)
),
piperacillin + tazobactam (Zosyn),
Zosyn),
imipenem + cilastatin (Primaxin)
Primaxin) .
dr. Edhie Djohan Utama, SpMK.

BETALACTAM GROUPS

STRUKTUR DINDING GRAM (+) & GRAM ((-)

dr. Edhie Djohan Utama,

Utama, SpMK
SpMK..

10

Amphotericin B
Nystatin
Colistin
Polymixin

Tidak digunakan untuk obat sistemik karena toksik

dr. Edhie Djohan Utama, SpMK.

11

- Chloramphenicol (50S) - Aminoglycoside (30S)

- Erythromycin (50S)
- Tetracyclin (30S)
- Lyncomycin (50S)
Ribosom Mamalia 80S, sedangkan bakteri 70S, reseptor
pada
d subunit
b it 30S atau
t 50S.
50S
Macrolides : erythromycin, roxithromycin,
roxithromycin, clarithromycin
clarithromycin,,
azithromycin;; digunakan untuk bakteri Gram
azithromycin
Gram (+) dan
beberapa bakteri Gram
Gram (-).
Lincomycin dan Clindamycin umumnya digunakan untuk
bakteri Gram (+).
dr. Edhie Djohan Utama, SpMK.

12

Aminoglycoside : Streptomycin,
kanamycin,, tobramycin,
kanamycin
tobramycin, and amikacin
amikacin..
Most of Aminoglycoside are effective
against Gram (+) and Gram (-) bacteria.
A i
Aminoglycoside
l
id :bactericidal,
b
bactericidal
i id l, others:
h
bacteriostatic
bacteriostati
c

dr. Edhie Djohan Utama, SpMK.

13

Selective antimicrobial action to a specific

attack
tt k on th
the 70S ribosome
ib
off b
bacteria
t i
Several medicallyy important
p
antibiotics owe their
selective antimicrobial action to a specific attack on the
70S ribosome of bacteria,
bacteria, with mammalian 80S
ribosomes left unaffected.
unaffected

Those that act on the 30S ribosome are:

Amikacin
Gentamycin
Kanamycin
Neomycin
i
Streptomycin
Tobramycin
y

dr. Edhie Djohan Utama, SpMK.

14

Antibiotics that act on the 50S

portion
i off the
h ribosome
ib
include:
i l d
Chloramphenicol
Clindamycin
Furadantin
Fusidic acid
Lincomycin
Nitrofuran
Puromycin
Quinopristin/
Quinopristin
/Dalfopristin
Spectinomycin
Tetracycline
dr. Edhie Djohan Utama, SpMK.

15

Sulfonamide (berkompetisi
(berkompetisi dengan PABA)
Trimethoprim (menghambat dihidrofolic acid
reducctase)
redu
Rifampicin (Streptomyces
Streptomyces,, menghambat
enziim RNA pol
enz
poliimerase
merase,, mencegah sintes
sintesis
is
RNA)
Pyrimidine
y
Quinolone : ((blokade
blokade DNA gyrase
gyrase))
- Nalidixic acid
- Cyprofloxacin
yp
- Norfloxacin
- Ofloxacin
dr. Edhie Djohan Utama, SpMK.

16

Quinolone
Fluoroquinolones (synthetic
chemicals) are broad spectrum and
examples include norfloxacin,
ciprofloxacin enoxacin
ciprofloxacin,
enoxacin,
levofloxacin, and trovafloxacin.
trovafloxacin.
The fluoroquinolones inhibiting one or
group
p of enzymes
y
called
more of a g
topoisomerase, enzymes needed for
bacterial nucleic acid synthesis.
y
dr. Edhie Djohan Utama, SpMK.

17

Inhibisi Pathwayy Folic Acid oleh

Sulfonamide dan Trimethoprim
Sulfonamide
Sulfona
mide

Trimethoprim

Pteridine H2
+

PABA
+

Glutamic acid

Purine
FAH2
(Dihydro
Dihydro--

FAH4 + C1
(Tetrahydro
Tetrahydro--

folic ac
acid
id))

Pyrimidine

folic ac
acid
id))

Amino acid

9
dr. Edhie Djohan Utama, SpMK.

18

Antimicrobial Spectrum
p
BROAD SPECTRUM : Drugs that are effective
against a variety of both gramgram-positive and
gram--negative bacteria (e.g., tetracycline,
gram
streptomycin,
p
y , cephalosporins,
cephalosporins
p
p
, ampicillin,
ampicillin
p
,
sulfonamides).

NARROW SPECTRUM : Those effective

against just Gram (+) bacteria, just Gram (-)
b t i or only
bacteria,
l a few
f species
i (e.g., penicillin G,
erythromycin, clindamycin,
clindamycin, gentamicin
gentamicin).
).
dr. Edhie Djohan Utama, SpMK.

19

Range of Activity

Organisms Affected

Narrow Spectrum

Gram-positives
G
(Actinomyces,
Macrolides (Erythromycin)
Corynebacteria, Bacillus,
Polypeptides (Polymyxin)
Clostridium, Pyogenic cocci,
Spirochetes)

Moderate Spectrum

Gram-positives plus
y
enteric and
systemic,
urinary tract Gramnegatives

Sulfonamides
Aminoglycosides
gy
(Streptomycin, Gentamycin,
Tobramycin)

Narrow/Moderate
Spectrum

Gram positives plus GramGram-positives

Gram
negatives

Beta-lactams
(Penicillin, Ampicillin,
Cephalosporins)

Broad Spectrum

All prokaryotes except

Mycobacteria and
Pseudomonas

Chloramphenicol
p
Tetracycline

Anti-mycobacterial

Mycobacteria

Isoniazid Ethambutol
Streptomycin Rifampin

dr. Edhie Djohan Utama, SpMK.

Example Antibiotics

20

Antibacterial activity (spectrum) of antimicrobial agents.

Aerobic
bacteria

Anaerobic
bacteria

Gram

Gram

Gram

Gram

(+)

(-)

(+)

(-)

Broad

cefoxitin, chloramphenicol, imipenam,

tetracyclines

Intermediate

carbenicillin, ticarcillin, ceftiofur,

penicillin/clavulanic acid, cephalosporins

ampicillin, amoxicillin

Spectrum

Narrow

aztreonam, polymyxin

aminoglycosides, spectinomycin,
sulfonamides, trimethoprim

enrofloxacin

+
+

: variable activity

Examples

benzyl
y p
penicillin G

lincosamides, macrolides,pleuromutilins,
vancomycin
bacitracin

nitroimidazoles

21

Antimicrobial Effects on Cells

Drugs that actually kill microorganisms are
termed bactericidal
bactericidal..
Drugs that only inhibit the growth of
microorganisms
g
are termed bacteriostatic
bacteriostatic..
The decision to use a bactericidal or
bacteriostatic drug to treat infection depends
entirely upon the type of infection.
Bactericid agent
agents
s will kill cells that are actively
growing. Bacteriostatics,
Bacteriostatics, will only inhibit the
growth of cells; ultimate elimination of the
organisms is dependent upon host phagocytic
activity..
activity
dr. Edhie Djohan Utama, SpMK.

22

Bactericidal and Bacteriostatic

Bacteriostatic
Some antimicrobial agents are cidal in
action: they kill microorganisms (e.g.,
(e g
penicillins, cephalosporins,
streptomycin neomycin).
streptomycin,
neomycin
neomycin)).
)
Others are static in action: they inhibit
microbial growth long enough for the
body's own defenses to remove the
organisms (e.g., tetracyclines,
erythromycin, sulfonamides).
sulfonamides).
dr. Edhie Djohan Utama, SpMK.

23

Choice of Antimicrobial
A narrow spectrum is preferable since it will cause less
destruction to the body's normal flora.
Indiscriminate use of broad spectrum antibiotics can
lead to superinfection by opportunistic
microorganisms,
i
i
such
h as Candida
C did (yeast
(
t iinfections)
f ti
)
and Clostridium difficile (antibiotic
(antibiotic--associated
ulcerative colitis), when the body
body'ss normal flora is
destroyed.
Other dangers from indiscriminate use of antimicrobial
chemotherapeutic agents include drug toxicity, allergic
reactions to the drug, and selection for resistant
strains
t i off microorganisms.
microorganisms
i
i
.
dr. Edhie Djohan Utama, SpMK.

24

Site of Activity

Example Antibiotics

Inhibition of cell wall integrity Lysozyme

Inhibition of cell wall synthesis :
1. Biosynthetic enzymes
(cytoplasmic)

F f
Fosfomycin,
i Cycloserine
C l
i

2. Membrane-bound phospholipid
carrier

Bacitracin

3. Polymerization of subunits

Beta-lactams

4. Combine with wall substrates

Vancomycin

Inhibition of membrane
integrity :

Surfactants, Polyenes,
Polypeptides

IInhibition
hibiti off membrane
b
synthesis :

None

Inhibition of nucleic acid

integrity :

Alkylating, Intercalating agents

Alkylating
(mitomycin, chloroquin)
25

Inhibition of nucleic acid synthesis :

1. Metabolism of DNA

5-Fluorocytosine, Acyclovir, NTP

analogs

2. Replication of DNA

Nalidixic acid, Novobiocin,

Nitroimadazoles

3 Synthesis of RNA
3.

Rifampin

Protein integrity :

Phenolics, Heavy metals

Protein synthesis :
1 30S Subunit
1.

Streptomycin, Kanamycin,
Tetracycline

2. 50S Subunit

Chloramphenicol, Macrolides
(Clindamycin, Erythromycin)

3. Folate metabolism

Sulfonamides, Trimethoprim
dr. Edhie Djohan Utama, SpMK.

26

Altered Receptors :
1. Beta-lactams

Altered Penicillin Binding Proteins

2. Macrolides

Methylation of 2 adenine residues in 23S

RNA of the 50S subunit

3 Rifampin
3.

Single amino acid change in RNA

polymerase -subunit

4. Sulfonamide/trimethoprim

Altered synthetase binds pABA

preferentially/altered reductase for TMP

5. Nalidixic acid

Altered gyrase

6. Streptomycin

Altered S12 protein in 30S subunit

Decreased Entry :
1. Tetracycline

Normally biphasic, active transport reduced

2. Fosfomycin (chromosomal)

Glucose-6-phosphate transport reduced

Destruction/Inactivation :
1. Chloramphenicol acetyltransferase

Acetylates chloramphenicol

2 Beta-lactamase
2.
Beta lactamase

Cleaves -lactam
lactam ring

3. Aminoglycosides

Acetylation or phosphorylation as drug

27
passes membrane

Side effects/Toxic effects

Examples
Intestinal (C. difficile), Vaginal
(Candida)

Overgrowth of pathogens
Depression
D
i off iintestinal
t ti l
symbiotes
Nephrotoxicity
Ototoxicity - 8th cranial nerve
Ophthalmic
p
toxicity
y
Aplastic anemia
Hypersensitivity
Bone seeking

Several
Polypeptides, Aminoglycosides
Aminoglycosides
Ethambutol
Chloramphenicol
Penicillin
Tetracycline

dr. Edhie Djohan Utama, SpMK.

28

Cephalosporins
1st
genera
eneration
tion

2nd
genera
eneration
tion

3rd
genera
eneration
tion

4th
genera
eneration
tion

Cefadroxil

Cefaclor

Cefdinir

Cefepime

Cefazolin

Cefamandole

Cefoperaxone

Cefpirom

Cefelixin

Cefonicid

Cefotaxime

Cephalothin

Ceforanide

Ceftazidime

Cephaprin

Cefotetan

Ceftibuten

Cephradine

Cefoxitin

Ceftizoxime

Cefuroxime

Ceftriaxone

Cefixime
Cefdinir
Cefetamet

29

The Future of Chemotherapeutic Agents

Many bacterial diseases, previously treatable with
antibiotics have become resistant to antibiotics.
antibiotics,
antibiotics
Chemicals produced by plants and animals are
providing new antimicrobial agents,
agents, including
antimicrobial peptides.
New antimicrobials include DNA that is
complementary to specific genes in a pathogen;
the DNA will bind to the pathogen's DNA or
mRNA and inhibit protein synthesis
synthesis.
dr. Edhie Djohan Utama, SpMK.

30

Message From the Director General

WHO (2000)
Drug resistance is the most telling sign that we
have failed to take the treat of infectious diseases
seriou
serio
usly. It suggests that we have mishandled of
disease fighting drugs, by misusing, underusing
and overusing them.
A World without Antibiotics. It could bring back
to a pre
pre--antibiotic age. We are vulnerable without
effective medicines.

dr. Edhie Djohan Utama, SpMK.

31

Impact of Resistance :
Staph
p aureus 99% sensitive to p
penicillin G
1940's and all other Beta lactam antibiotics.
Staph aureus 75% resistant to penicillin
1970's and ampicillin but still 99% sensitive to
flucloxacillin and cephalosporin.
Staph aureus 98% resistant to penicillin
and 20% resistant to flucloxacillin and all
1990's Beta lactams.
Vancomycin and Teicoplanin only
therapeutic options remaining.
remaining
Intensive care units - Acinetobacter and
1995 Moraxella species resistant to all
1996
antibiotics tested.

32

MICROBIAL RESISTANCE TO
ANTIMICROBIAL CHEMOTHERAPEUTIC
AGENTS
A common problem in antimicrobial
chemotherapy is the development of
resistant strains of bacteria
bacteria.. Most
bacteria become resistant to
antimicrobial agents by one or more of
the following mechanisms:
dr. Edhie Djohan Utama, SpMK.

33

Mekanisme terjadinya strain resiste

resisten
1. Producing enzymes which detoxify or
inactivate the antibiotic,
antibiotic, e.g., penicillinase
and other betabeta-lactamases
lactamases..
2. Altering the target site in the bacterium to
reduce
d
or bl
block
k binding
bi di
off the
h antibiotic,
antibiotic
ibi i ,
e.g., producing a slightly altered ribosomal
subunit that still functions but to which the drug
can't bind.
3. Preventing transport of the antimicrobial
agent into the bacterium,
bacterium, eg.,
eg., producing an
altered cytoplasmic membrane or outer
membrane.
membrane
dr. Edhie Djohan Utama,
Utama, SpMK
SpMK..

34

4. Developing
e e op g a
an a
alternate
te ate metabolic
etabo c
pathway to byby-pass the metabolic step
being blocked by the antimicrobial agent,
agent,
e g overcoming drugs that resemble substrates
e.g.,
and tie
tie--up bacterial enzymes.
5. Increasing the production of a certain
bacterial enzyme,
enzyme, e.g., overcoming drugs that
resemble substrates and tietie-up bacterial
enzymes.
dr. Edhie Djohan Utama, SpMK.

35

UJI KEPEKAAN BAKTERI

TERHADAP ANTIMIKROBA
O
CARA PENGENCERAN (Dilution
Methods) :
Memakai media cair
Memakai media padat

Cara ini kwantitatip

p dan akurat

CARA DIFUSI (Diffusion Methods) :

Memakai cakram antimikroba
Tablet antimikroba

Cara ini kwalitatip

p dan rutin
dilakukan
dr. Edhie Djohan Utama, SpMK.

36

CARA PENGENCERAN
KWANTITATIP
KHM (Kadar Hambatan Minimal = MIC)
KBM (Kadar Bunuh
Bunuh Minimal = MBC)
AKURAT
UNTUK PENELITIAN / PERMINTAAN KHUSUS

dr. Edhie Djohan Utama, SpMK.

37

CARA PENGENCERAN (lanjutan)

MEDIA CAIR
Cara Makro : seri 12 tabung reaksi
Cara Mikro : plat mikrotiter
ikrotiter,, pipet mikro
MEDIA PADAT
Mueller Hinton Agar
g
AM diencerkan kelipatan dua (1 ug,
ug, 0,5 ug
ug,,
0 25 ug
0.25
ug.. 0.125
0 125 ug
ug,, dst
dst))
Larutan bakteri log phase MacFarland 1
dr. Edhie Djohan Utama, SpMK.

38

CARA DIFUSI
MEDIA :

Mueller Hinton Agar

g atau Sensitest
Agar
Jika bakteri fastidi
fastidiu
us : Agar Darah
BAKTERI :
Bakteri Log phase,
phase kelarutan MacFarland 0,5
05
Disemaikan dengan kapas lidi steril 3 streak
CAKRAM :
Kertas saring
Tablet
dr. Edhie Djohan Utama, SpMK.

39

MEMBACA DAERAH INHIBISI

Daerah inhibisi diukur
menggunakan
gg
kaliper
p (jjangka
g
sorong)) atau penggaris
sorong
Lebar daerah inhibisi
di
disesuaikan
ik dengan
d
daftar
d f
dari setiap AM dan Bakteri
yang
y
g diujij kepekaannya
p
y
(setelah dieramkan 18
18--24
jam).
Di
Dinyatakan:
Dinyatakan
t k :
Sensitif (susceptible
Sensitif
usceptible),
),
Hampir
p resisten
resisten,,
Resisten
dr. Edhie Djohan Utama, SpMK.

40

ANTIMIKROBA

GENUS

Kandungan
disk (cakram
AM)

Diameter Zona Hambat (mm)

Resisten

Intermediat

Sensitif

14-16

>17

-LACTAMS

Ampicillin

Carbenicillin

Enterobacteriaceae

10 g

<13

Staphylococci

10 g

<28

>29

Enterococci

10 g

<16

>17

Pseudomonas

100 g

<13

14-16

>16

Gram (-)

100 g

<19

20-22

>23

13-Oct

>14

Methicillin

Staphylococci

5 g

<9

Mezlocillin

Pseudomonas

75 g

<15

Other Gram (-)

75 g

<17

18-20

>21

Nafcillin

Staphylococci

1 g

<10

12-Nov

>13

Oxacillin

Staphylococci

1 g

<10

12-Nov

>13

Penicillin

Staphylococci

10 units

<28

>29

Enterococci

10 units

<14

>15

Pseudomonas

100 g

<17

>18

Other Gram (-)

100 g

<17

Piperacillin

dr. Edhie Djohan Utama, SpMK.

>16

18-20

>21
41

FAKTOR PENYEBAB RESISTENSI

Faktor non genetik :
AM akan resisten jika bukan pada masa aktif
pembelahan bakteri. Pada umumnya semua
AM baru bisa bekerja baik pada masa aktif
aktif
pembelahan bakteri
bakteri..
Hilangnya struktur target untuk AM ((kehilangan
kehilangan
dinding
g sel
sel)), sehingga
gg obat betalaktam jjadi
resisten..
resisten
Faktor genetik : Terjadi per
peru
ubahan genetik
menimbulkan resistensi bakteri
bakteri..
Resistensi kromosomal
R i t
Resistensi
i ekstrakromosomal
k t k
l (melalui
( l l i Plasmid)
Pl
id)
42

CARA TERJADINYA RESISTENSI

INTRINSIC :
Hal ini biasa untuk semua spe
spessies dimana spes
spesies tertentu
tid k mempunyai
tidak
memp n i target
t get atau
t reseptor
e epto untuk
nt k antimikroba,
antimikroba
ntimik ob ,
atau ada barrier alamiah a.l.:
a.l.:
= Bakteri
a e a
anaerob
ae ob terhadap
e adap Aminoglik
Aminogl
og ikosid
osida
os
da
da
= Streptococcus resisten terhadap Aminogl
Aminoglik
ikosid
osida
a karena
mempunyai /adanya barier alamiah
alamiah..
= Enterobacteriaceae resisten terhadap PNCPNC-G

ACQUIRED : FAKTOR EKSTRA KHROMOSOMAL

Modifikasi genetik karena mutasi,
mutasi, tranfer gene melalui
transfer Plasmid (transformasi, transduksi, konyugasi) sebab
Plasmid membawa R Factor atau transposon
dr. Edhie Djohan Utama, SpMK.

43

PLASMID
Plasmid = closed loop of DNA, elemen geneti
genetikk yg sangat
kecil (berat kira2 1
1--3% kromosom bakteri)
bakteri), di luar
kromosom
romosom,, membawa gen resisten terhadap antimikroba
antimikroba..
Mampu bereplikasi
bereplikasi di dalam sel bakteri secara autonom
Bisa berpindah antar spe
spessies (broad host range)
Berada bebas dalam sitoplasma bakteri
Salah satu Plasmid adalah R Factor, beberapa R Factor
membawa transposon (gen resisten yang bisa berpindah
dari satu Plasmid ke Plasmid lainnya atau ke kromosom).
Kini dikenal lagi INTEGRON
Contoh lain : toksin bakteri dan faktor F ((fertility)
y).
dr. Edhie Djohan Utama,
Utama, SpMK
SpMK..

44

45

CARA PERPINDAHAN GEN

TRANSDUKSI
Plasmid DNA via Bak
Bakteriof
teriofaga
aga (biasa bakteri Gam positip
positip))
ditransfer ke populasi kuman lain.
lain

TRANSFORMASI (fragment DNA bebas dapat melewati

dinding sel dan kemudian bersatu dalam genom sel)

sel). Biasa
dil k k di laboratorium
dilakukan
l b t i
(rekayasa
k
genetik)
genetik
tik)). Pindah
tik
Pi d h
secara spontan
KONYUGASI
Melalui Fertility Factor maka RTF (Resista
(Resistant Transfer
Factor) pindah dari satu sel ke sel lain sering
menyebabkan multidrug resisten
resisten..

TRANSLOKASI / TRANSPOSISI
Perpindahan bagian kromosom dalam sel
dr. Edhie Djohan Utama, SpMK.

46

CONJUGATIVE TRANSPOSON
Telah dikenal type baru elemen conjugative yaitu Conjugative
Transposon
Terdapat didalam khromosom bakteri.
bakteri.
Conjugative Transposon terintegrasi didalam Plasmid atau
gg lebih susah untuk
berada di dalam khromosom bakteri sehingga
dideteksi..
dideteksi
Ada kemungkinan bertanggung jawab dalam kebanyakan
transfer Plasmid

Transfer terjadi tidak hanya antar species pada group Bakteri

Gram(+) atau antar group Bakteri Gram ((-) tetapi juga antara
Bakteri Gram (+) dan Bakteri Gram ((--)

Transposons or "jumping genes" are capable of integration into

the chromosome of a bacteria or into plasmids. The can be a
whole gene or part of a gene.
dr. Edhie Djohan Utama, SpMK.

47

INTEGRON
KINI DIKENAL ELEMENT INTERGRATING
BARU = INTEGRON
INTEGRON BERTANGGUNG JAWAB UNUN-TUK
BERBAGAI PLSMID YANG MEMBAMEMBA-WA
MULTIPLE DRUG RESISTANCE GENE
INTEGRON SEPERTI TRANSPOSON
ADALAH SEGMEN DNA LINEAR.
LINEAR

dr. Edhie Djohan Utama, SpMK.

48

RESISTENSI PADA BETALAKTAM :

Enzim -laktamase yang dihasilkan bakteri membuka
Enzi
( l
(cleaves)
) cincin
i i -laktam
l kt sehingga
hi
tdk aktif
akti
ktiff. Bakteri
kti
B kt i
Gram(--) menghasilkan -la
Gram(
lak
ktamase dalam periplasma
sedangkan bakteri Gram(+) : dalam cairan ekstraselula
ekstraselular.
Tidak adanya PBP (Penicillin Binding Protein) reseptor
bakteri menjadi resisten.
resisten. (Alteration of the target of the
antibiotic) Dalam hal ini penambahan -laktamase
inhibitor tidak berguna.
berguna.

dr. Edhie Djohan Utama, SpMK.

49

RESISTENSI PADA
BETALAKTAM :
Betalaktam tidak berhasil mengaktivasi
g
autolytic enzyme (yang menghancurkan
peptidoglik
peptidogl
ikan),
an), sehingga bakteri menjadi
toleran..
toleran
Resisten terhadap AM Glycopeptide : walau
belum jelas benar
benar,, tetapi 2 gene (vanA
(vanA &
vanH)) yang terlibat menyevanH
menye-babkan dihasilkan
protein yang berbeda yang tidak mengimengi-kat
V
Vancomycin.
Vancomycin
i .

dr. Edhie Djohan Utama, SpMK.

50

ANTI ENZYME BETALACTAMASE

Obat gol.
gol. betalaktam menjadi resisten karena bakteri
menghasilkan enzim betalaktamase yang
menghancurkan cincin beta
beta--laktam dari obat
obat..
Enzim betalaktamase tersebut bisa dirusak dengan
Enzi
menambahkan
b hk salah
l h satu
t zatt di bawah
b
h ini
i i:

+ Clavulanic acid (Augmentin

(Augmentin))
+ Sulbactam (Sulperazon)
Sulperazon)
+ Tazobactam
ob c
(Piperacillin
pe c
+ Tazobactam)
Tazobactam
ob c
)
Penambahan salah satu zat diatas menyebabkan obat
golongan
g
g betalaktam menjadi
j sensitif
sensitif kembali
kembali..
dr. Edhie Djohan Utama, SpMK.

51

MRSA,, VISA,
MRSA
VISA, VRSA,
VRSA, ESBLs
MRSA : Meth
Methiicillincillin-resistant S. aureus
MRSA refers to a type of bacteria (Staphylococcus
aureus) that is resistant to many antibiotics. It is a
common cause of hospital
hospitalp -acquired
q
infections.
Mupirocin ointment has also shown promising
results in decreasing
g nasal carriage.
g Wide spread
p
use
is only indicated in certain settings to avoid mupirocin
resistance.

VISA : Vancomycin Interme

Intermediate S. aureus
VRSA : Vancomycin Resistant S. aureus
dr. Edhie Djohan Utama, SpMK.

52

ESBL = Extended spectrum

p
beta lactamase
lactamase..
This term refers to beta lactamase enzymes
produced mainly by Klebsiella and E. coli that
encode for resistance to broadbroad-spectrum
-lactam antibiotics that normally have activity
against Gram (-) bacilli.
Examples are cefotaxime
cefotaxime,, ceftriaxone
ceftriaxone,,
ceftazidime,, aztreonam and cefpodoxime.
ceftazidime
cefpodoxime.
These enzymes are not active against the
cephamycins,, and are inhibited by clavulanic
cephamycins
acid.
id
dr. Edhie Djohan Utama, SpMK.

53

AMINOGLIK
AMINOGL
IKOSID
OSIDA
A
Bakteri
Bak
terissidal,
idal, inak
inakti
tiff pd pH rendah dan anaerob
dan MO intras
intraselular
Sinergistik dengan grup BetaBeta-la
lakktam
Ampuh untuk bakteri Batang Gram (-)
Toks
To
ksiik pada dosis tinggi
Menghambat sintes
sintesis
is protein dengan ber
berikatan
ikatan
pada 30S ribosomal unit sehingga tjd misreading
mRNA
Streptomycin, Kanamycin,
Kanamycin, Gentamycin,
Gentamycin,
Tobramycin,, Amikacin
Tobramycin
Amikacin,, Netilmicin
dr. Edhie Djohan Utama, SpMK.

54

RESISTENSI PADA AMINOGLIK

AMINOGLIKOSID
OSIDA
A
Reseptor subunit 30 S hilang
Terdapat enz
enziim yang menghancurkan
obat (acethylase
acethylase,, adenylase dan
fosforilase))
fosforilase
P
Permeabilitas
bilit terhadap
t h d obat
b t turun
t
turun,
,
transport obat ke dalam sel berkurang
sehingga
hi
tidak
tid k mencapaii Ribosom
Rib

dr. Edhie Djohan Utama, SpMK.

55

IMPLIKASI KLINIS RESISTENSI

Timbulnya resistensi bakteri terhadap antimikroba
bahkan terjadinya multiple drugs resisten (MDR)
bisa mengundang banyak problem berat dalam
pengobatan penyakit infeksi
Timbulnya Kuman Rumah Sakit yang amat
resisten sebab RS sering menggunakan dosis
tinggi dan dalam intensitas tinggi.
Antibiotik baru perlu riset yg lama (10(10-20 tahun)
sehingga bisa terjadi tiadanya antibiotika yang
bisa digunakan untuk mengobati penyakit infeksi.
dr. Edhie Djohan Utama, SpMK.

56

Prevention and control

of antibiotic resistance
Reduce selective pressures:
1. Use antibiotics for bacterial disease
1
2. Use appropriate dosing and length of time
3. Change medication if ineffective
4 U
4.
Use appropriate
i t medication
di ti ffor a specific
ifi site
it
5. Stop use of antibiotics in the animal husbandry for growth
p
promotion
6. Regulate prescribing practices in veterinary medicine
7. Establish antibiotic prescribing practices and distribution
especially in countries that allow over the counter
medications without precripton
8. Educate the public to the dangers of overuse/misuse of
antibiotics
tibi ti
dr. Edhie Djohan Utama, SpMK.

57

Antifungal Drugs
1.Polyenes, such as nystatin and amphotericin B,
combine
bi with
ith plasma
l
membrane
b
sterols
t l andd are
fungicidal.
2. Azoles interfere with sterol synthesis and are used
to treat cutaneous and systemic mycoses.
mycoses
3. Griseofulvin interferes with eukaryotic cell division
and is used primarily to treat skin infections
caused by fungi.
dr. Edhie Djohan Utama, SpMK.

58

Antifungals
g that bind sterols :
Membrane structural differences :
The composition of the fungal plasma membrane differs
from the composition of the mammalian plasma
membrane particular in terms of the presence or absence
of certain kinds of sterols.
sterols
There exist antibiotics that, consequently, more effectively
recognize fungal plasma membrane than mammalian
plasma membrane.
Examples include:
= amphotericin B
= nystatin
= ketoconazole
= miconazole
dr. Edhie Djohan Utama, SpMK.

59

Antiviral Drugs
g
1. Amantadine blocks p
penetration or uncoating
g of
influenza A virus.
virus.
2 Nucleoside and nucleotide analogs such as acyclovir
2.
acyclovir,,
AZT,, ddI
AZT
ddI,, and ddC inhibit DNA or RNA synthesis.
synthesis.
3 Protease inhibitors,
3.
inhibitors, such as indinavir and saquinavir
saquinavir,,
block activity of an HIV enzyme essential for assembly of
a new viral coat.
coat.
4. Alpha
Alpha--interferons inhibit the spread of viruses to new
cells.
cells
dr. Edhie Djohan Utama, SpMK.

60

dr. Edhie Djohan Utama, SpMK.

61