Suharto

Divisi Peny Tropik Infeksi

Bagian IlmuPenyakit Dalam
FK Unair / RSU Dr Soetomo
Surabaya

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Antibiotic resistant mechanism
 Antimicrobial Resistance
FREQUENTLY ASKED
QUESTION
Q . What is antimicrobial
resistance?
Q . Why is antimicrobial
resistance a problem?
Q . How serious is the problem?
Q . Is the problem worse than in
the past?
Q . Is there special cause for
alarm?
Q . Why has this happened now?
Q . What are some of these
trends?
Q . What is the most important
cause of resistance?
Q . What constitutes
inappropriate” use of
antimicrobials?
Suharto
Antibiotic resistant mechanism
Q . Are other economic factors
involved?
Q . Does this mean that only
those populations living in
developing countries are
threatened by resistance?
Q . Which specific diseases are
most affected?
Q . Why are hospital-acquired
infections so dangerous?
Q . Does the use of growth
promoters and other drugs in
food-producing animals
contribute to the problem?
Q . What can be done?
Q . Who needs to take action?
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 RESISTENSI ANTIBIOTIKA
Masalah resistensi antibiotik  akibat langsung maupun tak langsung
memberi dampak medis dan sosio ekonomis.
pemilihan antibiotika menjadi terbatas dan memerlukan waktu,
sehingga infeksi tidak segera terberantas , yang mungkin
meluas sehingga berachir dengan sepsis; septic syok dan MOF.

angka morbiditas dan mortalitas meningkat bermakna,

biaya bertambah tinggi akibat length of stay yang panjang,
antibiotika yang lebih mahal terpaksa dipakai,
beban tugas laboratorium bertambah untuk surveillance dll.

Pemahaman bagaimana resistensi antibiotika timbul perlu

dimiliki agar tindakan pencegahan bisa maksimal.
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Antibiotic resistant mechanism
 PATHOPHYSIOLOGY CLINICAL PRESENTATION OF SEPSIS

DEATH DEATH

mof mof
lung, ards,
cv failure septic shock

sirs,altered severe
organ perfusion
sepsis
SIRS sepsis

Local inflammatory
respon local infection

Characteristics
bacteria Site of
focus of the particular
fungi, viruses infection
pathogen
parasites
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Antibiotic resistant mechanism
 bacterial intelligence
A colony of Paenibacillus
dendritiformis bacteria,
which some researchers
say can organize
themselves into different
types of extravagant
formations to maximize
food intake for given
conditions. According to
some, this reflects a
bacterial intelligence.
(Courtesy Eshel Ben-
Jacob, Tel Aviv
University, Israel)

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Antibiotic resistant mechanism
Suharto PETRI XIII 6
Antibiotic resistant mechanism
 History
Mekanisme kerja antibiotika
Mekanisme resistensi obat
Upaya mengatasi resistensi obat
Upaya mencegah resistensi

RESISTENSI
ANTIBIOTIKA

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Antibiotic resistant mechanism
 HISTORY OF MEDICAL SCIENCE

500 BC Hippocratic Oath is written

1875 Cohn publishes early classification of bacteria using Baccillus for
the first time
1879 Neisser attributes chronic disease gonorrhea to a microbe.
1928 Fleming discovered mold was effective against pathogenic
bacteria
1935 Domagk uses first chemically synthesized anti metabolite
(sulfanilamide)
1939 Chain and Florey use penicillin to save patients
1944 Schatz, Bugie and Wakeman discover streptomycin
1945 Chain, Florey & Fleming receive Nobel prize for discovering
penicillin
1952 J & E Lederberg show bacterial mutation responsible for
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1954 Hazen and Brown discover fungal antibiotic Nystatin
1959 Finland, Jones and Barnes comment on antibiotic resistance as a
response to antibacterial agents
1966 Kirby and Bauer establish standards for antibiotic susceptibility testing
1981 First case of methicillin-resistant Staphylococcus aureus (MRSA)
reported in Canada
1993 First case of vancomycin-resistant Enterococcus (VRE) reported in
Ontario
1995 Dramatic increase in methicillin-resistant Staphylococcus aureus
(MRSA) reported across Canada
1995 Venter, Smith and Fraser show first complete gene sequence of a
microorganism (Haemofilous influenza)
2000 World Health Organization describes perilous global situation in their
Report on Infectious Diseases: "Overcoming Antimicrobial
Resistance"

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Antibiotic resistant mechanism
Problem Antimicrobial Resistance

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Antibiotic resistant mechanism
 Five Basic Mechanisms of Antibiotic
Action against Bacterial Cells

1. Inhibition of Cell Wall Synthesis

(most common mechanism)
2. Inhibition of Protein Synthesis (Translation)
(second largest class)
3. Alteration of Cell Membranes
4. Inhibition of Nucleic Acid Synthesis
5. Anti metabolite Activity

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Antibiotic resistant mechanism
 Resistensi innate antibiotik
1. resistensi yang secara alamiah ada, antara lain melalui
mekanisme: non-permeable pada bahan antimikroba,
2. tidak mempunyai binding site,
3. tidak mempunyai jalur metabolisme yang dapat menjadi sasaran,
4. secara alamiah menghasilkan enzyme yang merusak antibiotika

Mekanisme perubahan presistensi antibiotik

1. perubahan permeabilitas terhadap antibiotika,

2. perubahan target binding site,
3. memakai alternative metabolic pathway,
4. perubahan gene untuk antibiotics-destroying enzyme dan
5. menerima gene baru untuk antibiotics–destroying enzyme.

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Antibiotic resistant mechanism
 
Antibiotics generally work in one of five ways.

1. Inhibition of nucleic acid synthesis

(e.g. Rifampicin; Chloroquine)
2. Inhibition of protein synthesis (e.g.
Tetracyclines; Chloramphenicol)
 3. Action on cell membrane (e.g.
 4.
Polyenes; Polymyxin)
Interference with enzyme system (e.g.
Sulphamethoxazole)
5. Action on cell wall (e.g. Penicillin;
Vancomycin)



Figure 2. Mechanisms of Antibiotic Resistance

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Antibiotic resistant mechanism
 Antibiotics generally
work in one of five
ways.

1. Inhibition of nucleic acid

synthesis (e.g.
Rifampicin; Chloroquine)
2. Inhibition of protein
synthesis (e.g.
Tetracyclines;
Chloramphenicol)
3. Action on cell membrane
(e.g. Polyenes;
Polymyxin)
4. Interference with enzyme
system (e.g.
Sulphamethoxazole)
5. Action on cell wall (e.g.
Penicillin; Vancomycin)

Fig. 1. Four major biochemical mechanisms of antibiotic resistance

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Antibiotic resistant mechanism
 Five Basic Mechanisms of Antibiotic
Action against Bacterial Cells

1. Inhibition of Cell Wall Synthesis

(most common mechanism)
2. Inhibition of Protein Synthesis (Translation)
(second largest class)
3. Alteration of Cell Membranes
4. Inhibition of Nucleic Acid Synthesis
5. Anti metabolite Activity

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Antibiotic resistant mechanism
 1. Inhibition of Cell Wall Synthesis

Beta-Lactams  Inhibition of peptidoglycan synthesis (bactericidal)

Resistance 
(1) fails to cross membrane (gram negatives)
(2) fails to bind to altered PBP’s
(3) hydrolysis by beta-lactamases

Vancomycin  Disrupts peptidoglycan cross-linkage

Resistance  (1) fails to cross gram negative outer membrane (too large)
(2) some intrinsically resistant (pentapeptide terminus)

Bacitracin  Disrupts movement of peptidoglycan precursors (topical use)

Resistance  fails to penetrate into cell
Antimycobacterial agents  Disrupt mycolic acid or arabinoglycan synthesis
(bactericidal)
Resistance  (1) reduced uptake
(2) alteration of target sites

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Antibiotic resistant mechanism
2. Inhibition of Protein Synthesis (Translation)

30S Ribosome site

a. Aminoglycosides  Irreversibly bind 30S ribosomal proteins
(bactericidal)
Resistance  (1) mutation of ribosomal binding site
(2) decreased uptake
(3) enzymatic modification of antibiotic

b. Tetracyclines  Block tRNA binding to 30S ribosome-mRNA

complex (b-static)
Resistance 
(1) decreased penetration
(2) active efflux of antibiotic out of cell
(3) protection of 30S ribosome

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Antibiotic resistant mechanism
2. Inhibition of Protein Synthesis (Translation)
50S Ribosome site
a. Chloramphenicol  Binds peptidyl transferase component of 50S
ribosome, blocking peptide elongation (bacteriostatic)
Resistance 
(1) plasmid-encoded chloramphenicol transferase
(2) altered outer membrane (chromosomal mutations)

b. Macrolides  Reversibly bind 50S ribosome, block peptide

elongation (b-static)
Resistance 
(1) methylation of 23S ribosomal RNA subunit
(2) enzymatic cleavage (erythromycin esterase)
(3) active efflux

c. Clindamycin  Binds 50S ribosome, blocks peptide elongation;

Inhibits peptidyl transferase by interfering with binding of amino acid-
acyl-tRNA complex
Resistance  methylation of 23S ribosomal RNA subunit
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 3. Alteration of Cell Membranes

a. Polymyxins (topical)  Cationic detergent-like activity (topical use)

Resistance  inability to penetrate outer membrane

b. Bacitracin (topical)  Disrupt cytoplasmic membranes

Resistance  inability to penetrate outer membrane

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 4. Inhibition of Nucleic Acid Synthesis

DNA Effects
a. Quinolones  Inhibit DNA gyrases or topoisomerases required for
supercoiling of DNA; bind to alpha subunit
Resistance 
(1) alteration of alpha subunit of DNA gyrase (chromosomal)
(2) decreased uptake by alteration of porins (chromosomal)

b. Metronidazole  Metabolic cytotoxic byproducts disrupt DNA

Resistance 
(1) decreased uptake
(2) elimination of toxic compounds before they interact

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 4. Inhibition of Nucleic Acid Synthesis

RNA Effects (Transcription)

a. Rifampin  Binds to DNA-dependent RNA polymerase inhibiting
initiation & Rifabutin of RNA synthesis
Resistance 
(1) altered of beta subunit of RNA polymerase (chromosomal)
(2) intrinsic resistance in gram negatives (decreased uptake)

b. Bacitracin (topical)  Inhibits RNA transcription

Resistance  inability to penetrate outer membrane

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 5. Antimetabolite Activity

a. Sulfonamides & Dapsone  Compete with p-amino benzoic acid

(PABA) preventing synthesis of folic acid
Resistance  permeability barriers (e.g., Pseudomonas)

b. Trimethoprim  Inhibit dihydrofolate reductase preventing

synthesis of folic acid
Resistance 
(1) decreased affinity of dihydrofolate reductase
(2) intrinsic resistance if use exogenous thymidine

Trimethoprim-Sulfamethoxazole synergism

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Antibiotic resistant mechanism
 GENETIC MECHANISMS OF PNEUMOCOCCAL ANTIBIOTIC
RESISTANCE

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Antibiotic resistant mechanism
 GENETIC MECHANISMS OF PNEUMOCOCCAL ANTIBIOTIC
RESISTANCE

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Antibiotic resistant mechanism
  LACTAM
ANTIBIOTICS

Paling bervariasi, paling banyak dipakai

1928 ditemukan benzyl penicilin,
1940 dipakai diklinik
Dikembangkan natural dan sintetik beta lactam
50% antibiotik yang dipakai
Keberhasilan karena toksisitas rendah dan dapat
diperoleh banyak derivat
Resistant : mycobacteria, pathogen intraselular, cell
wall deficient species, few bacteria resist all 
lactam
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Antibiotic resistant mechanism
 FAKTA :
•  lactam paling banyak dipakai
• angka antibiotic resistance (AR)
didunia 
• mekanisme paling sering AR :
produksi  lactamase, mutasi akibat
pemakaian antibiotik yang sering, 
 lactamase ihibitor / ESBL
extended spectrum lactamase
RSU dr Soetomo?
• mutasi pada TEM dan SHV genes
E coli 29%
pada strain E coli, K pneumonia
K pneumonia 36%
• perseorangan atau outbreak, di
Mutasi pada enzim TEM
dan SHV
critical care unit
cost treatment naik, LOS panjang

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Antibiotic resistant mechanism
 RESISTANCE  LACTAM Resistant bacteria;

= MIC diatas yang ditentukan

= Any elevation of in vitro MIC correlated with
less efficient treatment of infection given
pathogen

• Modifikasi normal PBP

• Use of alternative peptidoglycan transpeptidase

• Impermeability
• Production of beta lactamase

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Antibiotic resistant mechanism
 Gene yang mengkode resistance acquired antibiotic
dapat dipindahkan

Pada spesies yang sama,

juga pada genus yang
lain.
Dengan demikian akan
terjadi perluasan
resistensi pada bakteria
yang sebelumnya
sensitif.
Gene bacterial resistance,
seperti fragmen DNA
yang lain, dapat di
transmisikan dengan
mekanisme
transformasi,
transduksi,
konyugasi serta
transposon dan
integron.

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Antibiotic resistant mechanism
 The WHO Global Strategy for Containment of
Antimicrobial Resistance addresses this challenge

It provides a framework of interventions to slow the emergence and

reduce the spread of antimicrobial-resistant microorganisms through

— reducing the disease burden and the spread

of infection
— improving access to appropriate
antimicrobials
— improving use of antimicrobials
— strengthening health systems and their
surveillance capabilities
— enforcing regulations and legislation
— encouraging the development of appropriate
new drugs and vaccines.

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Antibiotic resistant mechanism
Abate dan Barriere: Antimicrobial regimen selection, Dalam buku : Pharmacotherapy, pathothysiological approach 4 ed,
Vol II, 1999. p 1920.

Fungsi ginjal
Pasien dengan
dan fungsi obat lain yang
rash reaction:
hepar diberikan,
hati-2 termasuk
AM empiris : supplement
tempat infeksi, nutrisi harus
patient history direview

Kombinasi AM
diindikasikan
untuk infeksi
1 polymicrobial
pemeriksaan PRINCIPLE
biakan dan uji
sensitifitas
OF PHARMACO
sebelum THERAPY
pemberian AM
Biakan pos
dievaluasi
dengan hati
hati
Kepustakaan
primer selalu
di review Pasien tak
memberi Terapi MO
periodik
respon dalam spesifik pakai
Semua pasien AM yang
2-3 hari setelah
yang berspektrum
pemberian AM
mendapat AM, sempit.
yang tepat,
dievaluasi
direview
Suharto efikasinya
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Antibiotic resistant mechanism
Table 3: Centers for Disease Control - Campaign to Prevent
Antimicrobial Resistance in Hospitalized Adults
1. Vaccinate (influenza and pneumococcal vaccine for
high risk patients)
2. Remove catheters
3. Target the pathogen (maximize dose, proper route,
monitor response)
4. Access the experts (consult infectious-disease
experts)
5. Practice antimicrobial control (hospital-based
programs to optimize usage)
6. Use local data (know hospital formulary, hospital
susceptibility patterns)
7. Treat infection, not contamination
8. Know when to say “no” to vanco (appropriate uses
and differentiation of staphylococcal infection vs
colonization or contamination)
9. Stop antimicrobial therapy (discontinue if infection
adequately treated, not diagnosed or unlikely)
10. Isolate the pathogen
11. Break the chain of contagion (universal precautions,
appropriate isolation precautions, stay home if sick)

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 RANGKUMAN
• Infeksi bacterial salah satu penyebab morbiditas dan
mortalitas klinik penting.
• Berbagai kelompok antibiotika telah dikembangkan;
menghadapi masalah resistensi obat
• Berbagai mekanisme timbulnya resistensi telah dikenal,
antara lain dengan kemampuan MO menghasilkan beta
lactamase
• Untuk mengatasi MO yang menghasilkan beta lactamase
dipakai obat dalam bentuk sediaan tunggal antibiotika dan
inhibitor beta laktamase.
• Untuk mencegah timbulnya resistensi obat, perlu antara
lain : pemakaian antibiotika secara rasional, penetapan
antibiotika policy, pembatasan pemakaian antibiotika
diluar bidang medik.

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Antibiotic resistant mechanism