Antibiotic Resistance

Dr. Sharifah Shakinah

Supervisor: dr. Eppy SpPD KPTI

Definition

 The ability of a microorganism to avoid the harmful effects of an antibiotic by destroying it,
transporting it out of the cell, or undergoing changes that block its effects.

 Bacteria can develop resistance to multiple drugs and antibiotics, further facilitating their
spread.

 Three possible outcomes when antibiotics are introduced:

1. Death (Bacteriocidal)
2. Growth Inhibition (Bacteriostatic)
3. Resistance
MECHANISMS OF RESISTANCE

 Enzymatic inhibition
 Alteration of bacterial membranes
 Outer membrane permeability
 Inner membrane permeability

 Rapid ejection of the drug [efflux] or reduced drug influx.

 By pass of antibiotic inhibition.
 Alteration of target sites
 Altered ribosomal target sites
 Altered cell wall precursor targets
 Altered target enzymes
Misuse/Overuse of Antibiotics

 Plays a substantial role in the emergence of resistant strains of bacteria.

 Although resistance is natural, the proportion of resistant bacteria multiply when antibiotics
are used carelessly.

 Millions of people take antibiotics unnecessarily every year.

 Antibiotics have no effect on viral illnesses such as:

 Colds
 Flu
 Sore Throats
 Bronchitis

 Use of antibiotics for feed animals and livestock also a major factor.
Factors promoting drug resistance

 Exposure to sub-optimal levels of antimicrobial

 Exposure to microbes carrying resistance genes
 Inappropriate drug use-
 Lack of quality control in manufacture or outdated antimicrobial
 Inadequate surveillance or defective susceptibility assays
 Poverty or war
 Use of antibiotics in foods-
 Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote
growth Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef
fed antibiotics
Mechanisms of Resistance

• Change the antibiotic structure so that it is no longer

able to perform its function

• Break down the antibiotic

• Pump the antibiotic out of the cell

http://www.scq.ubc.ca/attack-of-the-
superbugs-antibiotic-resistance/
Mechanisms of Resistance

http://www.scq.ubc.ca/attack-of-the-
superbugs-antibiotic-resistance/
1.Enzymatic inhibition

Enzymes inactivating antibiotics

 Beta-lactamases-split amide bond of the beta lactam ring.
 There are many types-characterised by amino acid and nucleotide
sequencing
 Class A MWT 29000-Preferentially hydrolyze penicillins e.g. TEM-1 prevalent in
many gram neg
 Class B-metalloenzymes have a zinc –binding thiol group required for beta
lactamase activity
 Class C mwt 39000 –mainly cephalosporinases
 Class D-oxacillin –hydrolyzing enzymes
Many beta lactamases are plasmid mediated all are produced constitutively there
are 6 main groups
1. Those that hydrolyze benzylpenicillin
 Beta lactamases

1. Those that hydrolyze oxacillin and related penicillins

2. Carbenicillinases
3. Those that break extended spectrum beta lactams like aztreonam
4. Those that break down oxyimino B lactams
5. Carbapenemases-found in pseudomonas
Most cephalosporinases are inhibited by clavulanate,sulbactam or
tazobactam. Carbapenamases are metalloenzymes inhibited by EDTA
but not clavulanate or sulbactam

Production of enzymes modifying antibiotics

 Aminoglycosides, chloramphenicol-coded by plasmids or
chromosomal genes
Beta lactamases site of action
Modifying enzymes

 Reactions are-
 N-acetylation
 O nuleotidylation
 O phosphorylation
 Chloramphenicol acetyltransferase-inactivates the drug by 3-o-acetylation-plasmid
mediated/chromosomal
 Erythromycin esterase-seen in E coli-hydrolyze lactone ring thus deactivating it-limits utility
of oral erythromycin in reducing the aerobic gram neg flora of the GIT prior to Gi surgery.
2. Alteration of bacterial membranes

 Outer membrane permeability—outer membrane of gram neg acts as a barrier to

antibiotics esp hydrophobic ones.
 Inner membrane permeability- rate of entry of aminoglycosides into bacterial cells is a
function of them binding to a non saturable anionic transporter,where they retain their
positive charge and are pulled across the cytoplasmic membrane by the internal charge
of the cell.This is an energy dependent process. The energy generation or proton motive
force may be altered through mutation
 Promotion of antibiotic efflux-major mechanism for tetracycline resistance in gram neg-
plasmid/chromosomal/transposone mediated
3. Modification of target sites

 Alteration of ribosomal target sites-hence failure to inhibit protein synthesis and cell
growth.
 Affected antibiotics are aminoglycosides, tetracylines, macrolides ,lincosamides.
Altered cell wall precursor targets

 Glycopeptides like vancomycin-bind D-alanine-D-alanine which is present at the termini of

peptidoglycan precursors.
 The large glycopeptide molecules prevent the incorporation of the pre cursors into the
cell wall
Alteration of target enzymes

 Alteration of PBPs in B lactams

 SMX/TMP-production of a dihdropteroate synthetase that is resistant to binding by
sulphonamides-plasmid mediated
 Quinolones-DNA gyrase is made up of gyr Aand gyr B genes-mutations in gyr A result in
resistance
By pass inhibition

 Development of auxotrophs-have growth factor requirements different from those of wild

strain these mutants require subtrates that normally are synthesized by the target enzymes
and if these are present in the environment the organisms grow despite inhibition by
synthetic enzymes
BACTERIA
Methicillin-resistant Staphylococcus
aureus (MRSA)

 Strain Staphylococcus aureus yang memiliki gen resisten terhadap penicillinase-resistant

penicillins, seperti methicillin or oxacillin
 Habitat S. aureus : nares (resevoir primer) axillae , lipat paha, vagina, faring, permukaan
kulit yang rusak

Tong SY, Chen LF, Fowler VG Jr. Colonization, pathogenicity, host susceptibility, and therapeutics for Staphylococcus
aureus: what is the clinical relevance? Semin Immunopathol. 2012 Mar;34(2):185-200
TATALAKSANA-MRSA

 Infeksi kulit komplikata (rawat inap) , selam 7-14 hari :

 vancomycin 15-20 mg/kg IV tiap 8-12 jam
 linezolid 600 mg oral atau IV 2 x sehari
 daptomycin 4 mg/kg IV sehari sekali =
 telavancin 10 mg/kg Ivsekali sehari
 clindamycin 600 mg oral atau IV 3 x sehari

Clin Infect Dis 2011 Feb 1;52(3):285

MRSA- CAP/HAP

 Vancomycin 15-20 mg/kg Ivtiap 8-12 jam

 Linezolid 600 mg oral ATAU IV 2 X SEHARI
 Klindamycin 600 mg oral atau IV 3 x sehari
Selama 7-21 hari
Terapi empiris jika : klinis perburukan cepat sehingga membutuhkan ICU, infiltrat nekrosis dan
kavitas, empiema

Clin Infect Dis 2011 Feb 1;52(3):285

ESBL

 Resisten :resistensi seluruh pensilin, sefalosporin (cefotaxime, ceftazidime, ceftriaxone,

cefuroxime, and cefepime) dan aztreonam
 Dihasilkan oleh : Enterobacteriaceae (seperti Escherichia coli and Klebsiella
pneumoniae), Pseudomonas aeruginosa, and Acinetobacter species
 Pilihan terapi : Karbapenem, aminoglikosida (amikacin, gentamicin, atau tobramycin),
beta laktam +beta laktamase inhibitor : peperacilin tazobactam

Crit Care 2012 Nov 13;16(6):R218

Mutidrug-resistant (MDR) gram negatif

Resisten terhadap salah satu dari golongan antibiotik : karbapenem,

aminoglikosida, fluorokuinolon, penisilin, sefalosporin

Adkinson F et al.Treatment recommendations for adult inpatient: Antibiotic Guidelines 2015-2016.John Hopkins Medicine.2015.
 Carbapenemase-produsing
Enterobactericeae(CRE)

 Karbapenemase merupakan enzim yang mneyebabkan resistensi

terhadap semua penisilin, sefalosporin, salah satu karbapenem dan
aztreonam
 Obat pilihan : kombinasi Karbapenem (misal : Meropenem 3x2 gram
intfus selama 3 jam) ditambah satu agen yang masih sensitif:
Aminoglikosida- Amikasin, Tigecyline, Colistin/Polimiksin

Adkinson F et al.Treatment recommendations for adult inpatient: Antibiotic Guidelines 2015-2016.John Hopkins Medicine.2015
Tuberculosis

•Mycobacterium tuberculosis

•Can survive long exposures to acids, detergents, oxidative

bursts, and antibiotics.

•Treatment typically takes over six months, allowing the bacteria

ample time to adapt and mutate.

•Four antibiotics used: isoniazid, rifampicin, pyrazinamide, and

ethambutol.

•Most of the antibiotics are aimed at inhibiting the synthesis of http://dujs.dartmouth.edu/winter-2009/new-trickes-for-an-old-foe-the-

mycolic acids, a major component of the cell wall. threat-of-antibiotic-resistant-tuberculosis

•Multi–drug-resistant tuberculosis is resistant to two antibiotics,

Extensively drug resistant tuberculosis is resistant to three, with
a cure rate of only 30%.
Terima Kasih