Chapter 3.5-Antimicrobial Agents and Resistance

General Bacteriology:
Antimicrobial Agents and

Antimicrobial Resistance
Learning objectives
At the end of the session, the students will be able to understand:
▰ Classification of antimicrobial agents
▰ Intrinsic and acquired antimicrobial resistance
3
Essentials of Medical Microbiology
ANTIMICROBIAL
AGENTS
4
ANTIMICROBIAL AGENTS
▰ Agents that kill or inhibit the growth of microorganisms.
5
Classification
▰ Classified in various ways:
1. According to microorganisms against which they are used - antibacterial,

antifungal, antiparasitic, antiviral agents, etc.
2. According to their ability to kill or inhibit the microorganism, e.g.

bactericidal and bacteriostatic.
6
Classification
3. According to the source:
 Antibiotics
 Chemotherapeutic agents
7
Classification (Cont..)
4. According to their site of action and usage-
 Disinfectants
 Antiseptics
 Antibiotics
8
Classification (Cont..)
5. According to the chemical structure and mechanism of action -
9
Antimicrobial agents—classification,
indication, and mechanism of
resistance
Class/ Drugs Spectrum of activity Mechanism of resistance
mechanism
Inhibit Cell Wall Synthesis
Penicillin Penicillin G Gram positive bacteria- 1. Drug inactivation (by
Aqueous penicillin G  Streptococcus pyogenes producing β-lactamase
Procaine penicillin G  Pneumococcus enzyme)
Benzathine penicillin  Corynebacterium diphtheriae (diphtheria) 2. Alteration of target site
3. Decreased permeability
G  Clostridium tetani (tetanus)
Penicillin V  Clostridium perfringens (gas gangrene)
Others-
 Meningococcal infection
 Gonococcus (penicillin resistance has
been reported)
 Treponema pallidum (syphilis)
10
indication, and mechanism of resistance
(Cont..)
mechanism
Penicillinase- Methicillin Same as penicillin plus 1. Drug inactivation (by
resistant- Oxacillin Penicillinase producing Staphylococcus producing β-lactamase
penicillins Cloxacillin aureus enzyme)
Dicloxacillin 2. Alteration of target site
Aminopenicillin Ampicillin Same as penicillin plus

s Amoxicillin  Enterococcus faecalis
(extended  Escherichia coli, Klebsiella
spectrum)  Helicobacter pylori
 Salmonella (resistance reported)
 Shigella (bacillary dysentery)
11
(Cont..)
mechanism
Anti- Carbenicillin Same as Aminopenicillins plus 1. Drug inactivation (by
pseudomonal Ticarcillin Pseudomonas aeruginosa producing β-lactamase
penicillins Piperacillin enzyme)
2. Alteration of target site
β lactam + β Aminopenicillins or Same as aminopenicillins or anti-
lactamase Antipseudomonal penicillins pseudomonal penicillins spectrum
inhibitors plus plus β lactamase producing
 Clavulanic acid or bacteria
 Sulbactam or
 Tazobactam
 Avibactam
12
(Cont..)
mechanism
Cephalosporins
1st generation Cefazolin  Staphylococcus aureus ESBL (extended spectrum
Cephalexin  Staphylococcus epidermidis β-lactamases)
 Some Gram-negatives like Escherichia coli &
Klebsiella
2nd generation Cefoxitin  Same as 1st generation plus
Cefaclor  ↑ Gram-negative activity
Cefuroxime  ↑ Anaerobic activity (cefoxitin and cefotetan)
3rd generation Ceftriaxone  Decreased activity against Gram positives compared
Cefotaxime to the 1st and 2nd generation.
Ceftazidime  ↑ Gram-negative activity
 Some are active against Pseudomonas
(Ceftazidime) 13
(Cont..)
mechanism
Cephalosporins
4th generation Cefepime Good activity against Gram positive and negative ESBL (extended spectrum
Cefpirome bacteria including Pseudomonas β-lactamases)
5th generation Ceftobiprole Same as 4th generation and MRSA (only β lactam to be
Ceftaroline effective against Methicillin resistant Staphylococcus
aureus, i.e. MRSA)
14
(Cont..)
mechanism
Carbapenems Imipenem Broadest range of activity against most 1. Produce carbapenemases

Meropenem bacteria, which include Gram positive 2. Efflux pump
Doripenem cocci, Enterobacteriaceae, Pseudomonas,
Ertapenem Listeria, anaerobes like Bacteroides fragilis
and Clostridium difficile; MRSA,
Mycoplasma etc.
Monobactam Aztreonam Gram-negative rods ESBL
15
(Cont..)
mechanism
β lactam + β Ampicillin-sulbactam*  Same as spectrum of respective β
lactamase Amoxicillin-clavulanate* lactam drug plus active against β
inhibitors Cefoperazone-sulbactam lactamase producing bacteria
Ceftazidime-avibactam  *Have excellent anaerobic
Ceftolozane-tazobactam coverage
Piperacillin-tazobactam*
Meropenem-vaborbactam
16
(Cont..)
mechanism
Other Cell Wall Inhibitors
Glycopeptides Vancomycin Active against most gram-positive bacteria including Alteration of target
(bactericidal: Teicoplanin MRSA (drug of choice), and for Clostridium difficile
disrupt infection (CDI)
peptidoglycan
cross-linkage)
Fosfomycin Fosfomycin Inactivates the enzyme UDP-Nacetylglucosamine-3- 1. Alteration of target
enolpyruvyltransferase, also known as MurA; 2. Producing enzymes that
required for cell wall synthesis. inactivates fosfomycin
Active against urinary tract pathogens; against
both gram-positive and gram-negative bacteria
such as Enterococcus faecalis, Escherichia coli, etc.
Bacitracin Bacitracin Topical gram-positive cocci infections Not defined
17
(Cont..)
Class/mechanism Drugs Spectrum of activity Mechanism of resistance
Protein Synthesis Inhibition
Anti-30S ribosomal subunit
Aminoglycosides Gentamicin Aerobic Gram-negative bacteria 1.Drug inactivation by

(bactericidal: Neomycin Often used for empirical therapy in adjunct aminoglycoside-modifying
irreversible binding Amikacin with third generation cephalosporins in enzyme
to 30S) Tobramycin respiratory infections, meningitis and subacute 2.Decreased permeability
Streptomycin bacterial endocarditis through Gram-negative
outer membrane
3.Decreased influx of drug
18
(Cont..)
Tetracyclines Tetracycline Rickettsiae, Chlamydiae, Mycoplasma, 1. Decreased intracellular

(bacteriostatic: bind Doxycycline Spirochetes drug accumulation (active
to 30S subunit of Minocycline Yersinia pestis, Brucella, efflux)
ribosome and block Demeclocycline Haemophilus ducreyi, 2. Ribosomal target site
tRNA attachment) Campylobacter alteration
Vibrio cholerae
Glycylglycines Tigecycline Staphylococcus, Enterococcus Active drug efflux pump
Acinetobacter, and E. coli
19
(Cont..)
Chloramphenicol Chloramphenicol Haemophilus influenzae 1. Drug inactivation by

Pyogenic meningitis producing
Brain abscess chloramphenicol
Anaerobic infection acetyltransferase enzyme
Enteric fever (Salmonella)- not used now due to 2. Altered membrane
development of resistance transport (active efflux)
Macrolides Erythromycin Streptococcus 1.Alteration of ribosomal
Azithromycin Haemophilus influenzae target
Clarithromycin Mycoplasma pneumoniae 2.Active efflux of
antibiotic
20
(Cont..)

Lincosamides Clindamycin Bacteroides fragilis Alteration of target (ribosomal
Lincomycin
Staphylococcus aureus(toxic shock syndrome) methylation)
Excellent bone penetration
Oxazolidinones Linezolid Resistant Gram-positives like MRSA Alteration of target site
Streptogramins Quinupristin Streptococcus pyogenes and Staphylococcus 1. Alteration of target
Dalfopristin aureus skin infections (dalfopristin)
MRSA infections 2.Active efflux (quinupristin)
VRE (Vancomycin resistant enterococci) 3.Drug inactivation (quinupristin
infections and dalfopristin)
21
(Cont..)
Nucleic acid Synthesis Inhibitors

DNA synthesis inhibitors
Fluoroquinolones Inhibit DNA gyrase (A subunit) and topoisomerase IV, thus inhibiting DNA synthesis
Nalidixic acid Coliform Gram negative bacilli 1. Alteration of target (mutation

of DNA gyrase genes)
Fluoroquinolones Norfloxacin Enterobacteriaceae- such as E.coli, 2.Poor transport across cell
1st generation Ciprofloxacin Klebsiella, Enterobacter, Salmonella, Shigella, membrane
Ofloxacin Proteus, Yersinia
Fluoroquinolones Levofloxacin Others-Neisseria, Haemophilus,
2nd generation Lomefloxacin Campylobacter , Vibrio cholerae,
Moxifloxacin Pseudomonas, Staphylococcus aureus
Sparfloxacin
22
(Cont..)
DNA synthesis inhibitors
Nitroimidazoles Metronidazole, Anaerobic organisms 1. Decreased drug uptake
tinidazole 2. Active efflux
secnidazole 3. Decreased drug activation
Nitrofuran Nitrofurantoin Urinary tract infection Altered drug activating

(E. coli, Klebsiella, Enterococcus) enzyme
23
(Cont..)
RNA synthesis inhibitors
Rifamycins Rifampicin, M. tuberculosis, M. leprae Alteration of target (mutation
rifaximin Nontuberculous mycobacteria of rpoB gene)
Staphylococcus aureus
Prophylaxis for H. influenzae meningitis
Prophylaxis for meningococcal
meningitis
Mycolic Acid Synthesis Inhibitors
Isonicotinic acid Isoniazid (INH) Tuberculosis Mutations in enzyme
hydrazide Latent TB processing isoniazid into active
metabolites (KatG enzyme)
24
(Cont..)
Folic acid Synthesis Inhibitors
Bacteriostatic: Competitively inhibit enzymes involved in two steps of folic acid biosynthesis
PABA(para-amino-benzoic acid) folate synthase Dihydrofolic acid dihydrofolate reductase Tetra-hydrofolic acid
Sulfonamide blocks Trimethoprim blocks
Antifolates Sulfadiazine Sulfadiazine: Production of insensitive

Sulfacetamide Used topically in burn wound surface targets [dihydropteroate
Co-trimoxazole Co-trimoxazole is indicated in: synthetase (sulfonamides)
• Urinary tract and respiratory tract and dihydrofolate reductase
infections (trimethoprim)] that bypass
Active against Serratia, Klebsiella, metabolic block
Enterobacter
25
(Cont..)
Antimicrobial agents that act on cell membrane
Gramicidin Topical use against cocci (gram-positive Not defined
and
negative)
Lipopeptides Daptomycin Bactericidal against gram-positive Not defined
bacteria
including VRE and MRSA
Polymyxins Polymyxin B Gram-negative infections 1. Alteration of LPS
Colistin or 2. Efflux pump mediated
Polymyxin E
26
ANTIMICROBIAL
RESISTANCE
27
ANTIMICROBIAL
RESISTANCE
▰ Refers to development of resistance to an antimicrobial drug by a
microorganism.
▰ Can be of two types:
 Intrinsic resistance.
 Acquired resistance.
28
Acquired Resistance
▰ Emergence of resistance in bacteria that are ordinarily susceptible, by

acquiring the genes coding for resistance
▰ Overuse and misuse of antimicrobial agents is the single most important

cause of development of acquired resistance.
29
Acquired Resistance (Cont..)
▰ Use of the particular antibiotic poses selective pressure in a population

which in turn promotes resistant bacteria to thrive and the susceptible
bacteria to die off.
▰ Resistant bacterial populations flourish in areas of high antimicrobial

use, where they enjoy a selective advantage over susceptible populations.
30
Factors favoring the spread of antimicrobial resistance include:
▰ Poor infection control practices in hospitals
▰ Inadequate sanitary conditions
▰ Inappropriate food-handling
▰ Irrational use of antibiotics by doctors
▰ Uncontrolled sale of antibiotics over the counters without prescription.
31
32
Intrinsic Resistance
▰ Refers to innate ability of a bacterium to resist a class of antimicrobial

agents due to its inherent structural or functional characteristics
33
Intrinsic Resistance (Cont..)
Organisms Intrinsic resistance to the following antimicrobial agents
Enterobacteriaceae Members of family Enterobacteriaceae are intrinsically resistant to
antimicrobials specific for gram-positive organisms such as: clindamycin,
daptomycin, fusidic acid, glycopeptides (vancomycin), lipoglycopeptides
(oritavancin, teicoplanin, and telavancin), linezolid, tedizolid, quinupristin-
dalfopristin, rifampin, and macrolides (erythromycin, clarithromycin, and
azithromycin).
Exceptions: Salmonella and Shigella spp. are susceptible azithromycin
Klebsiella pneumoniae Same as for Enterobacteriaceae plus ampicillin and ticarcillin

Citrobactér species Same as for Enterobacteriaceae plus ampicillin, first and second generation ce
ph
alosporins, cephamycins, amoxicillin-clavulanate and ampicillin-sulbactam
Enterobacter species Same as for Enterobacteriaceae plus ampicillin, first generation cephalosporins
and cephamycins, amoxicillin clavulanate, ampicillin sulbactam. 34
Non-fermentative Non-fermentative gram-negative bacteria are intrinsically resistant to penicillin (i.e.,
gramnegative benzyl penicillin), cephalosporins I (cephalothin, cefazolin), cephalosporin II
bacteria (cefuroxime), cephamycins (cefoxitin, cefotetan), clindamycin, daptomycin, fusidic
(NF-GNB) acid, glycopeptides (vancomycin), linezolid, macrolides, quinupristin- dalfopristin,
and rifampin.
Pseudomonas Same as for NF-GNB, plus ampicillin, ceftriaxone, amoxicillin-clavulanate,
aeruginosa ampicillin-sulbactam, Ertapenem, tetracyclines, tigecycline, co-trimoxazole and
chloramphenicol.
Acinetobacter Same as for NF-GNB, plus ampicillin, amoxicillin, amoxicillin-clavulanate,
baumannii ertapenem, aztreonam, chloramphenicol and fosfomycin.
Stenotrophomonas Same as for NF-GNB, plus ampicillin, amoxicillin, cefotaxime, ceftriaxone, cefepime,
maltophilia amoxicillin-clavulanate, aztreonam, imipenem, meropenem, ertapenem, polymyxins
(polymyxin B and colistin), aminoglycosides,
chloramphenicol and fosfomycin.
35
Gram-positive Gram-positive bacteria are intrinsically resistant to aztreonam, polymyxin B/colistin,
bacteria and nalidixic acid.
S. aureus Same as for other Gram-positive bacteria
Enterococcus Same as for other Gram-positive bacteria plus cephalosporins, aminoglycosides,

species clindamycin and co
trimoxazole. .
36
Mutational and Transferable Drug
Resistance
In presence of selective antibiotic pressure, bacteria acquire new genes mainly

by two broad methods:
▰ Mutational Resistance
▰ Transferrable Drug Resistance
37
Mutational Resistance
▰ Resistance developed due to mutation of the resident genes.
▰ E.g. Mycobacterium tuberculosis – ATT
▰ Low level resistance, developed to one drug at a time- overcome by using

combination of different classes of drugs.
38
Transferrable Drug Resistance
▰ Transferrable drug resistance is plasmid coded - transferred by conjugation
or rarely transduction, transformation.
▰ Resistance coded plasmid (called R plasmid) - carry multiple genes, each

coding for resistance to one class of antibiotic.
▰ Results in high degree of resistance to multiple drugs, which cannot be

overcome by using combination of drugs.
39
Mutational vs transferable drug
resistance
Mutational drug resistance Transferable drug resistance
Resistance to one drug at a time Multiple drug resistance at the same time
Low-degree resistance High-degree resistance
Resistance can be overcome by combination of drugs Cannot be overcome by drug combinations
Virulence of resistance mutants may be lowered Virulence not decreased
Resistance is not transferable to other Resistance is transferable to other organisms.

organisms but spread to off- springs by vertical Spread by: Horizontal spread (conjugation, or
spread only rarely by transduction/transformation)
40
Mechanism of Antimicrobial
Resistance
1. Decreased Permeability across the Cell Wall :
▰ Bacteria modify their cell membrane porin channels - either in frequency,

size, or selectivity;
▰ Preventing the antimicrobials from entering into the cell.
▰ Seen in Pseudomonas, Enterobacter and Klebsiella species against drugs,

such as imipenem, aminoglycosides and quinolones.
41
Mechanism of Antimicrobial Resistance
(Cont..)
2. Efflux Pumps :
▰ Mediate expulsion of the drugs from the cell - thereby preventing the
intracellular accumulation of drugs.
 Escherichia coli and other Enterobacteriaceae against tetracyclines,
chloramphenicol
 Staphylococci against macrolides and streptogramins
 Staphylococcus aureus and Streptococcus pneumoniae against
fluoroquinolones.
42
(Cont..)
3. By Enzymatic Inactivation:
▰ Inactivate the antimicrobial agents by producing various enzymes:
 β lactamase enzyme production - It breaks down the β lactam rings,
there by inactivating the β lactam antibiotics.
 Aminoglycoside modifying enzymes - destroy the structure of
aminoglycosides
 Chloramphenicol acetyl transferase - destroys the structure of
chloramphenicol.
43
(Cont..)
4. By Modifying the Target Sites:

 MRSA -Target site of penicillin i.e. penicillin binding protein (PBP)
gets altered to PBP-2a.
 Streptomycin resistance in Mycobacterium tuberculosis- due to
modification of ribosomal proteins or 16S rRNA.
 Rifampicin resistance in Mycobacterium tuberculosis- due to mutations
in RNA polymerase.
44
Beta Lactamase Enzymes
▰ Capable of hydrolyzing the β- lactam rings (the active site) of β lactam
antibiotics; thereby deactivating their antibacterial properties.
▰ Produced by both gram-positive and gramnegative organisms
▰ Plasmid coded - transferred from one bacterium to other mostly by

conjugation, (except in Staphylococcus aureus where they are transferred
by transduction).
45
Beta-lactamases are of various types
Extended spectrum β lactamases (ESBL):
▰ Resistant to all penicillins and 1st, 2nd and 3rd generation cephalosporins
and monobactams.
▰ Sensitive to carbapenems and cephamycins.
▰ Resistance can be overcome by use of β lactam along with β lactamase

inhibitor
46
(Cont..)
AmpC beta-lactamases:
▰ In addition to the antibiotics to which ESBL producers are resistant, AmpC

beta-lactamase producers are resistant to cephamycins .
▰ Sensitive to carbapenems.
▰ Resistance cannot be overcome by β lactam + β lactamase inhibitor

combination.
47
(Cont..)
Carbapenamases:
▰ Resistant to all those antibiotics to which AmpC beta-lactamase producers
are resistant - In addition, they are also resistant to carbapenems.
▰ Resistance cannot be overcome by BL/BLI.
▰ Important carbapenemase enzymes are:
 Klebsiella pneumoniae carbapenemase (KPC)
 New Delhi metallo-beta-lactamase (NDM)
48
Questions:
▰ Q1. All of the following antimicrobial agents act on cell membrane, except:
a. Gramicidin
b. Daptomycin
c. Polymyxins
d. Vancomycin
49
Questions:
▰ Q2. Extended spectrum β-lactamases (ESBL) producing organisms are
resistant to all, except:
a. All penicillins
b. 3rd generation cephalosporins
c. Monobactam
d. Carbapenems
50

Chapter 3.5-Antimicrobial Agents and Resistance

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Chapter 3.5-Antimicrobial Agents and Resistance

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General Bacteriology:

Antimicrobial Agents and

At the end of the session, the students will be able to understand:

▰ Classification of antimicrobial agents

▰ Intrinsic and acquired antimicrobial resistance

▰ Agents that kill or inhibit the growth of microorganisms.

▰ Classified in various ways:

1. According to microorganisms against which they are used - antibacterial,

2. According to their ability to kill or inhibit the microorganism, e.g.

3. According to the source:

4. According to their site of action and usage-

Aminopenicillin Ampicillin Same as penicillin plus

Carbapenems Imipenem Broadest range of activity against most 1. Produce carbapenemases

Monobactam Aztreonam Gram-negative rods ESBL

Aminoglycosides Gentamicin Aerobic Gram-negative bacteria 1.Drug inactivation by

Tetracyclines Tetracycline Rickettsiae, Chlamydiae, Mycoplasma, 1. Decreased intracellular

Chloramphenicol Chloramphenicol Haemophilus influenzae 1. Drug inactivation by

Protein Synthesis Inhibition

Nucleic acid Synthesis Inhibitors

Nalidixic acid Coliform Gram negative bacilli 1. Alteration of target (mutation

Nitrofuran Nitrofurantoin Urinary tract infection Altered drug activating

Antifolates Sulfadiazine Sulfadiazine: Production of insensitive

▰ Can be of two types:

▰ Emergence of resistance in bacteria that are ordinarily susceptible, by

▰ Overuse and misuse of antimicrobial agents is the single most important

▰ Use of the particular antibiotic poses selective pressure in a population

▰ Resistant bacterial populations flourish in areas of high antimicrobial

▰ Refers to innate ability of a bacterium to resist a class of antimicrobial

Klebsiella pneumoniae Same as for Enterobacteriaceae plus ampicillin and ticarcillin

Enterococcus Same as for other Gram-positive bacteria plus cephalosporins, aminoglycosides,

In presence of selective antibiotic pressure, bacteria acquire new genes mainly

▰ Transferrable Drug Resistance

▰ Resistance developed due to mutation of the resident genes.

▰ E.g. Mycobacterium tuberculosis – ATT

▰ Low level resistance, developed to one drug at a time- overcome by using

▰ Resistance coded plasmid (called R plasmid) - carry multiple genes, each

▰ Results in high degree of resistance to multiple drugs, which cannot be

Low-degree resistance High-degree resistance

Resistance can be overcome by combination of drugs Cannot be overcome by drug combinations

Virulence of resistance mutants may be lowered Virulence not decreased

Resistance is not transferable to other Resistance is transferable to other organisms.

▰ Bacteria modify their cell membrane porin channels - either in frequency,

▰ Preventing the antimicrobials from entering into the cell.

▰ Seen in Pseudomonas, Enterobacter and Klebsiella species against drugs,

4. By Modifying the Target Sites:

▰ Produced by both gram-positive and gramnegative organisms

▰ Plasmid coded - transferred from one bacterium to other mostly by

Extended spectrum β lactamases (ESBL):

▰ Sensitive to carbapenems and cephamycins.

▰ Resistance can be overcome by use of β lactam along with β lactamase

▰ In addition to the antibiotics to which ESBL producers are resistant, AmpC

▰ Resistance cannot be overcome by β lactam + β lactamase inhibitor

b. 3rd generation cephalosporins

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