Introductory pharmacology

1. Antibiotic Resistance
Mechanisms, Antibiotic
Stewardship
Dr C E Anozie
Dept of Medical Microbiology
GUU
26/07/2023
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2. Basis of Antimicrobial Action
Antimicrobial agents act by interfering with
• cell wall synthesis - ß-lactams, such as penicillins and cephalosporins, which inhibit
peptidoglycan polymerization, and by vancomycin, which combines with cell wall
substrates
• plasma membrane integrity-Polymyxins disrupt the plasma membrane, causing leakage
• nucleic acid synthesis -Quinolones bind to a bacterial complex of DNA and DNA gyrase,
blocking DNA replication. Rifampin blocks RNA synthesis by binding to DNA directed
RNA polymerase
• ribosomal function -Aminoglycosides, tetracycline, chloramphenicol,
erythromycin, and clindamycin all interfere with ribosome function
• folate synthesis-Sulfonamides and trimethoprim block the synthesis of the folate
needed for DNA replication
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3. 3

4. 4

5. Antibiotic resistance
• Antibiotic resistance is the ability of a microorganism
to withstand the effects of an antibiotic.
• Antibiotic resistance evolves naturally via natural
selection through random mutation
• it could also by engineered by applying an
evolutionary stress on a population.
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6. Factors responsible for antibiotics
resistance
• Overuse of broad-spectrum antibiotics, such as second-
and third-generation cephalosporins, greatly hastens the
development of methicillin resistance
• incorrect diagnosis
• unnecessary prescriptions
• improper use of antibiotics by patients
• the use of antibiotics as livestock food additives for
growth promotion. 6

7. Classification of Antibiotics Resistance
•Intrinsic/Natural/Innate
•Acquired
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8. Natural (inherent) Resistance
•Natural resistance means that the bacterial are
intrinsically resistant
•Bacteria may be resistant because:
• They have no mechanism to transport the drug
into the cell.
• They do not contain the antibiotic’s target protein.
• They naturally have low permeability to those
agents because of the differences in the chemical
nature of the drug and the microbial membrane
structures especially for those that require entry
into the microbial cell in order to effect their action
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9. ORGANISMS NATURAL RESISTANCE AGAINST: MECHANISM
Anaerobic bacteria Aminoglycosides Lack of oxidative metabolism to drive uptake
of aminoglycosides
Aerobic bacteria Metronidazole Inability to anaerobically reduce drug to its
active form
Gram-positive bacteria Aztreonam (a beta-lactam) Lack of penicillin binding proteins (PBPs) that
bind and are inhibited by this beta lactam
antibiotic
Gram-negative bacteria Vancomycin Lack of uptake resulting from inability of
vancomycin to penetrate outer membrane
Klebsiella spp. Ampicillin (a beta-lactam) Production of enzymes (beta-lactamases) that
destroy ampicillin before the drug can reach
the PBP targets
Stenotrophomonas. maltophila Imipenem (a beta-lactam) Production of enzymes (beta lactamases) that
destroy imipenem before the drug can reach
the PBP targets.
Lactobacilli and Leuconostoc Vancomycin Lack of appropriate cell wall precursor target
to allow vancomycin to bind and inhibit cell
wall synthesis
Pseudomonas aeruginosa Sulfonamides, trimethoprim, tetracycline, or
chloramphenicol
Lack of uptake resulting from inability of
antibiotics to achieve effective intracellular
concentrations
Enterococci Aminoglycosides Lack of sufficient oxidative metabolism to
drive uptake of aminoglycosides
All cephalosporins Lack of PBPs that effectively bind and are
inhibited by these beta lactam antibiotics
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10. Acquired Resistance
•Acquired resistance refers to bacteria that
are usually sensitive to antibiotics but are
liable to develop resistance.
•Acquired resistance is often caused by
• mutations in chromosomal genes
• Acquisition of mobile genetic elements such as
plasmids or transposons which carry the
antibiotic resistance genes
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11. Mechanism of Antibiotics Resistance
due to Chromosomal Mutation
•1. Reduced permeability or uptake.
•2. Enhanced efflux.
•3. Enzymatic inactivation.
•4. Alteration of the drug target.
•5. Loss of enzymes involved in drug activation.
•6.Development of altered enzymes
•7.Altered metabolic pathway .
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12. Reduced Permeability or Uptake
•Some Gram negative organism porins (protein
channels) in the outer membrane acquire mutation
which allow the entry of only small and hydrophilic
molecules but not large molecules.
• E.g Resistance of Neisseria gonorrhea to penicillin
and tetracycline,
• Enterobacter to ciprofloxacin
•Resistance to some Aminoglycosides
•Resistance to polymyxin
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13. Enhanced Efflux
•Membrane transport system act to pump the
antibiotics away.Examples are
• Tetracycline from Gram Negative organism like shigella
spp,.
• Macrolides from Gram positive cocci like
Staphyloccocus aureus.
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14. Enzymatic Inactivation
•Microorganisms produce enzymes that
destroy the active drug. Examples:
•Splitting of amide bond in beta lactam antibiotics
by beta lactamases producing organisms .
•Gram-negative bacteria resistant to
aminoglycosides produce adenylylating,
phosphorylating, or acetylating enzymes that
destroy the drug.
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15. Alteration of the Drug Target
•Microorganisms develop an altered structural
target for the drug Examples:
• Erythromycin-resistant organisms have an altered
receptor on the 50S subunit of the ribosome
• Resistance to some penicillins and cephalosporins is a
function of the loss or alteration of PBP E.g Penicillin
resistance in Streptococcus pneumoniae due to
altered PBP.
• Mutation in DNA gyrase A and B subunits in
quinolone resistance.
• Mutations in rpoB gene encoding beta-subunit of
RNA polymerase resulting in rifampicin resistance.
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16. Loss of Enzymes involved in Drug
Activation
•In this case, the antibiotic itself is a prodrug, which
has no direct activity against the bacteria. Rather, it
relies on the activation by a bacterial enzyme.
•Metronidazole is activated through RdxA
(nitroreductase) and then forms reactive substance
that damage the DNA. Thus, mutations in this
enzyme cause resistance to Metronidazole.
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17. Development of Altered Enzymes
•Microorganisms develop an altered enzyme that
can still perform its metabolic function but is much
less affected by the drug. Example:
• In trimethoprim-resistant bacteria, the dihydrofolic acid
reductase is inhibited far less efficiently than in
trimethoprim-susceptible bacteria.
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18. Altered metabolic pathway
•Microorganisms develop an altered
metabolic pathway that bypasses the
reaction inhibited by the drug. Example:
• Some sulfonamide-resistant bacteria do not
require extracellular PABA but, like mammalian
cells, can utilize preformed folic acid.
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19. Resistance to Antibiotics
Fig 20.20
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20. 20

21. Why is Resistance a Concern?
• Resistant organisms are becoming commonplace
• Bacterial resistance often results in treatment failure
and increased mortality and cost
• The problem is no longer confined to the hospital
setting
• Bacterial resistance will continue to worsen if not
addressed
• There are no antibiotics on the immediate horizon
with activity against these multi-drug resistant
pathogens
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22. …As Antibiotic Options Decline Rapidly
18
16
14
12
10
8
6
4
2
0
1983-87 1988-92 1993-97 1998-2002 2003-07 2008-10
Year
New
Antimicrobials
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23. The Bacterial Challenge
• Resistance to Antibiotics is high among Gram-
positive and Gram-negative bacteria that cause
serious infections in Nigeria and other parts of the
world.
• A large number of patients in the developing
countries including Nigeria die from infections
caused by multidrug-resistant bacteria.
• Infections due to these selected multidrug-resistant
bacteria result in extra healthcare costs and
productivity losses 23

24. Troublesome Bacteria
Ability to “escape” the effects of current antimicrobial therapy
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter species
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25. Redefining ESKAPE as ESCAPE
Enterococcus faecium
Staphylococcus aureus
Clostridium difficile
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacteriaceae
Acknowledges the growing
virulence of C. difficile
Captures Klebsiella,
Enterobacter, and other
resistant species including
E. coli and Proteus sp.
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26. Resistance in Gram Positive Bacteria
• Vancomycin Resistant Enterococcus (VRE)
– Non-existent as recently as 1989
– NNIS report (2004) –30% of all enterococcal isolates are
resistant
– Mediated by vanA and vanB genes resulting in alteration of
target site
– Clonal spread via poor infection control
– Various antibiotics may lead to VRE colonization
• Anti-enterococcal activity
• Biliary excretion
• Anaerobic activity
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27. Resistance in Gram Positive Bacteria
• MRSA (Methicillin Resistant Staph aureus)
– In Ibadan –35-40% of S. aureus are methicillin resistant
– Nosocomial
• mecA gene encodes low affinity for PBP resulting in
resistance to all beta-lactams
• Usually multi-drug resistant
– Community-acquired
• More virulent
• Skin and soft tissue infections in children and young adults
• Usually susceptible to non beta-lactam drugs
• VISA (Vancomycin Intermediate Staph aureus)
– Cell wall thickening
• VRSA (Vancomycin Resistant Staph aureus)
– Horizontal transfer of a vanA gene from VRE 27

28. Resistance in Gram Negative Bacteria:
Non-fermenters
• Acinetobacter
– It is not uncommon in Nigeria.
– Incidence as high as 10% in some geographic locations
– Carbapenems are drug of choice
• Pseudomonas aeruginosa
– Multi-drug resistance increasing nationwide
• Fluoroquinolones: 29% resistance (NNIS 2004)
• Beta-lactams: metallo-beta-lactamase producing
strains have been reported
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29. Resistance in Gram Negative Bacteria:
Enterobacteriaceae
• ESBLs (Extended Spectrum Beta Lactamase) a
growing concern
– Resistant to all penicillins, cephalosporins, and aztreonam
– Carbapenems are the drug of choice
• Fluoroquinolone resistance
– NNIS 2004 report: 8% E.coli resistant
– Chromosomal and plasmid mediated alterations in target
site or decreased access to target
• Carbapenem resistance
– Klebsiella pneumoniae carbapenemase
– Metallo-beta-lactamases
– ampC beta-lactamase + loss of outer membrane channels
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30. Carbapenem Resistance
• Emerging problem seen with Pseudomonas,
Acinetobacter and Enterbacteriaceae
• Risk factors include ICU stay, prolonged
healthcare exposure, indwelling devices, and
antibiotic exposure
• Severely limits treatment options
• Outbreaks reported in both single and multiple
institutions
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31. Klebsiella pneumonia
Carbapenemases (KPCs)
• Plasmid-mediated carbapenemase
• KPC- producing strains of Klebsiella pneumonia and
other Enterobacteriaceae
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32. KPCs cont
• Various centres in Nigeria have reported
cases.
• May appear susceptible to imipenem or
meropenem but with borderline MICs
– Usually ertapenem resistant
• Usually only susceptible to colistin , tigecyline,
and select aminoglycosides
• Easily spread in hospitals
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33. Acinetobacter baumannii
• Traditionally only an ICU organism
• Now being seen in general hospital population and
nursing homes
• Antimicrobial resistance is a MAJOR concern
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34. Emergence of multidrug-resistant,
extensively drug-resistant and
untreatable gonorrhea
• The new superbug Neisseria gonorrhoeae has
retained resistance to antimicrobials previously
recommended for first-line treatment
• It has now demonstrated its capacity to develop
resistance to the extended-spectrum
cephalosporin, ceftriaxone,
• the last remaining option for first-line empiric
treatment of gonorrhea.
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35. • An era of untreatable gonorrhea may be approaching,
which represents an exceedingly serious public health
problem.
• antimicrobial resistance (AMR) has emerged for
essentially all antimicrobials following their introduction
into clinical practice.
• treatment options have diminished rapidly due to
the emergence and spread of AMR to all drugs
previously used or considered for first-line treatment
(penicillins, tetracyclines, spectinomycin, narrow-
spectrum cephalosporins, amphenicols,
sulfonamide and trimethoprim combinations,
macrolides and fluoroquinolones). 35

36. • global susceptibility to the extended-spectrum
cephalosporins (ESCs), ceftriaxone (injectable)
and cefixime (oral),the only first-line options for
the antimicrobial monotherapy of gonorrhea in
most settings has markedly decreased
• it is of concern that during the last 2 years, the
first three extensively drug-resistant (XDR;
defined in N. gonorrhoeae strains with high-
level resistance to ceftriaxone, the last
remaining option for empiric single antimicrobial
treatment, were reported from Japan, France
and Spain.
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37. 37

38. Strategies for the Rational Use of Antibiotics Aiming to Prevent
and Reduce Resistance in the Hospital
• Targeted antimicrobial therapy
• Knowledge of local resistance Surveillance data
• Risk factors indicating the presence of MDR pathogens
• Application of PK/PDs
• Issues of De-escalation
• Appropriate Duration of Therapy
• Restriction in Overuse and Misuse of Antibiotic
• Consultation by Infections Diseases Specialists/Clinical
Microbiologists
• Infection Control
• Antibiotic Stewardship 38

39. Antibiotic Stewardship
Program (ASP)
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40. Definition of antimicrobial stewardship
• Refers to coordinated interventions designed to
improve and measure the appropriate use of
antimicrobial agents by promoting the selection of
optimal antibiotic drug regimens including dosing,
duration of therapy and route of administration
• -Infectious Diseases Society of America &
Paediatric Infectious Diseases Society
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41. • 2 core proactive evidence –based strategies
• Formulary restriction and pre-authorisation
• Prospective audit with intervention
and feedback
• Supplemental strategies
Stewardship tactics -many
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42.  The strategy involves
◦ limiting the use of specified antimicrobials to certain
approved indications.
◦ An antimicrobial committee creates guidelines
pertaining to the approved use of agents
◦ Designated personnel are made available for the
approval process.
 The strategy leads to
◦ direct control over antimicrobial use at an institution
◦ educational opportunities for prescribers when a
request is made.
Formulary Restriction and Pre-
Authorization
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43. Prospective Audit With Intervention
and Feedback
• Involves a daily review of targeted agents
for appropriateness.
• Follow-up intervention may involve contacting
the prescriber to recommend alternative
agents.
• Require an antimicrobial committee to develop
guidelines for appropriate use of targeted
agents,
• Personnel - Needed to perform the reviews
and follow-up communication on a daily
basis.
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44. • Education
• Guidelines and clinical pathways
• Antimicrobial order forms
• Streamlining or de-escalation
• Dose optimization
• IV-to-PO switch
• Antimicrobial cycling
• routine use of combination therapy is not
recommended
Supplemental strategies
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45. • ASP is a behaviour change program
• Needed to disperse information in an accurate and
timely fashion.
• Effective implementation of ASPs NEED TO
incorporate education along with other active
strategies eg prospective audit and intervention
Education – very effective
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46. • Multidisciplinary development of evidence-based
guidelines that incorporate local microbiology and
resistance patterns
• Other guidelines should be incorporated such as
– Diagnosis and testing,
– admission criteria,
– nursing care,
– conversion to oral medication
– discharge planning
Guidelines and clinical pathways
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47.  Decreases antibiotic consumption
 Implement automatic stop orders
 may require physicians to justify antimicrobial
use
 Challenge :
◦ Prescribers may view the process of filling out
these forms as inconvenient and time
consuming.
 Solution
◦ Computerized data entry systems may improve its
use and convenience
Antimicrobial order forms
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48.  Initial empiric therapy with a combination of agents to
ensure broad-spectrum coverage is followed by targeted
(preferably narrower) antibiotics once culture results
identify the pathogen
◦ Eg, if vancomycin is initially included in the
treatment regimen but culture results show an
absence of MRSA, vancomycin can then be
removed
 Decreases antimicrobial exposure in severe infection
 Saves costs without affecting clinical outcomes
De-escalation
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49. • When selecting the most appropriate
antimicrobial regimen takes into account factors
such as
– the pharmacokinetics and
pharmacodynamics of the agent,
– patient and pathogen characteristics,
– the site of infection
Dose optimization
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50. IV-to-PO switch
•Can be converted to oral therapy when then patient
meets the required criteria
•For drugs that have high bioavailability
•For which there is a substantial cost difference in IV
and PO formulations
•reduced incidence of catheter-related infections
•a decreased length of hospital stay
•a reduction in workload without sacrificing patient
safety
•Consistently shown to be safe and effective
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51. • Involves the deliberate scheduled removal and
substitution of specific antimicrobials or classes of
antimicrobials within an institution to avoid or
reverse the emergence of antimicrobial resistance.
• Challenge
– adherence can be difficult mainly because prescribers
may be unaware of the current scheduled antimicrobial
• insufficient data are available to recommend this
strategy for routine use.
Antimicrobial cycling
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52. GOALS of ASP
• Optimise antimicrobial therapy
• Reduce treatment related costs
• Minimise adverse events
• Decrease the risk of
development of antimicrobial
resistance
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53. Thank you
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54. Any Questions ?
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