This document discusses antimicrobials and antimicrobial resistance. It covers several topics: 1. It defines antimicrobial compounds and describes their importance in treating infections and medical procedures. However, it notes the need to understand resistance mechanisms. 2. It describes several classes of antibiotics including beta-lactams, aminoglycosides, fluoroquinolones, macrolides, tetracyclines, and glycopeptides. It explains their mechanisms of action. 3. It discusses antimicrobial susceptibility testing methods including manual, semi-automated, and automated methods and covers topics like interpretive criteria and quality control. 4. It mentions the diminishing pipeline of new drugs and drivers of antimicrobial

1. Antimicrobials & Antimicrobial
Resistance

2. PART I: Antimicrobials

3. Antimicrobial compounds
- Compounds that inhibit the growth of micro-organisms
- May be Anti-viral, Anti-bacterial, Anti-fungal or Anti-protozoan
- Antibacterial compounds have made significant contributions
in infectious disease treatment and in medical procedures
- However, there is a need to understand these compounds,
their Lab testing, reporting and resistance mechanisms

4. What makes an ideal antibacterial agent?
1. Safety
2. Potency
3. Bioavailability
4. Spectrum of activity
5. Cost effectiveness
etc.

5. Classification of antibacterial drugs
1. Natural or synthetic?
2. Mechanisms of action?
3. Bacteriostatic or bactericidal?
4. Broad or narrow spectrum?
5. Time dependent or concentration dependent?

7. A generalized process of antibiotic action
1. Antibiotic administration
2. Antibiotic contact with the target bacterial cell
3. Internalization/Uptake of the drug by the cell
4. Rise in concentrations of the drug at the target site
5. Inhibitory action of the antimicrobial compound –
Bacteriostatic or bactericidal

8. Mechanisms of antibiotic action

9. Considerations for antimicrobial testing and reporting
1. Pathogen factors: Identity, AST profiles, local epidemiology,
Site of isolation
2. Drug factors: Mechanism of action, tissue bioavailability,
toxicity, mechanism of resistance, drug-drug interactions
3. Patient factors: Age, pregnancy, hospitalization, co-
morbidities, allergies, site of isolation etc.

10. 1. Beta lactams

11. Selected antimicrobial compounds
1. Beta Lactams
- Compounds that inhibit bacterial cell wall synthesis
- Characterized by the presence of beta lactam rings
- Early forms were natural but synthetic modifications are made
- They act by binding to Penicillin binding protein (PBP) to inhibit
completion of cell wall synthesis
- Their action is bactericidal
- Action is time-dependent

12. Bacterial peptidoglycan

13. Sub-classes of beta lactams
1. Penicillins
- Native penicillins: Penicillin G, Penicillin VK
- Amino-penicillins: Amoxicillin, Ampicillin
- Anti-staphylococcal Penicillins: Oxacillin, Dicloxacillin, Flucloxacillin
- Anti-Pseudomonal Penicillins: Ticarcillin (Carboxy), Piperacillin
(Ureido)

14. Sub-classes of beta lactams
2. Cephalosporins
- First generation: Cefazolin and cephalexin
- Second generation: Cefoxitin, Cefuroxime and Cefuroxime axetil
- Third generation: Ceftazidime, Cefotaxime, Ceftriaxone and
Cefixime
- Fourth generation: Cefepime
- Fifth generation: Ceftobiprole and ceftaroline

15. Sub-classes of beta lactams
3. Carbapenems - these antibiotics have a carbapenem attached
to the ring. Examples: Doripenem, Imipenem, Meropenem,
Ertapenem
4. Monobactams - The beta-lactam ring stands alone and not
fused to another ring. Example: Aztreonam
Beta-lactamase inhibitors - They work primarily by inactivating
serine beta-lactamases.
1st generation: Clavulanic acid, Sulbactam, Tazobactam
2nd generation: Avibactam, verbobactam

17. 2. Aminoglycosides

18. Aminoglycosides
- Composed of amino-sugars with glycosidic linkages
- Bind to 30S bacterial ribosomal sub-unit to inhibit protein synthesis
- Act intracellularly in a concentration-dependent manner
- They have poor lipid solubility and poor oral bioavailability
- Their action is bactericidal
- Characterized by post-antibiotic effect (PAE)
- Examples: Gentamicin, Tobramycin, Streptomycin, Amikacin
- Side effects: Ototoxicity, Nephrotoxicity, Neuro-muscular blockade

19. 3. Fluoroquinolones

20. Fluoroquinolones
- Fluoroquinolones affect bacterial DNA replication
- The bind to the ligase domain of DNA Gyrase leading to DNA
disintegration
- Bactericidal action that is concentration-dependent
- Excellent oral bioavailability and broad-spectrum activity
- Examples: Nalidixic acid, Norfloxacin, Ciprofloxacin, Moxifloxacin
- Side effects: QT prolongation, Tendonitis, Nausea, vomiting,
diarrhea

22. 4. Macrolides

23. Macrolides
- Act by binding to the larger ribosomal sub-unit to inhibit protein
synthesis
- Their action is bacteriostatic
- Advantages: Stability, Bioavailability, Broad spectrum,
Tolerability
- Examples: Erythromycin, Azithromycin, Telithromycin

24. 5. Tetracyclines

25. Tetracyclines
- Tetracyclines bind to a highly conserved 16S ribosomal RNA (rRNA) target in
the 30S ribosomal subunit.
- Binding leads to steric interference with the docking of aminoacyl-transfer
RNA (tRNA) during elongation.
- Tetracyclines are usually considered bacteriostatic antibiotics
- The drug passively diffuses through the outer membrane porins OmpF and
OmpC most likely as a Mg2+ chelate.
- Spectrum: Gram-positive and negative bacteria, spirochetes, obligate
intracellular bacteria, as well as protozoan parasites.
- Examples: Chlortetracycline, tetracycline, doxycycline, Minocycline

26. 6. Glycopeptides

27. Glycopeptides
- These antibiotics act by inhibiting cell wall synthesis.
- Glycopeptides bind to the terminal D-ala sub-unit and inhibit
the binding of the Peptidoglycan binding protein (PBP)
- Action is bactericidal
- The common structural motif is a core heptapeptide scaffold
- Sugar residues, chlorine atoms and lipid chains are added by
oxidative cross-linking

28. Categories of antimicrobial resistance
1. Clinical resistance: Pathogen MIC above those that can safely
be attained in vivo
2. Environmental resistance: Presence of physical and chemical
materials such as Ions, pH, Oxygen, Metabolites may affect
susceptibility
3. Intrinsic resistance: Natural genetic, structural and physiologic
state.
Anaerobes & enterococci (Aminoglycosides), GPs (Aztreonam), GNs
(Vancomycin), K. pneumo (Ampicillin), Pseudo (SXT, 1st & 2nd gen cephs,
Tet)
4. Extrinsic resistance: Arise from chromosomal mutations and
horizontal gene transfer

29. Mechanisms of antimicrobial resistance
1. Reduced uptake: Mycobacteria, Gram negatives, Gram
positives, Mycoplasmas
2. Active efflux pumps: Some are broad, others narrow.
Transporter families include ABC, MATE, SMR, FMS and RND.
3. Modification of targets: Tetracyclines, Macrolides, Beta lactams
etc.
4. Inactivation of drugs: Aminoglycosides, Beta lactams,
tetracyclines etc.

30. Mechanisms of antibiotic efflux

31. PART II: Antimicrobial
Susceptibility testing

32. 1st Generation AST methods - Manual
Kirby-Bauer
Microdilution
E-test strips
Broth Dilution

33. KIRBY- BAUER DISC DIFFUSION AST
1. ISOLATE: Purity, Concentration, viability
2. DRUG: Number, positioning, concentration
3. MEDIA: Sterility, viability,
4. CONDITIONS: Time, temperature
5. INTERPRETATION & REPORTING: CLSI, EUCAST
guidelines

34. 2nd Generation methods: Semi-automation
ADAGIO platform
ADAGIO output
ADAGIO Setup ADAGIO output

35. 3rd Generation methods – Automated platforms
Microscan
VITEK
Phoenix

36. EXERCISES!!!

37. Part III: Antibiotic stewardship

38. Diminishing pipeline of new drugs

39. Drivers of AMR
- Poor prescription practices
- Antibiotic misuse and overuse
- Poor regulation by the government
- Inadequate infection prevention and hygiene
- Inadequate diagnostic microbiology practices
………….Discuss others

41. Can we stop AMR development?
- Water hygiene and sanitation
- Vaccinations
- Adequate diagnostic microbiology
- Antibiotic stewardship
- Government regulation
- Patient practices
- Research and development
………….Discuss others