To understand the mechanisms of antimicrobial action and the classification of antimicrobial drugs. To explain the process of microbial resistance. To understand the spread of resistant microbes. Outlines the prevention of microbial resistance.

1. Antimicrobial Drugs
PHARMACOLOGY AND TOXICOLOGY II
Antimicrobial Drugs
Presented for Department of Pharmacy
University of Darussalam Gontor - Indonesia
Surya Amal
Part II

2. Learning objectives
1. To understand the mechanisms of antimicrobial
action and the classification of antimicrobial
drugs.drugs.
2. To explain the process of microbial resistance.
3. To understand the spread of resistant microbes.
4. Outlines the prevention of microbial resistance.

3. The Action of Antimicrobial DrugsThe Action of Antimicrobial Drugs

4. Protein Synthesis InhibitorsProtein Synthesis Inhibitors

5. Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis : Penicilins
Penicillins
– Natural penicillins:
G, V
– Semisynthetic
penicillins
• “-cillin “ suffix• “-cillin “ suffix
• Carbapenems
• Monobactam

6. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis :
Cephalosporins
• Cephalosporins
– 2nd, 3rd, and 4th
generations moregenerations more
effective against
gram-negatives

7. Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis: Polypeptides
• Polypeptide antibiotics
– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin– Vancomycin
• Glycopeptide
• Important "last line"
against antibiotic resistant
S. aureus (e.g. MRSA)

8. Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis: Anti-Mycobacterials
Antimycobacterium antibiotics
– Isoniazid (INH)
• Inhibits mycolic acid synthesis
– Ethambutol
• Inhibits incorporation of mycolic acid

9. Antibacterial Antibiotics
Injury to the Plasma Membrane
Polymyxin B
– Topical
– Combined with bacitracin and neomycin in over-
the-counter preparationthe-counter preparation

10. Antibacterial Antibiotics
Inhibitors of Nucleic Acid Synthesis
• Rifamycin
– Inhibits RNA synthesis by RNA polymerase
– Antituberculosis
• Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase so blocks DNA polymerase
– Urinary tract infections

11. Antibacterial Antibiotics
Competitive Inhibitors
– Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum

12. TMZ - Trimethoprim + Sulfamethoxazole : Synergism

13. Antifungal Drugs
Damage through Ergosterol
• Leakage through
binding ergosterol
– Amphotericin B
• Inibitors of
Ergosterol Syntehsis
– Miconazole,
fluconazole
– Triazoles

14. Antifungal Drugs
Inhibition of Cell Wall Synthesis
• Echinocandins
– Inhibit synthesis of -
glucan
– Cancidas is used against
Candida andCandida and
Pneumocystis

15. Other Antifungal Drugs
• Inhibition of Nucleic Acids
– Flucytocine: cytosine analog interferes with RNA
synthesis
– Pentamidine isethionate for Pneumocytis : binds to
DNADNA
• Inhibition of Mitosis (microtubule beakers)
• Griseofulvin
– Used for superficial mycoses
• Tolnaftate
– Used for athlete's foot; action unknown

16. Antiviral Drugs
Nucleoside and Nucleotide Analogs

17. Antiviral Drugs
Nucleoside and Nucleotide Analogs

18. Antiviral Drugs
Enzyme Inhibitors
• Protease inhibitors
– Indinavir
• HIV
• Inhibits attachment
– Zanamivir– Zanamivir
• Influenza
• Inhibits uncoating
– Amantadine
• Influenza
• Interferons prevent spread of viruses to
new cells
• Viral hepatitis

19. • Chloroquine
– Inhibits DNA synthesis
• Malaria
• Diiodohydroxyquin
– Unknown
• Amoeba
Antiprotozoan DrugsAntiprotozoan Drugs
• Amoeba
• Metronidazole (Flagyl)
– Damages DNA after becoming toxic from fermentation enzymes
• Entamoeba, Trichomonas, Giardia (no mitochondria!)
• (also works on obligately anaerobic bacteria like Clostrdium)

20. • Niclosamide
– Prevents ATP generation
• Tapeworms
• Praziquantel
– Alters membrane permeability
• Flatworms
• Pyantel pamoate
Antihelminthic Drugs
• Helminths
are macroscopic
multicellular eukaryotic
organisms: tapeworms,
roundworms, pinworms,
hookworms (cacing pita,
cacing gelang, cacing• Pyantel pamoate
– Neuromuscular block
• Intestinal roundworms
• Mebendazole
– Inhibits nutrient absorption
• Intestinal roundworms
• Ivermectin
– Paralyzes worm
• Intestinal roundworms
cacing gelang, cacing
kremi, cacing tambang)

21. MICROBIAL RESISTANCEMICROBIAL RESISTANCE

22. The term of microbial resistance
Antimicrobial resistance is the ability of microbes, such as
bacteria, viruses, parasites, or fungi, to grow in the presence of
a chemical (drug) that would normally kill it or limit its growth.
Credit: NIAID

23. Antibiotics resistance
o Natural Resistance : Bacteria may be inherently resistant
to an antibiotic. Streptomyces has some genes
responsible for resistance to its own antibiotic; or a
Gram- bacteria have an outer membrane as a
permeability barrier against antibiotic (e.g., penicillin); orpermeability barrier against antibiotic (e.g., penicillin); or
an organism lacks a transport system for the antibiotic; or
efflux pumps; or it lacks the target (e.g. INH-mycolic acid
synthesis) of the antibiotic.
o Acquired Resistance : Bacteria can develop resistance to
antibiotics due to (1) mutations; (2) mobile genetic
elements, e.g., plasmids or transposons carrying
antibiotic resistance gene.

24. Basically there are four main mechanisms by
which these processes occur;
1. Drug inactivation (enzyme inactivation),
Processes of antimicrobial resistance
1. Drug inactivation (enzyme inactivation),
2. Cellular access (decreased permeability),
3. Site modification (altered target site),
4. Biochemical Feedback (by pass).

25. Processes of antimicrobial resistance
Modified from : Neu HC. The Crisis in antibiotic resistance. Science 1992;257

26. A. DRUG INACTIVATION (enzyme inactivation)
The mechanism is a process by which bacterial enzymes
either completely destroy the antimicrobial, or modify the
Processes of antimicrobial resistance
either completely destroy the antimicrobial, or modify the
drug by adding a molecule to it and rendering it incapable
of specific activity. Examples of these two activities are β-
lactamase; which destroy the β-lactam ring, the
acetylation of chloramphenicol, the modification of
aminoglycoside by acetylation or other additions.

27. B. CELLULAR ACCESS (decreased permeability)
 The mechanism is controlled in terms of allowing entry
to the bacterial cell, or an active process of ejecting
drugs via an efflux pump.
Processes of antimicrobial resistance
drugs via an efflux pump.
 Coincidental with these processes is intrinsic resistance
due to physical barriers – e.q. Gram-negative outer
membrane provides resistance to some β-lactams.
 Efflux pump mechanisms are increasingly recognized as
a common method by which bacteria can remove a
wide range of antimicrobials, from tetracyclines to
quinolones.

28. C. SITE MODIFICATION (altered target site)
Site modification – involves alteration of the target site
of an antimicrobial agent so that the fit is no longer
Processes of antimicrobial resistanceProcesses of antimicrobial resistance
of an antimicrobial agent so that the fit is no longer
sufficient to exert activity. Analogous to a lock and key
situation, wherein a small change in the lock can render
the key useless; a good example would be the alteration
of the 23s ribosome to prevent macrolides, such as
clarithromycin, from binding to the ribosome.

29. D. BIOCHEMICAL FEEDBACK (by pass)
Biochemical feedback – via target hyperproduction is
best represented by the folic acids pathway in which an
Processes of antimicrobial resistanceProcesses of antimicrobial resistance
best represented by the folic acids pathway in which an
organism may deliberately over-produce an enzyme so as
to saturate all the sulfonamide or trimethoprim present
and still be able to catalyze the biosynthetic pathway.

30. Genetic Resistance
Genetic resistance : due to chromosomal
mutations or acquisition of antibiotic
resistance genes on plasmids or transposons.
Plasmid, merupakan elemen genetik ekstrakromosomalPlasmid, merupakan elemen genetik ekstrakromosomal
yang dapat melakukan replikasi secara independen, dan
dapat membawa gen pengkode untuk resistensi terhadap
suatu antimikroba.
Transposon, merupakan bagian dari elemen genetik yang
dapat menyisip bagian genom di tempat lain. Transposon
dapat mengkode suatu enzim yang menginaktivasi suatu
antimikroba.

31. Resistance Mechanism and Their Genetic Bases
Bacteria posses a remarkable number of
genetic mechanisms for resistance to
microbials. They can undergo chromosomal
mutations, express a latent chromosomalmutations, express a latent chromosomal
resistance gene, or acquire new genetic
resistance material through direct exchange of
DNA (by conjugation), through a bacteriophage
(transduction), through extrachromosomal
plasmid DNA via transformation.

32. Resistance Mechanism and Their Genetic Bases
The information encoded in this genetic material enables
a bacterium to develop resistance through three major
mechanisms :
 production of an enzyme that will inactivate or production of an enzyme that will inactivate or
destroy the antibiotic;
 alteration of the antibiotic target site to evade action
of the antibiotic; or
 prevention of antibiotic access to the target site.

33. Examples of organisms that are known to possess resistance
mechanisms of the various types

34. Examples of organisms that are known to possess resistance
mechanisms of the various types

35. Examples of organisms that are known to possess resistance
mechanisms of the various types

36. Examples of organisms that are known to possess resistance
mechanisms of the various types
Modified from : Neu HC. The Crisis in antibiotic
resistance. Science 1992;257

37. Selecting an Antimicrobial
• Confirm the presence of infection
– History and physical
– Signs and symptoms
– Predisposing factors
• Identification of pathogen
– Collection of infected material
– Stains
– Serologies– Serologies
– Culture and sensitivity
• Selection of presumptive therapy
– Drug factors
– Host factors
• Monitor therapeutic response
– Clinical assessment
– Lab tests
– Assessment of therapeutic failure

38. Susceptibility Testing Methods
• Disk Diffusion (Kirby-Bauer disks)

39. • Broth Dilution
Susceptibility Testing Methods

40. • E-test (epsilometer test)
Susceptibility Testing Methods

41. Culture Results
• Minimum inhibitory concentration (MIC)
– The lowest concentration of drug that prevents visible bacterial
growth after 24 hours of incubation in a specified growth medium
– Organism and antimicrobial specific
– Interpretation
• Pharmacokinetics of the drug in humans
• Drug’s activity versus the organism
• Site of infection
• Drug resistance mechanisms
• Report organism(s) and susceptibilities to antimicrobials
– Susceptible (S)
– Intermediate (I)
– Resistant (R)

42. Culture Results
Example