antimicrobial drugs (part 2)

Antimicrobial Drugs

PHARMACOLOGY AND TOXICOLOGY II

Antimicrobial Drugs

Presented for Department of PharmacyUniversity of Darussalam Gontor - Indonesia

Surya Amal

Part II

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.

The Action of Antimicrobial DrugsThe Action of Antimicrobial Drugs

Protein Synthesis InhibitorsProtein Synthesis Inhibitors

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis : Penicilins

Penicillins– Natural penicillins:

G, V

– Semisynthetic penicillins

• “-cillin “ suffix• “-cillin “ suffix

• Carbapenems

• Monobactam

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis : Cephalosporins

• Cephalosporins– 2nd, 3rd, and 4th

generations more generations more effective against gram-negatives

Antibacterial AntibioticsInhibitors 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)

Antibacterial AntibioticsInhibitors of Cell Wall Synthesis: Anti-Mycobacterials

Antimycobacterium antibiotics

– Isoniazid (INH)

• Inhibits mycolic acid synthesis

– Ethambutol

• Inhibits incorporation of mycolic acid

Antibacterial AntibioticsInjury to the Plasma Membrane

Polymyxin B– Topical

– Combined with bacitracin and neomycin in over-the-counter preparationthe-counter preparation

Antibacterial AntibioticsInhibitors 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

Antibacterial AntibioticsCompetitive Inhibitors

– Sulfonamides (Sulfa drugs)

• Inhibit folic acid synthesis

• Broad spectrum

TMZ - Trimethoprim + Sulfamethoxazole : Synergism

Antifungal DrugsDamage through Ergosterol

• Leakage through binding ergosterol

– Amphotericin B

• Inibitors of Ergosterol Syntehsis

– Miconazole, fluconazole

– Triazoles

Antifungal DrugsInhibition of Cell Wall Synthesis

• Echinocandins– Inhibit synthesis of -

glucan

– Cancidas is used against Candida and Candida and Pneumocystis

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

Antiviral DrugsNucleoside and Nucleotide Analogs

Antiviral DrugsEnzyme Inhibitors

• Protease inhibitors– Indinavir• HIV

• Inhibits attachment– Zanamivir– Zanamivir• Influenza

• Inhibits uncoating– Amantadine• Influenza

• Interferons prevent spread of viruses to new cells

• Viral hepatitis

• 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)

• 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


• Ivermectin

– Paralyzes worm


cacing gelang, cacing kremi, cacing tambang)

MICROBIAL RESISTANCEMICROBIAL RESISTANCE

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

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); or permeability 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.

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).


Modified from : Neu HC. The Crisis in antibiotic resistance. Science 1992;257

A. DRUG INACTIVATION (enzyme inactivation)

The mechanism is a process by which bacterial enzymes either completely destroy the antimicrobial, or modify the


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.

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.


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.

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.

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.

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 ekstrakromosomalyang dapat melakukan replikasi secara independen, dandapat membawa gen pengkode untuk resistensi terhadapsuatu antimikroba.Transposon, merupakan bagian dari elemen genetik yang dapat menyisip bagian genom di tempat lain. Transposon dapat mengkode suatu enzim yang menginaktivasi suatuantimikroba.

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 chromosomal mutations, express a latent chromosomal resistance gene, or acquire new genetic resistance material through direct exchange of DNA (by conjugation), through a bacteriophage (transduction), through extrachromosomalplasmid DNA via transformation.

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.

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

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

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

Susceptibility Testing Methods

• Disk Diffusion (Kirby-Bauer disks)

• Broth Dilution


• E-test (epsilometer test)


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)

Culture ResultsExample

antimicrobial drugs (part 2)

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