ANTIMICROBIAL

THERAPY

(PART 1)

DR. AMADIN A. OLOTU

LECTURER/CONSULTANT MEDICAL MICROBIOLOGIST

BOWEN UNIVERSITY/BOWEN UNIVERSITY TEACHING HOSPITAL OGBOMOSO

OUTLINE

• DEFINITIONS AND INTRODUCTION

• BRIEF HISTORY

• CLASSES OF ANTIBACTERIAL DRUGS

• RESISTANCE TO ANTIMICROBIAL DRUGS

• CLINICAL USE OF ANTIBIOTICS

• OTHER CLASSES OF ANTIMICROBIALS

• Antimicrobials: Substances that kill or inhibit the growth of microorganisms.

They may be natural, semisynthetic, or synthetic in origin.

• The use of antimicrobial substances to treat infections is known as

antimicrobial therapy.

• Chemotherapy: use of chemicals for therapy in diseases which may be

infections or malignancies

• Antibiotics: Natural chemical substances produced by microorganisms that selectively

kill or inhibit the growth of bacteria at low concentrations without causing

considerable harm to the host.

• In current usage the term antibiotics also includes semisynthetic and synthetic

substances.

• Note all antibiotics are antimicrobials but not all antimicrobials are antibiotics.

• Bacteriostatic: Ability to inhibit the growth of bacteria.

• Bactericidal: Ability to kill bacteria.

• Selective toxicity: the property of an antimicrobial drug to kill or inhibit the

target organism without injuring the host’s cells

• Recorded reports show that substances with antimicrobial properties have

been used for at least 2000 years.

• Ancient Egyptians and ancient Greeks used specific molds and plant extracts

to treat infections

• Oral history in Africa shows poultices and plant extracts were used to treat

wounds and certain conditions that may have been infectious in origin

• 1600s – Bark of the Cinchona tree was used for the treatment of malaria

• In 1820, quinine was extracted and isolated from the bark and became the standard treatment for malaria

• Ipecacuanha, the powdered root of the Brazilian plant, Cephaelis ipecacuanha, was used in India from about 1858 to treat dysentery.

• Emetine was shown to be the principal active alkaloid in ipecacuanha in

1911

• In 1912, the effectiveness injectable emetine was for amebiasis, amebic

dysentery and amebic abscess caused by Entamoeba histolytica was

demonstrated

• 1900-1910 Arsphenamine synthesized for syphilis

• Paul Ehrlich the father of chemotherapy coined the term "magic bullet“.

• He postulated the possibility of chemicals with activity against specific sites on parasitic organisms and with no activity on the host.

• His efforts lead to an arsenic derivative, arsphenamine called “Salvarsan”, with modest activity against syphilis.

• In 1908 he won the Nobel Prize in Physiology or Medicine for his work in a different area of laboratory medicine – antigen antibody interactions

• In 1928, Alexander Fleming discovered a natural antimicrobial substance which he

named penicillin.

• It was extracted from the fungus Penicillium spp

• In 1935 the discovery of Prontosil the first sulphonamide drug

and its activity against bacterial infections was reported.

• In 1939 Gerhard Domagk won the Nobel Prize in Physiology or Medicine for that.

• Sulphonamides became the first widely used antibiotics

• 1940s Penicillin – became available for general use

• 1945 Nobel Prize in Physiology or Medicine awarded to

Alexander Fleming, Howard Florey and Ernst Chain for

the discovery of penicillin

CLASSES OF ANTIMICROBIALS

On the basis of susceptible organisms

• Antibacterial

• Antiviral

• Antifungal

• Antiprotozoan

• Antihelmintic

Antibacterials

• Mechanisms of action

• Cell wall synthesis inhibitors

• Cell membrane inhibitors

• Protein synthesis inhibitors

• Nucleic acid synthesis inhibitors

• Metabolic pathway inhibitors

Sites of action of different antibacterial agents

Cell wall synthesis inhibitors

• The peptidoglycan in bacterial cell walls is an important cellular component

• It functions in the maintenance of shape and protection from lysis due to osmotic pressures

• Peptidoglycans are unique to prokaryotic organisms

• They consist of a backbone of repeating units of a dissacharide: N-acetylmuramic acid (NAM) in a β-1-4 glycosidic linkage with N-acetyl-glucosamine (NAG), and Peptide chains are highly cross-linked with bridges in

• Gram-positive bacteria such as Staphylococcus aureus

• Gram-negative bacteria such as E. coli have fewer cross-links.

PEPTIDOGLYCAN BUILDING BLOCK

The peptidoglycan of

the cell wall is

composed

of a series of identical

subunits. The terminal

D-alanine is split off

each time a new cross

link is synthesized.

• The biosynthesis of peptidoglycan can be divided into three different stages.

• The first stage occurs in the cytoplasm and leads to the synthesis of the

precursors Uridine Diphosphate (UDP) -N-acetylglucosamine (NAG)(UDP-

NAG) and UDP-N-acetylmuramyl(NAM) -pentapeptide (UDP-NAM-

pentapeptide)

• UDP-NAM is synthesized from UDP NAG and phosphenol pyruvate in a

reaction catalyzed by UDP-N-acetylglucosamine-3-enolpyruvyltransferase.

• Fosfomycin is used orally in its stable salt form fosfomycin trometamol. It

inhibits this early stage of bacterial cell wall synthesis.

• Its an analog of phosphoenolpyruvate.

• It inhibits the cytoplasmic enzyme UDP-NAG-3- enolpyruvate transferase

by covalently binding to the cysteine residue of the active site and blocking

the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine.

• It is bactericidal to gram positive and gram negative organisms

• Three amino acids are added to the NAM to yield a tripeptide to which two

more amino acids are subsequently linked.

• The dipeptide D-alanyl-D-alanine is synthesized from two molecules of D-

alanine by the enzyme D-alanyl-D-alanine synthetase.

• D-alanine is produced from L-alanine by an alanine racemase.

• Cycloserine inhibits both alanine racemase and D-alanyl-D-alanine

synthetase

• It is an antibiotic produced by Streptomyces orchidaceus

• Due to the structural similarity of cycloserine and D-alanine and to the fact

that cycloserine actually binds to the enzymes better than the D-alanine.

• Cycloserine may be bacteriocidal or bacteriostatic depending on its

concentration at the site of infection.

• The second stage of cell wall synthesis is catalyzed by membrane-bound enzymes.

• The nonnucleotide portion of the precursor molecules previously made are transferred sequentially to a carrier in the cytoplasmic membrane.

• This carrier is a phosphorylated undecaprenyl alcohol.

• The lipid carrier is a point of attachment to the membrane for the precursors and transports the subunits across the cytoplasmic membrane, from the hydrophobic interior to the outside surface.

• Bacitracin is a cyclic peptide antibiotic first obtained from the Tracy strain of Bacillus subtilis in

1943.

• It specifically interacts with the pyrophosphate derivate of the undecaprenyl alcohol,

preventing further transfer of the NAM-pentapeptide from the precursor nucleotide to the

growing peptidoglycan chain.

• Bacitracin is bactericidal

• It is nephrotoxic when administered systemically, it is therefore limited to topical use.

• The third stage of cell wall synthesis involves polymerization of the subunits and the

attachment of nascent peptidoglycan to the cell wall.

• The new peptidoglycan is attached to preexisting cell wall peptidoglycan by a

transpeptidase reaction that involves peptide chains in both polymers, one of which

must possess a D-alanyl-D-alanine terminus.

• The transpeptidase reaction is catalyzed by a group of proteins called penicillin binding

proteins

• Beta-lactam antibiotics bind to the penicillin-binding proteins (PBPs) and

inhibit bacterial cell wall synthesis.

• This eventually results in cell lysis in an isotonic environment.

• In a markedly hypertonic environment, the microbes change to protoplasts

or spheroplasts.

• The effect of ß-lactam antibiotics is seen against actively dividing bacteria.

• The ß-lactam antibiotics are the penicillins, cephalosporins, (including

cephamycins), monobactams, and carbapenems.

• They are all bacteriocidal.

By Fvasconcellos 19:02, 23 October 2007 (UTC) - Own work, Public Domain,

https://commons.wikimedia.org/w/index.php?curid=2962617

Core structure of beta-lactams: ① (top) penicillin

② (bottom) cephalosporins.

β-lactam ring in red

• Penicillin: Penicillin G, Penicillin V

• Aminopenicillins: Ampicillin, Amoxicillin

• Penicillinase-Resistant Penicillin: Methicillin, nafcillin, oxacillin, cloxacillin

and dicloxacillin

• Anti-Pseudomonal Penicillins: Ticarcillin, Carbenicillin, Piperacillin and

Mezlocillin

• Beta-Lactamase Inhibitors: Clavulanic Acid, Sulbactam, and Tazobactam

Combinations Available Trade

Name

Amoxicillin and clavulanic acid Augmentin

Ticarcillin and clavulanic acid Timentin

Ampicillin and sulbactam Unasyn

Piperacillin and tazobactam Zosyn

CEPHALOSPORINS

• 1st generation: cephalothin, cephapirin, cefazolin, cefadroxil, cephradine, cephalexin

• 2nd generation: cefuroxime, cefaclor, cefamandole, cefmetazole, cefonicid, cefprozil, (cephamycins – cefoxitin and cefotetan)

• 3rd generation: ceftriaxone, ceftazidime, cefotaxime, ceftizoxime, cefixime, cefoperazone, cefpodoxime

• 4th generation: Cefipime, Cefpirome

• 5th generation: Ceftaroline, Ceftobiprole

• Monobactam (They are relatively resistant to

• lactamases and active against gram-negative rods. They have no activity

against gram-positive bacteria or anaerobes): Aztreonam

• Carbapanem: Imipenem, Meropenem,

• Glycopeptides:

• antimicrobials like vancomycin and teicoplanin interrupt cell wall synthesis by forming a complex with the C-terminal D-alanine residues of peptidoglycan precursors.

• Complex formation at the outer surface of the cytoplasmic membrane prevents the transfer of the precursors from a lipid carrier to the growing peptidoglycan wall by transglycosidases.

• Biochemical reactions in the cell wall catalyzed by transpeptidases and carboxypeptidases are also inhibited by vancomycin and other glycopeptideantimicrobials.

• Because of its large size and complex structure, vancomycin does not

penetrate the outer membrane of gram negative organisms.

• Vancomycin is useful for treating infections due to gram positive organisms

resistant to beta-lactam antibiotics

Cell Membrane Function Inhibitors

• A number of antimicrobial agents can cause disorganization of the membrane.

These agents can be divided into cationic, anionic, and neutral agents.

• The best-known compounds are polymyxin B and colistemethate (polymyxin E).

• These high-molecular-weight octapeptides inhibit Gram-negative bacteria that have

negatively charged lipids at the surface.

• Basically, polymyxins disorganize membrane permeability so that nucleic acids and

cations leak out and the cell dies.

• The polymyxins were only used locally previously because of their potential

to cause toxicity to the renal and nervous systems.

• However with the rise in cases of infection due to extended spectrum beta

lactamases they were used in treating such infections

Protein Synthesis Inhibitors

• Bacteria have 70S ribosomes, with 30S and 50S subunits

• Mammalian cells have 80S ribosomes, with 40S and 60S subunits

• Since the subunits of each type of ribosome differ chemically and

functionally, antimicrobial drugs can inhibit protein synthesis in bacterial

ribosomes without having a major effect on mammalian ribosomes.

Protein Synthesis Inhibitors

Protein Synthesis Inhibitors

• Most interfere with ribosomes

• By preventing ribosome function, polypeptide synthesis is inhibited

• Drug groups

• Aminoglycosides (e.g., streptomycin, gentamycin)

• Bind to 30S subunit

• Interferes with initiation complex

• mRNA localization to P site

• fMet tRNA

• Incorrect amino acid is incorporated into polypeptide

• Tetracyclines

• Bind to 30S subunit

• Prevents IF3 binding

• No tRNA binding

Protein Synthesis Inhibitors

• Others

• Macrolides - initiation complex, translocation

• Lincomycins - initiation complex, translocation

• Glycylcyclines - Tetracycline analogs; bind with higher affinity

• Chloramphenicol - Inhibits peptidyl transferase

• Streptogramins - Irreversible binding to 50S subunit; unknown

mechanism

• Oxazolidinones - Inhibit fMet tRNA binding to P site

Nucleic Acid Synthesis Inhibitors

• Types

• Rifampicin - RNA polymerase inhibitor

• Binds with high affinity to β subunit of DNA-

dependent RNA polymerase

• Prevents RNA synthesis

• Quinolones - inhibit bacterial DNA gyrase

Metabolic pathway inhibitors

• Sulfonamides

• Structural homologs of para-aminobenzoic acid (PABA)

• PABA is required for folic acid synthesis by dihydropteroate synthetase (DHPS)

• Folic acid is a nucleotide precursor

• Sulfonamides compete with PABA for the active site of DHPS

• Trimethoprim

• Inhibits bacterial dihydrofolate reductase (DHFR) the next enzymatic step after folic acid synthesis is blocked by sulfonamides.

• Trimethoprim is up to 50,000 times more active against bacterial DHFR than against the human enzyme.

• Trimethoprim interferes with the conversion of dihydrofolate to tetrahydrofolate

Resistance to Antimicrobial Drugs

• Mechanisms of resistance

• Enzymes that cleave or otherwise inactivate antibiotics

• β-lactamases

• Changes in bacterial permeabilities

• Prevents entry of antibiotic into cell

• Mutation in target molecule

• Alter binding characteristics of the antibiotics

• Alteration of metabolic pathways

• Some resistant bacteria can acquire PABA from the environment

• Molecular pumps (efflux systems)

• Secretion systems that export antibiotics faster than the rate of import

Nongenetic Origins of Drug Resistance

• Low replication rates

• Antibiotic is metabolized or neutralized before it act

• Mycobacteria spp.

• Alteration of cellular physiology

• Bacterial L forms are cell wall-free

• Colonization of sites where antibiotics cannot reach

• Gentamicin cannot enter cells

• Salmonella are thus resistant to gentamicin

Genetic Origins of Drug Resistance

• Chromosomal Resistance

• Genes that regulate susceptibility

• Often found in enzymes, rRNA and secretion system genes

• Mutations in RNA polymerase render it resistant to the effects of

rifampin

• Efflux pumps with specificity for antibiotics

• Found in all bacteria

• All possess large hydrophobic cavity for binding antibiotics

Genetic Origins of Drug Resistance

• Extrachromosomal Resistance

• Often account for interspecies acquisition of resistance

• Contribute to multi-drug resistance (MDR)

• Genetic elements are:

• Plasmids

• Transposons

• Conjugation

• Transduction

• Transformation

Drug Resistance

Antimicrobial Activity In Vivo

• Drug-Pathogen Relationships

• Environment

• State of metabolic activity: slow-growing or dormant bacteria less

susceptible

• Distribution of drug: CNS is often exclusionary

• Location of organisms: Some drugs do not enter host cells

• Interfering substances: pH, damaged tissues, etc.

• Concentration

• Absorption: some cannot be taken orally

• Distribution: some accumulate in certain tissues

• Variability of concentration: peaks and troughs

• Postantibiotic effect: delayed regrowth of bacteria

Antimicrobial Activity In Vivo

• Host-Pathogen Relationships

• Alteration of tissue response

• Suppression of microbe can reduce inflammatory responses

• Alteration of immune response

• Prevention of autoimmune antibodies (e.g., rheumatic fever)

• Alteration of microbial flora

• Expansion of harmful flora (e.g., C. difficile)

Clinical Use of Antibiotics

• Accurate diagnosis is important

• Selection of appropriate antibiotic

• Susceptibility testing is performed.

• An important aim is to determine the minimum

inhibitory concentration (MIC)

• The MIC is the lowest concentration of antibiotic necessary to

inhibit visible bacterial growth. It is measured in µg/ml

• It is usually done in a tube test

• Serial dilutions of an antibiotic are made, then a defined number of

bacteria are added to the tubes

• Tubes are read the following day (or days) for the endpoint

Minimal Inhibitory Concentration

• Susceptibility testing however is often

routinely performed with antibiotic discs

• A large zone of clearance may suggest

sensitivity however it must be measured

and compared to breakpoints on standard

charts

• Break points are related to the MIC

Dangers of Indiscriminate Use

• In some countries antibiotics are available OTC

• This has led to high levels of antibiotic resistance

• Often the wrong antibiotic is used

• The full regimen is not completed

• Changes in normal flora

Antimicrobial Chemoprophylaxis

• Exposure to specific pathogens (e.g., N. meningitidis)

• Health-related susceptibilities

• Heart disease/valve replacement

• Respiratory disease (e.g., influenza, measles)

• Recurrent urinary tract infections

• Opportunistic infections

• Post surgery

• Disinfectants

• Medical devices (e.g., catheters)

Effects when antimicrobial drugs used in

combination

• Indifference: the combined action is no greater than that of the more effective agent when used alone.

• Addition: the combined action is equivalent to the sum of the actions of each drug when used alone.

• Synergism: the combined action is significantly greater than the sum of both effects

• Antagonism: the combined action is less than that of the more effective agent when used alone

Reasons Antimicrobial are Drugs Used in

Combination

• 1. To give prompt treatment in severely ill patients suspected of having a life threatening microbial infection.

• Before such treatment is started, adequate specimens are obtained for identifying the etiologic agent in the laboratory.

• An example is suspected gram-negative or staphylococcal sepsis in immunocompromised patients.

• 2. To delay the emergence of microbial mutants resistant to one drug in chronic infections by the use of a second or third non cross-reacting drug.

• An example is active tuberculosis.

• 3. To treat mixed infections, particularly those following massive trauma or those involving vascular structures.

• Each drug is aimed at an important pathogenic microorganism.

• 4. To achieve bactericidal synergism or to provide bactericidal action.

• In a few infections, eg enterococcal sepsis, a combination of drugs is more likely to eradicate the infection than either drug used alone. Such synergism is only partially predictable, and a given drug pair may be synergistic for only a single microbial strain. Occasionally , simultaneous use of two drugs permits significant reduction in dose and thus avoids toxicity but still provides satisfactory antimicrobial action

Antifungal Drugs

Site of Action Class of

Drugs

Drugs Mechanism of Action Clinical Use

Fungal cell

membrane

Polyenes Amphotericin B

Nystatin

Cause formation pores in fungal membranes, which contain ergosterol

resulting in loss of intracellular content. However, mammalian

membranes are unaffected because they contain cholesterol

Amphotericin B for

serious systemic infections

while nystatin is only used

topically

Ergosterol

synthesis

Azoles Inhibit fungal P450 dependent enzyme lanosterol

14α-demethylase thus inhibiting ergosterol synthesis

Imidazoles are used

topically with the

exception of

ketoconazole which can

be taken orally. The

triazoles are all used in

treating systemic

infections

Imidazoles Ketoconazole,

Clotrimazole.

Miconazole

Triazoles Fluconazole,

Itraconazole,

Voriconazole,

Ergosterol

synthesis

Allylamines Terbinafine,

Naftifine

Interfere with ergosterol biosynthesis by inhibiting the fungal enzyme

squalene epoxidase leading to accumulation of squalene which is toxic

Terbinafine alone orally

both topically

Fungal cell wall

synthesis

Echinocandins Caspofungin,

Micafungin,

Anidulafungin

Block the enzyme (1-3)-β-D-glucan synthase and prevent synthesis of

the fungal cell wall

IV for systemic infections

and resistant candi

DNA synthesis Pyrimidine

Analog

Flucytosine It is taken up by fungal cells and then converted to forms that

selectively interfere with DNA and RNA synthesis in fungi

Combined synergistically

with Amphotericin B

Microtubule

assembly

Microtubule

Assembly

Inhibitor

Griseofulvin It interacts with microtubules to interfere with the formation of the

mitotic spindle and inhibit mitosis in dermatophytes

Given orally to treat

dermatophtoses

Antiprotozoal Drugs For Plasmodium spp. (Antimalarial Drugs)

Class of Drugs Drugs Stage Effective Against Mechanism of Action

4-Aminoquinoline Chloroquine, Amodiaquine Trophozoite, blood schizont Inhibition of haem polymerase, the enzyme that polymerises free haem to

haemozoin. Free heme is toxic to the parasite

8-Aminoquinoline Primaquine Hypnozoite, liver schizont,

trophozoite, gametocytes

Unknown but thought to be due to oxidative metabolites that affect

parasite pyrimidine synthesis and disrupt the mitochondrial electron

transport chain.

Quinoline methanol Quinine, Quinidine,

Mefloquine

Trophozoite, blood schizont Unknown but it inhibits the digestion of hemoglobin which may play a

role in its action.

Bisquinoline 4-aminoquinoline Piperaquine Trophozoite Unknown but thought to be similar to that of the related class 4 –

aminoquinolines

Folate metabolism antagonists Pyrimethamine, Proguanil Sporozoite, trophozoite,

blood schizont

Inhibit dihydrofolate reductase

Sulfadoxine (Sulfonamide),

Dapsone (Sulfone)

Sporozoite, trophozoite Competes with para-aminobenzoic acid for dihydropteroate synthetase

Sesquiterpene lactone

endoperoxides: Artemisinins

Artesunate, Artemether,

Dihydroartemisinin

Trophozoite, blood schizont Iron-catalyzed cleavage of the artemisinin endoperoxide bridge results in

the production of free radicals that are toxic to malaria parasites

Aryl-amino alcohol Lumefantrine Blood schizont Not well understood but thought to involve interaction with heme

Phenanthrene methanol Halofantrine Unknown

Hydroxynaphthoquinone Atovaquone Oocyst, liver schizont,

trophozoite

inhibits the electron transport system of parasites at the cytochrome bc1

complex

Mannich base acridine Pyronaridine Trophozoite Unknown

Tetracycline (Anibiotic) Doxycycline Trophozoite Inhibits protein synthesis in a plasmodial prokaryote-like organelle, the

apicoplast

Malaria lifecycle from CDC DPDx

The malaria parasite life cycle involves two hosts. During a

blood meal, a malaria-infected female Anopheles mosquito

inoculates sporozoites into the human host ❶. Sporozoites

infect liver cells ❷and mature into schizonts ❸, which

rupture and release merozoites ❹. (Of note, in P. vivax and P.

ovale a dormant stage [hypnozoites] can persist in the liver and

cause relapses by invading the bloodstream weeks, or even

years later.) After this initial replication in the liver (exo-

erythrocytic schizogony (A), the parasites undergo asexual

multiplication in the erythrocytes (erythrocytic schizogony (B).

Merozoites infect red blood cells ❺. The ring stage

trophozoites mature into schizonts, which rupture releasing

merozoites ❻. Some parasites differentiate into sexual

erythrocytic stages (gametocytes) ❼. Blood stage parasites are

responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female

(macrogametocytes), are ingested by an Anopheles mosquito

during a blood meal ❽. The parasites’ multiplication in the

mosquito is known as the sporogonic cycle The letter C. While

in the mosquito’s stomach, the microgametes penetrate the

macrogametes generating zygotes ❾. The zygotes in turn

become motile and elongated (ookinetes) ❿ which invade the

midgut wall of the mosquito where they develop into oocysts

⓫. The oocysts grow, rupture, and release sporozoites ⓬,

which make their way to the mosquito’s salivary glands.

Inoculation of the sporozoites into a new human host

perpetuates the malaria life cycle

WHO Recommended Artemisinin

Combination Therapy (ACT) for Malaria

• Artemether-lumefantrine

• Artesunate-amodiaquine

• Artesunate-mefloquine

• Dihydroartemisinin-piperaquine

• Artesunate-sulfadoxine-pyrimethamine

Antiprotozoal Drugs for protozoa other than Plasmodium spp

Organism: Disease Caused Drug - Comments – Mechanism of action (MA)

Protozoa found in the gastrointestinal tract

Entamoeba histolytica: Amoebiasis, amoebic

dysentery, amoebic abscess

Nitroimidazole: Metronidazole, Tinidazole – MA - Activated by reduction of the nitro group thus

forming reactive products that damage DNA

Giardia lamblia: Giardiasis Metronidazole – MA - See above

Cryptosporidium spp Nitozanide for immunocompetent patients

Cyclospora spp Co-Trimoxazole(Trimethoprim-sulfamethoxazole) - folate antagonist

Cystoisospora spp Co-Trimoxazole – MA- see above

Protozoa found in the urogenital tract

Trichomonas vaginalis: Trichomoniasis Metronidazole for both partners – MA - See above

Protozoa found in blood and tissue

Trypanosoma brucei gambiense: West African

trypanosomiasis; sleeping sickness

Hemolymphatic stage: pentamidine; CNS involvement: Eflornithine, Melarsoprol

Trypanosoma brucei rhodesiense: East African

trypanosomiasis; sleeping sickness

Hemolymphatic stage: Suramin; CNS involvement: Melarsoprol

Trypanosoma cruzi: Chagas disease Benznidazole – MA- not known

Leishmania species: Leishmaniasis various forms Sodium stibogluconate, meglumine, antimonite, miltefosine, Liposomal amphotericin B

Babesia microti Babesiosis Atovaquone plus azithromycin; clindamycin plus quinine

Antiprotozoal Drugs for protozoa other than Plasmodium spp continued

Organism: Disease Caused Drug - Comments – Mechanism of action (MA)

Protozoa found in the central nervous system

Toxoplasma gondii: Toxoplasmosis Pyrimethamine plus sulfadiazine

Naegleria fowleri: Primary amebic

meningoencephalitis

Amphotericin B, miltefosine

Acanthamoeba castellanii: Granulomatous amebic

encephalitis

Amphotericin B, miltefosine

Balamuthia mandrillaris: Granulomatous amebic

encephalitis

Amphotericin B, miltefosine

Antihelminth Drugs

Organism: Disease Caused Drug - Comments – Mechanism of action (MA)

Intestinal helminthic infections

Nematodes

Ancylostoma duodenale and Necator americanus: hookworm

infestation

Albendazole, Mebendazole – both Benzimidazoles – MA- They bind to β-tubulin and prevent assembly of

microtubules, interrupting cell division and metabolism.

Pyrantel pamoate- MA- targets the nicotinic acetylcholine receptor of nematode muscle, causing depolarization

of the neuromuscular junction, irreversible paralysis and natural expulsion of the worm

Ascaris lumbricoides: Ascariasis Albendazole, Mebendazole, Pyrantel pamoate –MA- see above

Trichuris trichiura: Trichuriasis Albendazole, mebendazole –MA- see above

Enterobius vermicularis: Enterobiasis Albendazole, Mebendazole, Pyrantel pamoate

Strongyloides stercoralis: StrongyloidiasisIvermectin - MA- activates neuromuscular membrane, glutamate gated chloride channels, causing an influx of

chloride, membrane hyperpolarization and muscle spasm and causes death.

Trematodes

Fasciolopsis buski : FasciolopsiasisPraziquantel- MA- increase the permeability of trematode and cestode cell membranes to calcium and causes an influx of calcium resulting in paralysis, dislodgement, and death

Cestodes

Taenia saginata: beef tapeworm infestation Praziquantel – MA – see above, Niclosamide -uncouples oxidative phosphorylation

Taenia solium: pork tapeworm infestation, Cysticercosis Praziquantel, Niclosamide –MA see above. For cysticercosis – Albendazole + Praziquantel –MA see above

Diphyllobothrium latum: fish tapeworm infestation Praziquantel, Niclosamide

Hymenolepis nana: dwarf tapeworm infestation Praziquantel

Antihelminth Drugs continued

Organism: Disease Caused Drug - Comments – Mechanism of action (MA)

Tissue helminthic infections

Nematodes

Brugia malayi: (lymphatic filariasis)Diethylcarbamazine -MA- immobilizes microfilariae and alters their surface structure, displacing them from

tissues and making them susceptible to host defenses. MA against adult worms is unknown.; Ivermectin

Loa loa: Loiasis Diethylcarbamazine, Ivermectin

Onchocerca volvulus: Oncocerciasis (river blindness) Ivermectin – MA- see above, Doxycycline for associated Wolbachia

Wuchereria bancrofti: Wuchereriasis, Bancroftian filariasis

(lymphatic filariasis)

Diethylcarbamazine, Ivermectin –MA- see above

Trichinella spiralis: Trichinellosis Mebendazole, Albendazole –MA- see above

Trematodes

Schistosoma haematobium, Schistosoma japonicum, Schistosoma

mansoni: Schistosomiasis

Praziquantel –MA- see above

Paragonimus westermani: Paragonimiasis Praziquantel –MA- see above

Fasciola hepatica: Fascioliasis Bithionol, triclabendazole- binds to β-tubulin of Fasciola hepatica and prevent assembly of microtubules also

inhibits protein synthesis

Clonorchis sinensis: Clonorchiasis Praziquantel –MA- see above

Cestodes

Echinococcus granulosus: Echinococcosis (hydatid cyst

disease)

Albedazole + Praziquantel –MA- see above

BIBLIOGRAPHY AND REFERENCES

• Mandel, Douglas and Bennetts’ principles and practice of infectious diseases. 9th

ed.Philadelphia. Churchhill Livingstone Elsevier

• Jawetz, Melnink and Adelberg’s medical microbiology. 28th edition

• Medical Microbiology, 4th edition Editor: Samuel Baron.

• Basic & Clinical Pharmacology 14th Edition Editor Bertram G. Katzung, MD, PhD

• Rang & Dale's Pharmacology 9th Edition

• World Health Organization: Guidelines for the Treatment of Malaria, 3rd ed. World Health

Organization. Geneva, 2015

THANK YOU

FOR YOUR

ATTENTION