•Chemotherapeutics

•&

• antibiotics

Chemotherapeutics

•Chemicals which are used within the body tissues to kill or inhibit the growth of pathogenic organisms

The Spectrum of antimicrobial Activity

•**it is easy to find or develop drugs that effective against prokaryotic cells ,& that do not affect the eukaryotic cells of humans

•**the problem is difficult when the pathogen is eukaryotic (fungus, protozoan, helminthes)

•**viral infection more difficult to treat

The Spectrum of antimicrobial Activity

•Prok.**-differ in cell wall

•- differ in fine structure of their ribosome

•- details of their metabolism

•Euk.**resemble the human cell

•**the virus is within the human cells

antibiotics

Antibiotics=are a metabolic products or a constituent of a microorganism which kills or inhibit the growth of another microorganism

Nowadays used are semi synthetic (Ampicillin) or synthetic (Sulfa drugs)

(produced wholly or partly by chemical synthesis(

Low concentrations inhibit the growth of m.o.

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Characteristics of a good chemotherapeutic or antibiotic

•1-it must kill or inhibit the growth of the pathogenic organism

•2-it must cause no damage to the host (it must have selective toxicity)

•3-it must cause no allergic reaction

•4-it must be stable in solid or dissolved state

•5-it must remain in the desired tissue for the sufficient length of time (pharmacokinetics)

•6 -it must kill the pathogenic organism quickly before it mutates and

becomes resistant to the drug

•Pharmacokinetics have to be desirable (absorption, disintegration)

•selective toxicity = toxic for the pathogenic organism and not toxic for the host == defined by the therapeutic index

• max. tolerated dose (toxic to the host)

•-------------------------------------------------------------- • min. curative dose (effective therapeutic dose)

•The high the therapeutic index the better the antibiotic is

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Therapeutic Index = Toxic Dose/Therapeutic DoseD

rug

Do

sag

e (p

er K

g B

od

y W

eig

ht)

Small Ratio(dangerous(

ModerateRatio

High Ratio(safe(

Most desirable.

Antibiotics activity

The Spectrum of antimicrobial Activity

•Narrow spectrum = affect only select group of microorganisms

• e.g Penicillin G affects Gram positive bacteria

•Broad spectrum = affect a broad range of Gram positive or Gram negative bacteria

• = affect a more diverse • range of microbes

e.g. Chloramphenicol.

Antibiotics activity

The type of activity

•Bactericidal : direct killing of microorganisms• = kill microorganisms directly

• (Streptomycin(

•Bacteriostatic = inhibit their growth• = prevent microorganism

• from growth (chloramphenicol(

= *#*# Host defenses usually destroy microorganisms by phagocytosis & antibody production

•Combination of

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Mechanisms of Antimicrobial Action

• Bacteria have their own enzymes for– Cell wall formation– Protein synthesis– DNA replication– plasma membrane– Synthesis of essential metabolites

Bacterial protein synthesis inhibitors

• ##initiation of protein synthesis

• ##elongation (=interfere with elongation factors(

Fusidic acid

Bacteriostatic

Gm+ve bacteria only

initiation of protein synthesis inhibitors

Antimicrobial that bind to the 50S ribosomal subunit

Antimicrobial that bind to the 30S ribosomal subunit

Chloramphenicol –

broad rang

LincomycinClindamycin

Restricted range

Tetracyclines

bacteriostatic broad spectrum

Tetracyclin ,Minocycline Doxycycline

Aminoglycosides

Bactericidal

Many gm.-ve bacteria &some gm+ve. Bacteria

StreptomycinKanamycinGentamycinNeomycinTobramycin

MacrolidesGm+ve bacteria &

Mycoplasma

Erythromycin

bacteriostatic

Inhibitors of nucleic acid synthesis & function

Inhibitors of RNA(DNA dependent RNA

polymerase(

Inhibitors of DNA(DNA gyrase(

Rifampin

Rifamycin

Rifampicin

Bactericidal

Wide spectrum Tuberculosis

Quinolones

Nalidixic acid

Ciprofloxacin

Bactericidal

Gm+ve bacteriaurinary tract infection

•Bacterial cell wall synthesis inhibitors

Bacterial cell wall synthesis inhibitors (bactericidal(

penicillins

•Bactericidal•Narrow range

•Effected by Stomach acidity=intramuscularly•Susceptible to penicillinase ( lactamase)

= are enzymes produced by many bacteria (Staph.) that clave the lactam ring

•

•Methicillin

•Oxacillin

•Ampicillin & amoxacillin & Mezlocillin=broad spectrum

• Carbapenems & Monobactam =broad

• Cephalosporins=gm-ve

• Vancomycin Bacitracin =gm+ve

• ++anti mycobacterial agents•Mycobacterium tuberculosis

• Antibiotics that interfere with mycolic acid synthesis or incorporation

– Isoniazid (INH)– Administerd simultaneously with other

drug (rifampin=rifampicin)

•Plasma membrane= phospholipids & protein

•Polymixin B interfere with phospholipids of plasma membrane

•Bactericidal

•Gm. – ve bacteria

Antimetabolite antimicrobials

• ++Inhibitors of folic acid synthesis•(bacteria cannot use pre-formed folic acid, they

synthesize their own folic acid(

bacteriostatic

•antifungal

Antifungal chemotherapeutics

•Fungi are Eukaryotes

•They may be unicellular ( yeast) or multicellular (mold).

•Cell wall compose of chitin

•Sterols in plasma membrane = ergosterol

AntifungalsMacrolide PolyenesAmphotericin B –mimic lipids, most versatile & effective, topical & systemic treatmentsNystatin – topical treatment

•Azole•Synthetic azoles – broad-spectrum;

ketoconazole, clotrimazole, miconazole (topical treatment of athlets foot)

•Allylamine•Recently developed antifungal=inhibit

ergosterols

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Antifungal drugs• Flucytosine – analog of cytosine;

coetaneous mycoses or in combination with amphotericin B for systemic mycoses

• **interfere with RNA biosynthesis

•Antiviral drugs

Antiviral drugs•Attachment

•Penetration

•Uncoating

•Nucleic acid synthesis (polymerases inhibitors(

•Assembly

•release

•Nucleoside & nucleotide analoges•(acyclovir, ribavirin, lamavudine(

•Lamavudine ==nucleoside analog=cytidine•Hepatitis B virus

•Reverse transcriptase inhibitor==HIV

Antiviral drugsAcyclovair=Zovirax=acycloguanosine=ACVGuanosine analogus

**Herpes simplex virus infection ) Genital, oral & eye(

**varicilla zoster virus) Shingles & Chickenpox in immunocompromised

patients(

###viral thymidine kinase phosphorelate the drug==this inactivate DNA polymerase

@@activity only inside virally infected cells@@

•Ribavirin==guanosin analoge

•stop viral RNA synthesis & mRNA

•===nucleoside inhibitor

•***hepatitis C virus

•***respiratory syncytial virus

•Amantadine ==symmetrel•***uncoating of influenza virus

•Tamiflue…..neuraminidase

•HIV inhibitors•Reveres transcriptase enzyme

inhibitors=retrovirus= nucleoside analoge•Protease inhibitors

•(Indinavir, saquinavir, ritonavir(•Zidovidine=rv.tr. inhibitor

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Interferon=protein(cytokines( produced by virally infected cells, that inhibit spread of the virus & protect other cells

***by the activation of the cell to produce certain enzyme

==prevent viral protein

synthesis

==kill virally infected cells

==the same way in which cancer

cells be killed (cancers) • (Viral hepatitis)

Antiviral Drugs

•Protozoa are unicellular Eukaryotic microbes

•Have variety of shapes ,

•Lives free or as parasite•They absorb or ingest organic compounds from

their environment

•Anti protozoa chemotherapeutics

•Anti malaria

•Malaria is an entirely preventable & treatable disease

•treatment==rapid & complete elimination of the parasite ------chronic & anemia

•prevention== of the spread & emerging resistance

Drugs used for malaria prophylaxis can work in one of three ways:

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Kill parasites in the liverCausal prophylaxisprimaquine ++++malarone ++

Kill asexual parasites in RBCs Suppressive prophylaxischloroquine ++++malarone ++++mefloquine ++++doxycycline ++++Kill sexual parasites

(gametocytes) in RBCsGametocytocidal prophylaxisprimaquine ++++

Mosquito Human

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Antihelminthic Drugs• Helminths are

macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms

Praziquantel

Albendazole

Surgery

Clinical uses of antimicrobial drugs

Clinical uses of antimicrobial drugs

•Inappropriate Antimicrobial Use Prescription not taken correctly

Antibiotics for viral infections

Antibiotics sold without medical supervision

Spread of resistant microbes in hospitals due to lack of hygiene

Proper selection of antimicrobial agent is based on a number of factors

•-**the identity of the pathogen•-**potential toxicity to the patient

•-**pharmacokinetics & pharmacodynamics of the agent

•-**site of infection•-**rout of administration

•-**drug resistance•-**possible drug interaction

•-**host factors•-**cost

•Drug selection should be based on it’s activity against infecting pathogen

•pathogen may be predictably susceptible to a particular drug

•Therefore lab. guidance is essential for safe prescribing

•Culture & sensitivity test

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Susceptibility Tests

Agar diffusion = disk-diffusion test Kirby-Bauer Disk Diffusion Test

Sensitive

Intermediate

resistant

(cont’d)

32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml

Sub-culture to agar medium

MIC = 8 ug/mlMBC = 16 ug/ml

Minimal Inhibitory Concentration (MIC)=the lowest concentration of drug capable of preventing bacterial growth

vs.Minimal Bactericidal Concentration (MBC)=the lowest concentration of chemotherapeutic agent that kills bacteria

•Minimum inhibitory concentration (MIC) •is determined when

•**a patient does not respond to treatment

•**thought to be adequate,

•**relapses while being treated

•**when there is immunosuppression.

Host factors play an important part in proper selection of antimicrobial drug

•-**age

•-**circulating & tissue phagocyte activity•e.g. hematological malignancy=acute

leukemia•Bactericidal= amino glycosides

• broad spectrum penicillins• cephalosporin

• quinolones

Pharmacological factors•By achieving satisfactory drug concentration at the site

of infection•Standard pharmacokinetics =absorption• distribution• metabolism

• excretion•Oral---- G.I. absorption should be satisfactory

• interaction with food• vomiting (surgery)

•***Parenteral agent will be required

Site of infection

•---lipid solubility of the drug•Amino glycosides are poorly lipid –soluble

=penetrate CSF poorly (bacterial meningitis(•Meningeal inflammation also affect drug

penetration into the tissues

•Beta-lactam agents achieve satisfactory concentration within CSF but the inflammation subsides drug concentration

super infection•Normal flora (skin & mucous membrane)

•Microbial overgrowth of resistant pathogen•Oral & vaginal candidiasis

•Broad spactrum-(ampicillin or tetracycline)

•Pseudo-membranous colitis•Toxin-producing strain of clostridium

•Following the use of clindamycin•Managed by oral vancomycin

•surgery

Proper selection of antimicrobial agent is based on a number of factors

•-**the identity of the pathogen•-**potential toxicity to the patient

•-**pharmacokinetics & pharmacodynamics of the agent

•-**site of infection•-**rout of administration

•-**drug resistance•-**possible drug interaction

•-**host factors•-**cost

Drug resistance

•Intrinsic= inherent properties of bac. are responsible for preventing antibiotic action ==always chromosomally mediated

• 0r

•Acquired= occurs when bac. which were previously susceptible then become resistance

• ==occur by mutation in the chromosome or by acquisition of genes coding for resistance from external source (plasmid(

•Plasmid mediated resistance has been recognized among Gm.-ve bact.== can code for multiple resistant ##cephalosporins, chloromphinicol, amino glycosides

•==enzymatic inactivation

•hospitals & intensive care units

Multi-drug resistance

•Methicillin resistant Staph.aureus (MRSA)

•=resist to many antibiotics

•Hospitals, intensive care units, burn ,cardiothoracic units

•Glycopeptides , vancomycin

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Enzymatic destruction of drug (B lactamase( Drug inactivation – penicillinases

Prevention of penetration of drug to its target site within the bacteria (tetracycline resistance( Decreased permeability to drug or increased elimination of drug from cell

Mechanisms of Antibiotic Resistance

Mechanisms of Antibiotic Resistance

Alteration of drug's target site(a.a changes in the ribosome( Change in metabolic patterns

Rapid ejection of the drug Change in drug receptors

•Efflux pump= antibiotic is rapidly extracted from the cell by an energy-dependent mechanism ( tetracyclines & macrolides)

• ++Inpaired cell wall or cell envelope penetration

• ++Enzymatic inactivation

• ++Altered binding sites• ++Efflux pump= antibiotic is rapidly

extracted from the cell by an energy-dependent mechanism( tetracyclines & macrolides)

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What Factors Promote Antimicrobial Resistance?

Exposure to sub-optimal levels of antimicrobial

Exposure to microbes carrying resistance genes

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To lower Antimicrobial Resistance Development

• Use more narrow spectrum antibiotics

• Use antimicrobial cocktails

Effects of combinations of drugs

• SynergismPenicillin and streptomycin, Sulfa and trimethoprim

• AntagonismPenicillin and tetracycline

• Addition

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Com

bina

tion

of

Dru

gs

For antibiotics “A” and “B” used in combination:

Actual killing rate = A + B Additive

Actual killing rate > A + B Synergistic

Actual killing rate < A + B Antagonistic

Typically bacteriostatic agents are antagonistic to bactericidal agents.

Bacteriocidal agents can be synergistic (think of the latter as one antibiotic weakens more bacteria than it kills, making the not-killed bacteria more susceptible to additional insult by the second antibiotic).

Additive means that the two (or more) antibiotics neither hinder nor help each other’s ability to kill.

Also relevant to rates of mutation to resistance.

•Second term exam.•Good luck