ChemotherapyChemotherapy

Principles of antimicrobial Principles of antimicrobial drugsdrugs

ChemotherapyChemotherapyDrugs used in treating infectious diseases and Drugs used in treating infectious diseases and

cancercancer Infectious diseases are a major cause of Infectious diseases are a major cause of

death worldwide (Kozier, et al. 2008). death worldwide (Kozier, et al. 2008). The control of the spread of microbes & The control of the spread of microbes &

the protection of people from the protection of people from communicable diseases & infections communicable diseases & infections are carried out on the international, are carried out on the international, national, community, and individual national, community, and individual levelslevels

History:History:2500 years ago: anti-infective substances 2500 years ago: anti-infective substances

were found:were found:• Chinese used moldy soya beans for Chinese used moldy soya beans for

carbuncles & boilscarbuncles & boils• Greeks (Hippocrates) used wine to treat Greeks (Hippocrates) used wine to treat

woundswounds• 19001900’’s: Syphilis treated with arsenics: Syphilis treated with arsenic• 1936: Sulfonamides discovered 1936: Sulfonamides discovered • 19401940’’s: Penicillin & Streptomycin s: Penicillin & Streptomycin

discovereddiscovered• 19501950’’s: Golden age of antimicrobialss: Golden age of antimicrobials

Infection related concepts:Infection related concepts: - - Infection: is an invasion of body Infection: is an invasion of body

tissue by microorganisms (MO’s) & tissue by microorganisms (MO’s) & their growth theretheir growth there

- Such a MO is called: infectious - Such a MO is called: infectious agentagent

- If the MO produces no clinical - If the MO produces no clinical evidence of disease, the infection is evidence of disease, the infection is called subclinical or asymptomaticcalled subclinical or asymptomatic

- A detectable alteration in normal - A detectable alteration in normal tissue function is called diseasetissue function is called disease

- - Pathogenicity: is the ability to Pathogenicity: is the ability to produce disease; thus a pathogen produce disease; thus a pathogen is a MO that causes disease is a MO that causes disease

- - True pathogen causes disease or True pathogen causes disease or infection in a healthy individualinfection in a healthy individual

- - Opportunistic pathogen causes Opportunistic pathogen causes disease only in a susceptible disease only in a susceptible individualsindividuals

- Communicable disease:- Communicable disease: is the is the ability of the infectious agent to ability of the infectious agent to be transmitted to an individual be transmitted to an individual by direct or indirect contact or as by direct or indirect contact or as an airborne infectionan airborne infection

E.g.; common cold virus is more E.g.; common cold virus is more readily transmitted than the readily transmitted than the bacillus that causes leprosy bacillus that causes leprosy (Hansen’s disease)(Hansen’s disease)

Types of MOs causing infectionsTypes of MOs causing infectionsFour major categories of MOs cause Four major categories of MOs cause

infectionsinfectionsin humans:in humans:1. Bacteria: 1. Bacteria: the most common, hundred the most common, hundred

species can attack humans, transferred species can attack humans, transferred by air, water, food, soil, body tissues & by air, water, food, soil, body tissues & fluids, and inanimate objects. fluids, and inanimate objects.

2. Viruses: 2. Viruses: consist primarily of nucleic consist primarily of nucleic acid, therefore must enter living cells in acid, therefore must enter living cells in order to reproduce (e.g.; rhinovirus, order to reproduce (e.g.; rhinovirus, hepatitis, HIV)hepatitis, HIV)

3. Fungi: 3. Fungi: include yeasts & molds. include yeasts & molds. Candida albicansCandida albicans is a normal flora is a normal flora in human vaginain human vagina

4. Parasites: 4. Parasites: live on other living live on other living organisms examples: protozoa that organisms examples: protozoa that causes malaria, helminths (worms), causes malaria, helminths (worms), arthropods (mites, fleas, ticks)arthropods (mites, fleas, ticks)

Community-acquired:Community-acquired: e.g. e.g. nosocomialnosocomial

General manifestations of infection:General manifestations of infection:Infection caused by bacteria take Infection caused by bacteria take

many forms, ranging from mild local many forms, ranging from mild local infection to life-threatening systemic infection to life-threatening systemic infection infection

- Fever, chills, rigors- Fever, chills, rigors- Pain or aches- Pain or aches- Nausea- Nausea- Vomiting- Vomiting- Weakness- Weakness Infection vs inflammationInfection vs inflammation

AntimicrobialsAntimicrobials

Classified into 1. antibiotics and Classified into 1. antibiotics and

2. chemotherapeutic 2. chemotherapeutic agentsagents

AntibioticsAntibiotics

Agents or antimicrobials that interfere Agents or antimicrobials that interfere with the growth or multiplication or with the growth or multiplication or kill microorganisms like bacteria, kill microorganisms like bacteria, fungi and they are of natural source fungi and they are of natural source e.g. Penicillin'se.g. Penicillin's

ChemotherapeuticsChemotherapeutics

Agents or antimicrobials that Agents or antimicrobials that interfere with the growth or interfere with the growth or multiplication or kill multiplication or kill microorganisms and they are of microorganisms and they are of synthetic source e.g. synthetic source e.g. SulfonamidesSulfonamides

AntisepticsAntiseptics

Agents that kill or inhibit growth Agents that kill or inhibit growth of microorganisms when applied of microorganisms when applied to tissuesto tissues

DisinfectantsDisinfectants

Agents killing or inhibiting Agents killing or inhibiting growth of microorganisms when growth of microorganisms when applied to nonliving objectsapplied to nonliving objects

- Cidal - Cidal ((Irreversible inhibition of growth)Irreversible inhibition of growth) An agent that kills microorganismsAn agent that kills microorganisms Bactericidal, fungicidal, viricidalBactericidal, fungicidal, viricidal……etcetc e.g. Penicilline.g. Penicillin’’s, Cephalosporins, Cephalosporin’’s, s,

AminoglycosidesAminoglycosides……etcetc- Static - Static ((Reversible inhibition of growth)Reversible inhibition of growth) An agent that inhibits growth of An agent that inhibits growth of

microorganismmicroorganism Bacteriostatic, fungistatic, viristaticBacteriostatic, fungistatic, viristatic……etcetc e.g. Sulfonamides, Tetracyclines, e.g. Sulfonamides, Tetracyclines,

MacrolideMacrolideantibioticsantibiotics……etcetc

A static agent in large doses becomes A static agent in large doses becomes cidal and cidal agents in low doses cidal and cidal agents in low doses become staticbecome static

One drug ( chloramphenicol) could be One drug ( chloramphenicol) could be bacteriostatic for one organism bacteriostatic for one organism (gram negative rods), & cidal for (gram negative rods), & cidal for another (S. pneumoniae)another (S. pneumoniae)

MICMIC: (Minimal Inhibitory : (Minimal Inhibitory Concentration) Lowest concentration Concentration) Lowest concentration of antibiotic that prevents visible of antibiotic that prevents visible microbial growthmicrobial growth

MBCMBC: (Minimal Bactericidal : (Minimal Bactericidal Concentration) Lowest concentration Concentration) Lowest concentration of antibiotic that reduces the number of antibiotic that reduces the number of viable cells by at least 1000-foldof viable cells by at least 1000-fold

The MBC of a truly bactericidal agent is The MBC of a truly bactericidal agent is equal to or just slightly above its MICequal to or just slightly above its MIC

AALAAL: The Attainable Anti-biotic Level is : The Attainable Anti-biotic Level is the concentration of the drug that can the concentration of the drug that can be reached in the target tissues be reached in the target tissues without causing toxic side-effectswithout causing toxic side-effects

Trough Levels:Trough Levels:

Levels of antibiotics reach minimal levels Levels of antibiotics reach minimal levels (troughs) at roughly predictable times after (troughs) at roughly predictable times after administrationadministration

The troughs may be at, or below the MICThe troughs may be at, or below the MIC

This may or may not be a problem because of This may or may not be a problem because of two factors:two factors:

- Post Antibiotic Effect, a prolonged - Post Antibiotic Effect, a prolonged period before bacteria resume growthperiod before bacteria resume growth

- Synergism between host defenses and - Synergism between host defenses and sub- MIC levels of antibioticssub- MIC levels of antibiotics

Post-antibiotic effect (PAE):Post-antibiotic effect (PAE):- PAE is a persistent suppression - PAE is a persistent suppression

of microbial growth that occurs of microbial growth that occurs after levels of antibiotic have after levels of antibiotic have fallen below the MIC.fallen below the MIC.

- Antimicrobial drugs exhibiting a - Antimicrobial drugs exhibiting a long PAE (several hours) require long PAE (several hours) require only one dose per day (e.g. only one dose per day (e.g. Aminoglycosides & Aminoglycosides & Fluroquinolones).Fluroquinolones).

Trough levels may increase the Trough levels may increase the frequency of drug-resistant bacteriafrequency of drug-resistant bacteria

- Frequency of developing - Frequency of developing resistance is greatly increased resistance is greatly increased at levels just above the MICat levels just above the MIC

- Development of resistance to - Development of resistance to ciprofloxacin is 10,000 times ciprofloxacin is 10,000 times more frequent at 2 times the more frequent at 2 times the MIC compared to 8 times the MIC compared to 8 times the MICMIC

The student should know:The student should know:

- Available antibiotics and - Available antibiotics and chemotherapeutic agentschemotherapeutic agents

- Their pharmacology, administration, - Their pharmacology, administration, absorption, distribution, metabolism, absorption, distribution, metabolism, side effectsside effects……etcetc

- Their mechanism of action- Their mechanism of action

- Mechanisms of drug resistance- Mechanisms of drug resistance

- Spectrum of activity- Spectrum of activity

- Whether the agent is cidal or static…- Whether the agent is cidal or static…

Mechanism of action:Mechanism of action:

Plasma membrane Cell wall

RNA

DNA

Ribosomes

( Protein synthesis)

- Inhibitors of cell wall synthesis- Inhibitors of cell wall synthesis

Penicillins, Cephalosporins, Bacitracin, Penicillins, Cephalosporins, Bacitracin, Vancomycin, CycloserineVancomycin, Cycloserine……etcetc

Most bacteria have rigid cell walls that are Most bacteria have rigid cell walls that are not found in host cells (selective toxicity)not found in host cells (selective toxicity)

Cell wall inhibitors work by inhibiting the Cell wall inhibitors work by inhibiting the formation of peptidoglycans that are formation of peptidoglycans that are essential in cell wall formationessential in cell wall formation

Disruption of the cell wall causes death of Disruption of the cell wall causes death of the bacterial cell (Bactericidal)the bacterial cell (Bactericidal)

- Interference with permeability or - Interference with permeability or function of plasma membranefunction of plasma membrane

Antifungal agents ( Colistin, Nystatin, Antifungal agents ( Colistin, Nystatin, Amphotericin B, Polymyxin BAmphotericin B, Polymyxin B ) )

- Inhibitors of DNA synthesis or - Inhibitors of DNA synthesis or replication ( DNA disturbers )replication ( DNA disturbers )

Quinolones ( Nalidixic acid ), Quinolones ( Nalidixic acid ), Fluoroquinolones, Griseofulvin, Fluoroquinolones, Griseofulvin, NovobiocinNovobiocin……etcetc

- Inhibitors of RNA- Inhibitors of RNA RifampicinRifampicin

- Inhibitors of protein synthesis- Inhibitors of protein synthesis

Aminoglycosides ( Streptomycin, Aminoglycosides ( Streptomycin, GentamicinGentamicin……), Chloramphenicol, ), Chloramphenicol, Tetracyclines, Lincomycin, Tetracyclines, Lincomycin, ClindamycinClindamycin……etcetc

- Interference with metabolism of - Interference with metabolism of microorganismsmicroorganisms

Sulfonamides TrimethoprimSulfonamides Trimethoprim

PABA Folic acid PABA Folic acid Folinic Folinic

acidacid

Classification of antimicrobial:Classification of antimicrobial:According to:According to:- Mechanism of action- Mechanism of action- Chemical structure- Chemical structure- Antimicrobial activity (spectrum of - Antimicrobial activity (spectrum of

activity)activity)* * Narrow spectrumNarrow spectrum ( effective in G + ve ( effective in G + ve

coccicocci& bacilli ), drugs effective in G - ve bacilli& bacilli ), drugs effective in G - ve bacilli(Aminoglycosides ), drugs only effective in (Aminoglycosides ), drugs only effective in

specific infectios (Isoniazid is active only specific infectios (Isoniazid is active only against mycobacteria T.B)against mycobacteria T.B)

* * Broad spectrumBroad spectrum ( effective in G + ve & - ( effective in G + ve & - ve cocci & bacilli )ve cocci & bacilli )

Affect a wide variety of microbial species Affect a wide variety of microbial species ((This type could alter the nature of the This type could alter the nature of the normal flora & precipitate a normal flora & precipitate a superinfection)superinfection)

* * Extended-spectrum antibioticsExtended-spectrum antibioticsAgents that are effective against gram-Agents that are effective against gram-

positive organisms & also against a positive organisms & also against a significant No. of gram-negative bacteria significant No. of gram-negative bacteria or against specific microorganismsor against specific microorganisms

e.g Antipseudomonal e.g Antipseudomonal penicillin'spenicillin's

General considerations in the usage General considerations in the usage of antimicrobials:of antimicrobials:

- Is the antimicrobial agent indicated- Is the antimicrobial agent indicated

- Aim if indicated is to achieve a level - Aim if indicated is to achieve a level of antimicrobial activity at the site of antimicrobial activity at the site of infection that is sufficient enough of infection that is sufficient enough to inhibit or kill microorganisms to inhibit or kill microorganisms without affecting host cellswithout affecting host cells

- Antimicrobials are harmful drugs- Antimicrobials are harmful drugs

- New drugs are not necessarily better - New drugs are not necessarily better than old onesthan old ones

- Major consideration is identification - Major consideration is identification of the causative microorganism and of the causative microorganism and the use of proper dose for adequate the use of proper dose for adequate durationduration

- Sometimes there is a need to combine - Sometimes there is a need to combine more than one antimicrobialmore than one antimicrobial

Selection of an antimicrobial agent:Selection of an antimicrobial agent:Factors affecting selectionFactors affecting selection:: - Causative microorganism - Causative microorganism

((Susceptibility): The lack of Susceptibility): The lack of susceptibility guarantees therapeutic susceptibility guarantees therapeutic failure). failure). Determined from: Determined from:

- Clinical picture - Clinical picture - Bacteriological examination (culture and - Bacteriological examination (culture and

sensitivity)sensitivity)- Serology-measures antibody levels- Serology-measures antibody levels- Polymerase Chain Reaction (PCR) detects - Polymerase Chain Reaction (PCR) detects

the specific DNA for a specific organismthe specific DNA for a specific organism

- Pharmacokinetic factors:- Pharmacokinetic factors:

Site of infection CSF, CNS, Site of infection CSF, CNS, prostate, prostate, vitreous body of the eye…vitreous body of the eye…

Renal disease (Renal disease (poor kidney poor kidney function cause antibiotics that function cause antibiotics that ordinarily secreted by this route to ordinarily secreted by this route to accumulate & lead to serious accumulate & lead to serious adverse effects e.g. amino adverse effects e.g. amino glycosides).glycosides).

Liver disease (Liver disease (antibiotics that antibiotics that are concentrated or eliminated by are concentrated or eliminated by liver are contraindicated in liver liver are contraindicated in liver disease (e.g. erythromycin & disease (e.g. erythromycin & tetracycline)tetracycline)

Route of administrationRoute of administration

- Toxicity and side effects to antibiotic- Toxicity and side effects to antibiotic

- Interactions with other drugs- Interactions with other drugs

- Cost- Cost

- Host factors- Host factors Age (Newborn & old pts have less Age (Newborn & old pts have less

kidney and liver function compared to kidney and liver function compared to adults)adults)

Allergic reaction to a given Allergic reaction to a given antimicrobial agentantimicrobial agent

Host defense mechanisms (Host defense mechanisms (Alcoholism, Alcoholism, DM, HIV, malnutrition, poor hygiene, DM, HIV, malnutrition, poor hygiene, advanced age, neutropenia, & the use of advanced age, neutropenia, & the use of immunosuppressive drugs can affect a immunosuppressive drugs can affect a patientpatient’’s immunocompetency. Such patients s immunocompetency. Such patients need higher-than-usual doses or longer need higher-than-usual doses or longer courses of treatment)courses of treatment)

- Genetic factors- Genetic factors Sulfonamides, Chloramphenicol, Sulfonamides, Chloramphenicol,

Nitrofurantoin → severe hemolysis in Nitrofurantoin → severe hemolysis in G6PD deficient individualsG6PD deficient individuals

- Pregnancy Streptomycin → Deafness- Pregnancy Streptomycin → Deafness- Lactation- Lactation Sulfonamides → hemolysis in G6PD Sulfonamides → hemolysis in G6PD

deficient newborndeficient newborn- Local factors at site of infection e.g. - Local factors at site of infection e.g.

AbscessAbscess

Bacterial resistance:Bacterial resistance:Occurs:Occurs:- When clinical condition of host is impaired- When clinical condition of host is impaired- When normal flora have been suppressed- When normal flora have been suppressed- With interrupted or inadequate Rx- With interrupted or inadequate Rx- More frequently in certain types of bacteria - More frequently in certain types of bacteria

(Gram negatives possess an outer (Gram negatives possess an outer membrane and cytoplasmic membrane membrane and cytoplasmic membrane preventing passage of antibiotec through preventing passage of antibiotec through pores)pores)

- With widespread use of broad spectrum - With widespread use of broad spectrum antibioticsantibiotics

- In poor environmental setting of host- In poor environmental setting of host

Mechanisms of bacterial resistance:Mechanisms of bacterial resistance:

- - Natural resistanceNatural resistance

*Absence of a metabolic process or an *Absence of a metabolic process or an enzyme or protein in the bacteria enzyme or protein in the bacteria which is required for the action of which is required for the action of the antimicrobialthe antimicrobial

*Absence or hard cell wall making the *Absence or hard cell wall making the antimicrobial difficult to penetrateantimicrobial difficult to penetrate

* The need of antimicrobial drug * The need of antimicrobial drug in large amounts at site of action in large amounts at site of action above its concentration in the above its concentration in the plasmaplasma

To overcome this type of To overcome this type of resistance the drug has to be resistance the drug has to be given in very large doses which given in very large doses which leads to severe side effectsleads to severe side effects

- - Acquired resistanceAcquired resistance

Development of resistance in a Development of resistance in a previously sensitive microorganism. previously sensitive microorganism. This could occur in the following This could occur in the following ways:ways:

- Mutation or genetic change- Mutation or genetic change

- Adaptation- Adaptation

Production of enzymes breaking Production of enzymes breaking the antimicrobial e.g. the antimicrobial e.g. ββ- lactamases- lactamases

- Infectious or multiple drug - Infectious or multiple drug resistanceresistance

Through:Through:

TransductionTransduction by bacteriophage by bacteriophage which transfers chromosomal or which transfers chromosomal or extrach-extrach-

romosomal DNA ( plasmid ) to bacteriaromosomal DNA ( plasmid ) to bacteria

TransformationTransformation, transfer of , transfer of DNA responsible for resistance from DNA responsible for resistance from environment to bacteriaenvironment to bacteria

- - ConjugationConjugation Passage of resistant genes Passage of resistant genes

from cell to cell by direct contactfrom cell to cell by direct contact

** Most of resistance is acquired due ** Most of resistance is acquired due to misuse or abuse of antibiotics e.g. to misuse or abuse of antibiotics e.g. improper dose & DOA, Rimproper dose & DOA, Rx x of of suppurative diseases, Rsuppurative diseases, Rx x of viral of viral infections with antibacterial agentsinfections with antibacterial agents

Examples on mechanisms of resistance:Examples on mechanisms of resistance:

- Generating enzymes that inactivate the - Generating enzymes that inactivate the antibiotic (beta lactamase)antibiotic (beta lactamase)

- Changing structure of target site e.g. - Changing structure of target site e.g. PBP’s (beta lactams and PBP’s (beta lactams and aminoglycosides)aminoglycosides)

- Preventing cellular accumulation of - Preventing cellular accumulation of antibiotic by altering outer membrane antibiotic by altering outer membrane proteins or using efflux pumps e.g. G-veproteins or using efflux pumps e.g. G-ve

- Changing the metabolic pathway that is - Changing the metabolic pathway that is being blocked (sulfa drugs)being blocked (sulfa drugs)

- Overproducing the target enzyme or - Overproducing the target enzyme or protein to overpower the effects of protein to overpower the effects of antibioticsantibiotics

- Mycoplasma lacks a cell wall making it - Mycoplasma lacks a cell wall making it impervious to penicillin'simpervious to penicillin's

- Sulfonamides have no impact on - Sulfonamides have no impact on bacteria that obtain their folate from bacteria that obtain their folate from environmentenvironment

Combined therapy:Combined therapy: Indications:Indications:- To obtain synergism or reduce the - To obtain synergism or reduce the

dose of a toxic drugdose of a toxic drug

- To reduce emergence of resistance- To reduce emergence of resistance

- Treat mixed infections with - Treat mixed infections with microorganismsmicroorganisms

of different sensitivitiesof different sensitivities

- Treat infections at different - Treat infections at different anatomical sites ( bile, CSF )anatomical sites ( bile, CSF )

- Treat infections of unknown - Treat infections of unknown etiology especially in patients at etiology especially in patients at high risk of developing infections high risk of developing infections e.g. AIDS patients or patients e.g. AIDS patients or patients with agranulocytosiswith agranulocytosis

Outcome of combined chemotherapy:Outcome of combined chemotherapy:

- Indifference- Indifference

- Antagonism Cidal + static- Antagonism Cidal + static

- Synergism ( Penicillins + - Synergism ( Penicillins + aminoglycosides )aminoglycosides )

Disadvantages of combined Disadvantages of combined chemotherapy:chemotherapy:

- Toxicity- Toxicity

- ↑ cost- ↑ cost

Prophylactic use of antibacterial agents:Prophylactic use of antibacterial agents:Indications:Indications:- Protection of healthy individuals against- Protection of healthy individuals againsthighly contagious disease or infections highly contagious disease or infections

e.g.e.g.syphilis, gonorrhea, T.B, meningococcalsyphilis, gonorrhea, T.B, meningococcalMeningitisMeningitis- Prevent 2º infection in very ill patients- Prevent 2º infection in very ill patients e.g. AIDS, before major surgeries, e.g. AIDS, before major surgeries,

delivery, organ transplantation, delivery, organ transplantation, recurrent UTI’s…etcrecurrent UTI’s…etc

Prophylaxis is successful if: Prophylaxis is successful if:

- A single antibiotic is used- A single antibiotic is used

- The dose required for prophylaxis is - The dose required for prophylaxis is less than the therapeutic doseless than the therapeutic dose

- The drug is needed or used for a - The drug is needed or used for a brief period brief period

( chronic therapy or prophylaxis is ( chronic therapy or prophylaxis is notnot

advised → bacterial resistance )advised → bacterial resistance )

Complications of antibiotic therapy:Complications of antibiotic therapy:- Hypersensitivity- Hypersensitivity- Direct toxicity- Direct toxicity- Super infection- Super infectionAlterations of the normal microbial Alterations of the normal microbial

flora of the upper respiratory, flora of the upper respiratory, intestinal, and genitourinary tracts, intestinal, and genitourinary tracts, permitting the overgrowth of permitting the overgrowth of opportunistic organisms, especially opportunistic organisms, especially fungi or resistant bacteriafungi or resistant bacteria