Antibiotic Module

8/3/2019 Antibiotic Module

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Objectives

1. Enumerate Principles of antimicrobial

therapy

2. Verify Choice of the antimicrobial agents

3. State Misuse of antibiotics

4. Mention Causes of failure of antimicrobial

therapy5. Classify antimicrobial drugs


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Principles of antimicrobial

therapy


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What are the principles of antimicrobial therapy ?

Appropriate indication

Appropriate dosage

Suitable length of treatment period

When to start treatment

Target of therapy (prophylaxis or treatment).

Good knowledge of the drug's pharmacokinetics and

potential risk.

Combination only under certain conditions and rightchoice of combination.

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When do you start the treatment?

Ideally

when the organism is identified and its drug

susceptibility established

However,acutely ill patients usually require

immediate treatment

Empiric therapy :Therapy is initiated afterspecimens for laboratory analysis have beenobtained but before the results of the culture are

available.


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What are the purposes for use of

antibiotics ? (Aim of therapy )

Prophylaxis A Medical:

- Exposure to virulent pathogen (HIV, N. meningitis)

- Immunocompromised Bsurgical

- To prevent wound infections after surgical procedures.

To prevent Endocarditis inpatients with valvular heart disease undergoing

dental or other surgeries producing bacteremia. Empiric Therapy (usually up to 72 hours)

Definitive Therapy

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Combinations Of Antimicrobial Drugs

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Combinations Of Antimicrobial Drugs

Indication:1. Empiric therapy of severe infection in which cause is

unknown(unknown etiology)

2. In mixed infections(polymicrobial infections),e.g. intra-abdominalinfections.

3. To delay emergence of resistant strains

4. To enhance antimicrobial activity , i.e. achieve an effect notobtained by either alone(e.g. combinations of penicillin and

aminoglycoside antibiotics are effective against enterococci,whereas neither agent alone is bactericidal againstenterococci).

5. To reduce the incidence and intensity of adverse reactions.

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Antibiotic combination therapy:

Synergistic Effect: when the effects of a combination of antibiotics

is greater than the sum of the effects of the individual antibiotics.When two bactericidal antibiotics are used in combination (e.g.

penicillin + streptomycin)

Additive Effect:When two bacteriostatic agents with the same mechanisms

of action are used.

Antagonism: occurs when one antibiotic, interferes with the effects

of another antibiotic. Usually bacteriostatic antibiotics are

antagonistic to bactericidal agents.

(e.g. Chloramphenicol + penicillin)


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Choice of the antimicrobial

agents


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Choice of The Antimicrobial Agent

A- Factors related to drug:

Antibiotic spectrum and activity.

The minimal inhibitory concentration (MIC)

compared to concentration achieved at site of

infection

known risk of the antibiotic, like nephrotoxicity

with aminoglycosides Possibility of developing resistance.

Drug's phamacokinetic parameters: absorption,

distribution and clearance.


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Spectrum of Activity

Refers to the range of microorganisms that anantimicrobial agent can kill or inhibit

Broad spectrum

affect a wide range of bacteria used particularly in the cases of rapid onset life-

threatening infections, when there is no time to culture

the causative agent

can disrupt the normal flora of the body leading tosuperinfection.

Narrow spectrum

Affect a limited range of bacteria

requires the identification of the pathogen


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Antibiotic activity

Bacteriostatic - arrest the growth and replication of bacteria

at serum levels achievable in the patient .

They reversibly inhibit the growth of bacteria .They limit the

spread of infection while the body's immune system attacks,

immobilizes, and eliminates the pathogens.

If the drug is removed before the immune system has

scavenged the organisms, enough viable organisms may

remain to begin a 2nd cycle of infection. Therefore must be

given for enough duration of time.

If possible, bactericidal antibiotics should be used to treat

infections of the endocardium or the meninges. Host

defenses are relatively ineffective at these sites and the

dangers imposed by such infections require prompteradication of the organisms.


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Bactericidal - kill bacteria at drug serum levels

achievable in the patient. - often drugs of

choice in seriously ill patients.


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Concentration of antibiotic

Minimum inhibitory concentration (MIC):

The lowest concentration of AB that inhibits bacterial

growth after overnight incubation.

Minimum bactericidal concentration (MBC):

The lowest concentration of AB that results in a 99.9

percent decline in colony count after overnight incubation.


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Drug resistance

Bacteria are said to be resistant to an

antibiotic if their growth is not halted by the

maximal level of that antibiotic that can be

tolerated by the host


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Choice of The Antimicrobial Agent

B- Factors related to host1. Host's defense mechanisms

2. Host's clinical conditions

3. Local factors

4. Age

5. Genetic factors

6. Pregnancy and lactation

7. Drug allergy


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1. Host's defense mechanisms

Immune system:

The host defense system must eliminate invading

organisms.

Alcoholism, diabetes, immunodeficiency virus,

malnutrition, advanced age affect a patient'simmunocompetency.

if host defense are impaired in these individuals:

A bactericidalATB must be used : Higher-than-usual doses of

bactericidal ATB or longer courses of treatment .


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2. Host's clinical conditions

Renal dysfunction:

Poor kidney function (10 % or less of normal) - accumulation of ATB

(eliminated by kidney) - serious adverse effects adjust the dose of

ATB eliminated by the kidney and avoid nephrotoxic ABTs.

Hepatic dysfunction:

ATB concentrated or eliminated by the liver (e.g., erythromycin and

tetracycline) are contraindicated in liver disease.


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3-Local Factors

Access of antibiotic to sites of infection e.g.if the infection in the CSF the drug must pass

the blood brain barrier

Penetration of antibiotic into infected areassuch abscess is impaired because vascular

supply is reduced &antimicrobial activity may

be significantly reduced in pus. Presence of the foreign bodies reduces the

effectiveness of antibiotic.


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4-Age

Elderly patients - particularly vulnerable toaccumulation of drugs eliminated by the kidneys. The

number of functioning nephrons decreases with age.

Young children -Renal or hepatic elimination - oftenpoorly developed in newborns

Also newborns are particularly vulnerable to certain

antibiotics.


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5- Genetic Factors

A number of drugs (e.g. sulfonamides,

chloramphenicol) may produce acute

hemolysis in patient with glucose 6-phosphate dehydrogenase deficiency


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6- Pregnancy

Pregnancy may impose an increased risk of

reaction to antibiotic for both mother & fetus

Hearing loss in child with administration of

streptomycin to the mother during pregnancy

Tetracycline can affect bones & teeth of fetus .


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7- Drug allergy

-lactum ABTs e may provoke allergic reaction

Sulfonamides and erythromycin have been

associated with hypersentitivity reaction


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What are the causes of Misuse of

antibiotics?

Treatment of untreatable infection

Treatment of fever of undetermined origin

Improper dose

Reliance on chemotherapy with omission of

surgical drainage of purulent exudates or

necrotic tissue

Lack of adequate bacteriological information

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Causes of Failure of

Antimicrobial Treatment


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Causes of Failure of Antimicrobial

Treatment

Incorrect indication

Ineffective antibiotic Inapproapirate dosage

Inadequate duration

Development of resistance

Change of causative pathogens


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Classify Antibiotics

Classification of Antibiotics according:

Chemical Structure

Spectrum of Activity& effects Mechanism of Action

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Classify Antibiotics

Spectrum of Antibiotic activity

Narrow spectrum Antibiotic

Broad spectrum Antibiotic

Effects of Antibiotics

Bacteriostatic

Bacteriocidal


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Classification of some antibacterial agents by their sites of action

THFA = tetrahydrofolic acid; PABA = p-aminobenzoic acid

CELL WALLCELL MEMBRANE

DNA

THFA

PABARibosomes mRNA

Inhibitors of cellmembranefunction

IsoniazidAmphotericin B

Inhibitors ofnucleic acidfunction orsynthesis

FluoroquinolonesRifampin

Inhibitors ofmetabolism

SulfonamidesTrimethoprim

Inhibitors of cellwall synthesis

b-LactamsVancomycin

Inhibitors ofprotein synthesis

TetracyclinesAminoglycosidesMacrolidesClindamycinChloramphenicol


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Cell wall synthesis inhibitors

Summary of anti microbial agents affecting cell wall


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Summary of antimicrobial agents affecting cell wallsynthesis

INHIBITORS OF CELLWALL SYNTHESIS b-LACTAMASE

INHIBITORS

b-LACTAMANTIBIOTIC

OTHERANTIBIOTIC

PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS

1st GENERATION 2nd GENERATION 3rd GENERATION 4th GENERATION

Clavulanic acidSulbactamTazobactam

BacitracinVancomycin

Imipenem/cilastatinMeropenem*Ertapenem

Aztreonam

Cefepime

AmoxicillinAmpicillinCloxacillinDicloxacillinIndanyl carbenicillinMethicillin

NafcillinOxacillinPenicillin GPenicillin VPiperacillinTicarcillin

CefadroxilCefazolinCephalexinCephalothin

CefaclorCefamandoleCefprozilCefuroximeCefotetanCefoxitin

CefdinirCefiximeCefoperazoneCefotaximeCeftazidimeCeftibutenCeftizoximeCeftriaxone


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The Beta-lactams

Beta-lactams are a broad class of antibioticsthat have in common a four membered beta-

lactam ring structure. They include:

1. Penicillins,

2. Cephalosporins,

3. Carbapenems,

4. Monobactam

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b-lactam Antibiotics

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Monobactams

All of the drugs in this group containa -lactam ring in their structure

Penicillins

NO

S

Carbapenems

NO

NO

NO

S

Cephalosporins

Share similar features of chemistry,

mechanism of action Cross reactivity

Bacteria might develop resistance to

-lactam antibiotics by synthesizingbeta lactamase, an enzyme that

attacks the-lactam ring.


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What is the mechanism of action of

penicillin ?

Penicillins enter the bacteria via the cell wall

Inside the cell, they bind to penicillin-binding protein

Once bound, normal cell wall synthesis is disrupted

Result: bacteria cells die from cell lyses

Penicillins do not kill other cells in the body

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Penicillin Groups1. Penicillin G ( -Lactamase sensitive)

2. Depot preparations: (long actin preparations) ( -Lactamase sensitive)

3. Acid resistant penicillins (penicillin V) ( -Lactamase

sensitive).

4. -Lactamase -resistant penicillins (anti-

staphylococcal penicillins). 1,2 ,3 & 4 are narrow

spectrum

5. Broad spectrum penicillins ( -Lactamase sensitive)6. Antipseudomonal penicillins (extended spectrum

penicillin) ( -Lactamase sensitive)


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1- Penicillins G

Pharmacokinetics Penicillin G is rapidly hydrolyzed by gastric acidity, so it is

not given orally but only parenterally

There is poor penetration into CSF, unless inflammation is

present. Active renal tubular secretion results in a short half-life.

counteracted by

- Giving high doses

- Simultaneous administration of probencid

- Using the depot preparations

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What are the disadvantages of

Penicillins G?

1. Short duration of action.

2. Instability in acidic medium.

3. Destroyed by b-Lactamase enzymes.

4. Possess a narrow spectrum of activity(active

against some gram +ve and gramve ) .


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2- Depot preparations:(long actin preparations)

penicillin Gprocaine(used every 18-24 hours)

penicillin G benzathine (duration ofantimicrobial activity in the plasma is up to

one month) Such agents release penicillin G slowly from

the area in which they are injected andproduce relatively low but persistentconcentrations of antibiotic in the blood.


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3-Acid-stable Penicillins- penicillin V

- Theoralform of penicillins

- Indicated only in minor infections because of:

1. Poor bioavailability.

2. Frequent dosing 4-6 times per day.3. Narrow spectrum of activity.

4. -Lactamase sensitivity.

5. Cant be used for treatment of bacteraemia

because of high lethal dose needed.

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4 Lactamase resistant penicillins


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4- -Lactamase -resistant penicillins

(Anti-staphylococcal penicillins)

Nafcillin,(I.V)

Dicloxacillin (oral)

These antibiotics are most useful against infections

caused by -Lactamase -producing staphylococci.

Nafcillin is excreted in bile.

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d i illi


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5- Broad spectrum penicillins(Aminopenicillins) (ampicillin, amoxicillin)

- Developed to increase activity against gram-negative aerobes, including some strains of E.coli, Klebsiella, and Haemophilus. But not activeagainst Pseudomonas.

- Broad-spectrum penicillin but beta lactamasesensitive.

- Amoxicillin is often combined with clavulanate(b

lactamae inhibitor), and this combination can be

used for beta-lactamases producing organisms.

6 Antipseudomonal penicilins


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6- Antipseudomonal penicilins

Ticarcillin

These agents have similar spectrums of activity as the

aminopenicillins but with additional activity against

several gram negative organisms including many

strains of Pseudomonas aeruginosa. Like the

aminopenicillins, these agents are susceptible to

inactivation by beta-lactamases.

Chiefly used to treat serious infections caused by G-ve

microorganisms, particular P.aeruginosa

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Penicillin-beta-lactamase inhibitor

combination

Combination drugs:

Ampicillin + Sulbactam = Unasyn

Amoxicillin + Clavulanic acid = Augmentin


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Penicillins: Therapeutic uses

1. Meningitis,

2. Bacterial pneumonia,

3. Streptococcal infections,

4. Syphilis,

5. Prophylactic against:

Gonococcal infection Recurrence of rheumatic fever.


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Penicillins: side effects

Hypersensitivity

skin rashes, fever, and anaphylactic shock.

Cross-reactivity exists among all penicillins andeven otherb-lactams

Because the penicillins(especially broad

spectrum penicillins) may alter gut flora,antibiotic-associated diarrhea can occur, as

well as selecting out resistant bacteria in the

colon (superinfections).48


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Documents

Antibiotic Module