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 therapy 5. Classify antimicrobial drugs

Principles of antimicrobial therapy

What are antimicrobial drugs?

Antimicrobial drug a chemical that destroys pathogens, includes antibiotics and chemically synthesized drugs Antibiotic an antimicrobial agent produced naturally by a bacterium or fungus Have target specificity i.e. Injure target organism without affecting the host.

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 right choice of combination.

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 after specimens for laboratory analysis have been obtained but before the results of the culture are available.

What are the purposes for use of antibiotics ? (Aim of therapy )

Prophylaxis
A Medical:

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

- Immunocompromised B surgical - 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

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. intraabdominalinfections. 3. To delay emergence of resistant strains 4. To enhance antimicrobial activity , i.e. achieve an effect not obtained by either alone(e.g. combinations of penicillin and aminoglycoside antibiotics are effective against enterococci, whereas neither agent alone is bactericidal against enterococci). 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)

Choice of the antimicrobial agents

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.

Spectrum of Activity
Refers to the range of microorganisms that an antimicrobial agent can kill or inhibit
Broad spectrum
affect a wide range of bacteria used particularly in the cases of rapid onset lifethreatening infections, when there is no time to culture the causative agent can disrupt the normal flora of the body leading to superinfection.

Narrow spectrum
Affect a limited range of bacteria requires the identification of the pathogen

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 prompt eradication of the organisms.

 Bactericidal - kill bacteria at drug serum levels achievable in the patient. - often drugs of choice in seriously ill patients.

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.

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

Choice of The Antimicrobial Agent

B- Factors related to host
1. Host's defense mechanisms 2. Host's clinical conditions 3. Local factors 4. Age 5. Genetic factors 6. Pregnancy and lactation 7. Drug allergy

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's immunocompetency.
if host defense are impaired in these individuals: A bactericidal ATB must be used : Higher-than-usual doses of bactericidal ATB or longer courses of treatment .

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.

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 areas such 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.

4-Age
Elderly
- particularly vulnerable to accumulation of drugs eliminated by the kidneys. The number of functioning nephrons decreases with age.

patients

Young children -Renal or hepatic elimination - often poorly developed in newborns Also newborns are antibiotics. particularly vulnerable to certain

5- Genetic Factors
A number of drugs (e.g. sulfonamides, chloramphenicol) may produce acute hemolysis in patient with glucose 6phosphate dehydrogenase deficiency

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 .

7- Drug allergy
-lactum ABTs e may provoke allergic reaction Sulfonamides and erythromycin have been associated with hypersentitivity reaction

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

Causes of Failure of Antimicrobial Treatment

Incorrect indication Ineffective antibiotic Inapproapirate dosage Inadequate duration Development of resistance Change of causative pathogens

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

Classification of some antibacterial agents by their sites of action

CELL WALL CELL MEMBRANE DNA THFA Inhibitors of cell membrane function Isoniazid Amphotericin B Inhibitors of nucleic acid function or synthesis Fluoroquinolones Rifampin

PABA

Ribosomes mRNA

Inhibitors of metabolism Sulfonamides Trimethoprim

Inhibitors of cell wall synthesis b-Lactams Vancomycin

Inhibitors of protein synthesis Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol

THFA = tetrahydrofolic acid; PABA = p-aminobenzoic acid

Cell wall synthesis inhibitors

Summary of anti microbial agents affecting cell wall synthesis

INHIBITORS OF CELL WALL SYNTHESIS b-LACTAM ANTIBIOTIC OTHER ANTIBIOTIC
Bacitracin Vancomycin

b-LACTAMASE INHIBITORS
Clavulanic acid Sulbactam Tazobactam

PENICILLINS
Amoxicillin Ampicillin Cloxacillin Dicloxacillin Indanyl carbenicillin Methicillin Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin Ticarcillin

CEPHALOSPORINS

CARBAPENEMS
Imipenem/cilastatin Meropenem* Ertapenem

MONOBACTAMS
Aztreonam

1st GENERATION

2nd GENERATION

3rd GENERATION 4th GENERATION Cefdinir Cefixime Cefoperazone Cefotaxime Ceftazidime Ceftibuten Ceftizoxime Ceftriaxone Cefepime

Cefadroxil Cefazolin Cephalexin Cephalothin

Cefaclor Cefamandole Cefprozil Cefuroxime Cefotetan Cefoxitin

The Beta-lactams
Beta-lactams are a broad class of antibiotics that have in common a four membered betalactam ring structure. They include: 1. Penicillins, 2. Cephalosporins, 3. Carbapenems, 4. Monobactam

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b-lactam Antibiotics
All of the drugs in this group contain a -lactam ring in their structure
S S

Penicillins

Share similar features of chemistry, mechanism of action Cross reactivity

Cephalosporins
Bacteria might develop resistance to -lactam antibiotics by synthesizing beta lactamase, an enzyme that attacks the -lactam ring.

Carbapenems

Monobactams
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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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1. Penicillin G ( -Lactamase sensitive) 2. Depot preparations: (long actin preparations) ( Lactamase sensitive) 3. Acid resistant penicillins (penicillin V) ( -Lactamase sensitive). 4. -Lactamase -resistant penicillins (antistaphylococcal penicillins). 1,2 ,3 & 4 are narrow spectrum 5. Broad spectrum penicillins ( -Lactamase sensitive) 6. Antipseudomonal penicillins (extended spectrum penicillin) ( -Lactamase sensitive)

Penicillin Groups

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 gram ve ) .

2- Depot preparations:(long actin preparations)

penicillin G procaine (used every 18-24 hours) penicillin G benzathine (duration of antimicrobial activity in the plasma is up to one month) Such agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of antibiotic in the blood.

3-Acid-stable Penicillins- penicillin V

- The oral form of penicillins

- Indicated only in minor infections because of:

1. 2. 3. 4. 5. Poor bioavailability. Frequent dosing 4-6 times per day. Narrow spectrum of activity. -Lactamase sensitivity. Cant be used for treatment of bacteraemia because of high lethal dose needed.

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

- Developed to increase activity against gramnegative aerobes, including some strains of E. coli, Klebsiella, and Haemophilus. But not active against Pseudomonas. - Broad-spectrum penicillin but beta lactamase sensitive. - Amoxicillin is often combined with clavulanate(b lactamae inhibitor), and this combination can be used for beta-lactamases producing organisms.

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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Beta-lactamase inhibitors
Inactivate bacterial beta-lactamases Are used to enhance the antibacterial activity of beta lactam antibiotics sensitive to beta lactamase. - Only have weak antibacterial action. Example: Clavulanic acid, Sulbactam

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Penicillin-beta-lactamase inhibitor combination

Combination drugs:
Ampicillin + Sulbactam = Unasyn
Amoxicillin + Clavulanic acid = Augmentin

Penicillins: Therapeutic uses

1. 2. 3. 4. 5. Meningitis, Bacterial pneumonia, Streptococcal infections, Syphilis, Prophylactic against:
Gonococcal infection Recurrence of rheumatic fever.

Penicillins: side effects

Hypersensitivity
skin rashes, fever, and anaphylactic shock. Cross-reactivity exists among all penicillins and

even other b-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).
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