Principles of Antimicrobial Therapy Part 1

Principles of Antimicrobial Therapy
• Effective in the treatment of infections ( selective toxicity) • Ability to kill microorganism without harming the cells of the host

Microorganisms Source of Infection
• Bacteria • Viruses • Fungi

Topics
• • • • • Antibacterial agents AntiTB drugs Antifungal Antiviral UTI

Chain of Infection

Susceptibility of the body to infection
• 1. Age • 2. Exposure to pathologic organisms • 3. Disruption of the body’s normal barrier to infection • 4. Impaired Immune system • 5. Impaired circulation • 6. Poor nutritional status

Selection of Antimicrobial Agents:
• • • • • • • Organism’s identity and its sensitivity Site of infection Age of the patient Pregnancy / Lactation Safety of the agent Patient factors Cost of therapy

Empiric Therapy
• immediate administration of drug/s covering by both gram-positive and gram-negative microorganisms

Empiric Therapy
• • • • • • • • • • A. Empiric therapy prior to organism identification - The acutely ill patient - Selecting a drug – site of infection and patient history B. Identification and sensitivity of the organism - Gram stain - Culture - Microscopic examination - Sensitivity testing C. Laboratory methods of identification - Disk-diffusion

Empiric Therapy
• D. The effect of the site of Infection on therapy - Blood brain barrier - Prostate – pH of prostatic fluid 6.4 and plasma is 7.4

• •

Empiric Therapy
A. Status of the Patient • • • • • 1.Immune system - Alcoholism, DM HIV, malnutrition, advanced age and immunosuppressive drugs 2.Renal dysfunction - Poor kidney function 10% or less of normal Serum creatinine

• Status of the Patient

Empiric Therapy

• 3.Hepatic dysfunction • - Erythromycin and tetracycline • 4.Poor perfusion • - DM – decreased circulation to an anatomic area

Empiric Therapy
• • • • • • • 5. Pregnancy ALL ANTIBIOTICS CROSS THE PLACENTA Adverse effect are rare Tooth dysplasia and inhibition of bone growth (tetracycline) Antihelmintics – embryotoxic and teratogenic Aminoglycosides – ototoxic Streptomycin – auditory nerve damage

Empiric Therapy
• • • • • • • 6. Lactation drugs administered to a lactating mother may enter the nursing infant via the breast milk 7. Age Renal and hepatic elimination ( Newborns) Chloramphenicol and sulfonamides Tetracycline – bone growth Fluoroquinolones – cartilage growth

Empiric Therapy
• 8. Safety of the Agent • Penicillin the least toxic of all drugs • SAFETY IS RELATED NOT ONLY TO THE INHERENT NATURE OF THE DRUG BUT ALSO TO PATIENTS FACTORS THAT CAN PREDISPOSE TO TOXICITY • • G. Cost of Therapy

Bacteriostatic drugs
- arrest the growth and replication of bacteria at serum levels achievable in the patient, thus limiting the spread of infection while the body’s immune system attacks, immobilizes, and eliminates the pathogen - tetracyclines, erythromycin, lincomycin

Bactericidal drugs
• kills the bacteria and the total number of viable organisms decreases • e.g. Chloramphenicol – static for gram negative and cidal against Pneumococci • Cephalosporins, Polymyxin, vancomycin

Chemotherapeutic Spectra
• refers to the species of organisms affected by certain drug • 1. Narrow spectrum
– single or a limited group of microorganisms

• E.g Isoniazid

Chemotherapeutic Spectra
• b. Extended Spectrum
– antibiotics that are effective against gram-positive and gram-negative

E.g. Ampicillin

Chemotherapeutic Spectra

3. Broad Spectrum

wide coverage, drastically alter the nature of the normal bacterial flora and can precipitate a superinfection of the organism (Candida)

E.g. Tetracycline and Chloramphenicol

Combinations of Antimicrobial Drugs
• • • • 1. Advantages of drug combinations - B-lactams and aminoglycosides 2. Disadvantages of drug combinations - A number of antibiotics act only when organisms are growing. Concomitant administration of a second agent is usually bacteriostasis and may interfere with the action of the first drug that is bactericidal

Drug Resistance
• • • • • • • 1. Genetic alterations leading to drug resistance -Spontaneous mutation of DNA - DNA transfer of drug resistance 2. Altered expression of proteins in drugresistant organisms - Modification of target sites - Decreased accumulation - Enzymatic inactivation

Antibiotic therapy
• Prophylactic Antibiotics
– Before and after exposure to a disease entity

Complications of Antibiotic Therapy
• • • • • • 1. Hypersensitivity
- Penicillin

2. Direct toxicity / Organ toxicity - Aminoglycosides - Chloramphenicol – Aplastic anemia 3. Superinfections – broad-spectrum

Classification of Antimicrobial Agents
• • • 1. Inhibitors of Metabolism - Sulfonamides - Trimethoprim

Classification of Antimicrobial Agents
• • • 2. Inhibitors of cell wall synthesis - B-lactams - Vancomycin

Classification of Antimicrobial Agents
• • • • • • 3. Inhibitors of Protein Synthesis - Tetracycline - Aminoglycosides - Macrolides - Clindamycin - Chloramphenicol

Classification of Antimicrobial Agents
• • • 4. Inhibitors of Nucleic Acid function or synthesis - Fluoroquinolones - Rifampin

Inhibitors of metabolism Sulfonamides Trimethoprim

Inhibitors Of Nucleic Acid Function Or Synthesis Fluoroquinolones Rifampin

Inhibitors of Cell wall Synthesis B-Lactams Vancomycin

Inhibitors of Protein Synthesis Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol

I. Inhibitors of Metabolism
• Folate Antagonists • Folic acid coenzyme are required for the synthesis of purine and pyrimidine (RNA and DNA) and other compounds required for cellular growth and replication • In the absence of folic acid cells cannot divide.

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Amino acid biosynthesis

-

Purine synthesis

Pyrimidine synthesis

1. Sulfa drugs (SULFONAMIDES)
• Mechanism of action: • Inhibitors of folic acid synthesis, • - dye prontosil 1930’s • Indications: • hemolytic streptococcal infections • low cost and efficacy in certain bacterial infections UTI and trachoma • resistant strain, development of allergies and the advent of Penicillin

Sulfa drugs (SULFONAMIDES)
• synergistic effect with Trimethoprim mid 1970’s (SULFAMETHOXAZOLE) •

Sulfa drugs (SULFONAMIDES)
• Indications:
– Pneumocystis carinii pneumonia or Ampicillin-resistant or chloramphenicol resistant systemic salmonella infections – Bacteriostatic – Enterobacteria, chlamydia, nocardia

Sulfa drugs (SULFONAMIDES)
• Pharmacokinetics

1. Absorption • Oral, Rectal, IV and Topical (Silver sulfadiazine) 2.Distribution • body water, CSF, cross the placenta, breast milk 3.Metabolism - Stone formation 4. Excretion • glomerular filtration

Adverse Effects:
• • • • • 1. Crystalluria: Nephrotoxicity 2. HypersensitiVity – rashes and angioedema, StevenJohnson syndrome 3. Hemopoietic disturbances – hemolytic anemia, G6PD 4. Kernicterus 5. Drug potentiation

Contraindications
• A. Newborn • B. Infants less then 2 months • C. Pregnant women should not be given in patients taking methenamine for UTI

2.Trimethoprim

• • •

Mechanism of Action:

potent inhibitor of bacterial dihydrofolate reductase compounded with sulfamethoxazole 20 to 50 times more potent than the sulfonamides

• • •

Indications Acute UTI Bacterial prostatitis

Adverse effects:
1. folate defieciency • 2. megaloblastic anemia • 3. leukopenia and granulocytopenia • • Folinic acid can reversed the deficiency

3. Co- trimoxazole
• • Generic name Cotrimoxazole Brand name - Bactrim, Kathrex, Rimezone, Bacxal, Doctrimox, Triglobe, Triforam

• Mg/kg/day - 5 -8 mg/kg/day • Preparations – 800mg/160mg/tab; 400mg/80mg/cap 400mg/80mg/5ml; 200mg/40mg/5ml

Co- trimoxazole
• Trimethoprim plus sulfamethoxazole • Greater antimicrobial activity • Mechanism of Action: inhibition of two sequential steps in the synthesis of tetrahydrofolic acid; sulfamethoxazole inhibits the incorporation of PABA into folic acid and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate

Co- trimoxazole
• Ratio 20 parts of sulfamethoxazole and 1 part trimethoprim • Orally • IV in Severe pneumonia caused by Pneumocystitis carinii • Metabolites are excreted in the urine

Co- trimoxazole
• Adverse effects: • 1. Dermatologic • 2. Gastrointestinal: Nausea, vomiting, glossitis and stomatitis • 3. Hematologic: Megaloblastic anemia, leukopenia, thrombocytopenia • 4. HIV patients: PCP- drug-induced fever, rashes and diarrhea and pancytopenia

Co- trimoxazole
• Drug interactions: • 1. Prolonged Prothrombin time in-patient receiving warfarin. • 2. Phenytoin may be increased due to an inhibition of its metabolism. • 3. Methotrexate levels may rise due to displacement of albumin binding sites

II. Inhibitors of Cell Wall Synthesis
• • - B-lactams - Vancomycin

Inhibitors of Cell wall Synthesis

B-lactam antibiotics

Other antibiotics Vancomycin

Bacitracin

Penicillins

Cephalosporins

Carbapenems Imipenem Cilastin

Monobactams

Astreonam

Penicillins
• • • • • • • Penicillin G Penicillin V Methicillin Nafcillin Oxacillin Cloxacillin Dicloxacillin • • • • • • • Ampicillin Amoxicillin Carbenicillin Ticarcillin Piperacillin Mezlocillin Azlocillin

Cephalosporins
• • • • • • • 1st Generation Cefazolin Cefadroxil Cefalexin Cefalothin Cepharipin Cefadrin • • • • • • • • • • 2nd Generation Cefaclor Cefamandole Cefonizid Cefmetazole Cefotetan Cefoxitin Cefuroxime Cefprozil Loracarbef

Cephalosporins
• • • • • • • • • • • • 3rd generation Cefixime Cefoperazone Cefotaxime Ceftazidime Ceftriaxone Moxalactam Cefdinir Cefditoren pivoxil Cefpodoxime Ceftibuten Ceftizoxime • • 4th generation Cefepime (Maxipime)

B-Lactamase inhibitors
• Clavulanic acid • Sulbactam • Tazobactam

Penicillin’s
• • • – most widely effective antibiotics and are among the least toxic drugs - major adverse reaction (Hypersensitivity) bactericidal

Penicillins
• • • • • • • Penicillin G Penicillin V Methicillin Nafcillin Oxacillin Cloxacillin Dicloxacillin • • • • • • • Ampicillin Amoxicillin Carbenicillin Ticarcillin Piperacillin Mezlocillin Azlocillin

Penicillin’s
• Mechanism of Action:
– interfere with the last step of bacterial cell wall synthesis, exposing the osmotically less stable membrane

Mechanism of action/s:
• rapidly growing organisms that synthesize a peptidoglycan cell wall • Inactive against organisms devoid of Peptidoglycan cell wall, such as mycobacteria, protozoa, fungi, viruses • Inactivate proteins present on the bacterial cell membrane

Mechanism of action/s:
• Penicillin binding protein • Enzymes for the synthesis of the cell wall (morphology) • Methicillin-resistant Staphylococcus aureus • Inhibition of transpeptidase (cell wall integrity) • Autolysins – gram positive cocci • * Inhibition of cell synthesis and destruction of existing cell wall by autolysins

Antibacterial Spectrum
• Gram positive • Gram negative (lipopolysaccharide)

1. Natural Penicillin
• • – Penicillium chrysogenum Penicillin G (benzylpenicillin) – gram positive and gram negative cocci, gram positive bacilli and spirochetes Penicillin V - same spectrum with PenG, not used for treatment of bacteremia (MLC – minimum lethal concentration, mimimum amount of the drug needed to eliminate the infection), oral infections

2. Antistaphylococcal penicillins:
• Methicillin, Nafcillin, oxacillin, cloxacillin and dicloxacillin- penicillinase-resistant penicillins Penicillinase-producing Staphylococci Methicillin (toxic) (MRSA)

• •

3. Extended spectrum penicillins
• • • • Ampicillin and amoxicillin similar to PenG – gram-negative bacilli Ampicillin – gram-positive bacillus, Listeria monocytogenes Amoxicillin – dentists for abnormal heart valves Escherichia coli and Haemophilus influenzae (resistant

4. Antipseudomonal penicillins
• • • • A. Carbenicillin B. Ticarcillin C. Piperacillin – most potent Gram – negative bacilli but not klebsiella

5. Penicillins and aminoglycosides
• • – synergistic effect -eg Ampicillin plus Gentamicin

Pharmacokinetics
• • 1. Administration IV or IM - Methicillin, ticarcillin carbenicillin, mezlocillin, piperacillin, azlocillin, combination of ampicillin with sulbactam, ticarcillin with clavulanic acid and piperacillin with tazobactam Oral - Pen V , amoxicillin and amoxicillin combined with clavulanic acid

Pharmacokinetics

2. Absorption
Penicillins are incompletely absorbed after oral medication and reach the intestine in sufficient amount to affect the intestinal flora. Amoxicillin is completely absorbed.

• •

- dec. by food and acidic environment - 30-60 min before meals or 2 to 3 hours postprandially

Pharmacokinetics
• 3. Distribution
– cross the placental barrier but none teratogenic

- CSF insufficient

Pharmacokinetics
• • 4. Metabolism 5. Excretion – kidney

Adverse reactions:
• • • • • • A. Hypersensitivity B. Diarrhea C. Nephritis D. Neurotoxicity – Seizure E. Platelet dysfunction F. Cation toxicity – Sodium – hypokalemia

Cephalosporins
• • • • • • • 1st Generation Cefazolin Cefadroxil Cefalexin Cefalothin Cepharipin Cefadrin • • • • • • • • • • 2nd Generation Cefaclor Cefamandole Cefonizid Cefmetazole Cefotetan Cefoxitin Cefuroxime Cefprozil Loracarbef

• Antibacterial Spectrum: • 1. PenG substitutes that are resistant to Staphylococcal penicillinase • Proteus mirabilis, Escherichia coli and klebsiella pneumoniae (PECK) • e.g Cefazolin, Cefalexin*, Cephalothin, Cephapirin, Cephradine

First generation:

Haemophilus influenzae, some Enterobacter aerogenes and some Neisseria species (HENPECK) Gram-positive – weaker e.g Cefaclor, Cefamandine, Cefonizid, Cefmetazole, Cefotetan, Cefoxitin, Cefuroxime*

Second generation:

• •

Third generation
• • • • – gram-positive cocci, gram-negative bacilli Serratia marcencens Pseudomonas aeruginosa E.g Cefixime, Cefoperazone, Cefotaxime, Ceftazidime, Ceftizoxime, Ceftriaxone

4th generation
• Wide-coverage of microorganisms

Pharmacokinetics:
• • • • Administration Distribution Metabolism Elimination

Adverse effects:
• Allergic manifestations – 5 to 15 %. 1 to 2 % • Disulfiram –like effect (Cefamandole) alcohol • Bleeding – Cefamandole or Cefoperazone (antivita. K)

Other B-lactam Antibiotics
• 1. Carbapenems – Imipenem/Cilastatin • gram positive, gram negative, aerobes and Pseudomonas aeruginosa • Pharmacokinetics: Imipenem – IV CSF, GFR, Nephrotoxic • • • • • Adverse effects: Nausea Vomiting Diarrhea Seizure

Monobactams
• • • • • • • • • 1. Aztreonam Enterobacteria Aerobic gram negative rods Lacks activity against gram positive and anaerobes IV and IM Urine Adverse effects: Phlebitis skin rash Relatively nontoxic a safe alternative fro treating patients allergic to penicillins and cephalosporins

B- Lactamase Inhibitors
• A. Clavulanic acid • B. Sulbactam • C. Tazobactam

Other Agents Affecting the Cell Wall
• 1. Vancomycin • Mode of Action: • • • • •
– Inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization

Clostridium difficile or staphylococci Prophylactic treatment among dental patients Prosthetic heart valves Prosthetic devices Aminoglycosides for enterococcal endocarditis

Pharmacokinetics:
• • Slow intravenous infusion • Not absorbed after oral administration • Metabolism is minimal

Adverse effects:
• • • • • Fever Chills Phlebitis Shock Flushing (red man syndrome)

Bacitracin
• • • Gram- positive organisms Topical application Nephrotoxicity

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