Principles of Principles of Antimicrobial Antimicrobial

TherapyTherapyPart 1Part 1

Principles of Principles of Antimicrobial Antimicrobial

TherapyTherapyPart 1Part 1

Principles of Antimicrobial

Therapy

• Effective in the treatment of infections ( selective toxicity)

• Ability to kill microorganism without harming the cells of the host

MicroorganismsSource 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 TherapyA. 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

Empiric Therapy• Status of the Patient

• 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 drug-resistant 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

• 4. Inhibitors of Nucleic Acid function or synthesis

• - Fluoroquinolones• - Rifampin

Classification of Antimicrobial Agents

Inhibitors of Cell wallSynthesisB-Lactams

Vancomycin

Inhibitors of metabolismSulfonamidesTrimethoprim

Inhibitors of ProteinSynthesis

TetracyclinesAminoglycosides

MacrolidesClindamycin

Chloramphenicol

InhibitorsOf Nucleic

Acid FunctionOr Synthesis

Fluoroquinolones

Rifampin

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.

-

-

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, Steven-Johnson 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

Penicillins Cephalosporins Carbapenems Monobactams

Vancomycin

Bacitracin

ImipenemCilastin

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

First generation:• 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

Second generation:• Haemophilus influenzae, some

Enterobacter aerogenes and some Neisseria species (HENPECK)

• Gram-positive – weaker

• e.g Cefaclor, Cefamandine, Cefonizid, Cefmetazole, Cefotetan, Cefoxitin, Cefuroxime*

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