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
 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
 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

Inhibitors of Protein
Synthesis
Synthesis
B-Lactams
Tetracyclines
Vancomycin
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.
-
 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

Vancomycin

Bacitracin

Penicillins Cephalosporins Carbapenems Monobactams

Imipenem
Astreonam
Cilastin
 Penicillins
• Penicillin G • Ampicillin
• Penicillin V • Amoxicillin
• Methicillin • Carbenicillin
• Nafcillin • Ticarcillin
• Oxacillin • Piperacillin
• Cloxacillin • Mezlocillin
• Dicloxacillin • Azlocillin
 Cephalosporins
• 1st Generation • 2nd Generation
• Cefazolin • Cefaclor
• Cefadroxil • Cefamandole
• Cefalexin • Cefonizid
• Cefalothin • Cefmetazole
• Cepharipin • Cefotetan
• Cefadrin • Cefoxitin
• Cefuroxime
• Cefprozil
• Loracarbef
 Cephalosporins
• 3rd generation • 4th generation
• Cefixime • Cefepime (Maxipime)
• Cefoperazone
• Cefotaxime
• Ceftazidime
• Ceftriaxone
• Moxalactam
• Cefdinir
• Cefditoren pivoxil
• Cefpodoxime
• Ceftibuten
• Ceftizoxime
 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 • Ampicillin
• Penicillin V • Amoxicillin
• Methicillin • Carbenicillin
• Nafcillin • Ticarcillin
• Oxacillin • Piperacillin
• Cloxacillin • Mezlocillin
• Dicloxacillin • 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 • 2nd Generation
• Cefazolin • Cefaclor
• Cefadroxil • Cefamandole
• Cefalexin • Cefonizid
• Cefalothin • Cefmetazole
• Cepharipin • Cefotetan
• Cefadrin • 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