1. Principles of Anti-microbial Therapy Dr. Naza M. Ali
Lec 2-3

2. Antimicrobial drugs are effective in the treatment of infections because of their selective toxicity.
They have the ability to injure or kill an invading microorganism without harming the cells of the host.

3. Selection of antimicrobial agents
A. Identification of the infecting organism B. Empiric therapy prior to identification of the organism (time ,selection of a drug) C. Determination of antimicrobial susceptibility of infective organism D. Effect of the site of infection on therapy (BBB) E. Patient factors F. The safety of the agent G. The cost of therapy

4. A. Identification of the infecting organism
A rapid assessment of the nature of the pathogen can sometimes be made on the basis of the Gram stain, it is necessary to culture the infective organism

5. B. Empiric therapy prior to identification of the organism
Critically ill patient, a delay could prove fatal, and immediate empiric therapy is indicated.
Timing: For example,
a neutropenic patient (one who has a reduction in neutrophils, predisposing the patient to infections), or
a patient with meningitis ( severe headache, neck
rigidity, and sensitivity to bright lights)
require immediate treatment.
Therapy should be initiated after specimens for laboratory analysis have been obtained, but before the results of the culture are available.

6. Drug choice in the absence of susceptibility data is influenced by the
Selecting a drug:
Drug choice in the absence of susceptibility data
is influenced by the
site of infection and the patient’s history
previous infections, age, recent travel history, immune status,
and whether the infection was hospital- or community-acquired).

7. The penetration and concentration of Ab agent in CSF
is influenced by:
Lipid solubility of the drug:
The lipid solubility of a drug is important factor
Beta-lactam antibiotics are ionized at physiologic pH and have low solubility in lipids, so have limited
penetration through the BBB under normal
circumstances.

9. 2.Molecular weight of the drug:
A compound with a low molecular weight has an enhanced
ability to cross the BBB
whereas compounds with a high M.wt ( vancomycin)
penetrate poorly, even in the presence of meningeal
inflammation.
3.Protein binding of the drug:
A high degree of protein binding of a drug in the serum
restricts its entry into the CSF.

10. Patient factors Immune system(alcoholism, age, diabetes, malnutrition)
Renal dysfunction
Hepatic dysfunction
Poor perfusion
Age
Pregnancy and Lactation

11. Patient factors
Immune system:
2. Renal dysfunction:
Poor kidney function (10 % Poor kidney function causes accumulation of antibiotics that would be otherwise be eliminated.

12. 3. Hepatic dysfunction: Antibiotics that are concentrated or eliminated by the liver are must be used with caution when treating patients with liver dysfunction. 4. Poor perfusion: Decreased circulation to an anatomic area, such as the lower limbs of a diabetic, reduces the amount of antibiotic that reaches that area, making these infections notoriously difficult to treat.

13. 5. Age: Renal or hepatic elimination processes are often poorly developed in newborns 6. Pregnancy: Many antibiotics cross the placenta.

14. Bacteriostatic drugs
An antimicrobial drug that inhibits microbial growth but
requires host defense mechanisms to eradicate the
infection (dose not kill bacteria).
Arrest the growth & replication of bacteria, limiting the
spread of infection while the body's immune system
eliminates the bacteria.
If the drug is removed before the immune system has
scavenged the organisms, enough viable organisms may
remain to begin a second cycle of infection.

15. Bactericidal drugs
An antimicrobial drug that can eradicate an infection
in the absence of host defense mechanisms (kills
bacteria).
Are more aggressive, are often the drugs of choice
in seriously ill patients.

17. Minimum inhibitory concentration (MIC)
Is the lowest concentration of antibiotic that inhibits bacterial
growth.
Minimum bactericidal concentration (MBC):
minimum bactericidal concentration is the lower
concentration of antimicrobial agent that results in a 99.9%
decline in colony count after over night broth dilution
incubations.

18. Determinations of rational dosing
1) Concentration-dependent killing 2) Time-dependent killing 3) Postantabiotic effect

19. 1) Concentration-dependent killing
Increase in the rate of bacterial killing as the
concentration of antibiotic increases from 4- to
64-fold the MIC of the drug for the infecting
organism.
Example
Aminoglycosides

21. 2)Time-dependent killing (concentration- independent)
Increasing the concentration of antibiotic to higher multiples of the MIC does not significantly increase the rate of kill.
The percentage of time that blood concentrations of a drug remain above the MIC.
Example: Penicillins and cephalosporins

23. 3)Postantibiotic effect (PAE)
Is a persistent suppression of microbial growth
that occurs after levels of antibiotic have fallen
below the MIC.
Antimicrobial drugs exhibiting a long PAE
several hours often require only one dose per day.
example
Aminoglycosides
Fluoroquinolones

24. Chemotherapeutic Spectra
Narrow-spectrum antibiotics
ex. Isonaized act only on a single or a limited group of
microorganism.
B) Extended spectrum antibiotics
ex. Ampicillin is effective against gram-positive &
against significant number of gram-negative bacteria.
C) Broad-spectrum antibiotics
ex. tetracycline, chloramphenicol affect a wide variety of microbial species.

27. Combinations of Antimicrobial Drugs
Advantages of drug combinations
Combinations of antibiotics such as beta-lactams &
aminoglycosides show synergism (the combination is more effective than either of the drugs used separately).
When an infection is of unknown origin.
In the treatment of tuberculosis

28. Disadvantages of drug combinations
A number of antibiotics act only when organisms are multiplying.
Coadministration of bacteriostatic effect of tetracycline drugs may interfere with the bactericidal effect of penicillins and cephalosporins.

29. Drug resistance
Bacteria are said to be resistant to an antibiotic if the
maximal level of that antibiotic that can be tolerated by
the host does not stop their growth.
Some organisms are inherently resistant to an antibiotic.
Gram-negative organisms are inherently resistant to
vancomycin.
Resistant strains developed through spontaneous
mutation or acquired resistance and selection.

30. Prophylactic antibiotics
1)Prevention of streptococcal infections in rheumatic heart
disease.
2)Pretreatment of patients undergoing dental extractions
who have prosthetic devices.
3)Prevention of T.B or meningitis among individuals who
are close contact with infected patient.
4)Treatment prior to bowel surgery, joint replacement.
5)Treatment of HIV infected mother to protect the fetus.

33. Complications of Antibiotic Therapy
Hypersensitivity:
Penicillin's can cause serious hypersensitivity problems, ranging from urticaria to anaphylactic shock.
B. Direct toxicity
High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host
Aminoglycosides can cause ototoxicity
C. Superinfections
Drug therapy, particularly with broad-spectrum Ab or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, intestinal, and genitourinary tract.

34. Sites of Antimicrobial Action
Antimicrobial drugs can be classified in a number of ways.
1) by their chemical structure
like B-lactams, aminoglycoside
2) by their mechanism of action
like cell wall synthesis inhibitors
3) by their activity against particular types of organisms
like bacteria, fungi, or viruses

35. Classification of some antibacterial agents by their sites of action