This document discusses principles of antimicrobial therapy. It begins by classifying antimicrobials based on their source, mechanism of action, and spectrum. Narrow, extended, and broad spectrum antimicrobials are defined. The document emphasizes selecting the appropriate antimicrobial based on the infecting organism, patient factors, and pharmacokinetic properties. It stresses starting empiric therapy and then narrowing based on culture results. Monitoring treatment response and adjusting for toxicity or resistance is also highlighted. The goal of antimicrobial use is effective treatment of infection while limiting emergence of resistance.

1. Principles of
Antimicrobial

2. INTRODUCTION

3. Objectives
1)Review the classification of antimicrobials
2)Define pharmacodynamic principles and their relationship to
effective antimicrobial therapy
3)Discuss patient and drug related factors that influence the
selection of the appropriate antimicrobial agent
4)Identify monitoring parameters to evaluate antimicrobial
therapy

4. What are Antimicrobials?
Antimicrobials are drugs that destroy microbes, prevent their
multiplication or growth, or prevent their pathogenic action
 Differ in their physical, chemical, and pharmacological
properties
 Differ in antibacterial spectrum of activity
 Differ in their mechanism of action

5. Classification of Antimicrobials
A. According to source:
1.Natural compounds: e.g.penicillin, chloramphenicol.
2.Synthetic compounds: e.g.sulfonamides, quinolones.
3.Semisynthetic compounds: e.g.ampicillin.

6. B. Accordingto the effect on microorganisms:
1.Bactericidal agents: that kills the microorganism e.g.
penicillin.
2.Bacteriostatic agents: arrest growth of the microorganism
e.g. sulfonamides.

7. Inhibit cell wall synthesis
 Penicillins
 Cephalosporins
 Carbapenems
 Monobactams (aztreonam)
 Vancomycin
Inhibit protein synthesis
 Chloramphenicol
 Tetracyclines
 Macrolides
 Clindamycin
 Quinupristin/dalfopristin
 linezolid
 Aminoglycosides
Alter nucleic acid metabolism
 Rifamycins
 Quinolones
Inhibit folate metabolism
 Trimethoprim
 Sulfamethoxazole
Miscellaneous
 Metronidazole
 Daptomycin
C.Accordingto the effect on microorganisms:

8. Different mechanism of action for antimicrobials

9. D. According to antimicrobial spectrum:
1. Narrow spectrum drugs:
 Drugs affect mainly Gram +ve bacteria e.g. benzyl penicillin.
 Drugs affect mainly Gram –ve bacteria e.g. aminoglycosides.
2. Extended spectrum drugs:
 agents that affect Gram +ve & Gram –ve bacteria.
2.Broad spectrum drugs:
 agents act on wide range of Gram +ve & Gram –ve bacteria
and others (protozoa) e.g. tetracyclines.

10. Antimicrobial therapy
Empiric
 Infecting organism(s) not yet identified
 More “broad spectrum”
Definitive
 Organism(s) identified and specific therapy chosen
 More “narrow” spectrum
Prophylactic or preventative
 Prevent an initial infection or its recurrence after infection

11. CLINICAL APPROACHES FOR RATIONAL
PRESCRIBING OF ANTIBIOTICS

12. I. Confirm the presence of an infection
 CAREFUL history and physical exam including
relevant laboratory data and signs and symptoms
1) Fever:
o Is considered a hallmark of most infectious diseases.
o defined as elevated temperature >37.2◦C.
o May be present in absence of infection e.g. in
autoimmune disorders and several malignancies.
o May be absent in presence of infection if the immune
system is depressed.

13. 2) White blood cell count:
 Normal WBC is 4000-10,000 cells/mm3.
 Bacterial infections are associated with elevated granulocyte
counts (neutrophils, basophils, and eosinophils).
 Viral, TB and fungal infections are associated with elevated
lymphocytic count.
 Parasitic infections and allergic reactions are associated with
increased eosinophilic count.
3) Any swelling or erythema at a particular site
4) Purulent drainage from a visible site
5) Patient complaints

14. II. Selection of antimicrobial agents
1) Identification of the infecting organism:
 Infected body materials (e.g., blood, sputum, urine, wound
drainage, etc.) must be sampled and cultured before initiating
treatment.
 Empirical therapy before identification of the organism is
necessary in the following conditions:
o In all acutely ill patients with infections of unknown origin.
o Infection in a neutropenic patient, or a patient with meningitis.

15. Culture Results
 Minimum inhibitory concentration (MIC)
o The lowest concentration of drug that prevents visible bacterial growth
after 24 hours of incubation in a specified growth medium
o Organism and antimicrobial specific
 Report organism(s) and susceptibilities to antimicrobials
o Susceptible (S)
o Intermediate (I)
o Resistant (R)

16. Culture for micro-organism

17. 2) Patient factors:
 In neonates
- The use of chloramphenicol can lead to shock and
cardiovascular collapse(gray baby syndrome).
- The use of sulfonamides may lead to kernicterus (brain
damage)
 In growing children:
- the use of fluoiroquinolones can lead to arthropathy
-the use of tetracyclines can bind to growing bones and teeth
resulting in abnormal teeth and bone formation.

18.  In old age(>65years)
- The incidence of renal toxicity with aminoglycosides is
greater than in younger patients.
 In immunocompromised patients
- The use of bactericidal agents is necessary , as the host’s
immune system is not capable of final elimination of the
bacteria.
 Pregnancy:
- Many antibiotics cross the placenta and cause adverse
effects to the fetus e.g. aminoglycosides and tetracyclines.

19.  Genetic or metabolic abnormalities
o Glucose-6-phosphate dehydrogenase (G6PD) deficiency
 Renal and hepatic function
o Accumulation of drug metabolized and/or excreted by these
routes with impaired function
o risk of drug toxicity unless doses adjusted accordingly
o Renal excretion is the most important route of elimination
for the majority of antimicrobials

20. 3) Tissue penetration:
 The capillary lining in some tissues e.g. brain form natural barriers to
drug delivery due to presence of tight junctions of the capillary wall.
 Lipid soluble antibiotics e.g. chloramphenicol and metronidazole can
cross these barriers in normal conditions. Penicillin is ionized at
physiologic pH and cannot cross these barriers unless inflammation
is present.
 Poor perfusion of some area
- e.g. diabetic foot, reduces the amount of antibiotic reaching this area,
making treatment is difficult.

21. III. Determinants of the rational dosing
 Minimum inhibitory concentration (MIC):
o The MIC is the lowest concentration of antibiotic in body tissues
and fluids that inhibits bacterial growth.
 Concentration-dependent killing:
o Certain antibiotics(e.g.aminoglycosides) show enhanced bacterial
killing in concentration above the MIC.
o Giving these antibiotics by a single large dose per day achieves
high peak levels and cause rapid killing of bacteria.

22.  Time-dependent killing:
o depends on the time of the drug concentration to remain above
the MIC. So, preparations with long duration kill more bacteria.
o e.g.β-lactam antibiotics, macrolides, clindamycin, and linezolid
 Post-antibiotic effect (PAE):
o The PAE is a persistent bacterial suppression after levels of
antibiotic fall below the MIC.
o Antimicrobials with long PAE(e.g. aminoglycosides and
fluoroquinolones) usually require one dose per day.

23. IV. Monitoring
 Efficacy and toxicity of antimicrobials
 Clinical assessment
o Improvement in signs and symptoms
• Fever curve,  WBC
•  erythema, pain, cough, drainage, etc.
 Antimicrobial regimen
o Serum levels
o Renal and/or hepatic function
o Other lab tests as needed
o Consider IV to PO switch
 Microbiology reports
o Modify antimicrobial regimen to susceptibility results if necessary
o “Narrow” spectrum of antimicrobial if appropriate

24. Other Drug Factors
 Adverse effect profile and potential toxicity
 Cost
 Acquisition cost + storage + preparation + distribution + administration
 Monitoring
 Length of hospitalization + readmissions
 Patient quality of life
 Resistance
 Effects of the drug on the potential for the development of resistant
bacteria in the patient, on the ward, and throughout the institution
 Drug – Drug interactions

25. ADVERSE EFFECTS OF
ANTIMICROBIAL AGENTS

26. I. General adverse effects:
 Hypersensitivity or allergic reactions: In form of fever, skin
rash, arthralgia, cholestatic jaundice or hemolysis. More
serious reactions are agranulocytosis, bone marrow aplasia or
anaphylactic reaction.
 Reactions related to alterations in normal body flora,
superinfection or vitamin B deficiency may follow the use of
broad-spectrum antimicrobials. It is due to inhibition of
bacterial flora that suppresses commensal micro-organisms
which present in gut or that forms these vitamins, respectively.
 Resistance

27. II. Direct toxic reactions:
 resulting from high doses or drug interactions, on liver,
kidney, GIT, nervous system or CVS.

28. SUPERINFECTION
(Opportunistic infection)

29.  Administration of antimicrobials usually alter bacterial flora but with no
ill effect in most cases however, broad-spectrum antibiotics if used for
long time may alter or kill bacterial flora. So, the bacteria and fungi that
are normally inhibited by bacterial flora will multiply leading to
superinfection (its early manifestation may by diarrhea).
 caused by staphylococci, Pseudomonas, proteus, Candida albicans or
Clostridia difficile.

30. Cont..
 Superinfection may be vaginal, oral, pharyngeal or even systemic
infection e.g. staphylococcal enterocolitis, candidiasis or
Pseudomembranous colitis(=antibiotic-associated diarrhea).
 Treatment:
 Stop the causative agent and give drug, which kill the organisms
responsible for super infection e.g. staphylococcal enterocolitis,
which is treated by metronidazole or vancomycin orally, antifungal
nystatin for candidiasis.

31. ANTIBIOTIC RESISTANCE

32. I. Innate resistance:
 Is a feature of a particular species of bacteria e.g Pseudomonas.
 The gene(s)of resistance can be transferred between bacteria by
transfer of naked DNA(transformation),by conjugation with direct
cell-to-cellt transfer of extrachromosomal DNA(plasmids), or
through bacteriophage(transduction)..

33. II. Acquired resistance:
 Occurs when bacteria that were sensitive to certain antibiotic
become resistant with time.
 Mechanisms responsible :
i. Production of enzymes that inactivate the drug.
ii. Alteration of drug binding site.
iii. Reduction in drug uptake by the organism.
iv. Development of altered metabolic pathways.

34. Acquired Bacterial Resistance

35. Drug-Drug interactions
 Influences the selection of appropriate drug therapy, the dosage, and
necessary monitoring
 Drug interactions
  risk of toxicity or potential for  efficacy of antimicrobial
 May affect the patient and/or the organisms
 Pharmacokinetic interactions
o Alter drug absorption, distribution, metabolism, or excretion
 Pharmacodynamic interactions
o Alter pharmacologic response of a drug
o Selection of combination antimicrobial therapy ( 2 agents) requires
understanding of the interaction potential

36. COMBINATION OF ANTIBIOTICS
 Indications:
1. To obtain broader spectrum e.g. amoxicillin+clavulanic acid→ co-
amoxiclav.
2. To obtain synergism e.g. sulfonamides + trimethoprim → co-
trimoxazole.
3. In mixed bacterial infections e.g. diabetic foot or peritonitis.
4. In serious bacterial infections e.g. bacterial meningitis or septicemia.
5. To overcome bacterial resistance e.g.TB and pseudomonas infection.
6. To reduce toxicity of one drug by using smaller doses of two drugs.

37. Cont.
Results:
i. Bactericidal+bactericidal → synergism :
e.g. penicillin with aminoglycosides.
ii. Bacteriostatic+bacteriostatic → addition:
e.g. tetracyclines with sulfonamides.
iii. Bactericidal+bacteriostatic →
a. Antagonism: e.g. penicillin with erythromycin
b. Synergism: e.g. sulfadiazine with penicillin

38. GENERAL PRINCIPLES OF THERAPY
WITH ANTIMICROBIALS

39. 1. Antimicrobials should only be given when necessary and after antimicrobials
susceptibility test whenever possible.
2. The pharmacokinetics of the drug should be taken into consideration e.g.
the state of hepatic and renal functions of the patient.
3. In serious infection it is better to start with a parenteral loading of a
bactericidal agent to avoid emergence of resistant strains by giving
adequate dosage for sufficient duration and adapting proper combination
regimens.
4. Antimicrobials should be continued for 3 days after apparent cure is

40. Summary
 Antimicrobials are essential components to treating infections
 Appropriate selection of antimicrobials is more complicated than matching a drug to a
bug
 While a number of antimicrobials potentially can be considered, clinical efficacy, adverse
effect profile, pharmacokinetic disposition, and cost ultimately guide therapy
 Once an agent has been chosen, the dosage must be based upon the size of the patient,
site of infection, route of elimination, and other factors
 Optimize therapy for each patient and try to avoid patient harm
 Use antimicrobials only when needed for as short a time period as needed to treat the
infection in order to limit the emergence of bacterial resistance

41. Thank you!
Any Questions?