Principles of Antimicrobial Therapy

Kaukab Azim MBBS, PhD

 Learning Objectives
Definition
Classification
Bacteriostatic & bactericidal
Mechanism of action of each Major class
Empiric drug therapy with help of gram stain and
with knowledge of common pathogens
Out come of therapy, factors related to therapy
Development and mechanism of resistance
Various combinations; advantages &
disadvantages of combo therapy
 Antibiotic
A chemical substance produced by
various species of organisms that is
capable of killing or inhibiting the
growth of other microbes or cells

Penicillium chrysogenum
vs
Staphylococcus aureus
 Classification
Chemical classification

Mechanism of action

Bactericidal and bacteriostatic

Broad & narrow spectrum

 Classification of antibiotics
Cell wall Penicillin Cephalosporins Vancomycin Bacitracin Echinocandin
disruption

Cell membr Polyene antifungals Allylamines Azole antifungals

affecting

Protein 50 S ribosomal subunit Macrolides Chloramphenicol

synthesis
30 S ribosomal subunit Tetracycline Aminoglycosides

Cellular Affecting nucleic Rifampin Quinolones

component acids
affecting Antimetabolite Trimethoprim Sulfonamides

Antivirals Acyclovir Ribavirin, Zidovudine

 Mechanism of Action

Target: Cell wall synthesis;

all -lactam drugs
Target: Protein synthesis;
macrolides, chloramphenicol,
tetracycline, aminoglycosides
Target: RNA polymerase; rifampin
 Mechanism of Action
Affecting cellular components:
DNA gyrase inhibitors: Quinolones
DHF reductase inhibitor: Trimethoprim
PABA: Sulfonamides
Inhibit reverse transcriptase enzyme:
Zidovudine
Cell wall permeability: Amphotericin B;
Polymyxin B
Inhibitors of biosynthetic pathways:
Bacitracin
 Bacteriostatic
Protein Synthesis Inhibitors (except
aminoglycosides)
Tetracyclines
Macrolides
Clindamycin
Chloramphenicol
Linezolid
Sulphonamides
 Bactericidal
Agents affecting Cell wall synthesis
Examples of bactericidal drugs
Beta-lactam antibiotics
Vancomycin
Aminoglycosides
Fluoroquinolones
 Bactericidal antibiotics
Bactericidal drugs are preferred in:
Impaired host defense
Infections with poor blood flow (endocarditis,
endovascular infections)
Low WBC (<500)
Cancer patients
CSF penetration (meningitis)
 Effect of bactericidal and bacteriostatic
on bacterial growth

Log
 Narrow & Broad Spectrum
Broad Spectrum: Drugs which affect both
gram-pos and gram-neg bacteria;
tetracycline, imipenem, 3rd generation
cephalosporins
Narrow Spectrum: Drugs which have
activity against only gram-positive bacteria
i.e. antistaphylococcal penicillins and 1st
generation cephalosporins
 Selecting a Therapeutic Regimen
1. Confirm presence of infection:
(a). History (b) signs and symptoms
i. Fever
ii. Pain, tenderness and inflammation
iii. Symptoms related to organ
iv. WBC count and ESR
(c) Identify predisposing factors
2. Before selecting Empiric therapy
get material for c/s or for microscopy
3. Consider the spectrum of activity; narrow vs broad
spectrum
4. Special conditions like sepsis or meningitis
 Empiric therapy

To start empiric therapy

Know the microbiology of pathogens
Know the common pathogens
responsible for common infections
 Disease by staph. and strep. groups
Staphylococcus: pneumonia, abscesses, infective endocarditis,
surgical wound infections, food poisoning

Streptococci : pharyngitis, scarlet fever, rheumatic fever,

impetigo, acute glomerulonephritis

Streptococcus : Neonatal septicemia and meningitis

Streptococcus pneumoniae (diplococci): sinusitis, otitis media,

pneumonia, septicemia in aspleenic individual

Enterococcus: UTI, biliary tract infection, subacute

endocarditis, pyelonephritis
-Empiric therapy for pharyngitis is

A. Ampicillin (kind of penicillin)

B. Terbinafine
C. Ivermectin
D. Chloroquine
 Disease by gram negative cocci
Diplococci
1. Neisseria meningitidis:
Meningitis & meningococcemia
2. Neisseria gonorrhea:
Urethritis, endocervicitis, arthritis and
ophthalmia neonatum
3. Moraxella cattarhalis
Otitis media, bronchopneumonia in COPD,
bronchitis
 Bacilli or Rods
Bacilli

Gram-pos Gram-neg
Bacillus anthracis P. aeruginosa
Bacillus cereus H. influenzae
Clostridium species B. purtusis
C. diphtheria Brucella
Campylobacter
*Enterobacteriaceae

*Family consists of E. coli, Salmonella spp., Shigella spp.,

Klebsiella, V. cholera, Proteus spp.
 Identification of the pathogen
Collection of infected material before beginning
antimicrobial therapy

1. StainsGram or acid-fast (which is already done)

2. Serology
3. Culture and sensitivity
4. Thin layer smears

Minimal inhibitory concentration (MIC) is the

lowest concentration of antimicrobial that prevents
visible growth of microbes
Other factors for selection of therapy
HOST FACTORS

Allergy
Age
Pregnancy
Metabolic abnormalities
Organ dysfunction
Concomitant use of drugs
Comorbid disease states
 Selecting a Drug: Drug Factors
a. Resistance to drug ( ceftazidime)
b. Pharmacokinetic & Pharmacodynamic factors
i. Concentration-dependent killing & post
antibiotic effect. e.g. Aminoglycosides,
Fluoroquinolones
ii. Time-dependent killing
e.g. -lactum, vancomycin, macrolides,
linezolid
 Post-Antibiotic Effect / Loading Dose

The Post-Antibiotic Effect (PAE) shows the

capacity of an antimicrobial drug to inhibit the
growth of bacteria after removal of the drug
from the culture.

The PAE provides additional time for the

immune system to remove bacteria that might
have survived antibiotic treatment before they
can eventually regrow after removal of the
drug.
 Selecting a drug
Tissue penetration
CSF, abscesses, diabetic foot infection

Protein binding

Toxicity:
chloramphenicol, vancomycin,
aminoglycosides, clindamycin

Cost
Monitoring Therapeutic Response

Clinical assessment
Laboratory tests
Assessment of therapeutic failure
a. Due to drug selection
b. Due to host factors
c. Due to resistance
 Mechanisms Of Resistance
Resistance
Intrinsic Acquired

Mutation Transferred

Conjugation
Transformation
Transduction
 Mechanisms for acquired resistance
A mutation in a relevant gene occur as a random
selection under the pressure exerted by antibiotic;
trait can be passed vertically to daughter cells
Transfer of an extrachromosomal DNA carrier
(plasmid), is the most common of acquired
resistance; Transfer can occur via
1. Transduction
2. Transformation
3. Conjugation
1. Transduction; occurs when bacteria-specific
viruses (bacteriophages) transfer DNA between
two closely related bacteria
2. Transformation; is a process where parts of DNA
are taken up by the bacteria from the external
environment. This DNA is normally present in
the external environment due to the death and
lysis of another bacterium.
3. Conjugation; occurs when there is direct cell-cell
contact between two bacteria and transfer of
small pieces of DNA called plasmids takes place
 Cellular Resistance

ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science

Creative Quarterly. Jan 07
 Resistance in some antibiotics
- lactams: Hydrolysis , mutant PBP
Tetracycline: Active eflux from the cell
Aminoglycosides: Inactivation by enzymes
Sulfonamides: Overproduction of target
Fluoroquinolones: Mutant DNA gyrase
Bleomycin: Binding by immunity prot.
Chloramphenicol: Reduced uptake into cell
Vancomycin: Reprograming of D-ala-D-ala
Quinupristin/ dalfopristin:Ribosomal methylation
Macrolides Erythromycin: RNA methylation, drug efflux
Preventing/Decreasing Resistance
a. Consult experts!
b. Control use of antibiotics
c. Rotate drugs
d. Use narrow spectrum drugs
e. Combination chemotherapy
f. Pharmacodynamics principles
 Superinfections
1. New infection
2. Most common organisms
Enterobacteriaceae
Pseudomonas
Candida
3. Due to removal of inhibitory mechanisms
4. Spectrum alteration in normal flora
risk of superinfection
 Combination Therapy: Uses
1. Empirical therapy
2. Polymicrobial infections
3. Synergism desired
Prevent development of resistance

Good combo is 2 bactericidal e.g. cell

wall inhibitor & aminoglycosides.
 Synergism
Synergism is usually defined as a four-fold or
greater DECREASE in the MIC(Minimum inhibitory
concentration) or MBC(Minimum bactericidal
concentration) of the individual antibiotics when
they are present together.
E.g. Aminoglycoside with a cell wall synthesis
inhibitor (penicillin, cephalosporin, vancomycin).
Probably due to increase entry of the AG into the
bacterium where it interacts with the ribosome
inhibiting protein synthesis.
 Synergism may result if one drug inhibits the
inactivation of the other. E.g. clavlanate has little
antibacterial activity but in irreversibly inhibits
-lactamase and is used in combination with
penicillins.
Two drugs may act at different steps in a critical
metabolic pathway. E.g. trimthoprim and
sulfamethoxazole. Sulfonamides inhibit the
synthesis of folic acid and trimethoprim inhibits
the reduction of folate to tetrahydrofolate.
 ANTAGONISM
More likely to occur when a bactericidal drug (e.g.,
penicillin, aminoglycoside) is combined with a
primarily bacteriostatic drug (e.g. tetracycline).
The explanation is that the bactericidal drugs
require the cells to be growing or actively
synthesizing protein and that the bacteriostatic
drugs prevent growth or protein synthesis and
thereby counter the effect of the bactericidal drug.
The effect of the combination is not likely to be
less than the effect of the bacteriostatic agent
alone.
 GOOD COMBINITION

Two bactericidal e.g. cell wall inhibitor

& aminoglycosides

Two bacteriostatic e.g. Quinupristin

and dalfopristin
 Combination Tx: Disadvantages

1. Antagonism of antibacterial effect

2. Increased risk of toxicity
THE END