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 chrysogenumvs

• Staphylococcus aureus

Classification

• Chemical classification

• Mechanism of action

• Bactericidal and bacteriostatic

• Broad & narrow spectrum

Classification of antibioticsCell wall disruption

Penicillin

Cephalosporins

Vancomycin Bacitracin

Echinocandin

Cell membraffecting

Polyene antifungals

Allylamines Azole antifungals

Protein synthesis

50 S ribosomal subunit

Macrolides Chloramphenicol

30 S ribosomal subunit

Tetracycline

Aminoglycosides

Cellular component affecting

Affecting nucleic acids

Rifampin Quinolones

Antimetabolite Trimethoprim

Sulfonamides

Antivirals Acyclovir Ribavirin, Zidovudine

Mechanism of Action

• Target: Cell wall synthesis; all β-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

BacteriostaticProtein Synthesis Inhibitors (except

aminoglycosides) • Tetracyclines • Macrolides • Clindamycin• Chloramphenicol• Linezolid • Sulphonamides

Bactericidal Agents affecting Cell wall synthesis Examples

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. Feverii. Pain, tenderness and inflammation iii. Symptoms related to organ iv. WBC count and ESR

(c) Identify predisposing factors2. Before selecting Empiric therapy

get material for c/s or for microscopy 3. Consider the spectrum of activity; narrow vs broad

spectrum4. 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

Gram-positive and gram-negative

Gram-pos & gram-neg cocci GRAM POSITIVE COCCI

Chains / pairs Clusters

Staphylococcus Streptococcus AND Enterococci

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 gp. B: Neonatal septicemia and meningitis

• Streptococcus pneumoniae (diplococci): sinusitis, otitis media, pneumonia, septicemia in aspleenic individual

• Enterococcus: UTI, biliary tract infection, subacute endocarditis, pyelonephritis

Disease by gram negative cocci Diplococci

1. Neisseria meningitidis:Meningitis & meningococcemia

2. Neisseria gonorrhea:Urethritis, endocervicitis, arthritis and ophthalmia neonatum

3. Moraxella cattarhalisOtitis media, bronchopneumonia in COPD, bronchitis

Bacilli or RodsBacilli

Gram-pos Gram-negBacillus anthracis P. aeruginosaBacillus cereus H. influenzaeClostridium species B. purtusisC. 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. Stains—Gram or acid-fast (which is already done)2. Serologies 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 effecte.g. Aminoglycosides, Fluoroquinolones

ii. Time-dependent killinge.g. β-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.

Time (h)

Log 10

CFU

/mL

PAE

80 2 4 6

4 x MIC

3 x MIC2 x MICMICBroth

8

0

2

4

6

10

Concentration dependence & PAE

Wash

Time (h)

Log 10

CFU

/mL

80 2 4 6

> 5 x MICMIC

8

0

2

4

6

10Time-Dependent Killing

Wash

Duration-Based Drug Action

•

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 selectionb. Due to host factorsc. Due to resistance

Mechanisms Of Resistance

ResistanceIntrinsic Acquired

Mutation Transferred

Conjugation Transformation Transduction

Cellular Resistance

•

• • ATTACK OF THE SUPERBUGS:

ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly.

Jan 07

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

• Transduction

• Transformation

• Conjugation

Resistance in some antibiotics• Β- 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 of : RNA methylation, drug

Erythromycin efflux

Preventing/Decreasing Resistance

a. Consult experts!b. Control use of antibioticsc. Rotate drugsd. Use narrow spectrum drugse. Combination chemotherapyf. Pharmacodynamic principles

Superinfections

1. New infection2. Most common organisms

EnterobacteriaceaePseudomonasCandida

3. Due to removal of inhibitory mechanisms4. Spectrum alteration in normal flora

risk of superinfection

Combination Therapy: Uses

1. Empirical therapy2. Polymicrobial infections3. Synergism desired• Prevent development of resistance

• Good combo is 2 bactericidal e.g. cell wall inhibitor & aminoglycosides.

Combination Therapy: OutcomesLo

g 10 C

FU/m

LADDITIVE

Control

Drug B

Drug A

Drug A + B

0 12Time (h)

SYNERGISM

Time (h)0 12

Control

Drug B

Drug A

Drug A + B

Combination Therapy: Outcomes

Log 10

CFU

/mL

ANTAGONISM

Time (h)0 12

Control

Drug B

Drug A

Drug A + B

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