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 • SulphonamidesA relative term

Bactericidal Agents affecting Cell wall synthesis Examples

Beta-lactam antibiotics Vancomycin Aminoglycosides Fluoroquinolones

First two are time dependent killersLast two groups exhibit concentration

dependent killing & show Post Antibiotic Effect (PAE)

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

Empiric therapy for pharyngitis is

• 1. Ampicillin (kind of penicillin)

• 2. Terbinafine• 3. Ivermectin• 4. Chloroquine

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.

Empiric Therapy

GroupGram-posCocci(Catalase +)

OrganismStaph. aureus

DiseaseEndocarditisBacteremiaPneumoniaCellulitis

TherapyMethicillin or nafcillinVancomycin in MRSA

Catalase-negative

Streptococci-specie

Pharyngitis, Rheum fever Pneumonia, meningitis Endocarditis

Penicillin VCeftriaxonePen-G+ Gentamic.

Gram-neg cocci

N. MeningitidisandN. gonorrhea

Meningitis

Gonorrhea

Penicillin G Or Ceftriaxone

Empiric Therapy GroupGram-neg bacilii

OrganismE.Coli

DiseaseUrinary tract infection

TherapyFluoroquinolones

K. pneumoniae Pneumonia, UTI

Imipenem

Salmonella typhi Typhoid fever Ciprofloxacin

Shigella dysenteriae

Dysentery AmpicillinCiprofloxacin

Vibrio cholera Cholera Doxycycline

Brucella spp. Undulant fever

Rifampin plus doxycycline

L. pneumophila Legionnaire’s Dz

Macrolides

Helicobacter pylori infection

Gram-negSpiral flagellate

H. pylori Peptic ulcer disease

1. Proton pump inhibitor plus 2-3 antibiotics from list below OR

2. Ranitidine bismuth citrate +2-3 antibiotics

Antibiotics: amoxicillin, clarithromycin,

metronidazole, tetracycline HCl

Which of the following is the empiric therapy for PUD (H. pylori)?

• 1. A Proton pump inhibitor

• 2. Metronidazole• 3. Amoxicillin• 4. All of the above

Empiric Therapy Group Gram-pos bacilli

OrganismBacillus anthracis

DiseaseAnthrax

TherapyCiprofloxacin

C. perfringens Gas gangrene

Pen. G/clindamycin

C. Tetani Tetanus Pen.G/metronidazole

C. difficile Pseudomembranous colitis

Vancomycin

Treponema pallidum

Syphilis Penicillin G

Borrelia burgdorferi

Lyme dz. Doxicycline, ceftriaxone

Pneumocystis carnii

Pneumonia SMX-TMP

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

•

Pharmacodynamics

• Pharmacodynamic profile: A quantitative relationship

• 3 pharmacodynamic parameters quantify relation b/w in vitro susceptibility, time course of dg. concentration & response of microbes

• Ratio of the area under curve for plasma conc. Vs time curve to MIC

• T>MIC: plasma concentration during dosing interval exceeds min. inhibitory conc.

• C max / MIC: Ratio of maximum or peak drug concentration (C max) to MIC

Antibiotic Concentration vs TimeAn

tibio

tic C

once

ntra

tion

Time (h)

Cmax

MICConc. at t >MIC

Cmax > MIC(Concentration-Dependent)

(Time-Dependent)

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 of Pen. G with aminoglycoside (gentamicin) is a

• 1. Good combination

• 2. Bad combination• 3. Neutral

combination• 4. Antagonistic

combination

BAD COMBINITIONS

β-Lactams e.g.PenicillinsVancomycin

TetracyclinesTetracycline HClChloramphenicol

Aminoglycosides e.g. Streptomycin

Macrolides e.gErythromycin

Fluoroquinolones e.g. Ciprofloxacin

Clindamycin

Combination Tx: Disadvantages

1. Antagonism of antibacterial effect

2. Increased risk of toxicity

CASEA 65-yr old man, had undergone an emergency abdominal operation in which part of his bowel was resected. He was intubated throughout the postoperative period. During the 3rd week of his hospitalization he became confused and anxious; his blood pressure recorded as 70/30 mm/Hg and HR as 110 /min. His temp. was 40 C and his respiratory rate was 24 / min. Suction of the endotracheal tube reveals copious yellow green secretions. Cold extremities and circumoral pallor were prominent on general examination. On examination of respiratory system, ronchi with decreased breath sounds were heard on auscultation. His heart and abdomen was normal. Erythema (redness and swelling) was noted around IV lines. Chest radiograph revealed bilateral lower lobe infiltrates. Urine analysis revealed WBC count 20. Other important findings in reports included BUN= 56 mg/dl (N=8-18), WBC= 15000/ mm3 with bands present, blood sugar was 210 mg/dl. Blood, urine and tracheal aspirate cultures were pending.

THE END