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 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 Regimen1. Confirm presence of infection:
(a). History (b) signs and symptomsi. 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-negativeGram-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 infectionGram-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