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ANTIBACTERIAL CHEMOTHERAPY

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ANTIBACTERIAL CHEMOTHERAPY. The most important concept underlying antimicrobial therapy is selective toxicity Broad-spectrum antibiotics : active against several types of microorganisms Tetracyclines are active against Gram-negative rods, Chlamydiae, Mycoplasmas, Rickettsiae

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slide1
ANTIBACTERIAL CHEMOTHERAPY

The most important concept underlying antimicrobial therapy is selective toxicity

Broad-spectrum antibiotics: active against several types of microorganisms

Tetracyclines are active against Gram-negative rods, Chlamydiae, Mycoplasmas, Rickettsiae

Narrow-spectrum antibiotics: active against one or very few types of microorganisms

Vancomycin is active against Staphylococci & Enterococci

slide2
ANTIBACTERIAL CHEMOTHERAPY

Bactericidal drugs kill bacteria: e.g. Penicillin

Use indicated in:

Life-threatening infections

Endocarditis

PMN < 500/microliter

Bacteriostatic drugs inhibit bacterial growth

Immune response is necessary to kill the bacteria

slide3
MECHANISMS AND SITES OF ANTIBIOTIC ACTIVITY

Ampicillin

Penicillin

Gentamicin

Streptomycin

slide4
ANTIBACTERIAL CHEMOTHERAPY

Antibiotic susceptibility testing

slide5
ANTIBACTERIAL CHEMOTHERAPY

MIC (Minimum Inhibitory Concentration)

MBC (Minimum Bactericidal Concentration)

slide7
INHIBITORS OF CELL WALL SYNTHESIS

The peptides in adjacent

glycan chains are cross-

linked to each other by

membrane bound

transpeptidases.

Transpeptidases are also

penicillin-binding proteins.

Penicillins bind to a variety of penicillin-binding proteins.

slide9
The beta-lactam family

Common ring structure must be intact

Bactericidal to growing cells

Murein hydrolases (autolytic enzymes) are activated

Inactivated by beta-lactamases

slide12
INHIBITORS OF CELL WALL SYNTHESIS

Clavulanic acid inhibits beta-lactamase

slide14
Made by the Actinomycete Streptomyces

Effective against

G+ cocci

G- cocci (Neisseria)

G- rods ( Pseudomonas, Haemophilus)

Effective against Enterobacteriaceae & Pseudomonas

slide15
INHIBITORS OF CELL WALL SYNTHESIS

Vancomycin

Binds to the D-alanyl-D-alanine portion of the peptidoglycan pentapeptide, and blocks transpeptidase from binding

slide18
Prototype structure of aminoglycosides

Resistant bacteria can phosphorylate, adenylate or acetylate the antibiotic

Used against Gram-negative infections

(P. aeruginosa)

Nephrotoxicity, ototoxicity

Poorly absorbed orally

Ineffective vs anaerobes

slide20
INHIBITORS OF PROTEIN SYNTHESIS

Tetracyclines

Broad spectrum

Block aminoacyl-tRNA from entering acceptor site on the 30S ribosome

Their selectivity for bacteria is based on greatly increased uptake in susceptible bacterial cells

slide21
INHIBITORS OF PROTEIN SYNTHESIS

Tetracyclines

Resistance is common

Used against Mycoplasmas

Chlamydiae

Rickettsiae

Periodontal bacteria

Side effects:

Suppression of normal flora of GI tract

Deposition in teeth due to calcium chelation

slide23
INHIBITORS OF PROTEIN SYNTHESIS

Macrolides

Large ring structure

Bind to the 50S subunit

Blocks the release of the uncharged tRNA after the peptide bond has formed

Bacteriostatic

2 sugars

slide24
INHIBITORS OF PROTEIN SYNTHESIS

Macrolides

Bacteriostatic

Used against pneumonia caused by Legionella and Mycoplasma

And against G+ cocci in penicillin-allergic patients

slide26
INHIBITORS OF PROTEIN SYNTHESIS

Clindamycin is used against

anaerobic G+ bacteria (Clostridium perfringens)

anaerobic G- bacteria (Bacteroides fragilis)

Oral or iv

Oral administration can cause pseudomembranous colitis due to overgrowth of a drug-resistant strain of Clostridium difficile

slide27
INHIBITORS OF PROTEIN SYNTHESIS

Novel antibiotics

Linezolid (Zyvox)

Used in treatment of vancomycin-resistant Enterococcus faecalis (skin and blood infections, and pneumonia)

Administered orally

Synercid

Vs. vancomycin-resistant Enterococcus faecium

Administered iv

slide30
ANTIBACTERIAL CHEMOTHERAPY

Trimethoprim

Resembles folic acid

Inhibits dihydrofolate

reductase

slide31
Prevalence of penicillin-nonsusceptible

S. pneumoniae vs total antibiotic use in the outpatient setting

Albrich et al. 2004

Emerging Infectious Diseases 10, 514

slide32
Important bacteria that exhibit significant drug resistance

Type of bacteria Resistance to

Gram-positive cocci

Staphylococcus aureus Penicillin G, nafcillin

Streptococcus pneumoniae Penicillin G

Enterococcus faecalis Penicillin G, aminoglycosides, vancomycin

Gram-negative cocci

Neisseria gonorrhoeae Penicillin G

slide33
Important bacteria that exhibit significant drug resistance

Type of bacteria Resistance to

Gram-negative rods

Haemophilus influenzae Ampicillin

Pseudomonas aeruginosa ß-lactams, aminoglycosides

Enterobacteriaceae ß-lactams, aminoglycosides

E. coli

Klebsiella pneumoniae

Mycobacteria

M. tuberculosis isoniazid, rifampin

M. avium complex isoniazid, rifampin and others

slide34
A new antibiotic

Which molecular class does it belong to?

How does it work?

slide35
Tygacil

(Tigecycline)

A glycylcycline antibiotic

Administered IV

Use during tooth development may cause discoloration

Binds to the ribosome with 5 times higher affinity than tetracycline

Against Gram-positive pathogens including MRSA, MRSE and VRE

slide36
Indicated for the treatment of complicated

intra-abdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI) in adults

MRSA Methicillin-resistant Staphylococcus aureus

MRSE Methicillin-resistant Staphylococcus epidermidis

VRE vancomycin-resistant enterococci (Enterococcus faecalis & Enterococcus faecium)

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