ANTIBIOTICS

Types of antibiotic therapy Targeted – based on sensitivity tests • Empiric – based on the symptoms and habits – knowledge of local epidemiological data • Profilactic – e.g. intestinal operation, dentical surgery

Possible side effects • Allergy – penicillins! – type I hypersensitivity reaction (anaphylaxy) • Toxic effect – kidney, liver (alcoholism!), bone marrow – impaired hearing – bones, teeth (tetracyclin: complex with Ca2+) – fluoroquinolones: Achilles-tendon rupture • Disbacteriosis = killing of the normal flora – e.g. pseudomembranous colitis by C. difficile

MODE OF ACTIONS OF ANTIBIOTICS 

Possible targets • Inhibition of cell-wall synthesis – inhibition of peptidoglycan cross-linking (beta-lactams) – inhibition of peptidoglycan synthesis (vancomycin) • Disruption of cell membrane – polymyxins • Inhibition of protein synthesis – at 30S ribosomal subunit (aminoglycosides, tetracyclines) – at 50S ribosomal subunit (macrolides, chloramphenicol) • Inhibition of nucleic acid – inhibition of folic acid synthesis (sulphonamides, trimethoprim) – inhibition of DNA gyrase (fluoroquinolones) – inhibition of RNA synthesis (rifampin

 BETA lactams

• Inhibit transpeptidation ofpeptidoglycan chains

• Important questions:can be given orally? (acid stability) β–lactamase (enzyme-) stability?

good against Gram negatives?(Pseudomonas, Acinetobacter!)Structure of β–lactam ring: very vulnerable!

Penicillins Cephalosporins Carbapenems  Carbacephems Monobactams Glycopeptides Polypeptides

CLASSIFICATION ACCORDING TO SPECTRUM OF ACTIVITY.

Depending on the range of bacterial species susceptible to these agents, antibacterials are classified as broad-spectrum,

intermediate-spectrum, or narrow- spectrum. Note that the spectra of activity may change with acquisition of resistance genes,

as will be discussed in the next module.

1. Broad spectrum antibacterials are active against both Gram-positive and Gram-negative organisms. Examples include:

tetracyclines, phenicols, fluoroquinolones, “third-generation” and “fourth-generation” cephalosporins.

2. Narrow spectrum antibacterials have limited activity and are primarily only useful against particular species of

microorganisms. For example, glycopeptides and bacitracin are only effective against Gram-positive bacteria, whereas

polymixins are usually only effective against Gram negative bacteria. Aminoglycosides and sulfonamides are only

effective against aerobic organisms, while nitroimidazoles are generally only effective for anaerobes. 

Antibacterial Drugs

 Pathogen Infectious Disease Staphylococcus aureus skin and wound infection, abscess, bacteremia, nosocomial pneumonia, endocarditis, toxic shock syndrome Streptococcus pneumoniae upper respiratory infection, pneumonia, otitis, sinusitis, meningitis Streptococcus pyogenes pharyngitis, tonsillitis, skin and soft-tissue infection, scarlet fever Enterococcus faecalis bacteremia, endocarditis, urinary-tract infection, peri- tonitis Enterococcus faecium bacteremia, endocarditis, peritonitis Escherichia coli bacteremia, urinary-tract and gastrointestinal infection Klebsiella pneumoniae hospital-acquired pneumonia, bacteremia Proteus spp. urinary-tract infection Haemophilus influenzae respiratory infection, otitis, sinusitis, meningitis Moraxella catarrhalis respiratory infection Pseudomonas aeruginosa nosocomial pneumonia, burn infection, bacteremia Acinetobacter spp. pneumonia in immuno-compromised patients Mycobacterium tuberculosis

gram-positive •Bacillus - degrades complex macromolecules- dust, water, plants, animals fur •Bacillus anthracis: Common in cattle, Bioterrorism •Bacillus cereus:food, rice, potatoes, meat • Clostridium perfringens: progressive, toxins diffuse to healthy tissue, Surgical, compound fractures, sores, septic abortions,gunshot wounds, crushing injuries with dirt gram-negative cocci •sexually transmitted disease (Neisseria gonorrhoeae) • meningitis (Neisseria meningitidis) •respiratory symptoms (Moraxella catarrhalis). gram-negative bacilli •respiratory problems (Hemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa) • urinary problems (Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens) • gastrointestinal problems (Helicobacter pylori, Salmonella enteritidis, Salmonella typh

The mode of action of antibacterial compounds •Inhibition of metabolism (antimetabolites): Sulfonamides •Inhibition of bacterial cell wall synthesis: Penicillins, Cephalosporins, Vancomycin •Interaction with the plasma membrane: Polymyxin, Tyrothricin •Disruption of protein synthesis: Rifamycins, aminoglycosides, tetracyclines, chloramphenicol

 Other Antimetabolites

• Trimethroprim: Inhibits dihydrofolate reductase

Applications

• treatment of urinary tract infections

• eye lotions

• treatment of infections of mucous membranes

• treatment of gut infections

Resistance to Penicillins

• Gram -ve bacteria have a lipopolysaccharide (LPS) outer

membrane preventing access to the cell wall

• Penicillins can only cross via porins in the outer membrane

• Porins only allow small hydrophilic molecules that can exist as

zwitterions to cross

• High levels of transpeptidase enzyme may be present

• The transpeptidase enzyme may have a low affinity for

penicillins (e.g. PBP 2a for S. aureus)

• Presence of β-lactamases

• Concentration of β-lactamases in periplasmic space

• Mutations

• Transfer of β-lactamases between strains

• Efflux mechanisms pumping penicillin out of periplasmic space