PMOC: Antibacterial Agents

The Bacterial Structure

• Cell Membrane

• Cell Membrane

• Protein (30s and 50s ribosomal subunits)

• Nucleic Acid and Folates

Antibiosis

Against life (Vuillemin)

Antibiotic

A substance produced by microorganisms, which has the capacity of inhibiting the growth and even of destroying other microorganism

Characteristics of Antibiotics

• It is a product of metabolism

• It is a synthetic product produced as a structural analog of a naturally occurring antibiotic

• It antagonized the growth or survival of one or more species of microorganisms

• It is effective in low concentrations

Antibiotics

• B-lactams (Penicillins, Cephalosorins, Carbapenems, Monobactams)

• Aminoglycosides

• Tetracyclines

• Macrolides

• Lincomycins

• Polypeptides

• Unclassified Antibiotics

Synthetic

• Quinolones

• Nitrofurans

• Methenamine

• Sulfonamides

• Trinethoprim

• Sulfones

Bactericidal Agents | Cell Wall

Beta-Lactams & Polypeptides

Bactericidal Agents | Cell Membrane

Polymyxins

Bactericidal Agents | DNA Synthesis

Quinolone

Bactericidal Agents | RNA Synthesis

Rifamycin

Bacteriostatic Agents | 30s

Aminoglycosides & Tetracyclines

Bacteriostatic Agents | 50s

Macrolides, Lincomycins, Chloramphenocal

Bacteriostatic Agents | Folate Synthesis

Sulfonamides and Trimethoprim

Beta-Lactam Antibiotics

• B-Lactam Ring (Four-Membered Cyclic Amide)

• Dominant class antibacterial agents

• Broad-spectrum, bactericidal agents

• MOA: Inhibition of cell walla synthesis

  • D-transpeptidase: Cross-linking of peptidoglycan

  • D-alaninr carboxylpeptidase: Hydrolysis of D-alanine-D-alanine terminal peptide bonds

Beta-Lactam Antibiotics: Penicillins

• Discovered by Alexander Fleming

• Source: Penicillium notatum/ Penicillium chrysogenum

• Introduced by Florey and Chain into therapy (1938)

• Process: Freeze-drying

Beta-Lactam Antibiotics | Penicillins

Chemical Instabilities

• B-lactam amide bond: Hydrolyzed into carboxylic acid and amine

• Most penicillins are acids

  • Sodium and Potassium Salts: Increased absorption

  • Benzathine, Procaine, Hydrabamine: Depot forms of Penicillin

Beta-Lactam Antibiotics | Penicillins

Bacterial Resistance

• Penicillinases: Beta-lactamases and Acylases

• Decreased Permeability

Beta-Lactam Antibiotics | Penicillins

Immine Responses

Penicilloic acid (Hapten) + Proteins = Penicilloyl proteins → Antigenic (Allergic Reactions)

Beta-Lactam Antibiotics | Natural Penicillins

Penicillin G

• Chemical Name: Benzylpenicillin

• Narrow-spectrum

• Poor acid-resistance and oral absoprtion

• ROA: Parenteral

• Rapidly eliminated from the bloodstream via active tubular secretion

• DOC: Syphilis

Beta-Lactam Antibiotics | Natural Penicillins

Penicillin V

• Chemical Name: Phenoxymethylpenicillin

• The first orallt active penicillin

Beta-Lactam Antibiotics | Antistaphylococcal Penicillins

• Resistant to inactivation by the penicillinase found in staphylococci

• Structure: Increased steric hindrance in a-carbon of the acyl group

  • Steric Hindrance: works as a shield

Beta-Lactam Antibiotics | Antistaphylococcal Penicillins

Methicillin

• Chemical Name: 2,6-dimethoxyphenulpenicillin

• ROA: Parenteral

• A/E: Interstitial Nephritis

Beta-Lactam Antibiotics | Antistaphylococcal Penicillins

Nafcillin

• Chemical Name: 6-(2-ehoxyl-l-napthyl) penicillin

• ROA: Parenteral

Beta-Lactam Antibiotics | Antistaphylococcal Penicillins

Isoxazolul Penicillins

• Oxacillin

• Cloxacillin

• Dicloxacillin

Beta-Lactam Antibiotics | Aminopenicillins

• Active against gram-negative bacteria and enterococci

• a-amino: Confers an ability to cross cell membrane barriers

Beta-Lactam Antibiotics | Aminopenicillins

Ampicillin

• Chemical Name: D-a-aminobenzylpenicillin

• Prodrug: Bacampicillin

• Not resistant to penicillinase

• ROA: Parenteral or Oral

Beta-Lactam Antibiotics | Aminopenicillins

Amoxicillin

• Chemical Name: D-a-amino-p-hydroxybenzylpenicillin a

Beta-Lactam Antibiotics | Carboxypenicillins

Carboxyl: Improves penetration of the molecule throught cell wall barriers of gram-negative bacilli

Beta-Lactam Antibiotics | Carboxypenicillins Examples

• Carbenicillin

• Ticarcillin

Beta-Lactam Antibiotics | Ureidopenicillins

More active against some gram-negative and anaerobic bacteria

Beta-Lactam Antibiotics | Ureidopenicillins Examples

• Mezlocillin

• Piperacillin

• Azlocillin

Beta-Lactam Antibiotics | Carbapenems

Thienamycin

• Source: Streptomyces cattleya

• Susceptible to renal dehydropeptidase I (DHP-I) Enzyme

  • Renal dehydropeptidase I: Present in kidney; Metabolize the drug

Beta-Lactam Antibiotics | Carbapenems

Imipenem

• Semisynthetic Thienamycin

• Claved by dihydropeptidase which products nephrotoxic metabolites

• Combined with Cilastatin (Primaxin)

• A/E: CNS Effects

Beta-Lactam Antibiotics | Carbapenems

Meropenem

• Second-generation carbapenem (greater potency)

• Has greater potency against gram-negative and anaerobic bacteria

• Slightly less active than most gram-positibe spp.

• Resistant to DHP-I and B-lactamades

Beta-Lactam Antibiotics | Cephalosporins

• Source: Cephalosporium spp.

• Dihydrothiazine ring

• Nucleus: 7-aminocephalosphoranic acid (7-ACA)

• Cephamycins (Cefoxitin, Cefotetan, Cefmetazole)

  • Structurally cephalosphorins but from streptomyces spp.

Beta-Lactam Antibiotics | Cephalosporins

Spectrum of Activity

• Broad-spectrum

• ↑ Generation = ↑ Gram-negativr activity (but lower gram-positibr activity)

• More resistant to B-lactamases

• Permeability of bacterial cells

  • Intrinsic activity against bacterial enzymes involved in cell wall synthesis and cross-linking

Beta-Lactam Antibiotics | Cephalosporins Adverse Effects

• Allergic and hypersentivity reactions

• Hypoprothrombinemia (Bleeding)

• Dosulfiram-like reactions (Hang-over)

Beta-Lactam Antibiotics | Oral Cephalosphorins

Beta-Lactamd Antibiotics | Monobactams

• Aztreonam and Tigemonam

• 4-methyl group → ↑ Stability to B-lactamase and ↑ Activity against gram-negative bacteria

Polypeptides

• Source: Bacillus spp.

• A/E: Renal toxicity

Polypeptides Spectrum of Activity

• Bacitracin and Vancomycin:

  • Gram-positive bacteria (cell wall)

• Gramicidin:

  • Bacteria (cell membrane)

• Polymyxins:

  • Gram-negative bacteria (cell membrane)

Polypeptides | Vancomycin

• Source: Streptomyces orientalis

• A glycopeptide (Glucose ans Vancosamine)

• Active against gram-positive cocci

• DOC: Pseudomemvrabous colitis and MRSA

• ROA: Oral or IV

• A/E: Red man syndrome, Impaired auditory acuity, Renal damage, Phlebitis, and Radhes

Beta-Lactam Antibiotics | Parenteral Cephalosphorins

Polypeptides | Teicoplanin

• Source: Actinoplanes teichomyceticus

• Active against gram-positive bacteria

• ROA: IM or IV

Polypeptides | Bacitracin

• Source: Bacillus subtilis

• Zn+2 is required for activity

• ROA: Topical

Polypeptides | Polymyxin B

• Source: Bacillus polymyxa

• Has less kidney damage than other polymyxins

• Active against gram-negative organisms

• ROA: Topical or Parenteral

Polypeptides | Colistin

• a.k.a Polymyxin E

• Source: Aerobacillus colistinus

• Use: Refractory urinary tract infections

• ROA: IV

Polypeptides | Gramicidin

• Source: Bacillus brevis

• Primarily effective against gram-positive bacteria

• Restricted to local applications only

• ROA: Topical

Quinolones MOA

MOA: Inhibits the DNA gyrase (topoisomerase II)

Quinolones Synthetic Antibacterial Agents

• Quinolones: -floxacin

• Napthyridines: Nalidixic acid, Enoxacin

• Cinnolines: Cinoxacin

Quinolones Spectrum of Activity

Gram-negative urinary pathogens

Quinolones

• CNS Effects

• Phototoxicity

• Arthropathy: Tendon rapture (C/I → px below 18y/o)

• Chelation → Magnesium, Aluminum, Iron, Ca

Quinolones | Nalidixic Acid

• Prototype quinolone

• Use: UTI (Proteus spp.)

Quinolones | Norfloxacin

• Fluorine atom: ↑ Gram-positive potency

• Piperazine moiety: Improved antipseudomonal activity

• Not effective against obligate anaerobic bacteria

• Use: Uncomplicated gonorrhea

Quinolones | Ciprofloxacin

• Probenecid: Inhibits active tubular secretion

• Widely distributed

• Use: Gastroenteritis, Respiratory Infections, Venereal disease, Postexposure inhalational anthrax

• D/I: Crystalluria

Quinolones | Ciprofloxacin

• Probenecid: Inhibits active tubular secretion

• Widely distributed

• Use: Gastroenteritis, Respiratory Infections, Venereal disease, Postexposure inhalational anthrax

• D/I: Crystalluria

Quinolones | Sparfloxacin

• Once-daily dosing

• Has a higher potency against geam-positive bacteria

• 5-amino group: Least phototoxic

Quinolones | Levofloxacin

L-isomer of Ofloxacin

Aminoglycosides

• MOA: Inhibits the 30s ribosomal subunit (-cidal)

• Effective for anaerobic bacteria

• Synergistic with B-lactam antibiotics (in vivo)

• ROA: IM

• Mycin: from Streptomyces spp.

• Micin: macromonospara spp.

Aminoglycosides Spectrum of Activity

• Aerobic gram-negative bacilli

• Aerobic gram-negative cocci

• Aerobic gram-positive cocci

• Resistant: Anaerobic bacteria

• Adverse Effects:

  • Ototoxicity

  • Nephrotoxicity

Aminoglycosides | Streptomycin

• Source: Streptomyces griseus

• The most effective glycosides for TBZ

• Use: Tularemia/ Rabbit Fever

Aminoglycosides | Neomycin

• Source: Streptomyces fradiae

• The most nephrotoxic aminoglycosides

Aminoglycosides | Paromomycin

• Source: Streptomyces rimosus

• Use: Intestinal amoebiasis

Aminoglycosides | Kanamycin

• Source: Streptomyces kanamyceticus

• Use: Intestinal tract infections

Aminoglycosides | Amikacin

Semisynthetic aminoglycoside (from Kanamycin)

Aminoglycosides | Gentamicin

• Source: Micromonospora purpurea

• Active against Pseudomonas aeruginosa and Gram-negative enteric bacilli.

• Use: Skin infections and Nosocomial infections (Hospital acquired infections)

Aminoglycosides | Tombramycin

• Source: Streptomyces tenebrarius

• Use: Inhaled aminogkycosides for the treatment of Pseudomona infections in patients with cystic fibrosis

Aminoglycosides | Netilmicin

Semisynthetic aminoglycoside

Aminoglycosides | Sisomicin

Source: Micromonospora inyoensis

Aminoglycosides | Spectinomycin

• Source: Stretpmycrs spectabilis

• Use: Veterinary medicine

• Bacteriostatic agent

Tetracyclines

• Broadest Spectrum

  • Gram-negative

  • Gram-positive

  • Atypical Bacteria

• MOA: Inhibits the 30s Ribosomal Subunit

• Chemically octahydronaphthacenr → 4 annated 6-membered ring

Tetracycline Adversr Effects

• Photosensitivity

• Chelation

• Fanconi Syndrome

  • Affect the Kidney Organ

• May induce superinfections caused by the pathogenic yeast

• C/I: Pediatrics

Short-Acting Tetracyclines

Chlortetracycline and Oxytetracycline

Intermediate-Acting Tetracyclines

Demeclocycline and Methacycline

Long-Acting Tetracyclines

Doxycycline and Minocycline

Very Long-Acting Tetracycline

Tigecycline

Tetracyclines | Tetracyclines

For Acne vulgaris

Tetracycline | Chlortetracycline

• Source: Streptomyces aureofaciens

• Brand Name: Aureomycin

• Use: Vererinary medicine

• The first tetracycline discovered

  
  

Tetracycline | Oxytetracycline

Source: Streptomyces rimosus

Tetracycline | Demeclocycline

Source: Streptomyces aureofaciens

Tetracyclines | Melocycline

Semisynthetic oxytetracycline

Tetracyclines | Doxycycline

• PK: Long half-life, Well-absorbed, and Does not accumulate in patients with impaired renal function.

• Use: Leptospirosis (DOC) and Prophylaxis for Malaria

Tetracyclines | Minocycline

• The most potent tetracycline

• Use: Chronic bronchitis and other URTIs

Tetracyclines | Tigecycline

• A glycycycline

• Use: Skin and intra-abdominal infections

• ROA: IV

• A/E: Photosensitivity, Pancreatitis, and Pseudotumor Cerebri

Macrolides

• Source: Actinomycetes

• First: Picromycin

• MOA: Inhibits the 50s Ribosomal Subunit

Macrolides Structure

• Macrocyclic Lactone Ring (12, 14, or 16 atoms)

• Ketone (R-COOH)

• Glycosidically linked amino sugars

Macrolides Spectrum of Activity

• Resembles penicillin

• Mycoplasma

• Chlamydia

• Campylobacter

• Legionella

Macrolides Adverse Effects

• GI Effects

• Liver Effects

• QT Prolongation

Macrolides | Erythromycin

• Alternative for patients allergic to penicillin

• Source: Streptomyces erythraeus (From IloIlo)

• Use: Mycoplasma pneumoniae, Chlamydia, Campylobacter jejuni, Legionnaires disease

• Formulated as enteric-coated and

  delayed-release

• Estolate Salt: Choleststic Hepatitis

• D/I: Enzyme Inhibitir

• DOC: Diptheria pertussis & Legionnaires Disease

Macrolides | Clarithromycin

• Methylated Erythromycin

• Use: Helicobacter pylori, Pneumonia, and Cellulitis

Macrolides | Azithromycin

• Semisynthetic erythromycin

• An azalide (contains nitrogen)

• Long-half life → 3-5 days treatment

• More active against gram-negative bacteria

Macrolides | Dirithromycin

• Alternative to Erythromycin

• Once-daily dosing

Macrolides | Troleandomycin

Most potent enzyme inhibitor

Lincomycins

• MOA: Inhibits the 50s ribosomal subunit

• Source: Streptomyces lincolnensis

• Sulfur-containing

Lincomycins Spectrum Activity

Resembles the macrolides

Lincomycins Adverse Effect

• Pseudomembranous Colitis → TX: Vancomycin

• Rashes

Lincomycins | Lincomycins

• Most active and medially useful

• Active against gram-positive microorganisms

Lincomycins | Clindamycin

• Semisynthetic Lincomycin

• Chemical Name: 7-chloro-7-deoxylincomycin

• Use: Cellulitis, Osteomyelitis, and CNS Infections

Sulfonamides

• Discovered by Gerhard Domagk

• MOA: Inhibits Dihydropteroate Synthase or Compete with PABA

• Prontosil → Sulfanilamide

Sulfonamides Spectrum of Activity

• Gramp-positive and Gram-negative bacteria

• Nocardia

• Chlamydia trachomatis

• Some protozoa