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List of Bacteriocidal Antimicrobials
I. Penicillins
A. The narrow-sperum penicillins
1. Na+ and K+ penicillin G (benzylpenicillin)
2. Penicillin V (phenoxymethy1 penicillin)
3. Procaine penicillin G
4. Benzathine penicillin G
B. Penicillinase-resistant penicillins
1. Methicillin
2. Isoxazole compounds: oxacillin, cloxacillin, and dicloxacillin
3. Nafcillin Na
C. Broad spectrum penicillins
1. Ampicillin
2. Amoxicillin
3. Carbenicillin disodium
4. Carbenicillin indanyl
5. Hetacillin
6. Ticarcillin
D. Adjunct therapy
1. Clavulanate K+
II. Cephalosporins and Cephamycins
A. First generation
1. Cephalothin - painful IM
2. Cephaloridine - not used due to nephrotoxicity
3. Cephapirin - intramammary infusion
4. Cephalexin - per os
5. Cefadroxil - per os
6. Cefaclor - per os
B. Second generation
1. Cefoxitin - IV & IM, a cephamycin
C. Third generation
1. Moxalactam - IV
III. Aminoglycosides IV. Other antibiotics A. Streptomycin and dihydrostreptomycin A. Bacitracin
B. Gentamicin B. Polymyxin B
C. Kanamycin C. Colistin (Polymyxin E) D. Neomycin
E. Others Tobramycin V. Nitrofurans
Amikacin A. Nitrofurazone
B. Nitrofuradantoin
C. Furazolidine
D. Furaltadone
THE PENICILLINS
A. History and introduction
1. Discovery: Alexander Fleming, 1928
2. Synthesis and development: Florey, Chain, and Jennings,
3. Source
a. Penicillium notatum
b. Penicllium chrysogenum
B. Chemistry
1. Chemical properties
a. Weak acids; pKA,s around 2.7
b. Stable at pH of 6.0 to 6.5; practical range of pH 5.5 to 7.5
2. Structure
a. The structure of penicillin ccnsists of
1) Thiazolidine ring
2) Beta-lactam ring
3) Side chain 'R'
b. Common nucleus i.e. 6-aminopenicillanic acid(6 APA)
c. Sites of action
1) Beta lactamases such as penicillinase
i) Produced by many resistant organisms
ii) Cleave beta lactam ring
iii) Cleavage yields inactive penicillinoic acid
2) Amidase
i) Found in some resisistant organisms
ii) Splits side chain linkage
iii) Cleavage yields 6 amino-penicillanic acid
(6 APA)
iv) 6APA, an important discovery
v) Semisynthetic penicillins produced from 6 APA
3) Salt formation and attachment of different side chains
i) Sodium (Na+) and potassium (K+) salts
ii) Procaine salt of penicillin G
iii) Benzathine penicillin G
d. Other chemical properties
1) Gastric HCl hydrolyses most penicillins
2) Stable at pH = 6.0-7.0
3) Alkalinity of jejunum
3. Penicillin units
a. One international unit = 0.6 micrograms of penicillin G
b. 1 mg of sodium penicillin G = 1667 units
c. 1 mg potassium penicillin = 1595 units
C. Classification
1. Basis of classification
a. Sensitivity to penicillinase enzyme
b. Stability in acid environment
c. Spectrum of activity
2. Narrow spectrum (i.e. effective against non-penicillinase producing cocci, gram- positive bacilli, and spirochetes)
a. Natural penicillin
1) Penicillin G (benzyl penicillin)
a) Sodium penicillin G
b) Potassium penicillin G
c) Procaine penicillin G
d) Benzathine penicillin G
b. Acid-resistant
1) Penicillin V (phenoxymethyl penicillin)
3. Penicillinase-resistant penicillins (narrow-spectrum; effective against penicillinase-producing staphylococcus)
a. Acid-labile
1) Methicillin
b. Acid-resistant
1) Oxacillin
2) Cloxacillin
3) Dicloxacillin
4) Flucloxaci11in
5) Nafcillin (variable acid-resistance)
4. Broad-spectrum penicillins (effective against certain gram positive and gram- negative bacteria)
a. Aminopenticillins
1) Ampicillin (acid-resistant)
2) Amoxicillin (acid-resistant)
b. Active against pseudomonas
1) Carbenicillin (acid-sensitive)
2) Piperacillin (acid-sensitive)
3) Ticarcillin (acid-sensitive)
D. Mechanism of action - inhibit synthesis of bacterial cell wall
1. Bacterial cell wall
a. Provides rigidity and resists high intracellular pressure
b. Linear peptidoglycans composed of alternating blocks of N-acetyl- glucosamine (NAGA) and N-acetylmuramic acid(NAM)
c. Pentapeptide ending in D-alanyl-D-alanine attached to NAM
d. Peptidoglycans cross-linked by pentaglycine bridge
2. Three stages of synthesis of bacterial cell wall
a. Stage 1 - Precursor formation
1) Formation of the precursor uridine diphosphate-N-acetyl muramyl -pentapeptide (UDP-NAM) i.e. "Park nucleotide"
b. Stage 2 - Formation of long polymer
i) UDP-NAM bound to phospholipid in cell membrane and UDP released
ii) UDP-NAGA and five glycine residue added to NAM and UDP released
iii) Peptidoglycan cleaved from membrane-bound phospholipid
c. Stage 3 - Transpeptidation reaction completes final cross-link
i) Terminal glycine residue of the pentaglycine bridge linked to 4th residue of pentapeptide (D-alanine)
ii) 5th residue (also D-alanine) released
iii) Reaction catalyzed by membrane-bound transpeptidase
3. Action of penicillins
a. Beta-lactam competitively bind to penicillin-binding proteins (PBP) in bacterial cell membrane
b. PBP,s probably transpeptidases and carboxypeptidases
c Transpeptidation reaction inhibited thus preventing cross- linking
d. Morphological changes possibly resulting in lysis and death i.e. bacteriocida1
e Most effective against rapidly growing organisms
E. Mechanisms of bacterial resistance
1. Penicillinases (a beta-lactamase)
2. Organisms capable of producing penicillinase include
a. Staphylococcus aureus
b. Bacillus species
c. Bacteroides
d. E. coli
e. Proteus species
f. Pseudomonas aeruginosa
g. Mycobactarium tuberculosis
3. Acquisition of ability to produce penicillinase
F. Spectrum of activity of penicillin G and other narrow spectrum penicillins
1. Effective against many, but not all, non-penicillinase producing cocci, gram-positive bacilli, and spirochetes
2. Many gram-negative bacilli strains are sensitive to high concentrations of penicillin G
3. Sensitive organisms
a. Streotococcuss b. Staphylococcus (most strains produce penicillinase)
c. Bacillus anthracis d. Clostridia
e. Erysipelothrix f. Klebsiella
g. Proteus h. Fusobacteria
i. Actinomyces j. Leptospira
k. Pasteurella multocida 1. Corynebacterium
G. Pharmacokinetics
1. Oral administration
a. Gastric acidity
b. Amount of penicillin G reaching system of monogastrics
c. Absorption mainly from duodenum
d. Alkalinity of jejunum
e. Effects on microflora in G.I.T. of herbivores
2. Parenteral administration
a. Routes of parenteral administration
i) Na+ or K+ penicillin G - IV, IM, & SC
ii) Oil preparations - IM
iii) Benzathine penicillin - IM
iv) Procaine penicillin G - IM or SC, Don't go IV
b. Absorption: Association between absorption and duration
i) Soluble Na+ and K+ salts
ii) Procaine penicillin
iii) Vegetable oil as vehicle
a) Unfavorable tissue reactions in horses
iv) Benzathine penicillin G
3. Topical administration
a. Not recommended
b. Induction of bacterial resistance.
c. Allergic reactions
4. Intrammary Infusion
a. Can combine with systemic administration
b. Mastitis
c. Milk from treated and untreated quarters
i) Discard for 96 hours
ii) Can sensitize susceptible individuals
iii) Can encourage development of bacterial resistance
iv) Legally considered an adulterant in milk and milk products
5. Distribution
a. Rapid but unven distribution
b. Low volume of distribution
c. Reversibly bound to plasma albumin(50% to 60%)
d. Passes through placenta
6. Metabolism and excretion
a. Small portion of penicillin G metabolized
b. Majority of penicillin G excreted unchanged in urine
c. 60%-90% of IM dose of penicillin G excreted within lst hour
d. Small but detectable concentrations of penicillin can be excreted in the milk
7. Duration of action
a. Half-life is short. e.g. t1/2 of penicillin G in horse is 53 mins.
b. Probenecid prolongs duration by competing with the penicillins
c. Best way to prolong duration is to slow absorption
H. Toxicity
1. Direct toxic effects at therapeutic doses is rare
a. LD50 of pure penicillin G administered IV
b. Concentrations of 300 units penicillin/ml in spinal fluid causes convulsions
c. Acute toxicity of procaine penicillin
2. Hypersensitivity reactions to penicillin represent most serious untoward effects
a. Rate of occurrence
b. Range of reactions
c. Occurrence of anaphylactic shock
I. The narrow-spectrum penicillins
1. Spectrum of activity same as for penicillin G
2. Aqueous solutions
a. For achieving rapid blood levels
3. Repository forms
a. Insoluble salts that slow absorption
4. Sodium and potassium salts of penici1lin G (benzyl penicillin)
a. Very soluble in water
b. Give IV, SC, IM, or as intramammary infusion
c. Administer every 4-6 hours
5. Penicillin V (phenoxymethyl penicillin)
a. Soluble form resistant to acid
6. Procaine penicillin G
a. Sparsely soluble in water
b. Procaine moiety deadens pain after IM injection
c. Administer IV every 12-24 hours
d. Procaine toxicity following IV administration
i) High ooncentration of procaine in blood may cause procaine toxicity
ii) Horses especially susceptible, also swine
iii) Procaine toxicity characterized by CNS signs
7. Benzathine penicillin G
a. Very low solubility
b. Effective blood levels persist 7-10 days
8. Benzathine penicillin G + procaine penicillin G
J. Penicillinase-resistant penicillins
1. Semisynthetic penicillins
2. Narrow spectrum of activity
a. Effective against same bacteria as penicillin G
b. Penicillin G is preferred for susceptible infections
c. Also effective against penicillinase producing strains of staphylococcus.
3. Penicillinase-resistant penicillins used for penicillinase (beta lactamase) producing bacteria
4. Methicillin
a. 1/20th potency of penicillin G
b. Produces therapeutic concentrations in CNS
c. Used to treat penicillinase-resistant staphylococcus
d. Strains of staphylococcus can become resistant to methicillin
5. Isoxazole compounds: oxacillin, cloxacillin, and dicloxacillin
a. Semisynthetic penicillins
b. Differ structurally in number of chloride atoms on phenyl ring
c. Acid stable
d. Used for penicillinase producing strains of staphylococcus
e. Benzathine cloxacillin for mastitis treatment
6. Nafcillin Na
a. Semisynthetic penicillin
b. Penicillinase resistant and variably acid stable
c. Used for penicillinase producing staphylococcus
d. Used for infections of the respiratory system, soft tissue, suppurative osteomyelitis
e. Excreated in bile
f. Increases susceptibility of staphylococcus to phagocytosis by macrophages
K. Broad spectrum penicillins
1. Ampicillin
a. First semisynthetic penicillin to show significant activity against gram-negative organisms
b. Good against some gram-positive organisms as penicillin G
c. Also good against E. coli. Salmonella Proteus, and Klebsiella
d. Acid stable; can give orally, IM, IV, or SC
e. Not penicillinase resistant
2. Amoxicillin
a. Semisynthetic
b. Same spectrum as ampicillin
c. More acid stable than ampicillin
d. Administer orally
e. Injectable trihydrate salt for IM or SC
f. Produces higher blood levels than ampicillin
g. Penicillinase sensitive
h. Amoxicillin trihydrate plus clavulinate potassium
3. Carbenicillin disodium
a. Not acid-stable
b. Not resistant to penicillinase
c. Same spectrum as ampicillin plus effective against indole-positive Proteus and Pseudomonas
d. Synergistic with gentamicin
4. carbenicillin indany1
a. Acid stable
5. Hetacillin
a. Convert to ampicillin and acetone in the body
6. Ticarcillin
a. Lebeled for intrauterine administration in mares