1.2. ÉL NACIONALISMO Y EL GOMUNITARISMO
1.2.1. Maclntyre ante el nacionalismo norteamericano
Beta-lactam Antibiotics
These are a group of antibiotics which share a common structure, the beta-lactum ring. These groups include the penicillins, cephalosporins and cephamycins, monobactams and carbapenems
Penicillins
1. Penicillins are the most popular in this group of antibiotics.
2. These impair bacterial cell wall development because of their ability to inhibit transpeptidase enzymes involved in the cross linking of the peptidoglycan strands in the final stage of cell wall synthesis.
3. The net effect is bactericidal due to formation of defective cell walls and osmotic-lysis of the bacterial cell.
4. Penicillins are most active when applied during the period of rapid bacterial growth (logarithmic phase)).
5. These drugs have little effect on formed bacterial cell walls and require that organisms must be actively multiplying or growing.
6. Pharmacokinetic features:
a. Absorption is enhanced in a slightly acidic environment (pH) 5.5-6.5) b. Penicillins in aqueous solutions are generally rapidly absorbed
parenterally.
c. Following absorption/ these are distributed in fluids and tissues.
d. Penicillins do not readily traverse normal physiological barriers but high
concentrations and inflammatory coaditions of these barriers permit the passage of effective penicillin levels into the protected areas.
e. Penicillins are generally eliminated unchanged but small fractions are metabolized (usually less than 20%) and the formed metabolites (penecilloic acid derivatives) are allergenic.
f. About 60-90% of a parenterally administered penicillin is excreted in urine; of these, about 20% occurs by glomerular filtration and the rest by tubular secretion.
7. Physicochemical properties:
a. Poorly soluble, weak organic acids
b. Unstable and sensitive to heat, light, pH extremes, heavy metals, oxidizing and reducing agents
c. Easily deteriorate in aqueous solutions (therefore reconstitution with diluents is necessary just before injection
d. Usually administered parenterally as suspension in water, oil, or as water-soluble salts.
e. Only acid- stable penicillins are administered orally 8. Side-effects:
a. Organ toxicity is rare
b. Hypersensitivity reactions to occur (particularly in cattle) 1) skin reactions 5) vasculitis
2) agioedema 6) eosinophilia 3) drug fever 7) anaphylaxis 4) serum sickness
9. Interactions
a. Displaced by salicylates, phenylbutazone, sulfonamides, and other weak acids concurrently administered from plasma-protein binding.
b. Absorption or ampicillin is impaired by presence of food.
c. Some never generation should penicillins not be mixed with aminoglycosides.
d. Pen G and ampicillin are not compatible with other drugs and should not be mixed.
10. Some important penicillins:
a. Penicillin G (benzylpenicillin)
1) This is commonly employed in Vet. Med.
2) Predominantly active against gram-positive and anaerobes and a few gram-negative bacteria like Hemophilus sp.
3) Available in a variety of formulations.
4) Disadvantages:
a) Susceptible to acid hydrolysis in stomach and so is not administered orally
b) Destroyed by beta-lactamase (penicillinase) enzymes b. Ampicillin and Amoxicillin
1) Modified semi-synthetic penicillins.
2) Have less marked acitivity against gram-positive than does Pen G but has significant activity against gram-negative organism B including some enterobacteria. Activity against Proteus spp., Pseudomonas aeruginosa and Klebsiella spp. is poor.
3) Both are resistant to acid-hydrolysis and so can be given PO.
4) Both are susceptible to beta-lactamase.
5) Both are pharmacologically equivalent but amoxycillin is pharmacokinetically superior because it is absorbed more rapidly and plasma peak concentration is achieved earlier than ampicillin.
6) Amoxycillin also has a more rapid bactericidal action than ampicillin.
Cephalosporins
1. The physical and chemical properties of these drugs are similar to the penicillins.
2. These are also weak acids and are more stable to pH and temperature changes.
3. Contain beta-lactass nucleus which is susceptible to beta-lactamase (cephalosporinase).
4. The cephalospirinases that hydrolyze cephalospins may or may not attack penicillins.
5. The mechanism of action is similar to penicillins.
6. Pharmacokinetic properties:
a. Absorption - orally administered cephalosporins are acid-stable - well absorbed orally or parenterally
- peak plasma levels can be reached in about 30 minutes b. Distribution - widely distributed in tissues and fluids
- poorly penetrates the CSP even in inflammation
c. Biotransformation - actively deacetylated primarily in the liver but are also biotransformed in other tissues
d. Excretion - excreted in the kidneys mainly by renal tubular secretion biliary exceretion is employed largely by newer cephalosporins
e. Plasma half-lives - 30-120 minutes
- third generation cephalosporins have longer half-lives
7. Side effects
a. Relatively nontoxic but cephaloridine may be nephrotoxic in some species.
b. Hypersensitivity reactions may be encountered particularly in animals with history of penicillin allergy
c. Superinfection
8. Source: isolated from Cephalosporium acremonium (a marine fungus) 9. First Generation (Narrow Spectrum)
Oral Parenteral Microbiologic Activity
Cephradrine Cefacetrile - every active vs. Grant + mod. vs. Gram - bacteria Cefadroxil Cefapirin
Cephalexin Cephazolin - relatively susceptible to cephalosporinases Cephaloglycin Cephalothin - not effective vs. anaerobes
- no activity vs. Proteus
and Psuedomonas (rapidly dev. resistance
10. Second Generation (Moderate Spectrum)
Oral Parenteral Microbiologic Activity
Cefachlor Cefamandole - active vs. Gram + and – org.
Cefonicid
Ceforanide - relativelyresistantto cephalosporinase Cefoxitin
Cefuroxime - ineffective vs. enterococci, Pseudomonas, Cefotiam Actinomyces, and obligate anaerobes
11. Third Generation (Broad Spectrum)
Oral Parenteral Microbiologic Activity
Ceftriaxones Cefotaxime - moderate activty vs. Gram + Ceftizoxime Cefoperazone
Ceftazidine Cefsulodin - active vs. gram – bacteria Cefmenoxime Moxalactam including Proteus, Pseudomonas
( Latamoxef) ** Citrobacter
- very good activity vs.
enterobacter - high resistance to
cephalosporinase
Legend:
* a cephamycin (from Streptomycin)
** a cephamycin (synthesis form)
Note:
1. Cephalosporins discovered before 1975 are spelled with "ph' and after 1975, with an "f.
2. First and second generation cephalosporins are not capable of penetrating the outer roeroberanes of Pseudomonas aeruginosa
BETA-LACTAMASE INHIBITORS
1. Introduced in Vet. Med. in combination with penecillin to produce broad-spectrum antibacterial activity and overcome limitations of these drugs.
2. Synergestic with a number of penicllins and cephalosporines that are easily hydrolyzed by plasmid-mediated beta-lactamases.
3. MOA: irreversibly inhibit beta-lactamase enzymes allowing the beta-lactam antibiotics to act on the bacterial pathogens. .
4. Effect: Beta-lactum antibiotics are protected from the enzymatic destruction by beta-lactamases and their antibacterial activity is extended.
5. Most commonly used beta-lactamase inhibitors:
a. clavulanic acid b. sulbactam 6. Clavulanic acid:
a. Produced Streptomyces clavigerus
b. Resembles penicillin in structure but has no significant antibacterial activity.
c. Has good activity against plasmid-mediated beta-lactamases and chromosomally mediated penicillinases.
d. Has little activity against chromosomally mediated cephalosporinases.
7. Sulbactam (penicillinic acid sulfone)
a. A synthetic derivative of aminopenicillanic acid.
b. Affinity to beta-lactarnases is less than that of clavulanic acid.
c. Binds to B-lactamases of Citrobacter, Enterobacter, Proteus, and Serratia sp. to which calvulanic acid does not.
8. Examples of potentiated beta-lactams:
a. Clavulanic acid - armoxicillin (2:1) (Coamoxiclav)
b. Clavulanic acid - ticarcillin (15:1) c. Sulbactam - ampicillin
d. Sulbactam - cefoperazone
9. The combination is useful in situations wherein the organisms have developed resistance to the beta-lactam alone but sensitive to the combination.
10. Contraindications:
a. Oral administration in herbivores
b. Injection to horses, rabbits, guinea pigs, hamsters, and gerbils MONOLACTAMS
1. Monolactams possess the monocyclic beta-lactam ring amd do not have the thialodine ring.
2. Aztreonam was the firstdrug of this group to be introduced in human medicine.
3. It is synthetic analogue of an antibiotic isolated from Streptomyces sp.
4. MOA: It binds to the PBP3 (penicillin binding protein) causing disruption of cell wall synthesis
5. It is not susceptible to the action of most beta-lactamases.
6. May also be hydrolyzed by beta-lactamase that hydrolyze group II parenteral cephalosporins.
7. Activity is limited to gram-negative aerobic bacteria including the fastidious Haemophilus spp., Pasteurella.spp and Enterobacteriaciae
8. Resistant organisms include gram-positive bacteria and anaerobic bacteria, some (Pseudomonas spp., Citrobacter spp and. Enterobacter spp.)
9. Pharmacokinetics:
a. Not absorbed following oral administration.
b Widely absorbed after IM administration.
c. Penetrates the CSF when meningitis is present d. Excreted mainly in the kidneys.
10. Side effects:
a. Toxicity similar to B-lactam antibiotics.
b. No apparent cross-allergic reactions.
11. Exhibits synergistic.with aminoglycoside antibiotic
12. Main use in human medicine is for treatment of urinary tract infections.
CARBAPENEMS
1. These are newer beta-lactam antibiotics.
2. Imipenem is used in human medicine in combination with cilastin, a drug that inhibit hydrolysis in the kidney.
3. It is highly active against almost all clinically important gram-positive, gram negative and aerobic bacteria.
4. There is rapid development of resistance against Psuedomonas aeroginosa.
5. Pharroacokinetics:
a. Mot absorbed following oral administration.
b. Widely distributed to following IV administration, including the CSF in meningitis.
c. Mainly excreted in the kidneys and metabolized in the renal tubules.
d. Renal metabolism is inhibited by cilastin.
6. Side effects:
a. Gastrointestinal disturbances (most common) b. Hypersensitivity reactions (rash)
c.Seizures (associated with high doses, renal failure underlying neurological abnormalities)
7. Use in human medicine in treating nasocomial infections, infections caused by resistant organisms and mixed infections.
OTHER CELL WALL INHIBITORS Bacitracin
1. Discovered in 1945 by Johnson and his colleagues.
2. Was isolated from a Bacillus sp. of.bacteria taken from the fractured tibia of Margaret Tracy, hence the name bacitracin.
3. Chemistry:
a. These are basically polypeptides.
b. Also contains a thiazolidine ring present in penicillin.
4.. Pharmacokinetics
a. Fully absorbed from the gut.
b. Absorbed drug is excreted via glomerular filtration.
5. Spectrum of activity:
a. A narrow-spectrum antibiotic b. Bactericidal in nature
c. Activity is not affected by organic materials
d. Effective against: aerobic and anaerobic gram-positive rods, spirochaetes, penicillin-resitant organism.
e. Often combined with aminoglycosides or .with polymyxin B for broadspectrum activity in treating minor skin wounds.
6. MOA: Interferes with the phospholipid which carries the wall materials from the center of the cell to the cell-wall structure.
7. Toxicity: strongly nephrotoxic when given parenterally 8. Resistance develops slowly and is rare.
9. Clinical applications;
a. Feed additive, of pigs, poultry, and cattle b. For growth promotion purposes
c. Prevention and treatment of Clostridium perfringens and C.
spiroforme (rabbits)
d. Topical treatment of superficial infections of skin and mucosal surfaces Vancomycin
1. A glucopeptide produced by Streptomyces orientalis.
2. MOA: inhibits peptidoglycan synthesis by binding with D-alanyl-D-alanine terminal of muramyl dipeptide.
3. Spectrum of activity; narrow (limited to gram-positive organisms) 4. Pharmacokinetics:
a. Fully absorbed from the gut
b. Fully penetrates tissue and CSF, except when inflamed
c. Half-life in man is 6 hours, in dogs 2 hours
5. Used in humans, hamsters, and guinea pigs for treatment of antibiotic-induced Clostridium deficile infections.
II. DISRUPTORS OF CELL MEMBRANE FUNCTION