Npsc521P Lecture 13 Penicillins

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Define: (NOT AN OBJECTIVE)

– Antimicrobial:
– Infection:
– Antibiotic:
– Antibacterial:
– Bactericidal:
– Bacteriostatic:
– Bacterial resistance:
– Minimum inhibitory concentration (MIC):
– Narrow spectrum antibiotic:
– Broad spectrum antibiotic:
– Superinfection:
– Antibiotics and oral contraceptives:
– Remember: Penicillin has a 5 ring structure with a sulfur. Cephalosporines are a 6 – ring structure with an amino group (effective for gram - )

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– Antimicrobial: a general term for drugs that kill or inhibit the actions of microbes
– Infection: entry into the body of pathogenic microbes (usually bacteria) and the response of the body’s immune system to that invasion.
– Antibiotic: chemicals that are produced by living organisms and are toxic to other organisms such as bacteria.
– Antibacterial: any chemical that is used to kill or inhibit the growth of organisms including infectious bacteria.
– Bactericidal: an antibiotic that kills bacteria
– Bacteriostatic: an antibiotic that inhibits the growth of bacteria
– Bacterial resistance: invading bacteria are not susceptible to the antimicrobial actions of the drug.
– Minimum inhibitory concentration (MIC): lowest concentration of antimicrobial needed to inhibit the growth of an organism in a culture plate 18-24 hours after incubation.
– Narrow spectrum antibiotic: acts primarily against gram-positive bacteria.
– Broad spectrum antibiotic: acts against a wide range of gram-positive bacteria and gram-negative bacteria
– Superinfection: antibiotic causes reduction of normal bacteria in oral cavity which allows for overgrowth of Candida albicans. These are also referred to as opportunistic infections.
– Antibiotics and oral contraceptives: ATB reduce the effectiveness of birth control pills. ATB reduce intestinal flora which hydrolyzes conjugated estrogen from the pill so it can be reabsorbed. This reduction of active estrogen may result in ovulation  pregnancy
– This lecture will study 3 important penicillin type ATB: Penicillin VK, amoxicillin and ampicillin. They are used to treat oral-facial infections and to prevent bacterial infection in susceptible patients undergoing invasive dental treatment.
– Remember: Penicillin has a 5 ring structure with a sulfur. Cephalosporines are a 6 – ring structure with an amino group (effective for gram - )

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1. Describe the uses of penicillin VK and amoxicillin in treating oral infections

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Both penicillin VK and amoxicillin are active against the bacteria which are involved in causing oral-facial infections. These bacteria are gram positive cocci (staphylococcus, streptococcus), and gram positive bacilli (bacteroides). Sometimes amoxicillin is preferred over penicillin VK because amoxicillin requires less frequent dosing (tid vs qid).

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2. Describe the differences in bacterial action between penicillin VK and amoxicillin

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Penicillin VK has a relatively narrow spectrum of antibacterial effect. The bacteria are mostly Gram postive cocci and a few Gram positive bacilli, examples of which are mentioned above. Amoxicillin has a slightly broader spectrum of antibacterial action. It is active against the same organisms as penicillin VK and some additional organisms such as Hemophilus influenzae. In general, the slight differences in antibacterial spectrum between the two are not enough to favor amoxicillin over penicillin VK in treating oral infections.

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3. What is ampicillin?

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Ampicillin is a member of the penicillin family and has an antibacterial spectrum which is a little broader than penicillin VK and similar to amoxicillin. Since it is poorly absorbed when taken as a capsule or liquid, it is most often given as IM or IV injection.

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4. What is the mechanism of antibacterial action of the penicillins?

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Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin binding proteins (PBP); which in turn inhibits the transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

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5. Describe the mechanism of bacterial resistance to the penicillin antibiotics.

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a. Changes in structures of the penicillin binding proteins (PBPs)
Sensitive bacteria can develop high molecular weight PBPs that have decreased affinity for the antibiotic. Because the beta-lactams inhibit many different PBPs in a single bacterium, the affinity for the antibiotics of several PBPs must decrease for the bacteria to be resistant. Altered PBPs are acquired by recombination between PBP genes of different bacterial species. For example, 4 of the 5 PBPs of the most highly pencillin-resistant S. pneumoniae have a decreased affinity for penicillin as a result of recombination of the PBP genes through interspecies acquisition of those genes. Further, penicillin resistance in viridans streptococci emerged as a result of replacement of its PBPs with resistant PBPs from S. pneumoniae.
Methicillin-resistant S. aureus (MSRA) are resistant via acquisition of an additional high molecular weight PBP with a very low affinity for all the beta-lactam antibiotics.
b. Inability of the beta-lactam molecule to penetrate through the bacteria to its site of action
In gm-negative bacteria, the antibiotic must pass through a virtual impenetrable outer membrane of the bacteria to get to the PBPs. This passage occurs through aqueous channels in the outer membrane formed by proteins called porins. The hydrophilic broader spectrum penicillins such as amoxicillin and most of the cephalosporins diffuse through these pores with ease compared to penicillin G and penicillin VK. P. aeruginosa, lacks these pores, and is highly resistant to the beta-lactams.
c. Increases in efflux pumps within the bacteria which remove the antibiotic from the site of action before it can act
These pumps are energy-dependent efflux systems within the bacterial membrane for pumping the antibiotic out of the bacteria. The pumps traverse both the outer and inner membranes of the gm-negative bacteria. The pumps are composed of at least three different types of proteins and the increased expression of the pumps is an important cause of antibiotic resistance.
d. Enzymatic destruction of the beta-lactam molecule by bacterial beta-lactamases
In general, gm-positive bacteria produce a large amount of beta-lactamase, which is secreted extracellularly. Most of these beta-lactamases are penicillinases. The information on these enzymes are encoded in a plasmid and may be transferred by bacteriophage to other bacteria. In gm-negative bacteria, beta-lactamases are found in much smaller amounts. They are located between the inner and outer cell membrane (strategically located for maximal protection.) Beta lactamases in gm-negative organisms may hydrolyze penicillins, cephaolsoporins or both. They are encoded either in chromosomes or in plasmids and transferred between bacteria by conjugation.
The major mechanism is the changing and configuration of PBPs. And the 2nd major mechanism is efflux pumps

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6. What is Augmentin and why is it active against those beta-lactamase secreting bacteria resistant to penicillins?

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Augmentin is the brand name of a combination of Amoxicillin and Clavulanate Potassium. This drug is active against beta-lactamase secreting bacteria because Clavulanate Potassium (clavulanic acid) binds and inhibits beta-lactamases that would otherwise inactivate amoxicillin.

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7. Describe penicillin allergy.

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10% of the population of this country is allergic to penicillins. Clinical manifestations are a delayed-t type reaction resulting in skin rash, or a toxic-type reaction resulting in anaphylaxis. The delayed-type reaction is more prevalent.

There is a high incidence of cross-allergenicity between penicillins, in that if a patient is allergic to penicillin VK, they will be allergic to amoxicillin, ampicillin and Augmentin.

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8. What are some medical infections that penicillins are used to treat?

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Infections caused by susceptible organisms involving the respiratory tract, otitis media, sinusitis, chronic bronchitis, tonsillitis, pharyngitis, skin and urinary tract infections.

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9. What are the chemical differences between penicillin VK, amoxicillin and ampicillin?

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The chemistry of the penicillins is shown below. Amoxicillin and ampicillin are aminopenicillins because they have an amino group (NH2) which allows them to get into some gram – bacteria. Since VK is not an aminopenicillin it is not that effective against gram – bacteria.
They all have a benzene ring. Amoxicillin has an aromatic Hydroxyl group that allows for a faster uptake from the GI tract compared to Penicillin VK. For this reason is recommended for prophylaxis in patients who are going to undergo dental treatment. Ampicillin doesn’t have the aromatic hydroxyl group and it has difficulty being absorbed orally. For prophylaxis it should be given IM or IV

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10. Describe the pharmacology of penicillin VK

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a. Use in medicine: Treatment of infections caused by susceptible organisms involving the respiratory tract, otitis media, sinusitis, skin and urinary tract; prophylaxis in rheumatic fever.
b. Significant adverse effects: mild diarrhea, oral Candidiasis.
c. Time to peak blood levels after oral administration = 0.5 to 1 hour
d. Half-life elimination from blood = 30 mins
e. Should be taken on empty stomach 1 hour before or 2 hours after meals.
f. Metabolism = 10% to 30%.
g. Excretion - Elimination: Penicillin V and its metabolites are excreted in urine mainly by tubular secretion
h. Important drug interaction: Increased or decreased effect/toxicity
i. Penicillin may increase levels of methotrexate (rheumatoid arthritis).
ii. Probenecid (uricosuric agent) may increase levels of penicillin
iii. Penicillin may be decreased by tetracycline derivatives, because tetracyclines inhibit growth (protein synthesis) and penicillins work better when bacteria divides.

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11. Describe the penicillinase-resistant penicillins: methicillin, cloxacillin; dicloxacillin

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Less potent against bacteria sensitive to Pen VK but are effective against penicillinase-producing S. aureus because of their STERIC HINDRANCE.
Steric hindrance is the sterically addition of molecules to a compound to change the properties of the compound. They took the penicillin molecule and added methoxy groups so the newly formed compound blocks the acces by the lactamse enzyme to the beta-lactam ring  protecting it.
Methicilling is not longer in the market because of increased resistance by bacteria. We still have cloxacillin and dicoxacillin to kill penicillinase producing staph.

Use for cloxacillin, dicloxacillin: Treatment of susceptible bacterial infections, notably penicillinase-producing staphylococci causing respiratory tract, skin and skin structure, bone and joint, urinary tract infections

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12. Describe the pharmacology of the aminopencillins: amoxicillin, ampicillin

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Aminopencillins: amoxicillin; ampicillin: Extended spectrum to include some Gm-negative organisms.
Mechanism = (against Gm-positive) same as Pen VK
Mechanism = (against Gm – negative). Surface structures of Gm-negative bacteria are more complex and have an outer membrane which is impenetrable to some antibiotics. Small hydrophilic antibiotics can diffuse through aqueous channels called porins. The amino penicillins and cephalosporins diffuse through these pores more rapidly than Pen VK. Once the aminopenicillins get through these pores, they inhibit penicillin binding proteins to block the cell wall synthesis.

f. Amoxicillin:
i. Use: Treatment of otitis media, sinusitis, and infections caused by susceptible organisms involving the respiratory tract, skin, and urinary tract; prophylaxis of bacterial endocarditis in patients undergoing surgical or dental procedures; as part of a multidrug regimen for H. pylori eradication
ii. Significant adverse effects: diarrhea, oral Candidiasis.
iii. Time to peak blood levels after oral administration: capsules 2 hours, suspension 1 hour
iv. Half-life elimination from blood = 0.7 – 1.4 hours
v. May be taken with food.
vi. Metabolism - partially hepatic.
vii. Excretion – Elimination in urine: Amoxicllin excreted 80% as unchanged in urine because it is actively secreted thru the renal tubular cells before it is metabolized by the liver.

g. Ampicillin
i. Use: Treatment of susceptible bacterial infections (nonbeta-lactamase-producing organisms); susceptible bacterial infections caused by streptococci, pneumococci, nonpenicillinase-producing staphylococci, Listeria, meningococci; some strains of H. influenzae, Salmonella, Shigella, E. coli, Enterobacter, and Klebsiella
ii. Time to peak blood levels after oral administration: within 1 to 2 hours
iii. Half-life elimination from blood = 1 - 1.8 hours
iv. Take on empty stomach 1 hour before or 2 hours after meals.
v. Excretion – Urine (90% as unchanged drug) within 24 hours

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13. What is ampicillin and sulbactam (Unasyn)?

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Sulbactam is similar to Augmentin given IM or IV. Sulbactam inhibits the lactamase enzymes from the bacteria allowing for ampicillin to be active and maintain its bactericidal effect

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14. Precautions/warnings with the pencillins =

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= Use with caution in asthmatic patients
a. Because they might be allergic to penicillin.