Antimicrobials: Cell Wall Synthesis Inhibitors: Penicillins

Question 1

Antimicrobial drugs can be classified in many different ways. The most common way is to classify by mechanism of action. Most antimicrobials act on a specific target in the bacterial cell. Any structure that is unique to the bacteria can be a potential target. What are the targets of antimicrobials?

Answer 1

1. Cell wall synthesis inhibitors (beta lactam, vancomycin, daptomycin, bacitracin and fosfomycin)
2. Protein Synthesis Inhibitors (tetracyclines, glycylcylines, aminoglycosides, macrolides, chloramphenicol, clindamycin, streptogramins, linezolid, fidaxomicin and mupirocin)
3. Drugs that affect nucleic acid synthesis (fluroquinolones, sulfonamides, and trimethoprim)
4. Miscellaneous and urinary antiseptics (metronidazole and nitrofurantoin)

Question 2

This deck of cards will focus on the Cell Wall Synthesis Inhibitors. What does this include?

Answer 2

1. Beta-Lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams)
2. Vancomycin
3. Daptomycin
4. Bacitracin
5. Fosfomycin

Question 3

How do cell wall synthesis drugs work?

Answer 3

Mammalian cells do not have a cell wall
--thus the mechanism by which this class of drugs work is selectively toxic to the bacteria 
These drugs require actively proliferating bacteria, cell wall synthesis must be occurring

Question 4

First up are the beta-lactam antibiotics. They are the most useful, well tolerated antimicrobial agents. They are called beta lactams due to the beta lactam ring that is common. How do the antibiotics work ?

Answer 4

The ring must remain intact for antimicrobial action
–beta lactamases (penicillinases and cephalosporinaes) are bacterial enzymes that hydrolyze the beta lactam ring of a certain penicillin and cephalosporin, rendering them inactive

Question 5

To discuss more on the MOA of beta lactam antibiotics. All beta lactam antibiotics are bactericidal. What does this mean?

Answer 5

Cell walls of bacteria are essential for their normal growth and development

• –antimicrobials inhibit cell wall synthesis resulting in cell lysis
• -bind to and inactivate enzymes involved in the final stage of cell wall synthesis (it is during this stage that peptidoglycan chains of polysaccharides and polypeptides cross link to form the cell wall)

Question 6

Beta lactams inhibit a family of related enzymes (each involved in different aspects of cell wall synthesis) . What is some of the action of these enzymes?

Answer 6

These Enzymes can be detected by their covalent bonding of radioactively labeled penicillin
—called penicillin binding proteins (PBPs)
Different beta lactam antibiotics bind to and inhibit certain PBPs more than others

Question 7

In regards to beta lactams the mechanism of bacterial cell killing is an indirect consequence of the inhibition of cell wall synthesis. Autolytic enzymes of peptidoglycan are normally present in the bacterial cell wall but ?

Answer 7

Are strictly regulated to allow breakdown of the peptidoglycan only at the growing points.
–beta lactam inhibition of cell wall synthesis leads to activation of the autolytic system – leads to cell death program

Question 8

There are three general mechanisms of bacterial resistance to the beta lactams. Each card will go through these three. The first is decreased penetration to the target site. What does this mean?

Answer 8

Wall of gram - bacteria provides an efficient barrier to the penetration of beta lactams
–to gain transmembrane entry and access the PBPs, beta lactams must pass through hydrophilic porins
–lack of these porins = resistance
Gram + have an easily crossed cell wall so no porins are needed

Question 9

The second mechanism of resistance to beta lactam antibiotics is alteration of the target site. What does this mean?

Answer 9

Alteration in PBPs may influence their binding affinity for beta lactams
—therefore sensitivity of the altered bacterial cell to inhibition by these drugs
(Ex: penicillin resistance in pneumococci, methicillin resistance in staph and vancomycin resistance in enterococci)

Question 10

The third mechanism of resistance of beta lactam antibiotics is inactivation by a bacterial enzyme. What does this involve?

Answer 10

Production of beta lactamases by most staph and gram negative bacteria is a major mechanism of resistance to the beta lactam antibiotics

• -such enzymes cleave penicillins (penicillianses), cephalosporins (cephalosporinases) or both (beta lactamases)
• -their production may be encoded within the bacterial chromosome or acquired on a plasmid.

Question 11

Moving on to the first beta lactam antibiotic is Penicillin. First up are the natural penicillins first is Penicillin G (IV), what is the use of this drug?

Answer 11

Highly active against:

• -gram positive cocci (except: beta lactamase producing staphylococi, penicillin resistant pneumococci, enterococci and MRSA)
• -gram positive rods (Ex. listeria and clostridium)
• -gram negative cocci (neisseria but not N. Gonorrhea– beta lactamase producing)
• -most anaerobes (except. bacteroides)
• -Certain spirochetes (treponema pallidum)

Question 12

Therefore Penicillin G is the drug of choice for what?

Answer 12

Syphilis (Benzathine)
Strep Infections (Esp to prevent rheumatic fever prophylaxis)
Susceptible pneumococci

Question 13

Next penicillin is penicillin V, what is this the drug of choice for?

Answer 13

Similar antibacterial spectrum to penicillin G

• -given orally
• –drug of choice for strep throat

Question 14

Next are the repository (IM) penicillins which include penicillin G procaine and penicillin G benzathine. Why were these drugs developed?

Answer 14

Prolong the duration of penicillin G

• -both agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of abx in the blood
• -peak concentrations of penicillin G procaine are seen within a few hours and therapeutic levels remain for approx 4-5 days
• -benzathine is absorbed very slowly from intramuscular depots and produces the longest duration of detectable abx. (26 days)

Question 15

Next in under the penicillins are the extended spectrum penicillins. Include amoxicillin and ampicillin. What are some features?

Answer 15

Gram + and gram - bacteria activity
Susceptible to beta lactamases
Clinical indications: E.coli, proteus mirabilis, salmonella, shigella, enterococci, and H. influenza
Used in combo with beta lactamase inhibitors (clavulanic acid) their antibacterial activity is enhanced

Question 16

What are some features of amoxicillin and ampicillin

Answer 16

Identical Spectrum of Activity
–Amoxicillin is better absorbed from the intestine when given orally = higher blood and urine levels
Amoxicillin: common oral abx prescribed for children and in pregnancy
Both drugs used to tx URI caused by S. pneumoniae and H. influenzae
Acute Otitis Media, strep pharyngitis, pneumonia, skin infections, UTIs
In enterococci and listerial infections, ampicillin is synergistic with aminoglycosides

Question 17

Fourth under the penicillins are the antistaphylococcal penicillins ,which include: methicillin (Not FDA approved), nafcillin (IV), oxacillin (IV) and dicloxacillin (oral) . What is the action of these drugs?

Answer 17

Inhibit Beta lactamase producing staphylococci
–inactive against MRSA
Very narrow spectrum and have less intrinsic activity than penicillin G for most bacteria
Ineffective for enterococci, listeria and neisseria

Question 18

The fifth and final penicillin group are the antipseudomonal penicillins (carbenicillin IV, ticarcillin IV and piperacillin IV). What is their activity?

Answer 18

Gram + bacteria
Gram - can penetrate the porins at high doses
Resistant to the beta lactamases of certain organisms (pseudomonas aeruginosa, proteus, and enterobacter species)

Question 19

In regards to the antipseudomonal, what does piperacillin do?

Answer 19

Superior activity against Pseudomonas Aeruginosa
–compared to the other antipseudomonals
Susceptible to some beta lactamases
Not used in combo with beta lactamase inhibitors
Also some activity against strains of Klebsiella

Question 20

In regards to the antipseudomonal, what does oral carbenicillin do?

Answer 20

Carbenicillin indanyl sodium is an Orally absorbed form of carbenicillin
–indicated for oral therapy of resistant UTIs
Not used for therapy outside of UTIs

Question 21

All of the antipseudomonal penicillins are commonly used to treat pseudomonas. So what drug is chosen?

Answer 21

Based on institution and cost

Question 22

Antipseudomonal are also used in the tx of moderate to severe infections of what?

Answer 22

Susceptible organisms

–infections where gram - are suspected (uncomplicated and complicated skin, gynecologic and intra abdominal infections)

Question 23

Moving on to the pharmacokinetics for penicillins. The half lives of penicillins and achievable levels in different body fluids generally are the same, but dose adjustment with renal insufficiency depends on the presence of non renal routes of excretion and differs among these drugs. First discuss the half lives of penicillins

Answer 23

All of the available penicillins (Excluding the repository forms) have relatively short half lives

Question 24

Next discuss the oral absorption of penicillins

Answer 24

GI absorption of nafcillin is erratic, so it is not suitable for oral absorption
Absorption of most oral penicillins is impaired by food, and the drugs should be administered at least 1-2 hours before or after a meal

Question 25

Next discuss the distribution of penicillins

Answer 25

Achieve therapeutic levels in:

• -pleural, pericardial, peritoneal, and synovial fluids and urine
• -bile levels are very high
• -levels in the prostate and eye are insufficient so not effective
• -penetrate the CSF poorly in the absence of inflammation but achieve therapeutic levels in patients with meningitis who are given high dose parenteral therapy.

Question 26

Finally discuss excretion of penicillins

Answer 26

Rapidly and primarily excreted by the kidney
–so half life can increase in renal failure
Nafcillin is cleared by biliary excretion while oxacillin and dicloxacillin are eliminated by both renal and biliary excretion (So these three drugs do not need to be adjusted in renal failure)

Question 27

Moving on to the adverse effects of penicillins. The first is hypersensitivity. These are the most common AE of penicillins. What is the MOA?

Answer 27

Penicilloic Acid is the major antigenic determinant
–present with pruritus, flushing, urticaria, angioedema, wheezing, laryngeal edema, serum sickness type reactions, hypotension and/or anaphylaxis
A low incidence of cross allergic rxs btw beta lactam abx do occur.

Question 28

The second adverse effect of penicillins is a maculopapular rash. What is the MOA?

Answer 28

Amoxicillin and Ampicillin

• -rash not due to allergic rxn
• -occurs when drugs are inappropriately prescribed for a viral illness

Question 29

The third adverse effect of penicillin is GI disturbances. What is the MOA?

Answer 29

Diarrhea
-nonspecific complication esp with oral ampicillin or amoxicillin
Occurs due to drugs changing the composition of microflora by eliminating sensitive microorganisms
Pseudomembranous colitis: related to overgrowth and production of a toxin by c. difficile has been associated with ampicillin tx.

Question 30

The fourth and fifth adverse effects of penicillin are allergic interstitial nephritis and hematologic toxicities. what are the features?

Answer 30

Allergic Interstitial Nephritis:
–all penicillins have the potential to cause this (this rxn is why methicillin is no longer used)
Hematologic Toxicities:
–Ticarcillin may cause a bleeding diathesis by inhibition of platelet function and prolongation of bleeding time

Question 31

Finally what are the sixth, seventh, eight and ninth adverse effect of penicillin?

Answer 31

Neurotoxic
--occurs with high dose penicillin therapy esp if excretion is delayed by renal disease or if preexisting neurologic disease is present 
Neutropenia:
--associated with use of nafcillin 
Hepatitis: 
--associated with use of oxacillin 
Secondary infection
--candidiasis

Question 32

Penicillins are often used clinically in combination with aminoglycosides to provide a wider spectrum of activity against gram negative bacilli and/or synergistic effect. How do aminoglycosides work?

Answer 32

Exert their effects on aerobic gram negative bacteria whist penicillins are active against gram positive bacteria
–aminoglycosides are protein synthesis inhibitors thus must cross the cell wall to have an effect
–penicillins are able to facilitate the movement of aminoglycosides through the cell wall
Therefore in combo the drugs have a greater effect.
NEVER GIVE IN THE SAME INFUSION BAG

Question 33

Penicillin + Aminoglycosides are used in combo for what (gentamicin)?

Answer 33

Infective endocarditis

–though in practice vancomycin is often substituted for penicillin due to the resistant strains

Question 34

Just a brief note on beta lactamase inhibitors. What are these?

Answer 34

Clavulanic Acid
Sulbactam
Tazobactam
—resemble beta lactam molecules but do not have significant antibacterial activity
Inhibitors of many bacterial beta lactamases
Protect hydrolysable penicillins from inactivation by these enzymes
Available in fixed combinations with specific penicillins