Penicillins | Pharmacology

Penicillin

The development of the sulfonamide antibiotics was a breakthrough in the treatment of bacterial infections. Since that time, there has been a quest to develop new and more effective antibiotic drugs. The antibacterial properties of natural penicillins were discovered in 1928 by Sir Arthur Fleming while he was performing research on influenza. Ten years later, British scientists studied the effects of natural penicillins on disease-causing
microorganisms. However, it was not until 1941 that natural penicillins were used clinically for the treatment of infections. Although used for more than 50 years, the penicillins are still an important and effective group of antibiotics for the treatment of susceptible pathogens (disease-causing microorganisms).
Another name for this class is the beta-lactam antibiotics, referring to their structural formula. The penicillin class contains five groups of antibiotics: aminopenicillins, antipseudomonal penicillins, beta-lactamase inhibitors, natural penicillins, and the penicillinase resistant penicillins.

ACTION

The The penicillins have the same type of action against bacteria. Penicillins prevent bacteria from using a substance that is necessary for the maintenance of the bacteria’s outer cell wall. Unable to use this substance for cell wall maintenance, the bacteria swell, rupture, assume unusual shapes, and finally die. The penicillins may be bactericidal (destroy bacteria) or bacteriostatic (slow or retard the multiplication of bacteria). They are bactericidal against sensitive microorganisms (ie, those microorganisms that will be affected by penicillin) provided there is an adequate concentration of penicillin in the body. An adequate concentration of any drug in the body is referred to as the blood level. An inadequate concentration (or inadequate blood level) of penicillin may produce bacteriostatic activity, which may or may not control the infection.
The enzymes that hydrolyze the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death (cytolysis).

In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell wall's peptidoglycans. The small size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the glycopeptide antibiotics vancomycin and teicoplanin, which are both much larger than the penicillins.

Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin.

Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell.

Penicillins, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants.

The chemical structure of penicillin is triggered with a very precise, pH-dependent directed mechanism, effected by a unique spatial assembly of molecular components, which can activate by protonation. It can travel through bodily fluids, targeting and inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria, meanwhile avoiding the surrounding non-targets. Penicillin can protect itself from spontaneous hydrolysis in the body in its anionic form, while storing its potential as a strong acylating agent, activated only upon approach to the target transpeptidase enzyme and protonated in the active centre. This targeted protonation neutralizes the carboxylic acid moiety, which is weakening of the β-lactam ring N–C(=O) bond, resulting in a self-activation. Specific structural requirements are equated to constructing the perfect mouse trap for catching targeted prey.

(an youtube video on the mechanism is attached at the bottom of the site link: https://youtu.be/4EJEr_lt5dM)

Identifying the Appropriate Penicillin

To determine if a specific type of bacteria is sensitive to penicillin, culture and sensitivity tests are performed. A culture is performed by placing infectious material obtained from areas such as the skin, respiratory tract, and blood on a culture plate that contains a special growing medium. This growing medium is “food” for the bacteria. After a specified time, the bacteria are examined under a microscope and identified. The sensitivity test involves placing the infectious material on a separate culture plate and then placing small disks impregnated with various antibiotics over the area.

After a specified time, the culture plate is examined. If there is little or no growth around a disk, the bacteria are considered sensitive to that particular antibiotic. Therefore, the infection will be controlled by this antibiotic. If there is considerable growth around the disk, then the bacteria are considered resistant to that particular antibiotic, and the infection will not be controlled by this antibiotic. After a culture and sensitivity report is received, the strain of microorganisms causing the infection is known, and the antibiotic to which these microorganisms are sensitive and resistant is identified. The primary health care provider then selects the antibiotic to which the microorganism is sensitive because that is the antibiotic that will be effective in the treatment of the infection.

USES

Infectious Disease The natural and semisynthetic penicillins are used in the treatment of bacterial infections due to susceptible microorganisms. Penicillins may be used to treat infections such as urinary tract infections, septicemia, meningitis, intra-abdominal infection, gonorrhea, syphilis, pneumonia, and other respiratory infections. Examples of infectious microorganisms (bacteria) that may respond to penicillin therapy include gonococci, staphylococci, streptococci, and pneumococci. Culture and sensitivity tests are performed whenever possible to determine which penicillin will best control an infection caused by a specific strain of bacteria. A penicillinase-resistant penicillin is used as initial therapy for any suspected staphylococcal infection until culture and sensitivity results are known.

ADVERSE REACTIONS
Common adverse reactions include mild nausea, vomiting, diarrhea, sore tongue or mouth, fever, and pain at injection site. Penicillin can stimulate a hypersensitivity (allergic) reaction within the body. Another adverse reaction that may be seen with penicillin, as well as with almost all antibiotics, is a superinfection (a secondary infection that occurs during antibiotic treatment).

Hypersensitivity Reactions A hypersensitivity (or allergic) reaction to a drug occurs in some individuals, especially those with a history of allergy to many substances. Signs and symptoms of a hypersensitivity to penicillin are highlighted in adjacent figure. Anaphylactic shock, which is a severe form of hypersensitivity reaction, also can occur. Anaphylactic shock occurs more frequently after parenteral administration but can occur with oral use. This reaction is likely to be immediate and severe in susceptible individuals. Signs of anaphylactic shock include severe hypotension, loss of consciousness, and acute respiratory distress. If not immediately treated, anaphylactic shock can be fatal. Once an individual is allergic to one penicillin, he or she is most likely allergic to all of the penicillins. Those allergic to penicillin also have a higher incidence of allergy to the cephalosporins . Allergy to drugs in the same or related groups is called cross sensitivity or cross-allergenicity.

Superinfections

Antibiotics can disrupt the normal flora (non-pathogenic microorganisms within the body) causing a superinfection. This new infection is “superimposed” on the original infection. The destruction of large numbers of nonpathogenic bacteria (normal flora) by the antibiotic alters the chemical environment. This allows uncontrolled growth of bacteria or fungal microorganisms, which are not affected by the antibiotic being administered. A superinfection may occur with the use of any antibiotic, especially when these drugs are given for a long time or when repeated courses of therapy are necessary. A superinfection can develop rapidly and is potentially serious and even life threatening. Bacterial superinfections are commonly seen with the administration of the oral penicillins and occur in the bowel. Symptoms of bacterial superinfection of the bowel include diarrhea or bloody diarrhea, rectal bleeding, fever, and abdominal cramping. Fungal superinfections commonly occur in the vagina, mouth, and anal and genital areas. Symptoms include lesions of the mouth or tongue, vaginal discharge, and anal or vaginal itching. Pseudomembranous colitis is a common bacterial superinfection; candidiasis or moniliasis is a common type of fungal superinfection.

INTERACTIONS

Some penicillins (ampicillin, bacampicillin, penicillin V) may interfere with the effectiveness of birth control pills that contain estrogen. There is a decreased effectiveness of the penicillin when it is administered with the tetracyclines. Large doses of penicillin can increase bleeding risks of patients taking anticoagulant agents. Some reports indicate that when oral penicillins are administered with beta-adrenergic blocking drugs. The patient may be at increased risk for an anaphylactic reaction. Absorption of most penicillins is affected by food. In general, penicillins should be given 1 hour before or 2 hours after meals.

References:

Roach - Introductory Clinical Pharmacology 7e (Lippincott, 2003)
Antibiotics: mode of action and mechanisms of resistance Kaufman G (2011) Antibiotics: mode of action and mechanisms of resistance. Nursing Standard.(25, 42, 49-55. Date of acceptance: February 10 2011.)
Wikipedia.