Penicillins: β-Lactum antibiotics

Penicillins

Β-Lactum Antibiotics

Members of penicillin family are β-Lactum antibiotics that act by inhibiting cell wall synthesis. Chemically penicillins consist of a 6-amino penicillanic acid nucleus with attached side chain (R). Members of penicillin family differ from each other by side chain (R) attached to 6-amino penicillanic acid. Antibacterial spectrum, bacterial enzyme susceptibility, GIT absorption depend upon side chain attached to 6-amino penicillanic acid.

                    

6-amino penicillanic acid consists of a β-Lactum ring and thiazolidine ring. Penicillin resistance bacteria produce enzyme penicillinase (β-Lactamase) that acts on the β-Lactum ring to break its ring structure. Β-Lactum ring is essential for antibacterial effect of penicillins.

Classification:

There are three classes of penicillins

      A.    Natural penicillins: Benzylpenicillin (Penicillin G), Phenoxy methyl penicillin (Penicillin V)

      B.     Semisynthetic penicillins:

a.   Penicillinase Resistance penicillin: Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin

b.      Broad Spectrum Penicillin:

                                                              i.      Aminopenicillin: Ampicillin and Amoxycillin

                                                            ii.      Carboxypenicillin: Carbenicillin

                                                          iii.      Ureidopenicillin: Piperacillin, Mezlocillin and Azlocollin

      C.     Reversed spectrum penicillins: Mecillinam, Pivmacillinam

Penicillins can also be classified into following classes depending upon their antibacterial spectrum.

·         Narrow spectrum Penicillins: They are narrow spectrum antibiotics. These are               Penicillin G and Penicillin V.

·       Broad Spectrum Penicillins (Extended spectrum Penicillins):  Ampicillin, Amoxycillin, Carbenicillin, Ticarcillin.

Natural Penicillins: Molds belonging to genus Penicillium produce natural penicillin. There are two types of penicillin depending upon culture media composition. These are

                     Benzylpenicillin (Penicillin G)

                     Phenoxy methyl penicillin (Penicillin V)

Semisynthetic penicillin: 6-amino penicillanic acid with side chain R is obtained from Penicillium chrysogenum. Its side chain is depleted from by enzyme amidase. This 6-amino acid penicillanic acid acts as a precursor to synthesize semisynthetic penicillins. In the laboratory, the side chain is attached to the β-Lactum ring of 6-amino penicillanic acid. This changes β-Lactum ring susceptibility to enzyme penicillinase. This leads to improved antibacterial spectrum and pharmacological properties of antibiotics.

Mechanism of action: Bacterial cell wall protects bacteria from autolysis. It is essential for normal growth and multiplication of bacteria. Bacterial cell wall has peptidoglycans that provide mechanical strength (rigidity) to the bacterial cell wall. Bacterial cells continuously synthesize peptidoglycans. The last step of peptidoglycan is cross-linking or transpeptidation by using enzyme transpeptidase. β-Lactum antibiotics such as penicillins, acylate transpeptidase enzyme. This blocks biosynthesis of peptidoglycans.

Penicillin acts by following three steps to produce a bactericidal effect.  
       

     1.  Protein binding: Several proteins are present in bacterial cell membranes that act as an enzyme in cell wall synthesis. This helps to maintain the morphological structure of bacterial cells. Penicillins bind with these proteins that inhibit bacterial wall synthesis and changes and weakens the morphological structure of bacterial cell wall. This leads to autolysis.

     2.Transpeptidase inhibition: Enzyme transpeptidase catalyzes transpeptidation or cross-linking of peptidoglycans chains. To form poly peptidoglycans. Polypeptidoglycan is essential for bacterial cell rigidity and strength.

Enzyme transpeptidase is acylated by penicillin and all β Lactum antibiotics. This transpeptidase acylation inhibits biosynthesis of poly peptidoglycans. This weakens bacterial cell wall that will be susceptible to autolysis.

      3.Autolysis: Several bacteria produce enzyme autolysin that removes several cell wall components. It helps in the remodeling of bacterial cells by replacing old cell wall components with new cell wall components. The penicillin blocks cell wall synthesis that makes autolysin more effective that leads to autolysis of bacterial cells.

Thus penicillins inhibit bacterial cell wall synthesis and lysis of bacterial cells.

Antibacterial Spectrum: Natural penicillins are narrow spectrum antibiotic. Their entry into bacterial cell depends upon bacterial cell wall components. In general, gram +ve bacteria are susceptible to penicillins and gram –ve bacteria are resistant to penicillins. Gram-ve bacteria cells have lipopolysaccharide membrane on their cell wall. It does not allow water-soluble penicillins into gram –ve bacterial cells. Some gram –ve bacteria have porins (pores in the cell wall that allow molecules to diffuse by passive diffusion) in their cell wall. Size, charges, number etc of porins determine the susceptibility of bacteria to penicillins.

  Penicillin G (Benzyl Penicillin): It is very active against gram +ve cocci, bacilli and spirochetes but less active against gram –ve cocci. It is inactivated by enzyme penicillinase (β-Lactamase enzyme) producing bacteria. Thus, penicillinase-producing bacteria are resistant to penicillin G. Penicillin G is also sensitive to acid. Thus it cannot be administered orally because gastric acid deteriorates penicillin G before absorption. It is administered by the parenteral route.

Penicillin V ( Phenoxy Methyl Penicillin): It is more acid resistant than penicillin G. Thus it can be administered orally. It is not used to treat bacterial infection due to high minimum lethal concentration (MLC). However, it can be used for minor infection of the respiratory tract, pharynx, middle year etc.

Antistaphylococcal Penicillins: Staphylococci produce the β-Lactamase enzyme. β-Lactamase enzyme (Penicillinase) break β-Lactam ring to make penicillin inactive. Penicillinase-resistant penicillin has acyl group in their side chain that protects β-Lactam ring from the β-Lactamase enzyme. Ex. Methicillin, Dicloxacillin, nafcillin, and flucloxacillin.

Methicillin is destroyed by gastric enzyme thus it is administered by the parenteral route. It is highly toxic penicillin thus it is not in use. Others are used to treat staphylococcal infections. They should be administered one after meal or one hour before meal because slow down absorption of these penicillins

Broad Spectrum Penicillins (Extended Spectrum Penicillins): Several synthetic penicillins are effective against gram +ve as well as gram –ve bacteria. Thus they are called broad-spectrum penicillins. But they are sensitive to the β-Lactamase enzyme. Thus β-Lactamase producing bacteria are resistant to broad-spectrum penicillins. Ex. Ampicillin, Amoxycillin, Carbenicillin, Ticarcillin.

Ampicillin is a drug of choice to treat gram +ve bacilli infection, respiratory tract infection, Salmonella typhi infection. Amoxycillin has the similar antibacterial spectrum as ampicillin. But amoxicillin has following advantages over ampicillin

·         Amoxycillin has better rate of absorption in GIT than Ampicillin

·         Food does not interfere with absorption of Amoxycillin

·    Ampicillin is administered four times on a day while amoxicillin is administered three times in a day.

·  Ampicillin has a tendency to produce diarrhea as side effects. Amoxycillin does not produce diarrhea.

Broad-spectrum antibiotics are sensitive to the β-Lactamase enzyme. Thus they are administered with β-Lactamase inhibitors like sulbactam or clavulanic acid. Salbactum and clavulanic acid both has property to protect ampicillin and amoxicillin from the β-Lactamase enzyme. However, their use has been declined due to development of bacterial resistance.

Antipseudomonal penicillins: Ex. Carbenicillin, ticarcillin, piperacillin. They are effective against Pseudomonas proteus organism and many gram –ve bacteria. They are destroyed by gastric acid and penicillinase enzyme. Thus, they are administered by the parenteral route along with β-lactamase inhibitors like sulbactam or clavulanic acid.

Penicillins with Aminoglycosides: Aminoglycosides with penicillins produce a synergistic effect. This increases penicillins antibacterial activity. Aminoglycosides increase penicillin ability to change bacterial cell wall permeability. This facilitates entry of penicillin into bacterial cells.

Precautions: Penicillins and aminoglycosides should not be an ingredient of one formulation. Positively charged aminoglycosides combine with negatively charged penicillins on prolonged contact. This forms an inactive complex.

Penicillin Resistance: Unwarranted use of penicillins develops penicillins resistance among penicillins sensitive bacteria. Following factors play an important role to develop penicillin resistance among penicillin sensitive bacteria:

·         Natural penicillins resistance: Following bacteria are naturally resistant to penicillin

o   Bacteria do not have poly peptidoglycan on their cell wall

o   Bacteria cell wall impermeable to Penicillins

·    Acquired penicillins resistance: Penicillins sensitive bacteria acquire Plasmid that promotes penicillins resistance. Some bacteria species have plasmid naturally. They have a natural resistance to bacteria. Some bacteria species acquire plasmids to develop penicillins resistance. This is called acquired penicillins resistance. Plasmid develops following changes in bacteria cells

o   β-Lactamase production: Plasmids stimulate β-Lactamase production in bacteria cells. Β-Lactamase hydrolyzes cyclic amide bond of the cyclic β-lactam ring of penicillins. This causes loss of penicillins bactericidal activity. Some penicillins are not affected by the β-lactamase enzyme. They act as bactericidal to β-lactamase producing bacteria.

Ex. Gonococci were susceptible to penicillins. Now they have developed resistance to penicillin by acquiring plasmids.

Pneumococci were susceptible to penicillins. They did not have β-Lactamase producing capacity. Now they are resistant to penicillins. Higher concentration of penicillins is required to produce the bactericidal effect.

o   Bacterial cell wall Permeability: Bacterial cells develop cell wall impermeable to penicillins.Thus penicillins cannot enter bacteria cell to combine penicillins binding proteins.

o   Alteration in protein binding proteins: Bacteria have modified their penicillins binding proteins. Thus penicillins cannot attain minimum effective concentration at penicillin-binding protein sites. Thus penicillin cannot restrict bacteria growth and their multiplication.

Adverse Effects: Penicillins are safest antibiotics. They are almost free from direct toxic effects. Adverse effects are mainly due to hypersensitivity reactions.

·   Hypersensitivity reactions (Sensitization reactions): Penicillins metabolites penicilloic acid and alkaline hydrolysis of host proteins are responsible for penicillins hypersensitivity reactions. Penicillins hypersensitivity reactions precipitate in about 5% patients. Penicilloic acid combines with host proteins to act as an antigen. Host body develops antibody to destroy antigens. This leads to antigen-antibody reactions (immunity reactions). 
     Symptoms: Symptoms of hypersensitivity reactions are skin rashes, fever angioedema (Swelling of tongue, lips and periorbital areas). Sometimes more serious effects like anaphylaxis may also develop with circulatory collapse, edema, and spasm in bronchi. The severity of hypersensitivity reactions depends upon the duration of penicillin administration and total dose penicillins administered. Hypersensitivity reactions may precipitate 10 to 12 days from the date of penicillins administration.

Cross allergic reactions among β-lactam antibiotics may also develop. Means patient suffering from penicillins sensitivity will also be sensitive to cephalosporin. (Cephalosporins are also β Lactam antibiotic).

·                                  Diarrhoea:  Penicillins kill GIT microbial flora that leads to diarrhea.

·                                  Nephritis

·                                  Neurotoxicity

·                                  Platelets agglutination

Therapeutic Uses:

  Natural penicillins: Penicillin G is used to treat several infections such as:

• ·         Pneumococcal infection: Pneumonia, meningitis, osteomyelitis.
• ·         Streptococcal infection: Pharyngitis, Sinusitis, Pneumonia, Meningitis, Endocarditis.
• ·         Meningococcal infection: Meningitis
• ·         Staphylococcal infection
• ·         Syphilis
• ·         Diphtheria
• ·         Anaerobic infection
• ·         Actinomycosis
• ·         Tetanus &
• ·         Gas Gangrene

Prophylactic Use: Rheumatic fever, Gonorrhoea, Syphilis

Therapeutic uses of Broad Spectrum Penicillins:

• ·         Respiratory Tract Infection
• ·         Urinary Tract Infection
• ·         Meningitis
• ·         Septicemia.,

  

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