Pharmacology broad spectrum ?-lactamase sensitive penicillin (certain bacteria’s

Pharmacology Assignment — Vyas Rutvi (MDS – Oral Radiology) Amoxicillin Amoxicillin is a semi-synthetic antibiotic, which is a type of penicillin and which can further be grouped under broad spectrum ?-lactamase sensitive penicillin (certain bacteria’s produce ?-lactamases enzymes which destroys this group of penicillins).

 They are effective against large numbers of gram-positive and gram-negative bacterias excluding the ones producing ?-lactamases enzymes and hence it is usually prescribed with clauvanic acid which is a ?-lactamase inhibitor.  Amoxicillin is also acid stable antibiotic, which means it can be taken orally and will provide large serum level availability of the drug. The molecular formula of the amoxicillin is C16H19N3O5S and the molecular weight is 365.404 g/mol.

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 Pic courtesy:    Mechanism of Action:  Amoxicillin has a bactericidal effect against the certain organisms, it acts during the active multiplication stage of the bacteria, it inhibits the cell wall synthesis by inhibiting the synthesis of cell wall mucopeptide.  Pic courtesy: UTAustinX: UT.4.01× Take Your Medicine – The Impact of Drug Development Amoxicillin binds to the Penicillin Binding Protein (PBPs are the group of the proteins that has affinity to bind to penicillin, they are part of normal constituents of certain bacteria) PBPs would mimic D-alanyl-D-alanine-transpeptidases substrate that usually binds to the enzymes and thus the two polypeptide strands needed for cross-linking are not available, leading to and hence cell wall formation of the bacteria remains unfinished.

 Certain gram-negative bacteria have external membrane of cell wall consisting of Lipopolysaccharides with narrow porin channels whose function is to restrict the permeability of the ?-lactam antibiotics, but amoxicillin being hydrophilic, it can diffuse through this narrow porin channels more easily. Amoxicillin can only act on these bacteria when they are actively dividing and synthesizing. Following are the bacteria on which amoxicillin has its anti-microbial effects.

 Aerobic gram-positive microorganisms: Enterococcus faecalis, Staphylococcus species excluding the ?-lactamase strains, ? and ? hemolytic strains of the streptococcus species, Streptococcus pneumoniae (it is most active against all orally taken ?-lactams effective against penicillin resistant streptococcus pneumoniae). Aerobic gram-negative microorganisms excluding the ?-lactamase strains: Escherichia coli, Haemophilus influenzae, Proteus mirabilis, Neisseria gonorrhoeae. Helicobacter pylori.  Pharmacokinetics and Pharmacodynamics of the amoxicillin:  Amoxicillin can be taken orally/parentally, it has better oral absorption, it is stable against the gastric acid secretions. Food intake does not interfere with the absorption of the drug; thus, it has increased and more sustainable blood level of the drug.

20% of the amount is protein bound and rest all is readily diffusible to the most of the body tissues and the fluids, except that of the brain tissues and spinal fluid, it can also diffuse through the spinal fluid if the meninges are inflamed. It can pass through the placenta to the developing embryo, as well as it is excreted in some amount in the breast milk. Half-life of the amoxicillin is 61.3 mins. The half-life of the drug is increased in cases of neonates, elderly people, as well as people with renal impairment.

In case of children and neonates as the renal function is incompletely developed, elimination of the drug can be delayed, certain patients with severe renal impairment, the half-life of the drug can be prolonged up to 7 – 20 hrs. Peak plasma concentration of the drug can be reached 2 hrs. and average 4 mcg/ml after the dose of 250 mg is administered orally.

 Approximately sixty percentage of the drug taken orally is excreted in the urine in unchanged form by the glomerular filtration rate and tubular secretion. A very small amount of the drug is also metabolized into penicilloic acid. Its excretion can be delayed to increase the bioavailability can be done by intaking the drug with probenecid. Hepatic transformation of the amoxicillin accounts for about 30% or less of the biotransformation like the other penicillin’s. It is categorized under Pregnancy Category B, and it is considered to have teratogenic effects to the fetus, although animal studies have shown no evidence of significant harm to the fetus. Amoxicillin is also secreted in the breast milk which can lead to sensitization the infant to it.

  Indications, dosage, (Therapeutic index) of Amoxicillin: Therapeutic index of a drug is the amount of drug which provides useful effect versus the amount which could potentially be lethal to the body, therapeutic index can be calculated by dividing Toxic dose to 50% of the population by Effective dose in 50% of the population, any drug which has high therapeutic index is considered to have a good safety margin, any drug should have a wide therapeutic index so that it provides maximum benefits to the population with minimum side effects within the effective dose. In general, Penicillin group of medicine are considered highest therapeutic index amongst all the antibiotics, they only have side effects or in patients who are allergic to penicillin it is very important to note this down, as it can cause anaphylactic reactions which can be lethal for the them.  Amoxicillin can be used in the treatment of the infections caused by the below-mentioned microorganisms. It is used in adult doses /pediatric doses for bacterial endocarditis prophylaxis, chlamydia infection, H-pylori infection, Lyme disease (Arthritis, Carditis, Erythema chronicum migrans), Pneumonia, Bronchitis, Sinusitis, UTIs, Pharyngitis and Tonsillitis, skin infections, cutaneous bacillus anthracis. According to the American Heart Association (AHA), the usual adult dose for the prophylaxis of the bacterial endocarditis is 2g of immediate release amoxicillin as a single dose 30-60 mins prior to the procedure.

 Pediatric dosage for the bacterial endocarditis is 50mg/kg orally, 30-60 mins prior to the procedure and no more 2g/dose should be administered Conditions which requires antibiotic prophylaxis are as follows: Prosthetic cardiac valves including transcatheter-implanted prosthesis and homograft’s. Prosthetic materials such as annuloplasty rings and chords used to repair cardiac valves. In case of structurally abnormal valve which needed cardiac transplantation recipients with valve regurgitation. Few congenital heart disease (CHD) like unrepaired cyanotic CHD, completely repaired CHD with prosthetic material or device during its first 6 months.  Adult dose recommendation by CDC for the chlamydial infection in pregnant patient is 500mg thrice a day for 7 days as an alternative to azithromycin. In case of H-pylori infection two adult regime are followed in combination with other drugs.

 Triple therapy: 1gm orally every 12hrs for 14days in combination with Lansoprazole and Clarithromycin Dual therapy: 1gm orally every 8hrs for 14days in combination with Lansoprazole Adult dose for Lyme disease recommended by Infectious Disease Society of America (IDSA) in case of (Arthritis, Carditis, Erythema chronicum migrans) is 500mg orally 3 times a day for 14 to 28 days. Pediatric dose for the Lyme disease recommended by IDSA would be Immediate-release amoxicillin of 50 mg/kg/day orally in 3 divides doses for 14 to 28 days, single dose should not exceed 500 mg. Adult dose treatment followed for the patients with Pneumonia is immediate release Amoxicillin 500mg orally every 8hrs. or 875mg every twelve hours. Protocol recommended by Infectious Disease Society of America(ISDA) and American Thoracic Society (ATS) is the 1gm immediate release amoxicillin taken orally 3 times a day, patient should be treated for at least 5 days and should be without any signs of community acquires Pneumonia for 48 – 72 hrs. Pediatric dosage for mild moderate and severe infections in patients younger than 3months old is immediate release amoxicillin is maximum of 30mg/kg/day given orally in divided doses every 12hrs. In kids more than 4months old and weighing less than 40kg is 40mg/kg/day given orally every 8hrs in divided doses or 45mg/kg/day given orally every 12hrs in divided.

In kids weighing at least 40kg is 500mg orally every 8hrs or 875mg orally every 12hrs. In Bronchitis patients the adult recommended dose is 500mg orally every 8hrs. Or 875mg every 12 hrs.

The dose recommended by ISDA and ATS is 1gm orally 3 times a day, and follows the same guidelines as Pneumonia for the duration of the dosage that is patient should be treated for at least 5 days and should be without any signs of community acquires Pneumonia for 48 – 72 hrs. Pediatric dosage for children 3 months or younger with mild, moderate and severe infections would require immediate release amoxicillin 30 mg/kg/day orally in divided doses every 12 hours, in children 4 months or older and which are less than 40 kg, 40 mg/kg/day orally in divided doses every 8 hours or 45 mg/kg/day in divided doses every 12 hours, in children which are at least 40 kg: 500 mg orally every 8 hours or 875 mg every 12 hours. IDSA and the Pediatric Infectious Diseases Society recommendations for the children 4 months or older would be Immediate-release formulations of amoxicillin and Empiric therapy for presumed bacterial pneumonia: 90 mg/kg/day orally in 2 divided doses; maximum 4 g/day and for Streptococcus pneumoniae 90 mg/kg/day orally in 2 divided doses or 45 mg/kg/day in 3 divided doses. Group A Streptococcus: 50 to 75 mg/kg/day orally in 2 divided doses and Haemophilus influenza typeable (A to F) or non-typeable 75 to 100 mg/kg/day orally in 3 divided doses    In patients with mild to moderate Sinusitis the adult dosage recommended is 250mg every 8hrs or 500mg every 12 hrs. and in patients with severe sinusitis the dosage is 500mg every 8hrs and 875mg every 12 hrs. Pediatric dosage for mild moderate and severe infections in patients younger than 3months old is immediate release amoxicillin is maximum of 30mg/kg/day given orally in divided doses every 12hrs.

In mild to moderate infections in kids more than 4months old and weighing less than 40kg is 20mg/kg/day given orally every 8hrs in divided doses or 25mg/kg/day given orally every 12hrs in divided. In kids weighing at least 40kg is 250mg orally every 8hrs or 500mg orally every 12hrs. In cases of severe infections for kids than 4months old and weighing less than 40kg is 40mg/kg/day given orally every 8hrs in divided doses or 45mg/kg/day given orally every 12hrs in divided doses. In kids weighing at least 40kg the dosage is 500mg orally every 8hrs or 875mg orally every 12 hrs.  In cases of Tonsillitis/Pharyngitis, the adult dosage regimen is 775mg of extended release Amoxicillin taken orally once a day for 10 days within 1hr of the food intake. It is very important to complete a full course of the medication for 10 days in order to be effective. The dosage recommended by ISDA is 1000mg once a day or 500mg twice a day.

 Pediatric dose for children 12 years or older would be Extended release amoxicillin 775 mg orally once a day within 1 hour after a meal for 10 days. IDSA recommendations would follow regime of using Immediate release amoxicillin of 50 mg/kg (maximum 1000 mg) orally once a day or 25 mg/kg (maximum 500 mg) twice a day Adult dosage recommendation for Cutaneous Bacillus Anthracis and for Anthrax prophylaxis is 1gm orally every 8 hrs. for 60 days. Pediatric dosage for the Otitis Media recommended by American Academy of Pediatrics (AAP) and American Academy of Family Physicians (AAFP) recommendations would be Immediate-release amoxicillin in the dosage of 80 to 90 mg/kg/day orally in 2 divided doses; some experts recommend 90 mg/kg orally in 2 divided doses as initial therapy, for very young children with severe disease at any age, a 10 day course is recommended for the children who are 6 years or older with mild or moderate disease would need 5 to 7 days of treatment.

  In cases of moderate to severe renal impairment doses of the medications needs to be reduced.  Precautions, Contraindications & Drug-interactions: During the therapy possibility of the superinfections with bacterial or fungal pathogens needs to be considered, also it is important avoid this medication in the patients who has mononucleosis as these patients would develop skin rashes. Certain antibiotic causes Superinfection, Mucocutaneous candidiasis. In younger children the safety and efficacy of the extended release medication has not yet been developed so it is very important to have a control in the amount of drug prescribed to the children. It is very important to make sure any allergic reactions to the penicillin, it is important to inquire about previous drug interactions or allergic episodes to the medication.

Allergic reaction to the drug can lead to severe fatal reactions, can cause hypersensitivity reactions and can also lead to anaphylaxis. In case unaware and any allergic reaction occurs, the drug should be stopped immediately and emergency treatment should be rendered as soon as possible. Thus, it is very important to inquire about the previous allergic reactions in the history to avoid anaphylactic reaction to the drug, Serum sickness–like reactions, erythematous maculopapular rashes, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, erythema multiforme, Stevens-Johnson syndrome, hypersensitivity vasculitis and urticaria. Anti-microbial agents including amoxicillin have shown to cause Clostridium Difficle Associated Diarrhea (CDAD), and it can range from mild to fatal severity. It can cause gastric upset leading to Nausea, vomiting, diarrhea, black hairy tongue, and hemorrhagic/pseudomembranous colitis.

 When taken in combination with Probenecid it is shown that Probenecid increases its availability and blood levels by reducing renal clearance of the drug. Other drugs like Macrolides, Sulfonamides, Chloramphenicol, and Tetracyclines may interfere with the bactericidal effects of the amoxicillin, also it is seen that amoxicillin interacts with the methotrexate. Amoxicillin has shown to change the microbial flora in the body, it has also shown to interfere with and reduce the efficacy of estrogen/progesterone contraceptives and oral anticoagulants. It also shows false positive for diabetes in case of urine test when used with Benedict’s Solution, or Fehling’s Solution. It can also cause Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis may occur. These are due to hypersensitivity and usually reversible on stoppage of therapy. Can affect central nervous system leading to Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness are seen rarely. Can affect liver in very cases causing cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis.

 Can cause Convulsions in patients with impaired renal function or in those receiving high doses or in patients with predisposing factors.  Rarely would it cause crystalluria, nephritis affecting kidneys. References: McGowan, Kelly; McGowan, Troy; Ivanovski, Saso; Journal of Clinical Periodontology, Jan2018; 45(1): 56-67.

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1371/journal.pone.0160260 McCormack PL; Keating GM; Drugs, 2005; 65(1): 121-136.

16p. (Journal Article – tables/charts) ISSN: 0012-6667 PMID: 15610061, Database: CINAHL Di Pietro, Pasquale; Della Casa Alberighi, Ornella; Silvestri, Michela; Tosca, Maria Angela; Ruocco, Anna; Conforti, Giorgio; Rossi, Giovanni A.; Castagnola, Elio; Merlano, Maria Caterina; Zappettini, Simona; Renna, Salvatore. Italian Journal of Pediatrics. 12/22/2017, Vol. 43, p1-13. 13p. DOI: 10.

1186/s13052-017-0432-2., Database: Academic Search Premier Faryal Ghaffar; Luz Stella Muniz; Kathy Katz; Jeanette L. Smith; Theresa Shouse; Phyllis Davis; George H.

McCracken, Jr. In: Clinical Infectious Diseases. 34(10):1301-1309; University of Chicago Press, 2002. Language: English, Database: JSTOR Journals 


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