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Newer Anti-microbials

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									Antibiotics…

Substances produced by micro-organisms which selectively suppress the growth of or kill other micro-organisms at a very low concentration.

Characteristics of an Ideal Antimicrobial

Selectively toxic to the microbe but non toxic to the host cell Microbicidal rather than microbistatic Relatively soluble functioning even when diluted in body fluids Remains potent long enough to act and is not broken down or excreted prematurely Doesn’t lead to the development of antimicrobial resistance Readily delivered to the site of infection Reasonably priced Doesn’t disrupt the host health by causing allergies or predisposing the host to other infections

Mechanism of Action of Antimicrobial Drugs

Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid synthesis Inhibition of metabolic pathways Interference with cell membrane integrity

History
Penicillin- the first Wonder Drug

Discovery of penicillin in 1928

Alexander Fleming

Continued….
The first antibiotic to be used clinically in 1941 In 1942 after world war 2, penicillin was widely used to treat the wound infections saving 12%-15% lives.

But the major problem of drug resistance started in 1950s leading to death of many people because of Global Flu in 1957. ‘Superpenicillin team’ was set to discover second generation penicillins such as methicillin and ampicillin.

Structure of Penicillin (B-Lactam Antibiotic)
The chemical structure determined by Dorothy Crowfoot Hodgkin in the early 1940s Consist of 3 parts: -thiazolidine ring -beta-lactam ring (3 carbon 1 nitrogen ring) -variable side chain dictating antimicrobial activity

Mechanism of Action
Interferes with the synthesis of bacterial cell wall. Cell wall consist of peptidoglycans linked together with enzymetranspeptidase Penicillin blocks the action of this enzyme. Dividing bacteria produce CWD (cell wall deficient) forms causing lysis of the wall and cell death.

Penicillin G
Antibacterial activity Has narrow spectrum activity limited to primarily gram positive bacteria. Cocci: such as Streptococci and Staphylococcus aureus Bacilli: such as Cornybacterium diphtheriae, Clostridium tetanae, Spirochetes, listeria.

Development of Resistance
Insensitivity - deeper location of target enzymes and PEPs. Production of Penicillinase - Bacteria such as E.coli, H.influenzae, gonococci, etc. produce penicillinase which opens up the B lactam ring making the drug inactive. Impermeability - occurs because of alteration of Porin, an outer membrane protein possessed by some gram –ve microbes. Trapping-β-lactamases - allows titration of the drugs, for lowering the intracellular concentrations of the antimicrobial drugs

Newer Penicillins
1) Acid resistant alternative to penicillin G -Phenoxymethyl penicillin (Penicillin V) 2) Penicillinase resistant penicllins - Cloxacillin - Methicillin 3) Extended spectrum penicillin -Aminopenicillin - Ampicillin, Amoxicillin -Carboxy penicillin - Carbenicillin, Ticarcillin -Ureido penicilin - Piperacillin, Mezlocillin -Amdinocillin - Mecillinam 4) B-lactamase inhibitors -Clavulanic acid -Sulbactam

Acid Resistant Altenative To Penicillin G
Phenoxymethyl Penicillin (Penicillin V) -Differs from penicillin G that it is acid stable. -but antibacterial spectrum is not comparable to penicillin G as it is less active against Neisseria and other gram negative bacteria.
Uses - used only for streptococcal pharyngitis sinusitis, otits media, prophylaxis of rheumatic fever, pneumococcal infection and trench mouth.

Penicillinase Resistant Penicillin
Protects the B lactam ring from attack by staph. penicillinase, the only indication being infections caused by penicillinase producing staphylococci. a) Methicillin - Highly penicillinase resistant but not acid resistant. - Causes haematuria, albuminurea and reversible intertstitial nephtritis - Methicillin resistant staph. aureus (MRSA) have emerged. b) Cloxacillin -Highly penicillinase resistant as well as acid resistant. -Used effectively against all staph. infections but not effective against MRSA.

3)Extended Spectrum Penicillin
 Ampicillin: -Active against all organisms sensitive to PnG in addition to many gram negative bacilli like H.influenzae , E.coli, salmonella -First line drug for meningitis and non penicillinase producing gonococcal infections -Adverse effect being diarrhoea.  Amoxicillin - Similar to Ampicillin in all aspects except better oral absorption and fewer incidences of diarrhoea. - Generally indicated for typhoid, bronchitis, UTI, gonorrhoea.

A) Aminopenicillin

B) Carboxy penicillins

 Carbenicillin -Effective against Pseudomonas Aeruginosas and Proteus. -Neither penicillinase nor acid resistant.
Ticarcillin -More potent against pseudomonas as compared to carbenicillin.

c) Ureidopenicillins  Piperacillin - Antipseudomonal penicillin. - Good activity against Klebesiella. - Used mainly for neutropenic/immunocompromised patients having serious gram –ve infections and in burns.

 Mezlocillin. - Inhibits pseudomonas as well as klebeseilla

d) Amdinocillin

Mecillinam
-Highly active against gram –ve bacilli like E.coli, salmonella, Klebesiella and Enterobacter but not against pseudomonas and gram +ve cocci. -Successfully used in typhoid, dysentery and UTI.

B Lactamase Inhibitors
B lactamase are a family of enzymes produced by many gram +ve and –ve bacteria that inactivate B Lactam antibiotics by opening the B lactam ring The two inhibitors Clavulanic acid and Sulbactam are available for clinical use.

Continued….
Clavulanic acid: - Called ‘suicide inhibitor’ as it gets inactivated after binding to enzyme. - It has no antibacterial activity of its own therefore given in combination with amoxicillin (co-amoxiclav). - Preferred for hospital acquired infection. Sulbactam -Similar profile of activity as clavulanic acid. -Doesn’t induce chromosomal B lactamase as compared to clavulanic acid. -Indicated for gonorrhoea and mixed anaerobic infections.

Uses

Uses
Cardiovascular system -Streptococcal Endocarditis -Enterococcal Endocarditis -Staphylococcal Endocarditis Drugs used - Benzylpenicillin - Amoxicillin - Flucloxacillin Respiratory system - Exacerbation of COPD - Pneumonia Drugs used - Amoxcilln

Endocarditis

Continued……
Central nervous system -Meningitis Drugs used -Penicillin G Blood -Community acquired septicemia -Meningococcal septicemia Drugs used -Penicillin G Dental -Abscess -Gingivitis Dental Abscess Drugs used -Amoxcillin

Meningitis

Continued……
ENT -Sinusitis -Otitis media -Throat infection Drugs used -Penicillin V -Amoxicillin -Flucloxacillin Other uses -Syphillis -Gas gangrene -Tetanus -Diphtheria

Otitis media

Syphillis

Gas gangrene

Adverse effects
Local irritancy
Angioneurotic Edema

Hypersensitivity

Morbiliform Rash
Urticaria

Exfoliative Dermatitis

How to Prevent Hypersensitivity…?

Intradermal Penicillin Hypersensitivity Test

Recent Clinical Trials In Penicillin

Sponsor
1) 2) 3) University of Nottingham,UK Meir Medical Center National Institute of Allergy and Infectious diseases, Hoffmann-La Roche

Condition
Cellulitis Penicillin Allergy

Intervention
Drug: Penicillin VK Drug: Penicillin

Phase
Phase IV Phase IV Completed

Neurosyphilis Penicillin G potassium

Conclusion
Penicillin functions by inhibiting bacterial cell wall synthesis. With advances in clinical trials of new genera antibiotics, penicillin may not have a mainstay but certain clinical conditions are still dependent on penicillin for treatment. Penicillin has proven utility in treating various bacterial infections like meningitis, gonorrhea, syphilis, diphtheria and prophylactic uses like rheumatic fever, bacterial endocarditis,agranulocytosis patients and so on…

Though it has ADRS like local irritancy, direct toxicity and hypersensitivity, its advantages and direct benefits far outweigh the ADRS. Combinations are frequently prescribed to overcome resistance, yet it remains a major concern. Hence, judicious use is recommended. Penicillin being the First Antibiotic, triggered ‘the age of antibiotics’ and is truly a ‘Wonder Drug’ of the century.

References
Books: 1)Essential of Medical PharmacologyK.D.Tripathi 2)Textbook of Medicine- Davidson

Websites: 1)www.penicillinwonderdrug.com 2)www.antibiotics.com/penicillin.html. 3)www.clinicaltrials.gov/penicillin/recent.html. 4)www.medlineplus.com


								
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