ANTIMICROBIAL DRUGS – General Considerations

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ANTIMICROBIAL DRUGS – General Considerations:

ANTIMICROBIAL DRUGS – General Considerations By – Dr. S. Varun Satpathy 2 nd Year PG Department of Pharmacology, SMIMS Moderator- Dr. Prakash Tomar Assistant Professor Department of Pharmacology SMIMS

CONTENT -:

CONTENT - INTRODUCTION AND DEFINITION HISTORY CLASSIFICATION MECHANISM OF ACTION TYPE OF ORGANISM AGAINST WHICH PRIMARILY ACTIVE SPECTRUM OF ACTIVITY TYPE OF ACTION ANTIBIOTICS- SOURCE PROBLEMS ARISING WITH USE OF AMAs PRINCIPLES OF ANTIBIOTIC DOSING CHOICE OF AMAs PROPHYLACTIC USE OF AMAs

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Antimicrobial drugs are the greatest contribution of the 20 th century to therapeutics Importance is magnified in developing countries where infective diseases predominate As a class, they are one of the most frequently used as well as misused drugs

Antibiotics -:

Antibiotics - These are substances produced by microrganisms , which selectively suppress the growth of or kill other microrganisms at very low concentrations Chemotherapeutic agent Antimicrobial agent (AMA)

HISTORY – divided into 3 phases:

HISTORY – divided into 3 phases Period of empirical use - * ‘ mouldy curd ’ on boils , chaulmoogra oil by the hindus in leprosy , chenopodium by aztecs for intestinal worms , mercury by Paracelsus (16 th century) for syphillis , cinchona bark (17 th century) for fever. Ehrlich’s phase of dyes and organometallic compounds ( 1890 – 1935 ): discovery of microbes in later half of 19 th century – arsenicals – atoxyl for sleeping sickness and arsphenamine & neoarsphenamine for syphillis – coined the term ‘chemotherapy’

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C . Modern era of chemotherapy – domagk - demonstrated therapeutic effect of prontosil  PYOGENIC INFECTION Penicillium mould  destroy staphylococcus – fleming (1929)- penicillin Chain & Florey (1939) – purified the penicillin – 1 st clinical use of penicillin (1941) Waksman ( 1944) – systematic search of actinomycetes as source – streptomycin

Classification -:

Classification - Chemical structure 1. Sulfonamides and related drugs : sulfadiazine and others, sulfones – Dapsone (DDS), Paraaminosalicylic acid (PAS) 2. Diaminopyridines : Trimethoprim , Pyrimethamine 3. Quinolones : nalidixic acid, norfloxacin , ciprofloxacin, prulifloxacin,etc . 4. β - lactam antibiotics : penicillins , cephalosporins , monobactams , carbapenems .

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5. Tetracycline s – oxytetracyclines , doxycycline,etc . 6. Nitrobenzene derivative : chloramphenicol 7 . Aminoglycoside : streptomycin, gentamicin , amikacin , neomycin etc. 8. Macrolide antibitoics : erythromycin , clarithromycin , azithromycin , etc. 9. Lincosamide antibiotic : lincomycin , clindamycin 10. Glycopeptide antibiotic : vancomycin , teicoplanin 11. Oxazolidinones : linezolid 12. Polypeptide antibiotics : polymixin B, colistin , bacitracin , tyrothricin 13. Nitrofuran derivatives : nitrofurantoin , furazolidone

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14. Nitroimidazoles : metronidazole , tinidazole , etc. 15. Nicotinic acid derivatives : isoniazid , pyrazinamide,ethionamide etc. 16. Polyene antibiotics : Nystatin , Amphotericin B, hamycin 17. Azole derivatives : miconazole , clotrimazole , ketoconazole , fluconazole 18.Others : Rifampin , spectinomycin , sod.fusidate , cycloserine , viomycin , ethambutol , thiacetazone , clofazimine , griseofulvin

B.Mechanism of action -:

B.Mechanism of action - 1. Inhibit cell wall synthesis : penicillins , cephalosporins , cycloserines , vancomycin , bacitracin 2. Cause leakage from cell membranes : polypeptides- polymyxins , colistin , bacitracin . Polyenes - amphotericin B, nystatin , hamycin 3. Inhibit protein synthesis : tetracyclines , chloramphenicol , erythromycin, clindamycin , linezolid 4. cause misreading of m-RNA and affect permeability : Aminoglycosides – streptomycin, gentamicin etc.

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5. Inhibit DNA gyrase – fluoroquinolones , ciprofloxacin and others 6. Interfere with DNA function – rifampin 7. Interfere with DNA synthesis – acyclovir, zidovudine 8. Interfere with intermediary metabolism – sulfonamides, sulfones , PAS, trimethoprim , pyrimethamine , metronidazole

C.Type of organisms against which primarily active -:

C.Type of organisms against which primarily active - Antibacterial : penicillins , aminoglycosides , erthryomycin , fluoroquinolones etc. Antifungal : griseofulvin , amphotericin B, ketoconazole , etc Antiviral : acyclovir, amantadine , zidovudine etc. Antiprotozoal : chloroquine , pyrimethamine , metronidazole , diloxanide etc. Antihelminthic : mebendazole , pyrantel , niclosamide , diethyl carbamazine etc.

D. Spectrum of activity -:

D. Spectrum of activity -

Type of action :

Type of action Primarily bacteriostatic – Sulfonamides Erythromycin Tetracyclines Clindamycin Chloramphenicol Linezolid Ethambutol Primarily bactericidal – Penicillins Cephalosporins Aminoglycosides Vancomycin Polypeptides Ciprofloxacin Rifampin Metronidazole Isoniazid Cotrimoxazole Pyrazinamide

Antibiotics are obtained from ::

Antibiotics are obtained from : Fungi – Penicillin Griseofulvin Cephalosporin Bacteria – Polymyxin B Tyrothricin Colistin Aztreonam Bacitracin Actinomycetes – Aminoglycosides Macroglycosides Tetracyclines Polyenes Chloramphenicol

Problems that arise with use of AMAs:

Problems that arise with use of AMAs TOXICITY Local irritancy Systemic toxicity – high therapeutic index – penicillins , some cephalosporins and erythromycin lower therapeutic index – aminoglycosides , tetracyclines , chloramphenicol very low therapeutic index - polymyxin B , vancomycin , amphotericin B

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2. HYPERSENSITIVITY REACTIONS 3. DRUG RESISTANCE - a) Natural resistance b) Acquired resistance

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4. SUPERINFECTION ( Suprainfection ) – Appearance of new infection as a result of antimicrobial therapy > common when host defence is compromised conditions predisposing to superinfections – Corticosteroid therapy Leukemias and other malignancies AIDS Agranulocytosis Diabetes , DIC

1. Genetic methods of Antibiotic resistance - :

1. Genetic methods of Antibiotic resistance - Chromosomal Method s : Mutations Extrachromosomal Methods : Plasmids r-genes  R-plasmids Plasmids which carry genes resistant to antibiotics METHODS – Transfer of r-genes from one bacterium to another – 3 mechanisms – CONJUGATION , TRANSDUCTION & TRANSFORMATION Transfer of r-genes between plasmids within the bacterium – * by Transposons * by Integrons

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By TRANSPOSONS – Transposons are DNA segments that cannot self-replicate but can self-transfer between plasmids or from plasmid to chromosomes Donor plasmid containing a Transposon , cointegrates with the target (acceptor) plasmid During the process of cointegration the transposon can now replicate Both plasmids then separate and each contains the r-gene carrying the transposon

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By INTEGRONS – Mainly the MDR , can also be spread by a larger mobile DNA unit called “ integrons ” Each integron is packed with multiple gene cassettes, each consisting of a resistant gene attached to a small recognition site These gene cassettes are encoded with several bacterial functions including resistance and virulence Currently , the gene cassettes have been identified for all antibiotics except fluoroqinolones

2. Biochemical mechanisms of resistance to Antibiotics -:

2. Biochemical mechanisms of resistance to Antibiotics - By producing an enzyme that inactivates the antibiotic * inactivation of β - lactam antibiotics * inactivation of Chloramphenicol * inactivation of Aminoglycosides Prevention of Drug accumulation in the Bacterium By Modification/Protection of the target site Use of alternative pathways for metabolic/growth requirement By Quorum Sensing

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5. Nutritional deficiencies 6. Masking of an infection

PRINCIPLES OF ANTIBIOTIC DOSING-:

PRINCIPLES OF ANTIBIOTIC DOSING- 4 Important characterstics that have a significant influence on the frequency of dosing of any Antibiotic are – M inimum I nhibitory C oncentration (MIC) C oncentration D ependent K illing(CDK) T ime D ependent K illing(TDK) P ost A ntibiotic E ffect (PAE)

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AMAs can also be classified on the basis of their CDK/TDK activity & their PAE as follows – Group 1 – CDK with prolonged PAE - * Aminoglycosides * Fluoroquinolones * Metronidazole analogues * Rifampicin Group 2 – TDK with shorter PAE – * β - lactam antibiotics * Clindamycin * Macrolides ( exp. Azithromycin & Clarithromycin )

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Group 3 – TDK with prolonged PAE – * newer macrolides – azithromycin , clarithromycin * longer acting tetracyclines

Choice of an Antimicrobial Agent - :

Choice of an Antimicrobial Agent - Patient factors – Age Renal and hepatic function Local factors Drug allergy Impaired host defence Pregnancy Genetic factors

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Organism related considerations – Clinical diagnosis itself directs choice of AMA A good guess can be made Choice to be based on bacteriological examination Bacteriological services are not available Bacteriological services are available, but treatment cannot be delayed Bacteriological services are available and treatment can be delayed for a few days

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Drug factors – Spectrum of activity Type of activity Sensitivity of the organism Relative toxicity Pharmacokinetic profile Route of administration Evidence of clinical efficacy Cost

Combined use of Antimicrobials:

Combined use of Antimicrobials To achieve synergism – general guidelines are – * 2 bacteriostatic agents – additive , rarely synergistic * 2 bactericidal drugs are freq. additive and sometime synergistic * combination of bactericidal with a bacteriostatic drug is additive if the organism has low sensitivity to cidal drug * combination of bactericidal with a bacteriostatic drug is antagonistic if organism has high sensitivity to cidal drug

Cont….:

Cont…. To reduce severity or incidence of adverse effects To prevent emergence of resistance To broaden the spectrum of anti-microbial action * Treatment of mixed infection * Initial treatment of severe infections *Topically

Disadvantages of antimicrobial combinations - :

Disadvantages of antimicrobial combinations - They foster a casual rather than rational outlook in the diagnosis of infections and choice of AMA . Increased incidence and variety of adverse effects. Increased chances of superinfections If inadequate doses of nonsynergistic drugs are used – emergence of resistance may be promoted Higher cost of therapy

Prophylactic use of Antimicrobials -:

Prophylactic use of Antimicrobials - PROPHYLAXIS AGAINST SPECIFIC ORGANISM - Rheumatic fever – a long acting penicillin G – d.o.c Tuberculosis – Children, HIV positive and other susceptible contacts of open cases need to be protected . Isoniazid alone or with rifampin is recommended Mycobacterium avium complex (MAC) – HIV/AIDS pts. may be protected against MAC infection by azithromycin / clarithromycin HIV infection

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2. PREVENTION OF INFECTION IN HIGH RISK SITUATIONS – Dental extraction, tonsillectomy, endoscopies cause damage to mucosa harbouring bacteria  bacteremia occurs – prophylaxis with amoxycillin or clindamycin may be given few hrs before to few hrs after manipulation Catheterization or instrumentation of urinary tract : cotrimoxazole or norfloxacion , pts with valvular lesions may be protected with ampicillin , gentamicin or vancomycin during catheterization To prevent recurrences of UTI in pts with abnormalities of the tract : cotrimoxazole or nitrofurantoin may be given on long term basis

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COPD, Chronic Bronchitis : ampicillin / doxycycline /ciprofloxacin – to prevent acute exacerbation - doubtful value Immunocompromised pts : penicillin/cephalosporin ± an aminoglycoside or fluoroquinolone are often used to prevent RTI & Septicemia , but incidence of superinfections is high

Prophylaxis of Surgical site infection -:

Prophylaxis of Surgical site infection - Purpose – reduce the incidence of SSI with minimal alteration of normal microbial flora of the host and min. adverse effects For grading the need and intensity of AMAs prophylaxis – operative wounds have been classified into 4 categories with increasing risk of SSI – BASED ON NATIONAL RESEARCH COUNCIL (NRC) CRITERIA -

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Systemic AMAs should be employed only when there is clear risk of SSI Important that AMAs are not started prematurely and is not continued beyond time Administration of AMAs has to be so timed that peak blood levels occur when clot is forming in surgical wound, and it is present throughout the procedure Most of oral drugs given 1 hr before incision While IV adm . Just before/after anesthesia- best ensures effective blood levels of the AMA during surgery

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Most AMA do not penetrate the clot once it is formed and is older than 3 hrs. In case of prolonged surgery, AMA may be repeated I.V during the procedure Post-operative adm . of AMA, esp. after 4 hrs of wound closure is recommended only in case of contaminated and dirty surgery , in which case it may be given for upto 5 days Commonly employed AMAs for prophylaxis in case of

clean and clean-contaminated surgeries - :

clean and clean-contaminated surgeries - Oral ( single dose given 1 hr before procedure) Amoxicillin 2 g (50 mg/kg) Cephalexin 2 g (50 mg/kg) Cefadroxil 2 g (50 mg/kg) Clindamycin 600 mg (20 mg/kg) for pts allergic to penicillin 5. Azithromycin 500 mg (15 mg/kg) 6. Clarithromycin 500 mg (15 mg/kg)

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Parenteral ( single injection just before procedure ) Ampicillin 2 g (50 mg/kg) i.m / i.v Cefazolin 1 g (25 mg/kg) i.v Vancomycin 1 g (20 mg/kg) i.v ( in MRSA prevalent areas / penicillin allergic pts ) Clindamycin 600 mg ( 20 mg/kg) i.v ( for penicillin allergic pts)

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Dirty contaminated wounds – (generally adm . for 5 days) Cefazolin 1 g iv 8 hrly + Vancomycin 1 g iv 12 hrly Cefoxitin 1 g iv 6 hrly / ceftizoxime 1 g iv 12 hrly Clindamycin 0.6 g iv 8 hrly + Gentamicin 80 mg 8 hrly Ampicillin 2 g iv 6 hrly / Vancomycin 1 g iv 12 hrly + Gentamicin 80 mg 8 hrly + Metronidazole 0.5 mg iv 8 hrly Amoxicillin 1 g + clavulanate 0.2 g iv 12 hrly All given for 5 days

References - :

References - ESSENTIALS OF MEDICAL PHARMACOLOGY : ANTIMICROBIAL DRUGS: GENERAL CONSIDERATIONS, TRIPATHI K D 7 TH EDITION , 686-700; 2013 PRINCIPLES OF PHARMACOLOGY, INTRODUCTION TO CHEMOTHERAPY:SHARMA HL, SHARMA KK 2 ND ED. 687-701; 2011 IMAGES ; WWW.GOOGLE.COM

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THANK YOU FOR YOUR PATIENCE … HAVE A GREAT DAY !!!

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