Essay 3: Clinical and Pharmacological Approaches for Treatment with Antimicrobial Drugs PDF
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This document details clinical and pharmacological approaches for treating infections with antimicrobial drugs, including different types of drugs, their mechanisms, and their applications. It covers various aspects of antibiotic therapy and considerations for patients.
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Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs What is an antibiotic? A drug used to treat infections caused by bacteria and other microorganisms Main principles Make a diagnosis as precisely as possible and define the site of infection, organisms responsible...
Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs What is an antibiotic? A drug used to treat infections caused by bacteria and other microorganisms Main principles Make a diagnosis as precisely as possible and define the site of infection, organisms responsible and their susceptibility to a range of antimicrobial agents All relevant samples are taken before treatment begins Remove barriers to cure- drain abscesses, remove urinary tract obstructions, infected IV catheters Decide whether chemotherapy (antibiotic therapy) is really necessary Duration of treatment Normally, it takes 5-10 days in cases where the type of infection is know Shorter than 5 days- acute cystitis without complications in women (1 days) Long lasting- only as an exception (osteitis, prostatitis, endocarditis etc) NB: Treatment with bactericidal antibiotics is shorter that wit bacteriostatic antibiotics!!! Route of administration Parenteral therapy is preferred for serious infections- high theraputic concentrations are achieved reliably and rapidly Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Initial IV therapy should be swapped to oral whenever possible once patient has improved clinically and as long as suitable oral drug is available Groups of antibacterial drugs Type I Effective against non-proliferating and proliferating microorganisms Includes drugs like aminoglycosides and fluoroquinolones that have fast and powerful antibacterial effects and less ADRs when peak concentrations are reached They produce a concentration-dependant effect Type II Effective against proliferating microorganisms This group contains the beta lactams They show highest antibacterial efficacy when their serum concentrations are 2-4 more than the MIC during most o the dosage interval Once begun, changing antibiotic therapy should be avoided unless necessary Type III Bacteriostatic drugs! Tetracycline Macrolides Amphenicols Lincosamides Sulphonamides Why are combinations used? To avoid drug resistance treating tuberculosis or some other rare disease To broaden the spectrum of antibacterial activity Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs For prophylaxis of massive contamination in open abdominal operations or treatment of nosocomial infections (hospital acquired) To obtain potentiation (or 'synergy'), i.e. an effect unobtainable with eithe drug alone, e.g. penicillin plus gentamicin for enterococcal endocarditis. To enable reduction of the dose of one component and hence reduce the risks of ADRs. Why is prophylactic antibiotic therapy used? True prevention of primary infection: rheumatic fever, recurrent UTIs. Prevention of opportunistic infections. Suppression of existing infection before it causes overt disease, e.g. tuberculosis, malaria. Prevention of acute exacerbations of a chronic infection, e.g. bronchitis, cystic fibrosis. Prevention of spread among contacts (in epidemics and/or sporadic cases). Criteria for choice of antibiotic Efficiency: Antimicrobial spectrum Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Pharmacokinetics Dose regimen Duration of treatment Mechanism of action Drug safety: Unwanted drug interactions Drug interactions Concomitant diseases Physiological state of patient (pregnancy) Convenience: Convenience of drug application Possibility for use of sick children, elders, pregnant women etc Price Bacterial resistance Resistance is the natural biological response to widely used antibiotics! Has enormous medical and social/economical significance Infections caused by resistant strains often result in hospitalisation, have prolonged duration and worsen the patient's prognosi When the first line therapy is not quite effective, second and third line drugs should be used. But, these are often more expensive, less safe and often not available All of these factors increase the direct and indirect costs of treatment and increases the risk of spreading resistant strains to society Pregnant women Majority of drugs are contraindicated! The drugs that can be used in pregnancy are: Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Penicillins Cephalosporins Fosfomycin Macrolides (only in the second half of pregnancy) Azithromycin Penicillins Classification Narrow spectrum Broad spectrum Protected/combined Pharmacokinetics M- poorly or not metabolised Suitable for liver disease patients E- mainly urine Suitable for UTI Pharmacodynamics Inhibit cell wall synthesis Spectrum Bactericidal Broad spectrum- active against gram negative Narrow spectrum- active against gram positive Protected- against anaerobes ADRs Dysbacteriosis Allergic reactions Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Morbilliform rash (measles rash) Local irritant action Drug interactions Synergism with other beta lactams Cloxacillin Ampicillin= Cloxampici Broad spectrum oral penicillins reduce effect of oral contraceptives Potentiation with beta lactamase inhibitors Cephalosporins Classification 1st gen 2nd gen 3rd gen 4th gen 5th gen Pharmacokinetics E- most excreted in urine Cefazolin (1), cefamandole (2) and ceftriaxone (3) are excre bile! Pharmacodynamics Cell wall synthesis inhbitors Spectrum Bactericidal ALL have a broad spectrum of action ADRs Allergic reactions Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Dysbacteriosis- GI disturbances, candidiasi Potentially nephrotoxic (1st gen Decreased PT (only in those that are excreted via bile) Drug interactions Synergism with penicillins. With loop diuretics and nephrotoxic antibiotics, the risk of kidney damage in 1st generation increases. Cephalosporins with bile excretion enhance the action of anticoagulants. Combined with beta-lactamases Carbapenems Classification Meropenem Imipenem Pharmacodynamics They are inhibitors of cell wall synthesis Spectrum ULTRA BROAD spectrum ADRs Allergic reactions Local irritant effect Convulsions (imipenem) Nephrotoxicity (imipenem) C.difficile infection Monobactams Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Classification Aztreonam Suitable for patients with allergy to penicillins! Pharmacodynamics Inhibition of bacterial cell wall synthesis Spectrum Bactericidal Narrow spectrum Glycopeptides Classification 1st gen- vancomycin, teicoplanin 2nd gen- telavancin, ortivancin Pharmacokinetics A- no oral absorption M- not metabolised E- urine Pharmacodynamics Inhibit bacterial cell wall synthesis Spectrum Bactericidal Narrow spectrum towards gram positive (including MRSA 2nd generation also towards VRE ADRs Local irritant effect Ototoxicity Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs Nephrotoxicity "Red man syndrome" (histamine release Allergic reactions Aminoglycosides Classification Gentamicin Amikacin Tobramycin Pharmacodynamics Inhibit 30s subunit Pharmacokinetics A- must be given parenterally (except neomycin) D- tissue conc may be subtheraputic and penetration into body fluids is variable Extracellular Dont cross BBB but they can cross the placental barrier M- not metabolised E- unchanged in urine Spectrum Broad spectrum Bactericidal! ADR Ototoxicity Nephrotoxicity Neuromuscular reactions Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Pain at site if given IM Tetracyclins Classification Tetracycline Doxycycline Minocycline Tigecycline Pharmacodynamics Inhibit 30s subunit Pharmacokinetics M- partial E- urine and bile Their bile concentration is higher than that in plasma ADRs Effects on calcified tissues- damages bones and teeth (brown discolouration, cavities, stunted growth, yellow nails) Hepatotoxicity (rare) Phototoxicity- sunburn Nausea and vomiting Dysbacteriosis Macrolides Drugs Azithromycin- cap 250mg, tab 500mg Clarithromycin- tab 250mg, flac 500mg Erythromycin- drag 250mg Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Spiramycin- tab 250mg Metronidazole Pharmacokinetics A- mostly oral Give on empty stomach! D- no barriers are crossed Extracellular and intracellular distribution! M- liver Macrolides are enzyme inhibitors! Clarithromycin Azithromycin E- saliva, bile, urine Pharmacodynamics Inhibit 50s subunit Spectrum Narrow spectrum mainly against gram positive Contemporary macrolides are extended spectrum Bacteriostatic! Contraindications Allergies Pregnancy (elevates risk of cerebral palsy) Epileptic patients Severe liver impairment ADRs GI disturbances Prolongation of QT and QTc intervals Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Increased levels of ALP and/or transaminases Prolonged therapy- cholestatic hepatitis and jaundice Amphenicols Classification Chloramphenicol Pharmacokinetics D- high conc in CSF M- liver (glucuronidation) It is an enzyme inhibitor!! Pharmacodynamics Inhibits 50s subunit Spectrum Bacteriostatic! Broad spectrum ADRs Hemopathies Bone marrow supression (aplastic anemia) Optic nerve damage Gray baby syndrome Liver damage Severe dysbacteriosis Lincosamides Classification Lincomycin Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Clindamycin Pharmacokinetics A- oral and parenteral D- good extracellular distribution, penetrate into bones and soft tissues Can cross BBB and FPB M- liver E- bile and urine Pharmacodynamics Inhibit 50s subunit They are bacteriostatic! Spectrum Narrow against g+ and anaerobes Especially against Staphylococcus! ADRs Gastrointestinal disorders, pseudomembranous colitis; IM injection is painful. Infiltrates and sterile soft tissue abscesses may form Impaired liver function Decreased leukocytes and platelets Allergic reactions Sulfonamides Classification Oral absorbable Short acting- sulfisoxazole (tab 500mg) Medium acting- Co-trimoxazole- 480mg Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Long acting- sulfadoxine, Fansidar (tab) Oral non absorbable Sulfaguanidine- tab 500mg Topical agents Sulfadiazine- cream 1% 25g Sulfacetamide- collyr 10% 20ml Combined sulfonamides (bacterocidal) Co-trimoxazole- tab 120mg, 480mg Sulfasalazine- tab enterosolv. 500mg Fansidar- tab These are combination between one sulphonamide and another agent Pharmacokinetics A- sulfaguanidine is not absorbed Used for GI tract infections D- bind to PP with high affinity Pharmacodynamics They are structure analogues of Para‐Amino‐Benzoic Acid (PABA) and i structure antagonists. Due to its structure they inhibit the enzyme dihydrofolate‐reductase and dihydrofolic acid decreases in the microbial cell. Therefore they inhibit the synthesis of bacterial dihydrofolic acid (folic acid synthesis is inhibited) They incorporate the structure of dihydrofolic acid and cause malfunction of the microbial cell Non-combined sulphonamides are bacteriostatic! Combined sulphonamides are bactericidal! Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Spectrum Broad spectrum (work against gram + and -) Work more against gram - (Urinary infections, GI infections Also work against protozoa (Plasmodium falciparium, Toxoplasma gondii ADR Nephrotoxicity- due to crystalluria Hypersensitivity reactions Kernicterus in newborns Dysbacteriosis Quinolones Classification 1st generation (non-fluorinated) Nalidixic acid This has a narrow spectrum of activity (only against gram -, they are bacteriostatic) Used for UTI 2nd generation (fluorinated) Ciprofloxacin Norfloxacin Ofloxacin Enoxacin 2nd generation are broad spectrum and they are bactericidal!! 3rd generation (fluorinated) Levofloxacin 4th generation (fluorinated) Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Moxifloxacin Trovafloxacin Pharmacokinetics D- excellent tissue and intracellular distribution M- enzyme inhibitors E- moxifloxacin is mainly excreted by liver Pharmacodynamics They exert their actions by inhibiting bacterial nucleic acid synthesis through disrupting the enzymes topoisomerase IV and DNA gyrase, and by causing breakage of bacterial chromosomes DNA gyrase found in gram - Topoisomerase found in gram + Therefore, fluoroquinolones are bactericidal! Spectrum Broad Effective against: Gram - (E.coli, P. aeruginosa Gram + (strep) Atypical organisms (Legionella, Chlamydia ADRs Joint cartilage erosion- should be avoided in children and pregnancy Dysbacteriosis GI symptoms Photosensitivity Neurotoxicity Cardiotoxicity- QT interval prolongation Essay 3- Clinical and pharmacological approaches for treatment with antimicrobial drugs 1 Hemolytic anemia- in those Pt with G6P-