Anti-microbial agents General consideration-3

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Anti-microbial agents General consideration-3

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Antimicrobial Agents:

Antimicrobial Agents Prof. R. K. Dixit Pharmacology and Therapeutics K.G.M.U. Lucknow

Chemical Classification (Public Loves GOOD Quality BATSMAN) :

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides- Polymyxin , Colistin , Bacitracin , Tyrothricin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin, Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Ethambutol , Clofazimine,Griseofulvin , etc Di aminopyrimidines - Pyrimethamine …………………. Trimethoprim , Q uinolones - Nalidixic acid, ciprofloxacin and many cins …. B eta- lactam - Penicillins , Cephalosporins , Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin , Neomycin, T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfadoxin , Dapsone, PAS,, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin , Azithromycin A zoles- Fluconazole , Clotrimazole , Miconazole N itroimidazoles - Metronidazole , Tinidazole , N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Cotrimaxozole Cell Wall Inhibition (BCV) Cell Membrane leakage (PP) Protein synthesis inhibition (MAT, LC) DNA gyrase inhition (Quinolones) RNA polymerase inhibition (MR) Metabolism inhibition (Folic acid synthesis inhibition) Cidal Mycolic Acid Inhibition in cell wall

Important Drug Interactions of Antimicrobials with other Drugs:

Important Drug Interactions of Antimicrobials with other Drugs Pharmaceutic’s Synergism/Addition/Antagonism At receptor level, cellular level, organ level Similar/Opposite type of effect Pharmacodynamic Pharmacokinetic (ADME) Clelation /Binding with metals, Ions (Antacids, Milk) Alteration of pH/ Ionization of drug Alteration with enterohepatic recirculation (OCP) Inducer (Barbiturates, Rifampicin , Griseofulvin , Carbamazepine ) Inhibitor ( Cimetidine , Chlolramphenicol , Erythromycin) Protein biding displacement of drug (Important with high protein binding drugs) Alteration with renal excretion (At tubular secretion, alteration of urinary pH) During drug manufacture, packaging, During drug administration

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Sulphonamides Oral hypoglycaemics Increased hypoglycemia Oral anticoagulants Increased anticoagulation Methotrexate Increased Methotrexate toxicity Diuretics Higher incidence of thrombocytopenia Fluoroquinolones Antacids (Al, Mg, Ca), Zinc, Iron, Sucralfate, Milk Reduced absorption of Fluoroquinolone Theophyllin Increased concentration due to decreased metabolism. (Least with Lome , Levo , Spar) Warfarin (Oral anti-coagulant) Enhanced effect due to decreased metabolism (least with Levo , Spar) Quinidine , Procainamide , Amidarone , Erythromycin, Cisapride , Astemizole , Terfenadine , Antidepressants Enhance Q-T interval leading to dangerous arrhythmia (life threatening) Not with Levofloxacin

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Ampicillin (Penicillin) Also (Cephalosporin) Contraceptive pills Failure of contraception Tetracycllines , Chloramphenicol , Erythromycin Antagonism of bactericidal action Aminoglycoside , Tetracyclines in same syringe Inactivation of both Hydrocortisone Inactivation of penicillin Allopurinol Increased incidence of non- urticarial maculo-papular rashes Probenicid Decreases tubular secretion of penicillin and increases action Clavulanic acid, Sulbactum Inhibition of Betalactamase leading to better effect in Beta lactamase cases

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Cephaloridine Cephalothin Frusemide Increased nephrotoxicity Rifampicin Warfarin Failure of anti-coagulation effect Oral contraceptive pills Failure of contraception Metronidazole and cefoperazone , cefotetan , cefamandole , Griseofulvin Alcohol Disulfiram like syndrome Nalidixic acid Oral anticoagulants Enhanced anticoagulation Nitrofurantoin Nalidixic acid Antagonises action of nalidixic acid Probenicid Reduced tubular secretion leading to decresed concentration Amphotericin -B Digitalis Amphotericine induced hypo- kalemia increases digitalis toxicity Erythromycin Theophylline , Carbamazepine , Statins , Warfarin , Terfenadine , Inhibition of metabolism (Inhibit CYP3A4) Terfenadine ( antihistaminics ) Q-T prolongation leading to life threatening ventricular arrhythmias Not with Azithromycin

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Linezolide MAO inhibitors Increased toxicity of MAO inhibiotors ( Linezolide is reversible inhibitor of MAO and may lead to cheese reaction with food containing tyramin and can precipitate Serotonin syndrome (confusion, hypertension, seizures, tachycardia and muscle rigidity) Streptogramins ( Pristinamycin ) Calcium channel blockers, Cyclosporine, Statins , Diazepam, Warfarin , Terfenadine , Cisapride Reduce liver metabolism of these drugs by pristinamycin

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Aminoglycoside Frusemide , Ethacrynic acid Increased Ototoxicity Skeletal muscle relaxants (curare like drugs) Enhanced and persistent neuromuscular blockade Tetracyclines Contraceptive pills Failure of contraception Antacids, Iron preparation, Milk , Food Decreased absorption due to chelation Chloramphenicol Oral hypoglycemic Increased hypoglycemic effect (due to enzyme inhibition by Chloramphenicol) Oral anti-coagulant Enhanced anticoagulant action

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Ketoconazole Cisapride , Terfenadine , Astemizole , Quinidenine , Warfarin , Cyclosporine, Tacromlimus Statins Ketoconazole inhibits CYP3A4 leading to decreased metabolism and accumulation of other drug (Least with Fluconazole ) H2 blockers, PPI, Antacids Decreased absorption of ketoconazole due to decreased gastric acidity Amphotericine B Ketoconazole inhibits the synthesis of ergosterol and produces depletion of membrane ergosterol reducing the binding sites for amphotericin B Griesofulvin Other drug Inducer of microsomal enzymes Clindamycin shows antagonism with erythromycin and chloramphenicol

General-Adverse effects of antimicrobials :

General-Adverse effects of antimicrobials Hypersensitivity reaction- Urticaria, Skin rashes, itching, Exfoliative dermatitis Contact dermatitis- Topical application Angioedema, Bronchospasm, Vasodilatation Stevens-Johnson syndrome- Suphonamides Photosensitivity- Sulphonamides, Chloroquine Phototoxicity- Tetracyclines (Demeclocycline > Doxy >…) Serum sickness Anaphylaxis, Procaine Penicllins, Sulphonamides, fluoroquinolones, tetracyclines, nitrofurantoin Test with Intra-dermal test, Tt with SONIA S teroid, (Hydrocortisone hemisuccinate) S upportive (Lying down, Legs elevated, ) O xygen with or without bronchodilators (Salbutamol, terbutaline) N ebulization I V fluid (Saline or plasma, Never plain dextrose) A drenalin {Physiological antagonist of histamine}, A nti-histaminics

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Gastrointestinal symptoms – Nausea, Epigastric pain, abdominal pain Gastric irritation Flatulence, Indigestion Mouth ulcers Esophagitis- Tetracycline (Capsule breaks in throat) Glossitis Stomatitis Cheilitis A ltered appetite A ltered salivation A ltered taste A ltered GI motility A ltered digestion and A ltered absorption (Mal-absorption syndrome)

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CNS- Headache Irritability Mental confusion Sedation, Drowsiness, Tinnitus Ataxia A ltered sleep A ltered vision A ltered concentration A ltered speech A ltered motor coordination

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Side effects with Injectable preparation Pain, Inflammation at site of injection Abscess formation, Thrombo-phlebitis in case of IV injection, Flushing redness in case of rapid IV (Vancomycin- Red man syndrome) Deficiency- Deficiency of vitamin B complex ( Folic acid- sulphonamides ) and Vitamin K , Failure of drugs which need entero -hepatic recirculation for their effect e.g.. Oral contraceptives

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Super -infections- (More common in patients with Diabetes, Immuno -suppression, Tetracyclines, Broad spectrum antimicrobials) Pseudo-membranous colitis ( CAT produces MeVa reduces, more common in colorectal surgery, Caused by Clostridium difficle ), Masking of infections- eg . Tt . Gonorrhea mask Syphilis Idiosyncratic response- Intolerance, Drug Fever Electrolyte imbalance Teratogenic - No antimicrobial is safe during pregnancy (No one is Category A). Those which are under category B and C can be given under special situation. Drugs of category D and X should not be prescribed to pregnant.

FDA Categorization of Drugs in Pregnancy:

FDA Categorization of Drugs in Pregnancy Category A (No antibiotic is under this) Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. Category B (Safe can be prescribed) Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Category C (Under special circumstance) Either studies in animals have revealed adverse effects on the fetus ( teratogenic or embryocidal or other) and there are no controlled studies in women , or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Category D (Under special circumstance with written consent) There is positive evidence of human fetal risk , but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Category X (Not prescribed) Studies in animals or human beings have demonstrated fetal abnormalities , or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. + ve + ve + ve + ve S A F E I N P R E G N A N C Y - ve - ve - ve - ve

Antibiotics in Pregnancy:

Antibiotics in Pregnancy FDA Category Antibiotics in Category A No Antibiotic …………………………………………….. B Penicillins , Cephalosporins , Carbapenems (except Imipenem ), Daptomycin , Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin , Metronidazole (avoid first trimester), Nitrofurantoin , Acyclovir, Amphoterocin B, Ethambutol C Quinolones, Chloramphenicol, Clarithromycin , Imipenem , Linezolid , Trimethoprim /Sulfa (D if used near term), Vancomycin (IV), Rifampin , INH, PZA, PAS, Fluconazole , Caspofungin D Tetracyclines (Doxy, Tige , Mino), Voriconazole , Aminoglycosides (some put gentamicin as a category C) X + ve + ve + ve + ve S A F E I N P R E G N A N C Y - ve - ve - ve - ve

Specific Side effects of antimicrobials contd…..:

Specific Side effects of antimicrobials contd ….. Bone marrow suppression- Chloramphenicol ( Aplastic anemia) Thrombocytopenia- Sulphonamides , Cephalosporins , ( Cefamandole , Cefoperazone , Cefotetam , Ceftriaxone ), Chloramphenicol Renal toxicity- Aminoglycosides (Least with Streptomycin), all Tetracyclines except Doxycycline, Cephalothin , Cephaloridine , Talampicillin , Nitrofurantoin , Nalidixic acid, Amphotericin B, Vancomycin, Ethambutol , Flucytosine , Methacillin , Hepatotoxicity - Rifampicin , Isoniazide (In fast acetylators due to accumulation of Acetyl- isoniazide and acetyl-hydrazine, More risk in alcoholics), Pyrazinamide, Tetracyclines, Erythromycin estolate , Talampicillin , Nalidixic acid, Trovafloxacin , Oxacillin , Photoxicity - Tetracyclines ( Demeclocycline >>> Doxyccyline >..), Quinolones ( Sparfloxacin )

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Ototoxicty - Aminoglycosides (Cochlear with (KAN) K anamycin and A mikacin , N eomycin rest produce vestibulo), Vancomycin (Hearing Loss) Diabetese inspidus - Demeclocycline (Antagonizes ADH) Neuromuscular block- A mino-glycosides (More with Neomycin and Streptomycin Least with Tobramycin , P olymyxin - B, C olistin (May cause respiratory paralysis in patients of Myasthenia gravis, Gaping of wound, Can be antagonized by IV calcium) Retinal damage- Chloroquine Neuropathy - Isoniazide (more in slow acetylators due to increased excretion of pyridoxine in urine and accumulated INH inhibits pyridoxine - kinase which converts pyridoxine to its active form pyridoxyl phosphate. ) Polypeptide antimicrobials, Amphotericin B, Nitrofurantoin , Carbenicillin

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Haemolysis (G-6-P-D deficiency), - G-6-P-D deficiency is X-Linked recessive. G-6-P-D is required for regeneration of NADPH . It is required in pentose phosphate metabolism of RBCs NADPH is required for reduction of oxidized glutathione Reduced glutathione protects –SH dependent enzymes and other proteins against oxidative injury In persons with G-6-PD deficiency oxidative stress occurs. In presence of pro-oxidants like Naphthalene, Methylene B lue, B eans ( Favasim ) Drugs- P rimaquine, S ulfa drugs, Nitrofurantoin , C hloroquine, Aspirin, N alidixic acid, I soniazid, D apsone, Furazolidione , Quinolones, Chloramphenicol Haemolysis occurs G-6-P-D Glutathion reductase Glutathione Glutathione disulphide NADP NADPH The NADPH in turn maintains the supply of reduced  glutathione  in the cells that is used to mop up free radicals that cause  oxidative  damage. C aught B y S P I N D elivery

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Discolouration of secretions – Rifampicin , (saliva, sweat, urine and skin) - Clofazimine , Nitrofurantoin Redman (Red neck) Syndrome- Vancomycin, Teicoplanin , Kernicterus - Sulphonamides Flu-like syndrome- Rifamapicin Anti-testosterone effect (Anti-androgenic)- Ketoconazole ( reudces synthesis of testosterone which leads to gynaecomastia ), Cimetidine , Spironolactone , Crystaluria - Sulphonamides Cholestatic jaundice- Erythromycin estolate , Nitrofurantoin , Fosfomycin , Optic neuritis- Ethambutol Tendon rupture- Fluoroquinolones Hyperuricemia- Pyrazinamide (Gout) Jarish Herxheimer Reaction- Penicillin in syphilis

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Allopecia - All anti-cancer drugs Fanconi Syndrome- Expiry date Tetracyclines- Characterized by Azotemia (blood urea), kidney damage due to formation of toxic metabolites epitetracycline Teratogenic - Aminoglycosides, Tetracyclines, Sulphonamides Pulmonary Eosonophilic syndrome- Eosinophilia with hilar lymphadenopathy - Tetracyclines Pseudotumor cerebri - and bulging fontanelles - Tetracyclines Vestibular toxicity- Minocycline (vertigo, ataxia) Disulfiram like reaction – Metronidazole , Cefoperazone , Cefotetan , Cefamandole , Griseofulvin , Tobutamide , Arrhythmia- Quinolones, Macrolides Antianabolic effect (reduce protein synthesis- Tetracyclines Discoloration of Teeth and bone damage- Tetracyclines

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Grey Baby Syndrome (Ashen Grey Cyanosis)- Chloramphenicol Pulmonary Fibrosis- Bleomycin , Nitrofuranoin Special- Gatifloxacin prolongs QT interval, produces life threatening arrythemia , causes hypo or hyperglycemia in patients of diabetes. Aminoglcosides have NONE side effects- N euromuscular block ( more with Neomycin and Streptomycin ), O totoxicity (Vestibular by Streptomycin, Gentamicin while Cochlear by Kanamycin , Amikacin,Neomycin ), N ephrotoxicity least with Streptomycin , E tc. Teratogenic ) High dose of Ceftriaxone can result into pseudo- lithiasis (Gall bladder sludge) Mafenide (A Sulphonamide )- have carbonic anhydrase inhibitor activity- May alkalinize urine and cause acidosis and hyperventilation. Demeclocycline - antagonizes ADH and produces Diabetes insipidus 8-Hydroxy-quinoines ( Iodochloro-hydoxyquin ( Enteroquinol )- produce SMON ( Subacute myelo -optic neuropathy)

Prophylaxis:

Prophylaxis Rheumatic fever- Streptococci- Long acting Penicillin ( Benzathine Penicillin) Tuberculosis- Mycobacterium tuberculosis- Isoniazide , Rifampicin Mycobacterium avium complex (Atypical tubercular bacteria)- Azithromycin , Clarithromycin Pneumocystis - Cotrimaxazole HIV exposed person- Zidovidine + Lamividine + Indinavir HIV in foetus – Zidovidine to mother Meningococcal menningitis - Rifmpicin / Sufadiazine Gonorrhoea / Syphilis- Ampicillin or Ceftrioxone Genital herpes – Acyclovir Malaria- Chlorquine , Mfloquine

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Influenza A- Amantadine Cholera- Tetracycllines Whooping cough – Erythromycin Plaque- Doxycycline Bird flu- Oseltamivir ( Tamiflu ) Dental extraction, Tonillectomy , endoscopies- Amoxicillin Catherization - Cotrimoxazole , Norfloxacin , Ampicillin , Gentamicin COPD- Ampicillin , Doxycycline Immunocompromised - Penicillin, Cephalosporins ± Aminoglycosides ± Fluroquinolones ± Metronidazole Surgical prophylaxis- BAM or CAM or FAM

Choice of antimicrobial agents:

Choice of antimicrobial agents Patient- Age- Paediatric -----------General---------------------Geriatric Gerneral condition (G.C)- Consiousness etc….. Hepatic functions- Renal Function- Pregnancy- Genetics- Immune status of patient- History of allergy Financial condition- Infection- Site Type (Microbe)- Guess, Confirm with C/S Intensity Presence of pus, clot, Haematoma Drug- Spectrum Sensitivity Dosage form availability Relative Toxicity (selection depends on patient) Acceptable pharmacokinetic profile

Causes of failure of antimicrobial therapy:

Causes of failure of antimicrobial therapy Improper selection of – D rug, D ose, D osage form, D uration by Less smart D octor Prescribing Drugs of D rug company of questionable authenticity D elay of treatment Failure to apply adjuvant measures Immune-compromised status Extra smart organism (Resistant, Dormant) Misuse (Underuse/Overuse)

Urinary Tract Infection:

Urinary Tract Infection Urinary Tract- Upper Urinary tract (Kidney, Ureter)- Less common, More dangerous, Long term therapy Lower Urinary tract (Bladder, Urethra)- More common, Less dangerous, short term therapy Organisms- Mostly Gram Negative ( E.coli ……… klebsiella , proteus , pseudomonas, enterobacter , staphylococcus, viral, fungal, …. Single in acute, mixed in chronic) Entry - Mostly from lower to upper (ascending ), some times directly from the surrounding sites or form blood ( bacterimia ) Pyelonephritis Ureteritis Urethritis Cystitis Vesico-ureteral Reflux Upper UTI Lower UTI

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Symptoms - ( P ain D uring UTI ) P ain (Pelvic, Rectal, lower abdomen or renal angle) P ungent smell of urine D ysurea (Burning), D enies urination D ischarge through urethra, Haziness (Clouding) in urine, D iscoloration of urine due to Haematuria, Pyuria, U rgency T emperature (Fever with chills) I ncomplete evacuation of bladder, persistent urge to urinate, I ncontinence of urine

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More common in Females- Due to anatomical factors (shorter urethra, More chances to have infections from surrounding areas. Other part involved in male- Prostate, Epidedimis, (Prostatitis, Epidedmitis) More common if S is present- S tones, S tructural abnormality, S trictures, S traight entry of ureter, S tents S exually active S tore urine S urgical (abdomen) S mall amount of fluid intake S emiconcious (Unconcious) S ite trauma

Treatment of UTI:

Treatment of UTI General- Increased Fluid Intake Analgesics, Antipyretics, Anti-inflammatory drugs, Frequent voiding Alteration of pH by Alkalisers …………. Helps in reducing dysurea , burning during urine Reduces growth of most of causative bacteria Enhances potency of most of antibacterials Beware of type of antimicrobials { not with Nitrofurantoin , Methenamine , Tetracyclines, Cloxacillin , Finafloxacin , } and Beware of microbe eg . Proteus which split urea and produce ammonia and produce urine alkaline) Acidify with vitamin C, Mandelic acid and Cranberry juice ( Rarely needed)

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Urinary analgesics- Phenazopyridine (Symptomatic relief, Urine color is orange red ) Urinary antiseptics- Nitrofurantoin (Generate nitro-anion superoxide to damage bacterial DNA, Dark brown urine , Peripheral neuritis, Intra-hepatic cholestatis Methenamine (releases formaldehyde in acidic urine, sulfonamides antagonize)

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Antimicrobials------------------------- (Q-BACTS) Q uinolones -(Nalidixic acid, Norfloxacin ……) B etalactams - Ampicillin / Amoxicillin, A minogycosides - Gentamicin , Amikacin , … C ephalospoirins - Third generation T etracycllines - S ulfonamides and C otrimoxazole , C hloramphenicol Other Antimicrobials- Chloramphenicol, Pipracillin , Methicillin , Carbenicillin etc……..

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Prophylaxis for UTI- Needed in catherised, uncorrectable anatomical abnormalities of tract, inoperable prostate, septicemia, immuno-compromised, trauma to tract etc. Note- if patients is having impaired renal functions avoid using Nitrofurnatoin, Nalidixic acid, Aminoglycosides, Potassium salt, and acidifying agents

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