Anitmicrobial agents General Considerations (2) MBBS June-July 2015

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Antimicrobial Agents (General considerations):

Antimicrobial Agents (General considerations) Prof. R. K. Dixit Pharmacology and Therapeutics K.G.M.U. Lucknow [email protected]

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Synergism/Addition/ Antagonism Combinations of more than one antimicrobial Combination of antimicrobial with other agents Pharmacodynamic Pharmacokinetic (ADME) Chlelation /(Antacids, Milk)- Tetracyclines Alteration of pH/ Ionization of drug- Penicillins Alteration with Enterohepatic recirculation- (OCP) Inducer (Barbiturates, Rifampicin, Griseofulvin, Carbamazepine) Inhibitor (Cimetidine, Chlolramphenicol, Erythromycin, Quinolones) Protein biding displacement of drug (Important with high protein binding drugs)- Sulphonamides Pharmaceutical During manufacture, packaging, Storage During drug administration During Mixing and injecting drug Mixing in oral solutions Mixing in solvent, In bottle, No drug in Blood, Plasma and Electrolyte solutions

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Pharmaceutical During Manufacture, Packaging, Storage During drug administration During Mixing and injecting drug Mixing in oral solutions Mixing in solvent, In bottle, No drug in Blood, Plasma and Electrolyte solutions

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Synergism/Addition(Cidal + Cidal, Static + Static) Antagonism (Cidal + Static) Combinations of more than one antimicrobial Combination of antimicrobial with other agents Pharmacodynamic

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Pharmacokinetic (ADME) Chelation /(Antacids, Milk)- Tetracyclines Alteration of pH/ Ionization of drug- Penicillins Alteration with Enterohepatic recirculation- OCP with antimicrobials Inducer- Rifampicin, Griseofulvin , Inhibitors- Chlolramphenicol, Erythromycin, Quinolones Protein biding displacement of drug- Sulphonamides

List of Important Interactions Related to Antimicrobials:

List of Important Interactions Related to Antimicrobials Sulphonamides Oral hypoglycaemics (Especially Sulphonylureas ) Increased hypoglycemia Oral anticoagulants Increased anticoagulation (Protein binding displacement) Methotrexate Increased methotrexate toxicity ( Folate deficiency)

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Fluoroquinolone Antacids (Al, Mg, Ca), Zinc, Iron, Sucralfate, Milk Reduced absorption of Fluoroquinolone Theophylline 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 , Antidepressant Enhance Q-T interval leading to dangerous arrhythmia (life threatening)

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

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Cephaloridine Frusemide Increased nephrotoxicity Rifampicin Warfarin and OCP Failure of anti-coagulation and contraception Griseofulvin Cefoperazone , Cefotetan , Cefamandole Metronidazole ( G ood C hief M inister) Alcohol Disulfiram like syndrome ( Aldehyde Syndrome)

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Nalidixic acid Oral anticoagulants Enhanced anticoagulation Nitrofurantoin Nalidixic acid Antagonises action of nalidixic acid Probenecid Reduced tubular secretion leading to decresed concentration Amphotericin -B Digitalis Amphotericin induced hypo- kalemia increases digitalis toxicity

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Erythromycin Theophylline, Carbamazepine , Statins, Warfarin, Terfenadine , Inhibition of metabolism (Inhibit CYP3A4) Terfenadine ( antihistaminics ) Q-T prolongation leading to life threatening ventricular arrhythmias Linezolide MAO inhibitors Increased toxicity of MAO inhibitors ( Linezolide is reversible inhibitor of MAO and may lead to cheese reaction with food containing tyramine and can precipitate Serotonin syndrome (confusion, hypertension, seizures, tachycardia and muscle rigidity)

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Streptogramins ( Pristinamycin ) Calcium channel blockers, Cyclosporine, Statins, Diazepam, Warfarin, Terfenadine , Cisapride Reduce liver metabolism of these drugs by pristinamycin

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Aminoglycosides 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

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Chloramphenicol Oral hypoglycemic Increased hypoglycemic effect (due to enzyme inhibition by chloramphenicol ) Oral anti-coagulant Enhanced anticoagulant

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Ketoconazole Cisapride , Terfenadine , Astemizole , Quinidine , Warfarin, Cyclosporine Tacrolimus 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 Griseofulvin Other drug Inducer of microsomal enzymes

Bacteriological Culture and Sensitivity Testing:

Bacteriological Culture and Sensitivity Testing Plate - Kirby-Bauer test Strip- Epsilometer test Dilution – T est tubes

Zones of inhibition (Kirby-Bauer) test:

Zones of inhibition (Kirby-Bauer) test Bacterial lawn Zone of inhibition

E-Test (Epsilometer test):

E-Test ( Epsilometer test) 19 The E-test as an alternative method to the Kirby-Bauer test

Test tubes:

Test tubes Turbid tubes Clear tubes Increasing concentration of drug

Culture and Sensitivity Results:

Culture and Sensitivity Results Minimum inhibitory concentration (MIC) The lowest concentration of drug that prevents visible bacterial growth after 24 hours of incubation Organism and antimicrobial specific Interpretation Drug’s activity versus the organism Site of infection Drug resistance mechanisms Report organism(s) and susceptibilities Susceptible (S) Intermediate (I) Resistant (R)

Culture Results Example:

Culture Results Example

Combination Therapy: Uses:

Combination Therapy: Uses 1. Empirical therapy 2. Poly-microbial infections (Suspected mixed infection) 3. Prevent development of resistance Good combo is 2 bactericidal e.g. cell wall inhibitor & protein synthesis inhibitors

Combination Antimicrobial Therapy:

Combination Antimicrobial Therapy Synergistic Antagonistic

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Uses of Antimicrobials in General Treatment and Prophylaxis CNS – Meningitis, Brain abscess Eye - Conjunctivitis, Blepharitis , Stye , Mouth and Face - Stomatitis, Gingivitis, Pulpitis , Pyorrhoea , Glossitis, Sinusitis ENT - Otitis, Rhinitis, Tonsillitis, Pharyngitis , Laryngitis, RTI- Tracheitis , Bronchitis, Bronchiolitis , Pneumonia, Pleuritis , Effusion, GITI- Dysentery, Gastroenteritis, Cholecystitis , Cholangitis , Appendicitis, UTI - Urethritis, Cystitis, Ureteritis, Pyelonephritis , Prostatitis, Epidydimitis Pelvic organ infections , Pelvic Organ Infections (PID)- Vaginitis, Cervicitis , Endometritis, STDs- Chancroid, Syphilis, Gonorrhoea, Non-specific urethritis (Chlamydia trachomatis), Granuloma inguinale, Donovanosis, Genital Herpes, Trichomonas Vaginitis Skin (and Soft tissue)- Boil, Carbuncles, Furuncles, Bone - Osteomyelitis , Special Infections- Typhoid, Tuberculosis, Leprosy, Nosocomial infections

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CNS Eye Mouth Sinuses ENT RTI GITI Skin Bones Sex STD Special

Selection of A Drug:

Selection of A Drug

Choice of antimicrobial agents:

Choice of antimicrobial agents Patient- Age- Pediatric -----------General---------------------Geriatric General condition (G.C)- Consciousness etc….. Hepatic functions- Renal Function- and other metabolic factors 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, Hematoma Drug- Spectrum Sensitivity Dosage form availability Relative Toxicity (selection depends on patient) Acceptable pharmacokinetic profile

Selecting a Therapeutic Regimen:

Selecting a Therapeutic Regimen Confirm presence of infection: History signs and symptoms Investigations Predisposing factors Before selecting Empiric therapy get material for c/s or for microscopy Consider the spectrum of activity; Narrow vs broad spectrum Special conditions like Sepsis or meningitis, Pt. with diabetes, Pt. with other co morbid illnesses

Antimicrobial therapy:

Antimicrobial therapy Empiric Infecting organism(s) not yet identified Experience based on Site, Size, Season, Spectrum More “broad spectrum ” Definitive Organism(s) identified Specific therapy chosen (“ narrow” spectrum) Prophylactic or preventative Prevent an initial infection or its recurrence

Empiric therapy:

Empiric therapy Know the common pathogens responsible for common infections Know the antimicrobial spectrum of activity Take sample before starting empirical therapy in complicated cases

Is the Patient Infected???:

Is the Patient Infected??? CAREFUL history and physical exam including relevant laboratory data and signs and symptoms Temperature White blood cell count (WBC) WBC in normally sterile fluids (e.g. CSF) Any swelling or erythema at a particular site Purulent drainage Patient other complaints Predisposing factors Surgery, Procedures , Co-morbid conditions including Diabetes, malignancy, immunosupression etc.

Selecting an Antimicrobial:

Selecting an Antimicrobial Confirm the presence of infection History, physical Signs and symptoms Predisposing factors Identification of pathogen Collection of infected material Culture and sensitivity Staining and Serologies Selection of presumptive therapy Drug factors Host factors Monitor therapeutic response Clinical assessment Lab tests Assessment of therapeutic failure

Drug Factors:

Drug Factors

Pharmacokinetics:

Pharmacokinetics Absorption IM, SC, topical, Oral, tube, or rectal administration Bioavailability = amount of drug that reaches the systemic circulation Distribution Affected by the drug’s lipophilicity, partition coefficient, blood flow , pH, and protein binding Metabolism Phase I Generally inactivate the substrate into a more polar compound Dealkylation, hydroxylation, oxidation, deamination Cytochrome P-450 system (CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2E1) Phase II Conjugation of the parent compound with larger molecules, increasing the polarity Generally inactivate the parent compound Glucuronidation, sulfation, acetylation Elimination Total body clearance (Half life) Renal + non-renal clearance Steady state concentrations reached after 4-5 half lives Affected by changes in end-organ function and protein binding

Pharmacodynamics:

Pharmacodynamics Drug concentrations to their effect in the body Desirable = Bacterial killing Undesirable = Side effects Bacteriostatic Inhibit growth or replication Bactericidal Cause cell death

Pharmacokinetics, Pharmacodynamics, and the MIC:

Pharmacokinetics, Pharmacodynamics , and the MIC Concentration vs. time-dependent killing agents Concentration dependent agents  bacterial killing as the drug concentrations exceed the MIC Peak/MIC (AUC/MIC) ratio important Quinolones, aminoglycosides Time-dependent agents kill bacteria when the drug concentrations exceed the MIC Time>MIC important Penicillins, cephalosporins Post antibiotic effect (PAE) Delayed regrowth of bacteria following exposure to the antimicrobial

Other Drug Factors:

Other Drug Factors Adverse effect profile and potential toxicity Resistance Effects of the drug on the potential for the development of resistant bacteria in the patient, on the ward. Cost Acquisition cost + storage + preparation + distribution + administration Monitoring Length of hospitalization + readmissions Patient quality of life

Host Factors:

Host Factors Pregnancy Fetus at risk of drug teratogenicity Penicillins, cephalosporins, erythromycin appear safe Altered drug disposition  intravascular volume,  glomerular filtration rate,  hepatic and metabolic activities Genetic or metabolic abnormalities Glucose-6-phosphate dehydrogenase (G6PD) deficiency Renal and hepatic function Accumulation of drug metabolized excreted by these routes with impaired function  risk of drug toxicity unless doses adjusted accordingly Underlying disease states Predispose to particular infectious diseases or alter most likely organisms

Site of Infection:

Site of Infection Most important factor for antimicrobial selection Defines the most likely organisms Especially helpful in empiric antimicrobial selection Determines the dose and route Efficacy determined by adequate concentrations of antimicrobial at site of infection Serum concentrations vs. tissue concentrations and relationship to MIC

Site of Infection Will the antibiotic get there?:

Site of Infection Will the antibiotic get there? Choice of A gent, D ose, and R oute important (ADR) Oral vs. IV administration Bioavailability, severity of infection, site of infection, function of GI tract Blood and tissue concentrations Ampicillin/piperacillin   concentrations in bile Fluoroquinolones   concentrations in bone Quinolones, TMP/SMX,  concentrations in prostate Ability to cross blood-brain barrier Dependent on inflammation, lipophilicity, ,protein binding, ionization 3 rd or 4 th generation cephalosporins, chloramphenicol, ampicillin, oxacillin Local infection problems Aminoglycosides inactivated by low pH and low oxygen tension Sulphonamides are ineffective in presence of PUS

Concomitant Drug Therapy:

Concomitant Drug Therapy Influences the selection of appropriate drug, dosage, and monitoring Drug interactions  risk of toxicity or potential for  efficacy of May affect the patient and/or the organisms Pharmaceutical Interactions Pharmacokinetic interactions Alter drug Absorption, Distribution, Metabolism, or Excretion Pharmacodynamic interactions Alter pharmacologic response of a drug Selection of combination antimicrobial therapy ( 2 agents)

Prophylactic use of antimicrobials in important conditions:

Prophylactic use of antimicrobials in important conditions Rheumatic fever- Benzathine Penicillin Tuberculosis - Isoniazid, Rifampicin Mycobacterium avium complex- Azithromycin, Clarithromycin Pneumocystis – Cotrimoxazole HIV exposed person- Zidovudine + Lamivudine + Indinavir HIV in foetus – Zidovudine to mother

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Meningococcal meningitis- Rifampicin / sulfadiazine Gonorrhoea / Syphilis- Ampicillin or ceftrioxone Genital herpes – Acyclovir Malaria- Chloroquine, mefloquine Influenza A- Amantadine Cholera - Tetracycllines Whooping cough – Erythromycin Plaque - Doxycycline Bird flu- Oseltamivir (Tamiflu)

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Dental extraction, Tonsillectomy, Endoscopies- Amoxicillin Catherization - Cotrimoxazole , Norfloxacin , Ampicillin , Gentamicin COPD- Ampicillin , Doxycycline Immunocompromised - Penicillin, Cephalosporins ± Aminoglycosides ± Fluroquinolones ± Metronidazole General Surgical prophylaxis- BAM or CAM or FAM

Monitoring Therapeutic Response:

Monitoring Therapeutic Response Clinical assessment Improvement in signs and symptoms Fever curve,  WBC  Erythema , pain, cough, drainage, etc. Laboratory tests Assessment of therapeutic failure Due to drug selection Due to host factors Due to resistance

Antimicrobial Factors in Drug Selection:

Antimicrobial Factors in Drug Selection

The Criteria of the Ideal Antibiotic::

The Criteria of the Ideal Antibiotic: Selectivity against microbes . Ability to reach at the desired site(BBB). Remains in body long enough to be effective Shelf life good Does not lead to resistance development Less expensive, Less allergic Microbiocidal rather than microbiostatic. Less suppression of normal flora

Causes of failure of antimicrobial therapy:

Causes of failure of antimicrobial therapy Improper selection of – D rug, D ose, D uration D osage form and Route D elay of treatment D rug quality questionable Failure to apply adjuvant measures Immune-compromised status Site of infection (Presence of pus etc.) Extra smart organism Resistant, Dormant

Summary :

Summary Antimicrobials are among the most important advances of modern medicine. The general concept regarding antimicrobials Antibacterial spectrum, Classification of antimicrobials Chemotherapeutic drugs Vs Pharmacodynamic drugs Bacteriostatic drugs, Vs Bactericidal drugs MIC Vs MBC Post antibiotic effect, General side effects of antimicrobials General Mechanisms of actions of antimicrobials (1-8) General Drug interactions of antimicrobials Antimicrobial Resistance- Selection of appropriate antimicrobial Causes of failure

Summary:

Summary Appropriate selection of antimicrobials is complicated . It is not only the matching a drug to a bug Antimicrobial selection depends on Clinical efficacy, Adverse effect profile, Pharmacokinetic disposition, and Cost ultimately guide therapy Once chosen, the dose, duration must be based on Age, Sex (pregnancy) and weight of the patient, Site, Severity of infection, Route of elimination, And other factors including co-morbid conditions Use antimicrobials Only when needed For optimum time period as needed to treat the infection In order to limit the emergence of bacterial resistance

End of antibiotics - the ultimate consequence:

End of antibiotics - the ultimate consequence

QUESTIONS?:

QUESTIONS?

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