Antimicrobial Agents (General considerations)

1. Antimicrobial Agents (General considerations) Prof. R. K. Dixit Pharmacology and Therapeutics K.G.M.U. Lucknow dixitkumarrakesh@gmail.com

2. Objectives…. • Uses of antimicrobials (Therapeutic and Prophylaxis) • Culture and sensitivity testing • Selection of appropriate antimicrobials • Precautions while prescribing antimicrobials • Reasons for failure of antimicrobial treatment

3. Bacteriological Culture and Sensitivity Testing • Plate – • Kirby-Bauer test • Strip- • Epsilometer test • Dilution – • Test tubes

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

5. E-Test (Epsilometer test) Zone of inhibition The E-test as an alternative method to the Kirby-Bauer test

6. Turbid tubes Clear tubes Test tubes Increasing concentration of drug

7. 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 • Report organism(s) and susceptibilities • Susceptible (S) • Intermediate (I) • Resistant (R)

8. Culture ResultsExample

9. 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

10. Combination Antimicrobial Therapy • Synergistic • Antagonistic

11. Uses of Antimicrobials in General • Treatment and Prophylaxis • CNS – Meningitis, Brain abscess • Eye - Conjunctivitis, Blepharitis, Stye, • Mouth and Face- Stomatitis, Gingivitis, Pulpitis, Pyorrhoea, 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,

12. CNS • Eye • Mouth • Sinuses • ENT • RTI • GITI • Skin • Bones • STD • Special

13. Selection of A Drug

14. Choice of antimicrobial agents • Patient- • Age- Pediatric -----------General---------------------Geriatric • General condition (G.C)- Consciousness etc….. • Hepatic, Renal functions- • Other metabolic factors • Pregnancy- • Genetics- (G-6-PD deficiency) • 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

15. Selecting a Therapeutic Regimen • Confirm presence of infection: • History signs and symptoms Investigations • Predisposing factors • Before selecting Emperic 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, Immunosupression • Pt. with other co morbid illnesses

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

17. Emperical therapy • Know the common pathogens responsible for common infections • Know the antimicrobial spectrum of activity • Take samplebeforestarting Emperical therapy in complicated cases

18. 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 • Other complaints • Predisposing factors • Surgery, Procedures, Co-morbid conditions including Diabetes, malignancy, immunosuppression etc.

19. 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

20. Drug Factors

21. 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

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

23. 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

24. Host Factors • Pregnancy • Fetus at risk of drug teratogenicity • Penicillin, cephalosporin, erythromycin appear safe • Altered drug disposition •  intravascular volume,  glomerular filtration rate,  hepatic and metabolic activities • Genetic 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

25. Site of Infection • Most important factor for antimicrobial selection • Defines the most likely organisms • Especially helpful in emperical 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

26. Site of InfectionWill the antibiotic get there? • Choice of Agent, Dose, and Route 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 • 3rd or 4th generation Cephalosporin, Chloramphenicol, Ampicillin, Oxacillin • Local infection problems • Aminoglycosides inactivated by low pH and low oxygen tension • Sulphonamides are ineffective in presence of PUS (Due to……..)

27. 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)

28. 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

29. Meningococcal meningitis- • Rifampicin / Sulfadiazine • Gonorrhoea / Syphilis- • Ampicillin or Ceftrioxone • Genital herpes – • Acyclovir • Malaria- • Chloroquine, Mefloquine • Influenza A- • Amantadine • Cholera- • Tetracyclines • Whooping cough – • Erythromycin • Plaque- • Doxycycline • Bird flu- • Oseltamivir (Tamiflu)

30. 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

31. Monitoring Therapeutic Response • Clinical assessment • Improvement in signs and symptoms • Fever curve,  WBC •  Erythema, pain, cough, drainage, etc. • Laboratory tests

32. Antimicrobial Factors in Drug Selection

33. The Criteria of the Ideal Antibiotic: • Selectivity against microbes . • Least toxic to the human cells • 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

34. Causes of failure of antimicrobial therapy • Improper selection of – • Drug, • Dose, • Duration • Dosage form and Route • Delay of treatment • Drug quality questionable • Failure to apply adjuvant measures • Immune-compromised status • Extra smart organism • Resistant, Dormant

35. 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

36. 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 • Try to limit the emergence of bacterial resistance

37. End of antibiotics - the ultimate consequence