Transcript Anitmicrobial Agents General Considerations 4 Pharmacology Prof

Antimicrobial Agents
(General considerations)
Prof. R. K. Dixit
Pharmacology and Therapeutics
K.G.M.U. Lucknow
[email protected]
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
Bacteriological Culture and Sensitivity Testing
• Plate –
–Kirby-Bauer test
• Strip–Epsilometer test
• Dilution –
–Test tubes
Zones of inhibition (Kirby-Bauer) test
Bacterial lawn
Zone of inhibition
E-Test (Epsilometer test)
Zone of inhibition
The E-test as an alternative method to the Kirby-Bauer test
5
Turbid tubes
Test tubes
Clear tubes
Increasing concentration of drug
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)
Culture Results
Example
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
• Synergistic
• Antagonistic
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,
CNS
Eye
Mouth
Sinuses
ENT
RTI
GITI
Skin
Bones
STD
Special
Selection of A Drug
Disease of Intention
Site, Intensity, Previous Tt,
Co-morbid Diseases
Other Drugs taken by Patient
Physiological condition,
Conscious / Unconscious,
DDI and DFI, DOTI
Financial Condition
Selection of (ADR)
Agent, Dose, Dosage form, Duration, Route,
Choice of antimicrobial agents
Patient•
•
•
•
•
•
•
•
•
Age- Pediatric -----------General---------------------Geriatric
General condition (G.C)- Consciousness etc…..
Hepatic, Renal functionsOther metabolic factors
PregnancyGenetics- (G-6-PD deficiency)
Immune status of patientHistory 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
• 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
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
Emperical therapy
• Know the common pathogens
responsible for common infections
• Know the antimicrobial spectrum of
activity
• Take sample before starting
Emperical therapy in complicated
cases
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.
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
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
• Drug concentrations to their effect in the body
– Desirable = Bacterial killing
– Undesirable = Side effects
• Bacteriostatic
– Inhibit growth or replication
• Bactericidal
– Cause cell death
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
• Pregnancy
Host Factors
– 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
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
Site of Infection
Will 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……..)
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
•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
•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)
•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
• Clinical assessment
– Improvement in signs and symptoms
• Fever curve,  WBC
•  Erythema, pain, cough, drainage, etc.
• Laboratory tests
Antimicrobial Factors in Drug Selection
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
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
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 ResistanceSelection of appropriate antimicrobial
Causes of failure
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
End of antibiotics - the ultimate
consequence