Principles of Antimicrobial use and Drug Resistance Omilabu S.A, Ph.D Department of Medical Microbiology and Parasitology, CMUL. 16 th January 2015

Introduction Antibiotics are unique among therapeutic agents Directed at treating or preventing microbial disease However, antimicrobial use differs from other medications by its potential for collateral damage: Patient Wider population Efficacy is continuously threatened by drug resistance

The antibiotic creed M microbiology guides therapy wherever possible Iindications should be evidence-based Nnarrowest spectrum required D dosage appropriate to the site and type of infection Mminimise duration of therapy Eensure monotherapy in most situations

Identification of the Infective Organisms History taking Physical examination Laboratory

History Taking Duration of fever Associated symptoms: Systematic review History of treatment Underlying diseases and Medication Occupation Living place Traveling Pets Vaccination and drug prophylaxis Illness in family Diseases outbreak Food consumption

Physical Examination

Laboratory Investigation in the Diagnosis of Infectious Agents Mandell, Douglas, and Bennett’s Principle and Practice of Infectious Diseases

Gram Stain

AFB Stain

FBC Increase in neutrophils indicates either Bacterial or fungi infection Lymppcyte elevation indicates aViral infection Monocyte elevation can indicate Infection with Listeria monocytogenes or M. tuberulosis Eosinophil elevation can indicateAllergic reaction, or parasitic infection Basophil elevation can indicate anAllergic response Malaria Microscopy, RDT, PCR etc Other parasites testing Other significant screening for infection

Factors affecting antimicrobial use and drug resistance Microbial Factors Host factors Antimicrobial factors

Microbial Factors: Antimicrobial susceptibility – Appropriate specimen collection and transport – Disk diffusion susceptibility testing – Minimal inhibitory concentration (MIC)

Microbial Factors: Antimicrobial Resistance Susceptible Bacteria New Resistant Bacteria Chromosomal mutations XX Resistant Bacteria Resistance Gene Transfer

Resistant Strains Rare x x Resistant Strains Dominant x x x x x x x x x x Antimicrobial Exposure Selection for Antimicrobial-resistant Strains

Mechanisms of Antimicrobial Resistance Levy, SB. The challenge of antibiotic resistance. Sci Am 1998:46-53.

Underlying diseases Drug allergy Pregnancy/Breast feeding Age Genetic or Metabolic abnormalities Sites of infection Immune status Hepatic and renal function Host Factors

Antimicrobial Factors Spectrum Mechanisms of action Pharmacokinet ic Pharmacodyna mic Drug interaction Side effect Drug monitoring

Mechanisms of Action Bactericidal agents Bacteriostatic agents Bactericidal agents

Pharmacokinetics of Antimicrobial Agents Absorption – Consider extent and rate of absorption via route of administration – Consider drug interaction and food effect Distribution to the site of infection – Volume of distribution (Vd) Water soluble drug, small Vd  high serum conc. Lipophilic drug, large Vd  extensively distributed in body fluid and tissue – Vascular supply

Pharmacokinetics of Antimicrobial Agents Distribution to the site of infection (cont.) – Protein binding – Local factor at site of infection: pH, dense population of organism, foreign body Metabolism – Mainly in liver – Active vs. Inactive metabolites – Route of metabolism esp. CYP P450 system Elimination – Route of elimination: mainly by kidney, liver – Rate of elimination: T 1/2

Pharmacodynamics of Antimicrobial Agents Pharmacodynamic characteristics – Time-dependent bactericidal action – Concentration-dependent bactericidal actions – Bacteriostatic action Postantibiotic effect Inoculum effect In vitro action of antibiotic combination

Indications for Antimicrobial Combinations Therapy Prevention of the emergence of resistant organisms Polymicrobial infections Empirical therapy Synergistic/Additive activity

Disadvantages of Inappropriate Use of Antimicrobial Combinations Antagonism Superinfection Cost Adverse effects

Reasons for Treatment Failure Delay in diagnosis or therapy Wrong or incomplete diagnosis No infection Nonbacterial infection Polymicrobial infection Errors in susceptibility testing Decreased activity at site of infection Chemical factor (pH and others) Antibiotic antagonism

Inadequate concentration of antibiotic at the site of infection Improper dose Decreased absorption from food or drug interaction Increased elimination of agent High protein binding Poor delivery (eg. shock, vascular diseases) Reasons for Treatment Failure

Other host factors Collection requiring drainage Necrotic tissue Foreign body Impaired immune defenses Development of drug resistance Superinfection

A major cause of antimicrobial overuse is “treatment” of contaminated cultures or colonization. Use Antimicrobials Wisely Treat infection, NOT contamination or colonization Use local data Know your local antibiogram Know your patient population Not all infections need antimicrobial therapy

When infection is cured When cultures are negative and infection is unlikely When infection is not diagnosed Use Antimicrobials Wisely Use Antimicrobials Wisely Stop antimicrobial treatment