Selection of Antimicrobials...Pharmacology

It depends on the peculiarities of

• Infecting organism
• Drug
• Patient

Objective is to have Selective action on infecting organism;

• For a desirable period
• With least effect on the host animal

Organism Related Factors

Target organism (Culture and identification, molecular biological techniques etc)

Sensitivity Pattern (Bacterial Sensitivity Test etc. like disc diffusion test.)

Drug Related Factors

Spectrum of activity: narrow vs. broad spectrum, combination of drugs.

Type of activity:  bacteriostatic vs. bactericidal.

Pharmacokinetic profile: Effective concentration at site of infection for adequate length of time.

Route of administration

Drug interactions (nsaid’s enhances CNS toxicity of fluoroquinolones)

Relative toxicity (penicillins are least toxic, chloramphenicol and clindamycin have serious toxicity)

Antimicrobial policy

Cost of therapy

Host Factors

Host defense mechanisms

Pathological conditions

• Renal Diseases
• Hepatic dysfunction
• Meningitis

Local factors

• Pus formation
• Hematomas
• pH
• Age
• Species
• Pregnancy
• Genetic Factors 

Bacterial Sensitivity Testing

Disc diffusion method

Tube dilution method

MIC

MBC

Combination of Antimicrobial Drugs

Objectives of combination

• To broaden the spectrum of activity
• To treat mixed infections
• To achieve synergism
• To prevent resistance
• To minimize toxicity

Guidelines for combination of antimicrobial drugs:

• Bactericidal + bactericidal = synergistic effect
• Bacteriostatic + bacteriostatic = additive effect
• Bactericidal + bacteriostatic = antagonistic effect 

Bactericidal: Bacteriostatic 

 Broad spect: Narrow spect

 

Tissue Distribution Pattern:

Drugs distributed to extracellular fluid

Penicillins, cephalosporins, aminoglycosides

Drugs in total body water

Fluoroquinolones, chloramphenicol, doxycyline, sulphonamides, erythromycin, clindamycin

Drugs to CSF

Sulphonamides, fluoroquinolones, doxycycline, metronidazole, rifampicin

Drugs in Bile

Doxycycline, erythromycin, clindamycin, rifampicin

Drugs in Urine

Fluoroquinolones, sulphonamides, nalidixic acid, nitrofurantoin, cephalosporins, penicillins, vancomycin

Prophylactic Use of Anti-Microbial Agents

• In dirty contaminated wounds
• After surgical operations
• To prevent secondary bacterial infections
• In disease outbreak
• In endemic areas with high transmission ratio prevent post-partum infections in dams

Bacterial Resistance to Antimicrobials

Unresponsiveness of micro-organisms to an antimicrobial drug even at the maximum level that is tolerated by the host e.g G – ve to penicillin G and Vancomycin

TYPES OF RESISTANCE

Natural Resistance

• Inherently or genetically resistant Due to
• Lack of penetration of drug into bacterial cell
• Absence of metabolic pathway or target site affected by drug
• Rapid inactivation of drug in bact. cell

Acquired Resistance

When an organism becomes resistant to an antimicrobial agent to whom it was previously sensitive Due to Widespread and inappropriate use.

Mechanisms of Acquired Resistance Transmission

Mutation

Spontaneously occurs in microorganisms

Occurs due to insertion, deletion or substitution of one or more nucleotides in the genome

Single step Mutation

• Enterococci to streptomycin
• Staphylococci to Rifampicin

Multi-step Mutation

• Erythromycin
• Tetracycline
• Chloramphenicol

Gene Transfer

Develops by transfer of genetic material coding for resistance from a resistant microorganism to a susceptible organism

Resistant genes can be transferred b/w bacteria through:

Transduction

Transformation

Conjugation

Biochemical Mechanisms of Resistance

Alterations in drug penetration:

Decreased penetrability of an antimicrobial agent into the bacterial cell may occur due to either change in permeability of cell wall or alterations in transport systems.

Alterations in binding sites:

Antimicrobials fail to bind to their specific sites and cannot perform their action. e.g.

Alterations in penicillin binding proteins can confer resistance against penicillin

Alterations in metabolic pathways:

Some sulphas resistant bacteria start synthesis of their own PABA.

Drug inactivating enzymes:

These are either inducible or constitutive. e.g

Chloramphenicol is inactivated by acetyltransferases

Aminoglycosides are inactivated by certain transferases

Cross Resistance:

A type of acquired resistance in which bacteria resistant to one antimicrobial agent also become resistant to another antimicrobial without having exposed to the latter

Complete Cross Resistance (two way cross resistance)

Bact. Resistant to one antimicrobial are also resistant to a second drug and vice-versa

i). Neomycin   Kanamycin

ii) Erythromycin Oleandomycin

Partial Cross Resistance (one way cross resistance)

Bact. Resistant to one antimicrobial are also resistant to second drug, but resistance to second antimicrobial does not lead to resistance to first antimicrobial agent.

Gentamycin                 Kanamycin                  Steptomycin 

Adverse Reactions to Antimicrobial Agents

Direct tissue toxicity

• nephrotoxicity        Aminoglycoside 
• hepatotoxicity        Tetracyclines,
• Neurotoxicity         Streptomycin,      
• Bone marrow depression     Chloramphenicol

Sensitivity reactions (penicillins, cephalosporins, sulphonamides)

Super infection /supra infection

Appearance of a new infection as a result of indiscriminate use of antimicrobial drugs

Common with broad spectrum antimicrobials like tetracycline

Nutritional deficiencies (vitamin K, B)

Failure of Antimicrobial Therapy

• Improper diagnosis of disease
• Improper selection
• Development of resistance
• Mixed infections
• Penetration to the site of infection (pus, exudates, tissue debris)
• Impaired host defense mechanism
• Improper route of drug administration
• Inadequate duration
• Relapse of dormant or refractory organisms
• Improper management (nursing care)
• Drug interaction
• Delayed start of treatment
• Expired or substandard drugs
• No compliance with therapeutic regimen

Guidelines for Successful Anti-Microbial Therapy

• Narrow spectrum (preferred for known organism) VS Broad spectrum (For unknown organism)
• Bactericidal (Preferred) Vs Bacteriostatic
• Less toxic (Preferred) Vs Potentially toxic
• Long interval (Preferred) Vs short interval
• Oral route (Preferred for less severe infections) Vs parenteral for severe infections)
• Proper dose and duration of time
• Proper combination of drugs
• Avoid misuse (over use)
• Cheap and easily available
• Reliable pharmaceutical firm
• Avoid antimicrobial use for untreatable infections