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
