Biochemical mechanisms:
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Production of inactivating enzymes: e.g. β-lactamases (by staph. and some gram-negative bacilli) inactivate β-lactam antibiotics.
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Reduced bacterial permeability to antibiotics: e.g tetracyclines accumulate by active transport mechanism in susceptible organisms. Resistant strains lack this mechanism.
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Modification of the receptor site: e.g. Loss or alteration of the receptor protein on 30S ribosome causes resistance to Aminoglycosides and 50S ribosome causes resistance to erythromycin.
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Development of an alternate metabolic pathway that bypasses the reaction inhibited by the drugs: e.g. sulfonamide-resistant bacteria can utilize pre-formed folic acid.
Genetic basis of acquired resistance
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Chromosomal resistance:
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Extrachromosomal resistance:
This results from transfer of genetic material from one bacterium to another.The genetic material may be in the form of plasmids . The genetic material and plasmids can be transferred by transformation, transduction, conjugation, or translocation.
Prevention of antimacrobial resistance:
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Choice of proper effective drug.
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Give the proper dose for sufficient time to maintain sufficiently high levels of the drug in tissues
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Drug combination e.g. in TB
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Avoid unnecessary exposure of microorganism to a particularly valuable drug by restricting its use (e.g. rifampicin mainly for TB)
Combinations of antimicrobials:
Clinical values (indications or aims) of antimicrobials combination:
1-To obtain better effect (synergism) or to increase the spectrum e.g.
- sulfamethoxazole plus trimethoprim to form co-trimoxazole.
- clavulanic acid plus amoxicillin as clavulanic acid inhibits β-lactamase. Another example is sulbactam with ampicillin
- Penicillin plus aminoglycoside.
2-To reduce the toxicity or incidence of adverse effects.
3-To prevent or delay the emergence of resistant strains especially in chronic infections as tuberculosis in which two or three agents are used.
4-In mixed infections as peritonitis (following colon perforation), a drug active against anaerobes and gram-positive bacteria (e.g. clindamycin) is combined with one active against gram-negative bacteria coliforms e.g aminoglycosides.
5-For emergency treatment of serious infections before laboratory studies are completed e.g. in suspected septicemia. Anti-staphylococcus (nafcillin) may be combined with a drug active against aerobic gram-negative bacilli (aminoglycosides).
Results of antimicrobial combinations:
Combining antimicrobial agents may result in the following:
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Bactericidal + bactericidal results in synergism:
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Bacteriostatic + bacteriostatic results in addition (summation):
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Bactericidal + bacteriostatic (antagonism):
- Synergism occurs when effect of two drugs together is greater than effect of either alone.
- Antagonism occurs when effect of two drugs together is less than the effect of either alone.
Disadvantages of antimicrobial combination
1-Antagonism: This may occur if a bacteriostatic (tetracycline, chloramphenicol) and a bactericidal (penicillin, cephalorporins, Aminoglycosides) drugs are used together.
2-Increase incidence of Adverse effects and cost.
3-Efforts toward accurate diagnosis may be neglected.
General principles of therapy with antimicrobials 1. Antimicrobials should only be given when necessary and after antimicrobials susceptibility test whenever possible.
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The pharmacokinetics of the drug should be taken into consideration e.g. the state of hepatic and renal functions of the patient.
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In serious infection it is better to start with a parentral loading of a bactericidal agent to avoid emergence of resistant strains by giving adequate dosage for sufficient duration.
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Antimicrobials should be continued for 3 days after apparent cure is achieved to avoid relapse.
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Bactericidal drugs should be used when there is leucopenia or the phagocytic cells can not get to the site of infection e.g. endocarditis
Why Do Antimicrobials Fail?
- Host Factors
- Immune System (poor host defense)
- Underlying Diseases
- Barrier Status
- Retained Foreign Bodies
- undrained pus (presence of dead tissue).
- Site of Infection
- CNS
- Intravascular
- Pulmonary
- Surgical Intervention
- Antibiotic Properties
- Improper route of administration, Metabolism & Elimination , poor penetration into the site of infection.(pharmacokinetics)
- Pharmacodynamics (Inappropriate choice, in adequate duration or dose)
- Adverse Event Profile
- Pathogen
- Species
- Virulence Factors
- Resistance Mechanisms
- superinfection