Principles of Antibacterials Flashcards
Bacteriostatic
Reversible inhibition of growth of bacteria
Does not kill the bacteria but stops bacteria from growing and relies on host immune mechanisms to clear the bacteria from body.
Bacteria can regrow when bacteriostatic antibiotic is removed.
Used in patients that are immune-competent or for treatment of mild infections.
Bactericidal
Irreversible inhibition of growth –> kill the bacteria and do not depend on the host immune system
Used in immune-compromised patients or to treat life-threatening infections.
Selective Toxicity
Ability to injure or kill an invading microorganism without harming host cells –> less adverse effects
Ideally target sites unique to infecting organism
Or taget site suitably different compared to host equivalent
Postantibiotic Effect
When the killing action continues once the drug plasma levels are below measurable levels
Mechanisms:
- lag time required to synthesise new enzymes or cell components
- persistence of agent at target site
- Enhanced susceptibility of bacteria to phagocytic/defence mechanisms
Broad spectrum antibiotics uses and disadvantages
Antimicrobial drugs which are effective against several groups of micro-organisms (eg: Gm+ and Gm - bacteria)
Uses:
- empiric therapy
- mixed infections
eg: peritonitis (intraabdominal infections) post surgery normally present with many different bacterial infections
Disadvantages:
- selection of multi-drug resistant bacteria
- disruption of normal flora
Narrow spectrum antibiotics uses and disadvantages
Antimicrobial drugs which are effective against only a specific group of bacteria (usually target one or 2 classes)
Use: treating infections of known origin
Disadvantages:
- must know causative agent
- not useful for empiric therapy
Extended spectrum antibiotics uses and disadvantages
Antimicrobial drugs which are effective against Gm + bacteria and some Gm - bacteria due to chemical modifications
Uses:
- empiric therapy
- mixed infections
Disadvantages:
- selection of multi-drug resistant bacteria
- disruption of normal flora
MIC
Minimum inhibitory concentration - lowest concentration of antibiotic that prevents visible growth
Measured using - broth or tube dilution method or disk sensitivity test
MBC
Minimum bactericidal concentration - lowest concentration of antibiotic that results in a 99.9% decline in colony count after overnight broth dilution incubation
MIC vs MBC of a truly bactericidal agent
MBC will be equal to or just slightly above its MIC
MIC vs MBC of a bacteriostatic agent
MBC will be way higher than the MIC. MBC is usually not clinically achievable as they are not designed to kill the bacteria
Criteria for selecting the right antibiotic (6)
1) Organisms identity and susceptibility to an agent
2) Necessity of empiric therapy
3) Site of infection
4) Pharmacology
5) Patient factors
6) Cost of therapy
Factors that influence drug penetration of blood brain barrier
Lipid solubility of drug - fluoroquinolone and metronidazole are lipid soluble but penicillin has low lipid solubility
Molecular weight
Protein binding of the drug
Bacterial cell walls - gram positive vs. negative
Gram positive bacteria have a thick mesh-like cell wall made of peptidoglycan + lipoteichoic acid and an inner cell membrane –> stain purple with gram stain
Gram negative bacteria have an extra out membrane with porins and LPS They have a narrow cell wall –> stain pink with gram stain
Examples of Gm - bacteria
E.coli Salmonella Shigella Psuedomonas Helicobacter Legionella Enterobacter Niesseria (meningitis, gonorrhea)
Examples of Gm+ bacteria
Staphylococcus Streptococcus Clostridium Listeria Actinobacteria Mycoplasma Bacillus Entercoccus
Advantages of giving combination therapy
To achieve synergistic effects
In emergency situations
To delay development of resistance
To treat mixed infections
To treat immunosuppressed
Disadvantages of combination therapy
Some agents will only act on multiplying bacteria. If combined with another agent that causes bacteriostasis, they will be less effective.
(eg: b-lactams and tetracyclines)
Can select for multi-drug resistant bacteria
Mechanisms of synergism caused by combination therapy
1) Sequential blockage - blocking two enzymes in the same cascade will maximise probability of killing bacteria (trimethoprim + sulfamethoxazole)
2) Blockade of drug-inactivavting enzymes (clavulanic acid + amoxicillin)
3) Enhanced drug uptake (increased permeability to aminoglycosides after b-lactam treatment which breaks down cell wall and allows aminoglycosides to get to ribosomes)
Antibiotic resistance
Occurs if maximal level of antibiotic tolerated by host does not halt bacterial growth
Antibiotic resistance mechanisms
Altered uptake of antibiotic - decrease in permeability, decrease in uptake mechanisms, increase in multi-drug resistance pumps
Altered target - change in receptor site affinity, modification of targeted metabolic pathway
Drug inactivation - bacterial production of enzymes that inactivate drug (e.g beta lactamases)
Primary antibiotic resistance
Structural absence of target for drug to act on
By nature, mycoplasma lack a cell wall so are resistant to penicillins
Acquired antibiotic resistance mechanisms
Spontaneous mutations of bacterial DNA
DNA transfer of drug resistance genes
Altered expression of proteins in drug-resistant organisms
Ways that bacteria can acquire resistance genes and fate of new DNA
Conjugation
Transposition
Transduction
Transformation
Newly introduced DNA
- Destroyed by bacterial endonucleases
- Circularization and maintenance as a plasmid
- Recombination and integration (recombination can be homologous or non-homologous)
Transformation of resistance genes
Ability to uptake DNA that is released by cell lysis from the environment (also known as competence) –> homologous DNA will undergo recombination and incorporation
Usually occurs between related bacterial species
Facilitated by bacterial DNA binding proteins located on bacterial cell membrane
Requires Ca2+
Conjugation of resistance genes
F+ plasmid (donor) contains genes required for sex pilus and conjugation. F factor (tra) plasmid encodes for the pilus which brings the donor and recipient cells into contact.
Recipient bacteria without this plasmid are F-
Pilus brings F+ and F- into contact –> single strand of plasmid DNA is transferred across the conjugal bridge –> synthesis of complementary strand and recircularization of plasmid in both –> completion of transfer and cells separate –> both bacteria are now F+ –> other genes like genes for antibiotic resistance can be only the F plasmid
**gram positive bacteria have no sex pilus so only occurs in gram negative –> are more difficult to treat and are more resistant
Transposition of resistance genes
Transposons are mobile genetic elements –> can transfer genes from plasmid to chromosome and vice versa
When excision occurs, may include some flanking chromosomal DNA, which can be incorporated into a plasmid –> plasmid can then be transferred to another bacteria
Transduction of resistance genes
Bacteriophage (virus that infects bacteria) injects DNA into host bacterial cell.
Can be generalised (random parts of the bacterial genome are transferred) or specialised (specific parts of the genome from immediate vicinity of prophage are transferred)
Generalized transduction of resistance genes
Generalized/lytic:
Lytic phage infects bacterium –> bacterial DNA cleavage –> Parts of bacterial chromosomal DNA may become packaged in phase capsid (instead of phage DNA) –> New bacteriophage are released and infect new bacterium and transfer the bacterial chromosome fragment that can carry the resistance genes
Random parts of the bacterial genome are transferred
Specialized transduction of resistance genes
Specialized/lysogenic:
Lysogenic phage infects bacterium –> viral DNA incorporates into bacterial chromosome at a specific location –> when phage excises, flanking bacterial genes may be excised with it –> DNA is packaged into phage capsid and can infect another bacterium, transferring the DNA
Specific parts of the genome from immediate vicinity of prophage are transferred
General complication of antibiotic therapy (3)
Hypersensitivity - frequent (can range from urticaria to anaphylactic shock)
Direct toxicity - directly affects host cellular processes (eg: ahminoglycosides and ototoxicity)
Superinfection - new or secondary infection that occurs during antibacterial therapy of a primary infection
Criteria for antimicrobial chemoprophylaxis
Giving antibacterial before patient acquires infection
- Should always be directed towards specific pathogen
- No resistance should develop
- Use should be for limited duration
- Conventional therapeutic doses should be given
- Should only be used in situations of documented drug efficacy
When should nonsurgical antimicrobial prophylaxis be given?
Prevention of CMV, HIV infections, influenza, meningococcal infections, TB
Animal or human bite wounds
Chronic bronchitis
When should surgical antimicrobial prophylaxis be given?
Limited to procedures that are associated with infection in > 50% of untreated cases under optimal conditions
Eg: GI procedures, vaginal hysterectomy, C-section, going replacement, open fracture surgery
