Antimicrobial therapies Flashcards
What are antibiotics?
Microbial drugs abide by the principle of selective toxicity. They interfere with the metabolism or function of the pathogen, with minimal damage to host cells.
What are the two classes of antibiotics?
Bacteriostatic and bactericidal
What are the mechanisms of bacteriostatic antibiotics? (2)
Anitmetabolites: Interupts nucleic acid synthesis, metabolic pathways (substrates)
Protein synthesis inhibitors: Prevents translation and transcription of structural genes
What are bacteriostatic antibiotics?
Drugs inhibits the growth of the microorganism.
What are are the three principal mechanisms for bactericidal antibiotics?
Beta lactams (disrupt peptidoglycan cell wall)
Cell membrane agents
DNA gyrase inhibitors
What pathway does sulphonamide interfere with?
Interferes with folic acid synthesis by preventing the addition paraminobenozinc acid through competing with the enzyme dihydropteroate synthetase.
What is the mechanism of tetracycline?
Prevention of transcription and translation of microbial genes. Tetracycline inhibits translation through preventing the association of amino-acyl tRNA within the ribosome.
What ribosomal subunit does chloramphenicol bind onto?
50s
What is the mechanism of a beta-lactam?
Ring mimics component of the peptidoglycan cell wall, inactivates enzyme transpeptidase, (Binds to penicillin binding proteins)_- Peptide cross linkages cannot form
What are broad spectrum antibiotics?
Destroy a wide range of harmful bacteria, whereas narrow-spectrum antibiotics target specific pathogens.
What factors affect drug efficacy?
pH level
Concentration
Antibiotic destruction
Sensitivity
What is the minimal inhibitory concentration (MIC)?
Lowest concentration of AB required to inhibit growth
What is the breakpoint?
The clinically achievable concentration
What is the process of antibiotic resistance? (Natural selection perspective)
Exposure to an antiobitic exerts a strong selection pressure on the bacterial population, bacteria with resistance to the antiobitic has a selective advantage, being more likely to survive and reproduce successfully.
Post-antibiotic exposure, on resistant strains terminated, resistant strains withstand environmental stress. Reduced intra-specific competition leads to exponential growth. Gut microbiota disrupted opening opportunity for bacteria to develop.
Due to binary fission, the daughter cells will inherit the alleles that confer resistance; the process of natural selection repeats for generations, causing changes in the allele frequency-.
Significant proportion of antibiotic resistant strains arises in population
How can antibiotic resistance be transferred?
Bacterial conjugation: Horizontal gene transfer of bacterial plasmids. Gain of antibiotic resitstance gene
Bacterial transformation: Inclusion of plasmids or alleles from the external environment into the bacterium genome.
Transduction: Natural AB resistance genes introduced by bacteriophages, occurs during transduction, piece of integrated AB gene transferred to another host cell during the lysogenic pathway
What are DNA plasmids?
Small circular pieces of DNA, containing variety of genes that encode for different proteins and enzymes
Have genes that express antibiotic resistance
How are plasmids transferred between bacterium?
Copied, shared and swapped through hollow tubular structure, pilus, allows a pore to form in the envelops of the cell, enables plasmid to be passed from a donor to recipient
Why is there a high prevalence of Antibiotic-resistant strains n healthcare?
Antibiotic resistant genes only possess an evolutionary advantage if a selection pressure is applied. Antibiotic exposure will ensure susceptible bacteria are destroyed, contrastingly bacteria with the acquired resistance will be able to survive and multiply to become prevalent in the environment (healthcare associated infections). Absence of antibiotic exposure puts bacteria at an evolutionary disadvantage (harbouring additional DNA requires a larger energy commitment to maintain the genetic information).
What are bacterial transposons?
Pieces of DNA with the ability to integrate and exchange between bacterial genomes independently from conjugation and transformation
What is bacterial transduction?
Lysogenic bacteriophages can remove bacterial DNA located within a proximity to the phage DNA attachment site. Bacterial DNA encoding for antibiotic resistance can therefore be extracted into the phage DNA, henceforth during further infection cycles the phage would insert the DNA into the new hosts genome; transferring antibiotic resistance.
What is bacterial transformation?
Bacterial cells taking up DNA fragments within the surrounding environment (contain genes that encode for proteins and enzymes). DNA fragments suspended in environment due to bacterial death. Multiple plasmids can be accumulating inside a bacterium, leads to variety of antibiotic resistant genes.
What are the four mechanisms of AB resistance?
Altered target site
Inactivation of antibiotic
Altered metabolism
Decreased drug accumulation
What alternative binding site does MRSA encode for?
PBP2a, with low affinity for beta lactams, inhibiting the binding mechanism
How is streptococcus pneumonia resistant to erythromycin?
Acquisition of the erm gene
Enzyme methylates the AB target site in the 50s ribosomal subunit
Chemical inhibition of the antibiotic
What is the enzyme that hydrolyse beta lactams?
Beta-lactamases
How do beta-lactamases work?
Breaks bond in B-lactam ring of penicillin, disabling the molecule
Choramphenical acetyl-transferase enzymatically targets the riNG
What is the term for broad spectrum beta lactamases (NDM-1)?
Extended spectrum beta lactamases (ESBLs)
What is altered metabolism?
Increased production of enzyme substrate to outcompete antibiotic inhibitor (PABA confers resistance to sulphonamides) .Competitive inhibitor (sulphonamide).
Bacteria can alternate and divert to other metabolic pathways, reducing the metabolic requirement for PABA.
How can bacteria decrease drug accumulation?
Reducing the bacterial cell permeability to AB, and increasing efflux of AB out of the cell (drug reaches insufficient concentration). Associated protein pumps can actively pump the AB.
What kind of bacteria is staphlyoccous?
Gram Positive
What kind of bacteria is E.coli?
Gram-negative
What is the mechanism of aminoglycosides?
Bactericidal
Targets protein synthesis (30s ribosomal subunit), RNA proofreading, and damages cell surface membrane
Dysfunctional misfolded proteins occur due to altered tertiary structure
Give two examples of aminoglycosides:
Gentamicin
Streptomycin
What is the mechanism of rifamycin?
Bactericidal
Targets RpoB subunit of RNA polymerase (mRNA synthesis is inhibited, transcription ceased)
Spontaneous resistance is frequent
What is the side effect of rifamycin use?
Secretions go orange, this impacts drug compliance.
What is the mechanism of Vancomycin?
Bactericidal, targets lipid II component of cell wall biosynthesis, as well as cross liking via D-ala residues
Polarised molecule disrupts the phospholipid bilayer
What are linezolids?
Bacteiostatic
Inhibits the initiation of protein translation by binding to the 50s rRNA subunit
What type of bacteria does linezolids target?
Gram positive spectrum
What is daptomycin?
Bactericidal targets bacterial cell membrane, gram positive spectrum of activity
What is the mechanism of macrolides?
Targets 50s ribosomal subunit, preventing amino-acyl transfer and thus truncation of polypeptides.
During protein translation peptide bonds cannot be formed between amino acids
Give two examples of macrolides?
Erythromycin and azithromycin
What is the mechanism of quinolone?
Synthetic, broad spectrum, bactericidal; targets DNA gyrase (ATP-dependent negative super-coiling of double stranded into linear circular loop) in gram-negative, and topoisomerase IV in gram-positive.
What are biofilms?
Thick layer of mucilage adhering to a solid surface, containing a community of bacteria, this minimises the penetration effect of antibiotics
Why are viruses difficult to treat (main reason) using antibiotics?
Pathogens with the ability to grow and reproduce inside host cells are difficult targets for antibiotics
What are spores?
Bacterial endospores are resistant to antibiotics, the spore coat is impermeable to antibiotics, preventing access to the target organelles
What are persister cells?
Dormant cells that form stochastically in microbial populations and are highly tolerant to antibiotics
Why does slow growth contribute to treatment failure?
Bacteriostatic antibiotics have limited use, life cycle of antibiotic ineffective to have adequate effect.
Why can commensal flora present an issue to antibiotics?
Secretion of beta lactase hydrolyses antibiotic
What can be implemented to reduce antibiotic resistance?
Not to be used to treat viral diseases Reduce use of broad spectrums Temporary withdrawal Quicker identification of infections caused by resistance strains Combination therpay Knowledge of resistance patterns
What is the patient responsibility for antibiotics?
Complete full course, increases the chances of eradicating the disease causing bacteria from the body
What responsibilities do health centres and hospitals have to reducing antibiotic resistance?
Ensure proper hygiene regulations Clean surfaces and bed linen Patient isolation Washing hands Using alcohol based gels
What is MRSA?
Menticillin resistant staphloccous aureus
Pencillinase enzyme hydrolyses methicillin.
What is c difficile?
Anaerobic pathogen,located in large intestine, produces spores.
What is the downside of using broad spectrum antibiotics?
Broad spectrum antibiotics used to treat bacterial infections destroy the microbiota as well as the target pathogens. Bacteria produces two different toxins that damage the lining of the intestine, causing severe diarrhoea that can lead to bleeding from the gut.
Why should chloride based disinfectant be used in replacement of alcohol based gels for hygiene?
Spores of C difficile cannot be destroyed by alcohol
What are the risks factors for HCAIs(Nosocomial)?
High number of ill people (immunosuppression)
Crowded wards
Presence of pathogens
Broken skin – surgical wound/IV catheter
Indwelling devices - intubation
AB therapy may suppress normal flora
Transmission by staff – contact with multiple patients
What are the two types of bacteria?
Gram positive & gram negative
What is the structure of gram positive bacteria?
Thicker layers of peptidoglycan, containing teichoic acid.
Alternating n-acetyl glucoamine (NAG) and N-acetyl muramic acid (NAM), held via glycosidic linkages, and peptide cross links
What is the relative structure of gram negative bacteria?
Gram-negative bacteria have thinner layers of peptidoglycan with non teichoic acid between the two layers of membrane. Gram-negative bacteria, unlike Gram-positive bacteria have an outer-membrane (phospholipid bilayer), which is made from lipopolysaccharides.
Lower lipid content
How are bacteria classified by shape? (3)
Spherical (Cocci)
Bacilli (Rod shaped)
Twisted (spirilla)
What is the class of bacteria that require oxygen for respiration?
Obligate aerobes
What are facultative anaerobes?
Have the ability to aerobically and anaerobically respire
What are obligate anaerobes?
Anaerobically respire
What are fungi?
Eukaryotes that digest food extracellularly through the secretion of hydrolytic enzymes; digest biopolymers to be absorbed for nutrition- 3 broad classes of human conditions.
What are the 3 classes of fungi?
Allergy, mycotoxicosis
mycoses
What are allergy fungi?
Allergic reactions to fungal productions
What is mycotoxicosis?
Ingestion of fungi and their respective toxin
What is mycoses?
Superficial, subcutaneous or systemic colonisation invasion or destruction of human tissue
What are the primary targets of anti fungal therapy?
Cell membrane,
Ergosterol hydrolysis
DNA synthesis, some compounds may be selectively activated by fungi arresting DNA synthesis; and cell wall, fungi cells have a cell wall composed of chitin.
What kind of antibiotic is protonsil and is it bacteriostatic or bacteriocidal?
Sulphonamide-Bacteriostatic
Give 5 non-genetic reasons of antimicrobial therapy failure
Inappropriate choice for organism
Poor penetration to target site
Inappropriate dose
Inappropriate administration
Presence of AB resistance with commensal flora