Antimicrobial Therapies Flashcards
What is prontosil?
The first example of a sulfonamide antibiotic
- bacteriostatic
- synthetic
- used to treat UTIs, RTIs, bacteremia and prophylaxis for HIV+ individuals
- becoming more common due to resistance to other microbials, despite some host toxicity
What was prontosil effective against?
puerperal sepsis (childbed fever)- caused primarily by S.pyogenes
- only effective against gram-positive bacteria
What is bacteraemia?
bloodstream infection
Why are anti-bacterials safe for humans to use?
They target proteins found in bacterial cells but not found in humans
Describe the mechanism of action of beta-lactams?
They have a beta-lactam ring which binds to the serine residue on penicillin binding protein, which inactivates the enzyme.
This means that the cross bridges between peptidoglycan molecules that form the outer layer of the bacteria cannot form so the cell wall doesn’t form.
This means that water enters into the bacteria and it dies
What are some examples of beta-lactams?
Penicillin and Methicilin
What do beta-lactams do?
interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
- binds to penicillin-binding proteins
- penicillin-binding proteins catalyse a number of steps in the synthesis of peptidoglycan
What is the definition of an antibiotic?
An anti-microbial agent produced by microorganisms that kills or inhibits other microorganisms
What are most antibiotics produced by?
soil-dwelling fungi (penicillium and cephalosporium) or bacteria (streptomyces and bacillus)
What is an antimicrobial?
A chemical that selectively kills or inhibits microbes (bacteria, fungi, viruses)
What is an antibiotic called when it kills the bacteria?
bactericidal
What is an antibiotic that stops the bacteria growing?
bacteriostatic
Which is better bactericidal or bacteriostatic?
no proof that one is better than the other
What is an antiseptic?
chemical that kills or inhibits microbes that is usually used topically to prevent infection
What is the minimal inhibitory concentration?
The lowest concentration of antibacterial which is required to inhibit growth
What is meant by the breakpoint?
clinically-achievable concentration
What are some effects of antibacterial resistance? (5)
- Longer time needed for therapy to be effective
- Require additional approaches
- Use of expensive therapy (newer drugs)
- Use of more toxic drugs
- Use of less effective “second choice” antibiotics
What happens if bacteria can grow past the breakpoint concentration?
the antibiotic won’t work
Give an example of how the use of antibiotics selects for resistant strains?
Some isolates of S.aureus were resistant to penicillin from the start. Routine use of penicillin provided selective pressure for the acquisition and maintenance of resistant genes.
Is there more resistance in hospitals or communities and why?
hospitals, as less penicillin is used in communities
- resistance in hospitals was never 0%
How does antibiotic resistance emerge?
A population of bacteria will have some bacteria that are resistant and some that are not due to genetic variation
A selection pressure then acts on the population such as the antibiotic - those that are not resistant die, and patient starts to feel better
Patient then stops course of antibiotic but those that can survive still do not die - they live and proliferative meaning the entire population/ high prevalence is now resistant
Do bacteria swap bacteria at a high or low frequency?
high frequency
When does resistance of an antibiotic usually emerge?
soon after the arrival of a nerw antibiotic
What does antibiotic resistance lead to?
increased mortality, morbidity, and cost
e.g., use of more toxic drugs e.g., vancomycin
What are the gram positive bacteria which are resistant to antibiotics?
Staphylococcus aureus (MRSA, VISA)
Wound and skin infect. pneumonia, septicaemia, infective endocarditis.
Streptococcus pneumoniae
Pneumonia, septicaemia.
Clostridium difficile
Pseudomembranous colitis, antibiotic-associated diarrhoea.
Enterococcus spp (VRE)
UTI, bacteraemia, infective endocarditis.
Mycobacterium tuberculosis (MDRTB, XDRTB)
Tuberculosis
What are gram negative bacteria which are resistant to antibiotics?
Pseudomonas aeruginosa
Cystic fibrosis, burn wound infections. Survives on abiotic surfaces.
E. Coli (ESBL)
GI infect., neonatal meningitis, septicaemia, UTI.
E. coli, Klebsiella spp (Carbapenase producing)
As above.
Salmonella spp. (MDR)
GI infect. , typhoid fever.
Acinetobacter baumannii (MDRAB)
Opportunistic, wounds, UTI, pneumonia (VAP).
Neisseria gonorrhoeae
Gonorrhoea.
What are aminoglycosides?
Bactericidal
Target protein synthesis (30S ribosomal subunit), RNA proofreading and cause damage to cell wall
Toxicity has limited use, but resistance to other antibiotics has led to increasing use
What are examples of aminoglycosides?
Gentamicin, streptomycin
What is rifampicin?
Bactericidal
Targets RpoB subunit of RNA polymerase
Spontaneous resistance is frequent
Makes secretions go orange/ red- affects compliance
What is vancomycin?
Bactericidal
Targets Lipid II component of cell wall biosynthesis, as well as wall crosslinking via D-ala residues
Toxicity has limited use, but resistance to other antibiotics has led to increasing use e.g., against MRSA
What is Linezolid?
Bacteriostatic
Inhibits the initiation of protein synthesis by binding to the 50S rRNA subunit
Gram-positive spectrum of activity
What is Daptomycin?
Bactericidal
targets bacterial cell membrane
Gram-positive spectrum of activity
Toxicity limits dose
Which different processes do antibiotics target?
DNA replication
Cell wall synthesis
Plasma membrane damage
Protein synthesis
- Transcription
- Translation
Enzymatic activity/synthesis of metabolites
antibiotics target many different bacterial processes and are selectively toxic
What are examples of antibiotics that target inhibition of cell wall synthesis?
Penicillins, cephalosporins, bacitracin, vancomycin
What are examples of antibiotics that inhibit protein synthesis/ translation specifically?
chloramphenicol, erythromycin, tetracyclines, streptomycin
What are examples of antibiotics that inhibit nucleic acid replication and transcription?
quinolones, rifampin
What are examples of antibiotics that inhibit synthesis of essential metabolites?
sulfanlimide
What are examples of antibiotics that injure plasma membrane?
polymyxin B
Why might you give a patient multiple different antibiotics?
They may act on different stages of bacterial growth and give a symbiotic effect.
e.g. sulfonamides and trimethoprim act on two different stages of bacterial development.
What happens to secretions like urine and sweat when a person is on Rifampicin?
Makes them turn orange / red
Why is linezolid effective against gram positive mainly?
due to the lipopolysaccharides present in gram positive bacterias outer membrane
What are the four main mechanisms of antibiotic resistance? AIMeD
Altered target site
Inactivation of antibiotic
Metabolism - altered metabolism
DEcreased drug accumulation
Describe with an example of how antibiotics can become resistant through altering the target site.
Acquisition of an alternative gene that encodes for a target-site modifying enzyme
E.g., MRSA encodes a different penicillin binding site with a low affinity for the antibiotic- encodes an alternative PBP (PBP2a)
How is Streptococcus pneumoniaeresistant to erythromycin?
occurs via the acquisition of theermgene, whichencodes an enzyme that methylates the AB target sitein the 50S ribosomal subunit.
Give an example of how a bacteria can inactivate an antibiotic (this is a mechanism of antibiotic resistance)
Beta-lactamases and chloramphenicol can degrade a wide range of beta lactam rings meaning they cannot bind to the penicillin binding protein on the bacteria
Give an example of how bacteria can be resistant to an antibiotic through altered metabolism?
This is where the bacteria produce another enzyme substrate which can outcompete antibiotic inhibitor eg increased production of PABA confers resistance to sulfonamides
Alternatively, bacteria switch to other metabolic pathways, reducing requirement for PABA
Describe how bacteria can show antibiotic resistance through decreased drug accumulation?
Reduced penetration of antibiotic into the bacterial cell due to increased efflux of antibiotic out of the cell - this means the drug does not reach the concentration required to be effective
How do bacteria efflux the drug out in order to confer antibiotic resistance?
efflux pumps
What are two examples of macrolide antibiotics?
Erythromycin and azithromycin
How do macrolides work?
Targets 50s ribosomal subunit preventing amino-acyl transfer and thus truncation of polypeptides
What types of bacteria do macrolides work on?
gram positive and some gram negative
How do quinolones work?
Target DNA gyrase in gram negative and topoisomerase IV in gram positive bacteria
What re quinolones?
they are synthetic, broad spectrum and bactericidal
What are three sources of antibiotic resistance?
Plasmids, Transposons and Naked DNA
Describe how plasmids act as a source of antibiotic resistance?
Plasmids are extrachromosomal circular DNA which often carry multiple antibiotic resistant genes - selection for one maintains resistance to all
What are transposons and how can they help to facilitate antibiotic resistance?
They integrate into chromosomal DNA. Allowing transfer of genes from plasmid to chromosome and vice versa.
What is naked DNA?
DNA that has been released into the surrounding environment from dead bacteria
What are the three mechanisms for horizontal spread of AB resistance in bacteria?
Transformation, conjugation and transduction
What is transduction?
Phage mediated DNA transfer
What is conjugation?
Pilus mediated DNA transfer
What is transformation?
uptake of extracellular DNA
What are the five non-genetic sources of antibiotic resistance/ treatment failure?
Biofilm
Intracellular location
Slow growth
Spores
Persisters
What are the 5 given reasons for treatment failure aside from AB resistance? DOPe AC
Inappropriate Dose (half life)
Inappropriate choice for Organism
Poor PEnetration of AB into target site
Inappropriate Administration (oral vs IV)
Presence of AB resistance within Commensal flora e.g. secretion of beta-lactamase
What has to be taken into consideration when measuring resistance using agar plates and zones of inhibition?
Measurements madee in vitro may not fully reflect the situation in vivo
What do hospitals provide for antibiotic resistance and how?
They provide a strong selection pressure
- large numbers of infected people receiving high doses and antibiotics- strong selective pressure for emergence/ maintenance of AB resistance
What are some examples of hospital-acquired infections?
- Methicillin-resistant S. aureus (MRSA)
- Vancomycin-insensitive S. aureus (VISA)
- Clostridium difficle
- Vancomycin-resistant enterococci (VRE)
- E. coli (ESBL/NDM-1)
- P. aeruginosa
- Acineterbacter baumannii
- Stenotrophomonas maltophilia
What are the risk factors associated with Hospitals Acquired Infections
Risk factors for HAIs CAB DIPS
High number of ill people
AB therapy may suppress normal flora
Indwelling devices (intubation)
Crowded wards
Antibiotic therapy
Broken skin (surgical wound/ IV catheter)
Devices (indwelling)
Ill and immunosuppressed patients
Pathogens present
Staff in contact with multiple patients (transmission by staff)
Describe how antibiotic therapy can impair commensal flora?
Normally, commensal organisms can out-compete pathogen WRT adhesion, metabolism, growth. Pathogen cannot colonise at levels sufficient for infection.
After AB therapy => pathogen has no competition which can lead to overgrowth.
When a pathogen then produces toxins which damages the host, it becomes a symptomatic infection, and can spread to other patients
How can we prevent the emergence of drug resistant bacteria and nosocomial infections?
Tighter controls on prescribing such antibiotics
Temporary withdrawal of certain classes
Restriction of ABs for certain serious infection
Reduce use of broad-spectrum antibiotics
Identify infections quickly
KNowledge of local strains/ resistance patterns
How can we overcome resistance?
Modification of existing medication to e.g., prevent cleavage (beta-lactams) or enhance efficacy e.g., methicillin
Combination of antibiotics + inhibitor of e.g., bata-lactaqmase e.g., augmentin
This is a reactice approach in response to emergence of resistance
What are the three broad classes of conditions that fungi can cause in humans?
Allergy - allergic reactions to fungal products
Mycoses - superficial, subcutaneous or systemic colonisation, invasion and destruction of human tissue
Mycotoxicoses - ingestion of fungi and their toxic products
What gram-negative organisms causes HA pneumonia, burn wounds and particularly effects the immunocompromised hosts and survives on abiotic surfaces?
Pseudomonas aeruginosa
What gram negative organism causes ITU infections, and survives on abotioc surfaces?
Acinetobacter baumannii
What gram-positive organism colonises the nasopharynx and causes blood stream infections and shows disseminated spread?
Staphylococcus aureus
What gram positive organism is a commensal or gastrointestinal tract, but can also cause blood stream infections and UTIs?
Enterococcus
What gram positive organism is a major cause of antibiotic associated diarrhoea and mortality?
Clostridium
What are the major Gram Positive antibiotic resistant bacterial pathgens?
Clostridium difficle
Enterococcus
Streptococcus Pneumoniae
What are the major gram negative antibiotic resistant bacterial pathogens?
Pseudomonas aeruginosa
E. Coli
Salmonella
