Hospital Acquired Infection and Antibiotic Resistance Flashcards
What is beta-lactams?
- Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall.
- Examples include Penicillin and methicillin.
- Bind to penicillin-binding proteins.
- PBPs catalyse a number of steps in the synthesis of peptidoglycan.
Describe antibiotics
- An antibiotic is an antimicrobial agent produced by a microorganism that kills or inhibits other microorganisms.
- Most antibiotics in use today are produced by soil-dwelling fungi (Penicillium and Cephalosporium) or bacteria (Streptomyces and Bacillus).
- However, antibiotics commonly used today encompass a range of natural, semi-synthetic and synthetic chemicals with antimicrobial activity.
What does antimicrobial mean?
chemical that selectively kills or inhibits microbes (bacteria, fungi, viruses).
What does bactericidal mean?
kills bacteria.
What does bacteriostatic mean?
stops bacteria growing.
What does antiseptic mean?
chemical that kills or inhibits microbes that is usually used topically to prevent infection.
Why does antibiotic resistance leads to increased mortality morbidity and cost?
- Increased time to effective therapy.
- Requirement for additional approaches – e.g. surgery.
- Use of expensive therapy (newer drugs).
- Use of more toxic drugs e.g. vancomycin.
- Use of less effective ‘second choice’ antibiotics
What are the major gram-negative antibiotic resistant bacterial pathogens?
Pseudomonas aeruginosa Cystic fibrosis, burn wound infections. Survives on abiotic surfaces. E. Coli (ESBL) GI infect., neonatal meningitis, septicaemia, UTI. E. coli, Klebsiella spp (NDM-1) As above. Salmonella spp. (MDR) GI infect. , typhoid fever. Acinetobacter baumannii (MDRAB) Opportunistic, wounds, UTI, pneumonia (VAP). Survives on abiotic surfaces. Neisseria gonorrhoeae Gonorrhoea.
What are the major gram-positive antibiotic resistant bacterial pathogens?
Staphylococcus aureus (MRSA, VISA)
Wound and skin infect. pneumonia, septicaemia, infective endocarditis.
Streptococcus pneumoniae
Pneumonia, septicaemia.
Clostridium difficle
Pseudomembranous colitis, antibiotic-associated diarrhoea.
Enterococcus spp (VRE)
UTI, bacteraemia, infective endocarditis.
Mycobacterium tuberculosis (MDRTB, XDRTB)
Tuberculosis
What is ahminoglycosides?
- E.g. Gentamicin, streptomycin.
- Bactericidal.
- Target protein synthesis (30S ribosomaml subunit), RNA proofreading and cause damage to cell membrane.
- Toxicity has limited use, but resistance to other antibiotics has led to increasing use.
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.
What are antibiotics?
Antibiotics target many different bacterial processes and are selectivity toxic
Large number of difference between mammals and bacteria result in multiple targets for antibiotic therapy - selective toxicity
What are the mechanisms of antibiotic resistance?
- Altered target site
- Inactivation of antibiotic
- Altered metabolism
- Decreased drug accumulation
What happens in altered target site?
- Can arise via acquisition of alternative gene or a gene that encodes a target-modifying enzyme.
- Methicillin-resistant Staphylococcus aureus (MRSA) encodes an alternative PBP (PBP2a) with low affinity for beta-lactams.
- Streptococcus pneumoniae resistance to erythromycin occurs via the acquisition of the erm gene, which encodes an enzyme that methylates the AB target site in the 50S ribosomal subunit.
What happens in inactivation of antibiotic?
- Enzymatic degradation or alteration, rendering antibiotic ineffective.
- Examples include beta-lactamase (bla) and chloramphenicol acetyl-transferase (cat).
- ESBL and NDM-1 are examples of broad-spectrum beta-lactamases (can degrade a wide range of beta-lactams, including newest).
What is altered metabolism?
- Increased production of enzyme substrate can out-compete antibiotic inhibitor (e.g. increased production of PABA confers resistance to sulfonamides).
- Alternatively, bacteria switch to other metabolic pathways, reducing requirement for PABA.
What is decreased drug accumulation?
•Reduced penetration of AB into bacterial cell (permeability) and/or increased efflux of AB out of the cell – drug does not reach concentration required to be effective.
What are macrolides?
- E.g. Erythromycin, azithromycin.
- Gram-positive and some Gram-negative infections.
- Targets 50S ribosomal subunit preventing amino-acyl transfer and thus truncation of polypeptides.
What are quinolone?
- Synthetic, broad spectrum, bactericidal.
* Target DNA gyrase in Gm-ve and topoisomerase IV in Gm+ve.
What re the sources of antibiotic resistance?
- Plasmids – extra-chromosomal circular DNA, often multiple copy. Often carry mutliple AB res genes – selection for one maintains resistance to all.
- Transposons. Integrate into chromosomal DNA. Allow transfer of genes from plasmid to chromosome and vice versa.
- Naked DNA. DNA from dead bacteria released into environment.
How does the spread of antibiotic resistant genes occur?
-Genes responsible for conferring antibiotic resistance can be shared between bacteria via several different mechanisms
What are non-genetic mechanisms of resistance / treatment failure?
- Biofilm
- Intracellular location
- Slow growth
- Spores
- Persisters
What are other reasons for treatment failure?
- Inappropriate choice for organism
- Poor penetration of AB into target site
- Inappropriate dose (half life)
- Inappropriate administration (oral vs IV)
- Presence of AB resistance within commensal flora e.g. secretion of beta-lactamase
What are hospital acquired infections (HAI)?
- Hospitals provide strong selective pressure for antibiotic resistance
- Large numbers of infected people receiving high doses of antibiotics - strong selective pressure for emergence/maintenance of AB resistance
What are examples of HAI?
- 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 for HAI?
- 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
How can AB therapy impair commensal flora (microbiota)?
- In health communal organisms can out-compete pathogen WRT adhesion, metabolism, growth
- Pathogen cannot colonise at levels sufficient for infection
How are we addressing resistance?
- Prescribing strategies – tighter controls, temporary withdrawal of certain classes. Restriction of ABs for certain serious infections
- Reduce use of broad-spectrum antibiotics
- Quicker identification of infections caused by resistant strains
- Combination therapy
- Knowledge of local strains/resistance patterns
How can we overcome resistance?
- Modification of existing medications to e.g. Prevent cleavage (beta-lactams) or enhance efficacy. E.g. Methicillin.
- Combinations of antibiotic + inhibitor of e.g. Beta-lactamase. E.g. Augmentin.
- However, this is a reactive approach in response to emergence of resistance!
What is in the future?
- New antibiotics
- New vaccines
- Better screening and decolonisation
- Novel approaches – phage lysins, photo-active compounds, siRNA, Quorum Sensing inhibitors
- Anti-infectives – MAb or peptide blocking
- Use of non-pathogenic competitor strains
