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Flashcards in 2: Hospital acquired infection and antibiotic resistance Deck (12):

-most in used today produced by

-antimicrobial activity
-bactericidal; bacteriostatic

antibiotic: antimicrobial agent produced by a microorganism that kills / inhibits other microorganisms
-Most in use today produced by soil-dwelling fungi (Penicillium and cephalosporium) / bacteria (Streptomyces and Bacillus)
-range of natural, semi-synthetic and synthetic chemicals w/ antimicrobial activity

-Antimicrobial activity: chemicals selectively kill or inhibit microbes (bacteria, fungi or viruses)
-Bactericidal - kill bacteria; bacteriostatic - stop bacteria from growing
-Antiseptics: chemicals that kill / inhibit microbes, used topically, to prevent infection


history of antibiotics
-Prior to discovery
-Penicillin was first discovered
-Since the discovery of penicillin

-Prior to discovery of penicillin, even minor infections were potentially fatal, with surgery being a major risk
-Penicillin was first discovered by chance by Sir Alexander Fleming at St. Mary’s Hospital -he realised that an irritating contaminant actually held the key to defeating bacterial infections
-Chain, Florey and Heatly contributed to developing ways to mass produce and administer penicillin, for which most the group was awarded a Nobel Prize in 1945 in medicine and physiology
-Since the discovery of penicillin, many AB have been identified. However, the progress of discovering these new AB has slowed down


antibiotic resistance


-problem started, now
-some already

-no selection pressure
-selection pressure

Minimal inhibitory conc (MIC): lowest [AB] required to inhibit growth

Resistance: breakpoint past MIC

-resistance problem started from beginning, now huge global problem
-some strains already resistant to penicillin when discovered

-pop contain cells w/AB resistance from mutations/acquired DNA, possible fitness cost (e.g.slow growth)
-no selection pressure (i.e. no AB), resistant strains have no adv (;may have disadv) --> low prevalence of antibiotic resistant strains in pop.
-selection pressure, resistant mutations outcompete stain without --> high prevalence of resistant strains in pop.


misconceptions at beginning of AB era:


AB resistance --> increase:

misconceptions at beginning of AB era:
-resistance against more than once class of AB at the same time would not occur
-no horizontal gene transfer
-resistant organisms are sig less “fit” (NB: sometimes true, sometimes not true)

**resistance emerges as soon as new AB developed

AB resistance --> increase mortality, morbidity & cost:
-increased time before effective treatment given; patients given AB before strain identified as being resistant
-additional approaches (e.g. surgery)
-expensive therapy (newer drugs)
-more toxic drugs
-less effective “second choice” AB


important multi-drug resistant bacteria
gram -ve:
o P a – causes 3 & can
o EC (2)– Infects, can cause 3
o S s – infects , can cause
o A a – type infections, targets, causes 2, can
o N g – causes

gram +ve:
o S a – targets, and can cause 3
o S p – causes 2
o C d – causes 2
o E s – Causes 3

gram -ve:
o Pseudomonas aeruginosa – causes cystic fibrosis, burn wound infections & can survive on abiotic surfaces
o E.Coli (ESBL, NDM-1)– Infects GI tract, can cause neonatal meningitis, septicaemia & urinary tract infections
o Salmonella spp. – infects GI tract, can cause typhoid fever
o Acinetobacter aumannii – opportunistic infections, which targets wounds, and causes pneumonia and urinary tract infections, can survive on abiotic surfaces
o Neisseria gonorrhoeae – causes gonorrhoea

gram +ve:
o Staphylococcus aureus – targets wound and skin infections, and can cause pneumonia, septicaemia & infective endocarditis
o Streptococcus pneumoniae – causes pneumonia and septicaemia
o Clostridium difficle – causes pseudomembranous colitis, and antibiotic associated diarrhoea
o Enterococcus spp – Causes urinary tract infections, bacteraemia and infective endocartitis


mechanisms of action of AB

-selective toxicity: large diff between animals & bacteria - multiple targets for AB

• B
o Interfere with
o e.g. 2
o bind to
• T
o are, exist
o inhibit
o bind
• Chloramphenicol:
o are, exist
o inhibit
o bind to
o Often
• Q
o are, are, exist
o Target
• S
o are, are
o not
o e.g. 2
o Used to treat 3
o Becoming
• A
o e.g. 2
o are
o target
o note
• M
o e.g.
o target
o targets

-selective toxicity: large diff between animals & bacteria - multiple targets for AB

• Beta-lactams:
o Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
o e.g. penicillin and methicillin
o bind to penicillin-binding proteins (PBPs)
o PBPs catalyse a number of steps in the synthesis of peptidoglycans
o Beta-lactams bind to these PBPs with high affinity and thus inhibit their function
• Tetracycline:
o They are bacteriostatic, and exist in a broad spectrum
o They inhibit protein synthesis
o They bind to the 16S component of the 30S ribosomal subunit, preventing the interaction of charged aminoacyl-tRNAs with the mRNA/ribosome complex, which prevents the elongation of the peptide
• Chloramphenicol:
o bacteriostatic and exist in a broad spectrum
o They inhibit protein synthesis
o They bind to the 50S ribosomal subunit and block peptide transfer steps
o Often used topically due to toxicity. However, increasing antibiotic resistance is renewing interest in chloramphenicol as a synthetic therapeutic
• Quinolones:
o They are synthetic, have a broad spectrum and are bactericidal
o Target DNA gyrase in gram negative bacteria, and topoisomerase IV in gram positive bacteria
• Sulphonamides:
o bacteriostatic
o not strictly antibiotics, and are synthetic
o e.g. trimethoprim and sulpha-methoxazole, which are sometimes used together in co-trimoxazole
o Used to treat urinary tract infections, respiratory tract infections and bacteraemia
o Becoming more common despite some toxicity due to resistance to other antimicrobials
• Aminoglycosides:
o These include gentamicin and streptomycin
o bactericidal
o They target the 30S ribosomal subunit, RNA proofreading and cause damage to the cell membrane
o Toxicity, so it has limited use, but resistance to other antibiotic has led to its increased use
• Macrolides:
o e.g. erythromycin
o target gram-+ve infections
o It targets the 50S ribosomal subunit, preventing amino-acyl transfer and thus truncation of the polypeptides occur


Mechanisms of antibiotic resistance

1) Altered target site:
-arise via acquisition of alternative gene or gene that encodes a target-modifying enzyme
-e.g. methicillin-resistant Staphylococcus aureus encodes an alternative penicillin binding protein with a low affinity for beta-lactams
-e.g. Streptococcus pneumoniae resistance to erythromycin occurs via acquisition of the erm gene, which encodes an enzyme that methylates the AB target site in the 50S ribosomal subunit

2) Inactivation of antibiotic:
-Enzymatic degradation / alteration
-e.g. beta-lactamase and chloramphenicol acetyl-transferase
-e.g. ESBL and NDM-1 (E.Coli): broad-spectrum beta-lactamases (can degrade a wide range of beta-lactams)

3) Altered metabolism:
-Increased production of enzyme substrate can out-compete antibiotic inhibitor (e.g. by increasing the production of PABA confers resistant to sulphonamides)
-or bacteria switch to other metabolic pathways, reducing the requirement for PABA

4) Decreased drug accumulation:
-Reduced penetration of AB into bacterial cell (permeability) and/or increased efflux of antibiotic out of the cell --> drug does not reach the conc required to be effective


Sources of antibiotic resistant genes

• Plasmids – extra-cellular circular DNA often in multiple copies. They often carry multiple AB resistant genes, and selection for one maintains resistance to all of them
• Transposons – integrated into the chromosomal DNA, and allow transfer of genes from plasmid to chromosome and vice versa
• Naked DNA- DNA from dead bacteria released into the environment
• The spread of antibiotic resistant genes: transformation (uptake of extracellular DNA), transduction (phage-mediated DNA transfer), conjugation (pilus-mediated DNA transfer)


treatment failures
Non-genetic mechanisms: 5
Other reasons: 5

Non-genetic mechanisms:
o Biofilm
o Intracellular location
o Slow growth
o Spores
o Persisters

• Other reasons:
o Inappropriate choice for organism
o Poor penetration of antibiotic into the target site
o Inappropriate dose
o Inappropriate administration (oral vs IV)
o Presence of antibiotic resistance within the commensal flora


Measuring resistance

-other approaches 2

***measurements made in vitro may not fully reflect the situation in vivo

1. Swabs are typically streaked out onto diagnostic agar to identify the causative organism
2. pathogen is streaked over a plate and then over-laid with antibiotic containing test strips or discs

-Other approaches include broth micro-dilution and PCR detection of resistant genes


Hospital acquired infections

-Hospitals provide a strong selection pressure for AB resistance

Hospital-acquired infections:
o Methicillin-resistant s.aureus
o Vancomycin-insensitive s.aureus
o Clostridium difficle
o Cancmycin-resistant enterococci
o E.coli (ESBL/NDM-1)
o Acineterbacter baumannii
o Stenotrophomonas maltophilia

Risk factors for hospital-acquired infections:
o High number of ill people
o Crowded wards
o Presence of pathogens
o Broken skin – surgical wound or IV catheters
o Indwelling devices, like intubation
o Antibiotic therapy may supress normal flora – in health, commensal organisms can out compete pathogen with respect to adhesion, metabolism, growth, so the pathogen cannot colonise at levels sufficient for infection. However, the antibiotic therapy may wipe out these commensal organisms, allowing a surface for pathogens to grow
o Transmission by staff – contact with multiple patients


Preventing the emergence of drug resistant bacteria and nosocomial infections


overcoming resistance


o Prescribing strategies – tighter controls, temporary withdrawal of certain classes and restriction of antibiotics in certain serious infections
o Reduce use of broad-spectrum antibiotics
o Quicker identification of infections caused by resistant strains
o Combination therapy
o Knowledge of local strains/resistance patterns

• Overcoming resistance:
o Mod existing medications to prevent cleavage or enhance efficacy
o Combinations of antibiotics and inhibitors
***reactive approach

• future:
o New antibiotics
o New vaccines
o Better screening and decolonisation
o Novel approaches – phage lysins, photo-active compounds, siRNA, Quorum Sensing inhibition
o Anti-infective – Mab or peptide blocking
o Use of non-pathogenic competitor strains