Week 6 - Clinical Microbiology 1 Flashcards
Describe the bacterial structure?
- Cell membrane
- Peptidoglycan cell wall (thicker in gram positives)
- Outer membrane
- Periplasm
- Positive/negative
List the 4 antibiotic targets?
- Cell wall peptidoglycan
- Metabolism
- DNA
- Ribosome
What are the 2 different ways that an antibiotic can act?
- Bactericidal
2. Bacteriostatic
Describe Bactericidal antibiotic action?
- Achieve sterilisation of the infected site by directly killing bacteria
- Lysis of bacteria can lead to release of toxins & inflammatory material
Describe Bacteriostatic antibiotic action?
- Suppresses growth but does not directly sterilise infected site
- Requires additional factors to clear bacteria- immune mediated killing
Describe the antibiotic spectrum?
- Spectrum refers to the range of bacterial species effectively treated by the antibiotic
- Antibiotic spectrum can vary widely even within the same antibiotic class
Describe the antibiotic spectrum of Meropenem?
- Active against almost all gram positive & gram negative species.
- Resistance is rare except for MRSA
Describe the antibiotic spectrum of
Benzyl-penicillin?
- Highly active against streptococci
- Most other disease causing bacteria are resistant
Describe Broad Spectrum antibiotics?
Treat most causes of infection but also have a substantial effect on colonising bacteria
Describe Narrow Spectrum antibiotics?
- Useful only where the cause of the infection is well defined
- Have a much more limited effect on colonising bacteria
Give 5 examples of gram negative bacteria?
- Pseudomonas
- Haemophilus
- Neisseria
- Other coliforms
- E. coli
Give 3 examples of gram positive bacteria?
- Streptococcus
- Enterococcus
- Staphylococcus
Give 2 examples of anaerobes bacteria?
- Clostridium
2. Bacteroides
What are the 3 uses of antibiotics?
- Guided therapy
- Empirical therapy
- Prophylactic therapy
Describe Guided therapy antibiotic use?
Depends on identifying cause of infection & selecting agent based on sensitivity testing
Describe Empirical therapy antibiotic use?
- Best (educated) guess therapy based on
clinical/epidemiological acumen - Used when therapy cannot wait for culture
Describe Prophylactic therapy antibiotic use?
Preventing infection before it begins
What 2 harms does antibiotic disruption of bacterial flora lead to?
- Overgrowth with yeasts- thrush
2. Overgrowth of bowel- diarrhoea
What 2 things is antibiotic use negatively associated with?
- Development of C. difficile colitis
2. Future colonisation & infection with resistant organisms
How could you compromise in antibiotic guided therapy?
- Use antibiotic which has limited action to the bacteria causing infection
- If possible limit penetration to site of infection
- Achieve clinical cure with as little impact on colonisation and resistance as possible
What type of antibiotic is best for guided therapy?
Narrow spectrum
What type of antibiotic is best for empirical therapy?
Broad spectrum
What are the 4 classes of β-Lactam Antibiotics?
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
What is the antibiotic combination in Augmentin/Co-amoxiclav?
Amoxicillin/clavulanic acid
What is the antibiotic combination in Tazocin?
Piperacillin/tazobactam
List the 6 common β-Lactam Antibiotics?
- Benzylpenicillin
- Flucloxacillin
- Amoxicillin
- Ceftriaxone
- Meropenem
- Aztreonam
Describe the Mechanism of action of β-Lactam Antibiotics?
- β-lactam motif analogue of branching structure of peptidoglycan
- Inhibits cross linking of cell wall peptidoglycan
- Causes lysis of bacteria
What type of antibiotic are β-Lactam Antibiotics?
Bacteriostatic
What are Beta-lactamases?
Enzymes that lyse & inactivate beta-lactam drugs
What 2 things commonly secrete Beta-lactamases?
Gram negatives & S.aureus
What can Beta-lactamases lead to?
Confer high level resistance to antibiotic: Total antibiotic failure is likely to result
How are most β-Lactam Antibiotics administered & why?
- Most β-lactams poorly absorbed from GI tract: IV
- Some can be effective orally: amoxicillin, flucloxacillin. Vomiting limits dose
How are β-Lactam Antibiotics secreted?
Usually unchanged in urine, some also via bile
What is the half life of β-Lactam Antibiotics?
Half life varies enormously: Benzylpenicillin ≈ 1 hour Ceftriaxone ≈ 8 hours
What are the 4 types of adverse effects seen with β-Lactam Antibiotics?
- GI toxicity
- Hypersensitivity
- Infection
- Miscellaneous rare reactions (seizures, haemolysis, leukopenia)
List the 3 GI toxicity effects of β-Lactam Antibiotics?
- Nausea & vomiting
- Diarrhoea
- Cholestasis
List the 3 hypersensitivity effects of β-Lactam Antibiotics?
- Type 1 Urticaria, anaphylaxis
- Type 4 Mild to severe dermatology
- Interstitial nephritis
List the 3 infection effects of β-Lactam Antibiotics?
- Candidiasis: Oral Vulvovaginal
- Clostridium difficile infection
- Selection of resistant bacteria
Describe the common Type I hypersensitivity allergic reaction to antibiotics?
- Most patients develop an urticarial rash
- Anaphylaxis is the most feared complication
- Cross reaction between classes is variable
What are the 3 factors associated with reported hypersensitivity syndrome?
- Non allergic
- Gastrointestinal symptoms
- Therapeutic failure
Describe penicillin cross reactivity?
Patients allergic to a penicillin will usually be allergic to other penicillins
Describe how penicillin cross reactivity can be managed with other antibiotic classes?
- Penicillin allergy may be safely managed with other β-lactams
- Particularly important if patient presents with life- threatening infection (esp. meningitis)
What are the 3 common penicillins?
- Benzyl-penicillin
- Amoxicillin
- Flucloxacillin
What is the common Cephalosporins?
Ceftriaxone
What is the common Carbapenems?
Meropenem
What is the common Monobactams?
Aztreonam
What are the 2 common β-lactam/β-lactamase inhibitor combinations?
- Co-amoxiclav
2. Piperacillin/tazobactam = tazocin
Describe how Benzylpenicillin is administered?
- Administered IV
- There is an oral agent (Penicillin V) but not often
used
What is Benzylpenicillin used for?
1st choice antibiotic for serious streptococcal infection (i.e. erysipelas)
Benzylpenicillin is a ______ spectrum agent?
Narrow
What 2 bacterias is Benzylpenicillin very effective against?
- Streptococcus
2. Neisseria
What is Amoxicillin?
Semi-synthetic penicillin
What is Amoxicillin used for?
- Increased activity against gram negative organisms (resistance)
- More orally bioavailable than natural penicillins
- Treatment of a wide range of infections
What are the 3 bacterias that Amoxicillin is very effective against?
- Streptococcus
- Enterococcus
- Neisseria
What is Flucloxacillin?
Synthetic penicillin developed to be resistant to beta-lactamase produced by staphylococci
What are the 2 bacterias that Flucloxacillin is very effective against?
- Staphylococcus aureus (not MRSA)
2. Streptococci
What is Flucloxacillin NOT effective against?
No activity at all against gram negative organisms
What is the route for Flucloxacillin?
Orally but nausea limits dose
What are Beta-lactamase inhibitors administered with & why?
- Penicillin antibiotic
- Greatly broadens spectrum of penicillins against Gram negatives & S. aureus
What are 2 Beta-lactamase inhibitors?
- Clavulanic acid
2. Tazobactam
What are the 5 bacterias that Co-amoxiclav is effective against?
- Streptococcus
- Enterococcus
- Staphylococcus (not MRSA)
- Neisseria
- Haemophilus
What are the 5 bacterias that Benzylpenicillin is NOT effective against?
- Bacteroides
- Staphylococcus
- Other coliforms
- Haemophilus
- Pseudomonas
What are Cephalosporins effective against?
Good activity against Gram positives & Gram negatives
What is more susceptible to beta-lactamases: Cephalosporins or penicillins?
Penicillins
Describe the multiple generations of cephalosporins?
- Gram negative spectrum increases with each generation
- Some loss of Gram positive activity
- Recent introduction of MRSA active cephalosporins
What are the 5 bacterias that Ceftriaxone are effective against?
- Streptococcus
- Staphylococcus (not MRSA)
- E. coli
- Neisseria
- Haemophilus
What are the 2 bacterias that Ceftriaxone are NOT effective against?
- Enterococcus
2. Pseudomonas
What are Carbapenems?
Ultra-broad spectrum beta- lactam antibiotics developed during search for beta-lactamase inhibitors
Describe what Carbapenems are effective/resistant against?
- Excellent spectrum of activity against Gram positive & Gram negative
- No activity against MRSA
- Resistant to beta-lactamases
What are the 2 ultra broad spectrum antibiotics?
- Meropenem
2. Tazocin
What is the only member of the monobactam class of antibiotics?
Aztreonam
Describe Monobactams?
Beta-lactam antibiotic but no cross reactivity to penicillins so can be given to those with penicillin allergy (except anaphylaxis)
How are Monobactams administered?
Only given IV, no oral absorption
What are the 4 bacterias that Aztreonam is effective against?
- E. coli
- Neisseria
- Haemophilus
- Pseudomonas
What are the 5 bacterias that Aztreonam are NOT effective against?
- Staphylococcus (not MRSA)
- Enterococcus
- Streptococcus
- Clostridium
- Bacteroides
How does Vancomycin work?
- Inhibits cell wall formation in Gram positives only
- Not dependent on PBP binding so effective against resistant organisms
What is the route for administering Vancomycin?
- Not absorbed from GI tract so IV
- Oral route only for C. diff
How common is Vancomycin resistance?
Occurs but is uncommon (esp. Staph)
What is Vancomycins half life?
Long half-life so loading doses usually given
What is the main clinical issue with Vancomycin?
Underdosing
Describe the 4 factors of toxicity with Vancomycin?
- Nephrotoxicity-more likely with higher doses
- Red-man syndrome if injected too rapidly
- Ototoxicity (rare)
- Therapeutic drug monitoring undertaken (narrow therapeutic index)
What is Red-man syndrome?
- Anaphylactoid reaction
- Very rare now infusion rates slow
What is the most effective antibiotic to treat cellulitis?
Flucloxacillin
What antibiotic is effective against MRSA?
Vancomycin
Why are beta-lactams the most important class of antibiotics?
- Wide spectrum of activity
- Excellent efficacy
- Low toxicity
What are the 5 most common infectious causes of death in low-income countries?
- Lower respiratory infections
- HIV/AIDS
- Diarrhoeal diseases
- Malaria
- Tuberculosis
List the 6 antibiotic resistant infectious diseases?
- MRSA = Methicillin-resistant Staphylococcus aureus
- VRSA = Vancomycin-resistant Staphylococcus aureus
- ESBLs = Extended spectrum beta-lactamase
- CPEs = Carbapenemase Producing Enterobacteriaceae
- MDRTB = Multidrug-resistant TB
- HIV = Human immunodeficiency viruses
What are the 7 multifactorial reasons behind the increase in infectious diseases/resistance?
- New patterns of travel (air) & trade (food)
- Developments in agricultural practices/animal husbandry
- Sexual behaviour
- Medical interventions/developments in technology
- Increasing populations at extremes of age
- Over/unnecessary use of antibiotics
- The breakdown of economic, social & political systems
What infectious disease is a common cause of death in high income countries?
Lower respiratory tract infection
What is the 2nd most common reason for empirical antibiotic therapy?
UTI
Describe the occurrence and effects HAI have?
- Increased morbidity, mortality, use of investigations, use of antibiotics, length of stay
- Decreased throughput
- Costs NHS in Scotland approx. £200 million per year
What is the 2nd most common cause of death after cardiovascular disease?
Sepsis (70% community acquired)
What are the 8 resistance mechanism?
- Loss of porins
- Beta-lactamases in periplasmic space
- Overexpression of transmembrane efflux pump
- Antibiotic-modifying enzymes
- Target mutations
- Ribosomal mutation or modification
- Mutations in lipopolysaccharide structure
What is Carbapenem-resistant K. pneumonia susceptible to?
- Colistin
- Tigecycline
- Gentamicin
What are the 3 critical bacterias that need new antibiotics?
- Acinetobacter baumannii, carbapenem-resistant
- Pseudomonas aeruginosa, carbapenem-resistant
- Enterobacteriaceae, carbapenem-resistant, ESBL-producing
What are the 4 big challenges facing antibiotic development in the 21st century?
- New antibiotics are needed to combat resistance
- New antibiotics are reserved to guard against resistance
- It can take in excess of 10 years from discovery to launch
- Est. to cost $1billion to bring a new drug to market
What are the 4 targets for antibiotics?
- Cell wall biosynthesis
- Protein biosynthesis
- DNA & RNA replication
- Folate metabolism
What are the 3 types of antibiotics that inhibit the 50S Ribosomal Subunit?
- Macrolides
- Clindamycin
- Chloramphenicol
Give 3 examples of Macrolides?
- Erythromycin
- Clarithromycin
- Azithromycin
What are the 2 types of antibiotics that inhibit the 30S Ribosomal Subunit?
- Aminoglycosides (Gentamicin)
2. Tetracyclines (Doxycycline)
What are macrolides effective against?
- Good spectrum of activity against Gram positives & respiratory gram negatives
- Active against Legionella, Mycoplasma & Chlamydia
How are Macrolides administered?
Oral even in severe infection
What are the 5 bacterias that Clarithromycin is effective against?
- Streptococcus
- Staphylococcus
- Neisseria
- Haemophilus
- “Atypicals”
What are the 5 “Atypicals” that Clarithromycin is effective against?
- Legionella
- Mycoplasma
- Coxiella
- Chlamydia
- Chlamydophila
What are the 3 adverse effects associated with Macrolides?
- Diarrhoea & Vomiting
- QT prolongation
- Hearing loss with long term use
What are the 3 drugs that interact with Macrolides (esp. Clarithromycin)?
- Simvastatin- Avoid co-prescription, Temporarily stop simvastatin
- Atorvastatin
- Warfarin
Why should Macrolides only be used in relatively non-severe infections?
Resistance among “typical” pathogens is relatively common
What is Clindamycin similar to in terms of mechanism of action & absorption?
Macrolides (oral)
What are the 2 key differences of Clindamycin compared to Macrolides?
- No action against aerobic Gram negatives or
“atypicals” - Excellent activity against anaerobes
What is Clindamycin highly effective at?
Stopping exotoxin production
What are 2 gram positive toxin mediated diseases that Clindamycin is used to treat?
- Toxic shock syndrome
2. Necrotising fasciitis
What are the 4 bacterias that Clindamycin is effective against?
- Bacteroides
- Clostridium
- Streptococcus
- Staphylococcus
What is Clindamycin particularly effective against?
Anaerobes, which means its particularly effective at disrupting colonic flora
What is Clindamycin notorious for causing?
C. difficile
Describe C. Differgic antibiotics?
- Antibiotics dramatically alter the colonic flora
- C. difficile commonly colonises the human colon
- Forms spores which can be difficult to eradiacate from hospitals
- Has developed resistance to common antibiotic classes
What are the 4C’s which cause C. diff?
- Clindamycin
- Co-amoxiclav
- Cephalosporins
- Ciprofloxacin
Describe Chloramphenicol?
- Inhibits 50S ribosome
- Excellent broad spectrum of activity
- Toxic
What are the 3 side effects of Chloramphenicol’s toxicity?
- Bone marrow suppression
- Aplastic anaemia
- Optic neuritis
What are the 2 modern uses of Chloramphenicol?
- Topical therapy to eyes
2. Bacterial meningitis with beta-lactam allergy
What are the 2 mechanisms of action for Gentamicin (Aminoglycosides)?
- Reversibly binds to the 30S ribosome (bacteriostatic)
2. Poorly understood action on the cell membrane (bactericidal)
List the 3 side effects of Aminoglycosides toxicity?
- Nephrotoxicity
- Ototoxicity- hearing loss, loss of balance, oscillopsia
- Neuromuscular blockade (usually only significant in myaesthenia gravis)
Describe the once-daily dosing of Aminoglycosides?
- Give high initial dose
- Leave long dosing interval (24-48hrs) to minimise toxicity
- Measure trough level to ensure drug not accumulating
- Give for 3 days only
List the 4 bacteria that Gentamicin is effective against?
- Pseudomonas
- Staphylococcus
- E. coli
- Other coliforms
Describe Tetracyclines?
- Similar spectrum of activity to macrolides
- Also active against “atypical” organisms
- Relatively non-toxic
Why should Tetracyclines not be used for children & pregnant women?
- Bone abnormalities
2. Tooth discolouration
What are the 5 bacterias that Doxycycline is effective against?
- Streptococcus
- Staphylococcus
- Neisseria
- Haemophilus
- “Atypicals”
List the 5 “Atypicals” that Doxycycline is effective against?
- Rickettsia
- Mycoplasma
- Coxiella
- Chlamydia
- Chlamydophila
What are 2 types of antibiotics that work by inhibiting DNA Repair & Replication?
- Quinolones (Ciprofloxacin & Levofloxacin)
2. Rifampicin
What are Quinolones?
Broad spectrum, bactericidal antibiotics
Describe Ciprofloxacin (Quinolones) & its uses?
- Good against Gram negatives, weaker against Gram positives
- Commonly used in UTI/abdominal infection
Describe Levofloxacin (Quinolones) & its uses?
- Sacrifices some Gram negative activity for stronger Gram positive action
- Respiratory tract
What is the route of administering Quinolones?
Excellent oral bioavailability: can use oral dosing even in severe infection
List the 3 side effects of Quinolones toxicity?
- Gastrointestinal toxicity
- QT prolongation
- Tendonitis
What are 2 other therapeutic problems with Quinolones?
- Resistance emerging on therapy/tendon damage
2. C. diff infection (esp. in North America)
What are the 6 bacterias that Quinolones are effective against?
- E. coli
- Other coliforms
- Neisseria
- Haemophilus
- Pseudomonas
- Atypicals
List the 5 “Atypicals” that Ciprofloxacin & Levofloxacin are effective against?
- Legionella
- Mycoplasma
- Coxiella
- Chlamydia
- Chlamydophila
What are the 3 bacterias that Levofloxacin is effective against?
- Streptococcus
- Staphylococcus
- “Atypicals”
What are the 2 indications for Rifampicin in the UK?
- Tuberculosis (in combination therapy)
2. In addition to another antibiotic in serious Gram positive infection (esp. Staph. aureus)
What are the 2 Rifampicin interactions?
- Rifampicin is a potent CYP450 enzyme inducer
2. Most drugs that undergo hepatic metabolism affected
What are the 3 problems with Tuberculosis?
- Slow growing
- High bacterial burden
- Limited access of drugs to granuloma (no vascular
supply)
What are the 2 solutions to Tuberculosis?
- Prolonged courses of therapy (usually 6 months)
2. Combination therapy to prevent resistance & kill growing and resting organisms
What are the 4 standard short course drugs used too treat Tuberculosis?
- Isoniazid
- Rifampicin
- Ethambutol
- Pyrazinamide
Describe Isoniazid & what it causes?
- Bactericidal to fast growing mycobacteria
- Causes hepatotoxicity, peripheral neuropathy, B3 deficiency prevented with pyridoxine
Describe Rifampicin & what it causes?
- Bactericidal against slowly replicating organisms in necrotic foci
- Liver, bone marrow & renal toxicity relatively uncommon
Describe Ethambutol & what it causes?
- Bacteriostatic against slow growing mycobacteria
- Principle toxicity is optic neuritis, watch for loss of colour vision
Describe Pyrazinamide & what it causes?
- Bactericidal, even against slow growing mycobacteria intracellularly
- Principle toxicity is hepatitis, also causes arthralgia
What does inhibition of the folate metabolism pathway lead to?
Impaired nucleotide synthesis & therefore impaired DNA replication
Describe Trimethoprim?
- Orally administered
- Good range of action against Gram positive & Gram negative
What is Trimethoprim limited to use in?
Uncomplicated UTI
Describe the 3 factors of Trimethoprim’s toxicity?
- Elevation of serum creatinine
- Elevation of serum K+, problematic in patients with chronic renal impairment
- Rash & GI disturbance relatively uncommon
What is Co-trimoxazole?
Trimethoprim / Sulfamethoxazole combination antibiotic
What are the 2 side effects of Co-trimoxazole toxicity?
- Bone marrow suppression
2. Stevens Johnson Syndrome
What are the 2 advantages of Co-trimoxazole?
- Used in certain uncommon infections by specialists
2. Pneumocystis jirovecii pneumonia
What is the mechanism of action of Metronidazole?
- Enters by passive diffusion & produces free radicals
- Effective against most anaerobic bacteria (not actinomyces)
What is Metronidazole often added to?
Therapy in intra-abdominal infections, esp abscess
What are the 2 side effects of Metronidazole?
- Unpleasant reaction with alcohol
- Peripheral neuropathy with long term use
What is an Uncomplicated UTI (cystitis)?
- Lower urinary tract symptoms
- Absence of sepsis or evidence of upper tract involvement (pyelonephritis)
Describe the treatment of an Uncomplicated UTI (cystitis)?
- Treatment only needs to sterilise urine, no need for systemic activity
- Low risk infection so can often wait for culture results
Describe Trimethoprim’s effect in lower UTI treatment?
- 1st line agent
- Avoid in 1st trimester of pregancy
- Penetrates well into prostate so good choice for men
Describe Nitrofuratoin’s effect in lower UTI treatment?
- Excellent, broad spectrum of activity
- Concentrated in urine so no effect on other tissues
- Failure to concentrate in urine in renal failure
- Relatively non-toxic in short courses
What is the toxic side effect of Nitrofuratoin with long term use?
Pulmonary fibrosis
What is the principle bacterial cause of a UTI?
E. coli
What antibiotic would you use for a woman with an uncomplicated UTI & no past medical history or systemic symptoms?
Trimethoprim
What antibiotic would you use for a women with a complicated UTI?
Ciprofloxacin
What 2 possible antibiotic would you use for a women with a UTI & is severely unwell?
- Amoxicillin
2. Gentamicin
What are 3 antibiotics that are thought to be safe in pregnancy?
- Most beta-lactams
- Macrolides
- Anti-tuberculants
What are 5 antibiotics that are NOT thought to be safe in pregnancy?
- Tetracyclines- Bone/tooth abnormalities
- Trimethoprim- Neural tube defects (1st Tri)
- Nitrofurantoin- Haemolytic anaemic (3rd Tri)
- Aminoglycosides- Ototoxicity (2nd/3rd Tri)
- Quinolones- Bone/joint abnormalities
Describe Inherently resistant antibiotics?
Lack a pathway or target which a drug interacts with, or the drug is unable to gain access to the target
Describe antibiotics with Acquired resistance?
Drug which was previously sensitive has gained some genetic material encoding for resistance
What are 2 examples of inherent resistance antibiotics?
- Vancomycin against Gram negative bacteria
2. Metronidazole against aerobic bacteria
What are the 4 ways main that antibiotics can develop resistance?
- Enzymes inactivate/modify antimicrobials (beta-lactamases)
- Change drug target so that antibiotic no longer has any effect
- Decreasing cell permeability to the drug (decreased porins), so the conc required to be effective is not achieved
- Bacteria export the drug from inside the cell (multi-drug resistance efflux pump)
What are the 4 main ways that a bacterial cell can become resistant to antibiotics?
- Chromosomal mutation
- Acquisition of a mobile piece of DNA (plasmid, integron or transposon)
- DNA uptake can also occur through transformation (only certain types of bacteria)
- Pieces of DNA can be transferred between bacteria by viruses
What is vertical gene transfer?
Genetic information passed from parent cell to progeny via binary fission
What is horizontal gene transfer?
Genes transferred other than through traditional reproduction
What is horizontal & vertical gene transfer the primary reason for?
Antibiotic resistance
What happens once a mutation coding for antibiotic resistance has occurred in a cell?
Transfer this mutation to all their progeny (vertical transmission)
What is treatment of infections with 2 drugs acting in different ways based on?
Principle that if a mutation occurs in 1 drug target the other drug will still kill the organism, this is because we don’t yet know the sensitivity of the organism
Give an example for when an infection is treated with 2 drugs?
Pseudomonas infection with tazocin & gentamicin
Describe bacterial conjugation?
- Requires cell to cell contact between 2 bacteria (don’t need to be same species)
- Small pieces of DNA called plasmids are transferred
- Horizontal gene transfer
What 2 things can be transferred in bacterial conjugation?
- Antibiotic resistance
2. Ability to use new metabolites
What are plasmids?
Pieces of circular double stranded DNA
What 2 things can be carried on plasmids?
- Genetic information (resistance to antibiotics, allow themselves to replicate, heavy metals, UV light)
- Genes which encode pili, mediate adherence & toxins (genes of interest to host cell)
What are the 2 ways plasmids can exist?
- Free within the cell
2. Integrated into the host chromosome
What are plasmids important in?
Horizontal gene transfer
What are plasmids capable of doing?
Replicating themselves independently of the bacterial chromosome
Where are plasmids found in?
Gram positives & Gram negatives & several different types of plasmids can exist within a single cell
What are 4 factors which make plasmids a very effective way of spreading resistance?
- Multiply in high numbers
- High rate of cell to cell transfer
- Can be picked up by different species
- Carry genes for resistance to several drugs at once
What does the most common resistance information carried on plasmids relate to?
Enzymes which break antibiotics down or modifications to membrane drug transport systems
What is transduction?
Small pieces of DNA are transferred between bacteria (usually same species) by a virus
What are Bacteriophages?
Viruses which infect bacteria
How is transduction different to conjugation/transformation?
- Unlike conjugation it does not require the cells to touch
- Unlike transformation its unaffected by DNAses in the bacterium environment
What is released when bacteria die & what happens to it?
- Some naked DNA is released into the surrounding environment
- Some bacteria are capable of taking naked DNA up & inserting it into their chromosome
What happens if the naked DNA released by a dead bacteria inserts into a coding region for penicillin binding protein?
Change in the penicillin binding protein meaning that it can still cross link the peptidoglycan precursors to form the cell wall but has a reduced affinity for beta-lactam antibiotics such as penicillin which will then no longer kill the bacteria
What has been seen clinically for the process of naked DNA inserting into a coding region?
Some strains of Strep pneumoniae have become resistant to penicillin
What is transformation a mechanism of?
Horizontal gene transfer
What makes a successful resistance mutation?
The balance between the fitness cost & the selection pressure
What happens in an environment without a selective pressure?
Slower growing mutants will be outgrown by their wildtype colleagues & will slowly die away
What does the time taken for bacteria to grown mutations depend on?
Significance of the fitness cost associated with that mutation
What can sometimes develop in the mutated bacteria to compensate for the fitness cost?
Other mutations may develop which allow the mutated bacteria to compete with wild type colleagues
What is 1 area that we can really influence the development of antibiotic resistance?
Selection pressure (changing culture of antibiotics —> resistance mutations less likely to persist)
Describe the timeline of resistance in Staphylococcus aureus?
- Penicillin introduced
- Penicillin resistant strains detected
- Methicillin introduced
- Methicillin resistant strains detected (MRSA)
- Increasing use of vancomycin
- Vancomycin intermediate strains detected
- Vancomycin resistant strains detected
Describe MRSA?
Strains are resistant to all Beta-lactams except some very new cephalosporins
What is the gene that codes for MRSA resistance?
MecA gene
What is the purpose of the penicillin binding protein?
Mediate the cross linking in the peptidoglycan which makes up the bacterial cell wall
What does the MecA gene cause?
Decreased affinity, which allows the bacteria to continue to produce cell wall even in high concentrations of the drug
What is a major risk factor for MRSA?
Nursing home care
What would the 1st line antibiotic be for cellulitis?
Flucloxacillin
Where does MRSA live in the human body?
Moist areas
Describe an MRSA screen?
Swab of the nose & perineum
What are the 3 common gut commensals?
- E. coli
- Klebsiella
- Enterobacter
What are coliforms?
Group of bacteria which live in the gut of humans & animals
What are E. coli, Klebsiella & Enterobacter causes of?
Infections such as UTI, intra-abdominal sepsis & hospital acquired pneumonia (HAP)
What are 4 antibiotics commonly used to treat resistance in coliforms?
- Penicillins (amoxicillin)
- Quinolones (ciprofloxacin)
- Cephalosporins
- Aminoglycosides (gentamicin)
What are the 2 side rings in the beta-lactam structure?
- Beta-lactam ring
2. Thiozolidine ring
What is resistance to beta-lactam antibiotics mediated by?
Family of antibiotic degrading enzymes called Beta-lactamases which hydrolyse the beta-lactam ring
Describe the beta-lactamase inhibitors: Clavulanate & Tazobactam?
- Compounds which have only weak antibacterial activity but which mainly act by binding the beta-lactamase
- Thus allowing the beta-lactam to continue to act
What are Extended Spectrum Beta-Lactamases (ESBLs) usually?
Plasmid encoded
Describe Extended Spectrum Beta-Lactamases (ESBLs)?
Enzymes which are able to hydrolyse the beta-lactam ring of not only penicillins but also cephalosporins
What are the 4 treatment options for Extended Spectrum Beta-Lactamases (ESBLs)?
- Ciprofloxacin
- Temocillin
- Gentamicin
- Meropenem
What do bacteria carrying ESBLs often also carry?
Resistance genes for other commonly used antibiotics so they can be quite difficult to treat & some situations Meropenem is one of the few options
What type of ESBL is the most widely spread in the UK?
CTX-M
What are carbapenemases?
A group of enzymes which are capable of hydrolysing Meropenem
What is another common mechanism for carbapenem resistance?
Combination of porin loss & increased production of a type of betalactamas enzyme known as AmpC
Regarding selection pressure, what happens when we use more Meropenem?
More likely that resistant mutants will survive
What are 4 reasons as to why Meropenem is being used more over the last 8 years?
- Changes to testing of tazocin
- Increased ESBL rates
- Avoidance of cephalosporins so tazocin is used more readily & patients failing on tazocin are moved to meropenem quickly
How can we avoid meropenem resistant mutants surviving?
Use Carbapenem sparing agents ie. Gentamicin & Temocillin
Why is the emergence of Klebsiella isolates resistant to carbepenems (such as meropenem) incredibly concerning?
These antibiotics are often the last option for treatment of multidrug resistant strains & if the resistance spreads we will have problems with infections that can’t be treated
What 2 other areas of medicine will be effected without effective antibiotics?
- Complex surgery
2. Bone marrow transplants
What bacteria is a master of antimicrobial resistance?
Pseudomonas aeruginosa
Describe the 3 factors which make Pseudomonas aeruginosa antimicrobial resistant?
- Multiple other modifying enzymes
- Porin down regulations
- 4 efflux pumps (1 is always expressed, the other can be unregulated in response to stressors)
What are the 3 non-genetic mechanisms of resistance?
- Protected environment (abscess)
- Resting stage
- Presence of a foreign body
Why can surgery in some situations be the best cure for an infection?
- When the body detects infection it can attempt to isolate it in 1 area i.e. abscess
- This provides the bacteria with an environment protected from antibiotics
Describe how “Resting stage” can lead to antibiotic resistance?
Bacteria which are not dividing i.e. ‘resting state’ are less susceptible to cell wall inhibiting agents such as penicillins & cephalosporins
Why are such long courses of anti-tuberculous drugs required?
- The bacteria is at “resting stage” and therefore resistant to antibiotics
- Slow growing dormat tubercule bacilli
List 2 reasons as to why the presence of a foreign body can lead to apparent resistance?
- Immune system is not as effective & removal of bacteria is often a team effort between antibiotics & the immune system
- Biofilm
What is the biofilm sometimes called?
Slime layer
What 2 prosthetic materials have biofilm on their surfaces?
- Indwelling lines
2. Prosthetic joints
Describe a biofilm?
Complex bacterial community with channels for diffusion of water, oxygen & nutrients
List the 3 ways that a biofilm can lead to resistance?
- Close proximity of bacteria facilitates gene exchange including exchange of resistance determinants
- Channels for diffusion of nutrients are sometimes too small for antibiotics
- Bottom of biofilm nutrients penetrate in smaller amounts & so the bacteria replicate slower making them less susceptible to cell wall agents
Why does using short courses of antibiotics prevent spread of antibiotic resistance?
The remainder of our commensal flora is exposed to selection pressure for a shorter period of time
What are 2 new antibiotic options that we could use instead of meropenem so to reduce resistance?
Aztreonam & Temocillin
What is the largest use of antibiotics worldwide?
Promoting the growth of livestock animals
What are the 4 main mechanisms of antibiotic resistance?
- Target change
- Inactivation
- Decreased entry
- Increased exit
Describe target change in Streptococcus pneumonia & MRSA?
Penicillin binding protein is altered such that it has a decreased affinity for the drug so peptidoglycan cross linking is not prevented
Give 3 examples of when drug inactivation can be seen?
- Beta-lactamases
- ESBLs
- Carbapenemases in coliforms
When can you see antibiotic resistance in the form of decreased entry?
Coliforms which can be carbapenem resistant through a combination of AMPC & porin loss
What are 3 conventional pathogens?
- Endogenous flora
- Hospital acquired
- Environmental organisms
What are 2 opportunistic pathogens?
- Coagulase-negative staphylococci (CoNS)
2. Aspergillus
What 6 medical interventions have led to an increasing population of often profoundly immunocompromised patients?
- Improved survival at extremes of life
- Improved cancer treatment
- Developments in transplant techniques
- Developments in intensive care
- Management of chronic inflammatory conditions
- Steroids
Give 4 reasons why the prevention & treatment of infection in immunocompromised hosts not that straightforward?
- Basic patterns are recognizable but organisms are unpredictable
- Isolated deficiencies are rare
- Malfunction of 1 part often influences another
- Underlying diseases & their treatment affect a range of mechanisms
What is neutropaenia defined as?
Neutrophils <0.5 x 109/L or <1.0 x 109/L & falling
What 2 things does cytotoxic chemotherapy therapeutic irradiation (TBI) cause?
- Decreased proliferation of haemopoietic progenitor cells
2. Depletion of marrow reserves
What is an important risk factor for infection?
Neutropaenia (risk increases with degree, duration & rate of fall)
What 3 ways does cytotoxic drugs, irradiation & steroids effect neutrophil function?
- Decrease chemotaxis
- Decrease phagocytic activity
- Decrease intracellular killing
List 4 gram positive cocci pathogens that effect neutrophil function?
- Staph. aureus
- Coagulase negative staphylococci
- Viridans streptococci (mitis, oralis)
- Enterococci (faecalis, faecium)
List 2 anaerobe pathogens that effect neutrophil function?
- Bacteriodes spp.
2. Clostridia spp.
List 4 gram negative bacilli pathogens that effect neutrophil function?
- E. coli
- Pseudomonas aeruginosa
- Klebsiella pneumoniae
- Enterobacter spp.
List 2 fungi pathogens that effect neutrophil function?
- Candida spp.
2. Aspergillus spp.
Describe Chronic Granulomatous Disease?
- Inherited disorder
- X linked most common
- Defect in gene coding for NADPH oxidase
What 2 things does a defect in gene coding for NADPH oxidase result in?
- Deficient production of oxygen radicals
2. Defective intracellular killing
What are the signs/symptoms of Chronic Granulomatous Disease?
- Recurrent bacterial & fungal infections –> abscesses lung, lymph nodes, skin
- Inflammatory responses with widespread granuloma formation
List the 3 common pulmonary infections which can occur in Chronic Granulomatous Disease?
- Aspergillus spp.
- Staph. aureus
- Nocardia spp.
List 7 things which suppress cellular immunity?
- DiGeorge syndrome (primary deficiency, rare)
- Malignant lymphoma
- Cytotoxic chemotherapy
- Extensive irradiation
- Immunosuppressive drugs
- Allogeneic stem cell transplantation especially if GVHD
- Infections
List 6 immunosuppressive drugs which effect cellular immunity?
- Corticosteroids
- Cyclosporin (used in organ rejection)
- Tacrolimus
- Alemtuzumab (anti-CD52 monoclonal)
- Rituximab (anti-CD20 monoclonal)
- Purine analogues ie. fludarabine
List 5 infections which suppress cellular immunity?
- HIV
- Mycobacterial infections
- Measles
- EBV
- CMV
List 3 things which suppress humeral immunity?
- Bruton agammaglobulinaemia (primary, rare)
- Antibody production decreases in lymphoproliferative disorders (CLL, multiple myeloma)
- Intensive radiotherapy & chemotherapy
In what type of cancer is the humeral immunity usually preserved?
Acute leukaemia
What does Intensive radiotherapy & chemotherapy ultimately cause?
Hypogammaglobulinaemia
What do splenic macrophages do?
Eliminate non-opsonized microbes ie. encapsulated bacteria
What is the site of primary immunoglobulin response?
Spleen
List 3 infections which can cause Humoral deficiency/ splenectomy/ hyposplenism?
- Strep. pneumoniae
- Haemophilus influenzae type b
- Neisseria meningitidis
What are the 3 principle barriers against microbial invasion?
- Skin
- Conjunctivae
- Mucous membranes- gut, respiratory tract, GU tract
List the 5 factors of skin which make it a physical barrier against microbial invasion?
- Desquamates
- Dry
- pH = 5-6
- Temp = 5oC lower
- Secretory IgA in sweat
What 2 things may impair the integrity of skin?
- Chemotherapy
2. Irradiation
What happens when the mucosal barrier is injured via chemotherapy & irradiation?
GI lymphoid tissue responds with inflammatory response = Mucositis
What are the 4 signs & symptoms of Mucositis?
- Pain
- Dysphagia
- Xerostomia (dry mouth)
- Ulceration
What does Mucositis lead to?
Impairment of GI function & alterations in permeability –> Altered nutritional status
What 4 things alter the gut microbiome?
- H2 antagonists
- PPIs
- Antibiotics
- Diarrhoea
What factors equal severe nutritional deficiency?
<75% ideal body weight OR Rapid weight loss +
Hypoalbuminaemia
What 4 things can cause impaired nutritional status?
- Anorexia
- Nausea & vomiting
- Mucositis
- Metabolic derangements
What does iron deficiency reduce?
Microbicidal capacity of neutrophils & T cell function
What may cause local organ dysfunction?
Tumours (obstruction –> infection)
What organ is particularly susceptible to tumours causing organ dysfunction?
Lungs
What are 2 signs of CNS tumours/spinal cord compression?
- Loss of cough/ swallow reflex
2. Incomplete bladder emptying
What 2 concurrent illnesses can cause organ dysfunction?
- Stress- reduced T cell function
2. Diabetes mellitus- reduced opsonization, chemotaxis
What were the 2 first solid organ transplants?
- Kidney
2. Pancreas
What solid organ transplant has the highest % of graft survival?
Kidney from living donor (95% 1yr, 89% 3yr)
What solid organ transplant has the lowest % of graft survival?
Lung (82% 1yr, 65% 3yr)
What are 6 general principles of decreasing the chances of infection in solid organ transplants?
- Optimal tissue typing
- Donor evaluation
- Organ procurement
- Surgical technique
- Tailored immunosuppressive regimen
- Prevention of infection
What % of liver transplants have an infection-related mortality?
23% (highest)
List the 4 general principles of infection in solid organ transplants?
- Potential aetiology is diverse- community acquired bacterial & viral infections, opportunistic infections
- Pulmonary infection can progress rapidly
- Inflammatory responses are impaired
- Diagnosis is often difficult- radiology, histology, serology, molecular methods
Describe the empirical therapy for infections in solid organ transplants?
Early diagnosis & prompt, aggressive Radiotherapy (toxicites/interactions common)
What should you focus on in infections with solid organ transplants?
Prevention- anti-bacterial, fungal, viral prophylaxis
What 2 solid organ infections would you use pre-emptive therapy?
- CMV
2. Fungal infection
What is the risk of infection following solid organ transplant related to?
Relationship between epidemiological exposure & net state of immunosuppression
List 7 community-acquired pathogens responsible for solid organ transplant infections?
- Bacteria- pneumococcus, listeria, salmonella, legionella
2. Viruses- influenza, parainfuenza, RSV
When are nosocomial infections in solid organ transplant common?
Early post transplant & if ventilated or prolonged length of stay
Give 3 examples of nosocomial infections in solid organ transplant?
- Resistant gram +ve & gram -ve bacteria
- Clostridium difficile associated disease (CDAD)
- Fungi
List 3 latent donor-derived infections following solid organ transplant?
- TB
- Syphilis
- Viruses (HIV, Hepatitis B, CMV)
List 4 active blood stream infections at procurement following solid organ transplant?
- Staphylococci
- Pneumococci
- Salmonella
- E. coli
List 2 reactivated infections which can occur following solid organ transplant?
- M. tuberculosis
2. Viruses: HSV, VZV, CMV
List 2 opportunistic pathogens which can occur following solid organ transplant?
- Aspergillus
2. Pneumocystis
What are the 4 types of Allogeneic stem cell transplants?
- Syngeneic
- Related
- Unrelated
- Haploidentical
What are the 3 types of stem cells?
- Bone marrow
- Peripheral Blood Stem Cell (PBSC)
- Cord blood
What are the 3 immune system defects associated with engraftment?
- Neutropaenia
- Lymphopaenia
- Hypogammaglobulinaemia
What are the 6 transplant related factors associated with engraftment?
- Mucositis
- Veno-occlusive disease (VOD)
- Central catheter
- Thrombocytopaenia
- Acute GVHD
- Chronic GVHD
What are the 8 high incidence infections associated with engraftment?
- HSV
- Adenovirus
- Candida
- CMV
- VZV
- Late/early aspergillus
- Viridans streps
- Coag neg staph
What are the 3 low incidence infections associated with engraftment?
- Encapsulated bacteria
- Pneumocystis
- Toxoplasma
What are 2/3 episodes of febrile neutropenia in cancer patients due to?
Infection
- Endogenous
- Exogenous (community, nosocomial)
List the 6 non-infectious causes of febrile neutropaenia?
- Malignancy
- Chemotherapy
- Transfusion
- Antibiotics
- Colony stimulating factors
- Allergies
What does neutropaenic fever equal?
Infection until proven otherwise
List 7 possible sites of infection in febrile neutropaenic patients with haematological malignancy & how common these are (%)?
- Bloodstream- 46.5%
- Mouth & pharynx- 18.5%
- Skin & soft tissues- 14%
- Respiratory tract- 11%
- Gastrointestinal tract- 6%
- Urinary tract- 2%
- Other sites- 1%
What are the 7 most common Gram positive aerobic bacteria in neutropaenic cancer patients?
- Coagulase negative staphylococci
- Staphylococcus aureus
- Viridans streptococci
- Other streptococci (S. pyogenes, S. pneumoniae)
- Enterococcus spp.
- Bacillus spp.
- Listeria monocytogenes
What are the 6 most common Gram negative aerobic bacteria in neutropaenic cancer patients?
- Escherichia coli
- Klebsiella spp.
- Pseudomonas spp.
- Proteus
- Enterobacter
- Serratia spp.
What are the 3 most common Anaerobic bacteria in neutropaenic cancer patients?
- Bacteroides spp.
- Clostridium spp.
- Fusobacterium spp.
What are the 3 most common Fungi in neutropaenic cancer patients?
- Candida spp.
- Aspergillus spp.
- Pneumocystis jirovecii
What are the 4 most common viruses in neutropaenic cancer patients?
- HSV
- VZV
- Influenza
- RSV
What is a fever?
Pyrexia OR Hypothermia (temperature > 38oC OR < 36oC)
What is SIRS (systemic inflammatory response)?
Sweats, chills, rigors, malaise, tachypnoea >20/minute, tachycardia >90bpm,
hypotension (patients may appear well perfused despite hypotension)
What is sepsis?
Evidence of infection (including SIRS) + Organ dysfunction i.e. ≥ 1 of hypotension, confusion or tachypnoea (Resp Rate ≥22/minute)
What is septic shock?
Sepsis induced hypotension requiring inotropic support or hypotension that is unresponsive (within 1hr) to adequate fluid resuscitation i.e. systolic BP <90mmHg or a reduction of >40mmHg from baseline
What is Neutropenic sepsis OR febrile neutropaenia?
- Neutrophil count < 0.5, or < 1 if recent chemotherapy (usually within 10 days but can persist for up to 21 days)
+ - Fever/Hypothermia or SIRS or SEPSIS/Septic shock
Describe the immediate clinical management of infections in the immunocompromised?
- Neutropaenic sepsis is a MEDICAL EMERGENCY
- Do not await confirmation of neutropaenia in patients who are haemodynamically compromised
- Assess within 15 minutes of presentation
What do you assess sepsis severity using?
NEWS
When should you institute sepsis 6?
Within 1hr of SEPSIS recognition
What is the treatment for someone with (standard risk) NEWS <5 & NOT allergic to penicillin/beta-lactam?
- Piperacillin/tazobactam 4.5g IV 6hy
- No routine gentamicin
What is the treatment for someone with (standard risk) NEWS <5 with an allergy to penicillin/beta-lactam?
- Vancomycin IV + Ciprofloxacin 400mg IV 12hy OR
- Aztreonam 2g IV 6hy
- Consider gentamicin
(based on local epidemiology)
What is the treatment for someone with (high risk) Septic shock or NEWS >5 & NO allergy to penicillin/beta-lactam?
- Piperacillin/tazobactam 4.5g IV 6hy +
- Gentamicin
(based on local epidemiology)
What is the treatment for someone with (high risk) Septic shock or NEWS >5 & an allergy to penicillin/beta-lactam?
- Vancomycin IV + Ciprofloxacin 400mg IV 12hy OR
- Aztreonam 2g IV 6hy + Gentamicin (based on local epidemiology)
In Acute leukaemia/ Allogeneic STC patients with sepsis requiring inotropic support or septic shock, what antibiotics should you consider?
Meropenem 1g 8hy + aminoglycoside
What antibiotic should you add if you suspect skin or soft tissue infection?
Vancomycin
What antibiotic should you add if you suspect atypical pneumonia?
Clarithromycin
What antibiotic should you use if there is a previous/known ESBL infection/carrier?
Meropenem
What is the 6 part chain of infection?
- Infectious agent
- Reservoirs
- Portal of exit
- Means of transmission
- Portal of entry
- Susceptible host
List 3 reservoirs for infection?
- Environment
- Animals
- Humans (symptomatic/asymptomatic, carriers)
What are 3 means of infection prevention?
- Water control
- Rodent control
- Isolation
What is the portal of exit for TB?
Respiratory tract
What is the portal of exit for Salmonella?
Faeces
What is the portal of exit for Norovirus?
Vomit
What is the portal of exit for Blood borne viruses?
Cuts & injuries
What is the portal of exit for Enterovirus?
Conjunctival secretions
What are the 2 direct modes of transmission of infection?
- Direct contact
2. Droplet spread
What are the 3 indirect modes of transmission of infection?
- Airborne
- Vehicle borne (food water fomites)
- Vectorborne (mechanical or biologic)
Give 4 examples of infection portal of entry?
- Respiratory tract
- Mucous membranes
- Skin- non-intact
- Mouth (faecal-oral)
List the 10 standard hospital precautions of infection prevention/control?
- Assess patients for infection risk & ensure they are cared for in a safe place
- Good hand hygiene
- Cover nose & mouth when coughing/ sneezing
- Suitable personal protective equipment
- Keep reusable care equipment clean & well maintained
- Keep care environment clean & tidy
- Safely handle used linen
- Safely clean up blood & body fluid spills
- Safely dispose of household & care activity waste
- Take corrective action if injured/exposed to blood & body fluids
What outbreak was linked to artificial nails in a neonatal intensive care unit?
Extended-spectrum beta-lactamase-producing Klebsiella pneumoniae
What are the 4 infective contact transmission based precautions?
- Isolation
- Cleaning
- Gloves
- Apron
What are the 2 infective droplet transmission based precautions?
- Surgical mask
2. Eye protection
What 7 factors make for a susceptible host?
- New host
- Immune status
- Vaccination
- Prophylaxis
- Nutrition
- Treatment of immuno-suppressive
- Protective isolation
What are the 6 strategies for a hospital acquired infection (HAI)?
- Isolation
- Screening
- Cohorting
- Standard & transmission based precautions
- Surveillence
- Antimicrobial stewardship
Describe the 9 procedures in an aseptic technique?
- Reduce activity in area
- Keep exposure of susceptible site to a minimum
- Check sterile packs for evidence of damage or moisture
- Ensure all fluids materials in date
- Do not re-using single use items
- Hand decontamination
- Use disposable apron
- Use sterile gloves.
- Appropriate waste disposal
Describe the maintenance of a central venous catheter (CVC)?
- Aseptic access technique
- Daily site review
- Remove CVC at earliest opportunity
What has “Matching Michigan” resulted in?
60% reduction in central line-associated bloodstream infection (CLABSIs)
Describe how antimicrobial resistance is ancient?
- Diverse collection of genes encoding resistance to β-lactam, tetracycline & glycopeptides
- Resistance is a natural phenomenon predating modern antibiotic use
What are the 2 key factors in antibiotics driving resistance?
Course duration x No. of courses
What 2 penicillins are narrow spectrum?
Benzylpenicillin & phenoxymethylpenicillin
What 2 penicillins are moderate/broad spectrum?
Flucloxacillin & Amoxicillin
What is an example of a broad spectrum combination penicillin?
Amoxicillin-clavulanate / Co-amoxiclav (Augmentin®)
What is the problem with broad spectrum antibiotics?
Collateral damage
List the 4 individual effects that collateral antibiotic damage causes?
- Antibiotic resistance
- Drug reaction / toxicity / interactions
- Diarrhoea (clostridium difficile)
- Vascular site infection (S.aureus bacteraemia)
List the 2 population effects that collateral antibiotic damage causes?
- Antibiotic resistance
2. Clostridium difficile
What correlates with rise in C. diff infection?
Increase in broad spectrum antibiotics (Cephalosporins)
What 5 countries have the highest % of E. coli resistant to Cephalosporins?
- India
- China
- Kenya
- Ghana
- Mexico
How much higher is the risk of death in patients infected with a resistant bug instead of a sensitive bug?
2x more likely with resistant bug
What 3 things does the antibiotic guardian state for reducing antimicrobial resistance?
- Value Antibiotics
- Prescribe & Support prescribing as responsibly as we can
- Preserve most Valuable Agents for our most complex infections
What is Antimicrobial Stewardship?
Programme to ensure safe & appropriate use of antibiotics
List the 5 aims of Antimicrobial Stewardship?
- Optimize outcome
- Minimise unintended consequences
- Reduce AMR & C. Difficile
- Patient at centre of prescription decision making
- Hospital & community
List 5 ways that Antimicrobial Stewardship is achieved through?
- Monitoring/ surveillance
- Guidelines/protocols
- Specific restrictions (reporting/antibiotics)
- Specific interventions
- Multidisciplinary working
Describe how to work out the volume of antibiotic prescribing?
- Measured through pharmacy records (not per individual)
- Stratified for antibiotic type (defined daily dose)
- Adjusted for population size (e.g. per 1000 population/ per admission/ occupied bed day)
What are the 5 key components of antimicrobial stewardship?
- Appropriate for target population (primary vs secondary, specialist vs generalist, national vs local adaptation)
- Decision support - when to avoid/use antibiotics
- Appropriate investigations to support management
- Takes into account epidemiology of infection including AMR
- Availability/ cost
List the 3 investigations that you could do in primary care to support antibiotic prescription?
- CRP, Near patient testing (“Strep test”)
- Urinalysis only if symptoms & failed on prior prescription
- Only “swab” infected- limited value as reflects commensal bacteria (MRSA)
What is the empirical guidance in primary care?
- Diagnosis often “syndromic”
- Limited potential to support with investigations
- Viral vs Bacterial (?Self limiting) vs No infection
- Electronic prescribing
How can you optimise lab diagnosis in the antimicrobial stewardship programme?
Sampling, testing & minimisation of “over diagnosis”
What is the purpose of lab restricted reporting of sensitivities?
Reduce use of inappropriate agents
What are the 6 steps to antibiotic prescribing?
- Is an antibiotic required?
- Which antibiotic?
- How should it be administered (severity)?
- Adjunctive measures?
- How long?
- REVIEW
Give 5 examples of when NOT to prescribe an antibiotic?
- Viral + Self limiting bacterial RTIs
- Asymptomatic bacteruria, uncomplicated cystitis
- Ingrowing toe nails
- Varicose eczema
- Systemic inflammatory response due to cancer, ischaemia, inflammation
How effective is the use of antibiotics in lower respiratory tract infections?
No better than placebo in primary care
What are the 3 different types of urinary tract infections?
- Asymptomatic bacteruria
- Uncomplicated UTI (cystitis)
- Catheter-associated UTI
How common is an Asymptomatic bacteruria (UTI) & how would you treat it?
- 40% of elderly women
- Confirm urinary symptoms: If not don’t treat!
How common is an Uncomplicated UTI (cystitis) & how would you treat it?
- 30% of cystitis is culture negative
- NSAIDs may be as effective as antibiotics
- Consider delayed antibiotics
How common is an Catheter-associated UTI & how would you treat it?
- Remove catheter
- Treat if symptoms / sepsis
What are the 4 non-antibiotic measures that can be applied in primary care for infections?
- Reassurance/explanation- Printed information
- Symptomatic measures: fluids, analgesia
- Delayed script
- Review date- “safety netting”
What are the 5 symptoms/signs of infection?
Fever, sweats, rigors, shivers and shakes
What are the 4 localised symptoms/signs of a bacterial infection?
- Dysuria & frequency
- Dyspnoea, cough + green/ brown sputum, crepitations
- Erythema, heat, swelling
- Sore throat with exudate & adenopathy
Describe the choice of antibiotic in a non severe infection (community or hospital)?
- Use narrow spectrum agents
- Lower respiratory tract: Amoxicillin or Doxycycline
- Lower UTI: Trimethoprim or Nitrofurantoin
- Mild Cellulitis: Flucloxacillin or doxycycline
Describe the choice of antibiotic in a severe/life threatening infection?
- Usually IV combination (Beta lactam + Gentamicin) initially
- Use of protected antibiotic if risk of multi-drug resistance
- Prompt (<1 hour) admin
What type of antibiotics can increase the risk of Clostridium difficile?
Any antibiotic of prolonged duration
Give 2 examples of rapidly progressive/immediately life-threatening infections?
- Organ dysfunction = sepsis
2. Deep seated/ involving vital organs- bacteraemia, CNS, cardiovascular, graft related
How should you assess the severity of infection in primary care?
Rapid admission to hospital + consider pre-hospital treatment
How should you assess a severe systemic infection of unknown source in secondary care?
- Urgent blood cultures then IV antimicrobial therapy within 1hr
- Chest X-ray & consider other imaging/lab investigations
When in a severe systemic infection of unknown source would you cover for S. aureus?
If healthcare associated, recent hospitalisation, post-op wound/ line related, IVDU
When in a severe systemic infection of unknown source would you cover for an MRSA infection?
Recent MRSA carrier or previous infection
When in a severe systemic infection of unknown source would you cover for a severe Streptococcal infection?
Pharyngitis/ erythroderma/ hypotension
What antibiotics would you give for a severe systemic infection of unknown source?
IV Amoxicillin 2g 6hrly + IV Gentamicin (max 3-4days)
What antibiotic would you add for a severe systemic infection if S. aureus was suspected?
ADD IV Flucloxacillin 2g 6hrly
What antibiotics would you give for a severe systemic infection if MRSA was suspected or patient has a true penicillin/beta-lactam allergy?
IV Vancomycin + IV Gentamicin (max 3-4 days)
What antibiotics would you add for a severe systemic infection if streptococcal infection was suspected?
ADD IV Clindamycin 600mg 6 hrly, duration reviewed with response/micro results at 72hrs
Describe the potency of Gentamicin?
Bacteriocidal + protein synthesis inhibition (Primarily anti Gram negative)
How would you use Gentamicin?
Empirically & short term, avoid >4 days, needs therapeutic drug monitoring
What are 2 areas that have toxic side effects of Gentamicin?
Renal & 8th cranial nerve (vestibulocochlear nerve)
How would you review antibiotics in primary care?
“Safety netting”or review to assess response
How would you review antibiotics in secondary care?
- Clinical, micro results
- De-escalate: Simplify or Switch or Stop
- Review IV daily : IVOST
- Document (3 day) review
- Record Specific Duration of treatment
- Consider Specialist input & Source Control
What does IVOST stand for?
IV to Oral switch therapy
What are 3 antimicrobial Stewardship Organisational
Aspects?
- Good clinical practice (all prescribers, all HCWs)
- Organisational priority
- Dedicated Team with expertise in infection
management, prescribing surveillance &
quality improvement
Describe the dedicated infection team?
- Infection specialist(s), Clinical Pharmacist
- Multi-disciplinary clinical network & committee
- Management engagement & IPC coordination
- Clinical Governance & patient safety
Describe restrictive antimicrobial stewardship intervention?
Short term benefits including reduction in resistance
Describe persuasive antimicrobial stewardship intervention?
Longer term benefits through behaviour change
What 2 Antimicrobial Stewardship Interventions result in a reduced mortality?
- Guideline adherence (empirical guideline & de-escalation)
- Infectious disease Physician consultation in Staphylococcus aureus bacteremia
What 4 things are reduced when you apply AMS and reduce total antibiotic use in primary care?
- Clostridium difficile
- MRSA
- Gram negative bacteraemia mortality
- AMR in Gram negative bacteraemia
What are the 2 main human factors effecting antibiotic resistance?
- Knowledge & experience- perception of resistance, misconception that spectrum of activity (efficacy), lack of confidence in diagnosis, fear of failure
- Prescribing culture- peer practice, hierarchy, speed of escalation of treatment, brand familiarity, fear of litigation
What are the 4 key factors of realistic medicine to optimise use & outcome?
- Reduce variation in prescribing practice
- Reduce waste (over prescribing, redundancy)
- Reduce harm (C. diff, AMR, penicillin allergy, toxicity)
- Personalised/Individualise (risk based treatment)
What are 4 factors for minimising antibiotic collateral damage?
- Importance of selecting the right antibiotic
- Restrict broad spectrum agents
- Knowing when antibiotics not required
- Promotion of shorter course therapy
What are 30% of cystitis?
Culture negative
What antibiotics would you prescribe for an uncomplicated UTI?
- Trimethoprim/ Nitrofurantoin in lower UTI
- 3 days (women) or 7 days (men)
What do 40% of elderly women have?
Asymptomatic bacteruria
What are the likely bugs that you should cover when treating a UTI?
Gram negative coliforms
How would you treat an upper UTI/Pyelonephritis,SEPSIS?
Gentamicin with oral switch (7 days total)
How is sepsis quantified?
- Increase in Sequential Organ Failure Assessment (SOFA) score of ≥ 2 for the organ in question
OR - “Quick SOFA” = Confusion or Hypotension or Tachypnoea
What is a high qSOFA score associated with?
High mortality
What is sepsis 6/BUFALO?
- Perform Blood cultures (other bacteriology)
- Broad spectrum antibiotics
- Oxygen to achieve target saturation
- Measure Lactate & Hb
- IV fluids
- Monitor urinary output hourly
What is an immediate penicillin allergy?
<1 hr, type 1 hypersensitivity reaction
What is a delayed penicillin allergy?
- Blistering rash & systemic illness
- Type IV hypersensitivity
What % of penicillin allergies aren’t actually an allergy?
80%
What 4 things is mislabelling of a penicillin allergy associated with?
- Increased treatment cost
- Admission length
- AMR
- Poor outcomes
Give 8 indications for IV antibiotic therapy?
- Sepsis syndrome, SIRs or rapidly progressing infection
- Infective endocarditis
- CNS infection
- Bacteraemia (S. aureus)
- Osteomyelitis (initially)
- Mod-severe skin & soft tissue infection
- Infection & oral route compromised
- No oral formulation of antibiotic available
What 3 bugs can cause cellulitis?
- Usually GAS (group A beta-hemolytic Strep) or groups B, C or G
- Staphylcoccous aureus
- Gram negatives uncommon
What antibiotic would you give for cellulitis?
Flucloxacillin
- oral 5 days if mild
- IV- (IVOST) if mod-severe 7-10 days
What antibiotics would you give in very severe cellulitis?
Add IV Clindamycin & Gentamicin to flucloxacillin therapy
What 3 bugs can cause necrotising fasciitis?
- Usually GAS (group A beta-hemolytic Strep) or groups B, C. G
- Staphylcoccous aureus
- Gram negatives rarely
Describe necrotising fasciitis?
- Pain out with appearance
- Masked by NSAIDs
- Rapidly progressive with multi-organ failure
What is the EAGLE effect associated with necrotising fasciitis?
- Static growth phase with excess toxin production
- Beta lactams not effective
What are the 2 treatments for necrotising fasciitis?
- Surgery
2. Immunoglobulin
What are 3 bugs presenting with gram positive cocci on blood culture at 24hrs?
- Staphylococcus aureus
- Staphylococcus epidermidis
- Meticillin resistant or sensitive
How would you investigate & treat S. aureus bacteraemia?
- Find & remove source of infection: vascular, bone/joint, prosthetic, cardiac
- ECHO (endocarditis) & other treatment for underlying source (eg spinal infection)
- Repeat BCs after 48-96 hours of effective IV antibiotics
What antibiotic would you give for a S. aureus bacteraemia?
Flucloxacillin 2g 6 hourly, ≥2 weeks
What would you give a S. aureus bacteraemia patient with a true penicillin allergy?
Vancomycin as per guidance/calculator, ≥2 weeks
When would you do a transoesophageal echocardiography (TOE) for a bacteraemia?
- Persistent fever or no improvement or further positive blood cultures
- Negative transthoracic echocardiogram (TTE) if PV or if endocarditis is still suspected
When would you give antibiotics in an exacerbation of COPD?
Purulent (green) sputum
What does yellow sputum mean?
Asthma
What antibiotics would you give in an exacerbation of COPD?
Amoxicillin or Doxycycline, use shortest duration
What are the 2 risk factors for Clindamycin?
- Substrate & inhibitor of CYP3A4
2. QTc prolongation
Give 3 drugs which interact with Clindamycin?
- Simvastatin
- Fluconazole
- Citalopram
What has gentamicin got a low risk of?
C. Diff infection
What should you do to avoid kidney infection & CNVIII toxicity with gentamicin?
Limit to 72hrs & switch to alternate IV or oral agent, stop at earliest signs as it may be irreversible
What are the 3 most common types of illnesses that travellers get?
- Gastrointestinal diagnoses
- Febrile illness
- Dermatological diagnosis
List the 6 most common bacterial causes of travellers diarrhoea?
- Enterotoxigenic E.coli
- Enteroaggregative E.coli
- Campylobacter sp
- Salmonella sp
- Shigella sp
- C.difficile
List the 3 most common viral causes of travellers diarrhoea?
- Norovirus
- Rotavirus
- Enteric adenovirus
List the 6 most common parasitic causes of travellers diarrhoea?
- Giardia
- Cryptosporidium
- Cyclospora
- Microsporidia
- Isospora
- Entamoeba histolytica
Describe the clinical manifestations of travellers diarrhoea?
- Often day 4 to 14 travel
2. Self limiting: 1-5 days, 8-15% last >1 week
List the 4 symptoms (ETEC) of travellers diarrhoea?
- Anorexia, malaise & abdominal cramps
- Watery diarrhoea (no blood)
- Fever, nausea & vomiting
- “colitic symptoms”- salmonella/shigella etc
List the 4 management plans for travellers diarrhoea?
- Fluid replacement
- Antibiotics (reduce duration by 24hrs)- Quinolones, Azithromycin
- Antimotility agents (caution)
- Investigation for other causes
What is the most common & most concerning problems with travellers diarrhoea?
- Most common: diarrhoea
- Most concerning: undifferentiated fever
List the 2 types of mosquitoes which can cause travellers diarrhoea?
- Aedes
2. Anopheline
Describe how the Aedes mosquito infects travellers?
- Dengue fever
- Female mosquito
- Bites in the morning
Describe how the Anopheline mosquito infects travellers?
- Malaria
- Bites from dusk –> dawn
What are the 3 ways to physically avoid mosquito bites?
- Indoors- AC, screens
- Impregnated netting- permethrin, “tucked in”, “mosquito free”
- Clothing- cover up, spray/soak
How often should you reapply 30% deet?
Every 3-4hrs
Describe the epidemiology of malaria?
- 27-48% hospitalised returning travellers
- Most common cause fever in travellers from sub
saharan Africa - Diagnosis initially missed up to 59% cases
What is the incubation period for P.falciparum?
7-14 days
What is the incubation period for P.vivax?
12-17 days
What is the incubation period for P.ovale?
15-18 days
What is the incubation period for P.malaria?
18-40 days (>1yr)
What are the 3 ways to diagnose Malaria?
- Antigen testing (common)
- Blood films (thick & thin)
- PCR
List the 8 clinical features of malaria?
- Fever
- Malaise
- Headache
- Myalgia
- Diarrhoea
- Anaemia
- Jaundice
- Renal impairment
List the 8 clinical features of severe malaria?
- Parasitaemia >2%
- Cerebral malaria
- Severe anaemia
- Renal failure
- Shock
- DIC
- Acidosis
- Pulmonary oedema
What are the 2 forms of treatment for Malaria?
- Artemether compounds e.g. Riamet
2. Quinine & Doxycycline
What are the 2 ways to prevent malaria?
- Bite avoidance
2. Chemoprophylaxis
List the 3 types of Malarial chemoprophylaxis?
- Mefloquine- Once weekly, Psychiatric side effects
- Doxycycline- Daily, Photosensitisation
- Malarone- Minimal side effects, Cost
What are the 2 types of enteric fevers?
- S. typhi
2. S. paratyphi
Describe Typhoid?
- Human reservoir only (no animal reservoir): Human to human
- ↑ innoculum = shorter incubation period/↑ attack rate
Describe the pathogenesis of Typhoid?
Contaminated food/water –> effects liver, spleen & lymph nodes –> eventually bacteraemic
What is the incubation period for Typhoid?
5-21 days
What 4 factors influence Typhoids incubation period?
- Age
- Gastric acidity
- Immune status
- Infectious load
List the clinical features of Typhoid?
- Fever
- Myalgia
- Headache
- Cough
- Abdo pain
- Constipation
- Diarrhoea
What 2 things can Typhoid lead to?
- Septic shock
2. Death
List the 4 GI symptoms associated with Typhoid?
- Diarrhoea v Constipation: 50:50, Diarrhoea more common in children
- Abdominal pain
- Rectal bleeding
- Bowel perforation: Hyperplasia Peyer’s patches
List the 4 other symptoms associated with Typhoid?
- Neurological: headache, enteric encephalopathy
- Bacteraemia: metastatic infection
- Relative bradycardia
- Rose spots
Describe enteric encephalopathy associated with Typhoid?
- Altered consciousness/confusion
- Increased mortality
- Steroids
What 4 ways do you diagnose Typhoid?
- Travel history- Area visited, Food & drink, pre travel vaccination/advice
- Blood culture- 60-80% positive
- Stool culture- 30% positive
- Serology- Poor sensitivity/specificity
What are the 3 treatments for Typhoid?
- Quinolones- Most effective agents, Resistance!
- Cephalosporins- Empirical therapy, Longer courses (14 days)
- Azithromycin- Very good activity with increasing evidence, Lack of evidence in severe disease, Oral option
What is the incubation period of Dengue fever?
5-14 days
List the 9 clinical features associated with “Breakbone fever” in Dengue fever?
- Headache
- Fever
- Retro-orbital pain
- Arthralgia/myalgia
- Rash
- Cough
- Sore throat
- Nausea
- Diarrhoea
List the 3 laboratory features in Dengue fever?
- Leucopenia
- Thrombocytopenia
- Transaminitis
How do you treat Dengue fever?
- Symptomatic
- No cure
What is the definition of Dengue Haemorrhagic fever?
- ↑vascular permeability
- Thrombocytopenia
- Fever
- Bleeding
List the 7 possible causes of viral haemorrhagic fever?
- Lassa
- Ebola/Marburg
- Crimean-Congo haemorrhagic fever
- SAVHFs
- Rift Valley Fever
- Dengue hemorrhagic fever
- Yellow fever
Describe the exposure of viral haemorrhagic fever?
- Rural > Urban
- Nosocomial
Describe the clinical presentation/development of viral haemorrhagic fever?
Exposure –> Non specific febrile illness –> Haemorrhagic manifestations –> Sepsis syndrome/shock –> Death
What is the incubation period for viral haemorrhagic fever?
Upto 21 days
In what 3 stages of disease can you treat viral haemorrhagic fever?
- Non specific febrile illness
- Haemorrhagic manifestations
- Sepsis syndrome/shock
How would you treat viral haemorrhagic fever?
- Supportive
- Correct coagulopathy/anaemia
- Ribavirin
What are 3 factors to consider when trying to diagnose travellers diarrhoea?
- Non travel related infection
- Some prediction from area visited
- Visit to malarious area = malaria until proven otherwise
List 7 crucial history questions you would ask when suspecting travellers diarrhoea?
- Where were they?
- For how long?
- What was purpose of visit?
- What did they get up to when there?
- Any pre travel vaccines/prophylaxis?
- How long are they back for?
- How long have they been unwell for?
What is the clinical assessment tool used to help identify at risk patients with community acquired pneumonia?
CURB-65 score for pneumonia severity
What are the 5 clinical criteria that the CURB-65 score for pneumonia severity is based on?
- Mental status/confusion
- Urea > 7mmol/L
- Respiratory rate >30
- Systolic BP <90 mmHg or diastolic BP <60 mmHg
- Age >65
Name the 4 most common bacterial causes of community acquired pneumonia?
- Steptococcus pneumonia
- Haemophilus influenzae
- Staphylococcus aureus
- Group A streptococci
Name the 3 most common atypical causes of community acquired pneumonia?
- Legionella spp.
- Mycoplasma pneumoniae
- Chlamydia pneumoniae
Name the 3 most common respiratory viruses causing community acquired pneumonia?
- Influenza A & B viruses
- Parainfluenza viruses
- Respiratory syncytial virus
What are 4 additional clinical/microbiological information that would be important when suspecting community acquire pneumonia?
- Travel history- epidemic pathogen exposures, potential antimicrobial resistance
- Previous (recent) antibiotic therapy
- Previous microbiology culture results
- Drug allergies/intolerances
What are the 5 specific samples that you would take for severe community acquired pneumonia?
- Respiratory samples- Routine Microbiology culture, Viral PCR (Gargle/throat swab can also be sent)
- Urine specimen for Legionella pneumophila urinary antigen testing (Serotype 1 only)
- PCR for Legionella species
- Blood culture
- MRSA Screen
What empirical antibiotics would you prescribe for severe community acquired pneumonia?
IV amoxicillin or IV co-amoxiclav with Clarithromycin
What empirical antibiotics would you prescribe for community acquired pneumonia with true penicillin/beta-lactam allergy?
Levofloxacin (IV only if oral route compromised)
What are 2 other legionella infections?
- Pontiac fever
2. Extrapulmonary Legionella disease
Describe Pontiac fever?
- Acute, self-limiting febrile illness
- Symptoms: nonspecific & include fever, headache, myalgia, nausea, vomiting & diarrhoea
Describe Extrapulmonary Legionella disease?
- Rare & can occur as a complication of Legionella pneumonia
- Seen in immunocompromised
- Manifestations: abscesses, septic arthritis, myocarditis, pericarditis, peritonitis & meningitis
What should always be considered in any patient presenting with pneumonia?
Legionella infection
What is Legionella infection associated with?
Contamination of water supplies in large facilities such as hospitals, hotels or apartment buildings
What are the 4 patient risk factors for Legionella infection?
- Old age
- Smoking
- Chronic lung, cardiovascular or renal disease
- Immunocompromised
What is the gold standard test for a Legionella infection?
Culture or PCR
What are the 4 most commonly identified bacterial causes of acute epiglottitis?
- Haemophilus influenzae
- Streptococcus pneumoniae
- Staphylococcus aureus
- Beta-haemolytic streptococci: Groups A, B, C, F, G
What empirical antibiotics would you prescribe for acute epiglottitis?
IV Ceftriaxone with Clindamycin
What oral antibiotic would be appropriate for the treatment of an invasive Group A streptococcal infection/acute epiglottitis?
Clindamycin
What is GAS (invasive streptococcus pyogenes infection)?
Gram positive cocci that causes a wide range of infections
List the virulence factors possessed by GAS (invasive streptococcus pyogenes infection)?
Streptolysins, DNases, Exotoxins, Streptococcal super-antigens
List the 9 clinical manifestations of GAS (invasive streptococcus pyogenes infection)?
- Skin & soft tissue infection
- Necrotising fasciitis
- Myositis
- Septic arthritis
- Pharyngitis & RTI
- Postpartum endometritis
- Puerperal sepsis
- Meningitis
- Toxic shock syndrome
What is the best treatment for GAS (invasive streptococcus pyogenes infection) when there is clinical evidence of shock?
Bacteriostatic antibiotics (such as clindamycin, linezolid) are superior to bactericidal antibiotics (such as beta-lactams)
GAS is inherently susceptible to ________?
Penicillin
