Infection & Immunology Julie Letchford Flashcards
TB is a major opportunistic infection in ___ patients
HIV and Aids patients
What microorganism is TB caused by? Which organ does it infect preferentially?
Myobacterium tuberculosis,
The lungs
The incidence of Tb is increasing by __% each year
It kills ___ million each year
5%
3 million
Mycobacterium tuberculosis. Fast or slow growing? What kind of bacteria?
Slow growing so takes a while to develop the infection
Bacillus
The mycobacterium tuberculosis cell wall is rich in lipids. What does this result in?
Very hydrophobic therefore resistant to drying and to weak disinfectants
What’s the mycobacterium tuberculosis complex?
M tuberculosis
M bovis
M africanum
And M microti
A group of genetically related mycobacterium species that can cause tuberculosis
What is stage 1 of the progression of primary TB?
Bacilli is inhaled in droplets (respiratory droplets from someone)
Then phagocytosed by macrophages non specifically
These do not destroy the bacilli!
What is stage 2 of the progression of primary TB?
Mycobacterium TB multiplies inside macrophages for 7-21 days
Macrophages burst
Other macrophages may phagocytose the released TB
What happens at stage 3 of the progression of primary TB?
Cell mediated response initiated
T cells and B cells and collagen fibres (show up well on X-ray) all accumulate
Tubercules form with a caseous necrosis centre of dead matter
Once the Tubercules are formed at stage 3 of TB progression, what three ways may the infection now go?
Infection cleared away by immune system
Infection lies dormant and deactivates at later date (latent)
Progressive infection
What happens at stage 4 of TB progression?
Bacteria multiply inside macrophages and there’s uncontrolled lysis (bursting)
Enzymes get released and destroy local tissue forming lesions
What can we see on an X-ray of TB?
White lesions formed from enzymes from broken down macrophages replace alveoli with scar tissue.
Collagen fibres show up well
What is the tuberculin skin test?
Tuberculin is injected into forearm
A positive result: skin lesion (red region) over 10mm diameter forms after 48-72 hours.
Tuberculin is a protein derived from the TB bacteria
To treat TB first line we tend to treat with ____ antibiotic drugs in one go
FOUR
Stops all the bacteria becoming resistant as there’s so many, if we used just one could easily become resistant
What are the four first line anti TB drugs?
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
Describe the effects of rifampicin on TB
Bactericidal- kills off dividing cells, inhibits RNA polymerase
Taken orally, fully absorbed
Decreased effects by food.
What are the side effects of rifampicin?
Liver damage Hypersensitivity Decreased activity of other drugs Red coloured body fluids (red wee)
Describe the characteristics of anti TB drug Isoniazid
Bactericidal or bacteriostatic
It’s a prodrug
Decreases synthesis of mycolic acid
Usually oral, but can be IV or IM
What are the side effects of anti TB isoniazid
Hypersensitivity
Peripheral neuropathy
Liver toxicity
Decreased effects of hormonal contraceptives
Describe anti TB pyrazinamide
Bactericidal prodrug Decreases synthesis of mycolic acid Damages the bacterial membrane This is the only drug that can truly kill dormant bacteria Well absorbed orally
What are the side effects of anti TB drug pyrazinamide?
Joint pain
Liver damage
Hypersensitivity
How does anti TB drug ethambutol work?
Bacteriostatic
Increases permeability of bacterial cell walls
Orally well absorbed
50% excreted unchanged in urine
What are the side effects of anti TB drub Ethambutol?
Optic neuritis (blurring, but reversible) Joint pain Not used in under 5s
Streptomycin and capreomycin are both amino glycosides. They are ___ line anti TB drugs
Second line
Cycloserine, Ciprofloxacin and azithromycin are examples of?
Second line anti TB drugs
What would be a treatment regimen for active TB (ripe)?
Rifampicin and isoniazid for 6-9 months
Pyrazinamide for 2 months plus ethambutol
What would be a treatment regimen for latent TB?
Treat with immuno suppressants
Rifampicin for 6 months
Or rifampicin and isoniazid for 3 months
Why do we need a long duration of therapy for treating TB?
Bacteria in macrophages and Tubercules: hard for drug to penetrate
Rupturing of lesions: renewed infection
Drugs are only bactericidal against actively growing organisms, not dormant ones
What does MDR-TB mean?
Moderate drug resistance in TB
Strains are resistant to 2 or more first line drugs
What does XDR-TB stand for?
Extreme drug resistance in TB
Strains are resistant to 2 or more first line drugs
AND 3 or more second line drugs!!
Microbials mostly only kill ____ bacteria
Actively growing
Peptidoglycan is present in bacterial cell walls. What’s this made up of?
Alternate NAM and NAG with glycosidic bonds between. These chains are cross linked to other chains via amino acid residues
Peptidoglycan in bacterial cell walls cross linking via an amino acid side chain requires 2 things, what are these?
Transpeptidases (also called penicillin binding proteins)
Loss of a terminal amino acid from the side chain.
What do beta lactams inhibit?
Inhibit cell wall synthesis.
What do the structure of beta lactams all have in common? And what differs?
All have a beta lactam ring
Differ in the Structure of the ring attached to the beta lactam ring and the side chains (R groups)
How do beta lactams work?
1) They bind penicillin binding proteins (PBPs) aka transpeptidases
This prevents cross linking in the bacterial cell wall, loosing rigidity.
2)They mimic d-ala-d-ala residues on peptide side chains
3) stimulate autolysins that break down the cell wall
Why do we have less beta lactams we can use for gram negative bacteria compared to gram positive?
Gram negative have an outer membrane
The beta lactam has to fit through pores in this membrane to access the PBPs
If the beta lactam is too big then won’t fit through the pores
Limited to only small beta lactams
Examples of classes of beta lactams?
Penicillin
Cephalosporin
Monobactams
Carbepenems
Examples of glycopeptides?
Vancomycin
Teicoplanin
How do glycopeptides work?
Bind to terminal d-ala d-ala on peptide side chain
This prevents transglycosylase enzyme from adding a peptidoglycan monomer (NAG—NAM with glycosidic bond) onto the glycan chain.
They can also prevent cross linking
How do polymyxins work?
Disrupt cell membrane
Leakage of cytoplasmic contents
Daptomycin also works at cell membrane
Examples of polymyxins?
Polymyxin A Polymyxin B (colistin)
How do sulphonamides and trimethoprim work?
Metabolic inhibitors of nucleic acid synthesis
How do fluroquinolones work?
Affect DNA replication
What class of antibiotic affect RNA polymerase?
Rifamycins
E.g rifampicin
Remember R and R!!
Nitroimidazoles affect _____
DNA
Ciprofloxacin inhibits DNA replication of bacteria. How?!
Decreases type II and or type IV topoisomerases.
Type II= DNA gyrase
DNA gyrase aids replication by removing supercoils of DNA ahead of replication, so remove DNA gyrase is going to decrease replication!
Top IV: separates DNA after replication.
Fluoroquinolones also act by inhibiting DNA gyrase
Inhibitors of protein synthesis tend to be bacterial______
Bacterial static
Chloramphenicol inhibits protein synthesis in bacteria. How ?
Binds to 50s subunit of bacterial RNA
Decreases peptide bond formation
Macrolides like erythromycin and Clarithromycin inhibit protein synthesis in bacteria. How?
Bind to 50s subunit of RNA
Decrease translocation and release of tRNA
Fucidic acid decreases protein synthesis in bacteria. How?
Binds to EF-G ribosome complex
Decreases translocation of tRNA from A to P site
Where do Cycloserine and bacitracin act?
Act on cell wall synthesis
Where do lincosamides and streptogramins act?
Affect bacterial protein synthesis
Where do sulphonamides and trimethoprim act?
Affect nucleic acid in bacteria
What is the way of remembering the 6 bacteria we are concerned with antibiotic resistance?
E S K A P E Enterococcus faecium Staphylococcus aureus Klebsiella pneumonia Acinetobacter buamanii Pseudomonas aeruginosa Enterobacter
What’s the prob with enterobacter and enterococcus faecium?
We are worried about resistance.
Both of these are opportunistic so if they end up in the wrong place they will cause infection.
Eg enterococcus faecium has been known to cause endocarditis even though it is commonly found in the gut
What is an issue with klebsiella pneumoniae and acinetobacter buamanii ??
Problems with resistance
Klebsiella causes respiratory and urinary tract infections in hospitals.
There are problems with resistance to staphylococcus aureus and pseudomonas aeruginosa. Where does pseudomonas infect?
Patients who have burns
What two bacteria is there problems with multi drug resistance to?
E. coli
M tuberculosis
What ways can bacteria aquire resistance?
Intrinsically (naturally)
Or aquired:
Phenotypic; adapt to environment, reversible
Genetic; through mutations, or new genetic material through conjugation passing on plasmids (most common)
What are multi-drug resistance plasmids?
Resistant to SIX different antibiotics plus the heavy metal mercury
What are transposons?
“Jumping genes”
They move from one location on one bacterial plasmid to another plasmid or chromosome
Plasmids can accumulate transposons
What is the arm called to touch another bacteria that plasmids use to conjugate?
Pilus
Pulls the other bacteria towards it
Transferosome and relaxosome form whilst the plasmid gets transferred
What are the three main ways bacteria can have resistance to antibiotics?
Inactivate or modify the drug
Alter the drugs target site
Alter the drugs uptake or exit
How do bacteria become resistant to Beta lactam antibiotics?
They produce B-LACATMASES (enzymes)
These break open the beta lactam ring.
Which bacteria have chromosomal resistance to beta lactams?
Staph aureus
Pseudomonas aeruginosa
What are TEM-1 and TEM-2?
Beta LACATMASES
Commonly found in E. coli
Only have a limited spectrum of activity
The genes for these enzymes are passed through plasmids
What are ESBLs?
Extended spectrum beta lactamase enzymes
Plasmid encoded
They hydrolyse both penicillins and cephalosporins that have an oxyimino side chain
What are CTX-M and NDM-1?
Extended spectrum beta Lactmases
CTX-M found in s. Thyphimurium and E. coli (gives us resistance against all Carbepenems)
NDM-1 found in E.coli
Where are the beta Lactmases found in gram positive and gram negative bacteria?
In gram negative they sit between the cell wall and the outer cell membrane, so any antibiotics that attempts the get through are broken down.
In gram positive bacteria the beta lactamases are released into the surrounding medium, so they’re outside the cell wall
What could you add to an antibiotic formulation to help with resistance?
Beta lactamase inhibitors
Help lengthen the shelf life of beta lactam antibiotics
Three examples of beta lactamase inhibitors?
Clavulanic acid (co amoxiclav, augmentin)
Sulbactam
Tazobactam
Some beta lactams work by binding to penicillin binding proteins. How could bacteria form resistance here?
Alter the structure of penicillin binding protein
Eg. Methicillin resistance in staph aureus (MRSA)
PBP2—> PB2a, results in 1000x less potent antibiotic
How does haemophilus influenzae become resistant to beta lacatms?
Alters it’s penicillin binding protein
PBP3—-> PBP3-a and 3b, it becomes two seperate molecules
How does streptococcus pneumoniae become resistant to beta lactams?
By altering it’s penicillin binding proteins
PBP1 becomes PBP1a and 1b
PBP2 becomes PBP2a
How can bacteria alter their surface to alter the uptake of beta lactams?
Reduce the number or size of porins
This decreases permeability and prevents uptake
How can bacteria become resistant to Vancomycin?
Change the terminal amino acids in the peptide chain if the peptidoglycan cell wall:
Vancomycin usually binds to d-ala d-ala to inhibit cross linking
Bacteria can change and ala to a lactate (d-ala d-lactate)
Lactate means one less Hydrogen bond can be formed between vancomycin and the peptide side chain so it’s UNSTABLE.
Some bacteria can be targetted by antibiotics by altering their nucleic acid synthesis eg synthesis of purines and pyramidines. How could bacteria become resistant to this?
Enzymes involved in the different conversions to make the pyrimidines and purines can be altered.
Eg dihydropterate synthase and dihydrofolate reductase: a plasmid encoded enzyme can come around that has reduced affinity for the drug
How can resistance to aminoglycosides come about?
The drug can be inactivated through enzymes making modifications to the drug, such as adnelylase adding AMP groups or phosphorylase adding phosphates
What are the three different enzymes that can modify aminoglycosides?
Adenylylase (adds AMP)
Acetylase (adds acetyl)
Phophorylase (adds phosphate)
Antibiotics can be pumped out of bacterial cells as a form of resistance. This is increases Efflux. What two antibiotics can you think of that may suffer this resistance?
Tetracycline
Quinolones
This will mean the drug will not reach it’s optimum concentration in the bacterial cell
What is AcrAB/ToIC?
An Efflux pump
Found in E. coli
Can pump out a wide range of compounds simultaneously
It is a form of chromosomal multiple-antibiotic resistance (mar)
What is MexAB/OprM?
An Efflux pump
Found in Pseudomonas Aeruginosa
Can pump out a wide range of compounds simultaneously
What is the QAC pump?
An Efflux pump
Found in staph aureus
Can pump out a wide range of compounds simultaneously
What is the mar operon?
Mar= multiple-antibiotic resistance
The mar operon controls the AcrAB/ToIC Efflux pump in E. coli
Mar A=activator
mar R= repressor
Inactivation of mar R induces the mar phenotype- pump becomes more active, more able to upom out antibiotics
Inactivation of mar R in the mar operon in E. coli causes what?
Inactivation of mar R induces the mar phenotype- AcrAB/ ToIC pump becomes more active, more able to upom out antibiotics
Different penicillins result from different __ groups
There are over __ different types of penicillins
Can be given IM, IV Or orally
R groups
Over 20
What is the main thing inhibiting the action of penicillins on gram negative bacteria?
The pore size in the outer membrane
If penicillin is too big then it won’t fit through the pores
What five factors can the R group on penicillins determine?
Selectivity (gram neg vs pos) Solubiltity Stability Bioavailability Beta lactamase resistance
Three types of beta lactamase sensitive penicillins? (Bad because they can get broken down by these)
Benzyl penicillin (penicillin G)
Benzathine benzylpenicillin
Phenoxyymethylpenicllin (penicillin V)
Two types of beta lactamase RESISTANT penicillins (this is good!!)?
Flucloxacillin: Co-fluampicil (this is flucloxacillin plus a beta lactamase inhibitor)
Temocillin: resistant to beta lactamases from gram negative, most common
Name some BROAD spectrum penicillins?
Ampicillin
Amoxicillin
Co-amoxiclav (augmentin)
But these won’t work against very resistant organisms like pseudomonas
Broad spectrum antibiotics like ampicillin and coamoxiclav will not work against some very resistant organisms like pseudomonas. What antibiotics will?
Piperacillin
Piperacillin + tazobactam (Tazocin)
Ticarcillin + clavulanic acid (timentin)
These last 2 contain beta lactamase inhibitors
Can benzyl penicillin (penicillin G) work orally?
Is it active against gram positive and gram negative?
No it must be administered by IM or slow IV. Injection or IV infusion.
Active against both But mostly against gram positive
Benzylpenicillin (penicillin G) has a long post antibiotic effect. What does this mean?
Concentrations continue to work once concentration has dropped below the MIC, this is good!!
What are the different dosing options for benzylpenicillin? Standard? Endocarditis?
Can give combined with benzathine benzylpenicillin as slow release from IM site. Or as slow IV or IV infusion
Standard dose: 1.2g 4x per day
Endocarditis dose: 2.4g every 4 hours (v high dose, shows it’s non toxic)
List some uses of benzylpenicillin?
Endocarditis Meningitis Pneumonia Cellulitis Osteomyelitis Throat infection
What is meningitis caused by?
Neisseria meningitidis is the main organism (gram NEG)
Also by streptococcus pneumoniae (gram POS)
and haemophilus influenzae (gram NEG)
Need to know these for exam!!
How do we treat meningitis ?
Treat with benzylpenicillin IMMEDIATELY if meningitis suspected
It will get into the CSF where meningitis is
What’s the difference between ampicillin and amoxicillin stability?
Ampicillin is stable in acidic conditions due to the nature of its R group
What is the dose of oral ampicillin? What’s its bioavailability? How’s it excreted?
0.25- 1g every 6 hours. Take 30 mins before food
It’s 40% orally absorbed
Excreted in bile and urine
If ampicillin is going to be give to treat meningitis what is the dose?
By IM or IV give 500mg every 4-6 hours
Used for listerial meningitis
Used with gentamicin. Same with amoxicillin
What can ampicillin / amoxicillin be used in combo with to treat cellulitis?
Flucloxacillin
What organisms are starting to show resistance to ampicillin/ amoxicillin?
40% resistance in E. coli
10% in H influenzae
And in MOST staphylococci
Often see amoxicillin for oral infections as good against these bacteria
What are the side effects of penicillins?
Hypersensitivity: 1-10% experience a RASH 0.05% anaphylaxis Also Neurotoxicity Renal failure Oral derivatives may cause diahorrea and pseudomembranous colitis
What do oral antibiotics cause diahorrea ?
Oral broad spectrum antiobiotics kill gut bacteria
Resistant pathogenic gut bacteria then go on to cause SUPER INFECTION
Results in diahorrea
And psudomembranous colitis (C difficile! Produces spores)
What are cephalosporins isolated from?
Cephalosporium acremonium
What are the specificity, selectivity and activity determined by in cephalosporins?
The composition of the R groups 1 and 2
What are cephalosporins resistant to?
Beta lactamases, which is good!
But they’re not resistant to ESBLs
How are cephalosporins similar to penicillins?
Cephalosporins have a similar spectrum of activity to penicillins (septicaemia, pneumonia, meningitis, etc)
They have similar pharmacokinetics
Eg most give by IM, IV but some oral
Low penetration into CSF except in meningitis
____% of penicillin sensitive patients are also allergic to cephalosporins
0.5 -6
What are some of the side effects of cephalosporins?
Hypersensitivity Diarrhoea Nausea C. difficile super infections Rarely vomiting, headache, haemorrhage
What are cefazolin and cefradine examples of?
1st generation cephalosporins remember the CEF!
1st generation cephalosporins are active against most gram positive COCCI. But not active against?
Enterococci
MRSA
Staph epidermidis
1st generation Cephalosporins are active against some gram negative bacteria such as?
E. coli
Klebsiella pneumoniae
Proteus mirabilils
As we go from first to fourth generation of cephalosporins what do they become?
More and more broad spectrum
4th generation are extended spectrum agents
How do Carbepenems work?
Inhibit cell wall synthesis
All end in ~penem
Carbenepenems have a broad spectrum of activity.
They’re active against gram positive and gram negative as well as anaerobes and Ps. Aeruginosa.
What are they NOT active against?
Not active against MRSA or E .faecium
This is because there has been mutations in PBPs
What are Carbepenems used for?
Septicaemia Hospital aq pneumonia Intra abdominal infection Skin and soft tissue infection Complicated UTIs
There are problems with emerging resistance to Carbepenems involving the extended spectrum beta lactamase enzyme _____?
NDM-1
Monobactams are inhibitors of cell wall synthesis.
They are stable to most beta lactamases but have quite a narrow spectrum.
What are they used for?
Used IM. Or IV for septicaemia and complicated UTIs
Note: they are less likely to cause hypersensitivity than other antibiotics
What are the very severe side effects that are possible with Co-trimoxazole (a combo of sulphonamides and trimethoprim)?
Liver damage
Bone marrow suppression
Stevens-Johnson syndrome
What class of antibiotic are vancomycin and teicoplanin? What are they used for?
Glycopeptides
Used for infections caused by B lactam resistant organisms
Gram positive cocci: MRSA and staph epidermis
Gram positive rods: C. difficile
What is Cycloserine active against?
Tuberculosis
It has a broad spectrum
What is polyfax made up of? What can it be used for?
Polymyxin B and bacitracin
Used for skin and eye gram negative infections
Prevents wound infections
How do lipopeptides have their antibiotic effect?
Depolarise cytoplasmic membranes
Used IV for skin and soft tissue infection, and endocarditis
What is co-trimoxazole made up of? What’s its use?
Trimethoprim and sulphonamides
Used for a specific type of pneumonia
Co-trimoxazoles side effects are serious, what are they?
Liver damage
Bone marrow suppression
Steven Johnson syndrome
Ciprofloxacin is used for UTIs, RTIs, STDs and GITs and typhoid.
What are some of its side effects?
Targets the GIT so C DIFFICILE is a risk CNS problems Cartilage and tendon probs Rash Renal impairment
Shouldn’t be taken with food as absorption is decreased by cations
What antiobiotic is good for putting in the cement of joint replacements?
Rifampicin
It’s also used for treating TB and meningitis
Effects bacterial RNA polymerase
Metronidazole is a prodrug affecting bacterial DNA and it should be given if an infection is suspected to be caused by _______ bacteria. It can cause brown or red urine, hypersensitivity, CNS and GIT effects.
Anaerobic bacteria
How do aminoglycosides work?
Bind to 30s of ribosome
Decrease assembly of initiation complex and binding of tRNA in A site
Gentamicin is an amino glycoside. What are some side effects to watch out for?
Nephrotoxicity
Ototoxcitiy (irreversible hearing loss)
Single daily doses are least toxic, don’t tend to use for over 7 days
Linezolid is used for treating very resistant bacterial infections. Used as last resort. What’s it active against and how does it work?
Active against gram positive
MRSA, vancomycin resistant Enterococci
It binds to the 23s of rRNA in the 50s subunit, decreases assembly of initiation complex
What’s a common use of tetracyclines?
Acne
But also for RTIs, chlamydia, mycoplasma, periodontal disease.
Many staph and strep species are now resistant to tetracyclines
What can happen to people’s teeth when they take tetracyclines?
Can be stained. It gets deposited in bones and teeth
Can also get sever sunburn!!
And GIT irritation and super infections
Telothromycin is a ketolide. How does it compare to macrolides?
It is designed to overcome some of the resistance problems with macrolides, it’s more POTENT than macrolides, binds to a second site on the bacterial ribosome.
Erythromycin is given as an enteric coated tablet, or a prodrug. Why?
Because it’s acid labile
What are lincosamides such as clindamycin used for?
IV IM or orally for staphylococcal bone and joint infections
Respiratory infections
Peritonitis (inflammed stomach)
Septicaemia
Can cause diahorrea as a side effect
What can chloramphenicol cause that can be fatal?
Aplastic aneamia
Bone marrow stem cells die
Normal haemopoeitic cells become absent
Spaces get filled with adipose tissue
Can also cause grey baby syndrome so shouldn’t be used in under 4s
What is fucidin used for?
Skin and eye infections (topical)
Used as an oral or IV infusion for osteomyelitis and endocarditis
