Wk6 - clinical microbiology 1 Flashcards
Structure of gram +ve bacteria wall
Cell membrane
Thick peptidoglycan cell wall
Structure of gram -ve bacteria wall
Cell membrane
Peptidoglycan cell wall
Outer membrane
Periplasm
Bacteriocidal
Achieve sterilisation of the infected site by directly killing the bacteria
Lysis of bacteria can lead to release of toxins and inflammatory material
Bacteriostatic
Suppresses growth but does not directly sterilise infected site
Requires additional factors to clear bacteria - immune mediated killing
Antibiotic spectrum
Spectrum refers to the range of bacterial species effectively treated by the antibiotic
Broad spectrum of antibiotics
Antibiotics that are active against a wide range of bacteria
Treat most causes of infection but also have a substantial effect on colonising bacteria
Action of Meropenem
Active against almost all gram +ve and gram -ve species.
Resistance is rare except
Broad spectrum antibiotic
Action of Benzyl-pencillin
Highly active against streptococci.
Most other disease causing bacteria are resistant
Narrow spectrum antibiotic
Narrow spectrum of antibiotics
Antibiotics that are active against a limited range of bacteria
Useful only where the cause of the infection is well defined
Have a much more limited effect on colonising bacteria
Different ways of using antibiotics (different therapies)
Guided therapy:
Depends on identifying cause of infection and selecting agent based on sensitivity testing
Narrow spectrum options - mostly
Empirical therapy:
Best (educated) guess therapy based on clinical/epidemiological acumen
Used when therapy cannot wait for culture
Broad spectrum - mostly
Prophylactic therapy:
Preventing infection before it begins
Antibiotic associated harm
Disruption of bacterial flora leads to:
Overgrowth with yeasts – thrush
Overgrowth of bowel – diarrhoea
Antibiotic use associated with:
development of C. difficile colitis
future colonisation and infection with resistant organisms
Beta-Lactam antibiotics - 4 main types
Penicillins
Cephalosporins
Carbapenems
Monobactams (Aztreonam)
Main examples of beta-lactam antibiotics
Benzylpenicillin Flucloxacillin Amoxicillin Ceftriaxone Meropenem Aztreonam
Mechanism of action of beta-lactams
All β-lactams share the same structural feature
β-lactam motif analogue of branching structure of peptidoglycan
Inhibits crosslinking of cell wall peptidoglycan
Causes lysis of bacteria - bacteriostatic
Beta-lactamases
Enzymes that lyse and inactivate beta-lactam drugs
Commonly secreted by Gram –ves and S. aureus
Confer high level resistance to antibiotic:
Total antibiotic failure is likely to result
How are beta lactams given?
Most β-lactams poorly absorbed from GI tract:
must be given IV
Some can be effective orally:
amoxicillin, flucloxacillin most commonly used
Vomiting limits dose
Half life of e.g.s of beta lactams
Benzylpenicillin ≈ 1 hour
Ceftriaxone ≈ 8 hours
Adverse effects of beta-lactams
Usually very well tolerated, eveen in high doses
GI toxicity, n&v, diarrhoea, cholestasis
Infection - candidiasis, c.diff
HYpersensitivity - Type 1 - anaphylaxis, Type 4 - mild to seevre dermatology, Iterstitial nephritis
Rare: seizure, haemolysis, leukoaenia
Type 1 hypersensitivty
Relatively common allergy (0.7 – 4% of penicillin courses)
Most patients develop an urticarial rash
Anaphylaxis is the most feared complication
Cross reaction between classes is variable
Cross reactivity
Patients allergic to a penicillin will usually be allergic to other penicillins
Cross reactivity with other antibiotic classes is much lower
Some patients with penicillin allergy may be safely managed with other β-lactams
Particularly important if patient presents with life-threatening infection (esp. meningitis)
Features of Benzylpenicillin
MOA of beta-lactams - Penicillins
Chemically similar to original penicillin
Administered by the intra-venous route
There is an oral agent (Penicillin V) but not often used
Remains the first choice antibiotic for serious streptococcal infection (i.e. erysipelas)
Narrow spectrum agent
MOA:
Attaches to penicillin-binding proteins on forming bacterial cell walls.
This inhibits the transpeptidase enzyme which cross-links the bacterial cell wall.
Failure to cross-link induces bacterial cell autolysis.
Amoxicillin provides some amount of gram-negative cover in addition to gram-positive drugs
Features of Amoxicillin
Semi-synthetic penicillin:
- Greatly increased activity against gram negative organisms (although resistance is now common)
- Much more orally bioavailable than natural penicillins
Widely used in the treatment of a wide range of infections
A lot of resistance to Amoxicillin now
Used against Streptococci (resp. tract infections)
FEatures of FLucloxacillin
Synthetic penicillin developed to be resistant to beta-lactamase produced by staphylococci
Antibiotic highly active against:
Staphylococcus aureus (not MRSA)
Streptococci
No activity at all against gram negative organisms
Can be given orally but nausea limits dose
Beta-lactamase inhibitors
Effectively inhibit some beta-lactamases
Co-administered with penicillin antibiotic
Greatly broadens spectrum of penicillins against Gram –ves and S. aureus
There are many beta-lactamases that are not inhibited leading to antibiotic failure
Co-amoxiclav - broad spectrum
Tazocin - very broad spectrum
Cephalosporins
- MOA of Cephalopsporins
Initially isolated from Sardinian sewage outflow
Found to have good activity against Gram +ves and Gram –ves
Less susceptible to beta-lactamases than penicillins (due to them having more side chains)
Multiple generations of cephalosporins
Gram negative spectrum increases with each generation
Some loss of Gram positive activity
Recent introduction of MRSA active cephalosporins
e.g. Ceftriaxone - broad spectrum
MOA:
Attaches to penicillin-binding-proteins on forming bacterial cell walls.
This inhibits transpeptidase enzyme which cross-links the bacterial cell wall.
Failure to cross-link induces bacterial cell autolysis.
Less susceptible to beta-lactamases than penicillins
- Provides both gram-positive and gram-negative cover
Carbapenems
Ultra-broad spectrum beta-lactam antibiotics developed during search for beta-lactamase inhibitors
Excellent spectrum of activity against Gram +ves and Gram –ves
No activity against MRSA
Resistant to beta-lactamases
New beta-lactamases are emerging which lyse carbapenems
e.g. Meropenem
Monobactams
Aztreonam only member of the monobactam class Beta-lactam antibiotic but no cross reactivity to penicillins so can be given to those with penicillin allergy (except anaphylaxis) Only given IV – no oral absorption
Only work against gram -ves
e.g. Aztreonam
Vancomycin - a Glycopeptide
MOA of Vancomycin
Discovered in 1950s but did not find widespread use until rise of MRSA
Inhibits cell wall formation in Gram +ves only (no Gram –ve action)
Not dependent on PBP binding so effective against resistant organisms
Resistance in clinical isolates is extremely rare
1st drug against MRSA
Not absorbed from GI tract so almost always given IV
Oral route only used for treatment of C. diff
Resistance occurs but is uncommon (esp. Staph)
Long half life so loading doses usually given
MOA:
Bactericidal, inhibiting cell-wall synthesis in gram positive bacteria
Toxicity of Vancomycin
Nephrotoxicity – more likely with higher doses Red-man syndrome if injected too rapidly Anaphylactoid reaction Very rare now infusion rates slow Ototoxicity - rare
Therapeutic drug monitoring undertaken
Narrow therapeutic range
Aim higher in severe illnesses
Main issue with vancomycin in clinical use is underdosing
Protein synthesis inhibitors - classes
50S ribosomal subunit: Macrolides Erythromycin Clarithromycin Azithromycin Clindamycin Chloramphenicol
30s Ribosomal subunit:
Aminoglycosides - Gentamicin
Tetracyclines - Doxycycline
Macrolides - features
MOA
Good spectrum of activity against Gram positives and respiratory Gram –ves
Active against “atypicals” (atypical pneummonia)
- Legionella
- Mycoplasma
- Chlamydia
Excellent oral absorption:
Oral even in severe infection
e.g. Clarithromycin - Strep, haemophilus, Atypicals - good for resp. tract infections
MOA:
Binds to 50s ribosomal subunit
Inhibits bacterial protein synthesis
Macrolides - adverse effects
Diarrhoea & Vomiting
QT prolongation
Hearing loss with long term use
Drug interactions with macrolides
Simvastatin - avoid co-prescription, temporarly stop simvastatin - increases risk of simvastatin toxicity
Atrovastatin
Warfarin - anticoagulant increases too much
Clindamycin - MOA
Similar in many respects to macrolides:
- Same mechanism of action
- Excellent oral absorption
- Principle action against Gram positives
Some key differences:
- No action against aerobic Gram negatives or “atypicals”
- Excellent activity against anaerobes
Clindamycin highly effective at stopping exotoxin production
Added to patients with Gram positive toxin mediated disease:
Toxic shock syndrome
Necrotising fasciitis
Streps, Staphs - sever gram +ve infection
Broad anaearobic cover - causes sever destruction of colonic flora –> causes high risk of C.difficile
How does clindamycin cause c.diff (and other 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
4Cs:
- Clindamycin
- Co-amoxiclav
- Cephalosporins
- Ciprofloxacin
All antibiotics cause C. Diff (even those that treat it)
Keep antibiotics as narrow spectrum as possible
Chloramphenicol
Also inhibits the 50S ribosome Excellent broad spectrum of activity Unfortunately very toxic: - Bone marrow suppression - Aplastic anaemia - Optic neuritis
Not used systemically
Used topically for eye infections
Used for bacterial meningitis with beta-lactam allergy
Aminoglycosides (e.g. Gentamicin)
MOA of aminoglycosides
30S inhibitors
Recommended dose is 3 days.
Increased in importance over the last 5 years in UK:
Improved dosing regimens
Restriction of other broad spectrum antibiotics
Use of gentamicin in Glasgow more than doubled
Used in severe gram-positive infections (e.g. biliary tract infection, pyleonephritis, HA pneumonia)
Some severe gram-positive infecdtions (such as soft tissue infection and endocarditis)
MOA:
Binds to 30s ribosomal subunit, inhibiting protein synthesis, inducing a prolonged post-antibiotic bacteriostatic effect.
Additionally, bacteriocidal action on bacterial cell wall results in rapid killing early in dosing interval and is prominent at high dosese.
Also provides a synergistic effect when used alongside other antibiotics (such as flucloxacillin or vancomycin in gram-positive infections)
How does Gentamicin work - MOA
Binds to 30s ribosomal subunit, inhibiting protein synthesis, inducing a prolonged post-antibiotic bacteriostatic effect.
Additionally, bactericidal action on bacterial cell wall results in rapid killing early in dosing interval and is prominent at high doses.
Also provides a synergistic effect when used alongside other antibiotics (such as flucloxacillin or vancomycin in gram-positive infections).
Poorly understood action on the cell membrane:
Bactericidal action
Prominent at high concentrations
Results in rapid killing early in dosing interval
Aminoglycosides toxicity (Gentamicin)
Nephrotoxicity Ototoxicity: Hearing loss Loss of balance Oscillopsia Neuromuscular blockade: Usually only significant in myaesthenia gravis (rare)
Aminoglycosides once-daily dosing
Give high initial dose to take advantage of rapid killing
Leave long dosing interval (24-48hrs) to minimise toxicity
Measure trough level to ensure drug not accumulating
Give for 3 days only (to prevent toxicity developing)
Gentamicin - what its used fro
Gram negatives
E.coli
Pseudomonas
Tetracyclines
Similar spectrum of activity to macrolides Also active against “atypical” organisms Relatively non-toxic Avoid in children and pregnant women: - Bone abnormalities - Tooth discolouration
Doxycycline -w hats its used for
Staphs, streps, Atypicals
The 2 types of antibiotics that affect DNA repair and replication
Quinolones
- Ciprofloxacin
- Levofloxacin
Rifampicin
Quinolones
MOA of quinolones e.g. ciprofloxacin
Subtype of DNA repair and replication inhibitors
Broad spectrum, bactericidal antibiotics
Two quinolones in common clinical use:
Ciprofloxacin: good against Gram –ves, weaker against Gram +ves – commonly used in UTI/abdominal infection – urinary tract
Levofloxacin: sacrifices some Gram –ve activity for stronger Gram +ve action – respiratory tract
Excellent oral bioavailability: can use oral dosing even in severe infection
Active against many “atypical” pathogens, inc legionella
MOA:
Interferes with bacterial DNA replication and repair.
Broad-spectrum bactericidal antibiotics; provides both gram-positive and gram-negative cover.
Toxicity of quinolones
- Gastrointestinal toxicity
- QT prolongation
- Tendonitis
Other therapeutic problems:
- Resistance emerging on therapy/tendon damage
- C. diff infection (esp. in North America)
Ciprofloxacin - what its used for
Mainly gram negatives
Atypicals
Levofloxacin
Mainly gram positives - Strep and Staph (use in resp. tract infections)
Atypicals
Rifampicin - what its used for and how it works
Subtype of DNA repair and replication inhibitors
Principally used for two indications in the UK:
Tuberculosis (in combination therapy)
In addition to another antibiotic in serious Gram positive infection (esp. Staph. aureus)
Interactions are very important:
Rifampicin is a potent CYP450 enzyme inducer
Most drugs that undergo hepatic metabolism affected
Important to look up interactions when starting
4 principle TB drugs
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol (only bacteriostatic)
Toxicity associated with all of them
Antibiotics - inhibitors of folate synthesis
MOA and examples
MOA:
Inhibition of folate metabolism pathway leads to impaired nucleotide synthesis and therefore impaired bacterial DNA replication
Examples:
Trimethoprim
Sulfamethoxaole
Trimethoprim
Orally administered antibiotic
Good range of action against Gram +ves and Gram –ves
However, resistance a major problem in clinical use
Today limited to use in uncomplicated UTI
Trimethoprim - toxicity
Elevation of serum creatinine
Does not reflect fall in GFR
Related to action on proximal tubules
Elevation of serum K+
Problematic in patients with chronic renal impairment
Rash and GI disturbance relatively uncommon
What is Co-trimoxazole
Combination of Trimethoprim and sulphamethoxazole
Significant additional toxicity: Bone marrow suppression Stevens Johnson Syndrome Relatively few advantages: Used in certain uncommon infections by specialists Pneumocystis jirovecii pneumonia
Metronidazole
Miscellaneous antibiotic
Enters by passive diffusion and produces free radicals
Effective against most anaerobic bacteria
Not actinomyces
Often added to therapy in intra-abdominal infections, esp abscess
Causes unpleasant reaction with alcohol
Peripheral neuropathy with long term use
How to treat lower UTI
Trimethoprim:
Currently first line agent for most cases
Avoid in 1st trimester of pregancy (as folate synthesis inhibitor)
Penetrates well into prostate so good choice for men
Nitrofuratoin:
Excellent, broad spectrum of activity
Concentrated in urine so no effect on other tissues
Failure to concentrate in urine in renal failure – avoid
Relatively non-toxic in short courses:
- Pulmonary fibrosis with long term use
Antibiotics in pregnancy
Thought to be safe: Most beta-lactams: Broad spectrum agents may be associated with NEC in premature infants Macrolides (e.g. clarithromycin) Anti-tuberculants
Not considered safe: Tetracyclines - Bone/tooth abnormalities Trimethoprim - Neural tube defects (1st Tri) Nitrofurantoin - Haemolytic anaemic (3rd Tri) Aminoglycosides - Ototoxicity (2nd/3rd Tri) Quinolones - Bone/joint abnormalities, tendon problems
Always need to consider risks vs benefits
