Sepsis Flashcards
1
Q
Aminoglycosides
Gentamicin
Common indications
A
- Severe infections, particularly those caused by G-ve aerobes (including Pseudomonas)
- Aminoglycosides lack activity against strep and anaerobes
- Severe sepsis- including where the source is unidentified
- Pyelonephritis and complicated UTI
- Biliary and other intra-abdominal sepsis
- Endocardiditis
2
Q
Gentamicin
MOA
A
- Aminoglycosides bind irreversibly to bacterial ribosomes (30S subunit) and inhibit protein synthesis.
- They are bactericidal (i.e. they kill bacteria), although this effect is likely to be due to additional mechanisms that are incompletely understood.
- Their spectrum of action includes Gram-negative aerobic bacteria, staphylococci and mycobacteria (for example, streptomycin was one of the first effective treatments for tuberculosis).
- Aminoglycosides enter bacterial cells via an oxygen-dependent transport system. Streptococci and anaerobic bacteria do not have this transport system, so have innate aminoglycoside resistance.
- Other bacteria acquire resistance through reduced cell membrane permeability to aminoglycosides or acquisition of enzymes that modify aminoglycosides to prevent them from reaching the ribosomes.
- As penicillins weaken bacterial cell walls, they may enhance aminoglycoside activity by increasing bacterial uptake.
3
Q
Gentamicin
Adverse effects
A
- The most important adverse effects are nephrotoxicity and ototoxicity.
- Aminoglycosides accumulate in renal tubular epithelial cells and cochlear and vestibular hair cells where they trigger apoptosis and cell death.
- Nephrotoxicity presents reduced urine output and rising serum creatinine and urea and is potentially reversible.
- Ototoxicity is often not noticed until after resolution of the acute infection, when the patient may complain of hearing loss, tinnitus (cochlear damage) and/or vertigo (vestibular damage). Ototoxicity may be irreversible.
4
Q
Gentamicin
Warnings
A
- Aminoglycosides are renally excreted.
- Monitoring of plasma drug concentrations with careful dose adjustment is essential to prevent renal, cochlear and vestibular damage, particularly in neonates and the elderly who are most susceptible and in patients with renal impairment.
- Aminoglycosides can impair neuromuscular transmission so should not be given to people with myasthenia gravis unless absolutely necessary.
5
Q
Gentamicin
Interaction
A
- Ototoxicity is more likely if aminoglycosides are co-prescribed with loop diuretics (e.g. furosemide) or vancomycin.
- Nephrotoxicity is more likely if aminoglycosides are co-prescribed with ciclosporin, platinum chemotherapy, cephalosporins or vancomycin.
6
Q
Gentamicin
Communication
A
- Explain that the aim of treatment is to get rid of the infection and improve symptoms. Ask the patient daily if they have noticed any change in their hearing, ringing in their ears or dizziness and advise them to let you know if this occurs.
- Ensure that the prescription clearly indicates that dosing depends on plasma concentrations and that measurement and recording of these have been organised, particularly at weekends.
7
Q
Gentamicin
Monitoring
A
- For efficacy, monitor symptoms and signs (e.g. pyrexia) and blood inflammatory markers (e.g. C-reactive protein) to ensure resolution of infection.
- For safety, renal function should be measured before (to guide dosing) and during (to detect toxicity) parenteral aminoglycoside therapy.
- The plasma drug concentration is usually measured 18–24 hours after the first dose (trough level).
- The next dose should only be administered if these have fallen to a safe level with a low risk of toxicity (e.g. gentamicin <1 mg/mL).
- If the plasma concentration is too high, the next dose should be withheld until repeat levels indicate that it is safe to give.
8
Q
Cephalosporins and carbapenems
cefotaxime, meropenem
Common indications
A
- Oral cephalosporins are 2nd/2nd line treatment options for urinary and respiratory tract infections
- IV ceph and carbapenems are reserved for treating infections that are very severe or complicated or caused by the antibiotic-resistant organism. Due to their broad antimicrobial spectrum, they can be used for most indications.
9
Q
Cephalosporins and carbapenems
MOA
A
- Cephalosporins and carbapenems are derived from naturally occurring antimicrobials produced by fungi and bacteria.
- Like penicillins, their antimicrobial effect is due to their β-lactam ring.
- During bacterial cell growth, cephalosporins and carbapenems inhibit enzymes responsible for cross-linking peptidoglycans in bacterial cell walls.
- This weakens cell walls, preventing them from maintaining an osmotic gradient, resulting in bacterial cell swelling, lysis and death.
- Both types of antibiotics have a broad spectrum of action. For cephalosporins, progressive structural modification has led to successive ‘generations’ (first to fifth), increasing activity against Gram-negative bacteria and less oral activity.
- Cephalosporins and carbapenems are naturally more resistant to β-lactamases than penicillins due to fusion of the β-lactam ring with a dihydrothiazine ring (cephalosporins) or a unique hydroxyethyl side chain (carbapenems).
10
Q
Cephalosporins and carbapenems
Adverse effects
A
- Gastrointestinal upset, such as nausea and diarrhoea, are common. Less frequently, antibiotic-associated colitis occurs when broad-spectrum antibiotics kill normal gut flora, allowing overgrowth of toxin-producing Clostridium difficile.
- This is debilitating and can be complicated by colonic perforation and death.
- Hypersensitivity, including immediate and delayed reactions, may occur
- As cephalosporins and carbapenem share structural similarities to penicillins, cross-reactivity may occur with some penicillin-allergic patients.
- There is a risk of central nervous system toxicity including seizures, particularly where carbapenems are prescribed in high dose or to patients with renal impairment.
11
Q
Cephalosporins and carbapenems
Warnings
A
- Cephalosporins and carbapenems should be used with caution in people at risk of C. difficile infection, particularly those in the hospital and the elderly.
- The main contraindication is the history of allergy to penicillin, cephalosporin or carbapenem, particularly if there was an anaphylactic reaction.
- Carbapenems should be used with caution in patients with epilepsy.
- A dose reduction is required for both drug classes in renal impairment.
12
Q
Cephalosporins and carbapenems
Interactions
A
- As broad-spectrum antibiotics, cephalosporins and carbapenems can enhance the anticoagulant effect of warfarin by killing normal gut flora that synthesises vitamin K.
- Cephalosporins may increase nephrotoxicity of aminoglycosides. Carbapenems reduce plasma concentration and efficacy of valproate.
13
Q
Penicillins
Common indications
A
- Streptococcal infection including tonsilitis, pneumonia (in combination with a macrolide if severe), endocarditis and skin and soft tissue infections (Fluclox)
- Clostridial infection e.g. tetanus
- Meningococcal infection e.g. meningitis, septicaemia
14
Q
Penicillin
MOA
A
- Penicillins inhibit the enzymes responsible for cross-linking peptidoglycans in bacterial cell walls.
- This weakens cell walls, preventing them from maintaining an osmotic gradient.
- The uncontrolled entry of water into bacteria causes cell swelling, lysis and death.
- Penicillins contain a β-lactam ring, which is responsible for their antimicrobial activity.
- Sidechains attached to the β-lactam ring can be modified to make semi-synthetic penicillins.
- The nature of the side chain determines the antimicrobial spectrum and other properties of the drug.
- Bacteria resist penicillins’ actions by making β-lactamase, an enzyme that breaks the β-lactam ring and prevents antimicrobial activity.
- Other resistance mechanisms include limiting the intracellular concentration of penicillin (reduced bacterial permeability or increased extrusion) or changes in the target enzyme to prevent penicillin-binding.
15
Q
Penicillins
Adverse effects
A
- Penicillin allergy affects 1–10% of people. This usually presents as a skin rash 7–10 days after first exposure or 1–2 days after repeat exposure (subacute [delayed] IgG-mediated reaction).
- Less commonly, an immediate (minutes to hours) life-threatening IgE-mediated anaphylactic reaction occurs with some or all of hypotension, bronchial and laryngeal spasm/oedema and angioedema.
- Central nervous system toxicity (including convulsions and coma) can occur with high doses of penicillin or where severe renal impairment delays excretion.
