General principles (Sources: Revision notes) Flashcards
What are the risk factors for infection in the critically ill?
- Patient factors - loss of natural barriers - ETT, vascular access, open wounds; Reduction in immune function - nutritional state, drug-induced immunosuppression, disease-induced immune suppression
- Environmental factors - relative over crowding, multiple staff contacts
- Organisms - resistant organisms more common in ICU - high antibiotic use, infection itself is more common
What is procalcitonin?
The precursor to calcitonin, synthesised in thyroid C cells
In the presence of bacterial infection its synthesised in neurohumeral tissue throughout the body
It’s relatively specific to bacterial infection
Rises as early as 4 hours postbacteraemia
What is the broad-range bacterial PCR?
Utilises polymerase chain reaction technique to identify the ribosomal RNA of bacteria, which negates the need to grow bugs
Whats B-D Glucan?
A component of most fungal cell walls
Detection in plasma is highly suggestive of invasive fungal infection
What is galatomannan?
A component of the cell wall of Aspergillus sp
Detection of it is highly suggestive of invasive Aspergillus
Which factors are associated with apparent failure of patients with infection to respond to treatment?
- Patient Related
Co-morbidities
-directly impeding recovery e.g. bronchial tumour in non-resolving pneumonia
-indirectly impeding recovery from infection e.g. neuromuscular weakness in non-resolving pneumonia
Immunosuppression - pathological e.g HIV, pharmacological
Ongoing contamination of sterile site - Antibiotic-related
Wrong antibiotic - bacteria not sensitive, inadequate tissue penetration
Inadequate dose
Antibiotic inactivation e.g. beta lactamase - Disease-related
Non-bacterial infection
Non-infective inflammatory process
Unrecognised secondary infection
Lack of source control
Development of collection
What is an antimicrobial?
A class of agents used to kill or suppress microorganisms
What is an antibiotic?
A specific term for a substance produced by a microorganism, which has the capacity to kill or inhabit the growth of another organism
What are antibiotics used for?
Treatment of infections - either imperial or targeted
Prophylaxis
Non-antimicrobial role e.g. erythromycin as pro-kinetic
What are the three guiding principles of antibiotic use?
Right agent
Right time
Right duration
How does critical illness impact upon the pharmacokinetics of antibiotics?
Absorption - gut oedema, impaired gut function, impaired splanchnic flow
Distribution - oedema and extracorporeal circuits increase volume of distribution
Protein binding - reduced protein availability, acid-base derangement, variable drug binding to extra corporeal circuits
Clearance - hepatic impairment reduces metabolism, biliary obstruction impairs hepatic excretion, renal imapriemtn reduces renal excretion
What are the 3 patterns of desired plasma levels for antibiotics?
- Maximum concentration dependent (Cmax:MIC) e.g. ahminoglycosides, metronidazole. Efficacy dependent upon peak plasma concentration, bolus dose regimen
- Time above ‘minimum inhibitory concentration (MIC)’ dependent (T>MIC) e.g. penicillins, carbapenems. Efficacy dependent upon the proportion of time with plasma concentrations greater than MIC, frequent dosing or continuous infusion utilised
- Time and concentration dependent: e.g. quinolone. Area under the curve above the MIC line is the most important marker of efficacy (AUC:MIC)
What are the two forms of antibiotic resistance?
Inherent or acquired?
What is inherent antibiotic resistance?
A natural resistance e.g. the outer membrane of Gram-negative bacteria is impenetrable to many antibiotics
What are the mechanisms of acquired antibiotic resistance?
- Inactivation of antibiotic by bacterial enzyme, either degradation of the antibiotic or modification of activity
- Decreased target site penetration e.g. impaired bacterial penetration or active efflux from the cell
- Altered target site e.g. alteration of the protein binding site in MRSA confers resistance to penicillins
Describe the main features of benzylpenicillin
Narrow spectrum
Inactivated by gastric acid - therefore must be given parenterally
Effective against Gram positive bacteria, Gram-negative cocci and come Gram-negative bacilli
Typically ineffective against Staph, Haemophilus and Psuedomonas
Describe the main features of flucloxacillin
A synthetic penicillin with moderate resistance to beta lactamase
Well absorbed orally
More effective against Staph than benpen, less effective against other Gram positive cocci
Highly protein bound, limited RRT clearance
Ca cause cholestatic jaundice
Describe the main features of ampicillin/amoxicillin
Same range of effectiveness as benzylpenicillin, with greater Gram-negative cover -Haemophilus, Salmonella, E.coli and enterococcus
Superior bioavailability, can be given orally
The addition of clavulanic acid to amoxicillin irreversibly inhibits a wide range of beta-lactamases and reduces the MIC
Describe the main features of piperacillin
Broader spectrum but less potent than benzylpenicillin
Particularly effective against pseudomonas, serrate and citrobacter
beta-lactamae sensitive, therefore combined with beta lactate inhibitor tazobactam
Describe the main features on Beta-lactams
Most commonly used group of antibiotics
Have a beta-lactam ring within their molecular structure
Absorption and distribution and both variable
Metabolism - excreted mostly unchanged
Excretion - short half-life, primarily really excreted, probenecid blocks active tubular excretion and therefore increases plasma levels, dose adjustment may be required in renal impairment, variable clearance via RRT
Plasma concentration should be 4-5 times MIC and plasma levels should be maintained as long as possible between doses
Often delivered as an infusion in ICU rather than in bolus doses
What are the pharmacodynamics of beta-lactams?
Bactericidal - the beta lactic ring bind to and inhibits bacterial transpeptidases thereby inhibiting cell wall synthesis
In Gram-positive bacteria they weaken the thick glycopeptide wall, killing bacteria
They have a synergistic effect with aminoglycosides
They lack post-antibiotic effects
In Gram negative bacteria they weaken the thin glycopeptide wall and liposacharide envelope
Cell death is dependent on the osmotic influx of water
What are the adverse effects of the beta-lactams?
Hypersensitivity in 10%
Anaphylaxis in 0.01%
Benzylpenicillin can cause encephalopathy in large doses, and reduce the seizure threshold
Carbepenems can also reduce the seizure threshold
Side effects include rash and GI upset
What are cephalosporins?
A broad and widely used group of beta-lactam antibiotics
Less susceptible to beta-lactamase
Wide distribution
Classified according to their generation
With each successive generation Gram-positive cover is maintained, and Gram negative cover improves, with some later generations having pseudomonas cover
What are the first generation cephalosporins?
Cefradine
Effective against beta-lactamase producing Staph, Strep and anaerobic Gram positive cocci
What are the second generation cephalosporins?
E.G cefuroxime
Increased Gram negative activity e.g. HI, Neisseria gonorrhoea, Klebsiella pneumonia and Enterobacter app.
Widespread resistance to E.faecalis, Acinobacter, Serrate, and Psuedomonas
Useful for abdominal cover but require additional aerobic cover
What are the third generation cepaholsporins?
E.g ceftriaxone and cefotaxime
Improved Gram-negative cover but slightly less effective against Gram-positive bacteria
Effective against Acinetobacter and Serrate
Ceftazidime is effective against Pseudomonas, although limited Staph cover
What are the fourth generation cephalosporins?
E.g. Cefepime
Similar Gram-negative cover to ceftazidime but better Gram-positive cover
What are the fifth generation cephalosporins?
e.g. Ceftaroline
Similar Gram-positive and negative cover to cefotaxmine but with activity against MRSA
What are carbapenems?
Broadest of spectrum of any antimicrobial with Gram-positive and Gram-negative aerobic and anaerobic cover
e.g. Imipenem and meropenem
What is the range of cover that macrolides have?
Similar range to penicillins Most Gram positive bacteria N.meningitides H.influenza Some anaerobes Also have specific cover against Mycoplasma pneumonia and Legionella
What are the pharmacokinetics of macrolides?
Absorption - good oral bioavailability
Distribution - good lung but limited CSF penetration, variable protein binding
Metabolism - primarily by the liver
Excretion - significant amount excreted unchanged, therefore dose reduction required in kidney injury
What are the pharmacodynamics of macrolides?
Primarily bacteriostatic
Bind to the 50s ribosomal subunit preventing replication
What are the adverse effects of macrolides?
GI effects common
Pro kinetic - used for therapeutic purposes
Prolonged QT interval
Drug interaction -augments theophylline, warfarin and digoxin
What is the range of cover of aminoglycosides?
Wide Gram-negative cover
Some Gram-positive cover e.g. staph and some strep
No anaerobic activity
Synergistic activity with beta lactase and vancomycin
What are the pharmacokinetics of aminoglycosides?
Absorption - none from GIT, therefore parenteral only
Distribution - large polar molecules, low protein binding, limited distribution - poor intracellular, css and sputum penetration
Metabolism - not metabolised, aminoglycosides and large and polar requiring active transport to access bacterial cells
Excretion - unchanged in the urine
What are the pharmacodynamics of the aminoglycosides?
Bactericidal
Bind to the ribosomal 30s subunit, blocking protein synthesis
Significant post-antibiotic effect
Administered as single doses with extended interval dosing
What are the adverse effects of aminoglycosides?
Narrow therapeutic index
Ototoxicity may occur if significant amoinoglycoside accumulation in the perilymph- risk related to peak plasma concentrations and increased by renal dysfunction and concurrent furosemide use
Nephrotoxicity - ATN occurs in up to 37% of ICU patients given gentamicin
Muscle weakness - aminoglycosides reduce the pre-junctional release and post-junctional sensitivity of acetylcholine at the neuromuscular junctions - effect of non-depolarising muscle relaxants is extenuated
What are the pharmacokinetics of the quinolones?
Absorption - good gut absorption, reduced by concurrent admin of magnesium, calcium and iron
Distribution - wide distribution with excellent penetration of the CSF, limited protein binding
Metabolism - limited
Excretion - largely unchanged
What are the pharmacodynamics of the quinolones?
Bactericidal
Inhibit subunit of DNA-gyrase
Some significant post-antibiotic effect
What are the adverse effects of the quinolones?
Reduction in seizure threshold
Nausea, vomiting and abdo pain
Haemolysis in the presence of glucose-6-phosphate deficiency
Interaction e.g. increases plasma levels of theophylline
Describe ciprofloxacin
The most commonly used quinolone
Broad Gram-negative cover, including pseudomonas, some gram positive cover
IV or oral
Agent of choice for anthrax and pneumonic plague
What is metronidazole effective for?
Potent inhibitor of obligate anaerobes and protozoa
Active against Clostridium app, Bacteroides spp, Treponema palladium and Campylobacter
What are the pharmacokinetics of metronidazole?
Absorption - well absorbed with almost 100% bioavailability
Distribution - minimal protein binding, widespread distribution including CSF, prostate, pleural fluid, cerebral abscess
Metabolism - metabolised to active compounds in the liver
Excretion - in urine, half life of active drug unchanged in renal insufficiency
What are the pharmacodynamics of metronidazole?
Unclear
Thought to be related to the nitro-group
Bacterial strand breakage leads to cell death
What are the adverse effects of metronidazole?
Nausea
Rarely - rash, pancreatitis, peripheral neuropathy
What are glycopeptides active against?
Virtually all Gram-positive bacteria
Their large molecular size prevents penetration of the lipid layer of Gram-negative bacteria
What are the pharmacokinetics of glycopeptides?
Absorption - not absorbed, therefore parenteral only for systemic infections, used enterally for GI infections
Distribution - variable protein binding, bone and css penetration with vanc is poor, better with tic
Metabolism - not metabolised
Excretion - excreted largely unchanged in urine, variable half-life, narrow therapeutic range, monitoring of plasma levels required
Peak plasma level os governed by dose, trough is governed by the interval
What are the pharmacodynamics of glycopeptides?
Bactericidal - glycopeptide is a synthase inhibitor
Glycopeptide cannot therefore be formed in the bacterial walls
What are the adverse effects of the glycopeptides?
Renal - toxicity is rare but more common with concurrent gent use
Ototoxicity - rare
Phlebitis - use dilute preparations for peripheral use
Red man syndrome - precipitated histamine release, manifests as tachycardia, hypotension and diffuse erythematous rash - avoided by limiting the rate of infusion
Haematological - neutopeania and thrombocytopenia have been reported
What bacteria are the lincosamides active against?
Clindamycin is highly active against Gram-positive bacteria, particularly anaerobes
Also has activity against falciparum malaria and Pneumocystis jirovici
Demonstrates suppression of the toxin production in toxin-elucidating strains of Staph and strep
What are the pharmacokinetics of the lincosamides?
Absorption - good oral bioavailability
Distribution - generally good penetration, esp bone and joints, poor csf
Metabolism - hepatic to active and inactive metabolites
Excretion - primarily in urine, some biliary excretion, half life increased in renal dysfunction
What are the pharmacodynamics of lincosamides?
primarily bacteriostatic
bactericidal against some strains of staph and strep
acts upon the 50s ribosomal subunit, thus disrupting protein synthesis\
What are the adverse effects of the lincodamides?
GI side effects are common
Increased risk of c.dif infection
a/w fever, rash, eosinophilia and thrombocytopenia
What is linezolid?
A novel antibiotic
What are the pharmacokinetics of linezolid?
Absorption: 100% oral bioavailability
Distribution: Limited protein binding, good penetration to all compartments
Metabolism: hepatic to inactive metabolites
Excretion: urinary, no dose adjustment needed in renal or liver failure
What are the pharmacodynamic of linezolid?
Bacterial protein synthesis inhibitor via the 50s ribosomal subunit but no cross-reactivity with other protein synthesis inhibitors
What are the adverse effects of linezolid?
Diarrhoea and nausea
More rarely, thrombocytopenia, peripheral neuropathy and lactic acidosis
What are the commonest used guanosine analogues?
Acyclovir and gancyclovir
What viruses are the guanosine analogues active against?
Herpes simplex (HSV)
Varicella Zoster (VSV)
Epstein-Bare (EBV)
Gancyclovir also has acitivy against cytomegalovirus (CMV)
What are the pharmacokinetics of the guanosine analogues?
Absorption - unpredictable absorption and limited oral bioavailability
Distribution - low protein binding and therefore wide distribution incl CSF
Metabolism - partial hepatic metabolism
Excretion - active tubular renal excretion - blocked by probenecid, risk of accumulation in renal failure
What are the pharmacodynamics of acyclovir?
Converted by thymidine kinase to acyclovir monophosphate and then acyclovir triphosphate infected cells
Thymidine kinase is not present in CMV-infected cells, hence the lack of efficacy against this virus
Acyclovir triphosphate is then incorporated into viral DNA as a surrogate for deoxyguanosine triphosphate
What are the adverse effects of the guanosine analogues?
Extravasation may lead to thrombophlebitis and ulceration
Renal impairment, secondary to crystallisation of acyclovir in renal tubules - a/w rapid admin and dehydration
Near effects include terms, seizures, confusion and coma
What are the neuraminidase inhibitors?
Oseltamivir, zanamivir and peramivir
Indicated in the prevention and treatment of influenza
What are the pharmacokinetics of the neuraminidase inhibitors?
Absorption - good oral bioavailability
Zanamivir is available as an IV prep where the enteric route is not available
Distribution - wide
Metabolism - first pass converts the majority of oseltamivir to its active metabolite
Excretion - renal cleared
What are the pharmacodynamics of neuraminidase inhibitors?
Sialic acid analogues, which competitively inhibit the enzyme neuraminidase on the surface of host cells, in doing so, the release of new virions from infected cells is prevented; the spread of infection within the host is thus prevented
What are the adverse effects of the neuraminidase inhibitors?
N+V
rarely neuropsychiatric disturbance has been reported in children
What classes of antifungals are there?
Azoles e.g fluconazole
Polyenes e.g. Amphotericin B
Echinocandins e.g. caspofungin
What are the azoles active against?
Candida Coccidiodes Cryptococcus Histoplasma Some are active against Asergillus e.g. miconazole
What are the pharmacokinetics of the azoles?
Absorption - normally good, fluconazole has 100% oral bioavailability
Distribution - Variable protein binding. Fluconazole has minimal and therefore good CNS penetration, Others are highly protein bound
Metabolism - Hepatic metabolism to inactive compounds
Excretion - biliary, no dose adjustment in renal failure needed
What are the pharmacodynamics of the azoles?
Blockage of 14 alpha demethylation disrupts synthesis of ergosterol: a key component of the fungal membrane
Direct ergosterol damage may occur at higher drug levels
What are the adverse effects of the azoles?
Drug interactions - e.g. enhances effect of warfarin
Inhibits steroid synthesis
What is amphotericin B active against?
Aspergillus
Candida
Cryptococcus
Describe the pharmacokinetics of amphotericin B
Absorption - systemic treatment is by intravenous route only
Distribution - highly protein bound, therefore limit penetration into CSF and urine
Metabolism - metabolised in the liver with no active metabolites
Excretion - no adjustment required in renal or hepatic impariment
Describe the pharmacodynamics of amphotericin B
Binds to the ergosterol component of fungal cell walls and creates pores
Increasing doses leads to larger pore formation and more rapid fungal death
What are the adverse effects of amphotericin B?
Nausea and vomitning Muscle pain Chills and riggers thrombophlebitis Blood dycrasias, seizures, hypokalaemia, hypomagnesaemia and hyperchloraemic acidosis AKI
What are the Echinocandins?
Caspofungin, micafungin and anidulofungin
Broad anti fungal activity with less resistance to Candida that the azoles
Describe the pharmacokinetics of the echinocandins
Absorption - poor oral absorption, therefore IV only
Distribution - highly protein bound and large molecular weight, therefore limited CSF distribution
Metabolism- Caspofungin degrades spontaneously
Excretion - dose adjustment in renal failure is not necessary
What are the pharmacodynamics of the echinocandins?
Inhibit the 1,3/3-D-glucan synthase enzyme, thereby inhibiting cell wall synthesis
What are the adverse effects of the echinocandins?
Better tolerated that other anti-fungals
S/E’s include elevated LFTs, delayed hypersensitivity reactions and GI side-effects
