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Infection > General principles (Sources: Revision notes) > Flashcards

General principles (Sources: Revision notes) Flashcards

1
Q

What are the risk factors for infection in the critically ill?

A
  1. Patient factors - loss of natural barriers - ETT, vascular access, open wounds; Reduction in immune function - nutritional state, drug-induced immunosuppression, disease-induced immune suppression
  2. Environmental factors - relative over crowding, multiple staff contacts
  3. Organisms - resistant organisms more common in ICU - high antibiotic use, infection itself is more common
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2
Q

What is procalcitonin?

A

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

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3
Q

What is the broad-range bacterial PCR?

A

Utilises polymerase chain reaction technique to identify the ribosomal RNA of bacteria, which negates the need to grow bugs

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4
Q

Whats B-D Glucan?

A

A component of most fungal cell walls

Detection in plasma is highly suggestive of invasive fungal infection

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5
Q

What is galatomannan?

A

A component of the cell wall of Aspergillus sp

Detection of it is highly suggestive of invasive Aspergillus

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6
Q

Which factors are associated with apparent failure of patients with infection to respond to treatment?

A
  1. 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
  2. Antibiotic-related
    Wrong antibiotic - bacteria not sensitive, inadequate tissue penetration
    Inadequate dose
    Antibiotic inactivation e.g. beta lactamase
  3. Disease-related
    Non-bacterial infection
    Non-infective inflammatory process
    Unrecognised secondary infection
    Lack of source control
    Development of collection
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7
Q

What is an antimicrobial?

A

A class of agents used to kill or suppress microorganisms

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8
Q

What is an antibiotic?

A

A specific term for a substance produced by a microorganism, which has the capacity to kill or inhabit the growth of another organism

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9
Q

What are antibiotics used for?

A

Treatment of infections - either imperial or targeted
Prophylaxis
Non-antimicrobial role e.g. erythromycin as pro-kinetic

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10
Q

What are the three guiding principles of antibiotic use?

A

Right agent
Right time
Right duration

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11
Q

How does critical illness impact upon the pharmacokinetics of antibiotics?

A

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

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12
Q

What are the 3 patterns of desired plasma levels for antibiotics?

A
  1. Maximum concentration dependent (Cmax:MIC) e.g. ahminoglycosides, metronidazole. Efficacy dependent upon peak plasma concentration, bolus dose regimen
  2. 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
  3. Time and concentration dependent: e.g. quinolone. Area under the curve above the MIC line is the most important marker of efficacy (AUC:MIC)
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13
Q

What are the two forms of antibiotic resistance?

A

Inherent or acquired?

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14
Q

What is inherent antibiotic resistance?

A

A natural resistance e.g. the outer membrane of Gram-negative bacteria is impenetrable to many antibiotics

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15
Q

What are the mechanisms of acquired antibiotic resistance?

A
  1. Inactivation of antibiotic by bacterial enzyme, either degradation of the antibiotic or modification of activity
  2. Decreased target site penetration e.g. impaired bacterial penetration or active efflux from the cell
  3. Altered target site e.g. alteration of the protein binding site in MRSA confers resistance to penicillins
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16
Q

Describe the main features of benzylpenicillin

A

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

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17
Q

Describe the main features of flucloxacillin

A

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

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18
Q

Describe the main features of ampicillin/amoxicillin

A

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

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19
Q

Describe the main features of piperacillin

A

Broader spectrum but less potent than benzylpenicillin
Particularly effective against pseudomonas, serrate and citrobacter
beta-lactamae sensitive, therefore combined with beta lactate inhibitor tazobactam

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20
Q

Describe the main features on Beta-lactams

A

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

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21
Q

What are the pharmacodynamics of beta-lactams?

A

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

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22
Q

What are the adverse effects of the beta-lactams?

A

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

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23
Q

What are cephalosporins?

A

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

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24
Q

What are the first generation cephalosporins?

A

Cefradine

Effective against beta-lactamase producing Staph, Strep and anaerobic Gram positive cocci

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25
Q

What are the second generation cephalosporins?

A

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

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26
Q

What are the third generation cepaholsporins?

A

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

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27
Q

What are the fourth generation cephalosporins?

A

E.g. Cefepime

Similar Gram-negative cover to ceftazidime but better Gram-positive cover

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28
Q

What are the fifth generation cephalosporins?

A

e.g. Ceftaroline

Similar Gram-positive and negative cover to cefotaxmine but with activity against MRSA

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29
Q

What are carbapenems?

A

Broadest of spectrum of any antimicrobial with Gram-positive and Gram-negative aerobic and anaerobic cover
e.g. Imipenem and meropenem

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30
Q

What is the range of cover that macrolides have?

A 
Similar range to penicillins
Most Gram positive bacteria
N.meningitides
H.influenza
Some anaerobes
Also have specific cover against Mycoplasma pneumonia and Legionella
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31
Q

What are the pharmacokinetics of macrolides?

A

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

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32
Q

What are the pharmacodynamics of macrolides?

A

Primarily bacteriostatic

Bind to the 50s ribosomal subunit preventing replication

33
Q

What are the adverse effects of macrolides?

A

GI effects common
Pro kinetic - used for therapeutic purposes
Prolonged QT interval
Drug interaction -augments theophylline, warfarin and digoxin

34
Q

What is the range of cover of aminoglycosides?

A

Wide Gram-negative cover
Some Gram-positive cover e.g. staph and some strep
No anaerobic activity
Synergistic activity with beta lactase and vancomycin

35
Q

What are the pharmacokinetics of aminoglycosides?

A

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

36
Q

What are the pharmacodynamics of the aminoglycosides?

A

Bactericidal
Bind to the ribosomal 30s subunit, blocking protein synthesis
Significant post-antibiotic effect
Administered as single doses with extended interval dosing

37
Q

What are the adverse effects of aminoglycosides?

A

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

38
Q

What are the pharmacokinetics of the quinolones?

A

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

39
Q

What are the pharmacodynamics of the quinolones?

A

Bactericidal
Inhibit subunit of DNA-gyrase
Some significant post-antibiotic effect

40
Q

What are the adverse effects of the quinolones?

A

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

41
Q

Describe ciprofloxacin

A

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

42
Q

What is metronidazole effective for?

A

Potent inhibitor of obligate anaerobes and protozoa

Active against Clostridium app, Bacteroides spp, Treponema palladium and Campylobacter

43
Q

What are the pharmacokinetics of metronidazole?

A

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

44
Q

What are the pharmacodynamics of metronidazole?

A

Unclear
Thought to be related to the nitro-group
Bacterial strand breakage leads to cell death

45
Q

What are the adverse effects of metronidazole?

A

Nausea

Rarely - rash, pancreatitis, peripheral neuropathy

46
Q

What are glycopeptides active against?

A

Virtually all Gram-positive bacteria

Their large molecular size prevents penetration of the lipid layer of Gram-negative bacteria

47
Q

What are the pharmacokinetics of glycopeptides?

A

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

48
Q

What are the pharmacodynamics of glycopeptides?

A

Bactericidal - glycopeptide is a synthase inhibitor

Glycopeptide cannot therefore be formed in the bacterial walls

49
Q

What are the adverse effects of the glycopeptides?

A

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

50
Q

What bacteria are the lincosamides active against?

A

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

51
Q

What are the pharmacokinetics of the lincosamides?

A

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

52
Q

What are the pharmacodynamics of lincosamides?

A

primarily bacteriostatic
bactericidal against some strains of staph and strep
acts upon the 50s ribosomal subunit, thus disrupting protein synthesis\

53
Q

What are the adverse effects of the lincodamides?

A

GI side effects are common
Increased risk of c.dif infection
a/w fever, rash, eosinophilia and thrombocytopenia

54
Q

What is linezolid?

A

A novel antibiotic

55
Q

What are the pharmacokinetics of linezolid?

A

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

56
Q

What are the pharmacodynamic of linezolid?

A

Bacterial protein synthesis inhibitor via the 50s ribosomal subunit but no cross-reactivity with other protein synthesis inhibitors

57
Q

What are the adverse effects of linezolid?

A

Diarrhoea and nausea

More rarely, thrombocytopenia, peripheral neuropathy and lactic acidosis

58
Q

What are the commonest used guanosine analogues?

A

Acyclovir and gancyclovir

59
Q

What viruses are the guanosine analogues active against?

A

Herpes simplex (HSV)
Varicella Zoster (VSV)
Epstein-Bare (EBV)
Gancyclovir also has acitivy against cytomegalovirus (CMV)

60
Q

What are the pharmacokinetics of the guanosine analogues?

A

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

61
Q

What are the pharmacodynamics of acyclovir?

A

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

62
Q

What are the adverse effects of the guanosine analogues?

A

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

63
Q

What are the neuraminidase inhibitors?

A

Oseltamivir, zanamivir and peramivir

Indicated in the prevention and treatment of influenza

64
Q

What are the pharmacokinetics of the neuraminidase inhibitors?

A

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

65
Q

What are the pharmacodynamics of neuraminidase inhibitors?

A

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

66
Q

What are the adverse effects of the neuraminidase inhibitors?

A

N+V

rarely neuropsychiatric disturbance has been reported in children

67
Q

What classes of antifungals are there?

A

Azoles e.g fluconazole
Polyenes e.g. Amphotericin B
Echinocandins e.g. caspofungin

68
Q

What are the azoles active against?

A 
Candida
Coccidiodes
Cryptococcus
Histoplasma
Some are active against Asergillus e.g. miconazole
69
Q

What are the pharmacokinetics of the azoles?

A

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

70
Q

What are the pharmacodynamics of the azoles?

A

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

71
Q

What are the adverse effects of the azoles?

A

Drug interactions - e.g. enhances effect of warfarin

Inhibits steroid synthesis

72
Q

What is amphotericin B active against?

A

Aspergillus
Candida
Cryptococcus

73
Q

Describe the pharmacokinetics of amphotericin B

A

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

74
Q

Describe the pharmacodynamics of amphotericin B

A

Binds to the ergosterol component of fungal cell walls and creates pores
Increasing doses leads to larger pore formation and more rapid fungal death

75
Q

What are the adverse effects of amphotericin B?

A 
Nausea and vomitning
Muscle pain
Chills and riggers
thrombophlebitis
Blood dycrasias, seizures, hypokalaemia, hypomagnesaemia and hyperchloraemic acidosis
AKI
76
Q

What are the Echinocandins?

A

Caspofungin, micafungin and anidulofungin

Broad anti fungal activity with less resistance to Candida that the azoles

77
Q

Describe the pharmacokinetics of the echinocandins

A

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

78
Q

What are the pharmacodynamics of the echinocandins?

A

Inhibit the 1,3/3-D-glucan synthase enzyme, thereby inhibiting cell wall synthesis

79
Q

What are the adverse effects of the echinocandins?

A

Better tolerated that other anti-fungals

S/E’s include elevated LFTs, delayed hypersensitivity reactions and GI side-effects

Infection (4 decks)

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