Complex infections and sepsis

What is a complex infection?

• Multi Resistant Infection (ESBL UTI, MRSA bacteraemia, TB)

• Difficult to treat infections (eg. Endocarditis)

• Deep seated infections (eg. bone infection)

• Infections in a patient with underlying co-morbidities (eg. Resistant pseudomonas in a patient with cystic fibrosis)

• Infection in more than one site

• Ongoing infection with unknown origin source

• Infection leading to a significant morbidity / mortality

• Infection leading to sepsis

What is the pharmacist role in dealing with complex infections?

• Procuring unusual antibiotics/antifungals/antivirals

• Dosing advice to optimise treatment

• Renal impairment – What if on dialysis?

• Patient weight – Obesity

• Type of infection – Pseudomonas

• Critically unwell patient and altered drug handling – Low albumin

• Route of treatment – What if no oral access?

• Managing interactions (e.g. Voriconazole (inhibitor), Rifampicin (inducer) & DOACs)

• Therapeutic Drug Monitoring and interpretation of levels – Taken at the correct times? When should we take levels?

• Managing Outpatient Parenteral Antibiotics (OPAT/ NHS@HOME)→ IVs given at home

• Managing Complex Oral outpatient Antibiotics (COPAT/ NHS@HOME)→ Long-duration orals with high risk profile e.g. Co-Trimoxazole

• Patient counselling → TB regimes, Fluoroquinolones, Linezolid and Tyramine interactions etc.

• Ask as a link with microbiologists

• Providing / Monitoring adjunct treatments → e.g. steroids in meningitis, IV immunoglobulins in necrotising fasciitis

What medications do the following drugs have interactions with

1. Rifampicin

2. Voriconazole

1. Rifampicin = enzyme inducer. Common interaction with Apixaban – decreases exposure

2. Voriconazole = enzyme inhibitor. Common interaction with Atorvastatin – increases level/effect

What is Sepsis?

Life-threatening organ dysfunction caused by a dysregulated host response to infection

→ Can be triggered by any infection, but most commonly occurs following infection of lungs, urinary tract, abdomen, soft tissue.

What organs can sepsis affect?

ALL

• Brain → confusion/ drowsiness/ coma

• Kidneys → reduced urine / AKI

• Lungs → hypoxia / respiratory failure

• Heart → reduced cardiac output

• Liver → metabolic dysfunction/ coagulopathy

What groups are high risk for sepsis?

• Extremes of age: <1yr, >75yr or frail

• Impaired immune systems (chemotherapy, diabetes, splenectomy, sickle cell, long term steroids (including long acting injections), immunosuppressants)

• Surgery or invasive procedure in the last six weeks

• Any breech in the skin integrity (cuts, burns)

• Recent long courses of antimicrobials

• IV drug use

• Indwelling lines or catheters

• Pregnant women, post-natal/termination/miscarriage in the past 6 weeks

→ Remember drug history à Long-acting steroid injections are immunosuppressant, as is recent MAb use for treatment of COVID-19 or multi-morbidity such as MS.

What are the six most common signs of sepsis?

• Slurred speech or confusion

• Extreme shivering or muscle pain

• Passing no urine (in a day)

• Severe breathlessness

• "I feel like I might die"

• Skin mottled or discoloured

What red flags might indicate sepsis?

AVPU = Alert, Voice, Pain, Unresponsive

1. Alert: Patient is fully awake (though not necessarily orientated), will have spontaneously open eyes, and will respond to voice (thought may be confused). They will have bodily motor function.

2. Voice: The patient makes some sort of response when you talk to them. This could be through the eyes, which open when you speak to them, or by voice which may only be as little as a grunt. Or, it could be by moving a limb when prompted to do so by the rescuer.

3. Pain: A patient may respond by using any of the three components when pain stimulus is used on them (Eyes, Voice, Movement). Recognised methods for causing pain are pinching the ear or pressing into the bed of a fingernail. A fully conscious patient will locate the pain and push it away, whereas a patient who is not alert and not responded to voice may only manifest involuntary flexion or extension of a limb. Performing pain stimulus should be used with caution as in extreme circumstances this could be considered assault.

4. Unresponsive: This outcome is noted if the patient does not give any Eye, Voice or Motor response to voice or pain.

 

Although inflammation is an essential host response, excessive levels of pro-inflammatory cytokines can lead to…

systemic endothelial damage, and high levels of anti-inflammatory mediators can result in immune suppression.

Outline pathogenesis of sepsis.

1. Stimulation of the host immune response by toxins causes an inflammatory response that can lead to endothelial damage.

2. Pro-inflammatory cytokines, such as tumour necrosis factor (TNF), interleukin-1 (IL-1) and IL-6, are released in response to infection with the aim of destroying damaged tissue and promoting wound repair. Normally, anti-inflammatory mediators (e.g. IL-10, IL-13) are subsequently released to regulate the inflammatory response and restore homeostasis.

In sepsis, the imbalance between pro-inflammatory cytokines and anti-inflammatory mediators results in…

1. stimulated coagulation response

2. inhibited anticoagulant response

3. inhibited fibrinolytic response

These processes lead to endothelial damage and loss of equilibrium between the coagulation and fibrinolytic mechanisms.

As a procoagulant state develops, thromboses may form in the microvasculature, and in severe sepsis, the condition may progress to acute organ dysfunction and eventually death

Pro-inflammatory cytokines (including tumour necrosis factor, interleukin-1 and interferon-gamma) and thrombin are important in the…

up-regulation of adhesion molecules.

Therefore, in sepsis where there is excessive inflammation and thrombin production, there can also be increased expression of adhesion molecules, which leads to further inflammation, vascular endothelial injury and selectin expression

Summarise the pathogenesis of sepsis include the key mediator molecules.

• Vasodilation and capillary leak – physiological response to infection

• Lots of mediator molecules involved in the inflammation process

→ Balance of this inflammatory response goes “bad” in sepsis!

• End result:  

1. Hypovolaemia

2. Hypoperfusion at tissue/cellular level

3. Cell death

4. Organ dysfunction

Describe the process of Septic Shock.

• “Septic Shock” Think about a hosepipe…..

• Low water pressure in your hosepipe:

→ Not enough water (leaky capillaries - decrease circulating volume)

→ Diameter too wide (vasodilation)

• Septic shock activates the coagulation system

• Microthrombi in capillaries: this is from fibrinogen converting to fibrin, which binds to platelets > endothelial injury and release of inflammatory mediators

• END RESULT: IMPAIRED BLOOD FLOW (AND OXYGEN) TO CELLS

• Septic shock activates the coagulation system, causing sepsis-associated coagulopathy.

1. Fibrinogen converts to fibrin, which binds to platelets to form microvascular thrombi.

2. A marked or sustained procoagulant response to septic shock can lead to disseminated intravascular coagulation and widespread tissue injury, including loss of digits and limbs.

3. Microvascular thrombi amplify endothelial injury by the release of inflammatory mediators and by tissue hypoxia because of obstruction to blood flow.

What questions should you be asking if you suspect infection in a patient?

• Can you identify the source?

• Are there risk factors for sepsis?

• Does the patients vital observations raise concern?

  Breathing rate

  Cold hands/feet

  Increased pulse, decreased BP, decreased urine output

  General appearance

• In essence always think…. Could this be Sepsis?

What campaigns have been in place to help implement sepsis 6?

• Hospital staff publicity campaign

• Public awareness campaign

• NHS 111 algorithims

Does sepsis 6 lead to increased antibiotic usage?

1. CQUIN on antibiotic usage at same time

• Review of antibiotics within 72 hours

• Overall antibiotic consumption

• Broad spectrum IV antibiotic consumption

2. Importance of “Start Smart then Focus”

State the Sepsis 6

GIVE 3

• Oxygen

• Antibiotics

• Fluids

TAKE 3

• Blood cultures

• Serum lactate

• Urine output

What are the keys point about Sepsis 6 - Ensure senior clinician attends?

• New addition to Sepsis 6 in 2019

• ST3+ or equivalent senior nurse

• Ensure optimum collaborative care

• Clinician experience is essential

• Recent addition that they can verbally advice before attending, and senior involvement should not delay any other stages of the sepsis 6 management

What are the keys point about Sepsis 6 - GIVE Oxygen?

• Imbalance between tissue oxygen supply and demand

  - Reduced BP

  - Tissue oedema

  - Abnormal blood flow at capillary level

  - Hyper-metabollic state – cellular oxygen demand increased

• Start if 0₂ sats <92%

• High flow oxygen initially

• Enough to keep saturations >94% to reduce hypoxia and possible organ damage

→ Correcting low saturations helps reduce hypoxia and organ injury

What are the keys point about Sepsis 6 - Obtain IV access and take bloods?

1. Blood cultures

• Help identify pathogen and direct antibiotic therapy (start SMART then FOCUS)

• Aerobic and anaerobic bottles from peripheral site

• Take before giving antibiotics if possible

• Consider other samples (CSF, urine, sputum)

2. Lactate

• Measured on arterial blood gases

• Marker of tissue hypoperfusion. Indicates anaerobic respiration in cells

• Helpful in initial diagnosis of sepsis and marker of effectiveness of therapy

• Aim for ≤2mmol/L

• Generally ≥4mmol/L concerning

3. Blood glucose

4. FBC, U&Es, CRP

What are the keys point about Sepsis 6 - GIVE IV Antibiotics?

• According to guidelines – consider:

Likely source of infection

 Allergies

 Adequate levels at suspected site of infection

• Broad is best…….???? Start SMART then FOCUS

• Treat for most likely cause of infection if known (not just “sepsis”)

• The GOLDEN hour

For each hour’s delay in administering antibiotics in septic shock, mortality increases by 7.6%*

What are the main causes of sepsis cases?

What are the keys point about Sepsis 6 - GIVE IV fluids

• Improve pre-load to heart by correcting hypovolaemia

• Improve blood pressure and cardiac output

• 500mL of crystalloid (e.g Hartmanns or Plasmolyte) quickly then further boluses according to response (Lactate, BP, clinical). More isotonic so remain in blood vessels

• May opt for NaCl if lactate is elevated

• Caution not to fluid overload

What needs to be monitored during sepsis?

1. Urine Output

• Decreases in hypovolaemia

• Used as an indicator of cardiac output

• Target 0.5mL/kg/hr. May require catheterisation for accurate assessment

• Use a fluid balance chart for accurate recording

2. Serial Lactates

• If initial lactate >2, monitor hourly

3. NEWS2

State the Sepsis 6 checklist

The NEWS is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice, when patients present to, or are being monitored in hospital. Six simple physiological parameters form the basis of the scoring system:

• respiration rate

• oxygen saturation

• systolic blood pressure

• pulse rate

• level of consciousness or new confusion

• temperature.

For each overall news score what monitoring is required for each one…

1. NEWS 0

2. NEWS 1-4

3. NEWS >5

4. NEWS > 7

1. monitor 12hrly

2. monitor 4-6hrly

3. monitor minimum hourly

4. continuous monitoring of vital signs