Guidelines for the Empirical Treatment of Sepsis in Adults (excluding

Neutropenic Sepsis)

Full Title of Guideline:
Author (include email and role):
Guidelines for the Empirical Treatment of Sepsis in Adults
(excluding Neutropenic Sepsis)
Dr Stephen Holden (Consultant Microbiologist)
(Stephen.holden@nuh.nhs.uk)
Riya Savjani (Senior Clinical Pharmacist: Antimicrobials)

Division & Speciality: All adult clinical specialities

Scope (Target audience, state if Trust Doctors, pharmacists, microbiology, nurses

wide):
Review date (when this version goes out June 2018
of date):
Explicit definition of patient group All adult directorates except obstetrics, and neutropenic haematology
to which it applies (e.g. inclusion and & oncology patients.
exclusion criteria, diagnosis):
Changes from previous version (not Addition of metronidazole to empirical treatment for High Risk Red
applicable if this is a new guideline, enter Sepsis of unknown origin for patients with mild penicillin allergy.
below if extensive): Change to wording for multi-resistant gram negative organisms.
Updated figures for surveillance data. Criteria for high risk red sepsis
Lactate and AKI added.
Piperacillin/tazobactam for abdominal and biliary infection removed
due to shortage. Abdominal and biliary infection split into two sections,
addition of amoxicillin in biliary infection.
Piperacillin/tazobactam for bone infections >75years removed due to
shortage.
Summary of evidence base this Guidance reviewed with local Microbiological surveillance data.
guideline has been created from:
UK Sepsis Trust (2014) Clinical Toolkits. Available from:
http://sepsistrust.org/ (accessed 26.03.15)
NICE Guideline 51. Sepsis: recognition, diagnosis and early
management. July 2016. Available from www.nice.org.uk
This guideline has been registered with the trust. However, clinical guidelines are
guidelines only. The interpretation and application of clinical guidelines will remain the
responsibility of the individual clinician. If in doubt contact a senior colleague or expert.
Caution is advised when using guidelines after the review date or outside of the Trust.
Guidelines for the Empirical Treatment of Sepsis in Adults (excluding
Neutropenic Sepsis)

Contents Page
1. General guidance 3-4

2. Current trends in antibiotic resistance 4-5

3. Sepsis of unknown origin

3.1 Clinical approach 5-6
3.2 Algorithm for management and empirical treatment 7

4. Guidance on initial antibiotic therapy by body site:

4.1 Abdominal infection 8
4.1.1 Biliary infection 9
4.2 Bone and joint infection 10-11
4.3 Cellulitis 11-12
4.4 Infective endocarditis 12
4.5 Line infection (peripheral and central) 13-15
4.6 Meningitis (see separate guidelines) 15
4.7 Pneumonia (see separate guidelines) 15
4.8 Urosepsis (separate guidelines.) 15

These guidelines detail the empirical antibiotic treatment of sepsis in

adults. Please see separate guidelines for the treatment of neutropenic
sepsis at:

http://nuhnet/diagnostics_clinical_support/antibiotics

Neutropenic patients should be discussed with a senior member of the

oncology or haematology team on-call.

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1. General Guidance

1. Clinical assessment to establish sepsis and the need for antibiotics

Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated

host response to infection

High risk RED SEPSIS is considered present if the patient has EWS/NEWS >3,
there is a proven or highly suspected site of infection and one or more of the
following:

Newly altered mental state

Resp rate >25/min OR new need for oxygen (>40% FiO2) to
maintain saturation >92% (or >88% in known COPD)
Heart rate >130/min
Systolic BP < 90 mmHg or >40 mmHg below normal
Not passed urine in previous 18hour, or <0.5ml/kg of urine/hour if
catheterised >2 consecutive hours
Mottled or ashen appearance cyanosis of skin, lips or tongue
Non-blanching rash
Lactate >2 or AKI in the presence of deranged physiology

High risk RED SEPSIS is a medical emergency. Seek senior medical support
and commence the Sepsis Six bundle

An isolated pyrexia in the absence of other parameters does not equate to

sepsis. If the patient is febrile with no evidence of a focus of infection and no
other parameters to suggest sepsis, cultures should be taken but urgent broad-
spectrum antibiotics are not indicated.

Septic shock is where hypotension persists despite adequate fluid challenge or

requires use of vasopressors or inotropes.

Further details about the management and investigation of sepsis can be found
at the Surviving Sepsis campaign website here, or the Trust intranet page here.

2. Take appropriate microbiological specimens

Appropriate microbiological specimens should always be taken before starting
antibiotics. This should include two sets (four bottles) of blood cultures, each set
taken from separate sites (20ml/set) even if the patient is apyrexial. Blood
cultures should also be taken from all intravascular devices present, including
central lines and Hickman lines and labelled stating which line they were taken
from.
Appropriate antibiotic therapy should be administered within one hour if there is
evidence of High Risk RED SEPSIS.

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3. Selection of antibiotics according to source
In cases of sepsis in adults in whom the diagnosis is unknown, empirical therapy
based upon the likeliest source of bacteraemia is necessary. If the source of
sepsis is unknown please refer to the algorithm on page 6.

4. Review recent microbiology results

Recent microbiology results should be reviewed to identify if the patient is at risk
of sepsis with a more resistant organism, which may not respond to standard first
line therapy.

2. Current Trends in Antibiotic Resistance

Multiresistant Gram Negative Organisms (MRGNO)

Recent local, national and international surveillance has identified a worrying

increase in multiple resistance to antibiotics in Gram-negative organisms;
particularly gentamicin, quinolone and cephalosporin resistant Escherichia coli.
Recent local surveillance of E. coli bacteraemias has shown: up to 12%
resistance to gentamicin and 13% resistance to 3rd generation cephalosporins
(usually Extended Spectrum Beta-Lactamase ESBL positive), 20% resistance to
ciprofloxacin and 40% resistance to co-amoxiclav. This is of concern as E. coli is
the most common cause of community and hospital acquired Gram-negative
sepsis.

Local surveillance has identified the following risk factors for ESBL positive
E. coli or multi- resistant Gram negative sepsis:
Previous history of isolation of ESBL positive E. coli or Multiresistant Gram
Negative Organism (MRGNO)
OR
Recurrent urinary or biliary tract infections (>3 in last year)
Sepsis despite current or recent (within the last week) treatment with broad-
spectrum antibiotics e.g. co-amoxiclav, cefuroxime or quinolones
(ciprofloxacin, levofloxacin)

To enable effective management of these patients, it is therefore important that

appropriate specimens (including blood cultures) are taken and their previous
microbiology reviewed.

MRSA and Serious Infection

At present in Nottingham about 4% of Staphylococcus aureus bacteraemias and
septicaemias in adult patients are due to meticillin resistant S. aureus i.e. MRSA;
which will not be sensitive to the agents frequently used for S. aureus sepsis, e.g.
flucloxacillin and cefuroxime.

MRSA infection is more likely in current inpatients, but patients admitted from the
community are at risk of MRSA infection if they have any of the risk factors listed
below:

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 Multiple recent hospital admissions in the last 6 months or as an
outpatient with an indwelling line
Previous MRSA infection or colonisation
Resident of a nursing or residential home with breaks in their skin e.g. leg
ulcers

Initial antibiotic treatment of sepsis of unknown aetiology or severe

staphylococcal infections should therefore be altered to cover the possibility of
MRSA in a patient who has any of these risk factors for MRSA infection. Further
therapy should be adjusted in light of the microbiological culture and sensitivity
results.

3. Sepsis of Unknown Origin

If a diagnosis of sepsis has been made (see general guidance), then

perform the following actions:

1. Clinical assessment

Carefully review the patient for a source of infection. Specifically review:

Body Site Features of Infection
Abdomen Pain, tenderness, distension
Enquire about bowel habit especially diarrhoea
Deranged LFTs / jaundice
Bones and joints, including Pain, swelling, erythema
spine
Cardiovascular New murmurs
Peripheral stigmata of infective endocarditis e.g.
splinter haemorrhages
Central nervous system Headache, drowsiness, confusion, neck stiffness,
focal neurological deficits
Chest Cough, shortness of breath, hypoxia
Line sites Systematic review for any indwelling lines
Check for erythema, pus and redness around line site
Skin Cellulitis, leg ulcers, pressure sores
Urinary tract Dysuria, frequency

2. Septic screen

- Take 2 sets of peripheral blood cultures

More than one set of cultures is essential in order to exclude
contamination of a single set
- In addition, take blood cultures from any intravascular devices
- Other microbiological specimens if indicated e.g. joint aspirates, wound
swabs, LP
- Perform other investigations as appropriate e.g. CXR

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3. Review past microbiology results

- Check alerts on Notis and previous relevant culture / sensitivity results.

4. Select antimicrobials

- If no source of infection is evident, refer to the treatment algorithm on

page 7.
- If a source is identified, refer to the specific guidance for antimicrobial
therapy for that body site.

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 Guideline for Empirical Treatment of Suspected Sepsis of Unknown Origin

In the absence of a clear source of infection, are there features

suggesting High-risk RED SEPSIS or septic shock (see page 3)?

YES NO

Has patient had?
Previous isolation of ESBL positive E. coli or MRGNO (see p4)
OR
Recurrent urinary or biliary tract infections (>3 last year)
Sepsis despite current or recent (within the last week) treatment with
broad-spectrum antibiotics e.g. co-amoxiclav, cefuroxime or
quinolones e.g. ciprofloxacin
Take blood cultures and cultures from other relevant sites .
If urgent IV therapy is still
Evaluate whether urgent antibiotic therapy is indicated based
clinically indicated
on overall clinical assessment and parameters indicative of sepsis.
If isolated pyrexia, consider withholding empirical antibiotics
pending further investigations / microbiology results.
Regularly reassess the patient.

YES NO

Take blood cultures and cultures from other relevant sites . Take blood cultures and cultures from other relevant sites .

st
1 line: Start Meropenem IV 500mg QDS* (review
antibiotics with microbiology within 48 hours) (Not to be
used in severe penicillin allergy, e.g. urticarial rash within
the first 72 hours, anaphylaxis or angioedema)
If severe penicillin allergy: Discuss with a medical
microbiologist / on-call infectious disease consultant.
*PLUS if High Risk RED SEPSIS or the blood pressure
fails to respond to initial fluid bolus: Gentamicin IV 5 mg/kg
(if normal renal function) as a single dose (max 500mg).
[See antibiotic website for dosing advice in renal impairment
and monitoring levels]
st
1 line: Start Piperacillin / tazobactam IV 4.5g TDS*.
If mild penicillin allergy: Cefuroxime IV 1.5g TDS (Not to be used in severe penicillin allergy,
e.g. urticarial rash within the first 72 hours, anaphylaxis or angioedema) plus Metronidazole IV
500mg TDS*.
If severe penicillin allergy: Vancomycin IV (see antibiotic website for dosing calculator) plus
st
Ciprofloxacin IV 400mg BD plus Metronidazole IV 500mg TDS*. Give the 1 doses of each
antibiotic, then discuss with a medical microbiologist/on-call infectious disease consultant prior
subsequent doses
*PLUS if High Risk RED SEPSIS or the blood pressure fails to respond to initial fluid
bolus: Gentamicin IV 5 mg/kg (if normal renal function) as a single dose (max 500mg).
[See antibiotic website for dosing advice in renal impairment and monitoring levels]

Two sets of blood cultures should be sent even if patient is apyrexial. Each set (two bottles) should be taken from separate venepuncture sites. NUH now uses
plastic blood culture bottles for all patients which CAN be sent via the airtube system. It is essential that cultures are sent as soon as they are taken as they can be
processed 24h a day. Delays in receiving samples can reduce the time to positivity. Samples are essential to enable the focusing/rationalisation of antibiotics.

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4. Guidance on Initial Antibiotic Therapy by Body Site
All doses that are recommended in this guide are for those with normal
renal function please check doses if renal impairment on the antibiotic
website: http://nuhnet/diagnostics_clinical_support/antibiotics

4.1 ABDOMINAL INFECTION

(See note regarding multi-resistant Gram negative organisms (MRGNO) on page
4)
E.g. perforation of abdominal / gynaecological viscus which is usually
polymicrobial:

First line Cefuroxime IV 1.5g TDS

+ Metronidazole IV 500mg TDS +
SINGLE dose of Gentamicin IV 5 mg/kg
(if normal renal function) as a single dose
(max 500mg).
Mild Penicillin Allergy (Not to be Cefuroxime IV 1.5g TDS
used in serious penicillin allergy, e.g. + Metronidazole IV 500mg TDS +
urticarial rash within the first 72 hours, SINGLE dose of Gentamicin IV 5 mg/kg
anaphylaxis or angioedema) (if normal renal function) as a single dose
(max 500mg).
Severe Penicillin Allergy (urticarial Ciprofloxacin PO 500mg BD (or if
rash within the first 72 hours, vomiting IV 400mg BD or if High Risk RED
anaphylaxis or angioedema) or SEPSIS give 1st dose as IV 400mg then
Cephalosporin Allergy convert to oral)
+ Metronidazole IV 500mg TDS +
SINGLE dose of Gentamicin IV 5 mg/kg
(if normal renal function) as a single dose
(max 500mg).
Further therapy
Review need for IV antibiotics at 48 hours with microbiology results
see IV-PO switch guideline on antibiotics website
If there are no culture results, convert Cefuroxime and Metronidazole
to Co-amoxiclav PO 625mg TDS or if penicillin allergic convert to
Ciprofloxacin PO 500mg BD plus Metronidazole PO 400mg TDS.
Total duration of IV+PO therapy 5-7 days

Or if risk of MRGNO (see page 4):

Meropenem IV 500mg QDS (review antibiotics with microbiology within

48 hours)
Not to be used in severe penicillin allergy, e.g. urticarial rash within the first 72
hours, anaphylaxis or angioedema; contact Microbiology for further advice.

If the patient has High Risk RED SEPSIS or septic shock: ADD Gentamicin
IV 5 mg/kg (if normal renal function) as a single dose (max 500mg). For advice
on dosing in renal impairment and for monitoring levels refer to the NUH Trust
antibiotic website.
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4.1.1 BILIARY INFECTION

First line Amoxicillin IV 1g TDS

+ Ciprofloxacin PO 500mg BD (or if
vomiting IV 400mg BD or if High Risk RED
SEPSIS give 1st dose as IV 400mg then
convert to oral)

Mild and Severe Penicillin Allergy Ciprofloxacin PO 500mg BD (or if

(urticarial rash within the first 72 hours,
anaphylaxis or angioedema)
vomiting IV 400mg BD or if High Risk RED
SEPSIS give 1st dose as IV 400mg then
convert to oral)
+ Vancomycin IV refer to antibiotic
website for dosing, or use vancomycin
dosing calculator available on the website.

If the patient has High Risk RED SEPSIS or septic shock:

ADD Gentamicin IV 5 mg/kg (if normal renal function) as a single dose (max
500mg). For advice on dosing in renal impairment and for monitoring levels refer
to the NUH Trust antibiotic website.

Or if risk of MRGNO (see page 4):

Meropenem IV 500mg QDS (review antibiotics with microbiology within

48 hours)
Not to be used in severe penicillin allergy, e.g. urticarial rash within the first 72
hours, anaphylaxis or angioedema; contact Microbiology for further advice.

Further therapy
Review need for IV antibiotics at 48 hours with microbiology results
see IV-PO switch guideline on antibiotics website
If there are no culture results, convert Amoxicillin and Ciprofloxacin to
Amoxicillin PO 500mg-1g TDS plus Ciprofloxacin PO 500mg BD
If penicillin allergic convert to Ciprofloxacin PO 500mg BD
Total duration of IV+PO therapy 5-7 days

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4.2 BONE AND JOINT INFECTION
Joint aspiration and or deep bone specimens for Gram stain and culture (prior to
treatment if possible) are mandatory to establish the diagnosis and further
management. If unable to obtain a specimen contact the on-call rheumatologist
or orthopaedic surgeon.

Please see separate guidelines for the management of prosthetic joint infections.

Table 1: Empirical treatment in an under 75 year old patient / NO risk

factors for MRGNO (also refer to other tables below).

Flucloxacillin IV 2g QDS
First line (covers both meticillin sensitive S. aureus and
streptococcal infections).
Clindamycin IV 600mg QDS

OR
Penicillin allergy
Cefuroxime IV 1.5g TDS
(Not to be used in serious penicillin allergy, e.g. urticarial
rash within the first 72 hours, anaphylaxis or angioedema
or cephalosporin allergy)

Table 2: Empirical treatment in an over 75 year old patient / risk factors for
MRGNO (also refer to other table below).
First line in patients:
> 75 years old and/ or,
Immunocompromised Meropenem IV 500mg QDS (review antibiotics
and/or, with microbiology within 48 hours)
Suspected / proven gram
negative infection. Not to be used in serious penicillin allergy, e.g.
If risk of MRGNO (see page 4) urticarial rash within the first 72 hours,
OR anaphylaxis or angioedema
in patients > 75 years old and
have mild penicillin allergy
In patients > 75 years old OR at
risk of MRGNO with severe Discuss with medical microbiology.
penicillin allergy.

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Table 3: Other options:
Vancomycin IV - refer to antibiotic website for
If MRSA infection is a
dosing, or use vancomycin dosing calculator
possibility (see page 4/5) and
available on the website.
patient < 75 years old
Add Vancomycin IV to the treatment
regimens in Table 2
If MRSA infection is a
- refer to antibiotic website for dosing, or use
possibility (see page 4/5) and
vancomycin dosing calculator available on the
patient > 75 years old
website.

Ceftriaxone IV 1g OD
Not to be used in serious penicillin allergy, e.g.
If suspected / proven urticarial rash within the first 72 hours,
gonococcal infection anaphylaxis or angioedema
Discuss with medical microbiology if serious
penicillin allergy.

Further therapy
Further therapy should be discussed with a medical microbiologist as antibiotic
choice will need to be modified following the results of the Gram stain and
culture. Staphylococcal bone and joint infections are commonly treated with more
than one agent. If infection is confirmed the treatment is usually given for a total
of 4-6 weeks of which at least 2 weeks is given IV.

4.3 CELLULITIS
Therapy is usually directed at Streptococcus pyogenes (group A -haemolytic
streptococcus) and Staphylococcus aureus

When there are no signs of systemic upset, sepsis, or rapidly progressing

cellulitis (not if known / likely MRSA infection - see page 4):

First Line Flucloxacillin PO 500mg-1g QDS

Penicillin Allergy Clarithromycin PO 500mg BD

When more severe or failed adequate doses of oral flucloxacillin

Community acquired:
Flucloxacillin IV 2g QDS (covers both methicillin
1st Line
sensitive S. aureus and streptococcal infections).
Clindamycin PO 450-600mg QDS or IV 600mg QDS
Penicillin Allergy if vomiting / High Risk RED SEPSIS (change to oral
when medically stable)

Notes:
Review need for IV antibiotics at 48 hours with microbiology results.
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 See IV-PO switch guideline on antibiotics website.
Usual total length of treatment (PO+IV) = 5-7 days.

Hospital acquired or where MRSA is a possibility (see page 4/5):

Vancomycin IV - refer to antibiotic website for dosing,
First Line or use vancomycin dosing calculator available on the
website.

If rapidly progressive cellulitis with shock, please discuss with a medical

microbiologist as the possibility of deeper infection, particularly necrotising
fasciitis should be considered, which is a medical and surgical emergency and
modification of the antibiotic therapy may be required.

Unresponsive infection may be due to another diagnosis e.g. varicose eczema,

where a dermatology opinion may be appropriate.

4.4 INFECTIVE ENDOCARDITIS

In patients with a chronic or subacute presentation, it is essential to collect three

sets of blood cultures, from separate sites (20ml per set) before treatment.

In patients with High Risk RED SEPSIS or septic shock, two sets of blood
cultures prior to antibiotic therapy are adequate in order to allow empirical
treatment to be commenced without undue delay.

NOTE: All therapy and investigation of cases of endocarditis or possible

endocarditis should be discussed with Microbiology / Infectious Diseases.
Therapy is determined by positive microbiology results.
In culture-negative endocarditis, therapy is directed to the likely causative
organisms as advised by microbiology but it is important to note that most
cases of culture-negative endocarditis are due to antibiotics being
commenced before blood cultures are taken.

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4.5 LINE INFECTIONS

PERIPHERAL CANNULA (VENFLON) SITE

Usually due to S. aureus, 10% of which are resistant to flucloxacillin i.e. MRSA.

Treatment:
Remove the cannula.
Take blood cultures and swab any pus.

If pus at site of an old venflon site, or mild erythema, but no signs of sepsis:

Doxycycline PO 100mg BD on day 1

First Line then 100mg OD for 6 days
(this is active against most MRSA and MSSA)

Any signs of severe infection, or spreading cellulitis:

Vancomycin IV - refer to antibiotic website for

First Line
If MSSA is isolated and
patient is not penicillin
allergic change to:
dosing, or use vancomycin dosing calculator
available on the website.
Flucloxacillin IV 2g QDS

Monitor line site closely to check response to treatment.

Review need for IV antibiotics at 48 hours with microbiology results see IV-
PO switch guideline on antibiotics website.
If meets criteria for oral switch and negative blood cultures Flucloxacillin PO
500mg-1g QDS or if penicillin allergic discuss oral option with microbiology.
Total duration of IV+PO therapy 7 days, 14 days if positive blood cultures

CENTRAL LINES (for haemodialysis, TPN and haematology lines see separate
specialty guidance)

Exit site infection (without sepsis)

If pain around exit site, purulent discharge or erythema / induration around
exit site, take blood cultures through the line and peripherally and swab
any pus.

For temporary central lines

Remove line.
Take blood cultures and swab any pus.

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First Line
If MSSA is isolated and
patient is not penicillin
allergic change to:
Vancomycin IV - refer to antibiotic website for
dosing, or use vancomycin dosing calculator
available on the website.
Review need for Vancomycin at 48 hours with
clinical response and blood culture results.
Flucloxacillin IV 2g QDS

Note:
Line-associated bacteraemia due to S. aureus should be treated with a
minimum of 14 days antibiotic therapy after line removal.

Central-line associated bacteraemia due to Coagulase negative staphylococci

may respond to antibiotics without line removal, but relapse is common.

Tunnelled line exit site infection

Assess tunnelled track for erythema, tenderness or induration and if present see
guideline below on tunnel-track infections.

Doxycycline PO 100mg BD on day 1

First Line
then 100mg OD for 14 days total
If known MSSA and
patient is not penicillin Flucloxacillin PO 500mg-1g QDS
allergic change to:

Tunnelled line track infections (Hickman lines and other tunnelled lines)
Remove line if possible.
Take blood cultures and swab any pus.
Vancomycin IV - refer to antibiotic website for dosing,
First Line or use vancomycin dosing calculator available on the
website.
If MSSA is isolated and
patient is not penicillin Flucloxacillin IV 2g QDS
allergic change to:
Review antibiotics with culture results
If difficult infection, discuss with microbiology regarding the addition of a
second agent.
Note:
Line-associated bacteraemia due to S. aureus should be treated with a
minimum of 14 days antibiotic therapy after line removal.

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For Central Line-associated Sepsis
Remove line if possible.
Vancomycin IV - refer to antibiotic website for
dosing, or use vancomycin dosing calculator
available on the website.

If the patient has High Risk RED SEPSIS or

First Line septic shock:
ADD Gentamicin IV 5 mg/kg (if normal renal
function) as a single dose (max 500mg). For advice
on dosing in renal impairment and for monitoring
levels refer to the Trust antibiotic website.

If MSSA is isolated and

patient is not penicillin Flucloxacillin IV 2g QDS
allergic change to:

Review antibiotic choice with culture results.

3.6 MENINGITIS - see separate guidelines.

3.7 PNEUMONIA - see separate guidelines.

3.8 UPPER URINARY TRACT INFECTIONS: Pyelonephritis and Systemic

infection of Urinary Tract origin - see separate guidelines

Nottingham Antimicrobial Guidelines Committee Produced: June 2015 (updated June 2017)
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