Guidelines for the Empirical Treatment of Sepsis in Adults (excluding Neutropenic Sepsis) Full Title of Guideline: Author (include email and role): Division & Speciality: Scope (Target audience, state if Trust wide): Review date (when this version goes out of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Changes from previous version (not applicable if this is a new guideline, enter below if extensive): Guidelines for the Empirical Treatment of Sepsis in Adults (excluding Neutropenic Sepsis) Dr Vivienne Weston (Consultant Microbiologist) (Vivienne.weston@nuh.nhs.uk) Tim Hills (Lead Pharmacist Antimicrobials and Infection Control) In consultation with members of NUH sepsis action group and antibiotic guidelines committee All adult clinical specialities Doctors, pharmacists, microbiology, nurses June 2021 All adult directorates except obstetrics, and neutropenic haematology & oncology patients. Change wording to clarify addition of gentamicin if septic shock or BP not responding to fluid bolus Addition of risk factors for Gram negative infection, and change from clarithromycin to doxycycline non severe infection in penicillin allergy cellulitis section Addition of a review of treatment section Summary of evidence base this Guidance reviewed with local 2017 Microbiological surveillance data. guideline has been created from: 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 I. General guidance 3-4 Page II. Current trends in antibiotic resistance 4-5 III. 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. -2
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> 3 or /NEWS >5, 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 resuscitation 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 broadspectrum 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, unless this will lead to an unnecessary delay. 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. -3
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 9% resistance to gentamicin and 9% resistance to 3 rd generation cephalosporins (usually Extended Spectrum Beta-Lactamase ESBL positive), 18% resistance to ciprofloxacin and 34% 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 multi- resistant Gram negative sepsis: Previous history of isolation of 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 broadspectrum 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 3% 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: Multiple recent hospital admissions in the last 6 months or as an outpatient with an indwelling line -4
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: I. 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 II. 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 and increase yield of causative organism(s) - 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 III. Review past microbiology results - Check alerts on Notis and previous relevant culture / sensitivity results -5
IV. 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. Document suspected source if identified and certainty of diagnosis V. Review of response to treatment If patient is in septic shock, or fails to improve from treatment within 1 hour of receiving IV antibiotics and IV fluid bolus or deteriorates further alert a Consultant to attend in person and contact CCOT +/- Critical Care Reassess the effectiveness of your interventions i.e. is the source controlled? Involve appropriate surgical team early e.g. general surgical or gynaecology teams, if intra-abdominal/pelvic infection is suspected VI. Further review and rationalisation of antibiotic treatment -6
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 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, piperacillin/tazobactam or quinolones e.g. ciprofloxacin YES If urgent IV therapy is still clinically indicated Take blood cultures and cultures from other relevant sites. Evaluate whether urgent antibiotic therapy is indicated based 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. NO Take blood cultures and cultures from other relevant sites. 1 st 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 doctor *PLUS if septic shock, blood pressure fails to respond to initial fluid bolus, or known MRSA carriage: 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] Take blood cultures and cultures from other relevant sites. 1 st 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 Ciprofloxacin IV 400mg BD plus Metronidazole IV 500mg TDS*. Give the 1 st doses of each antibiotic, then discuss with a medical microbiologist/on-call infectious disease consultant prior subsequent doses *PLUS if hospital acquired infection, in septic shock, blood pressure fails to respond to initial fluid bolus or known MRSA carriage: 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. -7
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 or Mild Penicillin Allergy (Not to be used in serious penicillin allergy, e.g. urticarial rash within the first 72 hours, anaphylaxis or angioedema) Severe Penicillin Allergy (urticarial rash within the first 72 hours, anaphylaxis or angioedema) or Cephalosporin Allergy Cefuroxime IV 1.5g TDS + Metronidazole IV 500mg TDS Ciprofloxacin PO 500mg BD (or if vomiting IV 400mg BD or if septic shock give 1st dose as IV 400mg then convert to oral) + Metronidazole IV 500mg TDS If the patient has 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 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 -8
4.1.1 BILIARY INFECTION (e.g. (e.g. cholangitis, cholecystitis) First line Mild and Severe Penicillin Allergy (urticarial rash within the first 72 hours, anaphylaxis or angioedema) 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) 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) + 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 -9
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). First line Penicillin allergy Flucloxacillin IV 2g QDS (covers both meticillin sensitive S. aureus and streptococcal infections). Clindamycin IV 600mg QDS OR 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 and/or, Suspected / proven gram negative infection. If risk of MRGNO (see page 4) OR in patients > 75 years old and have mild penicillin allergy In patients > 75 years old OR at risk of MRGNO with severe penicillin allergy. Piperacillin / tazobactam IV 4.5 g TDS Meropenem IV 500mg QDS (review antibiotics with microbiology within 48 hours) Not to be used in serious penicillin allergy, e.g. urticarial rash within the first 72 hours, anaphylaxis or angioedema Discuss with medical microbiology. -10
Table 3: Other options: If MRSA infection is a possibility (see page 4/5) and patient < 75 years old If MRSA infection is a possibility (see page 4/5) and patient > 75 years old If suspected / proven gonococcal infection Vancomycin IV - refer to antibiotic website for dosing, or use vancomycin dosing calculator available on the website. Add Vancomycin IV to the treatment regimens in Table 2 - refer to antibiotic website for dosing, or use vancomycin dosing calculator available on the website. Ceftriaxone IV 1g OD plus Azithromycin PO 1g single dose Not to be used in serious penicillin allergy, e.g. urticarial rash within the first 72 hours, 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 β-haemolytic streptococcus) and Staphylococcus aureus If the patient is severely immunocompromised, has poorly controlled diabetes or the cellulitis is secondary to an animal bite or water-based injury then other pathogens may need to be empirically covered please discuss with a medical microbiologist / infectious disease doctor. When there are no signs of systemic upset, sepsis, or rapidly progressing cellulitis (not if known / likely MRSA infection - see page 4): First Line Penicillin Allergy Flucloxacillin PO 500mg-1g QDS Doxycycline PO 100mg BD on day 1 then 100mg OD When more severe or failed adequate doses of oral flucloxacillin Community acquired: 1 st Line Flucloxacillin IV 2g QDS (covers both methicillin sensitive S. aureus and streptococcal infections). -11
Penicillin Allergy Clindamycin PO 450-600mg QDS or IV 600mg QDS if vomiting / High Risk RED SEPSIS (change to oral when medically stable). Note clindamycin resistance is uncommon but if repeated course of treatment previously or non responsive infection this needs to be considered as well as deep infection( see below) and seek further advice from a medical microbiologist or infectious disease doctor Hospital acquired or where MRSA is a possibility (see page 4/5): First Line Vancomycin IV - refer to antibiotic website for dosing, or use vancomycin dosing calculator available on the website. Notes: Review need for IV antibiotics at 48 hours with microbiology results. See IV-PO switch guideline on antibiotics website. Usual total length of treatment (PO+IV) = 5-7 days. If rapidly progressive cellulitis with shock, please discuss with a medical microbiologist or infectious disease doctor 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. -12
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: First Line Doxycycline PO 100mg BD on day 1 then 100mg OD for 6 days (this is active against most MRSA and MSSA) Any signs of severe infection, or spreading cellulitis: 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. 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. -13
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. First Line If known MSSA and patient is not penicillin allergic change to: Doxycycline PO 100mg BD on day 1 then 100mg OD for 14 days total Flucloxacillin PO 500mg-1g QDS Tunnelled line track infections (Hickman lines and other tunnelled lines) Remove line if possible. Take blood cultures and swab any pus. 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. Flucloxacillin IV 2g QDS 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. -14
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. First Line If MSSA is isolated and patient is not penicillin allergic change to: 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 Trust antibiotic website. Flucloxacillin IV 2g QDS 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 -15