Candidaemia and Invasive Candidiasis in Adult Patients - Guidelines for the Treatment of

Publication: 31/03/2011  --
Last review: 14/05/2019  
Next review: 01/05/2022  
Clinical Guideline
CURRENT 
ID: 2193 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2019  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines for the Treatment of Candidaemia and Invasive Candidiasis in Adult Patients

  • Treatment Algorithm
  • Summary
    Candidaemia and Invasive Candidiasis in Adult Patients

    • This guideline provides advice on the diagnosis and treatment of candidaemia and other causes of invasive candidiasis.
    • Guidelines cannot cover all clinical situations and it may be necessary to deviate from these recommendations, this would normally involve discussion with an infection specialist. Where there is deviation from these recommendations, the reasons should be clearly documented in the patient’s notes.
    • Exclusions: Localised syndromes such as infective endocarditis, meningitis, septic arthritis, osteomyelitis, prosthetic device infections, renal tract candidiasis or retinitis/endophthalmitis caused by Candida spp. and are not covered by this guideline and treatment should be carried out in consultation with the relevant LTHT guidelines or in consultation with a Microbiologist.
    • Please see (long terms and short term CVC guidelines) for management of intravascular catheter-related infections.
    • Many of the principles set out in this guideline will be applicable to paediatric patients but treatment choice in children should be discussed with a Clinical Microbiologist on an individual patient basis.
    • For neonates, please refer to the guidelines for invasive candidiasis in neonates.

    Management of a patient with candidaemia

    • Assess patient for the clinical source of Candida infection.
    • Commence empirical anti-fungal therapy; make sure this choice is still appropriate once culture and susceptibility results are available.
    • Central venous catheter removal should be considered at the time of diagnosis, even if not implicated as the source of candidaemia (removal is strongly recommended but not mandatory).1-2 If possible, aim for a period without an intra-vascular device. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles 22.
    • If candidaemia is associated with other prosthetic material (e.g. VP shunt, urological stent, prosthetic joint), this should be removed if at all possible. Preferably, a period without any prosthetic material should be achieved to reduce the risk of persistent infection.1
    • Repeat blood cultures should be taken after 48 hours, and if necessary repeated until negative.1, 3 Treatment duration is determined by the date of the first negative blood culture.
    • Dilated fundoscopy should be performed in the first week of diagnosis.1,4,5 If retinal deposits or endopthalmitis are detected, expert advice should be sought from an infection specialist.
    • Renal tract imaging should be considered in candidaemic patients with Candida spp. in urine cultures.5 This should also be considered if blood cultures remain positive after a period of treatment. Cases of confirmed renal candidosis should be discussed with an infection specialist.
    • All patients with candidaemia should have a transthoracic echocardiography (TTE) as soon as possible (preferably within 24 hours of diagnosis). If the heart is structurally normal with no evidence of endocarditis, treat as a Candida bloodstream infection (unless an alternative source is identified). If the echocardiogram is positive, equivocal or “at risk” lesions are seen, please refer to the Infectious Endocarditis team for advice on clinical management.

    Candidaemia (yeasts in blood cultures)

    Recovery of yeasts from blood cultures nearly always represents genuine infection and should be acted on quickly. Candidaemia is associated with a high morbidity and mortality, especially if treatment is delayed, and 30 day mortality was found to be 31.4% in a recent quantitative analysis from nine trials.1,2,3 Table 1 summarises the main risk factors for candidaemia. Infections can occur in patients without these risk factors but this is unusual.1

    Candidaemia is nearly always endogenous and not transmitted 4, with the exception of Candida auris which is known to be responsible for several nosocomial outbreaks, particularly in critically ill patients in high dependency settings. 2,3,4 Candida can spread haematogenously from the primary focus to distant sites in the body, most commonly eyes, heart valves and prosthetic devices. 4,5 These manifestations of secondary infection may be present at the time of diagnosis.5 Current evidence advocates early treatment and removal of infected prosthetic material (including central venous catheters) to reduce the duration of candidaemia and reduce mortality.2,3,5,6

    Table 1:

    Risk factors for candidaemia2,3,6,7

    Intra-vascular catheters

    Total parenteral nutrition

    Broad spectrum antibiotic use

    ICU admission

    Surgery (GI tract, heart surgery, solid organ transplantation)

    Immuno-compromise

    Recent growth of Candida from other sites (e.g. sputum, urine)

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    Clinical Diagnosis

    Definitions:

    • Candidaemia
      Blood culture that yields Candida sp.

    • Non-candidaemic invasive candidiasis
      The definition of “invasive candidiasis” for the purposes of this guideline is:8
      i) Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy from a normally sterile site (not mucous membranes) showing yeast cells with or without pseudohyphae or true hyphae. Note yeast cells may represent Candida sp. or other pathogenic yeast genera such as Cryptococcus.
      OR
      ii) Recovery of Candida spp. by culture of a sample obtained by a sterile procedure (including a freshly placed [≤24 h ago] drain) from a normally sterile site showing a clinical or radiological abnormality consistent with an infectious disease process

      Where Candida spp. is cultured from a line tip that has been removed, the patient should be assessed for signs of on-going infection to determine if this is likely to be due to contamination of the tip at the time of removal or evidence of catheter related infection. If signs of infection are present, a set of blood cultures should be taken and the patient should be treated according to this guideline. If there is no evidence of infection, the patient should be monitored carefully for signs of infection. See long term and short term CVC guidelines.

      In some patients invasive candidiasis is considered likely, but the criteria above are not met, usually through failure to grow Candida from a relevant clinical site (e.g. septic patients at high risk from candidiasis by virtue of recurrent surgery, upper gastrointestinal perforation, intensive care unit admission, broad spectrum antibiotic use). In these cases, the use (or otherwise) of antifungal therapy should be discussed with a Microbiologist on a case-by-case basis.

    Sources of candidaemia

    • Recovery of Candida spp. from blood cultures is considered definitive evidence of invasive disease, even in the absence of a clinically apparent source.1,3,5
    • Central venous catheters are the most common focus of infection in hospital patients. Other foci are included in table 2.1,3,5,6
    • Chronic disseminated candidiasis is occasionally seen following candidaemia, mostly following neutropenic episodes. This can occur even if appropriate anti-fungal treatment has been given.1

    Table 2:

    Sources of candidaemia

    COMMON

    Central venous catheters

    Intra-abdominal collections esp. following upper GI perforation/surgery

    Indwelling prosthetic material e.g. ureteric stents, peritoneal dialysis catheters

    UNCOMMON

    Prosthetic heart valves

    Other intra-vascular devices e.g. Pacing leads, pacemakers

    Complex urinary tract infection

    Bone/joint infection with or without prosthetic material

    Examination

    A thorough clinical examination is required for candidaemic patients to identify the probable source of infection. This should include examination of the abdomen, surgical sites, auscultation of the heart, dilated fundoscopy and evaluation of indwelling prosthetic material such as lines, stents or heart valves.

    Recommendation: All patients who are candidaemic should be referred to ophthalmology for a dilated fundoscopic examination , to look for evidence of candida retinitis/endophthalmitis within one week of diagnosis [Evidence level C]

    Microbiological diagnosis and susceptibility testing

    • Invasive candidiasis may be caused by a number of Candida species, the commonest of which is C. albicans. Other species include C. glabrata, C. tropicalis, C. parapsilosis, C. krusei and C. guillermondii.9
    • Gram stain morphology is not helpful in differentiating Candida species, further analysis must be performed which may take 24 hours or more.
    • In LTHT all Candida spp. that are considered to be causing invasive infection, including candidaemia, are subjected to identification and susceptibility testing.
    • Yeasts grow more slowly than bacteria so laboratory identification and susceptibility testing may take longer. However, susceptibility to Fluconazole can often be predicted by the identification of Candida spp. The exceptions include C. glabrata which can be susceptible dose-dependent (SDD) requiring a higher dose of fluconazole or resistant Candida auris which usually has reduced susceptibility to fluconazole and variable susceptibility to other antifungal agents and C. krusei which is inherently resistant to fluconazole. Therefore, susceptibility testing is required before definitive anti-fungal therapy can be chosen.
    • When yeast is detected in blood cultures, a number of rare organisms other than Candida spp. may be identified. These include infections such as Cryptococcus, Histoplasma and Trichosporon, amongst others. If there are no clinical or epidemiological features suggesting these diagnoses, yeast in the blood culture should be treated as candidaemia. If the patient has a clinical picture suggestive of a non-Candida yeast infection, please discuss with an infection specialist.
    • All Candida spp. are considered to be susceptible to amphotericin B (AmB).10 However, this agent is not recommended for treatment of C. lusitaniae, which develops AmB resistance more readily than other species.11
    • Testing for echinocandin susceptibility should be considered in patients who have had prior treatment with an echinocandin and among those who have infection with C. glabrata or C. parapsilosis (strong recommendation; low-quality evidence) [Evidence Level C].1

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    Investigation

    Direct detection

    Recommendation: Microscopy should be requested on aspirates and biopsy material from potentially-infected sites.
    [Evidence level C]

    Beta D Glucan

    D-glucan is available at LTHT and may be useful to exclude invasive candidiasis in patients who are culture negative. Several meta-analyses have been undertaken using data from cross-sectional, cohort and case–control studies on the diagnosis of candidaemia. The sensitivity of B-D-glucan detection was >65% in most studies with a cut-off value of 80 pg/mL, with specificity rates >80% and negative predictive values >85%.5 The use of albumin, gauzes, immunoglobulins, haemodialysis ? and GI translocation has been associated with false positive beta-D glucan results and this test has not been validated in children aged <6 months. Note BDG testing is only carried out on patients currently on antifungal therapy or after discussion with a consultant microbiologist or a mycologist.

    Candida PCR

    Candida DNA (PCR) detection testing is not undertaken at LTHT.

    Culture

    Recommendation: Samples from potentially-infected sites, including blood, aspirates and biopsy material should be cultured for Candida spp.
    [Evidence level C]

    Blood cultures should be taken, both from intra-vascular lines and peripherally, if candidaemia is suspected.

    If a patient has candidaemia, repeat blood cultures after 48 hours are required. These are used to confirm resolution of the candidaemia and are helpful when deciding the duration of therapy.

    The isolation of Candida spp. from respiratory secretions (including broncho-alveolar lavage fluid) is not considered to be a marker of infection as it usually represents oropharyngeal colonisation.

    Immunological tests

    Recommendation: The detection of Candida antibodies is not considered to be useful in the diagnosis of invasive candidiasis.
    [Evidence level C]

    European guidelines have recommended the use of a combination of Candida mannan and anti-mannan IgG (“mannan/anti mannan”) to assist in the diagnosis of candidaemia and chronic disseminated candidiasis 12 and possible invasive candidiasis.15 However, in a large German study published after both sets of guidelines, although the combined test had a sensitivity of 89.3% the specificity was unacceptably low, at 65.5%.16 If the test is used it has to be used on a prospective basis (i.e. by monitoring a predisposed population), which is very expensive, and the characteristics of the population who should be monitored have not yet been established. For these reasons the mannan/anti-mannan test is not used at LTHT.

    Please complete Candidaemia checklist, see below

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    Treatment
    Non-Antimicrobial Treatment

    Recommendation: In candidaemic patients, central venous catheters present at the time of blood culture should be removed,2 unless there is an absolute contraindication to do so. This applies whether or not there is evidence that the catheter is the source of infection.
    [Evidence Level B]

    Recommendation: If it is not possible to remove an indwelling central venous catheter from a patient with candidaemia the patient should be treated with an echinocandin or Ambisome Description: electronic Medicines Compendium information on Ambisome but not with an azole.
    [Evidence Level C]

    Recommendation: Where candidiasis is associated with other prosthetic material (e.g. ureteric stent, biliary stent, V-P shunt) removal of the prosthetic material is a mandatory component of treatment unless there is an absolute contra-indication.
    [Evidence Level C]

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    Empirical Antimicrobial Treatment

    Empirical therapy for candidaemia and patients with proven invasive candidiasis from other sources.

    First line therapy for candidaemia and invasive candidosis is Anidulafungin Description: electronic Medicines Compendium information on Anidulafungin (see table below for dosage) in both neutropenic and non-neutropenic patients.*17 Alternative empiric agents

    If the empirical treatment recommendations are contra-indicated or not tolerated, specialist advice should be sought. Other agents available to treat candidaemia include Fluconazole Description: electronic Medicines Compendium information on Fluconazole, lipid-formulated amphotericin B and Voriconazole Description: electronic Medicines Compendium information on Voriconazole. On rare occasions, flucytosine may be used as adjunctive therapy.

    Most Candida spp. are susceptible to amphotericin B (AmB), which is administered exclusively in a lipid formulation (e.g. Ambisome Description: electronic Medicines Compendium information on Ambisome). This agent is not usually used as first line treatment due to its relatively poor toxicity profile compared to the echinocandins and azoles.1,4 Exceptions to this are infections of the central nervous system, for which Ambisome Description: electronic Medicines Compendium information on Ambisome is the preferred treatment.1,5 Voriconazole Description: electronic Medicines Compendium information on Voriconazole may be used as oral step-down for fluconazole resistant Candida sp. but only if the isolate is susceptible and after discussion with an infection specialist. Therapeutic drug monitoring is required for patients taking Voriconazole Description: electronic Medicines Compendium information on Voriconazole consult mycology for advice on results.

    Antifungal dosages

    Anidulafungin Description: electronic Medicines Compendium information on Anidulafungin

    200mg loading dose then 100mg 24-hourly IV

    Liposomal Amphotericin B (Ambisome Description: electronic Medicines Compendium information on Ambisome ®)

    3-5 mg/kg/day IV depending on response.

    Fluconazole Description: electronic Medicines Compendium information on Fluconazole

    400mg 24-hourly*†
    OR
    800 mg 24-hourly*†
    If creatinine clearance is < 50 mL/minute:
    400mg stat dose then 200mg 24-hourly*
    OR
    800 mg stat dose then 400mg 24-hourly*
    In patients receiving CVVHD the dose should be increased 19-20

    Voriconazole Description: electronic Medicines Compendium information on Voriconazole

    ‡ 6 mg/kg 12-hourly IV for the first 24 hours, 4 mg/kg
    12-hourly thereafter (3mg/kg if patient is unable to tolerate the standard dose) OR 200 mg 12-hourly PO

    * Dose is dependent on Candida isolate and advice from Microbiology
    Fluconazole Description: electronic Medicines Compendium information on Fluconazole should be given orally unless gastrointestinal absorption is considered to be compromised.
    ‡Dose adjustment is required in hepatic impairment

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    Directed Antimicrobial Treatment (when microbiology results are known)

    Candida albicans
    Recommendation: Fluconazole Description: electronic Medicines Compendium information on Fluconazole is first line therapy.

    Candida glabrata
    Recommendation: Higher-dose Fluconazole Description: electronic Medicines Compendium information on Fluconazole 800 mg (12 mg/kg) daily if C. glabrata is susceptible dose-dependent (SDD).
    Recommendation: Anidulafungin Description: electronic Medicines Compendium information on Anidulafungin if C. glabrata is fluconazole resistant.
    [Evidence Level C]

    Candida parapsilosis
    Recommendation: Fluconazole Description: electronic Medicines Compendium information on Fluconazole is first line therapy.
    [Evidence level C]

    Candida krusei or other fluconazole-resistant Candida spp.
    Recommendation: Anidulafungin Description: electronic Medicines Compendium information on Anidulafungin is first line therapy.
    [Evidence level C]
    Other Candida species – Discuss with Microbiology

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    Duration of Treatment

    Recommendation: Assuming complete clinical and microbiological resolution of invasive candidiasis in the absence of candidaemia, antifungal therapy should be continued for 14 days.1
    [Evidence Level C]

    Recommendation: In candidaemia, treatment should be continued for 14 days from the date of the first negative blood cultures.1
    [Evidence Level C]

    Recommendation: Where candidiasis arises from a removable source (e.g. vascular catheter, ureteric stent) treatment should be continued for 14 days after removal of the source.
    [Evidence Level C]

    Recommendation: If recovery is delayed or there is evidence of refractory disease, antifungal therapy and its duration should be discussed with a Microbiologist.
    [Evidence Level D]

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    Switch to oral agent(s)

    In general, if the patient has a good clinical response to echinocandins (symptomatic improvement, apyrexial, improved CRP and WCC) and mycological recovery (repeat blood cultures negative), and the Candida sp. is identified as being fluconazole-susceptible or dose-dependent, treatment may be switched to oral fluconazole. This should be after at least 5 days iv anidulafungin treatment.22 Oral fluconazole should be used only if gastrointestinal absorption is adequate.

    Recommendation: Oral fluconazole should be used as oral switch therapy for fluconazole-susceptible or SDD Candida isolates.
    [Evidence Level C]

    Recommendation: Oral Voriconazole Description: electronic Medicines Compendium information on Voriconazole may be suitable oral switch therapy for other isolates, but susceptibility should always be confirmed before stepping down to this agent.
    [Evidence Level C]

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    Treatment Algorithm

    Candidaemia CHECKLIST

    Patient assessed for clinical source of Candida infection.

     

    Empirical anti-fungal therapy commenced

     

    Patient switched to an appropriate antifungal when microbiological results are known (IV to oral switch)

     

    Central venous catheter/prosthetic device removal

     

    Repeat blood cultures every 48 hours until negative

     

    Dilated fundoscopy within 1 week of positive blood culture

     

    TTE within 24 hours of positive blood culture

     

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    Treatment Failure

    Recommendation: If recovery is delayed or there is evidence of refractory disease, antifungal therapy and its duration should be discussed with a Microbiologist.
    [Evidence Level D]

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    Provenance

    Record: 2193
    Objective:
    • To optimise the diagnosis and treatment of invasive candidiasis in adult patients in LTHT.
    • To provide evidence-based recommendations for the appropriate investigation of possible invasive candidiasis.
    • To provide evidence-based recommendations for appropriate empirical and targeted antifungal therapy for invasive candidiasis
    • To recommend appropriate dose, route of administration and duration of antifungal agents in invasive candidiasis.
    Clinical condition:

    Candidaemia and invasive candidiasis

    Target patient group: Adult patients with candidaemia and/or invasive candidiasis
    Target professional group(s): Secondary Care Doctors
    Pharmacists
    Adapted from:

    Evidence base

    Reference List

    1. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50.

    2. Andes D R, Safdar N, Baddley JW et al. Impact of treatment strategy on outcomes in patients with candidaemia and other forms of invasive candidiasis: a patient-level quantitative review of randomised trials. Clin infect dis 2012;5(8)1110-22

    3. Schelenz S. Management of candidiasis in the intensive care unit. J Antimicrob Chemoth 2008 61 (Suppl.) i31-i34

    4. Mandell, Gerald L., ed. "Mandell, Douglas, and Bennett's principles and practice of infectious diseases." (2005).

    5. Cornely OA et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbial Infect 2012 18 (Suppl 7):19-37

    6. Kibbler C C, Seaton S, Barnes R A. Management and outcome of bloodstream infections due to Candida species in England and Wales. J Hosp Infect 2003;54:18-24

    7. Puzniak L, Teutsch S, Powderly W, Polish L. Has the epidemiology of nosocomial candidemia changed? Infect Control Hosp Epidemiol. 2004;25(8):628.

    8. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al.Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Groupand the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46(12):1813-1821.

    9. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect 2002; 50(4):243-260.

    10. Rex JH, Pfaller MA. Has antifungal susceptibility testing come of age? Clin Infect Dis 2002; 35(8):982-989.

    11. Michael A. Pfaller MA, Messer SA and Hollis RJ. Strain Delineation and Antifungal Susceptibilities of Epidemiologically Related and Unrelated Isolates of Candida lusitaniae. Diagn Microbiol Infect Dis 1994; 20:127-33.

    12. Cuenca-Estrella M et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures. Clin Microbial Infect 2012 18 (Suppl 7):9-18.

    13. Rello J, Esandi ME, Diaz E, Mariscal D, Gallego M, Valles J. The role of Candida sp isolated from bronchoscopic samples in nonneutropenic patients. Chest 1998; 114(1):146-149.

    14. Azoulay E, Cohen Y, Zahar JR, Garrouste-Org, Adrie C, Moine P et al. Practices in non-neutropenic ICU patients with Candida-positive airway specimens. Intensive Care Med 2004; 30(7):1384-1389.

    15. Mikulska M et al. The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Critical Care 2010; 14:R222

    16. Comparison of (1→3)-β-d-Glucan, Mannan/Anti-Mannan Antibodies, and Cand-Tec Candida Antigen as Serum Biomarkers for Candidemia. Held J et al. J Clin Microbiol 2013; 51(4): 1158–1164.

    17. Herbrecht R, Conte U, Biswas P. Efficacy and safety of anidulafungin in the treatment of invasive candidiasis in neutropenic patients: analysis of pooled data from five prospective studies. EHA Congress, Mila, Italy, 12-15 June 2014.

    18. Kett, Daniel H., et al. "Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis:

    support for the 2009 IDSA treatment guidelines for candidiasis." Crit care 15.5 (2011): R253.

    19. Yagasaki K, Gando S, Matsuda N, Kameue T, Ishitani T, Hirano T et al. Pharmacokinetics and the most suitable dosing regimen of fluconazole in critically ill patients receiving continuous hemodiafiltration. Intensive Care Med 2003; 29(10):1844-1848.

    20. Bergner R, Hoffmann M, Riedel KD, Mikus G, Henrich DM, Haefeli WE et al. Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg. Nephrol Dial Transplant 2006; 21(4):1019-1023.

    21. Pfaller MA, Diekema DJ, Ostrosky-Zeichner L, Rex JH, Alexander BD, Andes D et al.

    Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol 2008; 46(8):2620-2629.

    22. Vazquez, Jose, et al. Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC infectious diseases 14.1 (2014): 97.

    23. Public Health England. Guidance for the laboratory investigation, management and infection prevention and control for cases of Candida auris. August 2017 v2.0

    Evidence levels:
    A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
    B. Robust experimental or observational studies
    C. Expert consensus.
    D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

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    Approved By

    Improving Antimicrobial Prescribing Group

    Document history

    LHP version 1.0

    Related information

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