Sepsis - Undetermined Origin/Source Unclear

General

Assess likely focus of infection –e.g. urinary tract, skin/soft tissue, abdominal, chest, neurological and refer to the organ/organ system-specific sections of these guidelines if source of sepsis is known.

• Refer to NEWS Score of the adult patient observation chart and Sepsis Six.
• Identify the specific anatomic site of infection so that any source control interventions can be implemented as soon as possible.
• If indwelling intravascular access devices are a potential source they should be removed after alternative vascular access has been secured.
• Take blood cultures and other specimens for microbiological investigations before giving antimicrobials if doing so results in no substantial delay in starting therapy.
• Check previous microbiology results for history of colonisation or infection with MDROs e.g. ESBL, VRE, MRSA, and CPE as such a history will influence empiric antimicrobial choice. Discuss with microbiology if required.
• In patients with immunosuppression, hospital-onset sepsis and potential of travel-related infections, additional antimicrobials may be required. Please refer to relevant sections in these guidelines and/or discuss these patients with microbiology.

Antimicrobials

First Line if no obvious source:

Piperacillin-tazobactam 4.5g TDS/QDS IV (QDS dosing indication: severe infection, neutropenic sepsis or Pseudomonas aeruginosa infection)

+

Gentamicin/Amikacin once daily IV (please see Gentamicin / Amikacin dosing schedule)

Use Amikacin instead of gentamicin if history of infection or colonisation with gentamicin resistant Gram negative bacteria, severe illness or septic shock

+

Vancomycin in severe infection, septic shock, or history infection/colonisation with MRSA (Please see Vancomycin dosing      schedule)

Penicillin allergy

NOT IgE -mediated/anaphylaxis/severe reaction:

Ceftriaxone 2 g once daily IV

+

Metronidazole 500 mg TDS IV

+

Gentamicin/Amikacin once daily IV (please see Gentamicin/Amikacin dosing schedule)

Use Amikacin instead of gentamicin if history of infection or colonisation with gentamicin resistant Gram negative bacteria, severe illness or septic shock

+

Vancomycin in severe infection, septic shock, or history infection/colonisation with MRSA (Please see Vancomycin dosing      schedule)

IgE-mediated / anaphlyaxis/ severe penicillin allergy:

Ciprofloxacin* 400mg BD IV

+

Metronidazole 500mg TDS IV

+

Gentamicin/Amikacin once daily IV (please see Gentamicin/Amikacin dosing schedule)

Use Amikacin instead of gentamicin if history of infection or colonisation with gentamicin resistant Gram negative bacteria, severe illness or septic shock.

+

Vancomycin in severe infection, septic shock, or history infection/colonisation with MRSA (Please see Vancomycin dosing      schedule)

If history of colonisation or infection with ESBL - producing, OR gram negative bacteria resistant to piperacillin-tazobactam or cephalosporins use Meropenem 1g TDS IV. Note restricted antimicrobial agent, discuss with microbiology.

Review need for Gentamicin/Amikacin daily. The use of aminoglycosides in combination with other agents (e.g. co-amoxiclav) is rarely required for longer than 3 days. Discuss with microbiology if required.

* Please read the HPRA Drug Safety Alert issued in 2018 and the HPRA Drug Safety Newsletter issued in 2023 highlighting restrictions on use of fluoroquinolones (eg. ciprofloxacin, levofloxacin) due to the risk of disabling, long-lasting and potentially irreversible side effects (including tendon damage, QT prolongation, neuropathies and neuro psychiatric disorder). Use of fluoroquinolones in older patients, those with renal impairment, solid organ transplantation or on systemic corticosteroids increases the risk of tendon damage.

Comments

• Review gentamicin/amikacin prescriptions daily; a single or stat dose may be all that is required. Consider stopping at 48 hours if patient stable and no growth on cultures.
• Aminoglycoside treatment beyond 3 days is rarely required. If continued requirement, please discuss with microbiology.
• Empiric broad-spectrum therapy should be de-escalated or changed to targeted therapy once pathogen identification and susceptibilities are established and/or adequate clinical improvement is noted. Discuss de-escalation with microbiology if required.

Febrile Neutropenia

General points

Neutropenia = Neutrophil Count < 1.0 x 10 ⁹ /L

Severe Neutropenia = Neutrophil Count < 0.5 x10 ⁹ /L

Fever = Temp ≥38 ^o C

Febrile Neutropenia / Neutropenic sepsis is a medical emergency. IV antimicrobial therapy should be started without delay.

N.B. Check previous microbiology results for history of MDROs e.g. ESBL, MRSA, and CPE, as these pathogens may not be covered by all empiric regimes - contact microbiology for advice if required.

Blood cultures – send one set from each lumen of CVC and a peripheral set if possible OR peripheral X 2 if no CVC is present.

Respiratory tract swab for covid +/- other viruses if suspected, MSU/CSU for culture, sputum culture, stool sample if diarrhoea, wound swabs if applicable.

Many chemotherapeutic agents can cause nephrotoxicity and a review of renal function in active malignancy should be done when using aminoglycosides in these patients.

Antibiotics

First Line:

Piperacillin-tazobactam 4.5 g QDS IV

Add Gentamicin once daily IV ( see Gentamicin dosing schedule ) ( OR in multiple myeloma/cisplatin-based therapy Ciprofloxacin 400mg q8-12 hourly IV) if any features of haemodynamic instability e.g. tachycardia, hypotension, or hypothermia.

Add Teicoplanin ( please see Teicoplanin dosing schedule ) if history of MRSA colonization/infection OR suspected line-related sepsis OR critically ill OR active mucositis.

NOT IgE-mediated/anaphylaxis/severe penicillin allergy:

Ceftazidime 2g TDS IV (adjust dose in renal impairment).

+

Teicoplanin (please see Teicoplanin dosing schedule)

Add Gentamicin once daily IV ( please see Gentamicin dosing schedule ) ( OR in multiple myeloma/cisplatin-based therapy Ciprofloxacin 400mg q8-12 hourly IV) if any features of haemodynamic instability e.g. tachycardia, hypotension, or hypothermia.

IgE-mediated/anaphylaxis/severe penicillin allergy :

Ciprofloxacin 400 mg 8 to 12 hourly IV

+

Teicoplanin (please see Teicoplanin dosing schedule)

Add Amikacin once daily IV if any features of haemodynamic instability eg. tachycardia, hypotension, or hypothermia (please see Amikacin dosing schedule).

If known colonisation or previous infection with ESBL - producing OR gram negative bacteria resistant to piperacillin-tazobactam or cephalosporins use Meropenem 1g TDS IV. Note restricted antimicrobial agent, discuss with microbiology.

*In severe illness, haemodynamic instability, OR if history of infection/colonisation with gentamicin resistant Gram-negative bacteria replace gentamicin with Amikacin once daily in all combinations. (please see Amikacin dosing schedule)

** In a haemodynamically unstable patient, the benefit of gentamicin/amikacin may outweigh the risk – discuss with haematology consultant.

* Please read the HPRA Drug Safety Alert issued in 2018 and the HPRA Drug Safety Newsletter issued in 2023 highlighting restrictions on use of fluoroquinolones (eg. ciprofloxacin, levofloxacin) due to the risk of disabling, long-lasting and potentially irreversible side effects (including tendon damage, QT prolongation, neuropathies and neuro psychiatric disorder). Use of fluoroquinolones in older patients, those with renal impairment, solid organ transplantation or on systemic corticosteroids increases the risk of tendon damage.

Comments

• Consider stopping Gentamicin/Amikacin at 24-72 hours if afebrile, and no gram negative pathogen isolated from blood cultures. Other antimicrobials may need to be continued.
• If pathogen identified, target therapy in accordance with susceptibility test results.

If persistent fever on empiric antimicrobials and evidence of clinical deterioration:

• Re-evaluate patient for potential focus of infection.
• Contact microbiology for advice –may require escalation of gram negative cover +/- gram positive cover.
• Consider addition of anti-fungal agent if fever persists beyond 4 days.
• Consider investigations for opportunistic pathogens such as PJP, mycobacteria, viruses, fungi etc. as applicable.

References

Averbach et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4 ^th European Conference on Infections in Leukaemia. Haematologica 2013:98(12): 1826-1835.

Sepsis in Pregnancy

General points

See Sepsis and National Clinical Guideline No26 Sepsis management for adults including maternity 2021

See below for antimicrobial recommendations for

1. Sepsis in pregnancy (no identifiable source)

2. Severe sepsis (eg. septic shock) in pregnancy.

• NB. Check previous microbiology test results for antimicrobial resistance.
• Note Group B Streptococci (GBS) are universally susceptible to penicillins and most cephalosporins including cefuroxime and ceftriaxone. Between 20-30% of GBS isolates both locally and nationally are resistant to clindamycin therefore for empiric use (where susceptibility is unknown) clindamycin cannot be recommended.
• These regimes are not suitable for patients with known or suspected MDROs such as ESBL, CPE. Discuss these cases with Clinical Microbiologist.
• Take prior antimicrobial use into account when prescribing as recent exposure to a particular agent is a risk factor for resistance to same.
• Ensure appropriate microbiological specimens (blood, urine, swabs) sent before starting treatment where possible.
• Identify source of sepsis as soon as possible to ensure timely source control.
• The empirical antimicrobial regime should be rationalised as soon as microbiology test results available.
• Review need for Gentamicin/Amikacin daily.

Sepsis in Pregnancy (no identifiable source)

First Line (Empiric Therapy)

Co-amoxiclav 1.25g TDS IV + Gentamicin 5mg/kg OD IV (booking weight, max 480mg) (please see Gentamicin dosing schedule).

Note: Early escalation to Piperacillin-tazobactam 4.5g IV QDS + Gentamicin 5mg/kg OD IV (booking weight, max 480mg) may be warranted depending on clinical severity, recent microbiology test results or recent co-amoxiclav use.

If history of MRSA colonisation or infection consider adding Vancomycin 15mg/kg IV 12 hourly (booking weight, max 2g/dose), (please see Vancomycin dosing schedule) . Consider 25mg/kg (max 2g) loading dose if severe infection or septic shock.

In patients with a booking weight BMI ≥30kg/m ² use Obese Dosing Weight/Adjusted Body Weight ( Please see formulae for weight calculations ) and not Actual Body Weight to calculate gentamicin dose. (Please see Gentamicin dosing schedule) .

Penicillin Allergy (Empiric Therapy)

NOT IgE-mediated /anaphylaxis/severe penicillin reaction:

CefUROXime 1.5g IV QDS.

+ Metronidazole 500mg IV TDS.

+ Gentamicin 5mg/kg OD IV (booking weight, max 480mg). (Please see Gentamicin dosing schedule)

If history of MRSA colonisation or infection consider adding Vancomycin 15mg/kg IV 12 hourly (booking weight, max 2g/dose). Consider 25mg/kg (max 2g) loading dose if severe infection or septic shock. (Please see Vancomycin dosing schedule).

IgE-mediated /anaphylaxis/severe penicillin reaction:

Vancomycin 15mg/kg IV 12 hourly (booking weight, max 2g/dose). Consider 25mg/kg (max 2g) loading dose if severe infection or septic shock (Please see Vancomycin dosing schedule).

+ Gentamicin 5mg /kg once daily (use booking weight) (Please see Gentamicin dosing schedule)

+ Metronidazole 500mg IV TDS

Add clindamycin if invasive Group A Strep Infection suspected.

In patients with a booking weight BMI ≥30kg/m ² use Obese Dosing Weight/Adjusted Body Weight (See formulae for weight calculations) and not Actual Body Weight to calculate gentamicin dose. ( Please see Gentamicin dosing schedule )

Note: Both vancomycin and gentamicin can cause nephrotoxicity as an adverse effect. This risk is increased when both agents are used together and is increased further with the use of concomitant piperacillin-tazobactam and other nephrotoxic medications. Review use of these medications daily, monitor renal function and drug levels.

Sepsis (severe) in Pregnancy e.g. septic shock

First Line & Penicillin Allergy (Not IgE-mediated/anaphylaxis or non-severe penicillin allergy) Empiric Therapy

Meropenem 1-2g TDS

+ Clindamycin 1.2g QDS IV

+ Gentamicin 5mg/kg OD IV (booking weight, max 480mg) (Please see Gentamicin dosing schedule)

In patients with a history of Gentamicin resistant Gram negative infections (eg. UTI) use Amikacin 15mg/kg OD IV (booking weight, max 1.5g). (Please see Amikacin dosing schedule)

If history of or risk factors for MRSA colonisation or infection add Vancomycin 25mg/kg (max 2g) loading dose then 15mg/kg IV 12 hourly (booking weight, max 2g/dose). (Please see Vancomycin dosing schedule).

In patients with a booking weight BMI ≥30kg/m ² use Obese Dosing Weight/Adjusted Body Weight and not Actual Body Weight to calculate gentamicin/amikacin dose. (Please see formulae for weight calculation)

If there is a strong suspicion clinically that the septic shock may be relating to Group A Streptococcus, then IV immunoglobulin could be considered.

IgE-mediated/anaphylaxis or Severe Penicillin Allergy Empiric Therapy

Vancomycin 25mg/kg (max 2g) loading dose then 15mg/kg IV 12 hourly (Please see Vancomycin dosing schedule).

+ Clindamycin 1.2g QDS IV

+ Gentamicin 5mg/kg IV once daily  (booking weight, max 480mg) (Please see Gentamicin dosing schedule)

In patients with a history of Gentamicin resistant Gram negative infections (eg. UTI) use Amikacin 15mg/kg OD IV (booking weight, max 1.5g) (Please see Amikacin dosing schedule)

Ciprofloxacin 400mg BD IV may be added for additional Gram-negative cover.

OR

Meropenem can be considered for use in select cases (1-2% cross reactivity between penicillin and carbapenem). Discuss with Microbiology/Obstetric teams.

+ Clindamycin 1.2g QDS IV

+ Gentamicin 5mg/kg OD IV (booking weight, max 480mg) (Please see Gentamicin dosing schedule)

In patients with a history of Gentamicin resistant Gram negative infections (eg. UTI) use Amikacin 15mg/kg OD IV (booking weight, max 1.5g) (Please see Amikacin dosing schedule).

If history of or risk factors for MRSA colonisation or infection add Vancomycin 25mg/kg (max 2g) loading dose then 15mg/kg IV 12 hourly (booking weight, max 2g/dose) (Please see Vancomycin dosing schedule).

In patients with a booking weight BMI ≥30kg/m ² use Obese Dosing Weight/ Adjusted Body Weight and not Actual Body Weight to calculate gentamicin/amikacin dose. (Please see formulae for weight calculation)

Review Gentamicin/Amikacin daily with culture results and clinical response. If patient is clinically improving, consider stopping after 48 hours.

Note: Both vancomycin and gentamicin/amikacin can cause nephrotoxicity as an adverse effect. This risk is increased when both agents are used together and is increased further with the use of other nephrotoxic medications. Review use of these medications daily, monitor renal function and drug levels.

If there is a strong suspicion clinically that the septic shock may be relating to Group A Streptococcus, then IV immunoglobulin could be considered.