Sepsis - Carbapenem Resistant Enterobacteriaceae

General remarks:

1. Treatment only by or in close collaboration with infectious-disease specialist.
2. Aggressive source control is vital (removal of central venous catheters or urine catheters, repeated drainage of abcesses, etc)
3. All MIC’s should be confirmed by e-testing, not only by Vitek.

Treatment: Backbone: meropenem + polymyxine B. Add other agents depending on sensitivity*:

1. If meropenem MIC > 4-8 µg/mL: meropenem + polymyxin B
2. If meropenem MIC > 16 µg/mL:  meropenem + polymyxin B + (give 1 of 3 options ) tigecycline OR fosfomycin OR gentamicin (depending on sensitivity*)
3. If meropenem MIC > 32 µg/mL:  polymyxin B + (give 2 of 3 options) tigecycline OR fosfomycin OR gentamicin. (depending on sensitivity*)

• If colistine/polymyxin B resistant: meropenem + ertapenem (independent of meropenem MIC)  + (give 2 of 3 options) tigecycline OR gentamicin OR fosfomycin iv. (depending on sensitivity*). NB Double carbapenem dosing gives higher  risk of seizures.
• if KPC or OXA-48 positive (Not MBL) consider using ceftazidim-avibactam monotherapy (only if tested sensitive)

NB: pseudomonas is intrinsically resistant to tigecycline.

* Sensitivities:

• Tigecycline:
  • MIC ≤1 μg/mL consider tigecyclin
  • MIC >1 μg/mL consider alternative
• Fosfomycin:
  • MIC ≤32 μg/mL consider fosfomycin
  • MIC >32 μg/mL consider alternative
• Gentamicin:
  • MIC ≤2 μg/mL consider aminoglycoside (dosing dependant on MIC, see under)
  • MIC >2 μg/mL consider alternative

Doses:

• meropenem: loading dose 2 grams, maintencance dose 6 gram/ 24 H continuous infusion.
  • GFR 20-50: 4 gram/ 24H, continuous infusion
  • GFR 10-20: 2 gram/ 24H, continuous infusion
  • Hemodialysis: 2grams/ 24H, continuous infusion. 
• Polymyxine B:  loading dose 20.000 – 25.000 IU/Kg (dose on actual body weight), maintenance dose (12 hours later) 25.000 IU/Kg/day in 2 doses.
  • No dose adjustments for renal failure or dialysis (Morrill et al, OFID 2015)
• Tigecycline 200mg loading dose, next day 1x100mg. If  nausea: slow down the infusion rate, otherwise half the dose
  • No dose adjustments for renal failure or dialysis (renal drug handbook)
• Fosfomycin 4x4 gram INTRAVENOUS.
  • renal failure and > 70 years: 4x2 gram INTRAVENOUS (Michalopoulos, Clin Microb infect 2010)
• Gentamicine 1dd 5 mg/kg (als MIC < 0,5 ug/ml),  1dd 7 mg/kg (als MIC < 1- 2 ug/ml) (Drusano, CID 2007)
  • If trough levels  > 1 mg/l: raise dosing interval, do not lower total dose (that will only decrease the therapeutic effect) (Petrosillo, expert reviews 2014)
  • Renal failure:  dosing in accordance with hospital pharmacyst/nephrologist.
• Ertapenem 1dd1 gram
  • GFR 10-50: give normal dose
  • GFR < 10: dose 1 grams, 3x/week
  • Hemodialysis:  1dd500mg. dose after dialysis if dialysed that day. (renal drug handbook)