Question 23

College answer

Not available.

Discussion

a)

 Rationale:

• Clinical efficacy of β-lactams depends on time spent above MIC
• This may be difficult to achieve in septic patients (variable erratic pharmacokinetics)
• Inadequate dosing may result in treatment failure and the development of resistance (Martinez et al, 2012)
• High peaks seen with intermittent dosing can increase the risk of drug toxicity
• Critically ill patients should benefit most  (clearance mechanisms are most erratic, organisms are most resistant, )

b)  

Advantages:

• More rapid rates of clinical improvement and decreased morbidity/mortality
• Continuous infusion should prevent drug-related adverse effects
• Less nursing workload to set up on 24 hr infusion
• Potential for treatment in the community (decrease healthcare costs)
• The total dose of the drug may be lower, as clinical resolution may occur sooner
• Less underdosing, thus less resistance development

Disadvantages

• Many drugs have clinically significant post-antibiotic concentration-dependent killing effects, including beta-lactams in gram positives
• Boluses may achieve the higher concentration required to penetrate tissues
• MIC targets are not consistently agreed upon
• MIC is not always measured, nor are drug levels
• Not all drugs are suitable for a 24-hour infusion because of their stability in room temperature solution
• The 24 hour infusion usually takes out one whole lumen of a line

c)

Evidence

• The evidence for mortality benefit is conflicting 
• The larger trials with robust methodology (Dulhunty et al, 2013; BLING II; 2015; BLISS, 2016)have not produced any mortality benefit or ICU length of stay improvement
• The overall literature is heterogeneous, with everybody using different antibiotic regimens, infusion standards, MIC targets, patient populations and follow up strategies. 
• One thing which has emerged is a consistent signal that there is no harm with continuous infusion
• Of the (admittedly, low quality and largely observational) studies that report better outcomes with continuous infusions, the populations which seem to benefit the most are critically ill patients, i.e. low acuity patients do not seem to benefit.
• BLING III should hopefully shed more light on this by enrolling 7,000 ICU patients