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Infusing antipseudomonal beta-lactam antibiotics over longer periods could save lives in sepsis over intermittent bolus dosing, according to a systematic review and meta-analysis of randomized trials.
Vardakas et al aggregated data from studies of patients with sepsis receiving infusions of carbapenems, cephalosporins, and penicillins with antipseudomonal activity. Studies included compared prolonged infusion (over at least three hours), vs. hour-long infusions or shorter. They included 22 randomized trials with 1,876 patients.
Prolonged infusion of antipseudomonal beta-lactams reduced mortality by 30% compared with shorter infusions. Findings were published in Lancet Infectious Diseases.
Interestingly however, subjective outcomes (clinically observed cure or improvement) were not significantly better in the prolonged-infusion patients.
There were no observed differences in adverse events or emergence of antibiotic resistance.
The survival benefit is in concordance with an earlier analysis showing benefits in prolonged piperacillin-tazobactam infusions, and a previous 2013 meta-analysis. The current meta-analysis rated its strength as higher than previous analyses, with significant benefits observed, and high quality of supporting data leading to stronger conclusion of benefit.
Beta-lactams are most effective when their plasma levels remain at a steady state several multiples of a bacterial species' minimum inhibitory concentration (MIC). Prolonged infusions can maintain therapeutic bacteria-killing levels for longer periods, theoretically increasing the likelihood of an infection cure.
Obstacles to Prolonged Antibiotic Infusions
Continuous antibiotic infusions require local expertise, can make care more complex or conflict with other goals of care, and thus may not be easily implemented.
- They require an IV pump to be used for longer periods: although not usually a problem in ICU patients, it may result in frequent disruptive interruptions for patients on medical wards.
- Antibiotics may be incompatible with other necessary medications, requiring multiple intravenous lines, or tempting care teams to place central venous catheters that are not otherwise needed.
- The stability of beta-lactam antibiotics varies widely and can be influenced by their solutions and storage: for example, meropenem is only considered stable for 1 hour at room temperature, according to its manufacturer.
- Many antibiotics (e.g., ampicillin) lack commonly accepted standards for continuous infusions.
- Pharmaceutical companies may be unwilling or unable to provide explicit guidance outside their antibiotics' established administration schedules, due to regulatory or liability risk. Further, most antibiotics are produced by generic manufacturers, and delivered in contracts subject to abrupt change by hospital purchasers -- potentially resulting in a different preparation of the drug from another manufacturer.
Continuous infusions of antibiotics for sepsis are today primarily a local phenomenon, dependent on skilled and knowledgeable critical care pharmacists who can provide the required oversight and support to nursing to ensure consistently successful nonstandard antibiotic regimens. The increasing strength of the clinical data suggest that those ICU pharmacist teams who choose to blaze this trail, and do it well, could save lives.
Source: Lancet Infectious Diseases