By Richard R. Watkins, MD, MS, FACP, Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH, is Editor for Infectious Disease Alert.
Dr. Watkins reports no financial relationships in this field of study.
Source: Dulhunty JM et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013;56:236-244.
Despite notable advances in critical care medicine, mortality from severe sepsis remains unacceptably high. With current therapeutic strategies, nothing has proven more crucial than early and effective antibiotics. Among the most commonly utilized antibiotics in intensive care units (ICUs) are beta-lactams, such as piperacillin-tazobactam and meropenem. These agents are usually administered by intermittent bolus dosing. However, pharmocodynamic data have shown that continuous infusion administration results in greater blood and fluid exposure with more time above the minimum inhibitory concentration (MIC) compared to intermittent dosing. Dulhunty and colleagues sought to determine the clinical and pharmacokinetic differences between continuous and intermittent bolus dosing of beta-lactam antibiotics in patients with severe sepsis.
The study was a prospective, double-blind, randomized controlled trial conducted at several hospitals in Australia and Hong Kong between April 2010 and November 2011. Patient inclusion criteria included > 18 years of age, severe sepsis in the preceding 24 hours, treatment within the previous 24 hours with ticarcillin-clavulanate, piperacillin-tazobactam or meropenem, and expected or actual ICU stay greater than 24 hours. Patients were excluded if they were on continuous renal replacement therapy, lacked a central access catheter with at least 3 lumens, or received the study drug for > 24 hours. They were randomized to receive active infusion and placebo boluses (intervention group), or placebo infusion and active boluses (control group). On days 3 and 4 blood samples were taken to ascertain plasma trough levels. The primary endpoint was the time that antibiotic concentraton was above the MIC. Secondary endpoints were clinical response at days 7 to 14 after study drug cessation, time to clinical resolution, status at ICU and hospital discharge, and number of days alive and free of ICU admission in the first 28 days post-randomization. Sixty patients were enrolled, 30 in the continuous infusion group and 30 in the intermittent bolus group. The most common source of infection in both groups was lung, followed by blood, intra-abdominal, skin or skin structure, urinary tract, and central nervous system.
The patients who received continuous infusion compared to intermittent bolus administration achieved higher times above the MIC (82% vs. 29%, P = .001) and higher clinical cure (76.7% vs. 50%, P = .032). Moreover, there was less time to clinical resolution (11 days vs. 16.5 days, P = .14), lower ICU length of stay (7.5 days vs. 9 days, P = .50), better hospital survival (90% vs 80%, P = .47), and higher ICU survival (93.3% vs. 86.7%, P = .67) in the continuous infusion group, but these did not reach statistical significance. Plasma antibiotic concentration of meropenem was greater than the MIC in 100% of patients who received continuous infusion compared to 22% in the intermittent bolus group. Piperacillin-tazobactam and ticarcillin-clavulanate continuous infusions resulted in concentrations above the MIC 75% and 50% of the time, respectively. The corresponding intermittent bolus administration achieved concentrations above the MIC 36% and 0% of the time with piperacillin-tazobactam and ticarcillin-clavulanate.
Patients with severe sepsis are a challenge to treat, especially those with multi-drug resistant pathogens. This unfortunate situation is unlikely to improve in the near future given the lack of promising new antibiotics. One potential solution is to find innovative ways to use currently available agents. For example, maximizing the pharmacokinetic and pharmacodynamics properties of beta-lactams has been investigated in several animal studies and in a limited number of human ones. The present study exemplifies an unconventional approach that resulted in improved clinical outcomes. It is the largest prospective ICU trial of continuous vs. intermittent bolus administration of beta-lactams, as well as the first to be conducted in a blinded fashion with allocation concealment. Of the three beta-lactams studied, meropenem seems to be the best candidate for continuous infusion as it achieved the highest success for concentration above the MIC (100%). There were a few limitations, one being different patient characteristics (younger age, more males, more comorbidities, higher proportion of pre-ICU infections) in the intervention group compared to the control group. Another was the potential confounding effect of concurrently administered antibiotics (e.g. vancomycin, antifungals). Moreover, the study was likely underpowered which led to many endpoints not reaching statistical significance. No adverse events occurred to any of the patients as a result of the study drug or intervention. While this may have resulted from optimized dosing and judicious monitoring of renal function, equally plausible is that it was due to the relatively small number of patients in the two groups.
This study represents an important advancement in treating patients with severe sepsis. Indeed, the continuous administration of beta-lactams seems to be most helpful for infections caused by high MIC organisms, which are often found in ICUs. However, it may be advisable to wait for the results from a larger phase II randomized controlled multicenter trial with additional data on clinical outcomes, length of stay, and mortality before implementing a change to continuous infusion therapy. Hopefully these data will elucidate the types of infections (e.g. pneumonia, bacteremia) for which continuous infusion therapy will be most beneficial