By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: When compared to shorter infusion duration, prolonged infusion of anti-pseudomonal β-lactam antibiotics was associated with reduced mortality.

SOURCE: Vardakas KZ, Voulgaris GL, Maliaros A, et al. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: A systematic review and meta-analysis of randomised trials. Lancet Infect Dis 2018;18:108-120.

Vardakas and colleagues examined 22 clinical trials involving 1,876 patients prescribed intravenous anti-pseudomonal β-lactam antibiotics and who were randomized to receive them either as a brief (over 60 minutes) or prolonged ( 3 hours, including continuous) infusion. Almost all enrolled patients were receiving intensive care and were severely ill as indicated by a mean or median APACHE II score 20. The total daily antibiotic dose varied, but in 13 of the 22 trials, patients assigned to prolonged administration received 50-67% of the total daily dose received by those in the comparator arm.

Clinical cure or improvement (reported in 18 of the trials) did not significantly differ between the groups. However, a statistically significant all-cause mortality difference was observed in the 17 studies reporting this endpoint, with the results favoring prolonged infusion (relative risk [RR] 0.70; 95% confidence interval [CI], 0.56-0.87). When analyzed separately, both a penicillin with a β-lactamase inhibitor and carbapenems were each associated with significantly reduced mortality, while cephalosporins were not, possibly related to the smaller sample size and the possibility that their dosage was inadequate in both treatment arms.

COMMENTARY

The critical pharmacodynamic parameter for antibacterial efficacy of β-lactam antibiotics is the proportion of the dosing interval for which the serum concentration of the non-protein-bound fraction of the antibiotic remains above its minimal inhibitory concentration (MIC) vis à vis the targeted pathogen. This can be expressed as %ƒT > MIC. There is little benefit with concentrations greater than four times the MIC. The target for efficacy generally is in the range of 60% ± 20% of the dosing interval. The common use of short infusion times (often 30 minutes) is inferior to more prolonged infusion times with regard to pharmacodynamic target attainment (PTA) at these levels.

However, the clinical benefit of prolonged infusion has been difficult to demonstrate, and the reported results have been mixed. Among other obstacles, this is likely to depend to a significant degree on the actual MIC of the infecting pathogen. Thus, the duration of infusion probably has little potential effect when the MIC is at the extremes. If it is extraordinarily low, PTA is likely to be achieved readily regardless of the duration of beta-lactam infusion. If it is extraordinarily high, the duration of infusion is likely to be irrelevant — the antibiotic has little chance of efficacy. Thus, the greatest clinical benefit resides in the treatment of infections due to pathogens with MICs clustering around the breakpoint, both just below and just above it, and this limits the ability to detect treatment outcome differences when the overall study population is undifferentiated with regard to actual MIC.

A number of caveats must be considered in evaluating the results of this meta-analysis. There was no information on antimicrobial susceptibility, micro-biological eradication, or the frequency of significant immunocompromise in the study populations. Importantly, patients with renal insufficiency were excluded from the majority of studies included in the analysis. Several of the studies allowed administration of other antibiotics in combination with the beta-lactam. Some studies used loading doses, and this approach was not analyzed.

Another issue is that most patients studied were receiving intensive care and the majority had APACHE II scores 20, a population one would like to target in evaluating mortality as an endpoint. However, such patients are likely to exhibit a number of manifestations that affect antibiotic pharmacokinetics and pharmacodynamics. These include increased volume of distribution, hypoalbuminemia (important for highly protein-bound drugs), capillary leak, and, in the absence of renal impairment, augmented clearance. Prolonged antibiotic infusions have an improved chance of achieving PTA in these circumstances, but they may not exist in non-critically ill patients, raising the question of whether the results reviewed here have relevance in them.

This meta-analysis, which included only randomized trials, provides strong evidence of a 30% reduction in crude mortality in patients who received prolonged anti-pseudomonal beta-lactam infusions as compared to those whose individual infusions were of short duration. We implemented this approach at Stanford approximately two years ago by making prolonged infusion the default when these drugs are ordered.

One additional issue: We should realize that we are working in the dark ages with regard to beta-lactam therapy in these patients. It is becoming increasingly apparent that to further optimize outcomes, therapeutic drug monitoring, particularly in patients receiving renal replacement therapy, will be necessary.