This meta-analysis showed that CIF of beta-lactam antibiotics for critically ill patients is associated with lower hospital mortality and higher bacterial eradication rate than the traditional method of IIF.
Sepsis is an important public health issue owing to its considerable impact on in-hospital mortality and the high economic burden. The major factors influencing sepsis-associated mortality are the patient’s characteristics and comorbidities, including advanced age, male sex, liver cirrhosis, and chronic renal disease.[14–17] The APACHE II score is positively associated with mortality, with higher scores indicating higher mortality rates. Thus, our study could control for the disease severity to measure the mortality rate in sepsis patients with different administration regimens.
The strength of our study is that we included a homogenous population of sepsis patients admitted in the ICU, with mean APACHE II scores of ≥ 19. Further, all antibiotics administered belonged to the beta-lactam class. Meanwhile, our meta-analysis also has some limitations. First, we could not evaluate the safety of CIF because none of the studies reported the safety outcomes. Second, we could not analyze the effects of CIF on renal impairment patients due to the lack of subgroup analyses or related data from the included studies. There was also a lack of microbiologically proven infections in our studies, mostly due to a profound variation in the infection focus and pathogen of sepsis in patients with differing critical status.
In contrast to the previous meta-analysis and systematic review performed by Chen et al., we only included adult ICU patients treated with beta-lactam antibiotics. We consider this to be important because the disease status and patient characteristics are correlated with mortality, and healthcare support systems are profoundly different between ICU and non-ICU patients. Consequently, Chen et al. might not have provided sufficient evidence for a homogenous population because they included both adult patients in the ICU and ward.
Compared with other studies [21–23] that showed no significant benefit in clinical cure rate, our study findings indicate that the CIF of beta-lactam antibiotics has better efficacy and achieves better outcomes than IIF, especially for critically ill patients with sepsis. There are two possible explanations. First, severe disease causes pathophysiologic changes that lead to a more profound difference in drug levels under CIF or IIF of antibiotics . Two, due to a higher prevalence of pathogens with higher MIC levels in the ICU or critically ill population, CIF, rather than the traditional IIF, may be required to achieve the effective therapeutic concentration level [25–27].
Our study showed that compared to IIF, CIF reduced the risk of hospital mortality by 21%. The secondary outcome of bacterial eradication rate was significantly higher in the CIF group than in the IIF group. These findings correlate with the mechanism of the time-dependent effect that beta-lactam antibiotics have on bacterial eradication. This, in turn, should be enhanced by maintaining the duration of a sustained concentration above the MIC (time > MIC), which can be achieved with CIF. Drug pharmacokinetic parameters change due to the hyperdynamic state of sepsis, such as hypovolemia, hypoalbuminemia, and organ hypoperfusion (liver, kidney). In addition, pathophysiological changes in critical status also affect the volume distribution and drug clearance. This might lead to a lower-than-expected drug plasma concentration. Consequently, an important consideration in the medical treatment of critically ill patients with sepsis is how to attain the optimal concentration of antibiotics. Roberts et al. found that in the PK data, the CIF group had significantly higher Css (steady state) concentrations than the Cmin (minimum) of the IIF group. The same results were also found in plasma data. However, few studies have explored the effectiveness of CIF of concentration-dependent antibiotics. Tan et al. showed that CIF of colistin, which is a concentration-dependent antibiotic, has no pharmacodynamic benefits for treating an infection with a multidrug-resistant pathogen, such as Acinetobacter baumannii species.
Nonetheless, there are a few limitations to consider when interpreting for clinical use. First, although all included studies were RCTs, two of the studies belonged to the same author, and half of the studies had a smaller sample size, with fewer than 100 people. Second, most of the countries where these studies were conducted are developing countries, whose capacity to care for critically ill patients may not be comparable to European and American countries. Therefore, it is unknown whether the same effect might be observed in regions with higher levels of medical care. Third, although meropenem was used in all included studies, its stability might be of concern as the infusion should be completed within a certain period of time after meropenem has been diluted. However, in our review, this has not been well addressed in any studies, with varying infusion rates or protocols documented. Thus, this issue should be taken into consideration when applying CIF of meropenem to critically ill patients.
Despite the limitations of the studies included, this systematic review and meta-analysis provides summary information on the efficacy of CIF in comparison to that of IIF of beta-lactam antibiotics. The results support the clinical and bacterial eradication benefits in adult critically ill patients, and these findings may guide clinical discussions and decisions. It should be noted that disease severity in the included studies was generally moderate to severe, with the patients having a mean APACHE II score of ≥ 19.
As noted earlier, there is no censuses on the infusion rates or protocols among the studies reviewed, neither were the deficiency well-addressed. Future studies should focus on a standardized infusion regimen of beta-lactam antibiotics in the general or specific (e.g., those with renal impairment) population or when multidrug-resistant pathogens such as Acinetobacter baumannii species are present.