3.3 Clinical outcomes of differentfT>MIC
We calculated f T>MIC of all the patients using modelling software. In our research, three patients achieved 100% f T>MIC and 57.1% of participants were below 70% f T>MIC. Two patients were below 40% f T>MIC.
There were 35 (64.3%) patients who were defined as having clinical success and 19 (35.2%) patients who were defined as having clinical failure. The f T>MIC was 73.33±22.90% in the success group and 59.42±19.11% in the failure group. The f T>MIC was significantly different between the two groups (p=0.022). Thef T>4 MIC also showed a significant difference between the success and failure groups (p=0.031). The results were shown in Table 3.
The levels of WBC and PCT were considered necessary for clinical regimens. The WBC and PCT levels changed during the antibiotic treatment, especially during the first 5 days. Based on data from the regimens, the PCT level decreased to at least 20% of the peak level or below 0.5 ng/ml when patients’f T>MICwas greater than 70% or f T>4 MICwas greater than 50%. The WBC level decreased during the first 3 days and reached steady regimen values whenf T>MIC was greater than 70% orf T>4 MIC was greater than 50%. These results indicated that adjustedf T>MIChigher than 70% or f T>4 MIC higher than 50% may result in a better clinical outcome. These results are shown in Fig 3.
DISCUSSION
In this research, a pharmacokinetic model was established using Microsoft Excel software. The calculations in the software were based on pharmacokinetic formulas, and the PK/PD parameters were simulated. Compared to the multipoint sampling method, the PK profiles simulated by software can reflect the metabolism of imipenem in vivo .f T>MIC of imipenem in critically ill Chinese patients was assessed by software in this study. Approximately 64.3% of patients were defined as having clinical success. All the patients’ f T>MIC values were higher than 70% in the success group and showed a significant difference from the failure group (p=0.022). The levels of WBC and PCT decreased quickly during the first 3 and 5 days whenf T>MIC was greater than 70%, and the patients may obtain better clinical outcomes, especially with critical infections.
f T>MIC is the best pharmacokinetic/pharmacodynamic index correlating with imipenem clinical outcomes[11]. Although a significant association between PD exposure and microbiological or clinical outcomes was not found for imipenem, changing the infusion regimens and obtaining a proper f T>MIC is especially necessary for the treatment of critically ill patients[4]. In previous studies, most imipenem pharmacokinetic characteristics were assessed by a Monte Carlo model. Some PD parameters, such as f T>MICor f AUC/MIC, were assessed by a population PK model[12,13]. The PPK model involved imipenem free plasma concentrations and simulated the dosage regiment property. These PPK models refer to specialist patients, and we could not obtain the exact PD parameters individually. We could also not use these PPK models to evaluate the clinical efficacy of imipenem because of the particular physiology in critically ill patients. Camille[14]studied a PPK model in severe infection patients to evaluate the best dosage regimens. The pharmacokinetic parameters changed sensitively in the distribution of body fluids, and the PPK model can only be used for VAP and non-renal failure patients. In our study, we established pharmacokinetic formula software to calculatef T>MIC and PK parameters. Only two blood samples were needed in our research. Compared to the multiple sampling method, the simulated PK/PD parameters can reflect the metabolism of imipenem. We can use this pharmacokinetic software to calculate the imipenem PD parameters and guide the clinical outcomes on an individual basis.
Imipenem is used effectively as a therapy for severe infections by strains such as Klebsiella , Escherichia coli , andEnterobacter that are found in the ICU. A clear and compelling rationale suggests that when plasma drug concentrations are above the MIC for 40% of the dosing interval, imipenem dosing regimens may achieve favourable target attainment in patients[15]. However, for life-threatening severe infections in immunocompromised hosts, thef T>MIC target required for sufficient bactericidal effects is increased to almost 100%[16-18]. Dulhunty[19]et al assessed a trial in a randomized double-blind controlled method and indicated that increasing thef T>MIC of carbapenem to 82% may achieve a better clinical result compared with 22% in continuous infusion. Sutep Jaruratanasirikul[20] et alsuggest that a recommendation for high dosages of imipenem should be required and that plasma concentrations of imipenem 100% T>MIC for MICs of 2 and 4 mg/L are necessary for treatment of highly resistant microorganisms in life-threatening severe infections. In our study, the free plasma concentration of imipenem above the MIC 70% of the dosing interval produced significant differences in clinical outcomes between the clinical improvement and clinical failure groups. Pathophysiological changes in critically ill patients with severe infections had a greater impact on pharmacokinetic patterns of imipenem. Therefore, maintaining an adequate drug concentration to achieve af T>MIC greater than 70% may be a target for effective antimicrobial therapy in this patient population.
In our study, the changes in PCT levels refer to an important index in the clinical outcome evaluation. The international guidelines recommend PCT as a necessary and important laboratory marker for antibiotic stewardship strategies[21]. Procalcitonin-directed protocols for clinicians may be effective for the antibiotic treatment of clinically ill patients. Pierre[22] et al . assessed a cohort study including 180 patients who appropriately received empirical antibiotic therapy. The results showed that the patients’ overall survival was significantly associated with the decreased level of PCT between D2 and D3. Andreas Hohn[23] et al . studied procalcitonin-guided antibiotic treatment in critically ill patients. Their results showed that using PCT protocols may effectively direct antibiotic treatment[24]. In our research, the PCT levels of patients were collected during the first five days after imipenem infusion. The decreasing PCT levels were a better reflection of clinical antibiotic efficacy.
CONCLUSION
In conclusion, a PK model of imipenem forf T>MIC calculations was established in critically ill patients in this study. The imipenem PK/PD profiles in the model group were not significantly different from those in the non-model group. The PK model could be used for imipenem PK/PD evaluation. In clinical outcomes, maintaining an adequate drug concentration of imipenem above the MIC 70% of the dosing interval may achieve a better clinical result in critically ill patients.