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.