In the present study, 753 drug-related problems were identified during the treatment of the patients with septic patients in the intervention group. A total of 288 recommendations for drug selection were made, 83 (28%) of which were related to antimicrobial therapy. In a retrospective study by Weant and Baker to evaluate the role of the clinical pharmacist in the management of sepsis and septic shock, antimicrobials were reported to be the drug group most often requiring intervention, with 22% of the recommendations related to antimicrobial selection (13). These similar results show that clinical pharmacists make an important contribution in the rational use of antimicrobials, especially in patients being treated for sepsis and septic shock. The most frequent cause of the identified drug-related problems was dosing regimens. A total of 310 recommendations were made for dosing problems, accounting for 48.1% of all recommendations. In Weant and Baker's study, 53% of all recommendations were related to drug dosing (13). The majority of the dose recommendations in the present study were for antimicrobial drugs (n = 215). Numerous studies have investigated the use of anti-inflammatory and anticoagulation therapies in the treatment of sepsis, but it has been reported that none of these therapies is as effective as optimal antibacterial therapy (16). Optimal antimicrobial therapy in the treatment of sepsis depends on appropriate drug choice and timing, as well as administering the most appropriate dose. It has been observed that the responsibility for evaluating dosage appropriateness in the treatment of ICU patients falls largely on clinical pharmacists due to the clinical instability and numerous factors affecting drug pharmacokinetics in this patient group and the physicians’ workload.
Acute kidney injury is reported in 19–23% of patients with sepsis and 50% of patients with septic shock. These patients require individualized dosage adjustment due to multiple drug use and renal dysfunction (17). Comparison of the intervention and control groups in our study showed that the appropriate maintenance dose was prescribed to 33 (50.8%) of the patients in the control group and all patients (100%) in the intervention group (Table 4). In a study by Jiang et al. on sepsis patients receiving CRRT, 507 antimicrobial drugs required dosage adjustment in the control group without pharmacist intervention and 311 (61.3%) of them were used at the appropriate dose. In the study group, 526 antimicrobial drugs required adjustment and 482 (91.6%) were used at the appropriate dose (18). In the present study, 61.5% of the patients in intervention group had renal dysfunction and 29.2% were on CRRT. Drug databases can be used to determine appropriate dosing regimens for this patient group, but dose recommendations differ among available drug information sources (19, 20). Due to these differences, the task of using and interpreting these resources falls upon the clinical pharmacist, who has more knowledge of the pharmacokinetic and pharmacodynamic properties of drugs. In this study, we determined that 136 of the total 215 antimicrobial dosing recommendations were related to renal function status and CRRT. This finding indicates that clinical pharmacists contribute to the individualization of drug dosage not only in sepsis patients, but also in critical patients who have organ failure and altered pharmacokinetics.
De-escalation of antimicrobial therapy is associated with lower morbidity and mortality rates and is recommended within the first 48 to 72 hours (21). In our study, the time to de-escalation was significantly shorter in the intervention group (p < 0.001). Guo et al. reported in their 2016 meta-analysis that de-escalation tended to reduce mortality compared to continuing empiric therapy, but the difference was not statistically significant (22). In the study of Yamaguchi et al., it was aimed to evaluate the effect of daily 'Prospective audit and feedback' (PAF) implementation, focusing on the time to de-escalation of antimethicillin-resistant Staphylococcus aureus (MRSA) agents (23). To this end, study including patients treated with intravenous anti-MRSA agents during pre-PAF and post-PAF periods was conducted. It was stated the median time to de-escalation was significantly shorter in the post-PAF period than in the pre-PAF period (p < 0.001). It was showed daily PAF implementation for patients treated with intravenous anti-MRSA agents led to a shorter time to de-escalation and lower consumption of anti-MRSA agents without worsening the clinically important outcomes. It has also been reported that fewer adverse drug reactions (ADRs) were detected in patients whose de-escalation period was intervened. Although few studies have investigated the correlation between the duration of therapy with anti-MRSA agents and the risk of ADRs, several studies have suggested an association between longer duration of therapy with anti-MRSA agents and higher risk of ADRs (24, 25). Thus, it is possible that the shortening of the de-escalation contributed to the reduced incidence of ADRs.
Different studies have shown that the clinical pharmacist contributes to the clinical and cost outcomes of septic patients. Maclaren et al. showed in their national study that drug costs were significantly decreased in sepsis patients when clinical pharmacists intervened in their treatment (p = 0.04) (26). In the present study, we observed that the daily drug cost in the ICU after diagnosis of sepsis/septic shock was higher in the intervention group than the control group, but the difference was not statistically significant. As the control group was selected retrospectively from patients treated in an earlier period, this may be attributable to the increase in drug prices over time. However, when these costs are evaluated in USD, it is seen that the cost of the intervention group is lower. This is due to the rapid volatility of the dollar exchange rate in our country in recent years.
When the daily antibiotic costs in the ICU after sepsis/septic shock diagnosis were compared between the intervention and control groups, the difference between the two groups was found to be statistically significant, demonstrating that clinical pharmacist involvement reduced antibiotic costs (p = 0.001). There were 215 recommendations for antimicrobial dose selection in this study, and 136 of these recommendations were due to renal dysfunction and/or CRRT. When the daily antibiotic costs after sepsis/septic shock diagnosis were compared among patients with renal dysfunction, a statistically significant reduction was observed in the intervention group (p = 0.007). Jiang et al. also reported that including a clinical pharmacist in the treatment management of sepsis patients receiving CRRT resulted in a 34.7% reduction in antibiotic treatment costs (p = 0.046) (18). In our study, clinical pharmacist intervention reduced antibiotic costs significantly in patients with renal dysfunction, while the difference was not significant for patients with renal dysfunction receiving CRRT (p = 0.41). This may be attributable to the fact that drug doses are reduced in patients not receiving CRRT depending on the extent of renal dysfunction, whereas patients on CRRT receive relatively higher drug doses due to increased drug excretion.
There are some limitations to this study. The sample size was limited by the fact that a small proportion of patients treated during the study period met the inclusion criteria and not all of those patients’ treatments could be evaluated within the first 24 hours because the clinical pharmacist conducting the study was serving two different ICUs on a part-time basis. The infrequency of eligible patients and limited study period also prevented us from making exclusions to make the patient groups more homogeneous, as this would have further narrowed the sample. Therefore, the study included patients with different comorbidities who were using drugs for purposes other than sepsis treatment, which affected the distribution of costs. In addition to the factors that may have influenced the results of the intervention group, comparison with a retrospective control group is also a limitation of this study. However, we decided to use a retrospective control group because we considered it unethical not to intervene in drug-related problems in the presence of a clinical pharmacist.