Antibiotic stewardship implementation at the largest solid organ transplantation center in Asia: a retrospective cohort study

Solid-organ transplantation (SOT) is the best-known therapeutic option for numerous end-stage diseases in the acute and chronic stages. It has been associated with improved survival and enhanced quality of life for patients [1, 2]. In recent years, SOT has been associated with notable progress, and this improvement is more significant in the field of liver transplantation (LT) [3]. LT is currently considered the gold standard treatment for end-stage liver failure, with liver cirrhosis and hepatocellular carcinoma being the most common indications for LT worldwide [4]. Advances in surgical techniques, methods of diagnosis and prevention of infection, and immunosuppressive regimens have been associated with improvements in long-term post-transplant outcomes. However, surgical complications, infections, and rejection are some of the problems patients encounter after SOT [5]. Infection is the most common cause of death shortly after transplantation in many centers. Unfortunately, early detection of infection is delayed due to the effects of immunosuppressive agents, inhibition of normal inflammatory responses, and failure to recognize the signs associated with infection [6]. Infections caused by multidrug-resistant organisms (MDRs) have become more common in patients following (SOT). In these patients, prompt detection of infection and selection of suitable antibiotic treatment is linked to improved results [7]. End-stage patients who require organ transplants, such as dialysis or cirrhosis patients, have been exposed to broad-spectrum antibiotics prior to transplantation due to frequent hospitalizations, so the risk of developing microbial resistance is high [8]. Antimicrobial stewardship programs (ASPs) have received special support as the prevalence of antimicrobial resistance has increased. ASPs have improved antibiotic, antifungal, and antiviral therapies in clinical settings by promoting the selection of appropriate drug regimens, including dosing, duration of treatment, and route of administration [9‐12]. However, there is a paucity of data documenting ASPs for SOT recipients, preventing us from fully comprehending their potential influence on this population [9, 13, 14]. As previously stated, the rise in SOT, along with an increase in antimicrobial resistance and a scarcity of new effective antimicrobial agents, necessitates the use of effective antibiotic therapy to improve the outcomes of the procedure [15]. Variables unique to the SOT population, such as the time after transplantation, intensity and duration of immunosuppression, type of organ transplanted, and donor-derived infections may be overlooked when stewardship methods are applied broadly. The dearth of clinical evidence on particular ASP interventions and successful treatment duration among SOT patients necessitates the development of customized ASP therapies [16]. In the present study, the clinical and economical outcomes of designing and implementing ASPs in SOT recipients for the first time at Shiraz Organ Transplant Center as the largest SOT center in Asia and worldwide are investigated.

Two thousand seven hundred ninety-one patients participated in this study; they were waiting for transplantation or had undergone solid organ transplantation; of them, 1154 patients were related to the time before ASP and 1637 to the time after ASP. The mean age of this group of patients was 54.31 ± 13.21 years. The demographic information of the patients is shown in Table 2. The total number of 4051 interventions were made by ASP memberships during this study, as shown in Table 3. Measures performed by the ASP significantly reduced the use of all classes of antibiotics, so that before the intervention, 329 DDD/100PD, compared to 201 DDD/100PD (p = 0.04), was seen. Surgical wards have had a much higher reduction in the use of all classes of antibiotics than medical wards (p = 0.01). The clinical outcomes associated with ASP interventions are described in Table 4 and Additional file 1. Also, after the beginning of the ASP monitoring, the total cost of antibiotics purchased ($43.10 per PD) was significantly reduced compared to before ($60.60 per PD) the ASP measures (p = 0.03). The prevalence of different microorganisms before and after the ASP intervention is shown in Fig. 1.

In comparison between the patients waiting for transplantation and transplanted ones, the results of our study showed that the percentage of reduction in the usage of third generation cephalosporins (-13.90% vs. -18.92%), carbapenems.

Also, 51.59% of the ASP team interventions were for patients awaiting transplant, so that the most interventions in this category of patients included discontinuing unnecessary antibiotics, optimizing the dosage, and adjusting the antibiotic dosage based on GFR. Meanwhile, the most interventions of the ASP team among post-transplant patients included de-escalating broad spectrum antibiotic, starting necessary antibiotics, and discontinuing unnecessary antibiotics, respectively.

The mean duration of antibiotic use in patients candidate for transplantation is significantly longer than the transplanted ones before performing ASP (27.12 ± 13.10 vs. 20.18 ± 12.00 days, p = 0.021); after performing ASP, the mean duration of antibiotic use in patients waiting for transplant was significantly decreased compared to the transplanted patients (11.40 ± 25 vs. 11.90 ± 18.00, p = 0.03).

In our study, the number and costs of antibiotics and also the number of resistant pathogens were significantly lower following the ASP implementation and monitoring. Our results demonstrated the highest reduction in consumption with linezolid, beta-lactam/beta-lactamase inhibitors, and aminoglycosides. Reducing the usage of these antibiotics plays an important role in reducing MDR. The most common ASP program interventions in our study was the discontinuation of unnecessary antibiotics, most of which were aminoglycosides, beta-lactams beta-lactamase inhibitors, and linezolid. Many studies on ASP have also concluded that most antibiotics are unnecessary in most cases. According to the research conducted by Cusini et al., 32% of all antibiotics were given unnecessarily; it occured more in the surgical wards than in the medical wards [21]. Impaired inflammatory response due to suppression of the immune system reduces the signs and symptoms of an aggressive infection; therefore, it is essential to start taking antibiotics as soon as possible before the infection has spread [22]. In patients with immunocompromised status, discontinuation or de-escalation of broad-spectrum antibiotics should be done carefully as needed. As noted by Wooyoung Jang et al., inappropriate de-escalation of broad-spectrum antibiotics can result in a significant increase in the use of other classes of antibiotics, in addition to causing treatment failure [23]. Although this trend was not observed in our study, given that the duration of follow-up was one year, this issue should be examined in a larger period of time. These results also indicate the need to form an ASP team and carefully discontinue or de-escalate the antibiotics based on the patient's clinical condition. According to numerous studies on post-transplant infections, MDR pathogens, particularly gram-negative bacteria, are found in the majority of post-transplant infections [8, 24]. Most patients are colonized with a wide spectrum of resistant pathogens as a result of their long-term hospitalization before and after transplantation [25]. Over the course of a year, Cheon et al. found that strict antimicrobial stewardship, especially for carbapenems, significantly reduced the endemic MDR A. baumannii in the intensive care unit [26]. As a result, the ANTARCTICA coalition (Antimicrobial Resistance in Critical Care) has identified the implementation of ASP as one of the top priorities for preventing resistant bacterial colonization in hospitals [27]. ASPs can offset or reduce the costs while enhancing some patient outcomes, implying that they are of great value to some healthcare systems [28]. According to the IDSA/SHEA standards, comprehensive prevention programs can reduce antimicrobial use by 22–36 percent, resulting in significant cost savings [29]. The results of our study showed that the implementation of ASP significantly reduced the duration of antibiotic administration and consequently reduced the monthly and total cost of antibiotics. According to the results of our study, implementation of ASP significantly reduced the duration of antibiotic administration, and thus the monthly and total cost of antibiotics. The most significant cost savings were in the categories of carbapenems, beta-lactam/beta-lactamase inhibitors, and polymyxin, which saved a total of 190,000 dollars in a year by reducing antibiotic use. According to the results of a systematic review study [30], the ASP implementation resulted in a reduction of $448.25 per 100 patient days. Although the patients' length of stay was reduced after ASP implementation, the difference was not statistically significant. In this regard, some studies have found that implementing ASP has resulted in a significant reduction in the length of stay [30]. However, some studies have found no effect on patient duration of stay, and in some cases the length of stay has even risen after ASP [31]. It is important to remember that several potential confounders affect the entire hospital stay, making it difficult to correctly assess the impact of ASP. Infection-related hospitalization should better reflect the impact of an ASP and should be considered an important endpoint in future studies.

In addition to demonstrating the benefits of ASP interventions, such as increased compliance with the guidelines, reduced costs, and lower resistance rates, the results of our study should be considered with caution as it has a number of limitations. For example, only antibacterial drugs were evaluated in this study, but because antifungal and antiviral drugs are also utilized in patients undergoing SOT, ASP programs for these drugs should be considered as well. Also, a detailed and comprehensive analysis of time series cannot be done from retrospective studies, and this requires prospective studies.

Furthermore, our study lasted a year, whereas more accurate data can be extracted in greater detail over a longer length of time. The pattern of consumption resistance has been studied based on the phenotype, and due to the limited cost of the project, it has not been possible to study the genotypes of antibiotic resistance.

In conclusion, our study showed that, the number and costs of antibiotics and also the number of resistant pathogens were significantly lower following the ASP implementation and monitoring.