In pediatric LT, postoperative bacterial infections occur frequently and are potentially life-threatening. In this one-year, retrospective study, an incidence of 67.9% infection rate was observed, which was higher than a previous study in Iran, reporting an incidence of 54.3% bacterial infection among liver transplant pediatrics. [17]. Our findings are also in accordance with the limited reports worldwide regarding LT in pediatrics (51.9% in Germany and 70.8% in France). [18–22]. In a 23-year, retrospective single‐center study conducted by Kukreti et al, 49 incidents of microbiologically documented infection were observed among 145 pediatrics (34%) in post LT, which 79% had bacterial infections only during their stay in the pediatric ICU. [23]. Numerous factors have contributed to the amplified risk of by bacterial etiology in post-LT pediatrics especially during the early periods; including the difficulty of surgical procedures; high levels of immune suppression because of rejection; numerous points of access for microorganisms (eg probes, catheters, incisions); and patient’s poor health state [10, 18, 19, 23, 24].
Based on our results, more than 64.06% of the isolated pathogens were Gram-negative and 35.93% were gram-positive. Our data regarding the proportion of causative pathogens is in accordance with the previous study among post-liver transplant pediatrics in Iran, which showed Gram-negative isolates were comparatively as common as Gram‐positive isolates (51% vs 49%), with a predominance of Enterococcus spp (36.1%) and Staphylococcus spp (11.1%) as Gram‐positive bacteria and Enterobacteriaceae (21.3%), Acinetobacter spp (16.7%), as Gram‐negative ones. Gram negative predominance may be due to various factors such as LT patients’ longer stay in the ICU, longer duration of mechanical ventilation, along with the possibility of kidney failure after transplantation and the need for dialysis, as well as a long history of the use of preoperative broad-spectrum antibiotics due to recurrent hospitalizations and also biliary tract manipulation during surgery, all of which are risk factors for gram-negative infections [25, 26].
However, some studies have demonstrated a predominance of Gram-positive bacteria; such as in a French study, bacterial isolates showed a dominance of Gram‐positive bacteria (78%) which included Staphylococcus aureus (32%) and Staphylococcus epidermis (26%). It is also worth mentioning that all patients in that study were administered gentamicin, polymyxin, and nystatin during the time of their ICU stay for selective intestinal decontamination or until resumption of oral intake in order to reduce not only the predominance of Gram‐positive bacteria, but also the Gram‐negative aerobic bacteria in the intestinal flora [19, 27, 28].
Another concern for pathogens causing infection after transplantation is the emergence of resistant species such as MDR, XDR, and VRE. The results of our studies showed that about 25% of gram-negative species isolated from patients were XDR type; other studies in this field also pointed to the high incidence of MDR and XDR pathogens after solid organ transplantation [29–31].The increase in rates of resistant pathogen species not only affects the efficiency of common antibiotic regimes, but also increases the mortality rate [32, 33].Inappropriate administration of antibiotics in empirical conditions, longer hospital and ICU stays, frequent prescription of broad-spectrum antibiotics such as carbapenems and fluoroquinolones in treatment of spontaneous bacterial peritonitis conditions before LT, as well as the need for hemodialysis or Continuous Renal Replacement Therapies (CRRT) after LT are among the risk factors for emerging resistant pathogens after LT [25, 32].
In the case of gram-positive pathogens, the incidence of VRE infections has been reported to be about 31% in our study, while in the study of Pouladfar et al., 82% of Enterococcus species were VRE [17]. The reasons for this difference in the incidence of VRE can be attributed to the establishment and implementation of stewardship antibiotic programs in our hospital under the supervision of infectious disease and clinical pharmacist specialists in recent years, which has led to a dramatic reduction in the use of inappropriate broad-spectrum antibiotics such as vancomycin.
Our study revealed that Intra-abdominal Surgical Site Infections (SSI) were the most common site of infections in post-liver transplant patients. Based on the studies exploring infection in hospitalized pediatrics during the early periods after LT, the two most frequent sites of infection. [19, 22, 23] were the blood and abdomen. Execution of complex surgical procedures in LT pediatrics and the requirement for insertion of intra-abdominal JP Drain and central vein catheter can have a major impact on the developing infections in the abdomen and blood.
Based on our results, length of stay in ICU and hospital, length of mechanical ventilation after transplant, re-hospitalization and mortality rate were significantly higher in the infected group rather than in non-infected pediatrics. Furthermore, multivariate regression analysis showed that the only risk factor for bacterial infections after LT in pediatrics is the length of stay in the ICU. Factors such as a longer hospitalization and longer stay in ICU have been formerly described to be linked with increased infection in LT by other authors [17, 34, 35]. Although our study revealed that the tacrolimus level was higher in the infected group compared to the non-infected group, no statistical significance was observed. Dohna Schwake et al. demonstrated tacrolimus levels above 20 ng/ml were associated with a higher risk for bacterial infection, especially severe sepsis, septic shock, and SSI. However, this may be due to the complete avoidance of steroids in the absence of rejection in their study in which as a consequence, tacrolimus trough level targets might have been higher [36].
One of the goals of this study was to evaluate the success rate of different antibiotic regimens in empirical as well as definitive therapy. The results of our study showed that receiving carbapenem along with vancomycin, as an empirical regimen, shortens the mechanical ventilation duration compared to beta lactam -beta lactamase inhibitors, although non-significant. Nevertheless, neither of the two regimens was superior in reducing the signs and symptoms of infection. Although the use of carbapenems in the empirical treatment may seem to be necessary with the increase of MDR pathogen species amongst LT, the results of our study showed no difference regarding the administration of carbapenems compared to beta lactam- beta lactamase inhibitors, which is also supported by other studies [37–39].
Given that the use of carbapenems increases the risk of carbapenem-resistant Enterobacteriaceae pathogens [40], some studies have compared the efficacy of carbapenems with beta lactam- beta lactamase inhibitors, especially in the management of ESBL species. This suggests that the use of piperacillin-tazobactam might be a promising alternative to carbapenems for the management of Enterobacteriaceae bloodstream infections, especially when MIC piperacillin-tazobactam is low (MIC ≤ 0.5/4 µgL) or the source of bloodstream infection is the genitourinary tract or abdomen [37]. Furthermore, some studies have also suggested that piperacillin-tazobactam may be a potential alternative to carbapenems in the treatment of AmpC-producing Enterobacteriaceae [41].However, further studies are essential to provide a more accurate and definitive assessment of the effectiveness against beta lactam -beta lactamase inhibitors versus carbapenems, especially since some studies still consider carbapenems to be superior to others regimes [37, 41]. Furthermore, no studies have been conducted in this regard on pediatric LT until now.
Given the increasing trend of gram-negative XDR species, especially in the case of Acinetobacter pathogen, the use of polymyxin E (colistin) is inevitable. In our study, it was found that pediatrics receiving colistin had a significantly shorter length of stay in the ICU and hospital than those who did not receive colistin; however, no significant difference was observed in other factors such as mortality. Given that the number of patients receiving colistin in our study was low (n = 9), the generalization of their results is impossible. However, the results of other studies showed that in the treatment of XDR Acinetobacter baumannii (XDR- Ab) colistin-free regimen is not very successful, and a combination of colistin with carbapenems is most successful in the treatment of these pathogens [30].
The results of our study should be carefully evaluated because it suffers from some limitations; only bacterial infections were evaluated and other infections such as fungal and viral ones were not investigated. Also, the study is the result of a one-year evaluation, so more accurate results may be obtained by evaluating the patients during a longer period. Furthermore, lack of detailed information about the isolated pathogens, including the study of resistance genotypic patterns and the MIC value for MDR and XDR species, and also unavailability of some antibiotics in our centers, such as tigecycline or ceftazidime- avibactam, were the other limitations of our study.