The PF contamination rate was 53.36% in our study, and the incidence of p-DDIs was 3.94%, which was consistent with the rates reported in most studies [12]. In most cases, PF contamination seems manageable and harmless and would not lead to severe DDIs[13, 14]. However, when reported, the mortality rate of such infections is high[14, 15].
We remained vigilant about the monitoring and decontamination of PF, and ceftizoxime was previously used for PF decontamination because of its relatively broad-spectrum activity against commonly seen Gram-positive and Gram-negative bacteria[16]. We found that MDR Gram-negative pathogens accounted for a nonnegligible percentage of the contaminating pathogens (80/461, 17.35%) in the PF, and of all 34 patients with p-DDIs, 23 patients were confirmed to have MDR Gram-negative pathogen-related p-DDIs, suggesting that MDR Gram-negative pathogens were likely to escape the ceftizoxime decontamination and prophylaxis and contribute to pernicious infectious consequences. Hence, we adjusted the goal of decontamination from untargeted generic prevention to targeted prevention of MDR Gram-negative pathogen transmission.
Therefore, the focus is on the selection of an effective antibiotic for decontamination regimen against MDR Gram-negative pathogens and how to balance the benefits and potential risks, such as toxicity and increasing resistance. For tissue preservation, a widely implemented regimen includes cefmetazole, vancomycin, lincomycin, and polymyxin B[6, 7]. However, there is still a lack of clinical practice guidelines currently on the decontamination regimen.
To be suitable for PF decontamination, an antibiotic needs to exhibit valid performance and stability in PF at a temperature of 0-4°C, low toxicity, and most importantly, antibacterial activity targeted to MDR Gram-negative pathogens. Polymyxins are a class of cyclic polypeptide antibiotics[17] that are active against Acinetobacter spp., Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., Escherichia coli, etc.[18], and may also possess broad-spectrum antifungal properties[19, 20]. In clinical practice, polymyxins represent some of the last treatment options for MDR bacterial infections. Of the different isolated polymyxins, polymyxin B sulfate, colistin sulfate and colistin sulfomethate sodium are commercially available. Colistin sulfomethate sodium is an inactive pro-drug and was ruled out [21]. Both colistin sulfate and polymyxin B sulfate exhibited antimicrobial activity in vitro and exerted similarly high bactericidal activity when administered topically [21, 22]. While colistin sulfate showed less nephrotoxicity, little has been reported on the bactericidal effect of colistin sulfate under allograft preservation conditions [23, 24]. After the relaunch of colistin sulfate in May 2019 in China, we quickly changed our decontamination regimen from ceftizoxime to colistin sulfate for the purpose of preventing MDR Gram-negative pathogen-related p-DDIs.
In our study, 240 grafts were decontaminated using colistin sulfate. The contamination rate of PF in this group was similar to that in the ceftizoxime group, but the incidence of p-DDIs in the colistin sulfate group decreased to zero under the same empirical prophylaxis regimen. Colistin sulfate demonstrated a stronger capacity to stop the MDR Gram-negative pathogens in PF from causing related p-DDIs than ceftizoxime (p=0.002). Based on these results, colistin sulfate has become a routine PF decontamination regimen at our center.
Overall, although the relationship between PF contamination and DDIs has not been fully elucidated, we still recommend routine PF collection and culture. The goal of decontamination should be targeted at MDR Gram-negative pathogens, and colistin sulfate is recommended as the decontamination regimen for PF. However, there are several concerns and limitations of our study. It was difficult to fully determine the relationship between PF contamination and postoperative infection, as the surgical and medical data regarding organ procurement were incomplete (e.g. intestine/lung injury and donor antibiotic administration). Additionally, we did not study fungal contamination and infection. Some studies claimed that prophylactic antibiotics could increase drug resistance, especially in the setting of colistin-resistant bacteria emerging worldwide [17, 25, 26]. However, in this study, colistin sulfate was utilized in vitro in PF at a very high dose with a single administration, which could minimize the negative impact on the trend in drug resistance. Further evidence-based research needs to be performed to better assess the benefits and risks of colistin sulfate as a decontamination treatment for PF.