Background Studies on the effect of inadequate empirical antibiotic therapy on the outcome of patients with systemic infection have led to inconsistent results. Methods We analysed data from a comprehensive clinical database collected prospectively in a university hospital between 2008 and 2009. All adult patients who registered in the emergency department (ED) with a bloodstream infection (BSI) were enrolled. Empirical therapy was considered adequate if it included antimicrobials to which the specific isolate displayed in vitro susceptibility and that were administered within 24 h of ED admission. The propensity score (PS) was created by a logistic regression model predicting inadequate empirical therapy. PS-adjusted multivariate analysis was performed by the Cox regression model. The Mortality in Emergency Department Sepsis (MEDS) score was used for the adjustment of residual confounding due to differences in the baseline clinical severity of disease. Results Out of 937 episodes of bacteraemia, 255 (27.2%) patients received inadequate empirical antimicrobial therapy. A crude analysis showed that inadequate antibiotic therapy was associated with higher mortality rates (hazard ratio 1.78, 95% CI 1.30–2.45). PS-adjusted multivariate analyses also showed a significant adverse impact (hazard ratio 1.59, 95% CI 1.14–2.28). The clinical disease severity significantly modified the effect of inadequate antibiotic therapy on survival. The magnitude of the adverse impact of inadequate antibiotic therapy decreased with the increasing severity of sepsis (P = 0.009). Conclusions Inadequate empirical antimicrobial therapy for community-onset BSI was associated with higher 30 day mortality rates. Study populations with different clinical severities may have different results, which may help to partly explain the heterogeneous findings in many similar studies.

Naja atra envenomation is one of the most significant clinical snakebite concerns in Taiwan. Taiwanese freeze-dried neurotoxic antivenom (FNAV) is currently used clinically for the treatment of cobra snakebite, and has been shown to limit the mortality of cobra envenomation to less than 1%. However, more than half of victims (60%) require surgery because of local tissue necrosis, a major problem in patients with cobra envenomation. Although the importance of evaluating the neutralizing effect of FNAV on this pathology is recognized, whether FNAV is able to prevent the local necrosis extension induced by N. atra venom has not been investigated in detail. Cytotoxins (CTXs) are considered as the major components of N. atra venom that cause necrosis. In the current study, we isolated CTXs from whole cobra venom and used both whole venom and purified CTXs to develop animal models for assessing the neutralization potential of FNAV against venom necrotizing activity. Local necrotic lesions were successfully produced in mice using CTXs in place of whole N. atra venom. FNAV was able to rescue mice from a subcutaneously injected lethal dose of cobra venom; however, it was unable to prevent CTX-induced dermo-necrosis. Furthermore, using the minimal necrosis dose (MND) of CTXs and venom proteome data, we found a dose of whole N. atra venom suitable for FNAV and developed a workable protocol for inducing local necrosis in rodent models that successfully imitated the clinical circumstance of cobra envenoming. This information provides a more comprehensive understanding of the pathophysiology of N. atra envenomation, and serves as a guide for improving current antivenom strategies and advancing clinical snakebite management in Taiwan. Naja atra envenomation is an important public health issue in Taiwan. Although the mortality rate of cobra snakebite is controlled using antivenom, more than half of victims develop symptoms of local necrosis and require surgical intervention. Whether the Taiwanese freeze-dried neurotoxic antivenom (FNAV) currently in clinical use is able to prevent the local necrosis extension induced by N. atra venom is still unclear. In this study, we developed a dermo-necrosis animal model using purified cytotoxins (CTXs), the major necrosis-related proteins from N. atra venom. We found that FNAV was able to neutralize the lethality of whole cobra venom, but was unable to neutralize the necrosis induced by CTXs in vivo. This finding introduced an example that supplementary quality control assays may be necessary to determine the effectiveness of antivenoms in neutralizing specific pathology induced by the venom; only evaluating the rodent lethality prevention is insufficient. Our results provide insights that should help improve current antivenoms and advance cobra snakebite management in Taiwan.

Snakebite envenoming is a public health issue linked to high mortality and morbidity rates worldwide. Although antivenom has been the mainstay treatment for envenomed victims receiving medical care, the diverse therapeutic efficacy of the produced antivenom is a major limitation. Deinagkistrodon acutus is a venomous snake that poses significant concern of risks to human life in Taiwan, and successful production of antivenom against D. acutus envenoming remains a considerable challenge. Among groups of horses subjected to immunization schedules, few or none subsequently meet the quality required for further scale-up harvesting. The determinants underlying the variable immune responses of horses to D. acutus venom are currently unknown. In this study, we assessed the immunoprofiles of high-potency and low-potency horse plasma against D. acutus venom and explored the conspicuous differences between these two groups. Based on the results of liquid chromatography with tandem mass spectrometry (LC-MS/MS), acutolysin A was identified as the major component of venom proteins that immunoreacted differentially with the two plasma samples. Our findings indicate underlying differences in antivenoms with variable neutralization efficacies, and may provide valuable insights for improvement of antivenom production in the future.