At the 35th European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global conference held in Vienna, Austria from 11 April to 15 April 2025, the impact of sex differences in the management and outcome of patients with serious bacterial infections was discussed. The subject is under-researched but important as it could improve diagnosis and treatment, as well as understanding of the underlying pathogenesis of these infections.
Sex impacts many aspects of bacteremia, an infection caused by the presence of bacteria in the blood, although the interaction between sex and bacteremia is complex. Various studies analysing sex differences in Staphylococcus aureus bacteremia (SAB) have noted that females with SAB have higher mortality than males, although this effect has not been observed in all studies. One study in Denmark analysed 2,638 SAB patients, 39% of whom were female, between 2000 and 2011 and identified an increase in female mortality relative to males (HR 1.30). In a systematic review of more than 100,000 patients with SAB across 81 studies, there was an increase in mortality in females compared to males (a 1.12 ratio). Another nationwide cohort study in the UK, involving more than 7,000 SAB patients, confirmed increased mortality in women, with researchers stating that this was due to SAB.
Sepsis is a life-threatening organ dysfunction
One problem when analysing the relationship between sex and the management and outcome of bacteremia and sepsis is that there is typically an under-enrolment of females in these studies. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. In sepsis studies, only around 10% report outcomes by sex, and only 1 in 24 randomised controlled trials on emergency departments between 2010 and 2023 reported a sex-disaggregated analysis. The literature is therefore limited, with only between 5 and 10 studies available on SAB, but demonstrates that female mortality is higher than in males.
Fewer than five studies on bacteremia caused by Streptococcus pneumonia are available, although these show that male mortality is higher. There are between 10 and 15 studies on sepsis, and these also show that male mortality is higher. However, there is a lot of heterogeneity in sepsis studies as the type of infection and the causative agent vary, as do the source and endotypes, and thus it is difficult to draw conclusions.
Many different factors contribute to these sex-based differences in bacteremia and sepsis outcomes. Differences in clinical presentation, treatment and response to infection may all play a part. The Duke cohort of 3,384 SAB patients showed that female patients were more likely to be black, more likely to be dialysis-dependent, and less likely to have been treated with intravenous drugs. Women are also known to have longer symptom-to-diagnosis time, and this is seen in diseases such as myocardial infarction, stroke and tuberculosis. There are also differences in the infection source between men and women. Urinary tract infections (UTIs) are more prevalent in females, whilst males have higher rates of pneumonia. On average women have shorter antibiotic treatment courses and less frequent one-hour bundle sepsis therapy. In terms of immune responses, adult females generally produce a stronger innate and adaptive immune response, which results in faster clearance of pathogens and lower susceptibility to infection. This female protection is often associated with the immune-enhancing effects of estrogen, and the disadvantage in males with the immune suppressive capacities of testosterone. However, immune advantages are still present in post-menopausal women with sepsis.
Septic shock protection is probably due to female sex hormones
Animal models can also provide important insights into sex. In mouse models with a DUSP3 deletion, female mice were septic shock-protected. Septic shock is a subset of sepsis in which particularly profound circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. This protection was probably due to female sex hormones, as the deletion did not lead to septic shock protection in males or in females who had had their ovaries removed.
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By GlobalDataIn another mouse model, trained innate immunity was conducted by injecting beta-glucan into the peritoneum of the mice. Female mice were protected against sepsis by an upregulation of phagocytes and improved bacterial clearance, hence better organ protection, especially in the lungs, liver and kidneys. This was also likely to be estradiol-mediated because the advantage disappeared in females when their ovaries were removed. However, in contrast to animal models, another study showed that there was more bioavailable estradiol in sepsis patients compared to healthy controls. Moreover, there was more available estradiol in those that did not survive compared to those that did survive. This contrasts with the data from animal models, since estradiol in female mice appears to have a protective effect but in the study on human subjects it seems to have the reverse effect.
In conclusion, the interplay between sex and serious bacterial infections, including bacteremia and sepsis, is complex and more research is needed. Nonetheless, it is evident that there are differences between male and female responses. Equality in research inclusion is important to better understand the inconsistencies.
