When bacteria enter the bloodstream (bacteremia), they can cause severe infection leading to sepsis (the body's extreme reaction to infection or injury). These conditions require immediate medical attention because of their high morbidity and mortality rates and typically necessitate aggressive antibiotic therapy. However, the alarming prevalence of antimicrobial resistance (AMR) makes treatment of bloodstream infections (BSIs) increasingly difficult. How do BSIs develop? What are some of the factors driving this complicated equation and what can be done to combat resistant infections that become systemic?
What are Bloodstream Infections and Why Are They So Dangerous?
In normal physiological conditions, human blood is considered sterile and is mainly composed of blood cells, plasma and platelets. A few studies have detected low levels of bacteria, or their genetic material, in healthy blood specimens, but a shift in the composition and quantity of microbes can lead to infection, despite the presence of host immune barriers, like skin and mucous membranes, mucus, acids, fluids (sweat, tears etc.), and other immune cells circulating in the blood.
BSIs originate when bacteria, fungi or viruses from different body sites breach the above mentioned immune barriers and enter the bloodstream. This is particularly concerning since the blood is carried throughout the entire body, making it an alarmingly efficient delivery method for pathogenic microbes. BSIs are one of the major causes of mortality and illness worldwide. In 2020, around 48.9 million sepsis cases were reported globally, with 11 million sepsis-associated deaths. These infections have been reported to cause 15-30% mortality, either due to the infection itself, or because they have been exacerbated by other underlying health conditions and lifestyle factors.
The clinical manifestations of BSIs range from fever to systemic complications and widespread inflammation, which can lead to septic shock, a dramatic drop in blood pressure, damage to organs and death. Essentially, as microbes circulate in the blood, they trigger an elevation in the systemic inflammatory immune response and altered cytokine production. While these cytokines can help to kill the microbes causing the infection, they also damage host cells.
What Factors Contribute to BSIs?
The immune status of the host plays a key role in determining BSI risk and is informed by environmental factors, as well as patient demographics, including allostatic load, stress and age. Immunocompromised patients are at the greatest risk for developing severe infection. Studies show that sepsis has more dire consequences in infants and geriatric populations (as age is known to be accompanied by a general decline of immune strength).
Furthermore, a large portion (~40%) of hospital acquired infections (HIAs) are sepsis and septic shock cases. The presence of open wounds following injury or surgery may increase a patient's risk of BSI, as can exposure to immunosuppressive agents administered as anti-rejection medication to transplant recipients or as chemotherapy to cancer patients. In fact, research indicates that approximately 5% of cancer patients get severe sepsis, and hospitalized cancer patients have a 5x greater likelihood of that infection being fatal.
Another, less-discussed factor that has been associated with increased BSI risk, is the role of nutrition. For example, metabolic malfunction and malnutrition (lack of minerals and vitamins) have been linked to higher BSI severity and mortality rates, probably due to weakened immune conditions.
Which Microbes are Likely to Cause Bloodstream Infections and Contribute to AMR?
A range of microbial culprits have the potential to cause BSIs. However, some microbes are particularly concerning due to the rise in antimicrobial resistance (AMR), including the ESKAPE pathogens: Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus faecalis. Among these notorious bacteria, E. coli and S. aureus, in particular, have raised major alarm around the globe.
That is because both methicillin-resistant Staphylococcus aureus (MRSA) and E.coli may demonstrate resistance to third generation cephalosporins, a class of β-lactam antibiotics that are utilized as broad-spectrum antimicrobials with higher efficacy, less adverse effects and better pharmacokinetics for treatment compared to other conventional antibiotics like penicillin. Gram-negative bacteria may demonstrate cephalosporin resistance by producing an enzyme-extended spectrum β-lactamases (ESBL) that degrades the antibiotic.
What Are the Consequences of AMR in BSI?
Ultimately, rapid and accurate identification of BSIs is crucial, as the results will dictate the course of treatment. Microbes are usually detected in the bloodstream by conventional laboratory blood culture methods, and the advent of next generation genomic sequencing (16S sequencing), has improved the speed and accuracy of BSI identification.
Yet, treating BSIs is challenging, as the involved pathogens often have relatively fast growth rates, making it difficult for health care professionals to get ahead of the curve when it comes to slowing infections. Clinicians often begin with broad-spectrum antibiotics before narrowing down the treatment regimen based on culture or sequencing results, and when AMR is involved, the path forward becomes even murkier.
When BSIs are resistant to first- or even second-line antibiotics, the delivery of effective treatment is significantly delayed or non-existent. Multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains demand more complex treatment regimens. What's more, the heavier-hitting antimicrobials are often more toxic-not only to the microbes, but also the patient. For example, when E. coli and MRSA are resistant to third-generation cephalosporins, the infections must be treated with last 'resort drugs,' such as vancomycin for MRSA and carbapenems for E. coli. What's more, these antimicrobials are administered through intravenous injections only, which means that the patients must be hospitalized to receive treatment, mainly because patients are extremely ill, and no alternative treatments options are available.
Overall, AMR can lead to higher mortality rates, and resistant infections often require prolonged hospital stays, intensive care and increased use of medical resources, placing a burden on health care systems. In fact, the financial burden of AMR is immense, encompassing direct health care costs, lost productivity and expenses related to ongoing research and development of new antimicrobials.
How are We Tackling BSIs?
So, what can be done to interrupt this vicious problem of AMR BSIs? A multi-faceted approach involving clinical stewardship, robust surveillance and heightened public awareness is essential to mitigate this crisis. Persistent efforts in research, coupled with prudent antibiotic practices, can help safeguard the arsenal of antimicrobial agents for future generations.
Although there have been significant advances to culturing techniques and molecular based technology, like high throughput sequencing, diagnostic challenges continue to exist. Below are some additional methods to help mitigate the consequences of AMR BSIs.
- Stewardship Programs: Implement robust antimicrobial stewardship programs in health care settings to promote the appropriate use of antibiotics can curb the development of resistance.
- Surveillance Systems: Establish and maintain comprehensive surveillance systems to monitor the prevalence and spread of AMR. In 2020, 2 new indicators to monitor the proportion of BSIs due to MRSA and E. coli resistant to 3rd generation cephalosporins were added to the United Nations Sustainable Development goals (health target 3.d to strengthen the capacity of all countries, in particular developing countries, for early warning, risk reduction and management of national and global health risks). In 2021, WHO launched Global Antimicrobial Resistance and Use Surveillance System (GLASS), a collaborative initiative aimed at strengthening "knowledge through surveillance and research."
- Infection Prevention: Enhance infection prevention and control measures, such as hand hygiene, sterilization protocols and the judicious use of invasive procedures and medical devices.
- Research and Development: Invest in research for new antimicrobial agents, vaccines and diagnostic tools to stay ahead of evolving pathogens.
- Policy: Support a multidimensional domestic and global policy framework that champions bold solutions to addressing AMR and fosters antimicrobial stewardship
- Public Education: Educate the public on the risks and appropriate use of antimicrobials to reduce unnecessary consumption and misuse of antimicrobial therapies. This is particularly relevant in locations with large numbers of AMR cases.
How has antimicrobial resistance research informed the evolution of U.S. and international policy over the past 10 years? Microbiologists and policymakers play key roles in the fight against AMR. Learn how ASM is championing the fight against AMR and what you can do to get involved!
