Earlier this month, the first ever conference on Klebsiella was held, at the Institut Pasteur in Paris. The 3-day event drew a crowd of 400 scientists, with many more joining online. Given the growing clinical importance of Klebsiella pneumoniae, some expressed surprise it had not been the topic of a focused conference before, but the reality is Klebsiella has not been high on the research agenda – until now. 

What is Klebsiella?

Klebsiella pneumoniae are close relatives of E. coli and Salmonella, but behave quite differently. K. pneumoniae are ubiquitous – they are best known for colonising the gastrointestinal tracts of humans and all kinds of animals, but can also colonise the respiratory tract, as well as plants, surfaces, plumbing, and other diverse habitats. A natural part of human microbiomes, they can exploit vulnerabilities in their hosts to cause ‘opportunistic’ infections (most commonly urinary tract infections, pneumonia and wound infections, any of which can progress to cause sepsis). Most of the disease burden is therefore in hospital patients, where K. pneumoniae has long been a leading cause of healthcare-associated infections. These infections can stem from the bacteria a patient brings into the hospital as part of their own microbiome, or from strains acquired in hospital from other patients, or from contaminated objects or environments (the bacteria seem to love sinks and drains). 

Naturally resistant to penicillins, many K. pneumoniae have also acquired resistance to many different drugs, with high rates of resistance to third-generation cephalosporins and carbapenems. In many settings treatment options have become extremely limited, with reliance on older more toxic drugs (like colistin or tigecycline) or new expensive drugs (like beta-lactamase combination drugs, and cefiderocol). While these issues have been known for many years, the problem of antimicrobial resistant (AMR) Klebsiella seems to have crept up on us somewhat, and those outside the field are more likely to have heard of ‘MRSA’ or ‘C. difficile’ as the superbugs plaguing hospitals, with little to no public name-recognition for Klebsiella. 

Why does Klebsiella matter?

In the past year some key reports on the global AMR burden, and strategic priorities to address it, have been published, all highlighting the importance of Klebsiella. 

In September 2024, the “Global burden of bacterial AMR” estimates were released, identifying K. pneumoniae as one of just six organisms with an attributable burden estimated to exceed 100,000 AMR deaths in 2021.  K. pneumoniae was most significant in children under 5 years, in whom deaths associated with Streptococcus pneumoniae have reduced dramatically thanks to the introduction of pneumococcal vaccines. Overall, K. pneumoniae was estimated to be responsible for 19.4% of AMR-attributable deaths in the under-5s, and 12.7% of AMR-attributable deaths in people aged 5 years and older.  

The majority of Klebsiella deaths in children occur in low- and middle-income countries (LMIC). Data from the Child Health and Mortality Prevention Surveillance (CHAMPS) study, which assigns causes of death for children under 5 and stillbirths in sites located in seven African countries and Bangladesh, provides direct support for the importance of K. pneumoniae: it was identified in the causal chain for 21% of all deaths in this age group. In 20% of these cases, K. pneumoniae was identified as the underlying cause; in the remaining cases with K. pneumoniae in the causal chain, the underlying causes were non-bacterial and likely create vulnerabilities that K. pneumoniae exploit and exacerbate (preterm birth complications, perinatal asphyxia or hypoxia, and congenital birth defects in neonates; malnutrition and HIV in older children). The K. pneumoniae isolated post-mortem were largely resistant to the antibiotics recommended for empirical treatment of neonatal sepsis (84% resistant to ceftriaxone, 75% resistant to gentamicin), echoing recent reports from the NeoOBS study of neonatal sepsis which also identified K. pneumoniae as the most common pathogen isolated.  

What can we do about Klebsiella?

The updated “WHO Bacterial Priority Pathogens List”, released April 2024, identified carbapenem-resistant and third-generation cephalosporin resistant Klebsiella pneumoniae as critical threats, placing them at the top of the priority list of pathogens of public health importance requiring research and development, and strategies to prevent and control AMR. Klebsiella, along with other Gram-negative bacteria, was already identified as a priority for GARD-P (the Global Antibiotic Research & Development Partnership) and CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator fund), who are supporting new therapeutic strategies against the pathogen and other Gram-negative bacteria. 

As K. pneumoniae are already resistant to most of the drugs we have available, and have shown a remarkable capacity to acquire new resistances, there is also intense interest in the possibility of preventing infections (or reducing their severity) in vulnerable populations using vaccines. In April 2024, a Vaccine Value Profile for K. pneumoniae was published, describing two potential vaccine strategies: a vaccine delivered to pregnant women in LMIC to protect the fetus and young infant; and a worldwide vaccine for vulnerable children, adolescent and adult populations identified as at risk of K. pneumoniae infection (e.g. due to malnutrition, being immunocompromised, or intensive healthcare exposures). The WHO’s November 2024 report on the impact of vaccines in reducing AMR and antibiotic use rated a maternal vaccine with 70% efficacy and 70% coverage as ‘medium feasibility’ but with high impact, estimated to avert 27,500 neonatal deaths annually, reducing antibiotic use by 210,000 daily doses and saving $US279 million in hospital costs.

There was a lot of discussion at the KLEBS conference about potential vaccine strategies. The requirements for a maternal vaccine will be tough to meet – they must be single dose, cheap, and safe in pregnancy. Because of these aspects, most of the focus was on polysaccharide-conjugate vaccines as these have worked well for other bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.  

Other strategies presented include protein-based vaccines, monoclonal antibodies and phage therapy; these are considered less likely to be effective for neonates in LMICs, but could have high impact in other settings. There was also a focus on infection prevention and control, particularly in hospital settings where genomic surveillance data provides overwhelming evidence for the role of transmission in establishing K. pneumoniae infections. Critically, there were several talks at the conference presenting new aspects of disease pathogenicity as well as new models for K. pneumoniae infection, which will be very important to support pre-clinical development and testing of vaccines and other interventions. 

It was refreshing to see so many people gathered to focus the spotlight on Klebsiella – a problem that, as the latest burden and vaccine impact estimates highlight, we cannot afford to ignore.