Low-cost interventions reduce neonatal sepsis from Klebsiella pneumoniae

A new study found that a multifaceted infection prevention and control intervention could at least temporarily thwart outbreaks of infections from the Klebsiella pneumoniae bacterium, a leading cause of neonatal sepsis and mortality in Africa and South Asia.

Sepsis is a leading cause of neonatal mortality in low- and middle-income countries (LMICs), caused in large part by bloodstream infections from the multidrug-resistant pathogen Klebsiella pneumoniae (K. pneumoniae). As this pathogen becomes more resistant to common antibiotics, preventive measures to reduce its transmission are critical, particularly in low-resourced and overcrowded LMIC hospitals, where it is easy for bacterial and viral pathogens to spread and challenging for sepsis cases to be diagnosed quickly and accurately.

Low-cost infection prevention and control (IPC) measures present a valuable opportunity to mitigate the spread of K. pneumoniae, according to a new study led by researchers at Boston University School of Public Health (BUSPH) and the London School of Hygiene and Tropical Medicine (LSHTM). Published in the journal PLOS Global Public Health, the study utilized whole genome sequencing to assess the effects of a bundle of IPC measures on an outbreak of K. pneumoniae infections that led to sepsis in a Zambian neonatal intensive care unit (NICU), and found that these measures successfully disrupted a large and long-running bacterial outbreak.

However, the preventive measures did not eliminate the outbreak entirely. While K. pneumoniae transmission was initially contained, some of the bacteria reemerged along with new strains, sparking additional infections throughout the neonatal unit. Moreover, the majority of the bacteria that was tested produced extended spectrum beta-lactamases (ESBLs) enzymes, or hard-to-treat enzymes that are highly resistant to penicillin and other common antibiotics. The team also observed a few carbapenemase enzymes, a class of bacteria that are resistant to "last-resort" carbapenem antibiotics.

The findings underscore the value of whole genomic surveillance-considered the "gold standard" method for identifying bacteria-in providing a deeper understanding of how pathogens spread, as well as the need for continued IPC efforts in low-resource hospital settings to mitigate transmission of deadly infections among vulnerable populations worldwide. Sub-Saharan Africa and Southern Asia account for the majority of child deaths under five years old, the majority of which are attributed to sepsis. 

"Neonatal sepsis is one of the major causes of death among children in the first 28 days of life," says study senior author Dr. Davidson Hamer, professor of global health and medicine at BUSPH and BU Chobanian & Avedisian School of Medicine. "In low- and middle-income countries, the quality of infection prevention and control measures can be very limited and, as a result, there is a lot of cross-transmission from infected equipment or healthcare workers. Our study found that a variety of preventive measures worked to temporarily clear the main serotype while concurrently decreasing neonatal mortality, suspected sepsis, and confirmed bloodstream infections with true pathogens."

The new study utilized blood samples collected during the Sepsis Prevention in Neonates in Zambia (SPINZ) study, the original evaluation of the IPC interventions to mitigate sepsis in the Zambian NICU, which was published in Clinical Infectious Diseases in 2019. Implemented over a 12-month period, the low-cost IPC bundle consisted of IPC training for hospital staff, text message reminders of the training, alcohol hand rub produced onsite using a World Health Organization formulation, enhanced cleaning throughout the unit, and weekly bathing of babies using 2% chlorhexidine gluconate. The study detected multiple pathogens that caused neonatal sepsis throughout the NICU and found that neonatal mortality was lower during the IPC intervention period. 

The newest study focused specifically on the development and spread of the K. pnemouniae strains-which caused the majority of neonatal sepsis cases in the SPINZ study-before and after the implementation of the IPC bundle. In the analysis, the researchers analyzed WGS data of 411 K. pneumoniae blood samples and found that the majority of neonatal infections likely resulted from contaminated sources within the NICU, as opposed to sources outside of the hospital.

While most hospital-acquired infections take time to develop and usually occur after at least two days of a hospital stay, the team observed that nearly 35 percent of K. pneumoniae infections occurred within the first 24 to 48 hours of babies being admitted to the NICU, which indicates that these infections resulted from different sources within the hospital setting.

This early acquisition upon arrival in the NICU suggests that newborns may be directly exposed to substantial doses of bacteria, perhaps through contaminated reagents. Unfortunately there was no source screening for bacteria in this study, but infection control investigations in other NICUs have found contaminated IV fluids as a source of K. pneumoniae outbreaks."

Dr. Kathryn Holt, study corresponding author, professor of microbial systems genomics at LSHTM

More broadly, the researchers are also interested in understanding the characteristics of K. pneumoniae to inform a potential future vaccine that could be administered to mothers during pregnancy to target this bacterium and protect babies from developing these infections. An analysis in PLOS Medicine last January utilized the same data from the SPINZ study and found that a single vaccine targeting 20 strains of K. pneumoniae could possibly provide protection for at least 70 percent of K. pneumoniae neonatal sepsis cases in Africa and South Asia.

But absent an effective and widely accessible vaccine, the findings show that IPC measures can be a valuable alternative, even though this intervention did not fully suppress bacterial transmission.

"These interventions are sorely needed in many areas around the world as antimicrobial resistance continues to widen," Dr. Hamer says. Countries such as India and Thailand are already developing resistance to the last-resort class of carbapenem antibiotics, he notes. 

"That means that there are very few options left to treat certain infections, other than very new drugs or some older toxic drugs. If we can take low-cost preventive measures to limit the infections that these antibiotics treat, we will also limit the need to use these products and stall resistance to them."

The study's lead author is Dr. Laura Phillips, of the Department of Infection Biology at the London School of Hygiene & Tropical Medicine.