Early Acquisition of Antimicrobial Resistance in Newborns in Low- and Middle-Income Countries

Every year, it is estimated that nearly 7 million potentially serious bacterial infections occur in newborn babies, resulting in more 550 10 annual neonatal deaths. Most of these infections and deaths occur in LRICs, where often scarce resources can limit the ability to diagnose and treat sepsis. These issues are further complicated by the global increase in antimicrobial resistance (AMR), particularly the rapid spread of antibiotic-resistant gram-negative bacteria, including Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae which are no longer susceptible to antibiotics. ß-lactam antibiotics, such as ampicillin and ceftazidime. It is already estimated that antimicrobial resistance is responsible for approximately 5 million deaths per year worldwide and is expected to cause 10 millions of annual deaths by 2050.

Although neonatal sepsis represents a major health concern in LMICs, it remains unclear how, when and where newborns contract life-threatening infections. Additionally, the factors associated with the presence of RAM in these cases are also being elucidated. For example, no studies have been conducted in LMICs to determine whether the presence of antibiotic-resistant bacteria in mothers is linked to the development of sepsis in their newborns.

In a new study published in Character Microbiology, Dr Maria Carvalho, Dr Kirsty Sands and a network of international colleagues set out to examine the presence of antibiotic resistance genes (ARGs) in the gut microbiota – the collection of microbes in the human gut – mothers and babies from 7 LMICs in Africa and South Asia. As part of the “Stress of Antibiotic Resistance in Neonates from Establishing Societies” study, or BARNARDS – a network of 10 internet clinical sites across Bangladesh, Ethiopia, India, Nigeria, Pakistan, Rwanda and South Africa – they recruited 35 040 mothers and 35 217 newborns. From these they took 10 148 rectal swabs (10 217 from mothers and 2 931 of newborns, including 626 with sepsis), which were used to cultivate the bacteria present in these samples and assess the presence of clinically important ARGs in the microbiota of mothers and their babies. The authors found that a large number of samples carried genes linked to antibiotic resistance, suggesting that resistance to antimicrobials is much more prevalent in these settings than expected. For example, samples from approximately 1 in 5 neonates (18,5%) were positive for blaNDM, a gene which encodes New Delhi metallo-beta-lactamase, which is an enzyme that can destroy ß-lactam antibiotics, including commonly used carbapenems, resulting in bacteria being resistant to this drug. Importantly, the researchers found that ARGs were present in neonates within hours of birth, indicating that the initial colonization of neonates with antibiotic-resistant bacteria occurred at birth or shortly after birth. time after, probably through contact with the mother or from the hospital environment.

Samples collected from mothers and newborns were also used to identify bacteria resistant to antibiotics. In total, the authors isolated 1 072 gram-negative bacteria, the majority of them being K. pneumoniae, E. coli and E. cloacae . Whole genome sequencing revealed that although these bacteria are quite diverse from place to place, there are clear clusters associated with specific countries and hospitals. The BARNARDS team identified some cases in which bacterial isolates were shared by different neonates attending the same clinical web page, suggesting that in some cases transmission of resistant bacteria from the hospital environment or between neonates born may have occurred. Additionally, genomic analyzes have shown that some isolates of E. coli were indistinguishable between mothers and newborns, supporting that mother-to-child transmission can occur during or after labor.

Finally, the researchers identified the factors of risk associated with carrying ARGs, examining characteristics associated with water, sanitation and hygiene (Clean) and previous infections. The team found that frequent hand washing by mothers reduced the risk of carrying resistance genes (compared to occasional hand washing), while this risk was increased if mothers had reported a year infection or taken antibiotics in the 3 months preceding their enrollment in the study. Maternal carriage of these ARGs was also associated with an increased risk of adverse birth outcomes and neonatal sepsis.

These results demonstrate the high prevalence of resistance to antibiotics in the microbiota of mothers and their newborns in LMICs, including in the hours following birth. Furthermore, the study highlights that a better understanding of the transmission routes of ARGs, including from mother to child and in the clinical environment, is essential to prevent neonatal sepsis. Finally, the results reinforce the importance of access to clean water, sanitation and good hygiene in reducing antimicrobial resistance and reducing sepsis and neonatal mortality rates in LMICs.

Professor Tim Walsh, who supervised the study, underlined the novelty of the results: “This post demonstrates two new observations. The first is that the incidence of AMR carriage, including carbapenem resistance, is of grave concern, not only in South Asia but also in parts of Africa. The second is that the incidence of carbapenem resistance is very high in neonates, demonstrating that RAM carriage occurs within a few days of life. Obviously, this research raises many questions about transmission and also about how the acquisition of these drug-resistant strains might affect the growth of the baby – questions that we are currently working on within the ‘IOI and with our collaborators.”

Dr Kirsty Sands, who co-directed the study, highlighted how the study is beginning to elucidate the factors governing the spread of AMR: “The BARARNARDS group has worked together for over seven years to produce one of the largest studies that analyzes women’s gut bacteria. and their newborns. This study shows that transmission dynamics can be very complex, as we have found links between carriage, infection, sanitation and hygiene. We need to continue our research to fully understand these transmission dynamics, which could help guide better infection prevention. and control measures.”

As explained by Dr. Maria Carvalho, who co-led the research, the study also fostered capacity building in web sites local: “BARNARDS has developed and implemented a standardized methodology to achieve the common goal of minimizing the impact of morbidity and mortality in newborns in Africa and South Asian countries. We also looked at the specific needs of each website. For example, BARNARDS has set up an additional maternity ward (20 beds) and a microbiology laboratory at the Murtala Muhammad Specialty Hospital in Kano, Nigeria. different levels (clinical, research and outreach) has been a great achievement of BARARNARDS.”

Dr Rabaab Zahra, who led the study in Islamabad, Pakistan, emphasized the importance of these findings for understanding and controlling the spread of AMR: “Based on our knowledge of the prevalence of AMR, we had speculated about certain levels of resistance in newborns, but we did not I don’t think it started that early in life. This raises concerns about our policies on the use of antibiotics, as well as hygiene and infection control practices in healthcare facilities.

The impact of the current practice information study in some hospitals was also highlighted by Dr. Fatima Modibbo, who co-led the study in Kano, Nigeria: “Before the research began at Kano Hospital, blood cultures were not routinely implemented. However, during the study, we were able to identify patterns of bacterial resistance in blood cultures of neonates with sepsis that led to life-saving changes in empiric drug treatments and reduced neonatal mortality rates.

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