Among babies presenting with signs of serious infection, or who develop these signs whilst in hospital, bacterial resistance to the antibiotics that are normally used is increasing. This means that babies with infections may be at a higher risk of dying. In Africa, alternative antibiotics are often expensive and may themselves cause the bacteria to become resistant. Therefore, new treatment strategies are needed. Fosfomycin is a potentially inexpensive antibiotic that is licenced for use in children in Europe and may be useful to resource-poor countries. It has a good safety profile in children and is expected to be effective against infections that do not respond to the currently used antibiotics. However, more information is needed to inform how fosfomycin should be used in babies in Kenya.

We wanted to find out what doses of fosfomycin would be most suitable for sick newborns in Kenya in order to optimise its use in an effective and safe way. We also wanted to find out how well local bacteria that have been previously found (and stored) from patients at Kilifi County Hospital are able to be killed by fosfomycin.

The study took place in Kilifi County Hospital, Kilifi, Kenya.

The study measuring the levels of antibiotics in newborn babies, included 120 babies admitted to the hospital with presumed infection. Sixty-one (61) of these babies were given fosfomycin in addition to standard treatment and drug levels measured; the other 59 received standard treatment only.

We asked parents and guardians of all babies aged 28 days or less who were admitted to Kilifi County Hospital with signs of infection to participate, unless they were being transferred from another hospital, already received other antibiotics by injection, were very sick or premature, or had abnormally high salt (sodium) levels in their blood.

After providing information and answering any questions, informed consent was requested from the child’s parent or guardian. A doctor or study clinical officer examined the baby and took the usual admission investigations, then prescribed the two antibiotics that are currently recommended by the WHO for the treatment of presumed infection in babies (ampicillin and gentamicin).

Half of the babies were selected randomly to receive intravenous fosfomycin as well as the standard antibiotics. The nurse or clinical officer then took two blood samples to check fosfomycin levels. After a minimum of four doses of intravenous (IV) fosfomycin (over 48 hours), when their condition improved and they were tolerating feeds by mouth, the baby was then changed on to oral fosfomycin. A further two blood samples were collected after the first oral dose of fosfomycin, including one to check the kidney and liver function and level of salts in the blood (which is currently a routine investigation). Each of these blood samples was approximately 0.5ml, giving a total for this research of  approximately 2.5ml (half a teaspoon) for checking the drug levels, and a further 1ml (a quarter of a teaspoon) for checking the level of salts in their blood.

For all babies, a blood test was taken (which is normally part of routine care) at around 48 hours to check the blood count, kidney and liver function and level of salts in the blood. If a baby had a lumbar puncture as part of their normal treatment (if their doctor was concerned about an infection in their brain), the fosfomycin level in the fluid surrounding their brain was also checked.

The babies were closely followed by the study team, working together with the hospital staff to provide the best care available in the hospital. On day 7, any babies who remained as inpatients had a blood test to check blood count, kidney and liver function and level of salts in the blood (and 0.5ml drawn for fosfomycin levels in the group receiving this antibiotic). Breastfeeding and health counselling was given according to national guidelines. All babies were followed up in the outpatients’ clinic 28 days after their presentation to hospital and parents/guardians could also phone the study team directly on a study-specific mobile phone, or bring the baby to the ward prior to that review, in case of health concerns.

Additional staff (clinical officers and nurses) were recruited to undertake study duties and assist in general care on the ward, adding to the staff available. Training was enhanced for all paediatric ward staff on the treatment of babies presenting with infections, and on the prevention of infections within the hospitals. We also made available additional antibiotics as needed, if a baby continued to have signs of infection despite treatment or remained unwell. Drawing a blood sample carried the potential risks of bruising to the vein or infection, and careful training on procedures was done to help prevent these. There was a small risk of the baby having high levels of salt (sodium) in their blood due to the salt content of the fosfomycin injection. Improved monitoring of kidney function and blood salt levels was done to offset these risks.

This study done is leading up to a large clinical trial assessing how effective fosfomycin is to treat babies with infections, and if it is effective, will support efforts to make fosfomycin available at low cost for Kenya and other countries.  This will help babies to be more effectively treated when bacteria are resistant to the currently used antibiotics.

Antimicrobial resistance (AMR) has become a major issue in global health. Despite progress in the reduction of under 5 mortality rates in recent decades, the proportion of neonatal deaths occurring within this age group has increased, with almost one quarter of all neonatal deaths occurring due to serious bacterial infection. Common bacteria causing neonatal sepsis are now exhibiting widespread resistance to several classes of antibiotics. There is an urgent need to discover new, effective treatments and re-evaluate existing therapeutic agents to treat infections potentially caused by multi-drug resistant (MDR) pathogens. Gram-negative bacteria (GNB) predominate as the cause of neonatal sepsis, and are increasingly associated with high rates of resistance to the currently recommended WHO empirical therapy regimen of ampicillin/penicillin and gentamicin. There is therefore a need to develop an updated empiric regimen with improved efficacy in the context of increasing MDR sepsis in neonates. New antimicrobials under development will be expensive once licensed, and there are currently virtually no planned trials to assess their efficacy in neonates in low- and middle-income countries (LMICs).

One potential strategy is utilising an existing off-patent (and therefore affordable) antibiotic available in intravenous and oral formulations – fosfomycin. Fosfomycin has a wide spectrum of activity against Gram-positive and Gram-negative bacteria causing neonatal sepsis. It is mainly used for resistant urinary tract infections in adults, but has licenced neonatal and paediatric doses in Europe (though dosing regimens vary between countries). Both oral and IV formulations are available. A large clinical trial to assess the efficacy of a fosfomycin plus an aminoglycoside combination (compared to the current WHO recommended ampicillin and gentamicin) is anticipated, including sites in Kenya. The ultimate aim is for fosfomycin to be included in the WHO Essential Medicines List for children (EMLc) and be available for use in developing countries, where rates of resistance to ampicillin and gentamicin have been estimated at over 40%. The first steps before this trial are to clarify the pharmacokinetics (PK) and safety profile of fosfomycin in neonates, as well as generating further information regarding local patterns of bacterial susceptibility to fosfomycin. The aim of this study is to fulfil both these steps. Fosfomycin (IV and oral) PK will be investigated among 60 babies admitted to hospital and being treated for presumed sepsis; administered alongside the standard antibiotics. Another 60 babies receiving standard treatment only (without PK sampling) will be monitored in the same way to compare adverse events. In the laboratory at CGMR-C, previoiusly archived bacterial isolates will be tested for their sensitivity to fosfomycin.