Potential Antibiotics for the Treatment of Neonatal Sepsis Caused by Multidrug-Resistant Bacteria

Abstract

Neonatal sepsis causes up to an estimated 680,000 deaths annually worldwide, predominantly in low-and middle-income countries (LMICs). A significant and growing proportion of bacteria causing neonatal sepsis are resistant to multiple antibiotics, including the World Health Organization-recommended empiric neonatal sepsis regimen of ampicillin/gentamicin. The Global Antibiotic Research and Development Partnership is aiming to develop alternative empiric antibiotic regimens that fulfil several criteria: (1) affordable in LMIC settings; (2) activity against neonatal bacterial pathogens, including extendedspectrum β-lactamase producers, gentamicin-resistant Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (MRSA); (3) a licence for neonatal use or extensive experience of use in neonates; and (4) minimal toxicities. In this review, we identify five antibiotics that fulfil these criteria: amikacin, tobramycin, fosfomycin, flomoxef, and cefepime. We describe the available characteristics of each in terms of mechanism of action, resistance mechanisms, clinical pharmacokinetics, pharmacodynamics, and toxicity profile. We also identify some knowledge gaps: (1) the neonatal pharmacokinetics of cefepime is reliant on relatively small and limited datasets, and the pharmacokinetics of flomoxef are also reliant on data from a limited demographic range and (2) for all reviewed agents, the pharmacodynamic index and target has not been definitively established for both bactericidal effect and emergence of resistance, with many assumed to have an identical index/ target to similar class molecules. These five agents have the potential to be used in novel combination empiric regimens for neonatal sepsis. However, the data gaps need addressing by pharmacokinetic trials and pharmacodynamic characterisation. Key PointsAmikacin, tobramycin, fosfomycin, flomoxef, and cefepime are five safe and off-patent antibiotics with experience of use in neonates that can be potentially used as empiric treatment of neonatal sepsis in low-and middle-income settings where antimicrobial resistance complicates current standard-of-care regimens.The neonatal pharmacokinetics are well characterised for most, with cefepime and flomoxef needing some additional data.

Early-Onset Neonatal Sepsis in Low- and Middle-Income Countries: Current Challenges and Future Opportunities

“… 3 Ampicillin and gentamicin are amongst the most cost-effective choices for treatment, with cephalosporin and carbapenem antibiotics costing considerably more. 3 , 120 …”

“…Darlow et al suggest a combination of two agents including an aminoglycoside, 120 ß-lactam, and/or phosphoric acid derivative (such as fosfomycin), may improve upon the current empirical guidelines and clinical data from a multi-site study observational study (NeoOBS) is to be published in support of this. Moreover, there is potential of fosfomycin to treat multi-drug resistant infections, particularly those caused by ESBL-producing and carbapenemase-resistant bacteria, 127 and when combined with amikacin may improve treatment in neonatal sepsis.…”

“… 3 Additionally, access to and the related cost (/day) of fosfomycin may preclude wide usage in LMICs. Recent clinical trials advocate the use of Latamoxef for EOS, 129 and the potential for oxacephems (derivatives of cephalosporins) to treat EOS are similarly discussed elsewhere, 120 emphasising ongoing research to offer alternative antibiotics.…”

Flomoxef for neonates: extending options for treatment of neonatal sepsis caused by ESBL-producing Enterobacterales

“…Specifically, flomoxef is a synthetic oxacephem (oxacephems being derivatives of the cephalosporin class of antibiotics) that contains side chains that confer activity against Gram-positive and Gram-negative bacteria as well as anaerobes. These side chains also provide stability to hydrolysis by some β-lactamases, 3 which remain the most prevalent resistance mechanism against β-lactam antibiotics. While the oxacephems typically have several idiosyncratic toxicities, which include a coumarin-like coagulopathy and disulfiram-like effects, flomoxef is devoid of these adverse effects.…”

“…While the oxacephems typically have several idiosyncratic toxicities, which include a coumarin-like coagulopathy and disulfiram-like effects, flomoxef is devoid of these adverse effects. 3 …”