Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings

Abstract

Background Annual mortality from neonatal sepsis is an estimated 430 000–680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum β-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting. Objectives To assess the pharmacodynamics of flomoxef and amikacin in combination. Methods The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs. Results Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L. Conclusions We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

An Overview of Antibiotic Therapy for Early- and Late-Onset Neonatal Sepsis: Current Strategies and Future Prospects

“…In vitro studies are testing new combinations of antibiotics, such as Fosfomycin + Amikacin or Flomoxef + Amikacin, which would guarantee a synergistic effect with the expansion of the spectrum of action of the individual molecules and the effective prevention of resistance in EOS [ 62 , 63 ]. These studies give promising results for the empirical treatment of EOS in LMICs settings and seem to be suitable for further assessment in clinical trials [ 62 , 63 ].…”

Small-Molecule Antibiotic Drug Development: Need and Challenges

“…Clinical trials investigating the efficacy of combinations for a range of serious bacterial infections have mostly been small and inconclusive and even studies of pairwise combinations of antibiotics under growth-promoting conditions in the lab have struggled to predict whether any given combination of two antibiotics will act synergistically or antagonistically . However, hollow fiber models have identified some promising synergistic combinations for use in treating neonatal sepsis, for example. , Ideally, synergistic combination partners should have equivalent pharmacokinetic properties and tissue distribution, and achieving this is very challenging. Laboratory or animal models with good predictive power for efficacy in humans will greatly facilitate the investigation of these issues.…”

“… 81 However, hollow fiber models have identified some promising synergistic combinations for use in treating neonatal sepsis, for example. 46 , 82 Ideally, synergistic combination partners should have equivalent pharmacokinetic properties and tissue distribution, and achieving this is very challenging. Laboratory or animal models with good predictive power for efficacy in humans will greatly facilitate the investigation of these issues.…”