Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance

Abstract

Background Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO’s recommended empirical regimen of ampicillin and gentamicin. Objectives We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. Methods We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. Results Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. Conclusions These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials.

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

“…Significant kill and sterilization occurred only in strains with flomoxef MICs ≤0.5 mg/L. Combined with results from similar previous HFIM experiments, 22 flomoxef monotherapy sterilized 4/5 strains with flomoxef MICs ≤0.5 mg/L, all without significant AmpC production. This experience is consistent with adult clinical data of flomoxef against non-AmpC ESBL-producing bacteria.…”

“… 19 , 20 Both agents fulfil the above criteria, and each have been demonstrated to have in vitro synergy in combination with fosfomycin. 21 , 22 We therefore studied the potential utility of these agents in combination by assessing their in vitro activity, the presence and magnitude of any pharmacodynamic (PD) interaction using dynamic in vitro models, and assessed the potential utility of this candidate combination regimen using clinically relevant drug exposures.…”

Streptococcus gordonii empyema: A case report and literature review

“…Flomoxef is an oxacephem β-lactam with broad activity against Gram-negative and Gram-positive bacteria (including anaerobes, but not pseudomonads) [9] , that is widely used in Asia. In our case, we used 1 day of piperacillin-tazobactam followed by 7 days of flomoxef for broad-spectrum antimicrobial treatment with prompt surgical intervention for source control.…”

Identification of potential novel combination antibiotic regimens based on drug-susceptibility and genetic diversity of Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries

“…If flomoxef MIC values are between 1 and 32 mg/L, combination with fosfomycin or amikacin extends flomoxef’s spectrum of activity, but only when MIC of the associated drug is in the range of the corresponding MIC breakpoints, i.e. ≤32 mg/L for fosfomycin and ≤16 mg/L for amikacin [20, 21]. Success of fosfomycin-amikacin combination is predicted if the product of the two individual antibiotic MICs is ≤256 mg/L [R. da Costa, personal communication, August 31, 2023].…”

“…The susceptibility of the isolates to the proposed combination regimens was analyzed based on the novel combination breakpoint thresholds determined by HFIM model and checkerboard assays [20][21][22]. If flomoxef MIC values are between 1 and 32 mg/L, combination with fosfomycin or amikacin extends flomoxef's spectrum of activity, but only when MIC of the associated drug is in the range of the corresponding MIC breakpoints, i.e.…”