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.

Figure 1.

Fitted α values from the Greco model using chequerboard assays outputs for 16 strains. A total summary statistic using a meta-analysis of the 16 strains is demonstrated in the final row ('Total') with numerical values given above the figure.

Figure 2.

PD output of 16-arm flomoxef/amikacin combination experiment. Arms a-p represent individual hollow fibre experimental arms recieving the labelled exposure of each drug, given as fAUC_0-24.

Figure 3.

Summary of the outcome of the HFIM experiments replicating neonatal regimens of flomoxef and amikacin alone and in combination. ‘Success’ is defined as the achievement of sterility. Filled square = ‘success’ achieved by flomoxef monotherapy and combination regimens; filled circles = ‘success’ with combination regimen alone; open inverted triangle = failure to achieve sterility in all arms.