Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance

Abstract

Antimicrobial resistance (particularly by extended spectrum β-lactamase and aminoglycoside modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, causing significant mortality. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis; ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16 arm dose ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented emergence of resistance compared to monotherapy of either antibiotic. Modelling of the experimental quantitative outputs and data from checkerboard assays, indicated synergy. We further assessed the combination regimen at clinically relevant doses in HFIM with nine Enterobacterales strains with high fosfomycin/amikacin MICs and demonstrated successful kill to sterilisation in 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales - MIC F * MIC A < 256 (where MIC F and MIC A are MICs for fosfomycin and amikacin). Monte Carlo simulations predict that a standard fosfomycin/amikacin neonatal regimen will achieve a >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empiric treatment of neonatal sepsis and is suitable for further clinical assessment in a randomised controlled trial.

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

“…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. 128 Although fosfomycin has low AMR reported in other multi-site neonatal studies, 1 , 3 and in wider clinical evaluation; 127 recent microbiology data casts doubt on lasting efficacy due to the high frequency of induced resistance reported using in vitro assays. 3 Additionally, access to and the related cost (/day) of fosfomycin may preclude wide usage in LMICs.…”

Differences in the Distribution of Species, Carbapenemases, Sequence Types, Antimicrobial Heteroresistance and Mortality Rates Between Pediatric and Adult Carbapenemase-Producing Enterobacterales in Bloodstream Infections

“…We strive to use multiple-heteroresistance phenotypes to tackle the problems: combining the antibiotics showing multiple-heteroresistance phenotypes had a synergistic effect (20), and we discovered that the multiple-heteroresistance profiles of different species were different (Table 4). We finally identified a combination of FOS and AK showing the additive effect on a FOS-and AK-co-heteroresistant E coli strain by this way, and such a combination has been reported recently to be of efficiency without a theoretical basis (46). There were concerns about the toxicity of the two drugs, but reducing doses of the two drugs when combined together could decrease the toxicity of each drug (27,47,48).…”

Exposure to an Extended-Interval, High-Dose Gentamicin Regimen in the Neonatal Period Is Not Associated With Long-Term Nephrotoxicity

“…gentamicin dosing regimens and considering the use of other members of the aminoglycoside-family should be considered before moving to antibiotic-classes driving AMR (41,42). We therefore believe that long-term safety data may support clinical decision-making in favor of effective and safe aminoglycosidebased regimens.…”

“…Carbapenem-regimens may offer a better coverage than ampicillin and gentamicin in some low- and middle-income countries ( 39 ), but their use are accompanied with the vicious cycle of further increasing AMR. Aminoglycoside still offer a reasonably good coverage of Gram-negative bacteria ( 40 ) and further optimizing neonatal gentamicin dosing regimens and considering the use of other members of the aminoglycoside-family should be considered before moving to antibiotic-classes driving AMR ( 41 , 42 ). We therefore believe that long-term safety data may support clinical decision-making in favor of effective and safe aminoglycoside-based regimens.…”