Neonatal sepsis is a leading cause of morbidity and mortality in neonates, particularly in low and middle-income countries. The emergence of antimicrobial resistance is a rapidly growing global problem. A significant proportion of the pathogens that commonly cause neonatal sepsis are resistant to multiple antibiotics. Therefore, for the empirical treatment of neonatal sepsis, the repurposing of older antibiotics that are effective against multidrug-resistant pathogens is being investigated. This review aims to provide an overview of current research and experience using the repurposed antibiotics, Colistin and Fosfomycin, for the empirical treatment of neonatal sepsis. Based on current knowledge, Colistin and Fosfomycin may be potentially helpful for the empirical treatment of sepsis in neonates due to their efficacy against a wide range of pathogens and acceptable safety profile.

Klebsiella pneumoniae complex is one of the most commonly isolated bacteria within human infections. These microorganisms are opportunistic pathogens that pose a serious threat to public health due to possibility of transmission in the human population. Resistance to carbapenems is one of the most important antimicrobials resistance mechanisms amongst them. In this situation therapeutic options are limited. Therefore, the aim of this study was to evaluate fosfomycin, colistin, ceftazidime-avibactam and meropenem-vaborbactam in vitro activity against multidrug-resistant K. pneumoniae complex strains. The study involved 160 strains of Gram-negative rods: K. pneumoniae – 138 and K. variicola - 22. Minimal inhibitory concentration of fosfomycin was estimated by agar dilution method and for colistin by microdilution method. The susceptibility to ceftazidime-avibactam and meropenem-vaborbactam was determined by gradient strip method. All of the analysed K. pneumoniae complex isolates produced extended-spectrum beta-lactamases and 60.0% carbapenemases. The most of the analysed strains were susceptible to fosfomycin and colistin (62.5%). Among pandrug-resistant K. pneumoniae complex isolates the most were susceptible to colistin (43.9%). Fosfomycin has good activity against ESBL- and VIM-positive isolates from this complex. In turn, colistin has satisfactory in vitro activity against KPC- and VIM-positive isolates from K. pneumoniae complex. Ceftazidime-avibactam has good activity against K. pneumoniae complex strains producing ESBL, KPC and OXA enzymes. In turn, meropenem-vaborbactam has satisfactory in vitro activity against ESBL- and KPC-positive isolates from this complex.

Antimicrobial resistance has become a significant public health problem globally with multidrug resistant Gram negative (MDR-GN) bacteria being the main representatives. The emergence of these pathogens in neonatal settings threatens the well-being of vulnerable neonatal population given the dearth of safe and effective therapeutic options. Evidence from studies mainly in adults is now available for several novel antimicrobial compounds, such as new β-lactam/β-lactamase inhibitors (e.g. ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam), although old antibiotics such as colistin, tigecyclin and fosfomycin are also encombassed in the fight against MDR-GN infections that remain challenging. Data in the neonatal population are scarse, with few clinical trials enrolling neonates for the evaluation of efficacy, safety and dosing of new antibiotics, while the majority of old antibiotics are used off-label. In this article we review data about some novel and old antibiotics that are active against MDR-GN bacteria causing sepsis and are of interest to be used in the neonatal population.

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent “synergizer”. We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using 5 different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10), respectively. Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolated except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.