ABSTRACT
Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.
Subject(s)
Acinetobacter baumannii , Anti-Bacterial Agents , Gram-Negative Bacteria , Gram-Negative Bacterial Infections , Klebsiella pneumoniae , Microbial Sensitivity Tests , Neonatal Sepsis , Humans , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Neonatal Sepsis/microbiology , Neonatal Sepsis/drug therapy , Infant, Newborn , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/genetics , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/isolation & purification , Acinetobacter baumannii/genetics , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/isolation & purification , Klebsiella pneumoniae/genetics , Amikacin/pharmacology , Amikacin/therapeutic use , Fosfomycin/pharmacology , Fosfomycin/therapeutic use , beta-Lactamases/genetics , beta-Lactamases/metabolism , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli/isolation & purification , Developing Countries , Drug Resistance, Multiple, Bacterial/genetics , Drug Therapy, Combination , Serratia marcescens/drug effects , Serratia marcescens/genetics , Serratia marcescens/isolation & purification , Enterobacter cloacae/drug effects , Enterobacter cloacae/genetics , Enterobacter cloacae/isolation & purification , Bacterial Proteins/genetics , Bacterial Proteins/metabolismABSTRACT
Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines.
Our study describes neonates from low- and middle-income countries with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in high-income countries. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.
