KEY FINDINGS: Majority of antimicrobials have been discovered from prokaryotes and those which are of eukaryotic origin are derived mainly from fungal and plant sources. With this in mind, it is important to note that pests, such as cockroaches come across pathogenic bacteria routinely, yet thrive in polluted environments. Other animals, such as snakes thrive from feeding on germ-infested rodents. Logically, such species must have developed an approach to protect themselves from these pathogens, yet they have largely been ignored as a potential source of antimicrobials despite their remarkable capability to fight disease-causing organisms.
SUMMARY: Animals living in polluted environments are an underutilized source for potential antimicrobials, hence it is believed that several novel bioactive molecule(s) will be identified from these sources to counter increasingly resistant bacterial infections. Further research will be necessary in the development of novel antimicrobial(s) from these unusual sources which will have huge clinical impact worldwide.
METHODS: This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient's treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5-14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected.
DISCUSSION: With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent.
TRIAL REGISTRATION: The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437 . Registered on March 11, 2019.
MATERIALS & METHODS: This study was conducted in Hospital Kuala Lumpur, Malaysia from January 2016 to December 2017. A total of 303 isolates were included in this study which was obtained from 238 patients. The patients' microbiological worksheets and medical notes were reviewed to determine the antimicrobial susceptibility patterns, demographic data, classification of infection, and outcome (survival versus death).
RESULTS: Most of the patients were in the age group of one to less than five years old (41%) with 58% male and 85% Malay patients. Common causes of BSI were Staphylococcus aureus (17%), followed by Klebsiella pneumoniae (15%), Acinetobacter baumanii (10%), Pseudomonas aeruginosa (10%), and Escherichia coli (6%). Sixty percent of BSI episodes were caused by gram-negative bacteria, 34% by gram-positive bacteria, and 6% by fungi. Most of the infections were classified as hospital-acquired infections (72%), followed by healthcareassociated (20%) and community-acquired infections (8%). There were 33% of methicillin-resistant Staphylococcus aureus, 53% of extended-spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae, and 33% ESBL producing Escherichia coli. The overall case fatality rate (CFR) was 27% with the highest CFR caused by Serratia marcescens (53.3%).
CONCLUSIONS: The majority of paediatric bloodstream infections are hospital-acquired. Improvement in prevention strategies and revisions in antibiotic policies are important to overcome it.