Antimicrobial Susceptibility Study
Frequency and antimicrobial susceptibility of bacteria causing bloodstream infections in pediatric patients from United States (US) medical centers (2014–2018): therapeutic options for multidrug-resistant bacteria

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Abstract

Studies evaluating large series of pediatric patients with bloodstream infections (BSIs) are scarce. We evaluated the frequency and antimicrobial susceptibility of organisms isolated from pediatric patients with BSI and therapeutic options for BSI caused by multidrug-resistant (MDR) organisms. A total of 2423 organisms were consecutively collected from 33 US medical centers between 2014 and 2018, and susceptibility was tested by reference broth microdilution methods. Isolates with an extended-spectrum β-lactamase phenotype were screened for β-lactamase genes. Overall, 40.2% of organisms were Gram-negative bacteria, 57.0% Gram-positives, and 2.8% Candida spp. The 5 most common organisms were Staphylococcus aureus (26.0%), Escherichia coli (13.0%), coagulase-negative staphylococci (8.3%), Enterococcus faecalis (7.1%), and Klebsiella pneumoniae (6.9%). Among S. aureus, 26.0% were oxacillin-resistant and 99.8% were susceptible to ceftaroline (MIC50/90, 0.25/0.5 mg/L). Enterobacterales and Pseudomonas aeruginosa isolates combined represented >85% of Gram-negative bacteria, and all isolates (100.0%) were susceptible to ceftazidime-avibactam.

Introduction

The etiology of bloodstream infections (BSIs) may vary substantially according to the type of patient, source of infection, and other factors. Additionally, in the last few years, antimicrobial resistance patterns of bacteria causing BSI shifted, especially among Gram-negative organisms (Lake et al., 2018; Weiner et al., 2016). Data from the National Healthcare Safety Network showed that pathogens implicated in healthcare-associated infections and their antimicrobial susceptibility patterns vary greatly between adult and pediatric patients. Compounding these difficulties, most published studies evaluate only adult populations (Weiner-Lastinger et al., 2020).

Although there are still a few good therapeutic options to treat BSI caused by multidrug-resistant (MDR) Gram-positive bacteria, treatment alternatives for some MDR Gram-negatives, such as Klebsiella pneumoniae and Pseudomonas aeruginosa, are very restricted. Moreover, infections caused by MDR Gram-negative bacteria increased worldwide over the past few years (Castanheira et al., 2019; Sader et al., 2019). The spreading of extended-spectrum β-lactamase (ESBL)–producing Enterobacterales led to an increase in the clinical use of carbapenems followed by the emergence and dissemination of carbapenemase-producing Enterobacterales, mainly KPC-producing organisms (Tangden and Giske, 2015). P. aeruginosa represents another major therapeutic challenge since this organism exhibits intrinsically decreased susceptibility to many antimicrobial classes and possesses a great ability to develop resistance to multiple antimicrobial agents (Sader et al., 2018).

A few antimicrobial agents have been approved in the last years to treat MDR Gram-negative infections in adults. Ceftazidime-avibactam was approved by the United States Food and Drug Administration (US FDA) for treatment of complicated intra-abdominal infection (cIAI) in combination with metronidazole, as well as complicated urinary tract infections (cUTIs), including pyelonephritis, and hospital-acquired bacterial pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP) (AVYCAZ®, 2019; Zhanel et al., 2013). Also, ceftazidime-avibactam is currently (March 2020) approved in the US for treating cIAI and cUTI in pediatric patients ≥3 months old, and it is under clinical development for treatment of pediatric patients with HABP/VABP and for patients <3 months old (Bradley et al., 2019; Iosifidis et al., 2019). In this investigation, we evaluated the frequency and antimicrobial susceptibility of organisms isolated from pediatric patients with BSIs in US medical centers and the therapeutic options to treat BSI caused by MDR bacteria. Moreover, we assessed the activity and spectrum of 2 recently approved β-lactamase-inhibitor combinations, ceftazidime-avibactam and ceftolozane-tazobactam, against the performance of other antimicrobial agents currently used to treat BSIs.

Section snippets

Bacterial isolates

A total of 2423 bacterial isolates were consecutively collected (1 per patient) from pediatric patients (≤17 years old) with BSIs in 33 US medical centers in 2014–2018. The medical centers were distributed in 23 states from all 9 US census divisions. Only isolates determined to be significant by local criteria as the reported probable cause of infection were included in the investigation. Where necessary, standard biochemical tests and the MALDI Biotyper (Bruker Daltonics, Billerica, MA)

Results

The numbers of isolates per patients' age group were as follows: 1077 isolates from patients ≤1 yo, 502 isolates from patients 2–5 yo, 485 isolates from patients 6–12 yo, and 359 isolates from patients 13–17 yo. Overall, 40.2% of organisms were Gram-negative bacteria, 57.0% Gram-positive bacteria, and 2.8% Candida spp. The rank order varied among age groups. Staphylococcus aureus and coagulase-negative staphylococci (CoNS) were the first and third most common organisms, respectively, across all

Discussion

BSI is a major cause of morbidity and mortality in children (Pai et al., 2015). Gram-positive bacteria, mainly Staphylococcus species, are the main organisms isolated from central line-associated BSI, but Gram-negative BSIs are relatively common among infants and are reported to occur more frequently during the first year of life (Al-Hasan et al., 2011; Weiner-Lastinger et al., 2020). Moreover, mortality rates are high among children with nosocomial or healthcare-associated Gram-negative BSI,

Funding information

This study was performed by JMI Laboratories and supported by Allergan, which included funding for services related to preparing this manuscript.

JMI Laboratories were contracted to perform services in 2019 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amicrobe Advanced Biomaterials, Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas, Basilea

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