Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

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.

Antimicrobial Stewardship Programs in PICU Settings: A Systematic Review.

OBJECTIVES: Development of antimicrobial stewardship programs (ASPs) is strategy for prevention and management of emergence of antimicrobial-resistant organisms. In this study, we systematically reviewed the literature on antimicrobial stewardship interventions in PICUs and analyzed approaches, structure, implementation, and outcomes of the ASPs. DATA SOURCES: PubMed and Scopus databases were systematically searched for studies published from January 1, 2007, to December 31, 2020, reporting interventions on judicious use of antimicrobials in PICUs (last search performed February 28, 2021). DATA SELECTION: Studies that evaluated an intervention in a PICU setting or both in PICU and other settings and reported separate results for PICU were eligible for full-text review. Studies that had implemented stewardship in the entire hospital, including the PICU, but without presenting dedicated PICU data were excluded from the analysis. DATA EXTRACTION: The strategy of intervention, structure of ASP team, implementation, and outcomes were assessed with a checklist tool for all studies included in the analysis. Risk of bias was assessed with the Cochrane Risk-of-Bias in Nonrandomized studies of Interventions tool. DATA SYNTHESIS: Thirteen articles were found: 11 that applied ASP in PICUs, and two at hospital level. All PICU-dedicated ASPs applied a multimodal intervention combining strategies simultaneously; audit with feedback (6/11) and facility-specific clinical practice guidelines (7/11) were the most common strategies. A multidisciplinary team was formulated in all ASPs except for three biomarker-based interventions. Six of 11 studies included techniques to enhance behavior change and one implemented a behavior-based intervention. Antibiotic consumption was evaluated in all ASPs, cost in three of 11, antibiotic resistance in one of 11, length of hospitalization in six of 11, and mortality in eight of 11. All hospital-wide ASPs used audit with feedback in addition to facility-specific clinical practice guidelines and assessed antimicrobial consumption, expenditures, length of stay, and mortality. CONCLUSIONS: The prevalence of ASPs in PICUs is limited, and few programs follow all of the currently available recommendations.

Paediatric cutaneous mucormycosis: A case report and review of the literature.

BACKGROUND: Mucormycosis has emerged as an increasingly important fungal disease for immunocompromised children and neonates, with the cutaneous form being one of its most common presentations. METHODS: We present a cutaneous mucormycosis case in a 10-year-old girl and analyse reports of single cases and case series of cutaneous mucormycosis in ≤16-year-old patients, recorded in PUBMED from 1953 to 2020, for epidemiology, risk factors, diagnostic and therapeutic procedures and outcome. RESULTS: 113 cases were enrolled. Median age was 5 years (Interquartile Range [IQR] 10.9), without gender predominance. Underlying conditions were haematologic malignancies/disorders (25.7%), prematurity (23%), solid organ transplantation (3.5%), diabetes mellitus type 1 (4.4%), immunodeficiency and other diseases (14.2%), and no underlying conditions (29.2%). Inoculation occurred through major trauma (12.4%), including surgery and motor vehicle accidents, catheter sites (27.4%), dressings, patches and probes (11.5%), burns and farm-related accidents (8.8%). Rhizopus spp. was most frequently isolated (43.4%), followed by Lichtheimia corymbifera (9.7%), Saksenaea vasiformis (8%), Mucor and Rhizomucor spp. (5.3% each), other species/combinations (7.2%) and unspecified isolates (21.2%). Surgery was combined with antifungals in 62.8%. Each was performed solely in 27.4% and 6.2%, respectively. Amphotericin B was used in 78% (alone in 55.8% and combined with other antifungals in 22.2%) of the cases. Overall mortality was 26.5%. In regression analysis, prematurity and haematologic malignancies/disorders were associated with increased mortality, whereas combination of antifungals and surgery with improved survival. CONCLUSION: Cutaneous mucormycosis mainly affects premature infants and children with haematologic malignancies/disorders. Outcome is improved when active antifungal therapy and surgery are combined.

Antifungal Drug Usage in European Neonatal Units: A Multicenter Weekly Point Prevalence Study.

BACKGROUND: Data on antifungal prescribing in neonatal patients are limited to either single-center or single-country studies or to 1-day recording. Therefore, we assessed antifungal longitudinal usage in neonatal units (NUs) within Europe. METHODS: CALYPSO, a prospective weekly point prevalence study on antifungal drug usage in NUs in 18 hospitals (8 European countries), was conducted in 2020 during a 12-week period. All patients receiving systemic antifungals were included. Ward demographics were collected at the beginning; ward and patient data including indication, risk factors and antifungal regimen were weekly collected prospectively. RESULTS: Among 27 participating NUs, 15 (56%) practiced antifungal prophylaxis for neonates with birth weight <1000 g or <1500 g and additional risk factors. In total, 174 patients received antifungals with a median frequency per week of 10.5% ranging from 6.9% to 12.6%. Indication for antifungal prescribing was prophylaxis in 135/174 (78%) courses and treatment in 22% [39 courses (69% empirical, 10% preemptive, 21% targeted)]. Fluconazole was the most frequent systemic agent used both for prophylaxis (133/135) and treatment (15/39, 39%). Among neonates receiving prophylaxis, the most common risk factors were prematurity (119/135, 88%), mechanical ventilation (109/135, 81%) and central vascular catheters (89/135, 66%). However, gestational age <28 weeks was only recorded in 55/135 (41%) courses and birth weight <1000 g in 48/135 (35%). Most common reason for empirical treatment was late-onset sepsis; all 8 targeted courses were prescribed for invasive candidiasis. CONCLUSION: Antifungal usage in European NUs is driven by prophylaxis and empirical treatment with fluconazole being the most prescribed agent for both indications.

Epidemiology and outcomes of ventilator-associated events in critically ill children: Evaluation of three different definitions.

OBJECTIVE: Ventilator-associated pneumonia (VAP) is one of the most common healthcare-associated infections in pediatric intensive care units (PICUs), but its definite diagnosis remains controversial. The CDC Ventilator-Associated Event (VAE) module (validated in adults) constitutes a new approach for VAP surveillance. DESIGN: We described epidemiological characteristics of PICU VAE cases, investigated possible risk factors, and evaluated 3 different sets of diagnostic VAE criteria. SETTING: This study was conducted in a PICU in a tertiary-care general hospital in northern Greece during 2017-2019. PATIENTS: The study included patients aged 35 days-16 years who received mechanical ventilation. METHODS: From medical records, we retrieved epidemiological data, clinical data, and laboratory characteristics as well as ventilator settings for our analysis. We assessed "oxygen deterioration" for the tier 1 CDC VAE module using 3 sets of diagnostic criteria: (1) CDC adult VAE criteria [increase of daily minimum fraction of inspired oxygen (FiO2) ≥ 0.2 or positive end expiratory pressure (PEEP) ≥ 3 cmH2O for 2 days], (2) the US pediatric VAE criteria [increase of FiO2 ≥ 0.25 or mean airway pressure (MAP) ≥ 4 cmH2O for 2 days], and (3) the European pediatric VAE criteria (increase of FiO2 ≥ 0.2 or PEEP ≥ 2 cmH2O for 1 day or increase of FiO2 ≥ 0.15 and PEEP ≥ 1 cm H2O for 1 day). RESULTS: Among 326 children admitted to the PICU, 301 received mechanical ventilation. The incidence rate according to the CDC adult VAE criteria was 4.7 per 1,000 ventilator days. For the US pediatric VAE criteria the incidence rate was 6 per 1,000 ventilator days. For the European pediatric VAE criteria the incidence rate was 9.7 per 1,000 ventilator days. These results revealed statistically significant correlation of all 3 algorithms with adverse outcomes, including mortality. CONCLUSIONS: All VAE algorithms were associated with higher mortality rates. Our findings highlight the need for a unified pediatric VAE definition to improve preventive strategies.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Perioperative antimicrobial prophylaxis in adult patients: The first multicenter clinical practice audit with intervention in Greek surgical departments.

OBJECTIVE: To audit clinical practice and implement an intervention to promote appropriate use of perioperative antimicrobial prophylaxis (PAP). DESIGN: Prospective multicenter before-and-after study. SETTING: This study was conducted in 7 surgical departments of 3 major Greek hospitals. METHODS: Active PAP surveillance in adults undergoing elective surgical procedures was performed before and after implementation of a multimodal intervention. The surveillance monitored use of appropriate antimicrobial agent according to international and local guidelines, appropriate timing and duration of PAP, overall compliance with all 3 parameters and the occurrence of surgical site infections (SSIs). The intervention included education, audit, and feedback. RESULTS: Overall, 1,447 patients were included: 768 before and 679 after intervention. Overall compliance increased from 28.2% to 43.9% (P = .001). Use of antimicrobial agents compliant to international guidelines increased from 89.6% to 96.3% (P = .001). In 4 of 7 departments, compliance with appropriate timing was already >90%; an increase from 44.3% to 73% (P = .001) and from 20.4% to 60% (P = .001), respectively, was achieved in 2 other departments, whereas a decrease from 64.1% to 10.9% (P = .001) was observed in 1 department. All but one department achieved a shorter PAP duration, and most achieved duration of ~2 days. SSIs significantly decreased from 6.9% to 4% (P = .026). After the intervention, it was 2.3 times more likely for appropriate antimicrobial use, 14.7 times more likely to administer an antimicrobial for the appropriate duration and 5.3 times more likely to administer an overall appropriate PAP. CONCLUSION: An intervention based on education, audit, and feedback can significantly contribute to improvement of appropriate PAP administration; further improvement in duration is needed.

Reducing Duration of Antibiotic Use for Presumed Neonatal Early-Onset Sepsis in Greek NICUs. A "Low-Hanging Fruit" Approach.

Antibiotics are commonly prescribed in Neonatal Intensive Care Units (NICU), where stewardship interventions are challenging. Lowering antibiotic consumption is desperately needed in Greece, a country with high antibiotic resistance rates. We sought to assess the effectiveness of a low-cost and -resource intervention to reduce antibiotic use in Greek NICUs implementing a "low-hanging fruit" approach. A prospective quasi-experimental study was conducted in 15/17 public NICUs in Greece (9/2016-06/2019). The intervention selected was discontinuation of antibiotics within 5 days for neonates with gestational age ≥ 37 weeks, no documented signs or symptoms of sepsis, CRP ≤ 10 mg/L and negative cultures within 3 days of antibiotic initiation. Impact was evaluated by the percentage of discontinued regimens by day 5, length of therapy (LOT) and stay. Trends of antibiotic consumption were assessed with days of therapy (DOT) per 1000 patient-days. Overall, there was a 9% increase (p = 0.003) of antibiotic discontinuation in ≤5 days. In total, 7/13 (53.8%) units showed a ≥10% increase. Overall, 615 days on antibiotics per 1000 patients were saved. Interrupted time-series analysis established a declining trend in DOT/1000 patient-days relative to the pre-intervention trend (p = 0.002); a monthly decrease rate of 28.96 DOT/1000 patient-days (p = 0.001, 95%CI [-45.33, -12.60]). The intervention had no impact on antibiotic choice. Antibiotic use was successfully reduced in Greek NICUs using a "low-hanging fruit" approach. In resource-limited settings, similar targeted stewardship interventions can be applied.

Child Morbidity and Disease Burden in Refugee Camps in Mainland Greece.

The crisis conflicts in Syria have forced a lot of people to relocate and live in mainland Greece, where they are hosted in refugee camps. In the present study, our aim was to assess child morbidity and overall disease burden in two camps in northern Greece during a six-month winter period. A primary health care office was founded in each camp. Refugees of all ages with health problems were examined daily by specialty doctors. Cases were classified into two categories: Infectious or non-infectious. In total, 2631 patients were examined during this period (out of the 3760 refugees hosted). Of these patients, 9.8% were infants, 12.7% were toddlers, and 13.4% were children. Most of the visits for children aged less than 12 years old were due to infectious diseases (80.8%). The most common sites of communicable diseases among children were the respiratory tract (66.8%), the skin (23.2%), and the urinary (3.2%) and gastrointestinal tracts (6.2%). Non-communicable diseases were mostly due to gastrointestinal (20.2%), respiratory (18.2%), surgical (13.1%), and allergic (10.3%) disorders. Infants, toddlers, and children suffered more frequently from respiratory infections, while in adolescents and adults, non-infectious diseases were more common. Toddlers and children were more likely to fall ill in comparison to infants. Conclusions: During the winter period, infectious diseases, especially of the respiratory tract, are the main reason for care seeking among refugees in Greek camps, with toddlers suffering more than other age groups. The overall mortality and referral percentage were low, indicating that adequate primary care is provided in this newly established refugee hosting model.

Use of Ceftazidime-avibactam for the Treatment of Extensively drug-resistant or Pan drug-resistant Klebsiella pneumoniae in Neonates and Children <5 Years of Age.

BACKGROUND: Emergence of extensively drug-resistant (XDR) or pan drug-resistant (PDR) Enterobacteriaceae is a major public threat especially for young patients. Treatment options for these bacteria are extremely limited with no safety data existing for neonates and children. Ceftazidime-avibactam has activity against Gram-negative bacteria producing Klebsiella pneumoniae carbapenemase, but virtually no data exist on its use in neonatal and pediatric patients. METHODS: We present a single-center case series of neonates and children <5 years treated with ceftazidime-avibactam for XDR or PDR K. pneumoniae infections until August 2018. Medical records of patients who received ceftazidime-avibactam for at least 2 days (6 doses) were reviewed. Clinical, laboratory and microbiologic data were collected using a prestructured form. Adverse events and clinical/microbiologic responses and 15- and 30-day outcome were assessed. RESULTS: In our case series, 8 patients (median age 53 days, range from 13 days to 4.5 years) received 9 courses of ceftazidime-avibactam at a dose of 62.5 mg/kg q8h for suspected or proven XDR/PDR K. pneumoniae infections including bloodstream infections (8 courses), central nervous system infections (2 courses) and urinary tract infection (1 course). All patients were critically ill and received other antibiotics prior and concomitantly with the administration of ceftazidime-avibactam. There was no treatment discontinuation due to adverse events. Clinical and microbiologic responses occurred in all patients, and no patient died by day 30. CONCLUSIONS: Administration of ceftazidime-avibactam appears to be well tolerated and efficacious against in vitro susceptible XDR or PDR Enterobacteriaceae without being associated with significant adverse events.

Evaluation of the New Centers for Disease Control and Prevention Ventilator-Associated Event Module and Criteria in Critically Ill Children in Greece.

OBJECTIVE To evaluate the new adult Centers for Disease Control and Prevention (CDC) ventilator-associated event (VAE) module in critically ill children and compare with the traditionally used CDC definition for ventilator-associated pneumonia (VAP). DESIGN Retrospective observational study of mechanically ventilated children in a pediatric intensive care unit in Greece January 1-December 31, 2011. METHODS Assessment of new adult CDC VAE module including 3 definition tiers: ventilator-associated condition (VAC), infection-related VAC, and possible/probable ventilator-associated pneumonia (VAE-VAP); comparison with traditional CDC criteria for clinically defined pneumonia in mechanically ventilated children (PNEU-VAP). We recorded Pediatric Risk of Mortality score at admission (PRISM III), number of ventilator-days, and outcome. RESULTS Among 119 patients with mechanical ventilation (median [range] number of ventilator-days, 7 [1-183]), 19 patients experienced VAC. Criteria for VAE-VAP were fulfilled in 12 of 19 patients with VAC (63%). Children with either VAC or VAE-VAP were on ventilation more days than patients without these conditions (16.5 vs 5 d, P=.0006 and 18 vs 5 d, P<.001, respectively), whereas PRISM-III score was similar between them. Mortality was significant higher in patients with new VAE-VAP definition (50%), but not in patients with VAC (31.6%), than the patients without new VAE-VAP (14%, P=.007) or VAC (15%, P=.1), respectively. No significant association was found between PNEU-VAP and death. Incidences of PNEU-VAP and VAE-VAP were similar, but the agreement was poor. CONCLUSIONS VAE-VAP and PNEU-VAP found similar prevalence in critically ill children but with poor agreement. However, excess of death was significantly associated only with VAE-VAP. Infect Control Hosp Epidemiol 2016:1-5.