Modifiable risk factors associated with later gut decolonization of carbapenem-resistant Gram-negative bacteria in children: a prospective cohort study.

BACKGROUND: Nosocomial infections caused by carbapenem-resistant Gram-negative bacteria (CRGNB) are associated with increased mortality and prolonged hospitalization; thus, later CRGNB decolonization has significant clinical and public health implications. AIM: To investigate modifiable/non-modifiable risk factors for CRGNB later gut decolonization in children. METHODS: CRGNB carriers (aged from one day to 16 years) hospitalized in a tertiary level hospital (2018-2019) were included. Upon CRGNB carriage detection, rectal swab cultures were taken weekly, if patients were hospitalized, and monthly after discharge for 12 months. CRGNB decolonization was defined as three consecutive negative rectal-swab cultures obtained ≥1 week apart. Modifiable (treatment administered/medical devices) and non-modifiable (age/gender/comorbidities) risk factors were recorded. Cox regression for later CRGNB decolonization was performed. FINDINGS: One hundred and thirty CRGNB carriers were recorded. After 12 months, 5.4% remained carriers. Risk factors for later decolonization were immunosuppression (hazard ratio: 0.52; 95% confidence interval: 0.31-0.87), carbapenems (0.52; 0.30-0.91), proton pump inhibitors (PPIs) (0.39; 0.24-0.64) and their duration of use, duration of hospitalization (0.90; 0.81-0.92, per 10 days), number of readmissions (0.90; 0.86-0.96), abdominal surgery (0.33; 0.17-0.65), urinary catheter (0.42; 0.24-0.76), and duration of steroid administration per 10 days (0.86; 0.84-0.88). CONCLUSIONS: Carbapenems, PPIs and their duration of use, duration of steroids use, immunosuppression, urinary catheter, readmissions, duration of hospitalization, and abdominal surgery are associated with later CRGNB decolonization among children. Paediatric patients at risk of later decolonization should be under targeted screening and pre-emptive contact precautions. Known carriers at risk of later CRGNB decolonization should be under meticulously applied contact precautions for longer durations.

Implementation of the Greek national immunization program among nursery attendees in the urban area of Thessaloniki.

BACKGROUND: The growing phenomenon of vaccine hesitancy and the severe economic crisis may have affected compliance with the National Immunization Program (NIP) in Greece over the last years. We investigated compliance with the NIP among children attending nurseries in the urban area of Thessaloniki. METHODS: A cross-sectional study was conducted, including nursery attendees born between 01/01/2014-01/10/2015 in each of the municipalities of Thessaloniki urban area. Public and private nurseries were randomly selected. Immunization data were anonymously collected from the child's health booklet. Both coverage and timeliness of immunization were recorded for all recommended vaccines according to the NIP. RESULTS: In total, 432 children with a mean age of 2.9 years were studied, of which 245 (57 %) were attending private nurseries. Full coverage was >90 % for most of the recommended vaccines except for pneumococcal (81 %), meningococcal serogroup C (68.3 % and 82 % for 2011 and 2015 schedule, respectively), hepatitis A (38.9 %) and rotavirus (25.9%) vaccine. Delay rates for one or more doses ranged between 21-90.3 % for all vaccines; time of median delay ranged between 3.8-6.7 months. Lower coverage and higher delay rates were observed for Roma children. CONCLUSIONS: While high coverage appears to be sustained for most of the recommended vaccines, delay of scheduled shots may compromise age-appropriate protection. Suboptimal immunization against pneumococcal, meningococcal serogroup C, hepatitis A, and rotavirus infections may increase morbidity in this age group and needs to be addressed. HIPPOKRATIA 2019, 23(4): 147-153.

Impact of active surveillance and infection control measures on carbapenem-resistant Gram-negative bacterial colonization and infections in intensive care.

BACKGROUND: Carbapenem-resistant Gram-negative bacteria (CRGNB) infections constitute a global threat for critically ill patients and the outcome of their hospitalization. Early identification of CRGNB through rectal surveillance cultures and routine infection control measures including contact precautions, use of appropriate disinfectants, staff education on cleaning, and hand hygiene may reduce the dissemination of CRGNB. AIM: To assess the impact of enhanced infection control measures on CRGNB infections in a nine-bed polyvalent intensive care unit in a tertiary level hospital in an endemic area. METHODS: A quasi-experimental study, which included patients with CRGNB infection retrospectively for six months and those participating in an active surveillance programme prospectively for the subsequent 22 months. Active surveillance programme (weekly rectal swabs) was implemented including two sub-periods with infection control measures and enhanced infection control measures. CRGNB incidence, prevalence, colonization pressure, infections and compliance with infection control measures and enhanced infection control measures were recorded. Analysis was performed through time-series and interrupted time-series. FINDINGS: During the active surveillance programme, enhanced infection control measures led to a steeper downwards trend in incidence, prevalence, and colonization pressure for CRGNB compared to the infection control measures sub-period. The linear trend was for carbapenem-resistant Klebsiella pneumoniae (CRKP) and Pseudomonas aeruginosa (CRPA) infections to decrease from 19.6 to 8.1 infections per 1000 bed-days (IBD) (P = 0.001) and from 5.1 to 1.79 IBD (P = 0.043), respectively. By contrast, carbapenem-resistant Acinetobacter baumannii infections increased from 5.2 to 15.3 IBD (P = 0.001). CONCLUSION: Enhanced infection control measures including enhanced hand hygiene, active surveillance combined with contact precautions, education, audits and feedback policies and interventions could reduce CRKP and CRPA in endemic areas.

Fulminant Epstein-Barr virus-associated hemophagocytic syndrome in a renal transplant patient and review of the literature.

We describe a rare fulminant case of Epstein-Barr virus-associated hemophagocytic syndrome (HPS) in a 37-year-old female renal transplant patient, indistinguishable from severe sepsis clinically and in the laboratory. HPS involves rapidly escalating immune system activation, resulting in a cytokine cascade, which can, especially in immunocompromised patients, lead to multi-organ failure, and even death. Thirty-two Herpesviridae-associated HPS cases in renal transplant patients have been reported and are reviewed. Overall mortality is 47% (15/32 cases).

Renal abscess due to Pseudomonas aeruginosa: report of two cases.

We report two cases of renal abscess due to Pseudomonas aeruginosa in previously healthy children. The first patient was a nine-year old girl with a three-week history of intermittent fever and the second was a three-year old boy with a four-day history of fever. Pseudomonas aeruginosa was isolated from the urine cultures of both children. In both cases ultrasound and CT/MRI scans revealed the formation of a renal abscess. The patients were successfully treated with administration of antipseudomonal drugs for seven and five weeks, respectively. In both children no surgical intervention was required and the follow-up revealed no impact on the overall renal function or arterial pressure.

Immunotherapy of Cryptococcus infections.

Despite appropriate antifungal treatment, the management of cryptococcal disease remains challenging, especially in immunocompromised patients, such as human immunodeficiency virus-infected individuals and solid organ transplant recipients. During the past two decades, our knowledge of host immune responses against Cryptococcus spp. has been greatly advanced, and the role of immunomodulation in augmenting the response to infection has been investigated. In particular, the role of 'protective' Th1 (tumour necrosis factor-α, interferon (IFN)-γ, interleukin (IL)-12, and IL-18) and Th17 (IL-23 and IL-17) and 'non-protective' Th2 (IL-4, IL-10, and IL-13) cytokines has been extensively studied in vitro and in animal models of cryptococcal infection. Immunomodulation with monoclonal antibodies against the capsular polysaccharide glucuronoxylomannan, glucosylceramides, melanin and ß-glucan and, lately, with radioimmunotherapy has also yielded promising results in animal models. As a balance between sufficiently protective Th1 responses and excessive inflammation is important for optimal outcome, the effect of immunotherapy may range from beneficial to deleterious, depending on factors related to the host, the infecting organism, and the immunomodulatory regimen. Clinical evidence supporting immunomodulation in patients with cryptococcal infection remains too limited to allow firm recommendations. Limited human data suggest a role for IFN-γ. Identification of surrogate markers characterizing patients' immunological status could possibly suggest candidate patients for immunotherapy and the type of immunomodulation to be administered.

Serum levels of daptomycin in pediatric patients.

BACKGROUND: Limited data are available on the pharmacokinetics and optimal dosage of daptomycin, a lipopeptide compound possessing activity against Gram-positive bacteria, in the pediatric population, particularly in neonates and infants. We determined serum levels of daptomycin in hospitalized pediatric patients treated with various dosages of this agent. METHODS: Blood samples were obtained from pediatric patients of all ages with normal renal function who had received daptomycin between May 2009 and December 2010. Serum levels prior ("trough") and 30 min after end of the infusion ("peak") were determined using an ultra-performance liquid chromatography-UV detection method. RESULTS: A total of four daptomycin dosages and four patients were studied. Three patients were infants (gestational age: 29-38 weeks, age at sampling 26-65 days) and the fourth was a 7-year-old boy. A dosage of 6 mg/kg/12 h of daptomycin to the infants resulted in trough concentrations of <4-8.4 mg/l and peak concentrations of 10.9-17.7 mg/l. Comparable levels were observed after one of the infants received a dosage of 11 mg/kg/12 h, while a further dosage increase to 15 mg/kg/12 h yielded peak concentrations of 35.5 mg/l. The 7-year-old child received a daptomycin dosage of 12 mg/kg once daily; trough and peak levels were 4.2 and 103.4 mg/l, respectively. CONCLUSIONS: A dosage of daptomycin 6 mg/kg/12 h in small infants results in lower peak and similar trough concentrations compared with a dosage of 4 mg/kg/day administered to adults. This results suggests that daptomycin dosages of more than 6 mg/kg/12 h may be needed for this pediatric age group to achieve a similar drug exposure as adults.

Invasive fungal infections in congenital immunodeficiencies.

Both acquired and congenital immunodeficiencies may be associated with increased susceptibility to invasive fungal infections (IFIs), depending on the type of immune deficit. IFIs frequently occur in patients with phagocytic and cellular immune defects, but are rarely observed in those with humoral or complement deficits. Among congenital immune disorders, chronic granulomatous disease and hyper-IgE syndrome are most frequently associated with IFIs; variable susceptibility to fungal pathogens is also seen in patients with severe combined immunodeficiency, X-linked hyper-IgM syndrome, Wiskott-Aldrich syndrome, DiGeorge syndrome, common variable immunodeficiency, defects in the interferon-γ-interleukin-12 axis, and myeloperoxidase deficiency. Aspergillus, Candida, Cryptococcus, Histoplasma and other fungal genera are variably implicated in causing invasive infections in these patients. Prompt diagnosis of IFIs in this patient population requires a high degree of suspicion, together with a knowledge of their clinical presentation and the limitations of diagnostic modalities. Apart from administration of appropriate antifungal agents, successful management often requires the addition of surgical intervention. Adjunctive immunotherapy may be considered, although this has not been systematically studied. Prophylactic interferon-γ and itraconazole administration have been shown to reduce the risk of IFIs in patients with chronic granulomatous disease; however, the possibility of infections with azole-resistant organisms following long-term itraconazole prophylaxis should not be overlooked.

Cell senescence and a mechanism of clonal evolution leading to continuous cell proliferation, loss of heterozygosity, and tumor heterogeneity: studies on two immortal colon cancer cell lines.

Extensive karyotypic analysis was performed on early and late passages of two continuous human cell lines, SW480 and SW620, that were derived from the same colon cancer patient. We cultivated these two cell lines in vitro for a period of 24 months and periodically examined their chromosome constitution. SW480 cells, from passage 138, were injected subcutaneously into 20 nude mice. The tumors that grew in nude mice were then cultivated in vitro for several passages to compare histopathologic findings and tumor growth patterns with clonal chromosomal profiles. Despite some karyotypic diversity, the two cell lines exhibited common marker chromosomes and followed similar patterns of evolution. During subsequent passages, acquisition of new chromosomal abnormalities gave rise to sidelines with a near-diploid genome that frequently underwent endoreduplication. Genomic instability seemed to play an important role in the emergence, growth, and subsequent elimination of the heterogenous sidelines by selection, clonal expansion, and cell death by senescence. Despite continuous growth, both the cell lines occasionally showed telomeric associations and random dicentric and multicentric formations. These lesions were considered evidence of cell senescence and were related to the disappearance of particular sidelines through evolution. Successful evolutionary steps were characterized by elimination of pre-existing marker chromosomes that were subsequently replaced in the karyotype by their cytologically intact homologous chromosomes possibly after selective endoreduplication. Frequent loss of heterozygosity for the chromosomes taking part in this process is postulated. We suggest that one of the mechanisms by which cancer cells bypass senescence may be related to their potential for continuous clonal diversification.

Low-dose heparin treatment does not inhibit SW480 human colon cancer growth and metastasis in vivo.

We investigated heparin effects on the biological behavior of SW480 human colon adenocarcinoma cells in vivo. Tumor growth, pathological features, metastatic potential and karyotype, were studied after the twelve week low-dose heparin treatment of nude mice subcutaneously injected with SW480 cells. A non statistically significant increase in tumor growth was observed (0.05 < p < 0.1, compared to the control group). No differences in tumor histology and karyotype were detected. Two of the six heparin-treated animals exhibited an increase in tumor vascularization. Metastasis to the lungs and liver was not inhibited. These results do not support the role of heparin in the prevention of the in vivo growth and metastasis of SW 480 colon cancer cells.

In vitro effects of heparin on SW480 tumor cell-matrix interaction.

We investigated the in vitro effects of heparin on the growth and interaction of SW480 colon adenocarcinoma cells with the extracellular matrix proteins laminin, fibronectin and collagen IV. Cell adhesion assays were performed in wells precoated with the proteins mentioned. Tumor cell migration and invasiveness were assayed in Transwell cell culture chambers. SW480 cell adhesion to the matrix proteins and migration to laminin/fibronectin precoated filters were inhibited by heparin in a dose- dependent manner, whereas cell growth and invasion through collagen IV gel were not affected. Our results suggest that heparin influences the SW480 cell-matrix interaction in vitro and inhibits crucial steps of the metastatic process in an experimental model.