Stopping antibacterial prophylaxis in pediatric allogeneic hematopoietic cell transplantation: An internal audit.

BACKGROUND: Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. METHODS: The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. RESULTS: A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3 vs. 94.1%; p = .57) and bacterial infections (34.6 vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39 vs. 34; p = .002). Detection rates of resistant organisms were overall low. CONCLUSION: In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.

Impact of intensified contact precautions while treating hematopoietic stem cell transplantation recipients during aplasia.

BACKGROUND: Bacterial infections are a major complication for patients undergoing allogeneic hematopoietic stem cell transplantation (HCT). Therefore, protective isolation is considered crucial to prevent nosocomial infections in this population. Here, the impact of intensified contact precautions on environmental contamination and the occurrence of bloodstream infections (BSI) in patients on a HCT unit were compared between two contact precaution measures. METHODS: A 2-year retrospective observational study was performed. In the first year, strict contact precaution measures were applied (i.e., protective isolation, the use of sterile personal protective equipment (PPE) by healthcare workers and visitors and sterilization of linen and objects that entered the patient's room). After one year, contact precautions were reduced (i.e., no use of sterile PPE, no sterilization of linen and objects that entered the patient's room). Environmental contamination in randomly selected patient rooms was monitored by sampling six standardized environmental sites in the respective patient treatment units. In a before-and-after study, the number of BSI episodes of those patients, who were accommodated in the monitored rooms was compared. RESULTS: In total, 181 treatment units were monitored. No significant difference in the contamination of anterooms and patient's rooms between both groups was found. A total of 168 patients were followed for the occurrence of BSI during the entire study period (before: 84 patients, after: 84 patients). The total count of patients with BSI episodes showed a higher incidence in the period with reduced contact precautions (30/84 vs. 17/84, p = 0.039). The cause of this increasing number of BSI can be traced back to BSI episodes with common commensal bacteria (17/84 vs. 5/84, p = 0.011). CONCLUSIONS: The implementation of maximal barrier measures did not reduce the bacterial contamination of the patients' environment. The impact on the patients' outcomes remain controversial. Further research is needed to investigate the impact of infection prevention measures on the clinical outcome of patients undergoing HCT.

Long-Term Kinetics of Serum Galactomannan during Treatment of Complicated Invasive Pulmonary Aspergillosis.

Several studies have evaluated the serum galactomannan (GM) antigen assay in pediatric patients, and there is convincing evidence for its usefulness as a diagnostic tool for invasive Aspergillus infections in patients with acute leukemias or post allogeneic hematopoietic cell transplantation (HCT). Less is known about the utility of the assay in monitoring responses to treatment in patients with established invasive aspergillosis (IA). Here, we present the long-term kinetics of serum galactomannan in two severely immunocompromised adolescents with invasive pulmonary aspergillosis (IPA) who were cured after complicated clinical courses. We also review the utility of the GM antigen assay in serum as a prognostic tool around the time of diagnosis of IA and as a biomarker to monitor disease activity in patients with established IA and assess responses to systemic antifungal therapy.

Tularemia Presenting Solely with Cervical Lymphadenopathy and Fever.

A 52-year-old German female presented with cervical lymphadenopathy and fever. Despite the initial symptom-presentation leading to the consideration of sarcoidosis, lymphoma, tuberculosis, and toxoplasmosis, an extensive serologic and histo- and molecular pathologic workup eventually indicated a likely diagnosis of tularemia. This case brings to light that tularemia is a diagnostic challenge and requires high reliance on the epidemiological context thorough patient history, and an extensive interdisciplinary diagnostic workup.

Susceptibility of Burkholderia cepacia Complex to Ceftazidime/Avibactam and Standard Drugs of Treatment for Cystic Fibrosis Patients.

Burkholderia cepacia complex (Bcc) in airways of patients with cystic fibrosis (CF) is associated with an increased morbidity and mortality. A huge range of intrinsic antimicrobial resistances challenges the treatment of Bcc infections. The aim was to assess the susceptibility of Bcc to ceftazidime/avibactam and standard drugs for the treatment for CF patients and to determine the respective genomic determinants of resistance. Bcc isolates (n = 64) from a prospective multicenter study of CF airway pathogens (2004-2020, Germany) were subjected to broth microdilution and minimal inhibitory concentrations were interpreted with European Committee on Antimicrobial Susceptibility Testing and Clinical & Laboratory Standards Institute breakpoints. A synergism between aztreonam and avibactam was tested using ceftazidime/avibactam disks with or without aztreonam. Plasmids and chromosomes of all isolates were screened for antimicrobial resistance genes. The highest susceptibility rate was detected for trimethoprim/sulfamethoxazole (83%), followed by ceftazidime/avibactam (78%), ceftazidime (53%), levofloxacin (39%) and meropenem (27%). The median inhibition zone diameters of ceftazidime-avibactam and ceftazidime/avibactam plus aztreonam were equal. This was in line with the absence of known class B metallo-ß-lactamases in any of the isolates. The majority of isolates carried blapenA (98%) and blaampC (86%). Trimethoprim/sulfamethoxazole and ceftazidime/avibactam showed high susceptibility rates. Aztreonam in combination with ceftazidime/avibactam had no synergistic effect in our Bcc isolates.

Quiescence of Human Monocytes after Affinity Purification: A Novel Method Apt for Monocyte Stimulation Assays.

Several methods to isolate monocytes from whole blood have been previously published, with different advantages and disadvantages. For the purpose of cytokine release assessment upon external stimulation, the use of monocyte preparations consisting of non-activated cells is prerequisite. Affinity-isolated monocyte preparations from peripheral blood mononuclear cells (PBMCs), obtained via positive or negative selection using magnetic beads, released pro-inflammatory cytokines such as TNF-α and IL-6 even without adding external stimuli, hindering any assessment of an effect of bacterial lipoproteins on cell stimulation. Hence, the cell preparation protocol was modified by adding a quiescence step on repellent surface culture plates, dampening any monocyte pre-activation. This protocol now provides a robust method to prepare silent yet fully activatable, pure monocyte populations for further use in stimulus-elicited activation experiments.

Infectious Morbidity in Pediatric Patients Receiving Neoadjuvant Chemotherapy for Sarcoma.

The purpose of this retrospective, single-center cohort study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy. The review included all patients with a new diagnosis of Ewing sarcoma, osteosarcoma or soft tissue sarcoma between September 2009 and December 2018 who were enrolled in the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Primary endpoints were the occurrence of febrile neutropenia (FN) and microbiologically documented infection (MDI). Parameters with a potential impact on FN and MDI were also analyzed. A total of 170 sarcoma patients (median age: 13 years, range: 0-21; 96 m/74 f) received 948 chemotherapy courses (median: 6; range: 2-8). Of these patients, 58.8% had ≥1 FN episode and 20.6% ≥ 1 MDI. FN occurred in 272/948 courses (28.7%) with fever of unknown origin (FUO) in 231 courses and 45 MDI and 19 clinically documented infections (CDI) occurring in a total of 57 courses. Patients enrolled in EWING 2008 had significantly more FN (p < 0.001), infections (p = 0.02) and MDI (p = 0.035). No infection-related deaths were observed. Younger age, tumor type and localization, and higher median and maximum mucositis grades were significantly associated with higher numbers of FN (p < 0.001), and younger age (p = 0.024) and higher median mucositis grade (p = 0.017) with MDI. The study shows substantial infectious morbidity in sarcoma patients during neoadjuvant chemotherapy treatment and opportunities to improve prevention and management.

Toxoplasmosis after allogeneic haematopoietic cell transplantation-disease burden and approaches to diagnosis, prevention and management in adults and children.

BACKGROUND: Toxoplasmosis is a rare but highly lethal opportunistic infection after allogeneic haematopoietic cell transplantation (HCT). Successful management depends on screening, early recognition and effective treatment. OBJECTIVES: To review the current epidemiology and approaches to diagnosis, prevention and treatment of toxoplasmosis in adult and paediatric allogeneic HCT recipients. SOURCE: Search of the English literature published in MEDLINE up to 30 June 2020 using combinations of broad search terms including toxoplasmosis, transplantation, diagnosis, epidemiology, prevention and treatment. Selection of articles for review and synthesis on the basis of perceived quality and relevance of content. CONTENT: Toxoplasmosis continues to be a major challenge in the management of allogeneic HCT recipients. Here we provide a summary of published case series of toxoplasmosis in adult and paediatric patients post allogeneic HCT. We review and discuss the pathogenesis, epidemiology, clinical presentation, diagnosis and current recommendations for prevention and treatment. We also discuss impacts of toxoplasmosis in this setting and factors affecting outcome, emphasizing attention to neurological, neuropsychological and neurocognitive late effects in survivors. IMPLICATIONS: Apart from careful adherence to established strategies of disease prevention through avoidance of primary infection, identification of seropositive patients and implementation of molecular monitoring, future perspectives to improve the control of toxoplasmosis in allogeneic HCT recipients may include the systematic investigation of pre-emptive treatment, development of immunomodulatory approaches, antimicrobial agents with activity against the cyst form and vaccines to prevent chronic infection.

Upper airways colonisation of Streptococcus pneumoniae in adults aged 60 years and older: A systematic review of prevalence and individual participant data meta-analysis of risk factors.

BACKGROUND: Colonisation with Streptococcus pneumoniae can lead to invasive pneumococcal disease and pneumonia. Pneumococcal acquisition and prevalence of colonisation are high in children. In older adults, a population susceptible to pneumococcal disease, colonisation prevalence is reported to be lower, but studies are heterogeneous. METHODS: This is a systematic review and meta-analysis of prevalence of, and risk factors for, pneumococcal colonisation in adults ≥ 60 years of age (PROSPERO #42016036891). We identified peer-reviewed studies reporting the prevalence of S. pneumoniae colonisation using MEDLINE and EMBASE (until April 2016), excluding studies of acute disease. Participant-level data on risk factors were sought from each study. FINDINGS: Of 2202 studies screened, 29 were analysable: 18 provided participant-level data (representing 6290 participants). Prevalence of detected pneumococcal colonisation was 0-39% by conventional culture methods and 3-23% by molecular methods. In a multivariate analysis, colonisation was higher in persons from nursing facilities compared with the community (odds ratio (OR) 2•30, 95% CI 1•26-4•21 and OR 7•72, 95% CI 1•15-51•85, respectively), in those who were currently smoking (OR 1•69, 95% CI 1•12-2•53) or those who had regular contact with children (OR 1•93, 95%CI 1•27-2•93). Persons living in urban areas had significantly lower carriage prevalence (OR 0•43, 95%CI 0•27-0•70). INTERPRETATION: Overall prevalence of pneumococcal colonisation in older adults was higher than expected but varied by risk factors. Future studies should further explore risk factors for colonisation, to highlight targets for focussed intervention such as pneumococcal vaccination of high-risk groups. FUNDING: No funding was required.

Risk Factors for Long-Term Vancomycin-Resistant Enterococci Persistence-A Prospective Longitudinal Study.

Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens that require effective infection control measures, representing a challenge for healthcare systems. This study aimed at identifying risk factors associated with prolonged VRE carriage and determining the rate of clearance that allows the discontinuation of contact precautions. During a 2-year study, screening was performed in patients with a history of VRE or at risk of becoming colonized. After bacterial identification and antibiotic susceptibility testing, glycopeptide resistance was confirmed by PCR. Isolates were compared via whole genome sequence-based typing. Risk factors were recorded, and follow-up screening was performed upon readmission, defining patients as long-term carriers if still colonized ≥10 weeks after first detection. Of 1059 patients positive for VRE, carriage status was assessed upon readmission in 463 patients. VRE was cleared in 56.4% of the cases. Risk factors associated with long-term persistence were hospital stays (frequency, length), hemato-oncological disease, systemic treatment with steroids, and use of antibiotics. No specific genotypic clustering was observed in patients with VRE clearance or persistence. VRE clearance is possibly underestimated. The identification of risk factors favoring long-term carriage may contribute to a targeted implementation of infection control measures upon readmission of patients with history of VRE.

Prevalence of Multidrug Resistant Bacteria in Refugees: A Prospective Case Control Study in an Obstetric Cohort.

Purpose To determine the prevalence of multidrug resistant (MDR) bacteria in a cohort of pregnant refugee women. Methods In a prospective case control study, surveillance cultures for MDR bacteria (methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci [VRE], MDR Gram-negative bacteria [MRGN]) were analysed between October 2015 and June 2016 from a cohort of 50 pregnant refugee women and 50 resident controls in the obstetric unit of a German tertiary referral hospital. Results Prevalence of MRSA was noticeably higher among refugee women compared to residents (6 vs. 0%). In addition, a trend towards a higher prevalence of VRE and MDR Gram-negative bacteria in refugees was shown (1.8 vs. 0%). Conclusions Due to the higher prevalence of MDR bacteria, surveillance cultures are justified in order to prevent nosocomial spread of MDR bacteria.

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly.

Inhibition of programmed cell death pathways of mammalian cells often facilitates the sustained survival of intracellular microorganisms. The apicomplexan parasite Toxoplasma gondii is a master regulator of host cell apoptotic pathways. Here, we have characterized a novel anti-apoptotic activity of T. gondii. Using a cell-free cytosolic extract model, we show that T. gondii interferes with the activities of caspase 9 and caspase 3/7 which have been induced by exogenous cytochrome c and dATP. Proteolytic cleavage of caspases 9 and 3 is also diminished suggesting inhibition of holo-apoptosome function. Parasite infection of Jurkat T cells and subsequent triggering of apoptosome formation by exogenous cytochrome cin vitro and in vivo indicated that T. gondii also interferes with caspase activation in infected cells. Importantly, parasite inhibition of cytochrome c-induced caspase activation considerably contributes to the overall anti-apoptotic activity of T. gondii as observed in staurosporine-treated cells. Co-immunoprecipitation showed that T. gondii abolishes binding of caspase 9 to Apaf-1 whereas the interaction of cytochrome c with Apaf-1 remains unchanged. Finally, T. gondii lysate mimics the effect of viable parasites and prevents holo-apoptosome functionality in a reconstituted in vitro system comprising recombinant Apaf-1 and caspase 9. Beside inhibition of cytochrome c release from host cell mitochondria, T. gondii thus also targets the holo-apoptosome assembly as a second mean to efficiently inhibit the caspase-dependent intrinsic cell death pathway.