Observational multi-centre, prospective study to characterize novel pathogen-and host-related factors in hospitalized patients with lower respiratory tract infections and/or sepsis - the "TAILORED-Treatment" study.

BACKGROUND: The emergence and spread of antibiotic resistant micro-organisms is a global concern, which is largely attributable to inaccurate prescribing of antibiotics to patients presenting with non-bacterial infections. The use of 'omics' technologies for discovery of novel infection related biomarkers combined with novel treatment algorithms offers possibilities for rapidly distinguishing between bacterial and viral infections. This distinction can be particularly important for patients suffering from lower respiratory tract infections (LRTI) and/or sepsis as they represent a significant burden to healthcare systems. Here we present the study details of the TAILORED-Treatment study, an observational, prospective, multi-centre study aiming to generate a multi-parametric model, combining host and pathogen data, for distinguishing between bacterial and viral aetiologies in children and adults with LRTI and/or sepsis. METHODS: A total number of 1200 paediatric and adult patients aged 1 month and older with LRTI and/or sepsis or a non-infectious disease are recruited from Emergency Departments and hospital wards of seven Dutch and Israeli medical centres. A panel of three experienced physicians adjudicate a reference standard diagnosis for all patients (i.e., bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. Nasal swabs and blood samples are collected for multi-omics investigations including host RNA and protein biomarkers, nasal microbiota profiling, host genomic profiling and bacterial proteomics. Simplified data is entered into a custom-built database in order to develop a multi-parametric model and diagnostic tools for differentiating between bacterial and viral infections. The predictions from the model will be compared with the consensus diagnosis in order to determine its accuracy. DISCUSSION: The TAILORED-Treatment study will provide new insights into the interplay between the host and micro-organisms. New host- or pathogen-related biomarkers will be used to generate a multi-parametric model for distinguishing between bacterial and viral infections. This model will be helpful to better guide antimicrobial therapy for patients with LRTI and sepsis. This study has the potential to improve patient care, reduce unnecessary antibiotic prescribing and will contribute positively to institutional, national and international healthcare economics. TRIAL REGISTRATION: NCT02025699 . Registration Date: January, 1, 2014.

Non-fermentative Gram-negative rods bacteremia in children with cancer: a 14-year single-center experience.

PURPOSE: Data on non-fermentative Gram-negative rods (NFGNR) bacteremia in children with malignancies are limited. The aim of this study was to present clinical picture, antimicrobial susceptibility pattern, risk factors for resistance and outcome in NFGNR bacteremia in children with cancer. METHODS: All episodes of NFGNR bacteremia occurring during 2001-2014 in children with cancer in a tertiary-care hospital were retrospectively analyzed. Pseudomonas and Acinetobacter spp. resistant to three or more antibiotic classes and all Stenotrophomonas maltophilia (SM) were defined as multidrug-resistant bacteria (MDR). RESULTS: A total of 80 children (44 males, 0.8-18 years, median 5 years) developed 107 episodes (116 pathogens) of NFGNR bacteremia; Pseudomonas aeruginosa (PA) (51; 43.9%), Acinetobacter baumannii (AB) (21, 18.1%), SM (18, 15.5%); and others (27, 25.2%). The rate of NFGNR bacteremia in children with certain solid tumors (e.g. sarcoma, 12/134 (9.0%)) was comparable to that of hematological malignancies (52/429 (12.2%). Focal infection and septic shock occurred in 16 (14.9%) and four (3.7%) episodes, respectively. Thirty (25.8%) of 116 NFGNR were MDR. The most significant predictors of bacteremia with MDR PA or AB were severe neutropenia (<100 cells/mm3; OR 7.8, p = 0.002), hospital-acquired (OR 16.9, p < 0.0001) and breakthrough (OR 11.2, p < 0.0001) infection. Infection with MDR bacteria was associated with inappropriate empirical therapy. The 30-day mortality was 3/107 (2.8%), all in neutropenic patients with hematological malignancies. CONCLUSIONS: NFGNR bacteremia can present with nonspecific signs or symptoms. MDR NFGNRs are common and compromise treatment options, but mortality is relatively low. Knowledge of local epidemiology, pattern and risk factors for resistance is important to guide empirical therapy.

Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients.

PURPOSE: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. METHODS: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). RESULTS: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. CONCLUSIONS: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

European guidelines for prevention and management of influenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4 (2011), on behalf of ECIL, a joint venture of EBMT, EORTC, ICHS, and ELN.

Influenza may cause severe disease and mortality in leukemia patients and in hematopoietic stem cell transplantation recipients. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for prevention and management of influenza infections in these patients. Real-time reverse-transcription polymerase chain reaction is the diagnostic test of choice, as it is the most sensitive and specific test for influenza. The risks for severe influenza and fatal outcome include lymphopenia, older age, influenza soon after transplantation or chemotherapy, steroid treatment, and lack of early antiviral therapy. Neuraminidase inhibitors (oral oseltamivir or inhalation of zanamivir) are currently the most effective therapeutic agents for influenza. Main preventive measures include annual vaccination of patients, household contacts, and hospital staff. This review summarizes ECIL-4's main recommendations.

European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 (2011).

Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T-cell function. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for diagnosis and management of HAdV infections. The risk for HAdV-associated disease is increased in children, and risk factors for HAdV disease are T-cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft-versus-host disease grades III-IV, and lymphopenia. The recommended technique for monitoring of high-risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV-specific T-cell therapy is in development.

Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT.

These recommendations were prepared by the European Conference on Infections in Leukaemia following a predefined methodology. Literature searches were made to identify studies pertinent to management of CMV, HHV-6, -7 and -8 infections. For CMV, 76 studies were reviewed: 72 published and 4 presented as abstracts. Twenty-nine of these studies were prospective randomized trials. For the other herpesviruses, HHV-6, -7 and -8, no randomized controlled trial has been performed, although data from some studies with other primary endpoints have been used to assess the management of HHV-6 infection. Works presented only as abstracts were used to a very limited extent. The quality of evidence and level of recommendation were graded according to the Center for Disease Control (CDC) criteria.

Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT.

Over the last 25 years, the numbers of hematopoietic stem cell transplant (SCT) patients have increased rapidly. Infections have been major obstacles for successful transplantation. Thus, infection prevention is very important in transplant recipients. As the results of transplantation have improved, the number of long-term survivors has increased. Vaccination is a potentially important strategy for reducing the risk for vaccine-preventable infections after SCT. The EBMT produced recommendations for vaccination of SCT recipients published in Bone Marrow Transplantation in 1995. This paper updates the previous recommendations based on current knowledge.

Food-borne outbreak of group A beta-hemolytic streptococcal pharyngitis.

An outbreak of pharyngitis due to group A beta-hemolytic streptococci type T 12 occurred at a military base. An epidemiologic investigation indicated that the outbreak was food borne. Consumption of boiled egg salad at lunch was significantly associated with the illness. Immediate institution of antibiotic therapy and isolation of the patients prevented secondary respiratory spread of the infection. No cases of poststreptococcal suppurative and nonsuppurative complications were found during a 6-week period after the outbreak. Medical personnel should be aware of the possibility of food-borne streptococcal pharyngitis. Regular health surveillance of food handlers and food preparation processes are important for prevention of such outbreaks.

Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy.

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Nosocomial colonization, septicemia, and Hickman/Broviac catheter-related infections in bone marrow transplant recipients. A 5-year prospective study.

In this 5-year prospective study of 242 bone marrow transplantation (BMT) recipients from whom daily blood cultures via the indwelling Broviac/Hickman catheter were obtained, there was a median of 35 catheter-days during hospitalization, mean of 40 days, and total of 9,667 catheter-days which were divided almost equally between neutropenic (4,771) and non-neutropenic (4,896) days. One hundred twenty (50%) patients had a total of 161 episodes of nosocomial bacterial or candidal infections. Overall, 81 (33%) patients experienced 100 episodes of catheter-related infections and 90 (37%) patients experienced 112 episodes of septicemia, including 51 episodes of catheter-related septicemia. There was an incidence of 11.59 septicemia episodes, including 5.28 catheter-related septicemia episodes, 2.48 colonization only (without subsequent septicemia), and 2.59 exit site infections only, per 1,000 catheter-days. Over a period of a total of 6,593 afebrile days, 34 (14%) patients developed 40 episodes of colonization, a rate of 6.07 per 1,000 afebrile days, of which 16 developed into septicemia. Twenty-five patients had 1 episode each of exit site infection without bacteremia. There were 10 (4%) septicemia-related deaths, 4 of which were catheter-related; 50% of all deaths involved Pseudomonas aeruginosa. The mortality due to catheter-related septicemic episodes was not greater than that of the non-catheter-related episodes. Neutropenia was found to be a significant risk factor in our study: 76% of the septicemia episodes (85/112) and 65% of the catheter-related infectious episodes (65/100) occurred during neutropenia. There was a higher incidence of septicemic episodes during neutropenia than during non-neutropenic periods, 17.82 versus 5.51 per 1,000 days (p < 0.0001), and a higher rate of catheter-related infections during the neutropenic period, 13.62 versus 7.15 during non-neutropenic days per 1,000 days (0.001). Fourteen of 16 colonization episodes developed into septicemia during neutropenia versus 2/24 during non-neutropenic periods, a rate of 5.47 versus 0.47 per 1,000 afebrile days, respectively (p < 0.0001), and 9/10 deaths occurred during neutropenia.

Invasive pneumococcal infections. A comparison between adults and children.

A similar number of adults and children had invasive pneumococcal infection. There was male predominance, and different ethnic distribution between children and adults. The majority of adults (78%), had underlying diseases, but this was less frequent in children (24%). The presenting illness differed between adults and children. Complications of invasive pneumococcal infection occurred more frequently in adults than in children. The mortality rate in adults was 21.5%; in children, only 3.8%. The rate of penicillin-resistant pneumococci at our hospital was 23%, while cefotaxime resistance was 4.2%. Penicillin-resistant pneumococci were not isolated more frequently from children than from adults. Patients with penicillin-resistant pneumococci had longer duration of hospitalization and more nosocomially acquired infections. No difference in the mortality rate was found between patients with resistant or sensitive pneumococci. Ninety-five percent of strains were included in the current vaccine, but less than 2% of patients had been vaccinated. Isolates prevalent in Europe and the United States (19, 5, 1, 14, 6, 18, 12, 4, 9, 23, 7) were also most prevalent in Jerusalem. The distribution of serotypes differed between children and adults, and between patients from whom resistant organisms were isolated as opposed to sensitive organisms.

Nosocomial coagulase-negative staphylococcal infections in bone marrow transplantation recipients with central vein catheter. A 5-year prospective study.

The purpose of this study was to examine coagulase-negative staphylococcal infections in bone marrow transplantation (BMT) patients with central vein catheters by investigating incidence, clinical relevance, risk factors, methicillin resistance, clinical impact of initial empiric antimicrobial therapy without vancomycin, and management of documented catheter-related infections. A 5-year prospective study was conducted with daily evaluation of 242 BMT patients during hospitalization, including clinical assessment and blood culture via the Hickman/Broviac catheter. If fever or infected appearance occurred, peripheral blood cultures or exit site cultures, respectively, were done. Results showed a septicemia incidence of 7.0%, including in 6 patients following colonization, in 1 patient with tunnel infection, in 1 patient with thrombophlebitis, in 1 patient with exit site infection, and in 8 patients with septicemia of unknown origin. Total colonization incidence was 7%, with colonization only in 11 patients who had 16 episodes; incidence of exit site infection was 3.7%. Age > or = 18 years was the only identified risk factor for developing staphylococcal infection (P = 0.03). Despite a methicillin resistance rate of 45% and omission of vancomycin from the routine initial empiric antimicrobial regimen, the clinical course of coagulase-negative staphylococcal infections was relatively benign. A single patient, who experienced marrow rejection, died on day +31 with septicemia and only one patient experienced microbiological failure with recurrent colonization. Bacteria grown in both aerobic and anaerobic bottles were more likely true bacteremia than contaminant (P = 0.03). We conclude that the hazard of coagulase-negative staphylococcal infection does not mandate inclusion of a glycopeptide in the initial empiric antimicrobial regimen in BMT patients, even during febrile neutropenia. Hickman/Broviac-related staphylococcal infections, except for tunnel infection or thrombophlebitis, can usually be treated successfully without removing the catheter.

Parenteral-oral switch in the management of paediatric pneumonia.

In phase I of a 2-phase study, 56 evaluable children (0.8 to 5 years) with lobar or segmental pneumonia received intravenous or intramuscular ceftriaxone 50 mg/kg/day for 2 days followed by oral cefetamet pivoxil 20 mg/kg/day in 2 divided doses to complete 7 days of treatment. All patients achieved a clinical cure. In phase II, a randomised open multicentre study, 62 children with pneumonia received an identical regimen to phase I (arm A), and 59 children received ceftriaxone 50 mg/kg/day for 1 day followed by 6 days' treatment with cefetamet pivoxil 20 mg/kg/day (arm B). Patients from phase I and arm A were combined giving a total of 118 evaluable patients in arm A. At the end of treatment, 100% of patients in arm A and 96% in arm B achieved a clinical cure; cure was maintained in 99 and 98% of patients, respectively. Two (4%) patients in arm B failed therapy; in both cases, factors other than treatment failure may have accounted for the poor response. 11 and 12% of patients in treatment arms A and B, respectively, experienced adverse events; gastrointestinal events (nausea and/or vomiting) were reported in 9 and 8% of patients, respectively. In conclusion, 1 or 2 days' treatment with parenteral ceftriaxone before switching to oral cefetamet pivoxil was safe and effective in the treatment of childhood pneumonia. Therefore, parenteral-oral switch is a feasible treatment option in the treatment of serious paediatric community-acquired pneumonia.

Bacterial and fungal infections in children undergoing bone marrow transplantation.

Bacterial and fungal infections in pediatric BMT recipients are major causes of morbidity and mortality, although less than those in the adult BMT population. Early in the post-BMT period, when patients are neutropenic, the predominant pathogens are Gram-negative bacteria, mainly E. coli, K. pneumoniae and P. aeruginosa; Gram-positive bacteria, mainly coagulase-negative staphylococcus, S. viridans and E. faecalis; and fungi, mainly Candida spp. and Aspergillus spp. The emerging resistance of a variety of pathogens is of major concern and limits the use of prophylactic antibiotics. Mortality from invasive fungal infections is much greater than that caused by bacterial pathogens. Many centers are currently using prophylactic fluconazole, which may lead to emergence of infections with C. krusei and T. glabrata. Patients with GvHD are at continuous risk from bacterial and fungal pathogens. Late in the post-BMT period, S. pneumoniae may cause septicemia, meningitis, pneumonia and other respiratory infections. This may occur months or years following transplantation, with a significant mortality rate in patients with chronic GvHD. Development of rapid and reliable diagnostic methods for identifying fungal pathogens and of new therapeutic approaches for treating invasive fungal infections are now our greatest future challenges.

Treatment with itraconazole of widespread tinea corporis due to Trichophyton rubrum in a bone marrow transplant recipient.

An immunocompromised patient, 6 weeks after bone marrow transplantation, developed extensive skin infection due to Trichophyton rubrum. Because she could not tolerate ketoconazole and was hypersensitive to griseofulvin, she received itraconazole with complete recovery within 30 days. This case demonstrates that itraconazole may be effective treatment for dermatophytosis, even in immunocompromised hosts, and that there is no cross-reactivity between ketoconazole and itraconazole.

Interstitial pneumonitis in T cell-depleted bone marrow transplantation.

The incidence of interstitial pneumonitis (IP) was reviewed in 80 consecutive patients who received allogeneic T lymphocyte-depleted bone marrow transplantation (BMT) for malignant and non-malignant diseases. Pretransplant conditioning used in malignant disorders included total lymphoid irradiation (TLI) 150 cGy x 4, total body irradiation (TBI) 200 cGy x 6, and cyclophosphamide (CY) 120 mg/kg. In non-malignant diseases conditioning included no TBI, but adjusted doses of TLI in addition to CY (severe aplastic anemia) or CY and busulfan (severe beta-thalassemia major). In the malignant group only one patient developed graft-versus-host disease (GVHD) grade I; IP developed in 12 out of 61 patients (19.7%) and IP-associated fatality occurred in five patients (8.2%). Cytomegalovirus (CMV) was associated with only two of the five fatal IP. In the non-malignant group there was no GVHD; one patient out of 19 (5.2%) had IP, which was fatal and not associated with CMV. These data indicate that fatal IP may appear in the absence of GVHD. The relatively low incidence of IP-related mortality in recipients of allogeneic T lymphocyte-depleted BMT suggests that although prevention of GVHD and elimination of drugs used for GVHD prevention may reduce the incidence of fatal pulmonary complications, other approaches have to be investigated for complete prevention of IP which still represents a major complication in patients with malignant hematologic disorders treated by allogeneic BMT.

Oral tuberculosis following autologous bone marrow transplantation for Hodgkin's disease with interleukin-2 and alpha-interferon immunotherapy.

A patient with Hodgkin's disease (HD) underwent autologous bone marrow transplantation (ABMT). Six months later while receiving interleukin (IL)-2 and alpha-interferon immunotherapy, he developed a painful lesion in his oral cavity with a fistula in the buccal area. Excision biopsy disclosed necrotizing granulomatous inflammation with acid-fast bacillus. The patient received a 9-month course of isoniazide, rifampin and pyrazinamide, and recovered. The possible pathophysiological mechanism is discussed.

European survey of herpesvirus resistance to antiviral drugs in bone marrow transplant recipients. Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

A survey of herpesvirus resistance to antiviral drugs was conducted by mailing a questionnaire to the centers of the European Group for Blood and Marrow Transplantation (EBMT). Results from 68 centers were reported. The number of centers with proven or suspected resistance of herpes simplex virus (HSV) was 17 (25%), of varicella-zoster virus (VZV) was three (4%), and of cytomegalovirus (CMV) was 19 (28%). Acyclovir-resistant HSV strains were recovered from 10 patients with HSV disease. Replacement of acyclovir by foscarnet in seven of these patients resulted in improved or healed HSV disease in five (17%). Acyclovir-resistant VZV was isolated from one patient with zoster which improved after a change to vidarabine therapy. CMV resistance to ganciclovir was proven in only two patients but was suspected in 23. Ganciclovir was replaced by foscarnet in 15 of these 25 patients which resulted in better virological and/or clinical outcome in 13 (87%). These results suggest that herpesvirus resistance is an emerging problem in marrow transplant recipients, and that foscarnet treatment may prove to be a valuable alternative when the presence of acyclovir- or ganciclovir-resistant herpesvirus disease is documented in these patients.

Unusual cytomegalovirus complications after autologous stem cell transplantation for large B cell lymphoma: massive gastrointestinal hemorrhage followed by a communicating hydrocephalus.

Unusual cytomegalovirus (CMV)-related complications were seen after autologous stem cell transplantation (SCT) in a 50-year-old patient with diffuse large B cell lymphoma. One month after SCT, the patient developed life-threatening upper gastrointestinal tract (GIT) bleeding with several episodes of hemorrhagic shock. Endoscopy and subsequent explorative laparotomy revealed deep-seated bleeding ulcers containing intracellular CMV inclusion bodies distributed extensively in the GIT, from the lower esophagus to the small bowel. Later, she developed gradual loss of consciousness with communicating hydrocephalus which was possibly secondary to CMV-induced ventriculitis. She recovered completely after insertion of a ventriculostomy and subsequent V-P shunt.

Immune response to polio vaccination in bone marrow transplant recipients.

Following a small outbreak of poliomyelitis which occurred in the summer of 1988 in Israel, two sequential doses of inactivated polio vaccine (IPV) were administered to 42 bone marrow transplant (BMT) recipients (aged 2-50 years) who were 6-96 months (median 16 months) after transplantation. Prior to vaccination, only 68-80% patients (n = 42) had protective (greater than or equal to 4) antibody levels against the three serotypes of poliovirus, compared with 92-96% (n = 25) before BMT (p = 0.02 for types 1 and 3). After the second dose of IPV, 89-98% (n = 27) of the recipients had protective antibody levels. The pre-vaccination antibody titers were lower than before BMT (p = 0.006, 0.0007 and 0.0008 for types 1,2 and 3, respectively). After the first dose of IPV, antibody titers rose in the 42 patients (p = 0.002, 0.043 and 0.002 for types 1, 2 and 3, respectively) and following the second dose, a further increase in antibody levels was noted. Regression analysis revealed that graft-versus-host disease, pre-BMT polio antibody titers, age and type of transplantation (allogeneic versus autologous) were significant explanatory variables for the specific antibody levels, while the time lapse between BMT and vaccination, and primary disease proved of no significance. Vaccination against poliovirus after BMT is advocated, as it reinstates and raises the lost specific humoral immunity.