Bacteria causing bacteremia in pediatric cancer patients presenting with febrile neutropenia – species distribution and susceptibility patterns

PURPOSE Infections are a major cause of morbidity and mortality in pediatric cancer patients. The aim of this study was to establish the microbiological spectrum and the susceptibility patterns of bacteremia-causing bacteria in pediatric cancer patients with febrile neutropenia in relation to the use of prophylactic and empirical antibiotics. METHODS We analyzed positive blood cultures of pediatric cancer patients presenting with febrile neutropenia between 2004 and 2011 in Groningen and Amsterdam (the Netherlands) and in Bern (Switzerland), using different antibiotic prophylactic and empirical regimens. RESULTS A total of 156 patients with 202 bacteremias, due to 248 bacteria species, were enrolled. The majority (73%) of bacteremias were caused by Gram-positive bacteria. Gram-negative bacteria, especially Pseudomonas aeruginosa, were observed significantly more often in Bern, where no fluoroquinolone prophylaxis was used. Ciprofloxacin-resistant bacteria were cultured more often from patients who did receive ciprofloxacin prophylaxis, compared to the patients who did not (57 versus 11%, p = 0.044). CONCLUSIONS Gram-positive bacteria predominated in this study. We showed that the use of prophylactic antibiotics in pediatric cancer patients was associated with increased resistance rates, which needs further study. The strategy for empiric antimicrobial therapy for febrile neutropenia should be adapted to local antibiotic resistance patterns.

The influence of different fever definitions on the rate of fever in neutropenia diagnosed in children with cancer

BACKGROUND The temperature limit defining fever (TLDF) is based on scarce evidence. This study aimed to determine the rate of fever in neutropenia (FN) episodes additionally diagnosed by lower versus standard TLDF. METHODS In a single center using a high TLDF (39.0°C tympanic temperature, LimitStandard), pediatric patients treated with chemotherapy for cancer were observed prospectively. Results of all temperature measurements and CBCs were recorded. The application of lower TLDFs (LimitLow; range, 37.5°C to 38.9°C) versus LimitStandard was simulated in silicon, resulting in three types of FN: simultaneous FN, diagnosed at both limits within 1 hour; earlier FN, diagnosed >1hour earlier at LimitLow; and additional FN, not diagnosed at LimitStandard. RESULTS In 39 patients, 8896 temperature measurements and 1873 CBCs were recorded during 289 months of chemotherapy. Virtually applying LimitStandard resulted in 34 FN diagnoses. The predefined relevantly (≥15%) increased FN rate was reached at LimitLow 38.4°C, with total 44 FN, 23 simultaneous, 11 earlier, and 10 additional (Poisson rate ratioAdditional/Standard, 0.29; 95% lower confidence bound, 0.16). Virtually applying 37.5°C as LimitLow led to earlier FN diagnosis (median, 4.5 hours; 95% CI, 1.0 to 20.8), and to 53 additional FN diagnosed. In 51 (96%) of them, spontaneous defervescence without specific therapy was observed in reality. CONCLUSION Lower TLDFs led to many additional FN diagnoses, implying overtreatment because spontaneous defervescence was observed in the vast majority. Lower TLDFs led as well to relevantly earlier diagnosis in a minority of FN episodes. The question if the high TLDF is not only efficacious but as well safe remains open.

Management of fever and neutropenia in paediatric cancer patients: room for improvement?

PURPOSE OF REVIEW Fever and neutropenia is the most common complication in the treatment of childhood cancer. This review will summarize recent publications that focus on improving the management of this condition as well as those that seek to optimize translational research efforts. RECENT FINDINGS A number of clinical decision rules are available to assist in the identification of low-risk fever and neutropenia however few have undergone external validation and formal impact analysis. Emerging evidence suggests acute fever and neutropenia management strategies should include time to antibiotic recommendations, and quality improvement initiatives have focused on eliminating barriers to early antibiotic administration. Despite reported increases in antimicrobial resistance, few studies have focused on the prediction, prevention, and optimal treatment of these infections and the effect on risk stratification remains unknown. A consensus guideline for paediatric fever and neutropenia research is now available and may help reduce some of the heterogeneity between studies that have previously limited the translation of evidence into clinical practice. SUMMARY Risk stratification is recommended for children with cancer and fever and neutropenia. Further research is required to quantify the overall impact of this approach and to refine exactly which children will benefit from early antibiotic administration as well as modifications to empiric regimens to cover antibiotic-resistant organisms.

Core outcomes and definitions for pediatric fever and neutropenia research: a consensus statement from an international panel.

BACKGROUND There are no specific recommendations for the design and reporting of studies of children with fever and neutropenia (FN). As a result, there is marked heterogeneity in the variables and outcomes that are reported and new definitions continue to emerge. These inconsistencies hinder the ability of researchers and clinicians to compare, contrast and combine results. The objective was to achieve expert consensus on a core set of variables and outcomes that should be measured and reported, as a minimum, in pediatric FN studies. PROCEDURE The Delphi method was used to achieve consensus among an international group of clinicians, pharmacists, researchers, and patient representatives. Four surveys focusing on (i) the identification of a core set of variables and outcomes; and (ii) definitions of these variables and outcomes, were administered electronically. Consensus was predefined as more than 80% agreement on any statement. RESULTS There were forty-five survey participants and the response rate ranged between 84 and 96%. There was consensus on eight core variables and 10 core outcomes that should be collected and reported in all studies of children with FN. Consensus definitions were identified for all of the core outcomes. CONCLUSION Using the Delphi method, expert consensus on a set of core variables and outcomes, and their corresponding definitions, was achieved. These core sets represent the minimum that should be collected and reported in all studies of children with FN. This will promote collaboration and ensure consistency and comparability between studies.

Características clínicas da fase aguda da infecção experimental de felinos pelo vírus da imunodeficiência felina

A infecção dos felinos pelo Vírus da Imunodeficiência Felina (FIV) resulta no desenvolvimento da síndrome de imunodeficiência dos felinos. Gengivite, perda de peso, linfadenomegalia generalizada, anemia, insuficiência renal crônica, complicações neurológicas, diarréia crônica e infecções bacterianas são encontradas frequentemente. A fase aguda da infecção pode ser assintomática, retardando o estabelecimento do diagnóstico e a implantação de medidas profiláticas para restringir o contágio e a transmissão do agente aos felinos suscetíveis. Com a finalidade de estudar as características clínicas da fase aguda da infecção, dez felinos jovens, sem definição racial, com oito meses de idade foram inoculados por via endovenosa com 1mL de sangue venoso de um gato portador do FIV subtipo B. A confirmação da infecção foi obtida através de teste sorológico em quatro e oito semanas pós-inoculação (p.i.) e por nested-PCR. Foram realizados hemogramas semanais, exame ultrassonográfico do abdômen quinzenais e exame oftalmológico mensal, durante doze semanas p.i. Discreta tendência a linfopenia na segunda semana p.i. e a neutropenia entre a quinta e sétima semana p.i., febre intermitente em alguns gatos, linfadenomegalia e hepato-esplenomegalia entre a quarta e a 12ª semana p.i. foram as alterações clínicas observadas. Apenas um gato apresentou uveíte unilateral direita. A fase aguda da infecção transcorreu com alterações clínicas inespecíficas. A linfadenomegalia e a hepato-esplenomegalia observadas no decorrer da infecção, refletindo hiperplasia linfóide, sugerem a necessidade de se realizar o teste sorológico para o FIV, em todos os gatos que se apresentarem com essas alterações, o que permitirá o diagnóstico precoce da infecção e a adoção de medidas profiláticas no sentido de minimizar a propagação da infecção.

Population balance model of in vivo neutrophil formation following bone marrow rescue therapy

In this paper, we develop a simple four parameter population balance model of in vivo neutrophil formation following bone marrow rescue therapy. The model is used to predict the number and type of neutrophil progenitors required to abrogate the period of severe neutropenia that normally follows a bone marrow transplant. The estimated total number of 5 billion neutrophil progenitors is consistent with the value extrapolated from a human trial. The model provides a basis for designing ex vivo expansion protocols.

A new small molecule C5a receptor antagonist inhibits the reverse-passive arthus reaction and endotoxic shock in rats

C5a is implicated as a pathogenic factor in a wide range of immunoinflammatory diseases, including sepsis and immune complex disease, Agents that antagonize the effects of C5a could be useful in these diseases. We have developed some novel C5a antagonists and have determined the acute anti-inflammatory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as against some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS-induced neutropenia and elevated levels of circulating TNF-alpha, as well as polymorphonuclear leukocyte migration, increased TNF-alpha levels and vascular leakage at the site of immune complex deposition. These results indicate potent anti-inflammatory activities of a new C5a receptor antagonist and provide more evidence for a key early role for C5a in sepsis and the reverse Arthus reaction. The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.

Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance

Infections caused by the yeast Candida albicans represent an increasing threat to debilitated and immunosuppressed patients, and neutropenia is an important risk factor. Monoclonal antibody depletion of neutrophils in mice was used to study the role of these cells in host resistance. Ablation of neutrophils increased susceptibility to both systemic and vaginal challenge. The fungal burden in the kidney increased threefold on day 1, and 100-fold on day 4, and infection was associated with extensive tissue destruction. However, a striking feature of the disseminated disease in neutrophil-depleted animals was the altered pattern of organ involvement. The brain, which is one of the primary target organs in normal mice, was little affected. There was a threefold increase in the number of organisms recovered from the brains of neutrophil-depleted mice on day 4 after infection, but detectable abscesses were rare. In contrast, the heart, which in normal mice shows only minor lesions, developed severe tissue damage following neutrophil depletion. Mice deficient in C5 demonstrated both qualitative and quantitative increases in the severity of infection after neutrophil depletion when compared with C5-sufficient strains. The results are interpreted as reflecting organ-specific differences in the mechanisms of host resistance.

Excretion of ammonia by Lucilia cuprina larvae suppresses immunity in sheep

Attempts to immunise sheep against natural infestations by Lucilia cuprina larvae have not been effective. Yet it is known that the larvae excrete the immunosuppressant ammonium bicarbonate. The effect of larval ammonium and nonionic ammonia on immunopathobiology was evaluated in 12 infested sheep. The concentration of ammonium in veins draining infested sites was measured in another group of four sheep. Mean jugular unionized ammonia concentration increased 3.5 to 5.6 times above pre-infested control levels. Mean venous ammonium concentrations draining infested sites were 13 times higher than pre-infested jugular or carotid levels. Increases in jugular ammonia concentrations correlated with increased number of larvae, area of infestation, earlier death, neutropenia, eosinopenia, lymphocytopenia, large declines in serum globulins and zinc, and large rises in toxic neutrophils. The high concentrations of toxic unionized ammonia in blood directly permanently damaged neutrophils and lymphocytes and depressed serum globulin production. The results show that the ammonium from the excreta of larvae of L. cuprina may be highly immunosupressive. (C) 1997 Elsevier Science B.V.

Adverse Drug Reactions and Drug Interactions as Causes of Hospital Admission in Oncology

Context. Although several studies have evaluated the frequency of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) in general medicine, few studies have looked at the epidemiology of adverse drug events (ADEs) in oncology. Objectives. We sought to investigate how many hospital admissions in oncology are related to a DDI or an ADR. Methods. All cancer patients admitted to an oncology ward during an eight-month period had their charts retrospectively evaluated for reasons of hospitalization, using a 4-point scale (definitely, probably, possibly, or unlikely associated) to classify admissions by their probability of being associated with either a DDI or an ADR. Results. From September 2007 to May 2008, there were 550 hospital admissions and 458 were eligible. Among unplanned admissions (n = 298), 39 (13.0%, 95% confidence interval [CI] 9.4%-17.4%) were considered to be associated with an ADE, 33 (11.0%, 95% CI 7.7%-15.2%) with an ADR, and six (2.0%, 95% CI 0.7%-4.3%) with a DDI. The most common DDIs involved warfarin, captopril, and anti-inflammatory agents, and the most frequent ADR was neutropenic fever post-chemotherapy. Most patients were discharged completely recovered, but two patients died. Conclusion. Approximately one in 10 unplanned hospitalizations of cancer patients is associated with an ADE. Prospective and population-based studies are warranted to evaluate their magnitude in oncology. J Pain Symptom Manage 2011;42:342-353. (C) 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents

Background & Aims: This multi-center study aimed to prospectively evaluate the safety and efficacy of a genotype-based Pegylated Interferon alfa-2a/Ribavirin therapy in treatment-naive hepatitis C virus (HCV), positive HCV serology, and quantifiable HCV RNA, infected children. Methods: Eighteen children with genotypes 2 and 3 patients (group A) were assigned to medication for 24 weeks, and 47 children with genotypes 1, 4, 5 and 6 patients (group B) for 48 weeks. Results: Early response at week 12 was observed in 83% of group A patients and in 57% of group B patients (p <0.05). End of treatment response was achieved in 94% of patients in group A and in 57% in group B (p <0.001). Sustained virologic response was maintained in 89% of patients in group A and in 57% of patients in group B (p <0.01). Ten patients stopped prematurely the treatment, 2 for serious adverse event (acute hepatitis and thyrotoxicosis), and 8 because of no virologic response at week 24. Peginterferon alfa-2a and Ribavirin dose was adjusted in 15 patients (23%), 11 for neutropenia (17%), and 3 patients (5%), for anemia, respectively. Treatment-related adverse events included fever and flu-like symptoms (54%), irritability depression change of mood (34%), vomiting (23%), abdominal pain (38%), loss of appetite (21.5%) and dermatitis (29%). No influence on height growth was observed. Conclusions: Pegylated inteferon alfa-2a and Ribavirin treatment allowed to achieve SVR in 57% of pediatric patients with genotypes 1, 4, 5 and 6, and in 94% of genotypes 2 and 3. These results show an improved SVR as compared to reference series in adults with similar regimen. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Granulocyte-Colony Stimulating Factor (G-CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI(3)K in mice

Granulocyte-colony stimulating factor (G-CSF) is a current pharmacological approach to increase peripheral neutrophil counts after anti-tumor therapies. Pain is most relevant side effect of G-CSF in healthy volunteers and cancer patients. Therefore, the mechanisms of G-CSF-induced hyperalgesia were investigated focusing on the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase). JNK (Jun N-terminal Kinase) and p38, and PI(3)K (phosphatidylinositol 3-kinase). G-CSF induced dose (30-300 ng/paw)-dependent mechanical hyperalgesia, which was inhibited by local post-treatment with morphine. This effect of morphine was reversed by naloxone (opioid receptor antagonist). Furthermore, G-CSF-induced hyperalgesia was inhibited in a dose-dependent manner by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI(3)K (wortmanin) inhibitors. The co-treatment with MAP kinase and PI(3)K inhibitors, at doses that were ineffective as single treatment, significantly inhibited G-CSF-induced hyperalgesia. Concluding, in addition to systemic opioids, peripheral opioids as well as spinal treatment with MAP kinases and PI(3)K inhibitors also reduce G-CSF-induced pain. (C) 2011 Elsevier Inc. All rights reserved.

Interferon-gamma, interleukin-10, intercellular adhesion molecule-1, and chemokine receptor 5, but not interleukin-4, attenuate the development of periapical lesions

This study examines the role of Th1 (interferon-gamma [IFN-gamma]) and Th2 (interleukin-4 [IL-4] and IL-10) cytokines, an intercellular adhesion molecule (ICAM-1), and a chemokine receptor (CCR5) in the pathogenesis of periapical lesions at different stages of development in knockout mice. For lesion induction, the first molar was opened and inoculated with 4 bacterial strains and left open to the oral environment. After 21 and 42 days, the IFN-gamma, IL-10, ICAM-1, and CCR5 knockout animals presented periapical lesions larger than those of wild-type animals. There was no statistically significant difference between periapical lesions induced in IL-4 knockout and wild-type animals during the periods evaluated. Our findings suggest an important role for IFN-gamma, IL-10, ICAM-1, and CCR5 in the pathogenesis of experimentally induced pulp infection and bone destruction as endogenous suppressor of periapical lesion development, whereas IL-4 appears to present a nonsignificant effect on periapical lesion modulation.

Dilated cardiomyopathy in a case of Shwachman-Diamond syndrome

The Shwachman-Diamond syndrome is an autosomal recessive bone marrow failure syndrome with exocrine pancreatic insufficiency. Additional organ systems, such as the liver, heart and bone, may also be affected. We report a patient with a long history of cardiac failure and diagnosis of dilated cardiomyopathy with intermittent neutropenia. Periodic follow-up revealed progressive cardiac failure and pulmonary hypertension. A diagnosis of Shwachman-Diamond syndrome was made at the autopsy.

Transdermal Pharmacology of Small Molecule Cyclic C5a Antagonists

Overproduction or underregulation of the proinflammatory complement component C5a has been implicated in numerous immune and inflammatory conditions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous animal models of inflammation following intravenous, subcutaneous, intraperitoneal, and oral administration. In the present study the transdermal pharmacology of PMX53 and three analogs designed with increased lipophilicity, hydrocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administration (10 mg/50 cm(2) site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (I mg/kg i.v.). Interestingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (< 5 ng/ml) circulating levels following topical administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic effects. However, increasing lipophilicity in these compounds did not result in increased blood levels. Nonetheless, topical application of C5aR antagonists produced circulating levels of the drugs that antagonized the LPS-induced systemic responses of neutropenia and hypotension. This suggests that these small-molecule C5aR antagonists may be developed for topical administration for the treatment of local and systemic inflammatory conditions in the human and veterinary pharmaceutical markets.