Voriconazole prophylaxis in children with cancer: changing outcomes and epidemiology of fungal infections.

BACKGROUND: Invasive mould infections are a significant cause of morbidity and mortality in pediatric cancer patients, particularly in those undergoing aggressive myeloablative chemotherapy. Voriconazole has been described as an appropriate and effective prophylactic agent in adults with cancer. METHODS: We compared the etiology, predisposing factors and outcomes of invasive mould infection in patients treated for acute myeloid leukemia before and after implementation of voriconazole prophylaxis in a pediatric cancer center. RESULTS: We observed no difference in the number of invasive mould infection between groups. However, isolated organisms were markedly different, with a shift from aspergillosis to phaeohyphomycosis after the implementation of voriconazole prophylaxis. Survival at 90 days was improved in patients receiving voriconazole prophylaxis (P = 0.05). We did not identify a significant increase in the incidence of zygomycosis associated with routine use of voriconazole prophylaxis. CONCLUSIONS: Voriconazole prophylaxis was associated with improved survival in pediatric patients with acute myeloid leukemia, although other factors may be involved. Voriconazole prophylaxis was associated with a marked change in the pattern of mould infections, with a significant reduction in aspergillosis.

Timeline, epidemiology, and risk factors for bacterial, fungal, and viral infections in children and adolescents after allogeneic hematopoietic stem cell transplantation.

Advances made in the field of hematopoietic stem cell transplantations (HSCT) over the past 20 years may have had an impact on the distribution of posttransplantation infections. We sought to retrospectively analyze the epidemiology and risk factors for bacterial, fungal, and viral infections in children after allogeneic HSCT in a cohort of 759 children who underwent allogeneic HSCT in a single institution between 1990 and 2009. The association between infections and risk factors of interest at 0 to 30 days, 31 to 100 days, and 101 days to 2 years posttransplantation was evaluated using logistic regression. Difference among the subtypes within each category was studied. There were 243 matched-related donors, 239 matched-unrelated donors (MUDs), and 176 haploidentical donor transplantations. Era of transplantation (0-30 days), peripheral blood stem cell product, acute graft-versus-host disease (aGVHD; 31-100 days), and chronic GVHD (cGVHD; 101-730 days) were associated with higher risk for bacterial infections at the respective time periods. Patients with aGVHD (31-100 days), cGVHD, and older age (101-730 days) were at higher risk for fungal infections. Cytomegalovirus (CMV) donor/recipient (D/R) serostatus (0-100 days), era of transplantation, MUD HSCT (31-100 days), and cGVHD (101-730 days), influenced viral infections. Gram-positive outnumbered gram-negative bacterial infections; aspergillosis and candidemia were equally prevalent in all time periods. Haploidentical donor HSCT was not associated with an increased risk of infections. There seems to be a continuum in the timeline of infections posttransplantation, with bacterial, fungal, and viral infections prevalent in all time periods, particularly late after the transplantation, the risk affected by GVHD, CMV, D/R status, product type, older age, and use of unrelated donors.

Ethanol lock therapy in pediatric hematology and oncology.

Central venous catheters are essential for treatment of cancer and hematologic disorders in children. Central line-associated bloodstream infection (CLABSI) is the most common important complication and can lead to serious sequelae. Conventional antibiotic treatment is often unsuccessful. Ethanol lock therapy (ELT) has been shown to prevent CLABSI in various patient groups and might also be beneficial as adjunctive treatment for active infection. Efficacy and safety have not been adequately studied in the pediatric hematology/oncology population. Catheter occlusion and intraluminal clots have been reported. Routine use of ELT should not be recommended in this population until more data are available.

Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections.

BACKGROUND: Despite recent studies failing to demonstrate the value of routine chest radiography (CXR) in the initial evaluation of the febrile neutropenic patient with cancer, this screening test is advocated by some experts. We evaluated the benefits of CXR for early diagnosis of pulmonary infection at St. Jude Children's Research Hospital (SJCRH) with emphasis on early recognition of mould infections. PATIENTS AND METHODS: We reviewed the courses of 200 consecutive febrile neutropenic pediatric patients to determine if routine CXR at initial evaluation was useful in the identification of clinically occult pneumonia. We also reviewed all cases of proven or probable mould infections from the opening of SJCRH in 1962 until 1998 when routine CXR was no longer practiced in our institution to identify cases that were first recognized by routine CXR. RESULTS: Of 200 febrile neutropenic patients, pulmonary abnormalities consistent with pneumonia were detected by routine CXR in only five patients without pulmonary signs or symptoms. In only one case was a change in management considered. Of the 70 patients with pulmonary mould infection identified from 1962 to 1998, routine CXR was performed in 45 patients at the onset of a febrile, neutropenic episode in which a mould infection was diagnosed. Routine CXR was pivotal in the recognition of the mould infection in only two cases over this 36-year period. CONCLUSION: CXR is warranted in the evaluation of the newly febrile neutropenic pediatric oncology patient only when respiratory signs or symptoms are present.

Parainfluenza virus infections in children with hematologic malignancies.

BACKGROUND: Parainfluenza virus (PIV) infections are an important cause of morbidity in children with upper or lower respiratory tract infection (URTI and LRTI, respectively). However, the epidemiology of PIV infections in children with cancer has not been well studied. METHODS: This retrospective study sought to determine the epidemiology of PIV infections and risk factors for progression to an LRTI in 1381 children diagnosed with leukemia or lymphoma, between 2000 and 2009. RESULTS: PIV infections were diagnosed in 83 (10%) of 820 children tested for respiratory infections. PIV type 3 accounted for 49 (61%) of the PIV infections. Of the 83 infections, 75 (90%) were community acquired. Children less than 2 years of age were more likely to have PIV infection (P = 0.002; odds ratio, 2.69; 95% confidence interval, 1.5-4.8). PIV infections were more common in children with acute lymphoblastic leukemia as compared with other malignancies (P < 0.0001; odds ratio, 4.13; 95% confidence interval, 2.37-7.21). The majority of patients, 66 (80%), had URTI. Children with LRTI were a median age of 27 months as compared with 56 months for children with URTI (P = 0.005). Fever with severe neutropenia was more common in patients with LRTI than with URTI (P = 0.02). LRTI was significantly associated with absolute neutrophil count <500 cells/µL (P = 0.002) and absolute lymphocyte count <100 cells/µL (P = 0.008) at onset of PIV infection. There was no mortality attributed to PIV infections, although 3 children required mechanical ventilation for respiratory failure due to PIV infection. CONCLUSIONS: PIV was the second most common respiratory viral infection in this population after influenza (A and B). Young children were more likely to have PIV infection and LRTI. Severe neutropenia and lymphopenia were associated with LRTI.

Safe and successful implementation of CPOE for chemotherapy at a children's cancer center.

Computerized prescriber order entry (CPOE) for medications has been implemented in only approximately 1 in 6 United States hospitals, with CPOE for chemotherapy lagging behind that for nonchemotherapy medications. The high risks associated with chemotherapy combined with other aspects of cancer care present unique challenges for the safe and appropriate use of CPOE. This article describes the process for safe and successful implementation of CPOE for chemotherapy at a children's cancer center. A core principle throughout the development and implementation of this system was that it must be as safe (and eventually safer) as existing paper systems and processes. The history of requiring standardized, regimen-specific, preprinted paper order forms served as the foundation for safe implementation of CPOE for chemotherapy. Extensive use of electronic order sets with advanced functionality; formal process redesign and system analysis; automated clinical decision support; and a phased implementation approach were essential strategies for safe implementation of CPOE. With careful planning and adequate resources, CPOE for chemotherapy can be safely implemented.

Symptomatic parainfluenza virus infections in children undergoing hematopoietic stem cell transplantation.

Parainfluenza virus (PIV) infections cause significant mortality in adults undergoing hematopoietic stem cell transplantation (HSCT). Children are more prone to PIV infections than adults; however, data on the epidemiology of these infections in children undergoing HSCT are limited. This study examined the incidence of symptomatic PIV infections, risk factors for lower respiratory tract infection (LRTI), and the impact on mortality after pediatric HSCT. A total of 1028 children who underwent HSCT between 1995 and 2009 were studied. PIV infections were detected in 46 of the 738 patients tested for respiratory infection (6.2%). PIV infection was the most common symptomatic respiratory viral infection in this population. On multivariate logistic regression analysis, receipt of an allogeneic transplant (P < .0001) and total body irradiation-based conditioning (P < .0001) were associated with increased risk of acquiring symptomatic PIV infection. Of the 46 HSCT patients with PIV infection, 18 (39%) had an LRTI. LRTI was associated with PIV infection in the first 100 days post-HSCT (P = .006), use of steroids (P = .035), and absolute leukocyte count (ALC) <100 cells/µL at the onset of infection (P < .0001). An ALC of <500 cells/µL was associated with prolonged viral shedding (P = .045). Six (13%) HSCT patients died of PIV infection. Mortality was associated with African-American ethnicity (P = .013), LRTI (P = .002), use of steroids (P < .0001), mechanical ventilation (P < .0001), and ALC <100 cells/µL at the onset of infection (P = .01). PIV infection causes significant morbidity and mortality in children undergoing HSCT.

Managing fungal and viral infections in pediatric leukemia.

Despite steadily improving long-term outcomes, infections remain a major cause of morbidity and mortality in children receiving therapy for leukemia. Standardized approaches to the management of bacterial infections have been highly successful. However, management of fungal and viral infections remains challenging, especially given the shifting epidemiology of fungal infections. Significant advances in diagnostic and therapeutic modalities have been achieved for fungal and viral infections over the past decade, providing new opportunities for effective interventions. This article reviews the management of viral and fungal infections in children undergoing therapy for leukemia.

Increasing prevalence of nasal and rectal colonization with methicillin-resistant Staphylococcus aureus in children with cancer.

BACKGROUND: Infections with methicillin-resistant Staphylococcus aureus (MRSA), in community-settings, especially with strains carrying the Panton-Valentine Leukocidin (PVL) genes, have increased markedly in recent years. Colonization with S. aureus is a risk factor for infection. However, there are few studies that examine colonization and infection with PVL-positive strains of MRSA in cancer patients. PROCEDURE: The epidemiology of colonization and infection with MRSA was studied in children with cancer during two time periods: 2000/2001 and 2006/2007. PVL genes were screened and spa typing performed on the isolates. RESULTS: The prevalence of colonization with MRSA increased from 0.6% in 2000/2001 to 2.9% in 2006/2007 (P = 0.0003). MRSA colonization at admission was associated with infection (P < 0.0001; RR 38.32; 95% CI: 23.36-62.84). The prevalence of infection increased from 0.99% in 2000/2001 to 3.78% in 2006-2007 (P = 0.0002). Of the 32 colonized patients, 18 (56%) had infection. None of the 14 colonized but non-infected patients had dual colonization of nares and rectum, while 8 of the 18 infected patients had colonization of both of these sites (P = 0.004). Ten patients (31%) were colonized with PVL-positive strains. Patients colonized with PVL-positive strains were more likely to be colonized both in the nares and rectum (P = 0.005), and more likely to have infection (P = 0.001). Recurrent MRSA infections were seen in 22% of patients. CONCLUSION: An increasing prevalence of colonization with MRSA was observed in children with cancer at our institution. Colonization with MRSA especially with PVL-positive strains was associated with infection.

Staphylococcus aureus bacteremia in pediatric patients with cancer.

The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S.aureus (MSSA) in children with cancer has not been well studied. A total of 10 MRSA and 42 MSSA isolates from bacteremic episodes were collected from cancer patients from 2000 through 2007. Seventeen patients (33%) suffered from complications. Thirty-eight (73%) of the bacteremic episodes were catheter-related. Methicillin resistance was associated with increased catheter removal (P = 0.003), but no increase in complications or adverse outcomes was seen.

Short communication: methicillin-resistant Staphylococcus aureus infections in children and young adults infected with HIV.

The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) infections, in particular with Panton-Valentine leukocidin (PVL)-positive strains, has not been well characterized in children and young adults with HIV infection. It is not known if PVL-positive strains of MRSA cause an increased morbidity in this population compared to PVL-negative strains. The purpose of this study was to retrospectively analyze the epidemiology of PVL-positive and PVL-negative MRSA infections in children and young adults with HIV from 2000 to 2007. Molecular typing was performed by polymerase chain reaction (PCR) for detection of the PVL genes. Staphylococcus Cassette Chromosome (SCC) mec and spa typing were performed on all PVL-positive isolates. The number of HIV patients with MRSA infection increased significantly between 2000 and 2007 ( p=0.0015). Twenty seven (87%) of the 31 MRSA isolates were from skin and soft tissue infections (SSTI). Clindamycin resistance was observed in 19% of the MRSA isolates. PVL-positive isolates bearing the type IV SCC mec element comprised 16 of 31 (52%) MRSA isolates. All the PVL-positive isolates belonged to the USA300 pulsed-field type. There was no difference in the mean CD4 count and HIV viral load between patients with PVL-positive and PVL-negative MRSA infections. PVL-positive MRSA infections were associated with more SSTI ( p=0.043) but not with increased morbidity or a higher risk of complications compared to PVL-negative MRSA infections in children and young adults with HIV.

Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus infections in children with cancer.

BACKGROUND: New strains of methicillin-resistant Staphylococcus aureus (MRSA) which frequently carry the Panton-Valentine leukocidin (PVL) genes have been recognized to cause invasive infections in otherwise healthy children and adults. However, the epidemiology of PVL-positive MRSA infections has not been described in children or adults with cancer. PROCEDURE: The epidemiology of MRSA infections in patients with cancer was retrospectively studied from 2000 to 2007. Molecular typing was performed by polymerase chain reaction (PCR) for the detection of the PVL genes. Staphylococcus cassette chromosome (SCC) mec and spa typing was performed on all PVL-positive isolates. RESULTS: A total of 88 MRSA isolates from clinically distinct infectious episodes were collected from 88 patients with cancer during the 8-year study period. Infections were predominant in the skin and soft tissues (SSTI; P = 0.0003). PVL-positive isolates, bearing the type IV SCCmec element, encoding the gene for methicillin resistance, increased significantly during this period (P = 0.043) and comprised 35 of 88 (40%) MRSA isolates. Of these 35 isolates, 32 belonged to spa type 8 and were USA300 genotype. Patients infected with PVL-positive strains did not have more SSTI (P = 0.166) or bacteremia (P = 0.510) as compared to patients with PVL-negative strains. A greater percentage of PVL-positive isolates were susceptible to ciprofloxacin (P = 0.006). CONCLUSIONS: PVL-positive MRSA infections are not associated with a higher morbidity as compared to PVL-negative MRSA infections in children with cancer.

Cutaneous infection caused by Macrophomina phaseolina in a child with acute myeloid leukemia.

We report a case of Macrophomina phaseolina skin infection in an immunocompromised child with acute myeloid leukemia, which was treated successfully with posaconazole without recurrence after a hematopoietic stem cell transplant. The fungus was identified by DNA sequencing using both the internal transcribed spacer and D1/D2 region of the 28S ribosomal DNA gene.

Prophylactic antibiotics reduce morbidity due to septicemia during intensive treatment for pediatric acute myeloid leukemia.

BACKGROUND: The aim of this study was to determine whether antibiotic prophylaxis during periods of neutropenia reduced streptococcal (S. viridans) sepsis and overall bacterial sepsis. METHODS: The authors reviewed outcomes of 78 evaluable patients who were consecutively treated for acute myeloid leukemia (AML) from October 2002 through January 2007. Several successive prophylactic antibiotic regimens were used. All patients received antifungal prophylaxis with oral voriconazole. RESULTS: Oral cephalosporins did not significantly reduce the odds of bacterial sepsis (P = .81) or streptococcal (S. viridans) sepsis (P = .90) relative to no prophylaxis. Intravenous (iv) cefepime completely prevented streptococcal (S. viridans) sepsis and reduced the odds of bacterial sepsis 91% (P < .0001) relative to no prophylaxis, but resistant gram-negative bacteria emerged in 2 patients. Vancomycin with oral ciprofloxacin or a cephalosporin reduced the odds of bacterial sepsis by 93% (P < .0001) and streptococcal (S. viridans) sepsis by 99% (P < .0001). The fungal infection rate did not differ significantly between patients who did and did not receive antibiotic prophylaxis (1.0 per 1000 patient-days for both groups). The observed reduction in average hospital days per chemotherapy course for patients given vancomycin regimens or cefepime was 5.7 (P < .0001) and 4.1 (P = .0039) days, respectively. No reduction was observed with oral cephalosporins (P = .10). Furthermore, vancomycin regimens or cefepime were associated with a 20% reduction in healthcare charges (P = .0015) relative to using no antibiotics. One patient, who was on oral cefuroxime alone, died of septicemia. CONCLUSIONS: Prophylaxis with intravenous cefepime or a vancomycin regimen, and voriconazole, reduced morbidity in children with AML, and resulted in dramatic decreases in the incidence of septicemia and hospitalization days.

Computer-assisted bar-coding system significantly reduces clinical laboratory specimen identification errors in a pediatric oncology hospital.

OBJECTIVE: To assess the ability of a bar code-based electronic positive patient and specimen identification (EPPID) system to reduce identification errors in a pediatric hospital's clinical laboratory. STUDY DESIGN: An EPPID system was implemented at a pediatric oncology hospital to reduce errors in patient and laboratory specimen identification. The EPPID system included bar-code identifiers and handheld personal digital assistants supporting real-time order verification. System efficacy was measured in 3 consecutive 12-month time frames, corresponding to periods before, during, and immediately after full EPPID implementation. RESULTS: A significant reduction in the median percentage of mislabeled specimens was observed in the 3-year study period. A decline from 0.03% to 0.005% (P < .001) was observed in the 12 months after full system implementation. On the basis of the pre-intervention detected error rate, it was estimated that EPPID prevented at least 62 mislabeling events during its first year of operation. CONCLUSIONS: EPPID decreased the rate of misidentification of clinical laboratory samples. The diminution of errors observed in this study provides support for the development of national guidelines for the use of bar coding for laboratory specimens, paralleling recent recommendations for medication administration.

BK virus-induced tubulointerstitial nephritis in a child with acute lymphoblastic leukemia.

We report a case of BK virus-induced tubulointerstitial nephritis in a child with acute lymphoblastic leukemia. Primary BK virus infection was exacerbated by chemotherapy-induced immunodeficiency. Careful administration of chemotherapy and anti-viral therapy prevented further damage. This diagnosis should be considered in children who experience renal dysfunction during cancer treatment.

Diagnosis of catheter-related bloodstream infections among pediatric oncology patients lacking a peripheral culture, using differential time to detection.

BACKGROUND: Current methods for in situ diagnosis of catheter-related bloodstream infections require concurrent collection of central venous catheter (CVC) and peripheral vein (PV) blood cultures. Both the pain and inconvenience of PV cultures are undesirable. METHODS: A prospective study was conducted (August 2002 to March 2004) to assess the accuracy of diagnosing catheter-related bloodstream infections based on the difference in time to detection of blood cultures drawn concurrently from 2 lumens of a multilumen CVC. This difference in time to detection between 2 lumens was compared with results of the standard criterion with paired CVC and PV blood cultures. RESULTS: Twenty-one infectious episodes were categorized as catheter-related bloodstream infections and 38 as non-catheter-related bloodstream infections. With a cutoff in difference in time to detection between 2 lumens of > or =180 minutes, the sensitivity of this test to diagnose a catheter-related bloodstream infection was 61% (95% confidence interval, 39-80%) and the specificity was 94% (95% confidence interval, 82-99%). In 4 of 7 episodes with false-negative results, the colony counts in cultures from both lumens were >400 colony-forming units/mL (maximal value reported), indicating the limitation of this method when both lumens of the catheter are colonized. With the pretest probability of catheter-related bloodstream infections ranging from 28% to 54%, the positive predictive value of a difference in time to detection between 2 lumens of > or =180 minutes for diagnosis of catheter-related bloodstream infections ranged from 81% to 93% and the negative predictive value ranged from 67% to 86%. CONCLUSION: Within the context of its limitations, this novel method provides an alternative for diagnosing catheter-related bloodstream infections among patients with a CVC, without PV cultures.

Myositis complicating viridans streptococcal sepsis in childhood leukemia.

Hematogenous focal infections are a rare complication of bacteremia or sepsis caused by viridans-group streptococci. We describe two patients with acute leukemia who developed myositis during alpha-hemolytic streptococcal bacteremia. Children complaining of severe muscle pain associated with viridans streptococcal infections should be carefully evaluated for the presence of focal pyogenic complications and rhabdomyolysis. The severity of infectious myositis is highly variable, depending on the etiologic organism and host immunity, making individualized treatment the most effective approach.

Optimum management of pediatric patients with fever and neutropenia.

Fever with neutropenia is a common clinical problem in patients receiving cancer treatment. Prevention and optimum management of infectious complications is critical to the overall success of cancer therapy. This article provides an overview of the current status of this evolving subject. While the basic principles of rapid institution of broad spectrum antibiotics, early intervention with empiric antifungal therapy and continuation of antimicrobials during period of risk are unlikely to change, there is increasing interest in titrating this aggressive approach based on the projected risk of the development of a serious invasive infection. Oral antibiotic therapy and outpatient management are currently being studied in pediatric oncology patients, but even when successful these alternatives to the traditional "in hospital, parenteral antibiotic therapy" approach are unlikely to be applicable in all patient populations and clinical settings. While there is no replacement for clinical acumen and careful monitoring, judicious use of diagnostic resources such as blood cultures and imaging studies is a key component of optimum care. Selection of empiric antibiotics based on ongoing monitoring of antimicrobial susceptibility patterns is emphasized.