Management of children with fever and neutropenia: results of a survey in 51 pediatric cancer centers in Germany, Austria, and Switzerland

Due to their underlying disease and anticancer treatment, pediatric oncology patients are at an increased risk of infectious complications. Fever during neutropenia may be the only sign of an infectious episode, but in the majority of pediatric cancer patients with fever during neutropenia, the focus of the underlying infection remains unclear and cannot be documented microbiologically (e.g., bloodstream infection with a pathogen isolated) or clinically (e.g., pneumonia). Because of the risk of a complicated clinical course and the spectrum of pathogens causing severe and life-threatening bacterial infections in pediatric cancer patients, timely inpatient treatment with broad-spectrum antibiotics is the standard of care [1, 2].

Despite this consensus, previous surveys performed in pediatric cancer centers from different countries revealed a high level of heterogeneity in many key topics of clinical management [3‐8]. In May 2016, the working group for infectious complications in the immunocompromised child of the German Society for Pediatric Oncology and Hematology (GPOH) and the German Society for Pediatric Infectious Diseases (DGPI) released consensus recommendations [9], concerning the diagnostics and treatment of fever without a focus on neutropenic pediatric cancer patients (FN), excluding hematopoietic stem cell transplant recipients and children and adolescents with clinical signs of sepsis, septic shock or infection-related organ failure. The aim of the present survey was to explore the institutional standards of treatment of FN in pediatric oncology centers (POCs) from Germany, Austria, and Switzerland, to compare the current clinical practice with the recommendations of the new guideline [9] and to identify targets for improvement from the perspective of antimicrobial stewardship.

Referring to the recent German FN guidelines [9], the authors developed an Internet-based anonymized survey (Survey Monkey™; San Mateo, USA). The main topics and detailed questions were finalized after repeated rounds of internal discussion in the GPOH/DGPI working group (Supplemental Table 1 contains the questions and the corresponding information from the guideline). The survey did not include clinical case vignettes [8] and did not collect original local standard operation procedure documents [4]. It is important to emphasize that (by definition) the FN population comprised by the German guideline does not include children and adolescents with clinical signs of sepsis, septic shock or infection-related organ failure. In total, 70 pediatric oncology centers (POCs) were contacted by e-mail and asked for participation. Typically, the head of the department or a responsible senior pediatric oncology consultant was contacted. One reminder was sent out to hospitals which did not reply to the first e-mail. The survey was released on March 14, 2016, briefly before publication of the guideline [9], and closed on July 27, 2016, i.e., 2 months after the publication. The POCs were arbitrarily categorized into three different sizes, namely small (≤ 40 newly diagnosed patients/year), medium (41–75), and large (> 75) centers. In addition, we also analyzed whether the affiliation (university hospital vs. academic tertiary care children hospital) affected the results.

This multicenter survey describes the current clinical practice of the management of FN without a clinically or microbiologically defined focus on POCs in Germany, Austria, and Switzerland. The response rate (73%) is in the upper range of comparable surveys from other countries [4, 8, 10].

Most POCs in Germany, Austria, and Switzerland are affiliated at University hospitals or academic tertiary care pediatric facilities, which reflects the current situation in these countries with few small- and large-, but many medium-size POCs. Since our survey was performed in parallel to the release of the 2016 German AWMF guideline [9], the results depict the situation before the main components and recommendations of this guideline could be implemented. However, it is important to note that the international guidelines on FN in the pediatric setting have been available starting in 2012 (updated in 2017 [11]. The German guideline differs only in a few issues from these international guidelines [12], including that the German guideline is not applicable to patients, who need intensive care due to severe sepsis, it does not recommend a priori risk stratification in high- and low-risk groups, and it argues against the use of meropenem (a carbapenem) as first-line treatment in stable patients. One important purpose of this survey was to identify potential targets for antibiotic stewardship (ABS).

More than 90% of all participating POCs have a defined internal standard operation procedure concerning the management of FN. Most POCs used the same definition for fever and neutropenia [13, 14]. Remarkably, 41% of the participating POCs do not recommend one defined standard method for temperature measurement in outpatients. The definition of fever and the method of temperature measurement should be harmonized, also to enable comparison of results between POCs [15]. Otherwise, a specific patient may or may not be hospitalized and treated with IV antibiotics only depending on the POC he attends to [3]. In pediatric oncology patients with FN, the timely detection of those patients with severe sepsis is of utmost importance, since clinical management in case of severe sepsis clearly differs from patients who only have FN [16]. Most POCS follow the German guidelines [9] and draw at least one blood culture set from the central venous access device (CVAD) before they start empiric antibiotic treatment (eABT). In our survey, only half of all POCs (47%) recognize that there is a minimal blood culture volume required for in a child with a bodyweight of 15 kg (at least 5 ml per bottle) [17, 18], whereas some use bottles provided for culturing 1–3 ml of blood from neonates and infants < 10 kg in all patients. This practice may significantly reduce blood culture sensitivity. The question, whether more than at least one blood culture set drawn on day 1 and on day 2 of treatment is of any benefit for the clinical management, remains a matter of debate [19, 20]. Rosenblum et al. analyzed 220 FN episodes in 105 patients and identified a pathogen in 11% of repeated cultures drawn in those patients with persistent fever [21]. If the initial blood culture has yielded a pathogen, control cultures are mandatory to guide further therapy and to confirm that a single positive culture yielding, e.g., coagulase-negative staphylococci is not a contamination.

The heterogeneous utilization of different biomarkers in our survey reflects that in febrile neutropenic patients without a focus, no biomarker is capable to definitely confirm or exclude a bacterial infection and to predict the clinical course [22]. Relying on experience (not on study results), most POCs use the C-reactive protein to confirm the response to antibiotic treatment. In some patients, leukocyte recovery is accompanied by a second increase in CRP values.

Minimizing the time to antibiotics (TTA) has been defined as an important goal of treatment; there seems to be an association between longer TTA and impaired safety [23]. Half of all POCs regularly document the TTA. In general, the GPOH guideline [9] recommends a first-line monotherapy with piperacillin–tazobactam, ceftazidime or cefepime (the latter two agents not in patients with severe mucositis). In contrast to the international guidelines [11, 24], the German guideline strictly argues against the empirical use of carbapenems in the first-line treatment of pediatric FN to avoid the selection of carbapenem-resistant pathogens. Empirical use of meropenem is recommended in case of clinical signs of a severe infection or sepsis, and may be considered in patients colonized (or previously infected) with ESBL-producing bacteria [25‐27].

Keeping in mind the very low incidence of bloodstream infections due to ESBL-producing Gram-negative Enterobacteriacerales in recent studies from Germany, Switzerland, and the Netherlands [28, 29], the reason for the high percentage of POCs using initial combination therapy (48%) remains unclear. In this respect, national [9] and international guidelines [11] may help to promote substantial changes in clinical management concerning initial monotherapy [30]. Other surveys and multicenter evaluations addressed this issue too [3, 31]. In Switzerland, the use of ceftriaxone plus amikacin adds antipseudomonal activity to ceftriaxone [32].

In cases with AGL combination treatment, most POCs use tobramycin or gentamicin as short time infusion once daily. Nowadays, this mode of administration represents the state of the art [33, 34]. Interestingly, only 8% of all POCs determine the Cmax (target: 8–10 × MIC; e.g., 10–20 mg/L, referring to an MIC of 2 µg/ml) to evaluate the appropriateness of individual AGL dosing. In addition, out of all POCs, 20% do not regularly determine AGL trough levels in patients with normal serum creatinine, although many of these patients may have received other potentially nephrotoxic or ototoxic treatments (e.g., platinum derivatives, furosemide, irradiation, etc.). This topic of supportive care would probably benefit from a less heterogeneous approach.

The GPOH guideline recommends escalating the empiric ABT in stable patients with persistent fever after 72 h if the patient shows neutropenia without signs of recovery [9]. This cutoff (72 h) has been established in many studies investigating the use of different empirical antibiotics [30]. There is no data confirming the benefit of changing the eABT earlier in a stable patient (e.g., after 48 h, as done by 48% of the POCs). Some POCs (22%) decide about this question on an individual basis. This may include the decision not to change the initial eABT in a stable patient whose neutrophils are expected to recover in the next few days [11]. Watchful waiting at least 72 h or even longer in this situation may reduce the cumulative consumption of second- and third-line ABT.

Irrespective of hematological recovery, nearly two-thirds of all POCs (58%) stop antibiotics in a stable patient with negative cultures, who is afebrile for 24 h, and has no severe mucositis or clinical signs of a focal infection. The GPOH guideline [9] clearly supports this approach, but argues against the oral continuation of eABT in most cases.

In neutropenic patients, many POCs (68%) discharge the patient but continue treatment with oral antibiotics. Remarkably, those centers mentioned eight different oral antibiotics/antibiotic combinations, including fluoroquinolones. This heterogeneity clearly reflects a lack of evidence, since the risk of secondary infection, in particular with P. aeruginosa (fluoroquinolones) [35] in patients eligible for oral sequence treatment is very low [36, 37].

About one-third of all POCs continue IV treatment for more than 72 h. This may negatively affect the quality of life of the patients and their families and increases the risk of nosocomial infections [38]. Concerning empirical antifungal treatment (eAFT), the guideline defines certain groups with high risk of invasive fungal infection (IFI) [39]. The guideline suggests using liposomal amphotericin B or caspofungin after 96 h of fever despite eABT [9], and provides details on diagnostic tools to confirm or exclude an IFI, as much as possible. Notably, 14% of all POCs use voriconazole for eAFT, although this drug is not licensed for eAFT and needs therapeutic drug monitoring [40].

The final questions of the survey tried to elucidate the access to some core elements of Antibiotic Stewardship (ABS) programs in this particular setting, more precisely.

Such interdisciplinary conferences take place in only 46% of all POCs. In addition, only 46% of all POCs have access to PID consultations, which reflects the profound shortage of PID specialists in pediatric health-care facilities in Germany. Interestingly, university centers more often have PID services, and POCs with PID support less often use first-line combination therapy in pediatric patients with FN. Hopefully, the emerging threat of infections due to multidrug-resistant pathogens and adverse short- and long-term effects of inadequate ABT will lead to the implementation of ABS programs in all POCs in the near future.