Bacterial pathogens

When an infectious pathogen is identified as the source of FN, bacteria are the most common causes. Although bacteria as a group have remained as the most common identified etiology of pediatric FN, the epidemiology of causative pathogens has evolved. ^{, ,} The first reports on the epidemiology of bacterial infections during neutropenia most commonly implicated gram-negative pathogens, specifically Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. The transition from a gram-negative to a gram-positive bacterial predominance occurred in the latter 2 decades of the last century. This shift in pathogen type is likely multifactorial, but is often assumed to be related to increased reliance on central venous catheters and chemotherapy regimens that cause mucositis, resulting in an increase in pathogens such as viridans group streptococci. It is anticipated that gram-positive organisms will continue to predominate into the future as more centers will likely use prophylactic antibiotic regimens that have broader gram-negative activity in high-risk patient groups.

Despite the general predominance of gram-positive bacteria, significant variation in the epidemiology of bacteria during FN exists between centers. Table 8.1 displays identified bacterial pathogens across various international pediatric oncology studies between 1982 and 2018. ^{, , , ,} The variation by geographic location likely results from practice variation, such as approach to chemotherapy protocols, diagnostic testing practices, and prophylaxis regimens. Most recently, a pediatric randomized controlled trial of levofloxacin during periods of prolonged neutropenia in children with acute leukemia and those undergoing HCT was completed. Although levofloxacin was found to be effective, the rate of breakthrough infection was still 22% in the leukemia group and 11% in the HSCT group. Gram-positive organisms, most frequently viridans group streptococci, accounted for more than 77% of the breakthrough events.

Fungal pathogens

Invasive fungal diseases (IFDs) are rarely the source of the initial onset of fever during a neutropenic period. More typically, the concern for IFDs increases after a prolonged period of FN despite broad-spectrum antibacterial therapy. There are published consensus criteria for defining proven and probable IFDs that have been helpful to standardize the definition of IFDs across research studies and to provide some diagnostic criteria for clinicians. However, diagnosing IFDs by these published criteria can be difficult because invasive procedures are often needed to identify a fungal pathogen and patients with prolonged neutropenia cannot always tolerate such procedures. Therefore many published reports of IFD incidence as a source of FN may underestimate actual infection rates. Understanding these limitations, prospective multicenter data have documented a proven or probable IFD rate ranging from 3% to 5% of children hospitalized with fever and neutropenia. The rates of IFDs when considering prolonged neutropenia regardless of fever have been reported to be much higher. This highlights the fact that fever is not always present as a sign of IFD.

Candida species are the most common fungal pathogens identified during periods of FN. This is likely because Candida species commonly colonize the skin and intestinal tract and may become more dominant in the setting of prolonged exposure to broad-spectrum antibiotics. The skin and mucosal barriers are often compromised by the presence of central venous catheters and/or chemotherapy exposures that can allow for invasive of Candida isolates. Specific mortality data regarding invasive candidiasis in pediatric oncology patients and HSCT recipients are limited, but the attributable mortality of invasive candidiasis in all pediatric patients has been estimated to be 10%.

Episodes of invasive mold disease are less common but are much more challenging to treat and have significantly higher rates of case fatality. In contemporary pediatric cases series, less than two-thirds of patients with an invasive mold disease IMD responded to therapy in the first 12 weeks and 30% of patients died within the same time period. ^, Among the mold pathogens, Aspergillus species are most common, followed by organisms of the Mucorales order.

Viral pathogens

The advancement in viral diagnostic methodologies has resulted in better estimates of viral infections during periods of FN. Much of the interest in testing for a viral pathogen is the possibility that finding an explanation for fever may reduce the need for further diagnostic testing. The yield of viral testing in patients with FN has been reported in multiple studies ( Table 8.2 ). The frequency of laboratory-confirmed viral respiratory infection ranged from 8% to 59%. Of note, the study reporting an 8% incidence of viral respiratory infection obtained viral respiratory specimens via mouth swabs and thus likely underestimated the true rate. The range of infection rates for the remaining studies was 37% to 59%.

Although some authors have suggested these rates of viral detection support routine comprehensive viral testing at the time of presentation for FN, ^, the utility of routine viral testing is not clear. First, ideally the identification of a viral pathogen should inform clinical management decisions. However, identification of a virus does not necessarily exclude the possibility of a concomitant bacterial infection. The percentage of patients with both a viral and bacterial infection ranged from 13% to 33%. ^, Some clinicians are comfortable stopping antibiotics during the FN episode in the setting of a viral syndrome but only for low-risk patients with FN. Based on the possibility of both bacterial and viral infection, empiric antibiotics are often continued in high-risk FN episodes. Second, the sensitivity of viral polymerase chain reaction testing results in detection of virus well after clinical resolution, and thus viral detection by polymerase chain reaction may not always confirm the source of fever in a neutropenic patient. Finally, there are limited effective antiviral therapeutic agents available, and thus detection of some viruses will not inform targeted antiviral therapy. Considering these reasons collectively, viral testing should be limited to patients in whom positive results would allow for de-escalation of antibiotic therapy (e.g., in a low-risk FN episode) or initiation of an appropriate antiviral therapy (e.g., neuraminidase inhibitor for influenza). Of note, the hospital’s infection prevention and control division may desire testing for symptomatic patients to inform appropriate isolation precautions that could limit hospital transmission of viral pathogens.

Initial risk stratification

Early comparative studies highlighted the effectiveness of early initiation and continuation of empirical antibiotic and subsequently empirical antifungal therapy to reduce the morbidity and mortality associated with FN. ^, These studies served as the foundation for standards of care for FN management that have been applied for decades across all episodes of FN. However, use of empirical broad-spectrum antibiotics and antifungal agents for prolonged periods in all patients is not ideal as it presents risks for medication toxicities, prolongs hospital stays, and potentiates evolution of resistance. As not all FN episodes carry the same risk for infection, it is important to stratify each FN episode into risk groups for true infection. Such risk stratification can inform evidence-based decisions for more discriminant use of anti-infective agents and other health care resources.

Identifying which children are at a lower risk of complications can allow for a reduction in the intensity of anti-infective therapy and monitoring. Conversely, identifying children at higher risk of complications can allow for prophylactic approaches, rapid escalation of therapy, or closer observation. Fortunately, there have been substantial research efforts to identify criteria for stratifying FN episodes into low and high risk. Often, these studies leverage a composite of factors to derive risk prediction models or rules. More than 25 such risk prediction studies have been conducted in pediatric cancer. ^, These studies have been heterogeneous and have included different pediatric cancer populations and different clinical endpoints (such as bacteremia, serious infection, death, and intensive care unit admission), thereby reducing the ability to combine the individual study data into a composite analysis. However, review of the individual studies can be informative.

There have been six prediction models derived from pediatric cohorts that (1) focused on identifying patients at low risk for infection using data elements evident on a single FN assessment and (2) have been validated. Selection of a single schema that can be applied across all clinical scenarios has not been possible, potentially because of heterogeneity in clinical settings and resources. Therefore clinicians should review each of the validated low-risk stratification schemas, choose which schema matches their clinical setting, and determine if the application of that schema is feasible for their center. The choice of strategy should be determined by an institution’s ability to implement more complex rules and the timeliness of receipt of required components of the rule, such as C-reactive protein. Whichever schema is chosen, centers should establish a quality improvement infrastructure to routinely monitor their process for identification of low-risk FN episodes and outcomes of these episodes to ensure the chosen prediction model is safe and continues to have local applicability. Of note, these prediction models were derived in cohorts of children with cancer and chemotherapy-induced FN and thus their applicability to FN episodes in the post-HSCT period is not known.

Initial investigations

Regardless of risk stratification, when a child with FN initially presents to the health care center, timely triage and assessment are important. An evaluation for the cause of fever should be conducted and should include a careful history and physical examination. It is important to establish an updated interim social history that includes, but is not limited to, recent exposure to other symptomatic people, recent travel, new animal exposures, visitors from other regions, changes in diet, adherence to preventative measures, and any sustained local trauma (e.g., fall with skin abrasion). The physical examination should be equally thorough and warrants particular attention to the mouth to evaluate for mucositis and oral infections, central venous catheter tunnel and exit sites, and the entire skin surface, including the perianal area.

The standard evaluation should include blood cultures from each lumen of the central venous catheter if present. The utility of adding a peripheral blood culture at the initial evaluation of FN continues to be controversial. The value of peripheral blood cultures has been addressed in nine studies, ^, The estimate of the proportion of true bacteremia episodes detected by peripheral blood cultures alone, when central venous catheter culture results are negative, was 12% (95% confidence interval 8% to 17%), revealing that peripheral cultures consistently increase identification of true bacteremia compared with central cultures alone. Increased yield is likely related to timing or volume. However, contaminant identification from a peripheral culture is similar with an estimated rate at 13% (95% confidence interval 8% to 20%). Based on these data, the potential benefits of a peripheral culture include increasing the detection of bacteremia and providing data for a more accurate designation of central line–associated bloodstream infection. Conversely, the downsides of a peripheral blood culture include patient discomfort and anxiety and the potential to identify contaminants, leading to unnecessary antibiotic therapy. There are no data to inform whether peripheral blood culture results alter the outcomes of FN episodes. Centers need to consider the potential advantages and disadvantages of a peripheral blood culture and establish their own standard of care so that a consistent strategy can be implemented.

The importance of obtaining a urinalysis and/or a urine culture at the presentation of FN to evaluate for a urinary tract infections (UTIs) is also controversial. Typically, a UTI is suspected on the basis of pyuria or nitrites present on urinalysis. However, in this population, the presence of neutropenia negates a patient’s ability to mobilize neutrophils to the urinary tract and thus pyuria is not an expected sign to measure by diagnostic testing. Therefore the usefulness of a urinalysis would be reliant on nitrite testing, which is not ideal as nitrites are present only with pathogens capable of converting nitrates to nitrites and may be absent in younger children with UTIs. This makes the urinalysis a limited diagnostic tool in the setting of FN. A urine culture can be helpful to identify a causative pathogen for the FN episode and this identification may help direct antibiotic therapy. However, attaining a urine culture can be difficult, especially in younger children. Therefore many experts recommend that if a clean-catch or mid-stream urine sample can be easily and reliably obtained, then urinalysis and urine culture should be obtained at the onset of FN. Otherwise, these diagnostic tests should be omitted from the initial evaluation of FN, assuming the patient does not have in a previous history of UTIs or suspicious signs or symptoms. Antibiotic administration should not be delayed to obtain a urine sample.

Finally, the role of routine chest radiographs as a routine component, even in the absence of respiratory symptoms, of the diagnostic workup in pediatric FN has been assessed in six observational studies. The two most recent of these studies included children with FN after chemotherapy and HSCT and found rates of pneumonia that were less than 3% in children without respiratory symptoms. Furthermore, the incidental findings on chest radiographs in the few patients with pneumonia did not alter clinical care. Therefore routine chest radiographs should not be performed in children with FN who do not have localizing respiratory symptoms. A chest radiography should be performed in children who have concomitant respiratory symptoms at FN presentation.

Initial antibiotic therapy

As noted previously, the early epidemiology and comparative studies of FN identified significant risk for infection during this period and benefit from initiation of empiric combination broad-spectrum and intravenous antibiotic treatment. However, the recommended approach to FN has evolved through significant investigation over the past 4 decades and the prior “one-size-fits-all” approach for antibiotic administration in the setting of FN has proven to be unnecessary. This evolution in practice was first apparent in adults with FN and more recently has been changing among children with FN. In general, management decisions for FN are now dependent on risk stratification. Additional factors beyond risk stratification that can affect management decisions include prior infection history, clinically evident sites of infection, patient and institution bacterial resistance patterns, drug availability, and acuity of illness.

Consideration for patients with high-risk fever and neutropenia

For patients with high-risk FN, broad-spectrum intravenous antibiotic therapy is still recommended to provide good coverage for gram-negative organisms given their virulent nature. Additionally, empiric antibiotics for high-risk FN should include coverage for viridans group streptococci and P. aeruginosa as these are somewhat common causes of bacteremia and pose risk for severe infection. The original empiric antibiotic regimens for FN consisted of parental administration of two agents with antipseudomonal coverage. However, the role of combination antibiotic therapy versus monotherapy for FN has been assessed in multiple studies. In two separate meta-analyses, monotherapy was compared to a combination dual aminoglycoside-containing regimen in patients with FN. ^, Both analyses demonstrated that monotherapy was not inferior and was less toxic than combination therapy. In the pediatric setting, a systematic review of randomized trials concluded that no significant differences in failure rates, infection-related mortality, or overall mortality were observed with monotherapy compared to combination therapy, even among studies restricted to high-risk FN. A more specific pediatric meta-analysis compared monotherapy antipseudomonal penicillin monotherapy and antipseudomonal penicillin plus an aminoglycoside and found that monotherapy was not inferior to combination therapy. Collectively, these data debunk the prior belief that combination gram-negative antibiotic therapy is necessary for high-risk FN.

There are numerous possible monotherapy regimens that have been evaluated and thought to be reasonable options in children with FN, including antipseudomonal penicillins such as piperacillin-tazobactam, antipseudomonal cephalosporins such as cefepime, and carbapenems such as meropenem or imipenem. Ticarcillin–clavulanic acid was an additional available antipseudomonal penicillin but is no longer manufactured. In the systematic review of randomized trials, five studies were identified that compared antipseudomonal penicillin monotherapy to fourth-generation cephalosporin monotherapy and found no difference in treatment failure, infection-related mortality, or duration of fever. Two pediatric-specific evaluations found that treatment failure, mortality, and adverse effects were similar when antipseudomonal penicillins were compared to antipseudomonal cephalosporins or carbapenems. ^, Interestingly, although treatment failure rates were similar across groups in this study, cefepime was associated with increased all-cause mortality when compared to other β-lactam antiiotics. However, this finding was not replicated in other studies, and in one meta-analysis the point estimate for mortality actually favored the cephalosprin compared with antipseudomonal penicillin. Consequently, cefepime remains a first-line therapeutic option for empiric therapy of FN. Ceftazidime monotherapy lacks adequate gram-positive coverage and thus should not be used if these organisms are of concern, such as in patients with high risk for viridans group streptococci.

Routine empiric glycopeptides (such as vancomycin) should not be used. A meta-analysis of 14 randomized trials demonstrated that addition of a glycopeptide to empiric therapy did not lead to more success (if addition of a glycopeptide in the study control arm was not considered failure) but was associated with more adverse effects. Empiric glycopeptides should be reserved for patients in clinically unstable condition or those who have a signs or symptoms suggestive of a gram-positive infection, such as central venous line tunnel or exit site infection.

Considerations for patients with low-risk fever and neutropenia

Each institution should develop a tailored strategy to limit therapy intensity in patients with low-risk FN that will help limit unnecessary antibiotic exposures that can result in toxicity, reduce resource utilization, improve convenience, and optimize QOL. Although there has been an effort to identify a group of patients with FN who do not require any empiric antibiotics, this approach has not had widespread adoption. Rather, the two strategies commonly considered are outpatient management and enteral antibiotic administration. These two strategies are often used together and in adults with low-risk FN, outpatient management with enteral antibiotics is recommended in specific scenarios. Over the past several years, data have emerged suggesting that enteral and outpatient management of children with low-risk FN is also appropriate provided that suitable selection of patients and monitoring are achieved. A recent survey of pediatric hematology and oncology physicians showed that many North American clinicians have adopted outpatient management in some circumstances.

The advantages of outpatient management compared with inpatient management include better QOL for children, as well as reductions in health care utilization, health care–associated infection, and acquisition of resistant organisms. ^, Outpatient management can be initiated at the onset of FN or after a brief period of hospitalization (step-down management). In a systematic review of pediatric randomized trials, four studies were identified in which patients were randomly assigned to inpatient versus outpatient management; no differences in outcomes were observed. The point estimates favored outpatient management in the mortality analysis, and no infection-related deaths were observed in the 124 randomly assigned low-risk children treated as outpatients. This finding was replicated in a meta-analysis of observational trials in which no infection-related deaths were observed among the 953 children treated as outpatients. It is important to emphasize that outpatient management requires the establishment of infrastructure, training, and personnel to allow the safe implementation of ambulatory management of FN.

The second approach to reduced intensity of therapy for low-risk FN is the use of enteral antibiotic regimens. Enteral antibiotic administration is attractive because it facilitates outpatient management, is usually less expensive, and does not require intravenous access, and thus reduces the risk of central venous catheter−associated infections. Specific considerations unique to children include the requirement for suspension formulation in children who cannot take pills or tablets and refusal of oral administration of enteral formulations in some children, especially younger children. In a systematic review of pediatric randomized trials, eight studies randomly assigned pediatric patients with FN to intravenous versus enteral therapy in the same setting (inpatient or outpatient). There was no significant difference in treatment failure, and no infection-related mortality was observed among the 470 patients randomly assigned to receive enteral empiric therapy. To augment these data, more information about the safety of oral administration was obtained from a meta-analysis of prospective pediatric trials in which enteral antibiotics were started within 24 hours of FN onset. No infection-related deaths were observed among the 676 children given enteral antibiotics. Thus enteral antibiotic administration may be appropriate if the child can tolerate this route of administration reliably and does not have severe mucositis or diarrhea. Typical enteral antibiotic therapy options used in pediatric FN include fluoroquinolone monotherapy, fluoroquinolone and amoxicillin-clavulanate, and cefixime. Even for children with low-risk FN managed as inpatients, enteral administration may be advantageous as it reduces nursing resources and may facilitate early discharge (step-down management).

Modification of empiric antibacterial therapy

After initiating empiric antibiotics for FN, the empiric regimen should be modified to ensure appropriate coverage for any identified microorganisms or clinical focus of infection. If an organism is identified and is considered the source of the febrile episode, some experts have advocated that it is appropriate to narrow coverage to target that pathogen, whereas others support continuation of the empirical therapy regimen. Unfortunately, there are no published pediatric data to guide this decision and many centers often continue broader empirical therapy regardless of the sensitivity profile of the identified pathogen. In patients in whom empiric glycopeptides or dual gram-negative coverage was initiated at presentation, reassessment should be performed at 24 to 72 hours, and these additional antibiotics should be discontinued unless there is a specific microbiologic reason for their continuation. For children with persistent fever, vigilance for an undetected source of infection is important and continued evaluation may include repeat blood cultures from the central venous catheter, although the optimal frequency of cultures (for example, daily or every second day) is not known. Modification of antibiotic treatment for persistent fever alone, including the addition of empiric vancomycin, is not necessary in children whose conditions remain clinically stable. Children whose conditions deteriorate warrant broadening of empiric antibacterial therapy as infection with a resistant organism is possible. Thus broadening should include coverage for resistant gram-positive, gram-negative, and anaerobic organisms.

Cessation of empiric antibacterial therapy

Current pediatric FN guidelines recommend continuation of empiric antibiotic therapy until all of the following criteria are met: blood culture results are negative, the child is clinically well, fever has resolved, and there is evidence of bone marrow recovery. ^, A specific threshold defining neutrophil count recovery is not clear, although most clinicians consider a rising absolute neutrophil count sufficient. One randomized trial of pediatric low-risk patients found that cessation of antibiotics on day 3 irrespective of count recovery versus continuation of antibiotics was associated with similar outcomes. However, Enterobacter spp. bacteremia occurred in one child in the early cessation group. Consequently, it may be reasonable to discontinue antibiotics on day 3 in low-risk children with FN who are afebrile with negative culture results if careful monitoring is in place.

In high-risk patients, the optimal duration of antibiotic therapy is unknown in the setting of persistent profound neutropenia without bone marrow recovery. The initial pediatric FN study of 33 high-risk pediatric patients suggested that cessation of empiric antibiotics on day 7 may be associated with bacteremia and poor infection outcomes compared with continuation for 14 days. However, this study was conducted in the 1970s and it is not known whether these results are generalizable to the current era. A recent adult randomized trial of cancer patients and HSCT recipients with high-risk FN compared early cessation of empiric antibiotics with continuation of antibiotics until count recovery. Patients were enrolled only if they were afebrile for at least 72 hours and clinically well at the time of randomization. Patients with early cessation of antibiotics had an overall reduction in antibiotic exposures, similar rates of adverse events, and similar overall mortality. A similar study in children has not yet been performed but would prove informative as the continuation of antibiotics until neutrophil recovery in high-risk patients results in prolonged hospitals stays and increased resource use. Until such a study is completed, many experts recommend continuation of empiric antibiotics for at least 14 days for high-risk FN in the absence of evidence of neutrophil recovery. Whether this strategy is optimal in the setting of antibacterial prophylaxis (see “Prophylaxis Strategies” in later text) is not known.

Evaluation for invasive fungal disease

Children at high-risk for IFD were identified in a systematic review of risk factors for IFD in pediatric oncology and HSCT patients. Patients at high-risk for IFD are those with acute myeloid leukemia (AML), high-risk acute lymphoblastic leukemia, relapsed acute leukemia, and children undergoing allogeneic HSCT. All other patient groups should be categorized as IFD low-risk. However, IFD is still a possibility in low-risk groups of patients receiving chemotherapy (e.g., standard-risk acute lymphoblastic leukemia) or undergoing autologous HSCT, and thus clinical awareness of IFD is still important in these low-risk groups. The primary risk period in high-risk patients is during episodes of prolonged neutropenia. However, even in the absence of neutropenia, IFD is still a possibility in these patient groups, particularly in association with steroid exposure or during periods of graft-versus-host disease in HSCT recipients.

In terms of evaluation, a systematic review of fungal biomarkers in children receiving cancer treatments concluded that galactomannan has little value as a surveillance diagnostic tool during prolonged FN as it has poor positive predictive value. However, it is important to note that these studies were not performed upon identification of a suspicious lung nodule and the value of galactomannan in children in this setting is unknown. Serum beta-D-glucan and fungal polymerase chain reaction assays should not be used as diagnostic tests during prolonged FN owing to poor diagnostic properties in children and lack of standardization in the case of polymerase chain reaction.

Recommendations for imaging for the evaluation of IFD during prolonged FN (≥96 hours) despite broad-spectrum antibiotics have been derived from a systematic review in pediatric patients. ^, It is recommended that lung computerized tomography be performed in children with prolonged FN who are considered at high-risk for IFD because the lungs are the most frequent site of infection and characteristic radiographic signs can be observed. Abdominal imaging, even in the absence of localizing signs or symptoms, may be useful as findings on imaging consistent with, IFD were observed in many patients. The ideal abdominal imaging modality is not known, but ultrasonography is readily available, is not associated with radiation exposure, and usually does not require sedation and, as such, is likely preferable over computerized tomography or magnetic resonance imaging for abdominal assessment. Sinus imaging results were frequently abnormal in prolonged FN but abnormalities did not appear to distinguish between those with and without sinus IFD. Thus routine sinus imaging for prolonged FN is likely not warranted in the absence of localizing signs or symptoms.

The optimal timing for imaging to evaluate for IFD is not known. Some centers perform imaging at the time the patient meets criteria for prolonged FN, whereas others wait until blood counts recover. The former approach allows for early detection of possible IFD, but many argue that unless a diagnostic procedure is going to be performed, detecting possible IFD at that time will not change management because empiric antifungal therapy will be started anyway. Those advocating for waiting until blood count recovery hypothesize that the presence of neutrophils allows for increased ability to detection IFD lesions if present. These two approaches have not been compared in a systematic way, and thus centers need to decide which approach is most acceptable for their institution.

Empiric antifungal therapy

Patients at high-risk for IFD should start empiric antifungal therapy in the event of persistent or recurrent fever lasting 96 hours or longer after initiation of broad-spectrum antibacterial agents during a neutropenic period. Empiric antifungal therapy should consist of either caspofungin or liposomal amphotericin B as these two therapies were similarly effective, and liposomal amphotericin B was slightly better and less nephrotoxic than amphotericin B deoxycholate. Empiric antifungal therapy may be discontinued at resolution of neutropenia if the patient is clinically well without evidence of an IFD.

In terms of patients at low risk for IFD, one prospective study compared empiric antifungal therapy to withholding empiric antifungal therapy in neutropenic children with persistent fever in this population. No benefit with respect to fever resolution or IFD was detected with empiric antifungal therapy. Thus in patients at low risk for IFD with prolonged FN, empiric antifungal therapy may be withheld.

Preemptive therapy is an area of great interest. A randomized trial of 149 children with persistent FN who were at high risk for IFD compared empiric versus preemptive antifungal treatment. Preemptive therapy was associated with significantly shorter duration of antifungal treatment (6 vs. 11 days; P < .001) with similar rates of IFD, mortality, and IFD-related mortality, suggesting that preemptive therapy may be a reasonable approach in pediatric patients at high risk for IFD.

Antibacterial prophylaxis

There has been considerable interest in antibacterial prophylaxis for periods of neutropenia, resulting in a many published trials. A 2005 large meta-analysis of predominantly adult randomized trials found that antibiotic prophylaxis significantly decreased the risk of death, infection-related mortality, and bacteremia. Fluoroquinolones were the focus of many of the studies in this meta-analysis because of their broad-spectrum activity, preservation of gastrointestinal tract anaerobic flora, high fecal concentration, systemic bactericidal activity, tolerability, and favorable side effect profile. Despite the established benefits of prophylaxis, adult FN guidelines questioned their routine use because of uncertainty regarding the overall balance of benefits and harms. The benefits of prophylaxis must be weighed against potential negative consequences, including Clostridium difficile –associated diarrhea, bacterial resistance, and adverse effects including musculoskeletal toxicities. The Children’s Oncology group undertook a large randomized trial to determine whether prophylactic levofloxacin during neutropenia decreased the risk of bacteremia in children with acute leukemia or those undergoing HSCT. A total of 624 patients, 200 with acute leukemia and 424 undergoing HSCT, were enrolled to this trial. Among the 195 patients with acute leukemia, the risk of bacteremia was significantly lower in the levofloxacin group compared with the control group (21.9% vs. 43.4%, P = .001). Among the 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin group (11.0% vs. 17.3%, P = .06), although the clinical significance of this reduction in bacteremia can be argued. In terms of secondary endpoints, FN was less common in the levofloxacin group (71.2% vs. 82.1%, P = .002), thus demonstrating that levofloxacin was effective as prophylaxis in children with expected neutropenia. There were no significant differences in severe infection (3.6% vs. 5.9%, P = .20), C. difficile –associated diarrhea (2.3% vs. 5.2%, P = .07), or musculoskeletal toxicity at 2 months (11.4% vs. 16.3%, P = .15) or 12 months (10.1% vs. 14.4%, P = 0.28) between the levofloxacin and control groups. However, a C. difficile positive assay result was less frequent in the levofloxacin group (7.8% vs. 14.0%, P = .02). Total days and any exposure to antibiotics used to treat FN were fewer in the levofloxacin group ( P < .0001 for both). Thus levofloxacin prophylaxis should be used for children with acute leukemia receiving intensive chemotherapy and should be considered for HSCT patients, particularly those undergoing allogeneic HSCT. Despite the lack of harm detected in the targeted outcomes from this large pediatric trial, the study does not address the long-term impact of resistance. It is likely that with continued use of levofloxacin in this setting at a given hospital, that the hospital antibiogram may reveal increasing levofloxacin resistance, resulting in increased rates of breakthrough infection. Centers that use levofloxacin prophylaxis should initiate a monitoring system to monitor rates of breakthrough bacteremia. If rates return to preprophylaxis rates, then the benefits of prophylaxis may no longer be present.

Antifungal prophylaxis

Because IFDs are relatively difficult to diagnose and treat, there has been considerable interest in determining the efficacy of different prophylactic approaches in patients at high risk for IFDs. Fluconazole prophylaxis was compared with placebo in two randomized controlled trials of mostly adult allogeneic HSCT recipients. ^, Fluconazole decreased the occurrence of IFD owing to a reduction in invasive candidiasis. Because children undergoing allogeneic HSCT are at risk for molds in addition to yeasts and because fluconazole does not provide any coverage against molds, there has been great interest in exploring the role of prophylactic antimold coverage. However, thus far agents with antimold activity, including micafungin, voriconazole, and amphotericin B formulations, have not proven to have clinically significant advantages over fluconazole prophylaxis in the HSCT population. Furthermore, some agents such as itraconazole showed a higher rate of toxicity leading to withdrawal, and agents such as amphotericin B led to infusion-related toxicities and renal toxicity.

Posaconazole is an antifungal agent with broader antimold activity than voriconazole and thus represents a potentially better prophylactic option. In a randomized trial of adolescent and adult patients with AML or myelodysplastic syndrome and prolonged neutropenia, posaconazole prophylaxis, when compared with fluconazole or itraconazole, reduced the rate of proven or probable IFD. Furthermore, overall survival was significantly better in posaconazole-treated patients. However, only 16 adolescents between the ages of 13 and 18 years were included, and thus the generalizability of the results to children is limited. Furthermore, administration of posaconazole to children younger than 13 years is challenging because of the lack of dosing information and the requirement to administer the drug orally with adequate food intake, which can be a challenge for children receiving intensive chemotherapy.

The Children’s Oncology Group recently completed two antifungal prophylaxis randomized trials. One study compared fluconazole and caspofungin in children with AML; the second study compared either fluconazole or voriconazole to caspofungin in pediatric allogeneic HSCT recipients. Results of both studies are expected in the near future and may influence standard of care for antifungal prophylaxis. Until these study results are available, most experts support the use of fluconazole as a prophylaxis agent during neutropenia periods for children at high risk for IFD.