We investigated the clinical and laboratory characteristics of VSB in febrile neutropenic patients with hematologic malignancies and the antibiotic susceptibilities of the viridans streptococci. The data were compared between adults and children and also in patients with VSB susceptible and not susceptible to cefepime.
VSB occurred most commonly in AML patients (72.7%), 12 days (IQR: 10–14) after the beginning of consolidation chemotherapy (57.9%), and six days (IQR: 4–8) after the onset of neutropenia. This pattern of VSB occurrence was consistent with previous reports . While oral mucositis, a risk factor for VSB, occurred in roughly 60% of patients with VSB in previous reports [9, 19], it occurred at a lower rate of 20.3% in this study. On the other hand, gastrointestinal symptoms were common in all patient groups, and cough was common in children. Considering that viridans streptococci are normal flora of the gastrointestinal and upper respiratory tracts as well as oral mucosa [20, 21], and that mucosal damage can occur at these sites following chemotherapy or HCT, this was a predictable result. Since young children often cannot adequately complain of their oral and abdominal pain, and their parents or medical personnel might easily recognize objective symptoms, such as diarrhea and cough, the reported incidence of oral mucositis and abdominal pain might be lower in children than in adults. Other clinical and laboratory characteristics were not significantly different between adults and children, and the aforementioned symptoms occurred in less than one-third of patients. Therefore, we concluded that there were no distinctive characteristics to distinguish between VSB in adults and children.
The 12.9% occurrence rate of severe complications attributable to VSB was lower than that of previous reports, which showed an occurrence rate of 18-39%, and the 2.0% mortality attributable to VSB in this study was also lower than that of previous reports, which showed mortality up to 20% [8–10]. Although Martino et al. reported a higher occurrence rate of severe complications and death due to VSB in children than in adults, the occurrence rate of severe complications and death attributable to VSB and overall mortality were not significantly different between adults and children in the present study. Previous researchers did not find significant factors related to a worse prognosis in children, and there have been few studies comparing the clinical characteristics and prognoses between adults and children. Comparisons between adults and pediatric patients with severe complications attributable to VSB showed that children more commonly complained of cough and had a longer duration between the beginning of the preceding therapy and the diagnosis of VSB, similar to the comparison between all adults and children with VSB. When comparing patients with severe complications attributable to VSB and those without severe complications in this study, there was no significant difference except for the peak CRP level within a week after the diagnosis of VSB. This had a low positive predictive value of 23% for the occurrence of severe complications. Thus, we were also unable to identify a definite factor that could help anticipate severe complications in VSB.
Antibiotic susceptibility rates to cefotaxime, cefepime, and erythromycin were lower in children than in adults. Although we performed both univariate and multivariate analyses to determine risk factors for decreased susceptibility to cefepime, no significant factors were found. Recurrent antibiotic use may be related to the increase in antibiotic resistance [22, 23]; however, there was no difference between patients with VSB susceptible and not susceptible to cefepime in the number of antibacterial therapies for febrile neutropenia after previous conventional chemotherapy or HCT. The fact that the first-line antibiotic agent for patients with hematologic malignancies was cefepime or ceftazidime in most adults and piperacillin/tazobactam for almost all children in our hospital also supports the finding that previous antibiotic use is not related to decreased susceptibility to cefepime. We also analyzed the effect of prophylactic antibiotics on susceptibility to cefepime since ciprofloxacin, principally given to adults, has a limited effect on Gram positive bacteria [24, 25], while TMP/SMX, principally given to children, has a satisfactory effect [25, 26]. The effect of prophylactic antibiotics on decreased susceptibility to cefepime may be small since antibacterial prophylaxis has been reported to be unrelated to increased antibiotic resistance in a meta-analysis , and since patients in the present study received ciprofloxacin or TMP/SMX rather than β-lactam antibiotics and antibacterial prophylaxis with these antibiotics is not known to trigger antibiotic resistance in viridans streptococci [22, 28, 29]. Nevertheless, prophylactic antibiotic effects on decreased susceptibility to cefepime should not be ignored. Viridans streptococci can acquire β-lactam resistance through transfer of the mutated penicillin binding protein gene from Streptococcus pneumoniae[30, 31], and it has been reported that the resistance of S. pneumoniae to β-lactam antibiotics after TMP/SMX prophylaxis in human immunodeficiency virus-infected patients can increase by a factor of 1.71 . However, resistance to penicillin of S. pneumoniae was 0.3% in nonmeningeal isolates and 83.3% in meningeal isolates, and ceftriaxone resistance was 1.9% in nonmeningeal isolates and 0% in meningeal isolates from 2008 to 2009 in the Republic of Korea . The exact effect of prophylactic antibiotics on the development of antibiotic resistance remains controversial , and the type of antibiotics, duration of prophylaxis, bacterial species, and host factors may influence the development of antibiotic resistance [22, 34].
In this study, there were no definite differences in clinical and laboratory characteristics, mortality, or occurrence of severe complications between febrile neutropenic adults and children with VSB, despite a significant difference in antibiotic susceptibility to cefepime between the two groups. Antibiotic susceptibilities were not significantly related to the development of severe complications. Thus, our study results show that different antibiotic treatment strategies for adults and children with VSB are not necessary. The lower susceptibility rate of 66.1% to cefepime in children may indicate the need for initial glycopeptide therapy in febrile neutropenic children. However, bacteremia is diagnosed in 10-25% of febrile neutropenic children [1–3], and 20-30% of the bacteremia is caused by viridans streptococci [1, 4, 5]. In addition, since severe complications occurred in 6.6% of the patients with VSB according to our results, we estimate that the incidence of severe complications of VSB in febrile neutropenic children is 0.5%. Therefore, considering that antibiotic susceptibility is not significantly related to the prognosis of VSB in febrile neutropenia [5, 9], universal initial glycopeptide therapy targeting only 0.5% of febrile neutropenic children with hematologic malignancies should not be considered. Instead, we should consider glycopeptide therapy if antibiotic susceptibility tests revealed that the isolated viridans streptococci were not susceptible to antibiotics being administered to the patient and susceptible to glycopeptides.
This study has several limitations including its retrospective nature. We tried to eliminate selection bias by including all consecutive hematologic malignancy patients with VSB who were treated in the same hospital environment. Also, there were some limitations in our tests for antibiotic susceptibility. The results of the E-test and disk diffusion method for antibiotic susceptibility in this study may be different from results of broth microdilution methods. Additionally the clinical laboratory of our hospital did not perform piperacillin/tazobactam susceptibility test for viridans streptococci; thus, we assumed that cefepime susceptibility was similar to piperacillin/tazobactam susceptibility. This assumption may not be applicable to clinical settings. Lastly, past histories of antibacterial therapy for febrile neutropenia were reviewed to evaluate its effect on the differences in antibiotic susceptibility; however, information from 35 patients was missing. Although we assumed that previous antibacterial therapies should not influence β-lactam susceptibilities, the relationship should be further investigated.