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2022, Number 1

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Rev Latin Infect Pediatr 2022; 35 (1)

Bloodstream infections in pediatric patients with febrile neutropenia in a reference center from Bucaramanga, Colombia

Bello-Suárez, AK1; Cuesta-Armesto, MH2; Silva-Sánchez, MP3; Anteliz-Díaz, AK2; Sarmiento-Wilches, PE4

Language: English
References: 27
Page: 12-21
PDF size: 277.13 Kb.


ABSTRACT

Febrile neutropenia (FN) represents an important cause of mortality in patients with cancer due to the underlying serious invasive infections, mainly associated with bloodstream infections (BSIs), to which they are susceptible because of immunosuppression. The purpose of this study is to describe BSI in pediatric patients with onco-hematologic pathologies and FN, as well as establish their association with adverse outcomes and mortality. Retrospective cohort analytical study of patients between 1 month and 18 years with onco-hematological pathology who were hospitalized in a reference center in Bucaramanga, Colombia between 2013 and 2017, presenting FN, with positive blood cultures.130 patients with FN were included, for a total of 315 episodes. The incidence of BSI was 29.23/100 patients with FN. Intravascular devices were responsible for 15% of these infections. Gram-negative bacilli (GNB) (74.19%) were the main cause, led by Klebsiella pneumoniae (30.65%) and Escherichia coli (24.19%). When performing a bivariate analysis, an association was found between the presence of bacteremia and a higher probability of presenting hemodynamic instability, requirement for inotropics, need for ICU and death, in accordance with the literature. The GNBs were the main cause of BSI in patients with FN, as well as a greater association with mortality in the population studied.



INTRODUCTION

The immunocompromised state among hemato-oncology patients carries a high risk of infection, mainly of the bloodstream, with bacterial and fungal causes predominantly.1 The high risk of infection depends on the intensity and duration of the immunocompromised state.2 The effect of myelosuppressive and antineoplastic therapies is a major predisposing factor for BSI given its predominant effect in cells with high replication rate of both tumor origin and healthy tissue.3 In addition, the loss of mucocutaneous barriers as a result of chemotherapy and the use of medical devices, neutropenic patients have low or no response to the high proliferation rate of pathogenic microorganisms.4 Fever is the body's mechanism to alert the immune system that an inflammatory process is taking place and because this process is limited in these patients, fever is a reflection of an advanced infectious process, with possible bacteremia in this patient population 1) Febrile neutropenia (FN) is the main cause of mortality, leading to the need for intensive therapy and therefore constitutes a significant infectious emergency.1

The purpose of this study is to establish the incidence of bloodstream infections in pediatric patients with hemato-oncology pathologies and FN in the studied population, as well as the antimicrobial susceptibility of the isolated microorganisms, and to evaluate the association of bacteremia with adverse outcomes and mortality.



MATERIAL AND METHODS

A descriptive, retrospective cohort-type study was performed at the Clínica Materno Infantil San Luis (CMISL) (Bucaramanga, Colombia). All the patients aged one month to 18 years, hospitalized with an hemato-oncology pathology according to the CIE-10 code, and who presented FN between January 2013 and December 2017 were included. FN was defined as the simultaneous record of fever (axillary temperature > 38 oC), and absolute neutrophil count under 500 cel/mm3. All newborns and the patients whose FN was secondary to non-hematological nor oncological pathologies were excluded. The data from the medical records were collected in REDCap®.

The results of blood cultures were recorded, and episodes with positive isolations meeting the criteria for bacteremia according to the Center for Disease Control and Prevention (CDC)5 (Annex 1), were selected. Subsequently, the description of the isolated microorganisms and their susceptibility pattern based on antibiograms was performed (Annex 2).

The study was considered without risk and was approved by the research committee of the Universidad Industrial de Santander and CMISL in which verbal informed consent and assent were performed. The authors declare no conflict of interest.

Statistical analysis. The variables were described by percentages, proportions and ratios. In quantitative continuous variables, the median with the respective interquartile range was calculated, since they are all non-parametric.

For bivariate analysis of results associated with bacteremia, the following variables were used: need for PICU, length of stay in the PICU, need for inotropes, need for antibiotic staggering, need for mechanical ventilation, recurrent bloodstream infection, length of hospitalization, readmission, and mortality associated with infection. Pearson's χ2 test, was used for categorical variables, Fisher's exact test for low-number categorical variables, and Mann-Whitney test for continuous quantitative variables. In all analyses, a value of p < 0.05 was considered statistically significant with a 95% confidence interval. The Stata 14.0 program was used for the statistical analysis.



RESULTS

In the period from 2013 to 2017, 130 pediatric oncologic patients with FN were included, identifying 315 episodes of FN. Of these, 72 (22.85%) episodes had positive blood cultures. Upon applying the CDC criteria, the cumulative incidence of BSI was 29.23% (n = 38/130) of patients with FN during the study period, corresponding to 55 episodes, 5 of which presented more than one infection of the bloodstream during the episode. Table 1 describes the characteristics of these population.

A total of 60 BSIs were detected throughout the period, for a total of 62 isolated microorganisms; two of them were secondary to two microorganisms found in the same blood culture, considered pathogenic: S. pneumoniae - Fusarium spp. and P. aeruginosa - K. pneumoniae. One fulminating case was found due to invasive fungal infection caused by Fusarium spp. in 2017, an emerging fungus in immunocompromised patients.2 The isolated microorganisms are described in Table 2 and Figure 1 and the antimicrobial resistance of the isolated microorganisms in Figure 2.

The central venous catheters (CVC) related BSIs were found in 12 bacteremias (20.00%, CI95% 6.52-22.61), with rate of 0.00032 cases per 1,000 device days and a mortality of 7.62 cases per 1,000 cancer patients with FN and CVC during the period studied. According to the type of catheter, half were associated with totally implantable CVC and the other half with Nontunneled CVC. Of Nontunneled CVC-related BSIs, 4 (66.67%) cases were linked with insertion site infection; five cases (83.34%) corresponded to subclavian catheters and one case (16.67%) to internal jugular catheter.

In CVC related BSIs, the microorganisms isolated in order of frequency were Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Streptococcus pneumoniae and Enterococcus faecium.

Table 3 lists the outcome variables associated with bacteremia.



DISCUSSION

The incidence and microbiological characterization of FN-associated infections are essential to carry out institutional management protocols in accordance with the epidemiological reality in order to optimize the empirical treatment of patients with FN, and to evaluate their outcomes.

The incidence of BSIs was 29.23 per 100 patients with FN, corresponding to 17.46% of the total number of episodes during the period studied. This finding is compatible with some reports that describe bacteremia in 10-25% of all patients with FN.1,4,6 Others also report that among infections with microbiological isolation, bacteremia is the most frequent, accounting for approximately 20-25% of FN episodes and 74-85% of all infections with positive cultures.7,8

In our cohort, a total of 60 bacteremias were obtained during the entire period, of which 20.00% were associated with CVC. The nontunneled CVC and totally implantable CVC kept the same ratio. This allows us to call attention to the management and care of these invasive devices as potential sources of preventable infections. However, the rate of CVC-related BSI is 0.00032 cases per 1,000 days of use of the device, a figure significantly lower than those reported worldwide. Cumulative rates of central catheter-related infections of 4.1/1,000 device-days have been documented in adult ICUs in high-income countries. In 2014, the European Centers for Disease Control and Prevention (ECDC) documented an incidence rate of 3.3 cases/1,000 device-days. In contrast, only a few specific studies from some countries in Latin America identified that infections associated with central catheters correspond to 12.5 cases/1,000 catheter-days.9-11

Among the isolated microorganisms, the GNBs are predominant. As main agents, K. pneumoniae, E. coli and P. aeruginosa, accounted for 79.14% of the causes of bacteremia in the studied population, while 16.13% were by GPCs and almost 10% by fungus. According to the recent literature, the GPCs predominate among the bacteria isolated in the blood cultures (46.9-82.0%), mainly the SCNs.7 However, in some Latin American countries, the GNB's cause more than 80% of bacteremia, with infections due to E. coli, K pneumoniae and P. aeruginosa prevailing.7 Fungus were less frequent, but they gain great importance mainly in patients with prolonged and recurrent FN.1,2 A predominance of Candida spp. was observed, as in the other series.3 It is important to highlight that fluconazole prophylaxis has increased the presence of other resistant species such as Candida krusei and Candida glabrata.12,13 Table 4 describes the incidence of bacteremia in different studies, and the predominant isolated microorganisms.14-22

According to the interpretative reading of the antibiograms, it is determined that within the Enterobacteriaceae (EB), there is a predominance of multisensitive microorganisms and those with usual resistances, which together correspond to almost 40% of cases, compared to unusual resistances. A study conducted at a Melbourne pediatric hospital and another in Hospital Clinic from Barcelona documented that antibiotic resistance occurs most frequently in patients with FN and EB-BSI; as demonstrated in this study, where patients with FN and BSI had a higher risk of unusual resistance than those who did not have bacteremia (27 vs 2% respectively, p = 0.01).23,24 Another study in a Pediatric Hospital in Chile reported that the majority of resistant EB strains corresponded to ESBL producers, compatible with the results shown in this study, since they are the first cause of unusual resistance (15%) and slightly less than 5% of the isolations were from EB with a pattern suggestive of CBP.17

It has been noted that in those centers in which quinolone prophylaxis is not used, a predominance of GNB has been seen as a bacterial cause of infection in patients with FN, also important is the fact that the prophylaxis used in the patients studied was with TMP-SMX, and only in a few special cases ciprofloxacin was used.4 However, the use of prophylactic quinolones has also been associated with increased resistance in GNB, the latter correlated with the predominance of microorganisms with low resistance patterns.25

Using a bivariate analysis to assess the associations between bacteremia and some triggers, it was found that those children with FN and BSI, had a greater probability of presenting adverse outcomes such as some degree of hemodynamic instability, inotropic requirement, need for antibiotic stepping, required ICU stays, and the use of invasive devices such as mechanical ventilation and CVC placement, as well as a longer hospital stays and death, compared to those who did not document bloodstream infection. Hsin-Pao found a statistically significant association between patients with BSI and change in antibiotic, hypotension, transfer to the ICU, length of hospitalization, and risk of mortality based on PRISM II.26 In addition, most recently Hyo, showed that among the complications associated with P. aureginosa bacteremia, the need for mechanical ventilation was important. Some studies indicate that hypotension is an independent variable for deaths in populations similar to the one studied.27

Regarding mortality, in a multivariate analysis carried out by Paganini, bacteremia was identified as a mortality risk factor in patients with FN and malignant diseases.2 For his part, Basu in 2005 identified that the diagnosis of bacteremia in patients with FN, increases the mortality by 10 times.27 At the same time, the El-Mahallawy study shows a crude mortality of 10.40% in patients with documented bacteremia concomitant with FN in 2011, while in 2015, it decreased to 6%.15,21 Not far from the findings, our study shows the risk of mortality increases 8 times more in patients with bacteremia vs. those without. Different studies demonstrate that a high incidence of resistance in GNBs contribute to a higher mortality in pediatric patients with FN (20-30%).1,4,23 However, it would be interesting to perform a multivariate analysis to better delineate the factors associated with mortality in patients with FN and BSI.

Our study has some potential limitations. As the study was retrospective, we were not able to assess all the variables, and were limited by the documentation by the treating physician. Additionally, we did not collect physiologic data, details of comorbidities, and were not able to determine the secondary BSIs to other infectious sources. Furthermore, viral and fungal infection could not be interpreted properly due to the lack of instruments needed for their detection. Our data report a single center experience, and therefore results are most likely related to local epidemiological conditions. However, our study provides an opportunity to investigate potential risk factors for BSI's in pediatric oncologic patients with FN.



CONCLUSION

In the present study, GNBs were the main cause of bacteremia in patients with FN, and had a greater association with antibiotic resistance, hemodynamic complications, prolonged hospital stays, and mortality. Microbiological identification and characterization of bacteremia in hemato-oncology pediatric patients with FN is critical to have a knowledgeable use of available antibiotics and create protocols in line with institutional reality. This would be instrumental in reducing the risk of antimicrobial resistance, adverse effects of antibiotic therapy, decreasing mortality and reducing the cost of cancer care.


REFERENCES

  1. Consenso de la Sociedad Argentina de Infectología. Guías de recomendaciones sobre diagnóstico, tratamiento y prevención de infecciones en pacientes con cáncer 2013. Rev Argent Microbiol. 2014; 46 (1): 7-144.

  2. Paganini H, Santolaya ME, Álvarez M, Araña M, Arteaga R, Bonilla A et al. Diagnosis and treatment of febrile neutropenia in pediatric cancer patients. Consensus of the Sociedad Latinoamericana de Infectología Pediatria. Rev Chil Infectol. 2011; 28 (1): 10-38.

  3. Fisher B, Sung L. Chapter 68: The febrile neutropenic patient. In: Cherry J, Demmler-Harrison G, Kaplan S, Steinbach W, Hotez P, ed. by. Feigin and Cherry's textbook of pediatric infectious diseases. 8th, Houston, Texas, USA: Elsevier; 2018, 657-664.

  4. Manterola A, Romero P, Martínez E, Villafranca E, Arias F, Domínguez MA et al. Neutropenia and fever in the patient with cancer. An Sist Sanit Navar. 2004; 27 (3): 33-43.

  5. CDC. Bloodstream Infection Event (Central line-associated bloodstream infection and non-central line associated bloodstream infection (site internet). CDC.gov. Available in: https://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf

  6. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011; 52 (4): e56-93.

  7. Baro M. Predicción del riesgo de infección grave en niños con neutropenia febril secundaria a quimioterapia. [Tesis Doctoral]. Madrid: Programa de Doctorado en Investigación en Ciencias Médico-Quirúrgicas Universidad Complutense de Madrid; 2017.

  8. Santolaya ME, Farfán MJ, De La Maza V, Cociña M, Santelices F, Alvarez AM et al. Diagnosis of bacteremia in febrile neutropenic episodes in children with cancer: microbiologic and molecular approach. Pediatr Infect Dis J. 2011; 30 (11): 957-961.

  9. Instituto Nacional de Salud. Protocolo de vigilancia en Salud Pública: Infecciones asociadas a dispositivos. Vigilancia y análisis del riesgo en salud pública. Colombia, 2017. Disponible en: https://www.ins.gov.co/buscador-eventos/Lineamientos/PRO_Infecciones_asociadas_dispositivos.pdf

  10. Alsaad T, Qaisuddin M, AlSaad D, Chandra P, AlAbd O, Nasser AA et al. Central line-associated bloodstream infection in pediatric oncology patients in Qatar: A prospective study. J Appl Hematol. 2017; 8 (2): 49-53.

  11. Tsai HC, Huang LM, Chang LY, Lee PI, Chen JM, Shao PL et al. Central venous catheter-associated bloodstream infections in pediatric hematologye-oncology patients and effectiveness of antimicrobial lock therapy. J Microbiol Immunol Infect. 2015; 48 (6): 639-646.

  12. Lucero Y, Brücher R, Alvarez A, Becker A, Cofré J, Enríquez N et al. Invasive fungal infections in children with cancer and febrile neutropenia, in Chile. Rev Méd Chile. 2002; 130 (10): 1139-1146.

  13. Santolaya ME, de Queiroz F, Alvarado T, Lopes A, Zurita J, Tiraboschi IN et al. Recommendations for the management of candidemia in children in Latin America. Rev Iberoam Micol. 2013; 30 (3): 171-178.

  14. Greenberg D, Moser A, Yagupsky P, Peled N, Hofman Y, Kapelushnik J et al. Microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile neutropenic oncology patients: comparison between two consecutive time periods with use of different antibiotic treatment protocols. Int J Antimicrob Agents. 2005; 25 (6): 469-473.

  15. El-Mahallawy HA, El-Wakil M, Moneer MM, Shalaby L. Antibiotic resistance is associated with longer bacteremic episodes and worse outcome in febrile neutropenic children with cancer. Pediatr Blood Cancer. 2011; 57 (2): 283-288.

  16. Cortez D, Rodríguez N, Benadof D, Zamorano A, Tordecilla J. Bacteremia in cancer patients. Experience in a pediatric hospital. Rev Chil Infectol. 2012; 29 (2): 164-168.

  17. Solís Y, Álvarez AM, Fuentes D, De la Barra D, Avilés CL, Becker A et al. Bloodstream infections in children with cancer and high risk fever and neutropenia episodes in six hospitals of Santiago, Chile between 2004 and 2009. Rev Chil Infect. 2012; 29 (2): 156-162.

  18. Miedema KG, Winter RH, Ammann RA, Droz S, Spanjaard L, de Bont ES et al. Bacteria causing bacteremia in pediatric cancer patients presenting with febrile neutropenia--species distribution and susceptibility patterns. Support Care Cancer. 2013; 21 (9): 2417-2426.

  19. Reddy R, Pathania S, Kapil A, Bakhshi S. Review of spectrum and sensitivity of bacterial bloodstream isolates in children with malignancy: a retrospective analysis from a single center. Indian J Cancer. 2014; 51 (4): 425-427.

  20. Al-Mulla N, Taj-Aldeen SJ, Elshafie S, Janahi M, Al-Nasser A, Chandra P. Bacterial bloodstream infections and antimicrobial susceptibility pattern in pediatric hematology/oncology patients after anticancer chemotherapy. Infect Drug Resist. 2014; 7: 298-299.

  21. El-Mahallawy HA, Hassan SS, El-Wakil M, Moneer MM, Shalaby L. Increasing antimicrobial resistance monitored in surveillance analysis of blood stream infections in febrile neutropenic pediatric oncology Patients. Asian Pac J Cancer Prev. 2015; 16 (14): 5691-5695.

  22. Tural Kara T, Erat T, Yahsi A, Ozdemir H, Ileri T, Ince E et al. Bloodstream infections in pediatric hematology/oncology patients: Six years' experience of a single center in Turkey. Turk J Med Sci. 2019; 40: 1157-1164.

  23. Haeusler GM, Mechinaud F, Daley AJ, Satarr M, Shann F, Connell TG et al. Antibiotic-resistant Gram-negative bacteremia in pediatric oncology patients--risk factors and outcomes. Pediatr Infect Dis J. 2013; 32 (7): 723-726.

  24. Ortega M, Marco F, Soriano A, Almela M, Martínez JA, Rovira M et al. Epidemiology and outcome of bacteraemia in neutropenic patients in a single institution from 1991-2012. Epidemiol Infect. 2015; 143 (4): 734-740.

  25. Averbuch D, Orasch C, Cordonnier C, Livermore D, Mikulska M, Viscoli C et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistence: summary of the 2011 4th european conference on infections in leukemia. Haematol. 2013; 98 (12): 1826-1835.

  26. Cortes JA, Cuervo SI, Arroyo P, Quevedo R. Hallazgos microbiológicos en pacientes con neutropenia febril. Revista Colombiana de Cancerología. 2003; 7 (4): 5-11.

  27. Basu SK, Fernandez ID, Fisher SG, Asselin BL, Lyman GH. Length of stay and mortality associated with febrile neutropenia among children with cancer. J Clin Oncol. 2005; 23 (31): 7958-7966.



AFFILIATIONS

1 Pediatrician. Industrial University of Santander. Bucaramanga. Colombia.

2 Physician. Industrial University of Santander. Bucaramanga. Colombia.

3 Medical student. Industrial University of Santander. Bucaramanga. Colombia.

4 Pediatrician. Infectious disease specialist. San Luis Materno infantil Clinic. Bucaramanga. Colombia.



Funding/Support: No funding was secured for this study.

Conflict of interest disclosures: The authors have no conflicts of interest relevant to this article to disclose.



CORRESPONDENCE

Patrik Eliana Sarmiento Wilches. MD.. E-mail: pesw5@hotmail.com.




Received: 15-02-2022. Accepted: 01-03-2022.

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