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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 464-468
 

Clinical and microbiological profile of febrile neutropenia in solid tumors and hematological malignancies at a tertiary cancer care center in South India


1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
2 Department of Microbiology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication1-Feb-2016

Correspondence Address:
L A Jacob
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175330

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 » Abstract 

Background: Febrile neutropenia (FN) is a common but serious complication of chemotherapy in patients with solid tumors (ST) and hematological malignancies (HM). The epidemiology of FN keeps changing. Objective: The objective was to study the epidemiology of FN in adult patients with ST and HM at Kidwai Memorial Institute of Oncology, Bangalore – A tertiary cancer care center. Materials and Methods: Data of all episodes of FN that occurred during the period July 2011 to December 2011 were collected prospectively and analyzed. Results: A total of 75 episodes of FN was observed during study period involving 55 patients. Febrile neutropenic episodes were more frequent in HM than in ST (57% vs. 43%). The rate of bloodstream infection was 14.7%. Gram-negative organisms were the predominant isolates (56.25%). Overall mortality rate was 13.3%. Presence of medical co-morbidity and positive culture predicted high mortality. Mortality rate did not differ significantly between HM and ST (14% vs. 12.5%; P = 1.0). Gram-positive bacteremia was associated with greater mortality than Gram-negative bacteremia (P = 0.02). Conclusion: Empiric antibiotic treatment for FN should be tailored to the locally prevalent pathogens and their susceptibility patterns.


Keywords: Febrile neutropenia, hematological malignancy, India, solid tumor


How to cite this article:
Jacob L A, Lakshmaiah K C, Govindbabu K, Suresh T M, Lokanatha D, Sinha M, Vijaykumar B R, Sumathi B G, Jayashree R S. Clinical and microbiological profile of febrile neutropenia in solid tumors and hematological malignancies at a tertiary cancer care center in South India. Indian J Cancer 2014;51:464-8

How to cite this URL:
Jacob L A, Lakshmaiah K C, Govindbabu K, Suresh T M, Lokanatha D, Sinha M, Vijaykumar B R, Sumathi B G, Jayashree R S. Clinical and microbiological profile of febrile neutropenia in solid tumors and hematological malignancies at a tertiary cancer care center in South India. Indian J Cancer [serial online] 2014 [cited 2019 Aug 24];51:464-8. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/464/175330



 » Introduction Top


Febrile neutropenia (FN) is a common but serious complication of chemotherapy in patients with solid tumors (ST) and hematological malignancies (HM). Despite major advances in prevention and treatment, it is a major cause of morbidity and mortality.[1] It prolongs hospital stay, increases health care costs, and compromises chemotherapy efficacy due to delays and dose reductions. Prompt initiation of adequate antimicrobial therapy is the backbone of FN treatment. Knowledge of the locally prevalent pathogens and their resistance pattern is therefore of paramount importance in guiding antimicrobial therapy. Over the last 40 years, there has been a substantial fluctuation in the epidemiologic spectrum of pathogens isolated from febrile neutropenic patients. Until the mid-eighties, Gram-negative bacilli (Escherichia coli, Klebsiella sp., Pseudomonas aeruginosa) were the most frequently isolated organisms. Among the Gram-positive bacteria, Staphylococcus aureus predominated. Since then Gram-positive bacteria (coagulase-negative staphylococci [CONS], viridans streptococci) have gained predominance as the leading cause of infections in FN. Enterococci are in the majority responsible for colonization in neutropenic patients and raise the problem of resistance to antibiotics, mainly glycopeptides.[2]

Since the microbial etiology is often unknown at the initiation of treatment, choice of empiric therapy should depend on the locally prevalent pathogens and their sensitivities, the risk group (high or low risk for complications), the potential sites of infection and the cost of various regimens. At present, there are no national guidelines for treatment of FN in patients on cancer therapy in India. The Infectious Diseases Society of America (IDSA) guidelines are being followed by well-recognized treatment centers in India.[3]

This study was designed to review the recent pattern of microbial flora, their susceptibility pattern and important clinical variables among febrile neutropenic patients with ST and HM at our Institute.


 » Materials and Methods Top


This was a prospective surveillance study of FN episodes that occurred in adult patients (≥15 years of age) undergoing chemotherapy for HM and ST at the Medical Oncology Department of Kidwai Memorial Institute of Oncology, Bangalore, India between July 2011 and December 2011. Data of all episodes was collected prospectively and analyzed.

Febrile neutropenia was defined by the following criteria: A single oral temperature measurement of ≥101°F or a temperature of ≥100.4°F for 1 h with an absolute neutrophil count (ANC) <500/mm 3 or an ANC that was expected to decrease to <500/mm 3 during the next 48 h.[3]

Blood in all cases and urine, sputum, and pus samples whenever indicated, were collected and cultured using the conventional method. Organisms were identified according to routine bacteriological procedures. Antibiotic sensitivity testing was performed by the disc diffusion method.

All patients received initial empirical antibiotic therapy with cefoperazone-sulbactam with or without amikacin as per the Institutional policy. Vancomycin/teicoplanin was added to the initial empirical regimen only in specific circumstances (hemodynamic instability, suspected catheter-related infection, pneumonia, etc.). Empirical antifungal treatment with amphotericin was initiated in patients who continued to be febrile for >3 days despite adequate antibiotic treatment and negative blood cultures.

For outcome analysis, patients were stratified on the basis of age, sex, type of malignancy, severity and duration of neutropenia, presence or absence of comorbidity (such as hypotension, pneumonia, oral or gastrointestinal mucositis, and gastrointestinal symptoms at presentation), use of granulocyte colony-stimulating factor (GCSF) and culture results. The data are expressed in percentage.

Statistical analysis was done using Graphpad QuickCalcs. Data were evaluated by a 2 × 2 contingency table employing the Fisher's exact test. Results of P < 0.05 were considered statistically significant.


 » Results Top


A total of 75 episodes of FN was observed during the 6-month study period involving 55 patients. Of the 55 patients, 30 (54.5%) had HM while 25 (45.5%) had ST. Male-female distribution was more or less equal (51% male vs. 49% female). Only 16 patients (29%) were aged 50 years or above.

Of the total 75 episodes of FN, 43 (57.3%) occurred in patients with HM and 32 (42.6%) in patients with ST. Acute myeloid leukemia (AML) was the most common diagnosis (28%) among HM, followed by diffuse large B cell lymphoma (DLBCL) (13.3%). Among ST, head and neck cancer and osteosarcoma were the most common (9.3%) diagnoses [Table 1] and [Table 2].
Table 1: Frequency of FN episodes in HM

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Table 2: Frequency FN episodes in ST

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Totally, 50 (66.7%) episodes were in patients aged <50 years while 44 (58.6%) episodes were in males. 44 (58.6%) of the episodes had profound neutropenia with ANC ≤100/mm 3, whereas only 25 (33.3%) episodes were associated with prolonged neutropenia (>7 days). In 35 (46.6%) episodes, the patient had received prophylactic growth factors. There was an indwelling central venous catheter in 25 (33.3%) of the FN episodes. Comparison between episodes of ST and HM revealed that medical co-morbidities were significantly higher in ST while use of central venous catheter was more in HM. Use of prophylactic GCSF was significantly more in ST episodes [Table 3].
Table 3: Characteristics of patients with FN

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The culture positivity rate was 21.3%, blood being the most common site of positive culture (14.7%). 56.25% of the positive cultures yielded Gram-negative bacteria, 31.25% Gram-positive and 12.5% mixed (both Gram-positive and Gram-negative). There was only a single episode of invasive fungal infection – that of pulmonary aspergillosis. There was no significant difference either in the culture positivity rate or the bacteremia rate between ST and HM [Table 4].
Table 4: Details of culture

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Staphylococcus aureus was the most common Gram-positive organism and K. pneumoniea, E. coli and Acinetobacter the most common Gram-negative organisms isolated in FN patients. [Table 5] shows the 19 bacterial isolates from the 16 positive cultures.
Table 5: Organisms isolated and site of positive culture

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Among Gram-negative isolates, 100% sensitivity was observed for imipenem followed by meropenem and piperacillin-tazobactam (91.67%). 83.3% of the isolates were sensitive to cefoperazone sulbactam and amikacin. Least sensitivity was observed for ceftazidime and cefotaxime (50%). Two (66.7%) of the Klebsiella and one of the E. coli (33.3%) isolates were extended spectrum beta lactamase (ESBL) producers [Figure 1].
Figure 1: Antibiotic sensitivity pattern of Gram-.negative bacteria

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Among Gram-positive bacteria, both the isolates of Enterococci were resistant to Amikacin whereas the single Methicillin-resistant S. aureus (MRSA) isolate was sensitive. All the Gram-positive isolates were sensitive to linezolid, teicoplanin, and vancomycin [Table 6].
Table 6: Antibiotic sensitivity pattern of Gram--positive bacteria

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The overall mortality rate was 13.3%; 12.5% in ST; and 14% in HM. Significantly higher mortality was observed in those episodes with positive culture (31.3%) as against negative culture (8.5%) (P = 0.03). Presence of medical co-morbidities at presentation also predicted poor outcome (P = 0.03). Mortality in the bacteremia group was 45.5%. Type of cancer (solid vs. hematological), severity and duration of neutropenia, patients' age and sex or GCSF use did not have any significant effect on the mortality rate due to FN [Table 7].
Table 7: Correlation between FN mortality and other variables

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Of the 5 deaths (45.5%) in the bacteremia group, 4 (36.4%) were due to Gram-positive bacteremia and 1 (9.1%) due to Gram-negative bacteremia. Mortality from Gram-positive bacteremia was significantly higher than Gram-negative bacteremia (P = 0.02). Among the 4 deaths reported in the Gram-positive group, 2 were due to S. aureus and the other 2 due to Enterococcus. The 1 death in the Gram-negative group was due to E. coli. Among the deaths due to Gram-positive bacteria, 3 occurred in patients with acute leukemia (AML-2 and ALL-1) and 1 inpatient with osteosarcoma. Death due to E. coli was in a patient with AML.


 » Discussion Top


Indian data on FN have been largely on patients with HM.[4],[5],[6],[7] This prospective observational study included febrile neutropenic patients of both ST as well as HM. In our study, we found that FN episodes were more frequent in patients with HM than ST. AML was the most common diagnosis (28%) followed by DLBCL (13.3%) and head and neck cancer (9%). These findings are similar to those reported from Chile and Mexico.[8],[9]

In the present study, we observed a culture positivity rate of 21.3%. Al-Ahwal et al. and Zahid et al. reported culture positivity rate of 34.2% and 31%, respectively, in a mixed population of both ST and HM.[10],[11] The incidence of bloodstream infection was 14.7%. Various studies from the developed, as well as developing countries, report a wide range of incidence (13–34%) of bacteremia in similar patient populations.[10],[12],[13],[14],[15] Studies from India in patients with HM alone report a bacteremia rate of 13–36%.[4],[5],[6] The reason for the lower rate of culture isolation in our study could be because we used a conventional culture system in addition to the fact that many patients had received empirical antibiotics even before blood sampling.[16]

Gram-negative organisms were the predominant cause of infections in FN at our center. A rising incidence of Gram-positive bacteremia in febrile neutropenic patients has been reported over the past three decades, especially from the developed countries.[12],[17],[18] This has been attributed to the increasing use of indwelling venous catheters, quinolone prophylaxis, aggressive chemotherapy regimens, and H2 receptor blockers.[19] In our study, only one-third of the episodes had an indwelling venous catheter, and none of the patients had quinolone prophylaxis. That Gram-negative infection continues to be predominant in FN has been reported from various studies in India and other developing countries.[5],[6],[7],[11],[20]

The spectrum of bacterial isolates in our study was similar to what has been reported from other centers in India except that in the present study the incidence of pseudomonas infection was low.[5],[6],[7],[21] Emergence of Acinetobacter as one of the common Gram-negative isolates however is a cause of concern since it is associated with multi-drug resistance.[22] Antibiotic sensitivity pattern revealed a high level of resistance of the Gram-negative isolates to ceftazidime, cefotaxime, and ciprofloxacin. However, the prevalence of ESBL producers was low as compared to other studies.[6],[7] Higher sensitivity of the isolates to piperacillin tazobactam than cefoperazone sulbactam indicates the need for a revision of the antibiotic policy at our center.

The occurrence of MRSA was low. All staphylococcal and enterococcal isolates were susceptible to vancomycin, linezolid, and teicoplanin which is in agreement with the study by Swati et al.[6]

Recent studies report a wide range of mortality rate (7–33%) in FN patients.[10],[13],[14] Swati et al. and Gupta et al. reported a mortality rate of 20.3% and 17.9% respectively in FN patients with HM from India.[6],[7] The overall mortality rate in our study was 13.3%, which is compatible with these reports.

Outcome analysis based on stratification variables revealed a positive correlation only for culture result and the presence or absence of co-morbidity. Mortality rate in the culture positive group was significantly higher (P = 0.03) than in the culture negative group; in the bacteremia group it was even higher (45.5%). Mathur et al. from India reported that 48% of episodes of bacteremia had a fatal outcome.[5] Feld has also reported that the prognosis is worst in patients with proven bacteremia.[23] Presence of medical co-morbidities as defined by the IDSA panel also negatively impacted the outcome of patients in our study. This is consistent with other studies.[10],[24]

Even though the trend of mortality was higher in patients with prolonged neutropenia it did not reach statistical significance. This could be due to the fact that the number of episodes in our study was small. Patients in whom prolonged neutropenia is expected as a consequence of allogeneic hematopoietic stem cell transplantation (HSCT) preparation or induction chemotherapy for AML are the ones at highest risk for serious complications from FN whereas patients receiving autologous HSCT or consolidation therapy for leukemia appear to be at somewhat lower risk even though they may have prolonged neutropenic periods.[3] In the present study, AML inductions constituted only 17% of the total episodes, and there were no cases of allogeneic HSCT. The Multinational Association for Supportive Care in Cancer scoring system does not include the duration of neutropenia as a criterion of risk for serious infections whereas the IDSA panel considers it to be an important determinant.[3],[24] There was no significant difference in the mortality rate between ST and hematological HM. This is in agreement with a study from Saudi Arabia by Al-Ahwal et al.[10]

In the present study, even though isolation of Gram-negative organisms was more common than isolation of Gram-positive organisms; Gram-positive bacteremia was associated with greater mortality. This is in contrast to a large prospective observational study involving 2142 patients that reported higher mortality in Gram-negative bacteremia even though Gram-positive bacteremia was more common.[15] While CONS which are weak pathogens were the commonly identified cause of bacteremia in that study, S. aureus and Enterococcus known to cause fulminant infections was the common cause of Gram-positive bacteremia in our study. In a study from Israel, Paul et al. reported a lower mortality for bacteremia due to CONS as compared to Gram-positive bacteria other than CONS.[25] The high rate of mortality associated with Gram-positive bacteremia, however, points to the need for a revision in our initial antibiotic strategy. Addition of vancomycin to the initial empiric antibiotic regimen should be considered at least in patients of acute leukemia with FN following induction therapy. Vancomycin may be discontinued 2 or 3 days later if susceptible bacteria are not recovered.[3]


 » Conclusion Top


Empiric antibiotic treatment for FN should be tailored to the locally prevalent pathogens and their susceptibility patterns. Individual centers should monitor the epidemiology of infection at regular intervals to formulate appropriate regimens.

 
 » References Top

1.
de Naurois J, Novitzky-Basso I, Gill MJ, Marti FM, Cullen MH, Roila F, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol 2010;21 Suppl 5:v252-6.  Back to cited text no. 1
    
2.
Oppenheim BA. The changing pattern of infection in neutropenic patients. J Antimicrob Chemother 1998;41 Suppl D: 7-11.  Back to cited text no. 2
    
3.
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:e56-93.  Back to cited text no. 3
    
4.
Kumar L, Kochupillai V, Bhujwala RA. Infections in acute myeloid leukemia. Study of 184 febrile episodes. J Assoc Physicians India 1992;40:18-20.  Back to cited text no. 4
    
5.
Mathur P, Chaudhry R, Kumar L, Kapil A, Dhawan B. A study of bacteremia in febrile neutropenic patients at a tertiary-care hospital with special reference to anaerobes. Med Oncol 2002;19:267-72.  Back to cited text no. 5
    
6.
Swati M, Gita N, Sujata B, Farah J, Preeti M. Microbial etiology of febrile neutropenia. Indian J Hematol Blood Transfus 2010;26:49-55.  Back to cited text no. 6
    
7.
Gupta A, Singh M, Singh H, Kumar L, Sharma A, Bakhshi S, et al. Infections in acute myeloid leukemia: An analysis of 382 febrile episodes. Med Oncol 2010;27:1037-45.  Back to cited text no. 7
    
8.
Rabagliati RB, Fuentes GL, Orellana EU, Oporto JC, Dominguez IM, Benitez RG, et al. Etiology of febrile neutropenia episodes in adult patients with hematologic cancer and solid organ in the Catholic University Clinical Hospital, Santiago, Chile. Rev Chilena Infectol 2009;26:106-13.  Back to cited text no. 8
    
9.
Gaytán-Martínez J, Mateos-García E, Sánchez-Cortés E, González-Llaven J, Casanova-Cardiel LJ, Fuentes-Allen JL. Microbiological findings in febrile neutropenia. Arch Med Res 2000;31:388-92.  Back to cited text no. 9
    
10.
Al-Ahwal MS, Al-Sayws F, Johar I. Febrile neutropenia comparison between solid tumours and hematological malignancies. PAN Arab Med 2005;2:4-7.  Back to cited text no. 10
    
11.
Zahid KF, Hafeez H, Afzal A. Bacterial spectrum and susceptibility patterns of pathogens in adult febrile neutropenic patients: A comparison between two time periods. J Ayub Med Coll Abbottabad 2009;21:146-9.  Back to cited text no. 11
    
12.
Johansson PJ, Sternby E, Ursing B. Septicemia in granulocytopenic patients: A shift in bacterial etiology. Scand J Infect Dis 1992;24:357-60.  Back to cited text no. 12
    
13.
Sigurdardottir K, Digranes A, Harthug S, Nesthus I, Tangen JM, Dybdahl B, et al. A multi-centre prospective study of febrile neutropenia in Norway: Microbiological findings and antimicrobial susceptibility. Scand J Infect Dis 2005;37:455-64.  Back to cited text no. 13
    
14.
Horasan ES, Ersoz G, Tombak A, Tiftik N, Kaya A. Bloodstream infections and mortality-related factors in febrile neutropenic cancer patients. Med Sci Monit 2011;17:CR304-9.  Back to cited text no. 14
    
15.
Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents 2007;30 Suppl 1:S51-9.  Back to cited text no. 15
    
16.
Flayhart D, Borek AP, Wakefield T, Dick J, Carroll KC. Comparison of BACTEC PLUS blood culture media to BacT/Alert FA blood culture media for detection of bacterial pathogens in samples containing therapeutic levels of antibiotics. J Clin Microbiol 2007;45:816-21.  Back to cited text no. 16
    
17.
EORTC. Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. The International Antimicrobial Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer. Ann Intern Med 1993;119:584-93.  Back to cited text no. 17
    
18.
Rubio M, Palau L, Vivas JR, del Potro E, Diaz-Mediavilla J, Alvarez A, et al. Predominance of gram-positive microorganisms as a cause of septicemia in patients with hematological malignancies. Infect Control Hosp Epidemiol 1994;15:101-4.  Back to cited text no. 18
    
19.
Giamarellou H, Antoniadou A. Infectious complications of febrile leukopenia. Infect Dis Clin North Am 2001;15:457-82.  Back to cited text no. 19
    
20.
Butt T, Afzal RK, Ahmad RN, Salman M, Mahmood A, Anwar M. Bloodstream infections in febrile neutropenic patients: Bacterial spectrum and antimicrobial susceptibility pattern. J Ayub Med Coll Abbottabad 2004;16:18-22.  Back to cited text no. 20
    
21.
Prabhash K, Medhekar A, Ghadyalpatil N, Noronha V, Biswas S, Kurkure P, et al. Blood stream infections in cancer patients: A single center experience of isolates and sensitivity pattern. Indian J Cancer 2010;47:184-8.  Back to cited text no. 21
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22.
Wareham DW, Bean DC, Khanna P, Hennessy EM, Krahe D, Ely A, et al. Bloodstream infection due to Acinetobacter spp: Epidemiology, risk factors and impact of multi-drug resistance. Eur J Clin Microbiol Infect Dis 2008;27:607-12.  Back to cited text no. 22
    
23.
Feld R. Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents 2008;32 Suppl 1:S30-3.  Back to cited text no. 23
    
24.
Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-51.  Back to cited text no. 24
    
25.
Paul M, Gafter-Gvili A, Leibovici L, Bishara J, Levy I, Yaniv I, et al. The epidemiology of bacteremia with febrile neutropenia: Experience from a single center, 1988-2004. Isr Med Assoc J 2007;9:424-9.  Back to cited text no. 25
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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