Original Article
Management of febrile neutropenia in solid organ malignancies following chemotherapy ABSTRACT Background: Febrile neutropenia is a medical emergency and it requires immediate hospitalization for evaluation and administration of empiric broad‑spectrum antibiotics. The present study was undertaken to analyze the infectious agents, choice of empiric antibiotics, and outcome in high‑risk febrile neutropenia in the solid organ malignancies. Materials and Methods: In this study, 92 high risk febrile neutropenic episodes were analyzed in 72 patients with solid organ malignancies. We used cefoperazone‑sulbactum as an initial empiric antibiotic. Piperacillin/tazobactum or carbapenems were added to the patients who did not respond to initial antibiotic. Results: Among the 92 episodes treated, most patients received first‑line chemotherapy for locally advanced disease. Microbes were isolated in 25% of febrile neutropenic episodes. Gram‑negative organism (61.70%) constituted the most common isolates. The most common microbes identified were E. coli and Staphylococcus aureus in blood, Klebsiella pneumonia in sputum and E. coli in urine culture. Patients who had been treated with cefoperazone‑sulbactum improved clinically in 70.6% of febrile neutropenic episodes. Second‑ line antibiotics (piperacillin‑tazobactum with amikacin) were required in 24% episodes, while another 5.4% episodes required third‑line antibiotics (carbapenems). In this study, mortality was seen in 12% of febrile neutropenic episodes. Staphylococcus aureus was 100% sensitive to linezolid, teicoplanin, and vancomycin, whereas Gram‑negative organisms were 100% sensitive to imepenem and meropenem. Conclusion: Cephaperazone‑sulbactum is a reasonable initial choice for empirical therapy in high risk febrile neutropenic patients in solid organ malignancies. KEY WORDS: Cefoperazone‑sulbactum, E. coli, febrile neutropenias, solid organ malignancies, solid malignancies
INTRODUCTION
MATERIALS AND METHODS
regional cancer centre, south India were analyzed. Informed consent was taken from all the patients. All patients were aged more than 15 years. FN was diagnosed when a single oral temperature of greater than 38.3°C (101°F) or 38.0°C (100.4°F) for more than 1 hour was present along with absolute neutrophil count (ANC) less than 500/µl or less than 1,000/µl with predicted rapid decline during the next 48 hour.[4] All FN patients have been examined clinically and evaluated with appropriate laboratory investigations including, complete hemogram, liver function tests, renal function tests, serum electrolytes, chest X‑ray, blood culture from peripheral vein, urine culture, sputum and pus culture (if indicated). Blood cultures were repeated every 48 hours in case of persisting fever. Computed tomography (CT) scan of the paranasal sinuses or thorax was done in clinically suspected fungal infection of respective sites. All the patients’ co‑morbidities were documented such as diabetes mellitus, chronic obstructive pulmonary disease, renal dysfunction, and cardiac diseases.
In this study 72 patients with solid tumors diagnosed and treated for 92 high risk FN episodes from August 2011 to January 2013 in a
Once diagnosed with FN these patients were grouped under high‑risk category based on the Infectious Diseases Society of America (IDSA)
Febrile neutropenia (FN) is considered as a medical emergency. It causes significant economic loss, morbidity and mortality to the patients. Early detection, prompt initiation of empiric antibiotics leads to effective management of this condition. Hematological malignancies constitutes around 70-80% FN cases, whereas 5-30% of episodes are due to solid tumors.[1‑3] Even though there is plenty of information regarding the infectious agent, culture and sensitivity, choice of empiric antibiotics and outcome in hematological malignancies, data involving solid organ malignancies are sparse. This single center hospital based study evaluated the pattern of FN in solid organ malignancies, infectious agent, its sensitivity pattern and the outcome of treatment.
540
Kuntegowdanahalli C. Lakshmaiah, S. M. Abhayakumar, Rachan Shetty, D. Loknath, R. S. Jayashree, K. Govindbabu Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India For correspondence: Dr. S. M. Abhayakumar, PG Hostel Room No 108, Kidwai Memorial Institute of Oncology, Dr. Marigowda Road, Bangalore - 560 029, Karnataka, India. E-mail: dr.abhaymalabagi@ gmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.137908 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Lakshmaiah, et al.: Febrile neutropenia in solid organ malignancies
guidelines. High‑risk FN includes patients with profound or prolonged neutropenia, patients with hemodynamic instability, neurologic or mental status change of new onset, pneumonia, or hypoxemia. Patients with none of these signs or symptoms were classified as low risk.[5] Patients with only high‑risk FN were analyzed in this study. High‑risk patients were immediately admitted and started on empirical antibiotics with cefoperazone/sulbactum (100 mg/kg twice a day). Once the culture report was available antibiotics were modified accordingly. Vancomycin (30 mg/kg in two divided doses) was added to the current antibiotic in FN patients with any of the following conditions: (i) Hypotension (ii) skin infection (iii) pneumonia (iv) central venous catheter infection (v) tenderness or erythema around central line insertion site vi) gram positive isolate in the culture. Empirical antifungal drug amphotericin B (1‑1.5 mg/kg) was started to the patients with fever which was persisting on day 4 or 5, suspected fungal infection of the paranasal sinuses or lung, fungal organism identified on microscopy or in culture. In culture negative and stable patients same antibiotics were continued for 5-7 days or till ANC becomes ≥500/µl. Once ANC reaches ≥500/µl, parenteral antibiotics were stopped and started on oral antibiotics (amoxycillin/clavulanate, ciprofloxacin or levofloxacin). All culture positive patients were further analyzed for causative organism (gram positive or gram negative), site of culture positivity and their sensitivity to antibiotics. Correlation of febrile neutropenia outcome with variables like co‑morbidities, performance status, culture positivity and type of organism were analyzed. These outcomes were evaluated for all patients using the Kaplan Meier curve Statistical Package for the Social Sciences software (SPSS) 19 ‑ SPSS Inc, USA Inc, USA. RESULTS The clinical profile of patients was recorded as shown in the Table 1. Majority of the patients were male. The median age was 44 years (range 15-72 years), with 35% of the patients aged more than 55 years. The common solid tumors with FN in descending order were head and neck cancers (treated with platinum and taxane induction chemotherapy), followed by breast cancer (FEC‑D protocol), stomach (ECF/DCF), osteosarcoma (IAP) and esophagus (concurrent cispatin and radiotherapy). Most patients were receiving first‑line chemotherapy (11% were receiving second‑line therapy) for their malignancy. Majority were locally advanced (43%) cancer. In this study, 52% of FN episodes were observed in patients who received prophylactic growth factors. These patients presented clinically, with fever without localizing signs or symptoms in 40% cases, gastrointestinal symptoms like diarrhea (29.5%), respiratory symptoms like cough, dyspnea (20%), sinus and ear infection (5%), skin and soft tissue infections (4.5%), urinary tract symptoms (2%).
Overall culture positivity was observed in 25% (blood culture‑12%, sputum‑9.70%, urine‑2% and pus‑1.30%) patients. Gram positive and gram negative microbes were constituted to 36.30% and 61.70% FN episodes, respectively, and fungal isolation was identified in remaining 2% FN episodes. The most common organism isolated in blood was E. coli and Staphylococcus aureus. The most common microbe isolated in sputum and urine was K. pneumonia and E. coli respectively as shown in Table 2. The most common fungal infection noted was candidiasis which was detected on throat smear. Sputum smear was positive for Aspergillus in two episodes. In blood culture positive patients, gram positive and gram negative microbe isolates were accounted for 36.7% and 63.3% respectively. Staphylococcus aureus and E. coli (36% each) being the most common organism isolated in blood. Methicillin‑resistant Staphylococcus aureus (MRSA) constituted 1/4 th of Staphylococcus aureus isolates identified. In sputum culture of the positive patients, gram positive and gram negative microbes constituted to 33.4% and 66.6%, respectively. Aspergillus and Candida were identified in sputum in 11% of FN episodes. The most common isolates in sputum were Table 1: Clinical profile of 72 patients with 92 febrile neutropenic events Total number of episodes Male:female ratio Median age (range) Malignancies Head and neck Breast Stomach Esophagus Osteosarcoma Ewings sarcoma Soft tissue sarcomas Germ cell tumor Death
92 39:33 44 years (15-72) No of patients 22 18 9 7 7 4 3 2 11
Table 2: Microbiological profile Site Blood culture (11 isolates)
Gram positive (%) Overall – 4 (36.7) Individual organisms Staphylococcus aureus ‑ 3 MRSA‑1
Sputum culture (9 isolates)
Overall – 3 (33.4) Individual organisms Staphylococcus aureus ‑ 2 Streptococcus pneumoniae‑ 1 No
Urine culture (2 isolates) Pus culture (1 isolate)
Overall – 1 Staphylococcus aureus – 1
Gram negative (%) Overall‑ 7 (63.3) Individual organisms E. coli ‑ 4 K. pneumoniae ‑1 P. aeruginosa ‑ 1 Acinatobacter baumanii ‑ 1 Overall – 6 (66.6) Individual organisms K. pneumoniae ‑ 3 P. aeruginosa ‑ 2 H. influenza ‑ 1 Overall – 2 Individual organisms E. coli ‑ 2
MRSA=Methicillin‑resistant Staphylococcus aureus
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
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Lakshmaiah, et al.: Febrile neutropenia in solid organ malignancies
Klebsiella pneumonia (33%), Staphylococcus aureus (22%), and Pseudomonas aeruginosa (22%). Staphylococcus aureus was sensitive to ciprofloxacin in 83.33% of episodes and was 100% sensitive to linezolid, teicoplanin, and vancomycin. The culture sensitivity patterns of gram negative infection were indicated as given in Table 3. All microbes were fully sensitive to carbapenems. Patients treated with cefoperazone‑sulbactum as first‑line antibiotic with improvement of clinical condition in 70.6%. In the remaining patients, antibiotic changed to second‑line antibiotic piperacillin‑tazobactum and amikacin, to which 24% of episodes responded. In patients not responding to both antibiotics, third‑line antibiotics (imipenem/cilastin or meropenem) was added, to which 5.4% responded. Median time to defervescence was 2.5 days with first‑line antibiotics. When fever persisted with organ dysfunction, 15.2% of episodes required addition of vancomycin and 14.1% required addition of antifungal with second‑ or third‑line antibiotics, respectively. Twelve percent of the patients died during the treatment of these FN episodes. Factors associated with significant mortality was poor performance status at presentation, multiple co‑morbidities and prolonged neutropenia as shown in Table 4. Table 3: Sensitivity pattern of gram negative organisms AK Ca Ce Cfs Cf G Mr Im Pip E. coli 88.88 40 33.33 85 16.6 77.77 100 100 88.23 K. pneu 100 66.66 50 83.33 50 100 100 100 100 Ps. aeu 100 100 88.23 100 100 100 100 100 100 AK=Amikacin, Ca=Ceftazidime, Ce=Cefotaxim, Cfs=Cefoperazone/sulbactum, Cf=Ciprofloxacin, G=Gentamycin, Mr=Meropenem, Im=Imipenem, Le=Levofloxacin, Lz=Linezolid, Va=Vancomycin, K. pneu=Klebsiella pneumoniae, Ps. aeu=Pseudomonas aeruginosa
Table 4: Correlation with various factors and outcome Variable Performance status at presentation 0,1,2 3,4 Age (years) 50 Culture Positive Negative Growth factors use Yes No >2 Co‑morbidities Yes No Prolonged neutropenia Yes No Profound neutropenia Yes No 542
Patient alive (%)
Dead
Outcome
68 13
6 5
P=0.0358
52 29
8 3
P=0.7416
19 62
4 7
P=0.4578
37 44
6 5
P=0.7496
15 66
7 4
P=0.0033
24 57
9 2
P=0.0013
45 36
8 3
P=0.3440
DISCUSSION Antibiotics have revolutionized cancer care in the past century. This study highlights the common infectious agent and its sensitivity pattern in solid malignancy giving insight into its appropriate management. World data suggests the incidence of documented microbiological infection around 26-30%, and we had a similar data. However, the etiology varies, in western data gram positive is the most common agent followed by gram negative. We noted a higher gram negative infection probably due to less frequent use of central venous catheter. None of our patient had central venous catheter. The three most common sites of infection include respiratory tract (38%), blood stream (35%), and urinary tract (11%).[6,7] In our study three most frequent site of infection were gastrointestinal tract, respiratory tract, and blood stream infections. In gram positive infections the common agents in descending order are coagulase‑negative Staphylococcus aureus, and enterococcus species,[8] whereas Staphylococcus aureus was the most common gram positive organism in our study. In gram negative infections the most common agent being Enterobacteriaceae (frequently Escherichia coli and Klebsiella pneumonia) group followed by Pseudomonas aeruginosa.[9] In our study, Escherichia coli and Klebsiella pneumonia were most common gram negative bacterial infections in blood and urine, respectively. Regarding culture sensitivity pattern, in gram‑negative organisms, the highest sensitivity was seen for imipenem and meropenem, followed by amikacin, piperacillin‑tazobactum, gentamycin, cefoperazone‑sulbactum, and ceftazidime. These were least sensitive to ciprofloxacin and cefotaxim. Staphylococcus aureus was highly sensitive to linezolid, teicoplanin, and vancomycin but less sensitive to ciprofloxacin. Even though other studies from India noted a similar pattern of sensitivity for gram positive organisms, our study noted a lower sensitivity pattern of gram negatives to cefoperazone‑sulbactum, probably due to frequent use of this drug as first‑line agent without break.[10] The median time to recovery and mortality was similar to other studies from Indian and World series.[10,11] The use of growth factors may not reduce the mortality rate as seen in our study (P = 0.74). This has been proven in many randomized studies as well and its use reduces the duration of neutropenia, antibiotic use and hospitalization.[12] CONCLUSION In our study, treatment with cephoperazone‑sulbactum as a first‑line antibiotic led to satisfactory outcome with clinical improvement of >70% in FN episodes. Cephaperazone‑sulbactum is a reasonable initial antibiotic choice for empirical therapy in high risk FN solid organ malignancies.
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Lakshmaiah, et al.: Febrile neutropenia in solid organ malignancies
REFERENCES 1. Krell D, Jones AL. Impact of effective prevention and management of febrile neutropenia. Br J Cancer 2009;101 Suppl 1:S23‑6. 2. Zuckermann J, Moreira LB, Stoll P, Moreira LM, Kuchenbecker RS, Polanczyk CA. Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes. Ann Hematol 2008;87:139‑45. 3. Cullen M, Steven N, Billingham L, Gaunt C, Hastings M, Simmonds P, et al. Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/‑ Antibiotic in a Number of Tumours (SIGNIFICANT) Trial Group. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988‑98. 4. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730‑51. 5. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Infectious Diseases Society of America. 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. 6. Yadegarynia D, Tarrand J, Raad I, Rolston K. Current spectrum of bacterial infections in cancer patients. Clin Infect Dis 2003;37:1144‑5. 7. Rolston KV, Bodey GP. Infections in patients with cancer. In: Holland JF,
Frei E, editors. Cancer Medicine. 6 th ed. Montreal: BC Decker Publishers; 2003. p. 2633 ‑58. 8. Safdar A, Rodriguez GH, Balakrishnan M, Tarrand JJ, Rolston KV. Changing trends in etiology of bacteremia in patients with cancer. Eur J Clin Microbiol Infect Dis 2006;25:522‑6. 9. Rolston KV, Tarrand JJ. Pseudomonas aeruginosa‑‑still a frequent pathogen in patients with cancer: 11‑year experience at a comprehensive cancer center. Clin Infect Dis 1999;29:463‑4. 10. Ghosh I, Raina V, Kumar L, Sharma A, Bakhshi S, Thulkar S, et al. Profile of infections and outcome in high‑risk febrile neutropenia: Experience from a tertiary care cancer center in India. Med Oncol 2012;29:1354‑60. 11. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106:2258‑66. 12. García‑Carbonero R, Mayordomo JI, Tornamira MV, López‑Brea M, Rueda A, Guillem V, et al. Granulocyte colony‑stimulating factor in the treatment of high‑risk febrile neutropenia: A multicenter randomized trial. J Natl Cancer Inst 2001;93:31‑8. Cite this article as: Lakshmaiah KC, Abhayakumar SM, Shetty R, Loknath D, Jayashree RS, Govindbabu K. Management of febrile neutropenia in solid organ malignancies following chemotherapy. J Can Res Ther 2014;10:540-3. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
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Management of febrile neutropenia in solid organ malignancies following chemotherapy ABSTRACT Background: Febrile neutropenia is a medical emergency and it requires immediate hospitalization for evaluation and administration of empiric broad‑spectrum antibiotics. The present study was undertaken to analyze the infectious agents, choice of empiric antibiotics, and outcome in high‑risk febrile neutropenia in the solid organ malignancies. Materials and Methods: In this study, 92 high risk febrile neutropenic episodes were analyzed in 72 patients with solid organ malignancies. We used cefoperazone‑sulbactum as an initial empiric antibiotic. Piperacillin/tazobactum or carbapenems were added to the patients who did not respond to initial antibiotic. Results: Among the 92 episodes treated, most patients received first‑line chemotherapy for locally advanced disease. Microbes were isolated in 25% of febrile neutropenic episodes. Gram‑negative organism (61.70%) constituted the most common isolates. The most common microbes identified were E. coli and Staphylococcus aureus in blood, Klebsiella pneumonia in sputum and E. coli in urine culture. Patients who had been treated with cefoperazone‑sulbactum improved clinically in 70.6% of febrile neutropenic episodes. Second‑ line antibiotics (piperacillin‑tazobactum with amikacin) were required in 24% episodes, while another 5.4% episodes required third‑line antibiotics (carbapenems). In this study, mortality was seen in 12% of febrile neutropenic episodes. Staphylococcus aureus was 100% sensitive to linezolid, teicoplanin, and vancomycin, whereas Gram‑negative organisms were 100% sensitive to imepenem and meropenem. Conclusion: Cephaperazone‑sulbactum is a reasonable initial choice for empirical therapy in high risk febrile neutropenic patients in solid organ malignancies. KEY WORDS: Cefoperazone‑sulbactum, E. coli, febrile neutropenias, solid organ malignancies, solid malignancies
INTRODUCTION
MATERIALS AND METHODS
regional cancer centre, south India were analyzed. Informed consent was taken from all the patients. All patients were aged more than 15 years. FN was diagnosed when a single oral temperature of greater than 38.3°C (101°F) or 38.0°C (100.4°F) for more than 1 hour was present along with absolute neutrophil count (ANC) less than 500/µl or less than 1,000/µl with predicted rapid decline during the next 48 hour.[4] All FN patients have been examined clinically and evaluated with appropriate laboratory investigations including, complete hemogram, liver function tests, renal function tests, serum electrolytes, chest X‑ray, blood culture from peripheral vein, urine culture, sputum and pus culture (if indicated). Blood cultures were repeated every 48 hours in case of persisting fever. Computed tomography (CT) scan of the paranasal sinuses or thorax was done in clinically suspected fungal infection of respective sites. All the patients’ co‑morbidities were documented such as diabetes mellitus, chronic obstructive pulmonary disease, renal dysfunction, and cardiac diseases.
In this study 72 patients with solid tumors diagnosed and treated for 92 high risk FN episodes from August 2011 to January 2013 in a
Once diagnosed with FN these patients were grouped under high‑risk category based on the Infectious Diseases Society of America (IDSA)
Febrile neutropenia (FN) is considered as a medical emergency. It causes significant economic loss, morbidity and mortality to the patients. Early detection, prompt initiation of empiric antibiotics leads to effective management of this condition. Hematological malignancies constitutes around 70-80% FN cases, whereas 5-30% of episodes are due to solid tumors.[1‑3] Even though there is plenty of information regarding the infectious agent, culture and sensitivity, choice of empiric antibiotics and outcome in hematological malignancies, data involving solid organ malignancies are sparse. This single center hospital based study evaluated the pattern of FN in solid organ malignancies, infectious agent, its sensitivity pattern and the outcome of treatment.
540
Kuntegowdanahalli C. Lakshmaiah, S. M. Abhayakumar, Rachan Shetty, D. Loknath, R. S. Jayashree, K. Govindbabu Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India For correspondence: Dr. S. M. Abhayakumar, PG Hostel Room No 108, Kidwai Memorial Institute of Oncology, Dr. Marigowda Road, Bangalore - 560 029, Karnataka, India. E-mail: dr.abhaymalabagi@ gmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.137908 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Lakshmaiah, et al.: Febrile neutropenia in solid organ malignancies
guidelines. High‑risk FN includes patients with profound or prolonged neutropenia, patients with hemodynamic instability, neurologic or mental status change of new onset, pneumonia, or hypoxemia. Patients with none of these signs or symptoms were classified as low risk.[5] Patients with only high‑risk FN were analyzed in this study. High‑risk patients were immediately admitted and started on empirical antibiotics with cefoperazone/sulbactum (100 mg/kg twice a day). Once the culture report was available antibiotics were modified accordingly. Vancomycin (30 mg/kg in two divided doses) was added to the current antibiotic in FN patients with any of the following conditions: (i) Hypotension (ii) skin infection (iii) pneumonia (iv) central venous catheter infection (v) tenderness or erythema around central line insertion site vi) gram positive isolate in the culture. Empirical antifungal drug amphotericin B (1‑1.5 mg/kg) was started to the patients with fever which was persisting on day 4 or 5, suspected fungal infection of the paranasal sinuses or lung, fungal organism identified on microscopy or in culture. In culture negative and stable patients same antibiotics were continued for 5-7 days or till ANC becomes ≥500/µl. Once ANC reaches ≥500/µl, parenteral antibiotics were stopped and started on oral antibiotics (amoxycillin/clavulanate, ciprofloxacin or levofloxacin). All culture positive patients were further analyzed for causative organism (gram positive or gram negative), site of culture positivity and their sensitivity to antibiotics. Correlation of febrile neutropenia outcome with variables like co‑morbidities, performance status, culture positivity and type of organism were analyzed. These outcomes were evaluated for all patients using the Kaplan Meier curve Statistical Package for the Social Sciences software (SPSS) 19 ‑ SPSS Inc, USA Inc, USA. RESULTS The clinical profile of patients was recorded as shown in the Table 1. Majority of the patients were male. The median age was 44 years (range 15-72 years), with 35% of the patients aged more than 55 years. The common solid tumors with FN in descending order were head and neck cancers (treated with platinum and taxane induction chemotherapy), followed by breast cancer (FEC‑D protocol), stomach (ECF/DCF), osteosarcoma (IAP) and esophagus (concurrent cispatin and radiotherapy). Most patients were receiving first‑line chemotherapy (11% were receiving second‑line therapy) for their malignancy. Majority were locally advanced (43%) cancer. In this study, 52% of FN episodes were observed in patients who received prophylactic growth factors. These patients presented clinically, with fever without localizing signs or symptoms in 40% cases, gastrointestinal symptoms like diarrhea (29.5%), respiratory symptoms like cough, dyspnea (20%), sinus and ear infection (5%), skin and soft tissue infections (4.5%), urinary tract symptoms (2%).
Overall culture positivity was observed in 25% (blood culture‑12%, sputum‑9.70%, urine‑2% and pus‑1.30%) patients. Gram positive and gram negative microbes were constituted to 36.30% and 61.70% FN episodes, respectively, and fungal isolation was identified in remaining 2% FN episodes. The most common organism isolated in blood was E. coli and Staphylococcus aureus. The most common microbe isolated in sputum and urine was K. pneumonia and E. coli respectively as shown in Table 2. The most common fungal infection noted was candidiasis which was detected on throat smear. Sputum smear was positive for Aspergillus in two episodes. In blood culture positive patients, gram positive and gram negative microbe isolates were accounted for 36.7% and 63.3% respectively. Staphylococcus aureus and E. coli (36% each) being the most common organism isolated in blood. Methicillin‑resistant Staphylococcus aureus (MRSA) constituted 1/4 th of Staphylococcus aureus isolates identified. In sputum culture of the positive patients, gram positive and gram negative microbes constituted to 33.4% and 66.6%, respectively. Aspergillus and Candida were identified in sputum in 11% of FN episodes. The most common isolates in sputum were Table 1: Clinical profile of 72 patients with 92 febrile neutropenic events Total number of episodes Male:female ratio Median age (range) Malignancies Head and neck Breast Stomach Esophagus Osteosarcoma Ewings sarcoma Soft tissue sarcomas Germ cell tumor Death
92 39:33 44 years (15-72) No of patients 22 18 9 7 7 4 3 2 11
Table 2: Microbiological profile Site Blood culture (11 isolates)
Gram positive (%) Overall – 4 (36.7) Individual organisms Staphylococcus aureus ‑ 3 MRSA‑1
Sputum culture (9 isolates)
Overall – 3 (33.4) Individual organisms Staphylococcus aureus ‑ 2 Streptococcus pneumoniae‑ 1 No
Urine culture (2 isolates) Pus culture (1 isolate)
Overall – 1 Staphylococcus aureus – 1
Gram negative (%) Overall‑ 7 (63.3) Individual organisms E. coli ‑ 4 K. pneumoniae ‑1 P. aeruginosa ‑ 1 Acinatobacter baumanii ‑ 1 Overall – 6 (66.6) Individual organisms K. pneumoniae ‑ 3 P. aeruginosa ‑ 2 H. influenza ‑ 1 Overall – 2 Individual organisms E. coli ‑ 2
MRSA=Methicillin‑resistant Staphylococcus aureus
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
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Lakshmaiah, et al.: Febrile neutropenia in solid organ malignancies
Klebsiella pneumonia (33%), Staphylococcus aureus (22%), and Pseudomonas aeruginosa (22%). Staphylococcus aureus was sensitive to ciprofloxacin in 83.33% of episodes and was 100% sensitive to linezolid, teicoplanin, and vancomycin. The culture sensitivity patterns of gram negative infection were indicated as given in Table 3. All microbes were fully sensitive to carbapenems. Patients treated with cefoperazone‑sulbactum as first‑line antibiotic with improvement of clinical condition in 70.6%. In the remaining patients, antibiotic changed to second‑line antibiotic piperacillin‑tazobactum and amikacin, to which 24% of episodes responded. In patients not responding to both antibiotics, third‑line antibiotics (imipenem/cilastin or meropenem) was added, to which 5.4% responded. Median time to defervescence was 2.5 days with first‑line antibiotics. When fever persisted with organ dysfunction, 15.2% of episodes required addition of vancomycin and 14.1% required addition of antifungal with second‑ or third‑line antibiotics, respectively. Twelve percent of the patients died during the treatment of these FN episodes. Factors associated with significant mortality was poor performance status at presentation, multiple co‑morbidities and prolonged neutropenia as shown in Table 4. Table 3: Sensitivity pattern of gram negative organisms AK Ca Ce Cfs Cf G Mr Im Pip E. coli 88.88 40 33.33 85 16.6 77.77 100 100 88.23 K. pneu 100 66.66 50 83.33 50 100 100 100 100 Ps. aeu 100 100 88.23 100 100 100 100 100 100 AK=Amikacin, Ca=Ceftazidime, Ce=Cefotaxim, Cfs=Cefoperazone/sulbactum, Cf=Ciprofloxacin, G=Gentamycin, Mr=Meropenem, Im=Imipenem, Le=Levofloxacin, Lz=Linezolid, Va=Vancomycin, K. pneu=Klebsiella pneumoniae, Ps. aeu=Pseudomonas aeruginosa
Table 4: Correlation with various factors and outcome Variable Performance status at presentation 0,1,2 3,4 Age (years) 50 Culture Positive Negative Growth factors use Yes No >2 Co‑morbidities Yes No Prolonged neutropenia Yes No Profound neutropenia Yes No 542
Patient alive (%)
Dead
Outcome
68 13
6 5
P=0.0358
52 29
8 3
P=0.7416
19 62
4 7
P=0.4578
37 44
6 5
P=0.7496
15 66
7 4
P=0.0033
24 57
9 2
P=0.0013
45 36
8 3
P=0.3440
DISCUSSION Antibiotics have revolutionized cancer care in the past century. This study highlights the common infectious agent and its sensitivity pattern in solid malignancy giving insight into its appropriate management. World data suggests the incidence of documented microbiological infection around 26-30%, and we had a similar data. However, the etiology varies, in western data gram positive is the most common agent followed by gram negative. We noted a higher gram negative infection probably due to less frequent use of central venous catheter. None of our patient had central venous catheter. The three most common sites of infection include respiratory tract (38%), blood stream (35%), and urinary tract (11%).[6,7] In our study three most frequent site of infection were gastrointestinal tract, respiratory tract, and blood stream infections. In gram positive infections the common agents in descending order are coagulase‑negative Staphylococcus aureus, and enterococcus species,[8] whereas Staphylococcus aureus was the most common gram positive organism in our study. In gram negative infections the most common agent being Enterobacteriaceae (frequently Escherichia coli and Klebsiella pneumonia) group followed by Pseudomonas aeruginosa.[9] In our study, Escherichia coli and Klebsiella pneumonia were most common gram negative bacterial infections in blood and urine, respectively. Regarding culture sensitivity pattern, in gram‑negative organisms, the highest sensitivity was seen for imipenem and meropenem, followed by amikacin, piperacillin‑tazobactum, gentamycin, cefoperazone‑sulbactum, and ceftazidime. These were least sensitive to ciprofloxacin and cefotaxim. Staphylococcus aureus was highly sensitive to linezolid, teicoplanin, and vancomycin but less sensitive to ciprofloxacin. Even though other studies from India noted a similar pattern of sensitivity for gram positive organisms, our study noted a lower sensitivity pattern of gram negatives to cefoperazone‑sulbactum, probably due to frequent use of this drug as first‑line agent without break.[10] The median time to recovery and mortality was similar to other studies from Indian and World series.[10,11] The use of growth factors may not reduce the mortality rate as seen in our study (P = 0.74). This has been proven in many randomized studies as well and its use reduces the duration of neutropenia, antibiotic use and hospitalization.[12] CONCLUSION In our study, treatment with cephoperazone‑sulbactum as a first‑line antibiotic led to satisfactory outcome with clinical improvement of >70% in FN episodes. Cephaperazone‑sulbactum is a reasonable initial antibiotic choice for empirical therapy in high risk FN solid organ malignancies.
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
Lakshmaiah, et al.: Febrile neutropenia in solid organ malignancies
REFERENCES 1. Krell D, Jones AL. Impact of effective prevention and management of febrile neutropenia. Br J Cancer 2009;101 Suppl 1:S23‑6. 2. Zuckermann J, Moreira LB, Stoll P, Moreira LM, Kuchenbecker RS, Polanczyk CA. Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes. Ann Hematol 2008;87:139‑45. 3. Cullen M, Steven N, Billingham L, Gaunt C, Hastings M, Simmonds P, et al. Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/‑ Antibiotic in a Number of Tumours (SIGNIFICANT) Trial Group. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988‑98. 4. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730‑51. 5. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Infectious Diseases Society of America. 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. 6. Yadegarynia D, Tarrand J, Raad I, Rolston K. Current spectrum of bacterial infections in cancer patients. Clin Infect Dis 2003;37:1144‑5. 7. Rolston KV, Bodey GP. Infections in patients with cancer. In: Holland JF,
Frei E, editors. Cancer Medicine. 6 th ed. Montreal: BC Decker Publishers; 2003. p. 2633 ‑58. 8. Safdar A, Rodriguez GH, Balakrishnan M, Tarrand JJ, Rolston KV. Changing trends in etiology of bacteremia in patients with cancer. Eur J Clin Microbiol Infect Dis 2006;25:522‑6. 9. Rolston KV, Tarrand JJ. Pseudomonas aeruginosa‑‑still a frequent pathogen in patients with cancer: 11‑year experience at a comprehensive cancer center. Clin Infect Dis 1999;29:463‑4. 10. Ghosh I, Raina V, Kumar L, Sharma A, Bakhshi S, Thulkar S, et al. Profile of infections and outcome in high‑risk febrile neutropenia: Experience from a tertiary care cancer center in India. Med Oncol 2012;29:1354‑60. 11. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106:2258‑66. 12. García‑Carbonero R, Mayordomo JI, Tornamira MV, López‑Brea M, Rueda A, Guillem V, et al. Granulocyte colony‑stimulating factor in the treatment of high‑risk febrile neutropenia: A multicenter randomized trial. J Natl Cancer Inst 2001;93:31‑8. Cite this article as: Lakshmaiah KC, Abhayakumar SM, Shetty R, Loknath D, Jayashree RS, Govindbabu K. Management of febrile neutropenia in solid organ malignancies following chemotherapy. J Can Res Ther 2014;10:540-3. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
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