INTRODUCTION
Hematolymphoid malignancies comprise approximately 20-30% of all malignancies.[ 1 ] Sepsis due to bloodstream infections is a frequently encountered complication in patients with hematolymphoid malignancies and neutropenic fever.[ 2 ] The rate of bloodstream infections ranges from 11-38% in patients with cancer and febrile neutropenia, and this is particularly high in patients who have undergone bone marrow transplants, which is reported as 360 bloodstream infections per 1000 neutropenic episodes.[ 3–6 ] According to Indian studies, bloodstream infections have been reported in 6-23% of all patients with cancer and febrile neutropenia.[ 7 , 8 ] Blood culture positivity has been noted in approximately 65% of patients with acute myeloid leukemia.[ 9 ] The incidence of blood culture-positive infections varies according to the phase of treatment (approximately 48%), which is higher than that reported in Western data (29.6%).[ 9 , 10 ]
During the years 1960-70, Gram-negative bacteria were most frequently isolated (approximately 63%) from patients with cancer and neutropenia who had bloodstream infections. Among them, Escherichia coli (E. coli) was the most common organism (approximately 47%), followed by Pseudomonas aeruginosa (31%) and Klebsiella (K.) pneumoniae (14.5%). However, over the past 20-30 years, the spectrum of bloodstream infections has changed and Gram-positive organisms such as coagulase-negative Staphylococci , Streptococcus species, and Staphylococcus aureus have now increased by approximately 70-81%.[ 11 ] Enterococcus faecium is an exception; it is isolated more frequently from non-neutropenic patients, while most of the studies carried out in developing countries have reported a predominance of Gram-negative bacilli in patients with cancer and febrile neutropenia.[ 12 , 13 ]
The choice of effective empirical therapy depends on the prevalent antibiogram pattern of multidrug-resistant (MDR) bacterial strains in patients. The genes responsible for MDR in Gram-negative bacteria are extended-spectrum beta-lactamase (ESBL), carbapenemase-resistant genes (CRE), and AmpC, while in Gram-positive bacteria, the resistant genes are mecA and glycopeptide-resistant gene, which result in methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), respectively. Organisms carrying these resistance genes might not be sensitive to the standard empirical therapy and are being detected with increased frequency in neutropenic patients with cancer . Worldwide, various studies have reported that ESBL-producing strains account for 26-50% of all E. coli and K. pneumoniae isolates in neutropenic patients.[ 14 ] Recent data from developing countries including India, indicate a high incidence of MDR Gram-negative bacteria in the range of 35-64% among all the isolated strains in neutropenic patients with cancer .[ 14–16 ]
Several risk factors are responsible for the occurrence of bloodstream infections in neutropenic patients with cancer such as mucositis, the presence of central venous catheters, gut flora and its bacterial colonization, prolonged hospital stays, and the previous antibiotic regimen.[ 17 ] It is estimated that mucosal barrier injury constitutes approximately 40-50% of bloodstream infections in oncologic settings, while central venous catheter-associated bloodstream infections in neutropenic patients range from 24.3-16.2 per 1000 neutropenic days, though peripherally inserted central catheter (PICC)-related bloodstream infections are very low (0.05 per 1000 catheter days).[ 18 ] Fecal colonization with resistant strains is related to an increased probability of bloodstream infections caused by enteric bacteria; the relative risk ranges from 3.4-4.5 for ESBL-producing E. coli .[ 19 ] The overall mortality rate in adult patients with bloodstream infections with underlying malignancies varies from 18-42%.[ 20 ] In general, mortality rates in neutropenic patients with bloodstream infections have largely decreased from 25% to 6% in recent years; however, a rise in MDR Gram-negative bacteria may hamper this achievement. Gram-positive bloodstream infections usually result in a lower mortality rate than Gram-negative ones, yet the mortality rate is variable and ranges from 4-40%.[ 21 ]
In the era of MDR pathogens, the prevention of infections is particularly important. Applying various infection control measures is essential to prevent nosocomial transmission, and active surveillance for resistant pathogens should be performed. It is important for oncologists to understand the epidemiology of, and prevalence of MDR bloodstream infections in their institutes to establish rigorous infection control policies, correct empirical therapies, and implement the good practice of antibiotic stewardship. As ours is a newly established cancer center, we set out to study the prevalence of bloodstream infections in patients with hematological malignancies to characterize the microbiologic spectrum, and sensitivity patterns of the organisms.
MATERIAL AND METHODS
General study details
This observational study was conducted retrospectively over a period of 2 years, from April 2018 to July 2020 in the Departments of Microbiology and Medical Oncology, at the newly established Homi Bhabha Cancer Hospital/Mahamana Pandit Madan Mohan Malviya Cancer Center (commissioned January 2018, inaugurated February 19, 2019, by the Honorable Prime Minister), a 350-bed tertiary care cancer hospital in Varanasi (Uttar Pradesh, North India). This hospital comes under the units of the Tata Memorial Center, Mumbai (Grant-in-Aid Institution of the Department of Atomic Energy, Government of India). This cancer center caters to a population of nearly 40 crore people living in the states in and around Uttar Pradesh. Ethical approval was taken from the Institutional Ethical Committee (IEC) on November 28, 2020, with approval number IEC/2020/11000060/002 [Supplementary Appendix 1 ]. The IEC granted permission for a waiver of the requirement to obtain written informed consent from the participants, as it was a retrospective study. The study was not registered in a publicly accessible clinical trials database, as this was not mandated by our IEC, and it was a retrospective study. No funding was taken for the study. The study was conducted according to ethical guidelines established by the Declaration of Helsinki and other guidelines such as Good Clinical Practice Guidelines, and those established by the Indian Council of Medical Research.
Supplementary Appendix 1
Participants
We included all patients with febrile neutropenia who visited the Department of Medical Oncology, both in the outpatient and inpatient settings. All consecutive blood cultures from febrile neutropenic patients with hematolymphoid malignancies that had been sent to the microbiology laboratory between 2018 and 2020 were considered. Multiple blood cultures from a patient with febrile neutropenia were also included. Patients who had febrile neutropenia but did not have cultures taken, or for whom culture reports were unavailable were excluded from the study.
Aims/objectives
Our primary objective was to estimate the prevalence of MDR bloodstream infections in adult patients with hematolymphoid malignancies and febrile neutropenia.
Study methodology
Paired blood culture samples were collected from all participants under aseptic precautions in two automated blood culture bottles and sent to the microbiology laboratory within 2 hours of collection. The blood culture bottles were then processed in an automated system (Becton Dickinson, France). Blood culture bottles that flashed positive in the system were unloaded and cultured in the blood agar and MacConkey agar plates and incubated at 37°C for 24 hours. Gram staining was performed to morphologically characterize the bacteria as Gram-positive or Gram-negative, and further identification was carried out based on colony characteristics and biochemical reactions, as per standard microbiology techniques. The antibiotic susceptibility testing was performed using the Kirby-Bauer disk diffusion method and the broth microdilution method, whenever applicable. The results obtained were interpreted as per the Clinical and Laboratory Standards Institute (CLSI) guidelines (2020). The patients were identified from the hospital registry, and the data were entered into an Excel database. The clinical and demographic details were obtained from the hospital’s electronic medical record (EMR) system.
Definitions
Febrile neutropenia was defined as an oral temperature of 101°F or a temperature of >100.4°F sustained for 1 hour with an absolute neutrophil count (ANC) <500/mm3 or an ANC that was expected to decrease to <500/mm3 during the next 48 hours.[ 22 ] Hypotension was defined as systolic blood pressure <100 mmHg. Multidrug resistance was defined as per the international expert proposal for interim standard definitions for acquired resistance by the European Center for Disease Prevention and Control and Center for Disease Control and Prevention[ 23 ] and indicated bacterial organisms with resistance to at least one antimicrobial agent in three or more antimicrobial categories such as aminoglycosides, beta-lactams, fluoroquinolones, and beta-lactam–beta-lactamase inhibitors. Patients and their isolated pathogens were classified by the acquisition sites into a community-acquired infection or healthcare-associated infection. Healthcare-associated infection was defined as an infection in patients with at least one of the following four elements: (1) parenteral treatment within 30 days, (2) outpatient chemotherapy or hemodialysis within 30 days, (3) hospitalization for ≥2 days in the preceding 90 days, or (4) nursing home residence.[ 24 ] Bloodstream infection secondary to a documented source, or primary , that is, that is, without an identified origin. Secondary bacteremia was an infection that concurred with an infection at another primary location according to the location of the associated infectious process such as surgical site infection, urinary tract infection, lower respiratory tract infection, intra-abdominal infection, skin/soft tissue infection, and “other.”[ 25 , 26 ] Polymicrobial bloodstream infections were defined by positive blood cultures in a patient with two or more bacterial isolates along with systemic signs of infection.[ 25 ]
Statistics
This was a retrospective analysis with an observational study design; hence, we did not calculate a formal sample size. Statistical analyses were performed using the Statistical Package for the Social Sciences (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Baseline patient demographic details, microbiological data, treatment details, and outcomes were extracted from the EMR and represented by descriptive statistics and frequencies, percentages, mean, median, and interquartile range. A P < 0.05 was considered significant.
RESULTS
Baseline clinicodemographic data
A total of 1670 patients with hematolymphoid malignancies visited the Department (outpatient and inpatient) over the study period of 2 years. Blood cultures collected from 307 febrile neutropenic patients were sent to the microbiology laboratory for testing. The mean patient age was 41.8 ± 16.7 (range, 15- 82) years, with a male preponderance (n = 186, 61.0%). Baseline patients’ demographic details, clinical symptoms, and other epidemiological data are depicted in Table 1 .
Table 1: Baseline patient demographics, clinical characteristics, and epidemiological data of adult patients with hematolymphoid malignancies and febrile neutropenia
Microbiology
Blood culture positivity was noted in 74 (24.1%) patients. Active surveillance of stool and respiratory samples (sputum and bronchoalveolar lavage) revealed that the most common documented sources of secondary bloodstream infections were the gastrointestinal tract and lungs in 21 (28.4%) patients. The most frequently isolated organisms were E. coli in 28 (37.8%) patients, K. pneumoniae in 12 (16.2%), Pseudomonas aeruginosa in eight (10.8%), coagulase-negative Staphylococcus species in seven (9.5%), Staphylococcus aureus in five (6.8%), Streptococcus species in four (5.4%), Enterococcus species in three (4.1%), Citrobacter koseri in three (4.1%), Acinetobacter baumannii in two (2.7%), and Aeromonas species and Shewanella putrefaciens , in one (1.4%) each. The antimicrobial spectrum of resistance in Gram-negative bacilli and Gram-positive cocci is depicted in Figures 1 and 2 , respectively.
Figure 1: Antimicrobial resistance pattern of Gram-negative bacilli in patients with hematolymphoid malignancies and positive blood cultures (n=55, 74.3%)
Figure 2: Antimicrobial resistance pattern of Gram-positive cocci in patients with hematolymphoid malignancies and positive blood cultures (n = 19, 25.7%)
Prevalence of MDR bugs, in Gram-negative bacilli and Gram-positive cocci
Among all the Gram-negative bacilli, 21/55 (38.2%) were carbapenem-resistant, and among the Gram-positive cocci, 3/19 (15.8%) were MRSA (three of the five Staphylococcus aureus infections, 60%) and one (5.3%) was VRE (one of the three enterococcal infections, 33.3%). The prevalence of MDR bloodstream infections was 63.5% (n = 47); non-MDR bloodstream infections were noted in 27 (36.4%) febrile neutropenic patients with cancer .
Outcomes/mortality
Overall mortality occurred in 100 (32.6%) febrile neutropenic patients. Mortality seen in blood culture-positive patients was 23 (31.1%). The mortality rate was greater in patients with MDR bloodstream infections (20, 42.5%) than in those with non-MDR bloodstream infections (3, 11.1%, P = 0.004). Clinical details of the patients with bloodstream infections are provided in Table 2 . Cefoperazone-sulbactam (n = 60, 81.1%) was the most common empirical antibiotic used. A total of 18 (24.3%) patients required inotropic support in the intensive care unit. The flow of the study patients is depicted in Figure 3 .
Table 2: Clinical details of adult patients with hematolymphoid malignancies and febrile neutropenia with positive blood cultures
Figure 3: Flowchart representing study algorithm of the adult patients with hematolymphoid malignancies and febrile neutropenia
DISCUSSION
Febrile neutropenia is an oncological emergency in patients with hematolymphoid malignancies that predisposes them to bloodstream infections.[ 26 ] Febrile neutropenia remains a therapeutic challenge despite advances in cancer therapy, leading to a prolonged hospital stay, increased healthcare costs, and compromised efficacy of chemotherapy.[ 15 ] Blood culture is an important diagnostic modality in the management of febrile neutropenia and facilitates the identification of the causative organism with the antibiotic susceptibility pattern.[ 12 ] The failure of antibiotic treatment in patients with cancer increases the occurrence of sepsis and sepsis-related mortality. Prior studies have described the pattern of resistance to antimicrobial therapies in patients with cancer .[ 27–29 ] We noted that in our patients with hematolymphoid malignancies and febrile neutropenia, the prevalence of MDR bacteremia was 63.5% (47/74).[ 30 ] This finding was similar to that reported by another prospective observational survey of patients from Turkey, in which 90 of 420 (21.4%) febrile neutropenia episodes, were associated with bloodstream infections.[ 31 ]
The data on bloodstream infections from studies performed in India on the most common organism isolates and their antibiotic sensitivities are quite variable. The prevalence of bloodstream infections in hematolymphoid malignancies ranges from 6-23%.[ 13 ] Among the Gram-negative bacteria, E. coli followed by K. pneumoniae are commonly isolated and together they account for 18-43% of all bloodstream infections. Staphylococcus aureus has consistently been the most common Gram-positive bacterial isolate.[ 12 , 13 ] The findings from our study were in concordance with those from other Indian studies, as we had found that E. coli (n = 28, 37.8%), K. pneumoniae (n = 12, 16.2%), Pseudomonas aeruginosa (n = 8, 10.8%), coagulase-negative Staphylococcus species (n = 7, 36.8%), and Staphylococcus aureus (n = 5, 26.3%) were the most frequent bacterial isolates. Our findings were in contrast to those from Western studies, which have reported a predominance of Gram-positive isolates in bloodstream infections in patients with cancer .[ 32 , 33 ] Various studies conducted in the United Kingdom, Northern Europe, and the United States reported that 62% of bloodstream infections in patients with hematolymphoid malignancies were caused by Gram-positive cocci.[ 34 ]
The universal increase in resistant bacteria in patients with cancer has important consequences for the choice of an effective empirical therapy or prophylaxis. We found a high proportion of carbapenem-resistant Gram-negative bacterial isolates (n = 21, 38.2%) when compared to the data from other countries like Turkey, which reported that carbapenem-resistant Gram-negative bacteria were isolated in only 9% of all the bacteremia episodes.[ 35 ] The emergence of carbapenem resistance is alarming as it has been associated with a prolonged hospital stay, increased mortality, and limited treatment options. Antimicrobial resistance among Gram-positive bacteria, which comprises a resistance to methicillin in Staphylococci and to vancomycin in Enterococci , has been reported for almost two decades and is considered less problematic than MDR Gram-negative bacteria since novel antibiotic options (levonadifloxacin, daptomycin, and ceftaroline) exist. The rate of methicillin-resistant coagulase-negative Staphylococci was very high in our patients with cancer in our study. The pooled MRSA prevalence rate was 2% (95% CI, 1-5) in a total of 1351 bloodstream infections’ isolates from eight studies.[ 30 ] Four of them were conducted in Europe, two in the Western Pacific, one in Southeast Asia, and one in the Eastern Mediterranean.[ 36–39 ]
Various studies have reported that the overall infection attributable mortality rate in febrile neutropenic patients with hematolymphoid malignancies ranged from 7-55%. In our study, the overall mortality rate in blood culture-positive patients was 31.1% (n = 23), similar to that reported in other studies; in Turkey, 34% of patients with bloodstream infections died.[ 40 ]
Optimal treatment for MRSA infections is an area of intense debate, vancomycin and teicoplanin are the most widely used drugs.[ 41 ] Treatment of MRSA infection with vancomycin is associated with side effects and a substantial failure rate. These failures have motivated the search for alternative anti-MRSA agents, and during the past decade, new drugs active against MRSA have been developed including teicoplanin, quinupristin-dalfopristin, linezolid, tigecycline, and daptomycin.[ 41 ]
The rising number of ESBL-producing organisms has resulted in the use of cefoperazone-sulbactam as a common empirical antibiotic. This was noted in our patients as well; 60 (81.1%) were started on empirical cefoperazone-sulbactam. In our study, carbapenem was empirically used in critically ill patients or in those with a past history of severe MDR sepsis, in six (8.1%) patients. Thus, carbapenems may be started directly in a combination with other antibiotics in some situations at the discretion of the treating physician and then the antibiotic regimen may be tailored according to the sensitivity pattern of the blood cultures. It is important for the infection control team to ensure that antibiotics are discontinued after complete clinical resolution of sepsis and documentation of negative cultures. In case of persistence, worsening, or breakthrough sepsis, antibiotics should be escalated to carbapenems or colistin, only after consultation with the treating physician and according to the blood culture sensitivity patterns. In our study, the combination of carbapenem with colistin was started in one patient. De-escalation of antibiotics may be based on clinical improvement. Regular microbiological stool surveillance should be strongly encouraged in oncology centers to adequately characterize the resistance pattern of gut flora. Colistin-resistant and carbapenem-resistant strains can be screened by rectal swab surveillance in patients with hematolymphoid malignancies at the time of hospitalization in a newly developed oncology setup.[ 41 ]
Our study had various limitations. First, this was a retrospective study, and we were unable to collect some clinical parameters such as the duration of hospital stay and the grading of febrile neutropenia. These limitations may have created biases in the analysis of the variables. Second, we were unable to investigate the class of antibiotic resistance based on the type of beta-lactamase production or ESBL due to the conventional nature of laboratory workup. Since this study was conducted during the early phase of commissioning of the laboratory, automated identification and sensitivity testing were not available. If available, it could have provided a preliminary idea of the resistance mechanisms.
CONCLUSION
There is a high rate of MDR Gram-negative bacilli bloodstream infections in adult patients with hematolymphoid malignancies and febrile neutropenia. There is a need for introspection regarding infection control and antibiotic usage policies in India. Special emphasis must be given to the training and education of not only the medical and paramedical staff, but also patients and caregivers in the basics of hygiene and hand washing. With limited antibiotic options left for the clinician to use, there is an urgent need to reform or probably better understand the use of antibiotics in our daily practice.
Author contributions
Conception or design of the work: VB, TM, AB, AK; data collection: VB, TM; data analysis and interpretation: VB, AK, SB, AB, SB, RS, AM; drafting the manuscript: VB, TM, AK, AB; critical revision of the article: all authors; final approval of the version to be published: all authors; accountable for all aspects of the work: all authors.
Data sharing statement
Individual de-identified participant data will be made available on reasonable request, from Dr. Vijeta Bajpai ([email protected] ), until 10 years after publication. In addition, the study protocol including the statistical plan is already available as a supplementary appendix attached to this manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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