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Outcome of Surveillance Stool Culture Guided Selection of Antibiotics during Febrile Neutropenia in Patient with Acute Leukaemia

Aklima Khanam1, Shafiqul Islam2, Mohammmad Nazmul Islam3, Fahmida Ahmed4, Fatema Ahmed5, Md Shafiur Rahman6, Mesbah Uddin Ahmed7* and Farzana Rahman8 1Department of Haematology, Dhaka Medical College Hospital, Bangladesh 2Department of Haematology, Bangabandhu Sheikh Mujib Medical University, Bangladesh 3Department of Medicine, Sylhet MAG Osmani Medical College Hospital, Bangladesh 4Department of Haematology, Imperial Hospital Limited, Bangladesh 5Department of Haematology, Bangladesh 6Assistant Director, Hospital and Clinic, DGHS, Bangladesh 7Department of Microbiology, Bangladesh University of Health Sciences, Bangladesh 8Department of Haematology, Bangabandhu Sheikh Mujib Medical University, Bangladesh

• Sampling method: Random sampling method was used.
Every patient was given a number. Every odd patient was selected as case and even patient was selected as control. Due to time limitation 30 cases and 30 controls were taken in this study.

Inclusion criteria
Acute leukaemia patient with febrile neutropenia Patient able to give informed written consent.

Exclusion criteria
Patient unable to give informed written consent. Acute leukaemia patient without febrile neutropenia.

Research equipments
• Preformed structured data collection sheet • Demography of the patient.
• Surveillance stool culture and sensitivity report.

Data analysis
The collected data were edited by the principle investigator on the same day of collection. Data obtained was recorded then entered into the computer using microsoft excel and analyzed with SPSS version 23.0 software package with help of a statistician.

Procedure of maintaining confidentiality
For safeguarding confidentiality and protecting anonymity each of the patients was given a special ID no which was followed during examination and each and every step of the procedure. A signed written informed consent was taken from the patient convincing that privacy of the patient was maintained.

Ethical consideration
Before starting this study, the research protocol was submitted and approved by the Institutional review board of BSMMU, Dhaka.
All participants were informed about the objectives, methodology and purpose of the study in an easy understandable way. All information regarding benefits and hazards was delivered to the all participants & those who agree to participate were included in the study. Verbal and written consents were taken from all participants without any influences prior to sample collection. If the participants have any question or any other problems, they were requested to contact. Data obtained from the study was used only for the research purpose and the confidentiality of all study information was maintained strictly. Participants can discontinue themselves from the study any time even after giving consent.

Quality assurance
The study was done in the Department of Haematology under the guidance of specialist haematologists and patients stool sample were sent to microbiology department of BSMMU for surveillance culture and sensitivity in BSMMU. Table 1 shows majority patients belonged to age ≤40 years in both groups, which was 23(76.7%) in cases and 22(73.3%) in controls. The mean rank of age was found 32.02 years in cases and 28.98 in controls. The difference was not statistically significant (p>0.05) between two groups Figure 1.    Table 2 shows majority patients had AML in both groups, which was 18(60.0%) in cases and 24(80.0%) in controls. Eleven (36.7%) patients had ALL in cases and 6(20.0%) in controls. Only 1(3.3%) patient had mixed leukaemia in case group but not found in control group. The difference was not statistically significant (p>0.05) between two groups.             The association was not statistically significant (p>0.05).    defervescence of fever >1 day. The mean defervescence of fever was found 2.0±1.9 days in cases and 3.3±2.1 days in controls. Early defervescence of fever (≤1 day) was significantly (p<0.05) higher in case group than control group.   The mean duration of antibiotic used was found 5.8±2.0 days in cases and 7.7±3.4 days in controls. Duration of antibiotic used was significantly (p<0.05) longer in control group than case group   in control group. The differences was not statistically significant (p>0.05) between two groups.

Discussion
Patient with haematological malignagcy are immune compromised and frequently developed neutropenic fever due to disease condition and or chemotherapeutics and they routinely get prophylactic antibiotic hence high risk for carrying multidrug resistance microorganism. This is a study carried out with an aim to observe the outcome of surveillance stool culture-based selection of antibiotics during febrile neutropenia. A total 60 acute leukaemia patients after admission in department of Hematology who developed febrile neutropenia with or without chemotherapy between April 2017 to March 2018 were enrolled in this study.
The present study findings were discussed and compare with the previously published relevant studies. In this study it was observed that 76.7% patients belonged to age ≤ 40 years in cases and 73.3% patients in controls. The mean rank of age was found 32.02 years in cases and 28.98 years in controls. The difference was not statistically significant (p>0.05) between two groups. Paul, et al. [1] observed in their study in median age was 26 years (range 3-57) years. In this study majority patients 56.7% were male in cases (surveillance based) and 50% in control group (Empirical) difference was not statistically significant (p>0.05) between two groups. Paul, et al. [1] showed that 71.57% were male and 28.42% were female. In this study it was observed that majority patients 60% were suffering from AML in cases (surveillance based) and 80% in control (Empirical) group. The difference was not statistically significant (p>0.05) between two groups. Paul, et al.
[1] found 39.44% patients were AML, 24.21% were ALL, 10% were CML, 9.47% Were Aplastic Anaemia, 6.31% were MDS, 10.52% were other who received allogenic bone marrow transplant. In this study, it was observed that majority patients received remission of induction therapy which was 17(56.7%) in cases and 22(73.3%) in controls. 4(13.3%) patients in case and 6(20.0%) in control group received consolidation therapy. 5(16.7%) and 2(6.7%) in cases and controls respectively received no chemotherapy. [4] observed E. coli and Pseudomonas aeruginosa were the most frequent organism resistant to antibiotic, isolated and together they accounted for 48% of all resistant organism. In our study 10(40%) patient has history of prophylactic antibiotic use among those who were MDRO colonizer the association was not statistically significant (p>0.05) in between two groups. In our study majority patient 16(64%) belongs to AML, 8(32%) ALL group who are multidrug resistant the association was not statistically significant (p>O.05) in between two groups. In the present study majority patient 15(60%) received remission of induction therapy, 3(12%) received consolidation therapt, 4(16%) received no chemo therapy and 3(12%) received re-induction chemotherapy among those who are MDRO colonizer. The association was not statistically significant (p>0.05) in between two groups. In our study it was observed that 20(66.7%) patient in case and 25(83.3%) patient in control group ANC were <0.5x103 /µL during onset of neutropenic fever. In the present study majority patient 19(63.3%) had defervescence of fever ≤ one day in case group & 21(70%) patient in control group had defervescence of fever more than one day. Early defervescence of fever ≤ one day was statistically significant (p≤ 0.05) higher in case group then control group. Paul, et al. [1] observe 67(56.8%) patients in case group (surveillance-based selection) and 18(37.5%) patients in control group had defervescence of fever ≤one day and the different was statistically significant (p≤0.05). In the current study, we found majority patients had to used antibiotic for ≤7 days, which was 28(93.3%) in cases and 19(63.3%) in controls. The mean duration of antibiotic used was found 5.8±2 days in case and 7.7±3.4 days in control group. Duration of antibiotic used was significantly longer (p=0.011) in control group then case group. Paul, et al. [1] found in his study the medium duration total antibiotic used 17.5 days in group 1 (empirical) and 18 days in group 2 (surveillance-based selection) and p value was not statistically regarding duration of antibiotic used. In the present study it was found 16 (53.3%) patients ANC were ≥0.5x103µ L in case group and 16 (53.3) patients ANC were <0.5x103µ L in control group. The different was not statistically regarding (p>0.05). In the current study it was observed that 24(80%) patients in case group, 29(96.7%) in control group developed neutropenic fever after chemotherapy. The different was not statistically (p>0.05).
In the present study it was observed that 22(61.1%) AML patient and 4(25%) ALL patients developed neutropenic fever on day 11 to day 15 after chemotherapy. The different was not statistically (p>0.05). In our study it was found that 22(73.3%) patients in case and 14(46.6%) patients in control group respond to initial antibiotic therapy after developing fever neutropenic fever on the different was statistically significant (p<0.035). Paul, et al. [1] found in his study defervescence of fever to first line antibiotic therapy occurred in 23 (48%) in group 1 (Empirical based) and in group 2 (Surveillance based selection) it occurred in 78 (66%) patients (p=0.05). In the present study it was observed that in case group 8(26.7%) patients required second line antibiotic, compared to 16(53.3%) patients in control group. The different was statistically significant (p<0.05) between two groups. Paul, et al. [1] observed in his study that 34.5% patients required second line antibiotic among those whom surveillance based antibiotic selection was given compared to 54% patients in whom empirical antibiotic was given during febrile neultropenia without surveillance stool culture. The different was statistically significant (p<0.0294). In our study it was observed that 28(93.3%) patients recovered from febrile neutropenia in both case and control group and the different was not statistically significant (p>0.05) between two groups. Paul, et al. [1] also found in his study there was no significant different in infection related mortality between two groups.

Conclusion
Prevalence of MDRO colonization in stool surveillance specially to CRE and other broad-spectrum antibiotic use to treat neutropenic fever is alarmingly high in patient with acute leukaemia which has grave implication that can affect the treatment outcome. Selection of antibiotic from individual stool antibiogram leads to earlier defervescence of fever in higher number of patients, reduce the need for second line antibiotic, reduce duration of use of antibiotic during neutropenic fever in patient with acute leukaemia.