Early prediction of Gram negative bacteremia in febrile cancer patients: Correlation between some inflammatory mediators, exposure to gamma radiation and severity of infection
Amira Abuzeid Abdelbaset;
Abstract
Bloodstream infection (BSI) continues to be a life threatening condition. The systemic host response to microbial infection involves clinical signs and symptoms of infection including fever. In addition, inflammatory biomarkers are released, including C-reactive protein (CRP), Interleukin-6 (IL-6), Interleukin-8 (IL-8) and Complement C3.
In this study we assessed the value of serum inflammatory mediators levels(IL-6 and IL-8) at fever onset in comparison with routinely used markers as WBCs, CRP and C3 to predict Gramnegative bacteremia in cancer and non-cancer patients.
Severity of infection was also studied comparing enzymatic activity and antimicrobial susceptibility of some selected isolated bacterial strains with measured serum inflammatory marker mainly IL-6. Also, the effect of gamma irradiation on IL-6 serum levels in rats with induced fever of bacterial and non-bacterial origin was investigated through the animal model on forty-eight adult Wister rats and comparisons between groups were performed.
In this study,One hundred twenty four feverish in-patients were enrolled in the study. Serum and plasma samples separated from blood specimens at onset of fever were used for assay of inflammatory biomarkers (IL-6 and IL-8) using ELISA technique, CRP using turbilatex and C3 ussig diffu-palte. Total leukocytic count was determined by coulter counter. Blood culture was carried out for isolation of Gram negative organisms which were identified by API 20E technique and subjected to antibiotic susceptibility test that was performed using disc diffusion method. Lipase and protease enzymes detection was performed via tween and gelatin agar media, respectively. Assay of serum IL-6 in rats was also done using ELISA technique. Cesium 137 (137 Cs) Gamma cell 40 located at National Center for Radiation Research and Technology (Cairo, Egypt) was the irradiation source used in the study.
It was found that out of the 124 blood samples collected there were 70 samples cancer feverish patients and 54 non-cancer feverish patients with relative percentages of 56% and 44%, respectively. About 49% of blood culture samples collected from cancer patients showed positive bacterial growth and 51% showed negative growth. While, blood samples showing positive growth innon-cancerpatients were 54% against 46% negative growth.
In this study for cancer feverish patients the prevalence of E. coli was 41% followed by K. pneumoniae 23% then Pseudomonas sp 27%, while for non-cancer feverish patients K. pneumoniae prevalence was 41% followed by E. coli 38% then Pseudomonas sp. 14%.
Results showed that, IL-6 and IL-8 serum levels were higher in patients with Gram negative bacteremia than in those with non-microbial fever for both groups of patients (cancer and non-cancerpatients). For cancer patients with Gram negative bacteremia and those with out there was significant difference in IL-6 and IL-8 serum levels (P=0.0001 and 0.0059, respectively) and for non-cancer patients (P=0.0288 and 0.0059, respectively).
CRP serum concentrations in our study showed non-significant difference between bacteremic groups and groups of non-microbial fever. Cut-off levels to distinguish between bacteremic (positive blood cultures) and non-bacteremic (negative blood cultures) cases were chosen using receiver operating characteristic curves : 29 mg/l for cancer patients, 119 mg/l for non-cancer patientsand with 60% and 100% Sp, 77.8% and 66.7% Sn, NPV 60% and 62.5 %, PPV 77.8% and 100%, Efficacy 71.4% and 78.6%, respectively.
While, Cut-off levels of serum IL-6 to distinguish between bacteremic (positive blood cultures) and non-bacteremic (negative blood cultures): 398.6 pg/ml for cancer patients, 120.9 pg/ml for non-cancerpatients and with 100% Sp, 100% Sn, NPV 100%, PPV 100%, Efficacy100% for both groups. So the efficacy of IL-6 as marker to discriminate between positive and negative blood cultures was higher than that of CRP.The AUC was 0.844 and 1.000 for CRP and IL-6 respectively in cancer patients. While, it was 0.875 and 1.000 for non-cancerpatients.The diagnostic performance of CRP and IL-6 and their combination (via multi-ROC) for discriminating patients with positive cultures from those with negative cultures (all cancer and non-cancertested cases) resulted in that the AUC was improved from 0.735 for CRP only and 0.957 for IL-6 to 0.982 using the both markers.The usefulness of both markers (IL-6 and CRP) was proved to distinguish between bacteremic and non-bacteremic patients.On the other hand IL-8 showed 100% values of PPV, NPV, Sp and Sn.
For complement C3 there was non-significant differences among the tested groups.
Also, there was direct proportionality between IL-6 serum levels and WBCs count, meaning that IL-6 playing role in chemotaxis of white blood cells to site of infection in cancer patients.
For these critically ill patients (immunocompromised cancer patients) continuous monitoring of antimicrobial resistance must be considered.
Among some selected isolates recovered from cancer patients, the frequency of resistance of some selected isolates against antibiotics acting on inhibition of cell wall synthesis after in-vitro exposure to gamma irradiation at a dose level of 24.4 Gy increased against ampicillin /sulbactam (SAM) from 80% to 93.3%, amoxicillin/clavulanic acid (AMC) from 66.66% to 86.66%, tazobactam/piperacillin (TZP) from 40% to 46.66%. Meanwhile, for imipenem (IPM) 26.66% intermediate resistance changed to 6.66% intermediate resistance and 13.33% resistance. While, for antibiotics inhibiting protein synthesis, the selected isolates showed decreased resistance from 73.33% to 66.66% against tobramycin (TOB), increased intermediateresistance from 6.66% to 19.98 against amikacin (AK) , while, resistance against chloramphenicol (C) increased from 40% to 46.66%. While, for sulphamethoxazole/trimethoprim (SXT), the isolates showed increased resistance from 80% to 86.66% after exposure to in-vitro gamma radiation.Also, there was significant p-value = 0.0086, 0.0198 and 0.05 for AMC in E. coli strains, TOB in Pseudomonas strains and SAM in Acinetobacter strains, respectively before and after exposure to in-vitro gamma radiation. For bacterial strains recovered from non-cancer patients, the frequency of resistance changed after gamma radiation, for ampicillin /salbactam (SAM) and tazobactam/piperacillin (TZP) it changed from 100% to 88.88% and from 66.66% to 55.55%, respectively. However, intermediate resistance against cefepime (FEP) and cefotaxime (CTX) increased to 11.11%. Meanwhile, the tested isolates showed increased resistance against gentamicin (CN), chloramphenicol (C) and amikacin (AK) by 66.66%,55.55% and 33.33%, respectively. In case of ofloxacin (OFX), the tested isolates showed increased resistance reaching 77.77%. Also, for sulphamethoxazole/trimethoprim (SXT) resistance of the tested isolatesincreased from 77.77% to 88.88%.These data indicate thatexposure to γ-radiation at therapeutic doses, such as those used in radiotherapyregimens in cancer patients, may increasethe frequency of antibioticresistance.
In this study we assessed the value of serum inflammatory mediators levels(IL-6 and IL-8) at fever onset in comparison with routinely used markers as WBCs, CRP and C3 to predict Gramnegative bacteremia in cancer and non-cancer patients.
Severity of infection was also studied comparing enzymatic activity and antimicrobial susceptibility of some selected isolated bacterial strains with measured serum inflammatory marker mainly IL-6. Also, the effect of gamma irradiation on IL-6 serum levels in rats with induced fever of bacterial and non-bacterial origin was investigated through the animal model on forty-eight adult Wister rats and comparisons between groups were performed.
In this study,One hundred twenty four feverish in-patients were enrolled in the study. Serum and plasma samples separated from blood specimens at onset of fever were used for assay of inflammatory biomarkers (IL-6 and IL-8) using ELISA technique, CRP using turbilatex and C3 ussig diffu-palte. Total leukocytic count was determined by coulter counter. Blood culture was carried out for isolation of Gram negative organisms which were identified by API 20E technique and subjected to antibiotic susceptibility test that was performed using disc diffusion method. Lipase and protease enzymes detection was performed via tween and gelatin agar media, respectively. Assay of serum IL-6 in rats was also done using ELISA technique. Cesium 137 (137 Cs) Gamma cell 40 located at National Center for Radiation Research and Technology (Cairo, Egypt) was the irradiation source used in the study.
It was found that out of the 124 blood samples collected there were 70 samples cancer feverish patients and 54 non-cancer feverish patients with relative percentages of 56% and 44%, respectively. About 49% of blood culture samples collected from cancer patients showed positive bacterial growth and 51% showed negative growth. While, blood samples showing positive growth innon-cancerpatients were 54% against 46% negative growth.
In this study for cancer feverish patients the prevalence of E. coli was 41% followed by K. pneumoniae 23% then Pseudomonas sp 27%, while for non-cancer feverish patients K. pneumoniae prevalence was 41% followed by E. coli 38% then Pseudomonas sp. 14%.
Results showed that, IL-6 and IL-8 serum levels were higher in patients with Gram negative bacteremia than in those with non-microbial fever for both groups of patients (cancer and non-cancerpatients). For cancer patients with Gram negative bacteremia and those with out there was significant difference in IL-6 and IL-8 serum levels (P=0.0001 and 0.0059, respectively) and for non-cancer patients (P=0.0288 and 0.0059, respectively).
CRP serum concentrations in our study showed non-significant difference between bacteremic groups and groups of non-microbial fever. Cut-off levels to distinguish between bacteremic (positive blood cultures) and non-bacteremic (negative blood cultures) cases were chosen using receiver operating characteristic curves : 29 mg/l for cancer patients, 119 mg/l for non-cancer patientsand with 60% and 100% Sp, 77.8% and 66.7% Sn, NPV 60% and 62.5 %, PPV 77.8% and 100%, Efficacy 71.4% and 78.6%, respectively.
While, Cut-off levels of serum IL-6 to distinguish between bacteremic (positive blood cultures) and non-bacteremic (negative blood cultures): 398.6 pg/ml for cancer patients, 120.9 pg/ml for non-cancerpatients and with 100% Sp, 100% Sn, NPV 100%, PPV 100%, Efficacy100% for both groups. So the efficacy of IL-6 as marker to discriminate between positive and negative blood cultures was higher than that of CRP.The AUC was 0.844 and 1.000 for CRP and IL-6 respectively in cancer patients. While, it was 0.875 and 1.000 for non-cancerpatients.The diagnostic performance of CRP and IL-6 and their combination (via multi-ROC) for discriminating patients with positive cultures from those with negative cultures (all cancer and non-cancertested cases) resulted in that the AUC was improved from 0.735 for CRP only and 0.957 for IL-6 to 0.982 using the both markers.The usefulness of both markers (IL-6 and CRP) was proved to distinguish between bacteremic and non-bacteremic patients.On the other hand IL-8 showed 100% values of PPV, NPV, Sp and Sn.
For complement C3 there was non-significant differences among the tested groups.
Also, there was direct proportionality between IL-6 serum levels and WBCs count, meaning that IL-6 playing role in chemotaxis of white blood cells to site of infection in cancer patients.
For these critically ill patients (immunocompromised cancer patients) continuous monitoring of antimicrobial resistance must be considered.
Among some selected isolates recovered from cancer patients, the frequency of resistance of some selected isolates against antibiotics acting on inhibition of cell wall synthesis after in-vitro exposure to gamma irradiation at a dose level of 24.4 Gy increased against ampicillin /sulbactam (SAM) from 80% to 93.3%, amoxicillin/clavulanic acid (AMC) from 66.66% to 86.66%, tazobactam/piperacillin (TZP) from 40% to 46.66%. Meanwhile, for imipenem (IPM) 26.66% intermediate resistance changed to 6.66% intermediate resistance and 13.33% resistance. While, for antibiotics inhibiting protein synthesis, the selected isolates showed decreased resistance from 73.33% to 66.66% against tobramycin (TOB), increased intermediateresistance from 6.66% to 19.98 against amikacin (AK) , while, resistance against chloramphenicol (C) increased from 40% to 46.66%. While, for sulphamethoxazole/trimethoprim (SXT), the isolates showed increased resistance from 80% to 86.66% after exposure to in-vitro gamma radiation.Also, there was significant p-value = 0.0086, 0.0198 and 0.05 for AMC in E. coli strains, TOB in Pseudomonas strains and SAM in Acinetobacter strains, respectively before and after exposure to in-vitro gamma radiation. For bacterial strains recovered from non-cancer patients, the frequency of resistance changed after gamma radiation, for ampicillin /salbactam (SAM) and tazobactam/piperacillin (TZP) it changed from 100% to 88.88% and from 66.66% to 55.55%, respectively. However, intermediate resistance against cefepime (FEP) and cefotaxime (CTX) increased to 11.11%. Meanwhile, the tested isolates showed increased resistance against gentamicin (CN), chloramphenicol (C) and amikacin (AK) by 66.66%,55.55% and 33.33%, respectively. In case of ofloxacin (OFX), the tested isolates showed increased resistance reaching 77.77%. Also, for sulphamethoxazole/trimethoprim (SXT) resistance of the tested isolatesincreased from 77.77% to 88.88%.These data indicate thatexposure to γ-radiation at therapeutic doses, such as those used in radiotherapyregimens in cancer patients, may increasethe frequency of antibioticresistance.
Other data
| Title | Early prediction of Gram negative bacteremia in febrile cancer patients: Correlation between some inflammatory mediators, exposure to gamma radiation and severity of infection | Other Titles | "التنبؤ المبكر بعدوى الدم بالبكتيريا سالبة الجرام فى مرضى السرطان المصابون بالحمى: الارتباط بين بعض الوسائط الالتهابية والتعرض لأشعة جاما و خطورة العدوى" | Authors | Amira Abuzeid Abdelbaset | Issue Date | 2016 |
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