We identified 208 patients with neutropenia above 15 years of age and had CRGNBSI. Twenty-nine patients died before 48 hours of bacteremia, twenty patients did not have FUBC, and four patients did not receive appropriate therapy for the bacteremia. The 155 patients who fulfilled the eligibility criteria were included in the final analysis, of whom 93(60%) were male. The mean age of patients was 36.65 years (SD, 13 years). Klebsiella species were the most commonly isolated organism (80%). All recruited patients had an underlying active hematological condition, of which, 120 (77.42%) were malignant in nature.The most common malignant conditions were acute myeloid leukemia (42.5%) and acute lymphoblastic leukemia (27.5%). Among benign conditions, aplastic anemia (71.43%) followed by myelodysplastic syndrome (17.14) were the most common. A sizable proportion of patients developed CRGNBSI after bone marrow transplant (35.4%). Among transplant patients, CMV reactivation along with CRGNBSIs was minimal (10.9%). Polymyxin resistance complicated more than a fifth of our patients (21.2%) (Table 1).
Table 1
Baseline demographic and clinical characteristics
Characteristics | Total n = 155 | Survivors n = 81 (%) | Non-survivors n = 74 (%) | p-value |
Age(Mean ± SD) | 36.65 ± 12.93 | 35.96 ± 13.17 | 37.42 ± 12.71 | 0.485 |
Gender: Male | 93 | 46(56.79) | 47(63.51) | 0.393 |
Polymyxin resistance(n = 146) | 31 | 14(21.21) | 17(21.25) | 0.996 |
Risk factors Hematologic condition: Benign Acute myeloid leukemia Acute lymphoblastic leukemia Other malignant conditions | 35 51 33 36 | 14(17.28) 31(38.27) 17(20.99) 19(23.46) | 21(28.38) 20(27.03) 16(21.62) 17(22.97) | 0.307 |
No recovery from neutropenia | 66 | 15(18.52) | 51(68.92) | < 0.001 |
Prolonged and profound neutropenia a | 40 | 24(29.63) | 16(21.62) | 0.255 |
Transplant | 55 | 33(40.74) | 22(29.73) | 0.152 |
Intensive care requirement | 106 | 38(46.91) | 68(91.89) | < 0.001 |
Presence of septic shock | 107 | 37(45.68) | 70(94.59) | < 0.001 |
Dialysis requirement | 19 | 3(3.7) | 16(21.62) | 0.001 |
Infection details Primary organism: Klebsiella | 124 | 66(81.48) | 58(78.38) | 0.063 |
Previous bacterial infections | 44 | 22(27.16) | 22(29.73) | 0.723 |
Concomitant bacterial infections | 34 | 13(16.05) | 21(28.38) | 0.064 |
Cytomegalovirus reactivation b (n = 55) | 6 | 2(6.06) | 4(18.18) | 0.158 |
Source of bacteremia: Gut translocation | 109 | 58(71.6) | 51(68.92) | 0.715 |
Previous exposure to polymyxin | 94 | 46(56.79) | 48(64.86) | 0.304 |
Previous exposure to carbapenem | 142 | 74(91.36) | 68(91.89) | 0.905 |
Persistent bacteremia | 68 | 26(32.1) | 42(56.76) | 0.002 |
Treatment details Polymyxin-based therapy Ceftazidime-avibactam-based therapy Polymyxin with ceftazidime-avibactam combination Alternate agents | 75 20 53 7 | 34(41.98) 10(12.35) 33(40.74) 4(4.94) | 41(55.41) 10(13.51) 20(27.03) 3(4.05) | 0.299 |
No appropriate empirical therapy received | 45 | 31(38.27) | 14(18.92) | 0.008 |
a Prolonged and profound Neutropenia is defined as absolute neutrophil count < 100 cells/mm3 and a duration of 7 days.
b Cytomegalovirus reactivation- More than 1000 copies of cytomegalovirus present 7 days before or after bacterial isolation.
Our cohort of patients was very ill with septic shock (69%) and required intensive care. Nineteen (12.2%) patients required dialysis, of whom sixteen died within the follow-up period. More than half of our patients (60.6%) received polymyxins in the 30 days preceding the CRGNBSI. Almost all patients (91.6%) were exposed to carbapenems over the same time period. Over a quarter of our patients (28.3%) had laboratory confirmed bacterial infection in the last 30 days prior to index date, and 21.9% developed a concomitant bacterial infection,other than the infectious episode on index date, within their follow-up period. Gut translocation was identified as the major source of bacteremia in our patients (70.3%). Other sources included catheter, lung, skin, and soft tissue infections. Source control was achieved in our patients whenever clinically applicable. Persistent bacteremia was common in our patient cohort (43.8%). The median time for sending a FUBC was 2 days (IQR, 1–3 days). The median duration of persistent bacteremia was 4 days (IQR, 3–7.5 days).
The overall mortality rate was 47.7%, and mortality was significantly higher among individuals with persistent bacteremia (56.76%, p < 0.001) than among those without (32.10%). Among our cohort of patients, 40 (25.8%) had prolonged or profound neutropenia while 89 (57.4%) recovered from neutropenia. Among patients who survived during the follow-up period, 81.48% recovered from neutropenia. About half of the patients received a polymyxin-based therapy (48.4%), and 34.2% received polymyxin and ceftazidime-avibactam combination therapy. Other types of therapy included ceftazidime-avibactam-based treatment or alternate drugs, such as tigecycline. The majority of our patients received an appropriate empirical therapy (70.9%),of whom over half (54.5%) had poor outcomes at the 30-day follow-up.
We performed univariate analysis on all patients to determine risk factors associated with 30-day mortality. Non-recovery from neutropenia (HR,5.42;95%CI, 3.28–8.93), requirement of intensive care (HR,7.84;95%CI, 3.39–18.12), septic shock (HR,12.34; 95%CI, 4.5–33.88), requirement of dialysis (HR,2.75; 95%CI, 1.57–4.81) and persistent bacteremia (HR,2.15; 95%CI, 1.35–3.41) were significantly associated with 30-day mortality in univariate analysis. Not receiving appropriate empirical therapy did not predict mortality in our group of patients (HR,0.5; 95%CI, 0.28–0.89). The mean VIF among the factors significant on univariable analysis was 1.26 with no critical correlation among the factors. When adjusted to all the significant risk factors along with age and sex as natural confounders, non-recovery from neutropenia (aHR,4.28; 95%CI, 2.53–7.23), requirement of intensive care (aHR,3.12;95%CI, 1.23–7.93),presence of septic shock (aHR,4.42; 95%CI, 1.47–13.28), and persistent bacteremia (aHR,1.74; 95%CI, 1.05–2.89) emerged as significant associations that predicted poor outcomes in multivariable analysis (Table 2).
Table 2
Risk factors predicting 30-day mortality
Characteristics | Univariate analysis | Multivariable analysis | |
Hazards ratio(95% CI) | P value | Adjusted Hazards ratio(95% CI) | P value | |
Age | 1.01 (0.99,1.02) | 0.573 | 1(0.98,1.02) | 0.772 |
Male gender | 1.19(0.74,1.92) | 0.463 | 1.4(0.83,2.34) | 0.207 | |
Polymyxin resistance | 0.96 (0.53,1.74) | 0.904 | | | |
Hematologic condition: Acute myeloid leukemia Acute lymphoblastic leukemia Other malignant conditions Benign | 0.56(0.30,1.04) 0.73(0.38,1.40) 0.74(0.39,1.40) Reference | 0.065 0.34 0.353 - | | | |
No recovery from neutropenia | 5.42(3.28,8.93) | < 0.001 | 4.28(2.53,7.23) | < 0.001 | |
Prolonged and profound neutropenia a | 0.65(0.37,1.13) | 0.13 | | | |
Transplant | 0.67(0.41,1.11) | 0.121 | | | |
Intensive care requirement | 7.84(3.39,18.12) | < 0.001 | 3.12(1.23,7.93) | 0.017 | |
Presence of septic shock | 12.34(4.5,33.88) | < 0.001 | 4.42(1.47,13.28) | 0.008 | |
Dialysis requirement | 2.75(1.57,4.81) | < 0.001 | 1.68(0.92,3.05) | 0.091 | |
Primary organism: Klebsiella | 0.87(0.50,1.52) | 0.625 | | | |
Previous bacterial infections | 1.06(0.64,1.75) | 0.818 | | | |
Concomitant bacterial infections | 1.6(0.96,2.66) | 0.069 | | | |
Cytomegalovirus reactivation b | 2.31(0.78,6.85) | 0.132 | | | |
Source of bacteremia: Gut translocation | 0.89(0.54,1.45) | 0.639 | | | |
Previous exposure to polymyxin | 1.22(0.75,1.96) | 0.421 | | | |
Previous exposure to carbapenem | 0.99(0.43,2.28) | 0.983 | | | |
Persistent bacteremia | 2.15(1.35,3.41) | 0.001 | 1.74(1.05,2.89) | 0.031 | |
Treatment details: Ceftazidime-avibactam-based therapy Polymyxin with Ceftazidime-avibactam combination Alternate agents Polymyxin based therapy | 0.82(0.41,1.63) 0.61(0.36,1.04) 0.75(0.23,2.41) Reference | 0.569 0.067 0.624 - | | | |
No appropriate empirical therapy received | 0.50(0.28,0.89) | 0.019 | 0.77(0.42,1.41) | 0.389 | |
a Prolonged and profound Neutropenia is defined as absolute neutrophil count < 100 cells/mm3 and a duration of 7 days. |
b Cytomegalovirus reactivation- More than 1000 copies of cytomegalovirus present 7 days before or after bacterial isolation. |
Kaplan Meier survival curve (Fig. 1) demonstrates the survival among patients with and without persistent bacteremia in the 30-day follow-up period. Probability of survival was higher in patients without persistent bacteremia (63.2%) as compared to those with persistent bacteremia(38.2%). The difference observed in survival functions was statistically significant with p < 0.001.