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Open-Label Randomized Controlled Study of Ciprofloxacin vs Rifaximin as Neutropenia Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation
Gavriilaki, E., Mallouri, D., Laspa, E., Papakonstantinou, A., Lazaridou, A., Varelas, C., Baldoumi, E., Giannakopoulou, A., Demosthenous, C., Vardi, A., et al
Transplantation proceedings. 2024
Abstract
Loss of microbiota diversity has been clearly associated with poor outcomes in the allogeneic hematopoietic stem cell transplantation setting. However, the choice of the optimal antibiotic prophylaxis during the pre-engraftment phase remains unclear. We designed a prospective randomized study to compare our standard-of-care neutropenia prophylaxis (ciprofloxacin) with rifaximin. We enrolled 38 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplantation setting and were randomly assigned to receive ciprofloxacin (20 patients) or rifaximin (18 patients) at day -1. Pretransplant and transplant characteristics did not differ between groups. Cumulative incidence (CI) of acute graft-vs-host disease grade II to IV and moderate/severe chronic graft-vs-host disease was similar in both groups. With a median follow-up of 13.2 months (range, 6.8-30.2) in surviving patients, the 1-year CI of relapse was 20.8% in ciprofloxacin vs 17.8% in rifaximin (P = .616). Importantly, the 1-year CI of treatment-related mortality was significantly reduced in the ciprofloxacin group (10.2% vs 27.8%, P = .032), leading to higher 1-year overall survival (88.9% vs 74.6%, P = .038). In Cox-regression multivariate analysis, antibiotic prophylaxis remained the only predictor of overall survival, independently of donor type, disease risk index, and moderate/severe chronic graft-vs-host disease. Further studies are needed to assess the effects on microbiota diversity and confirm these outcomes.
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Prophylactic Trimethoprim-Sulfamethoxazole for Allogeneic Hematopoietic Stem Cell Transplant Recipients During the Pre-engraftment Period
Gaffney, K. J., Urban, T. A., Lucena, M., Rybicki, L., Majhail, N. S., Mossad, S. B.
Clinical hematology international. 2023
Abstract
BACKGROUND Our institution has used trimethoprim-sulfamethoxazole (TMP-SMX) as the antibacterial agent of choice for infection prophylaxis during the pre-engraftment period in the allogeneic transplant (allo-HCT) population. METHODS This retrospective, single center study was developed to compare the safety of that antibacterial prophylaxis to fluoroquinolones in allo-HCT. The primary endpoint was time to neutrophil engraftment. RESULTS A total of 366 patients were reviewed (TMP-SMX n = 332, fluoroquinolone n = 34). No difference in days to neutrophil engraftment was found (median 15 versus 16 days, p = 0.62). Hyperkalemia was more common in the TMP-SMX cohort (32.2% versus 14.7%, p = 0.035); this did not contribute to a higher rate of agent discontinuation or arrhythmia. There was no significant difference in the incidence of neutropenic fever; however, those in the TMP-SMX cohort were more likely to have microbiologically confirmed bacteremia (24.1% versus 8.8% respectively, p = 0.043). There was no significant difference in infections. No long-term implication of prophylactic antibacterial agent selection was observed in terms of graft-versus-host-disease, underlying disease relapse, or mortality. CONCLUSION The use of TMP-SMX was associated with a higher likelihood of bacteremia and hyperkalemia; however, this did not result in increased hospital stay, escalation of care, or mortality. The use of TMP-SMX for prophylaxis during the pre-engraftment period for allo-HCT recipients is safe and effective.
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3.
The clinical value of anal swabs for microbial detection in allogeneic haematopoietic stem cell transplantation
Gao, J., Lin, D., Hou, C., Shen, Y., Li, Y., Wu, D., Xu, Y.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND The intestinal microbiota plays critical roles in allogeneic haematopoietic stem cell transplantation (allo-HSCT). Rapid and effective microbial detection methods have important guiding value for the selection of intervention strategies for transplant patients. We evaluate the application of anal swab test before transplantation in allo-HSCT patients. STUDY DESIGN A total of 120 allo-HSCT patients who underwent anal swab testing before allo-HSCT were retrospectively analysed and divided into sterile (aseptic growth-negative), G+ (gram-positive bacterial colonization) and G- (gram-negative bacterial colonization) groups. RESULTS 16S rRNA sequencing showed that gram-negative bacteria predominated in the G- group before and after transplantation. Compared with the sterile group, NK cell percentage was higher and T cell percentage was lower after transplantation in the G- group at one month after transplantation. The percentage of CD4+T and CD4+CD8+ T cells was lower, and the percentage of Treg was higher in the G- group. The plasma levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6, and IL-17A) were lower in the G- group at 2 weeks after transplantation than in the sterile group. The cumulative incidence of grade III-IV aGVHD was lower in the G- group than in the sterile group. Gram-negative bacterial colonization before allo-HSCT was associated with low rates of BSI within 100 days posttransplatation, and CMV reactivation after 100 days to 2 years posttransplatation. Moreover, patients in the G- group had a higher rate of 2-year GRFS compared with patients in the sterile group. CONCLUSIONS The detection results using anal swabs were consistent with the gram-negative or positive bacteria abundance of 16S rRNA sequencing results and associated with immune homeostasis and clinical outcomes after allo-HSCT. Anal swab testing may have potential advantages as a simple and effective method for microbial detection in allo-HSCT.
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Risk factors and outcome of Stenotrophomonas maltophilia infection after allogeneic hematopoietic stem cell transplantation: JSTCT, Transplant Complications Working Group
Saburi, M., Oshima, K., Takano, K., Inoue, Y., Harada, K., Uchida, N., Fukuda, T., Doki, N., Ikegame, K., Matsuo, Y., et al
Annals of hematology. 2023
Abstract
Stenotrophomonas maltophilia (S. maltophilia) is an aerobic nonfermenting Gram-negative bacillus widely distributed in the environment that has inherent multidrug resistance to beta-lactam and carbapenem antibiotics. S. maltophilia infection (SMI) is known as an important fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its clinical characteristics have not been well clarified. A retrospective study to identify the incidence, risk factors, and outcomes of SMI after allogeneic HSCT was performed using the database of the Japanese nationwide registry, including 29,052 patients who received allogeneic HSCT in Japan between January 2007 and December 2016. A total of 665 patients developed SMI (sepsis/septic shock, 432; pneumonia, 171; other, 62). The cumulative incidence of SMI at 100 days after HSCT was 2.2%. Among risk factors identified for SMI (age ≥ 50 years, male, performance status 2-4, cord blood transplantation [CBT], myeloablative conditioning, Hematopoietic Cell Transplant-Comorbidity Index [HCT-CI] score 1-2, HCT-CI score ≥ 3, and active infectious disease at HSCT), CBT was the strongest risk factor (hazard ratio, 2.89; 95%CI, 1.94-4.32; p < 0.001). The survival rate at day 30 after SMI was 45.7%, and SMI before neutrophil engraftment was significantly associated with poor survival (survival rate 30 days after SMI, 40.1% and 53.8% in patients with SMI before and after engraftment, respectively; p = 0.002). SMI is rare after allogeneic HSCT, but its prognosis is extremely poor. CBT was a strong risk factor for SMI, and its development prior to neutrophil engraftment was associated with poor survival.
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Short-course empiric antibiotics in children undergoing allogeneic hematopoietic cell transplant
Patel, P. A., Teherani, M. F., Xiang, Y., Bernardo, V., Chandrakasan, S., Goggin, K. P., Haight, A., Horwitz, E., Liang, W. H., Parikh, S. H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Fever is common in children undergoing hematopoietic cell transplant (HCT). Empiric antibiotics (EA) are initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to complications such as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA have been studied in adults undergoing HCT without significant safety concerns but data in children are lacking. OBJECTIVE We instituted a single-center pre-/post-intervention quality improvement (QI) project to assess the feasibility of short-course EA for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. METHODS Patients were eligible for the intervention, limiting EA to 7 days for first fever, if admitted for their first allogeneic HCT, afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA for first fever and total broad-spectrum antibiotic use during the hospitalization period, defined as the start of the conditioning regimen to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and ICU admission within 3 days of stopping EAT. Project criteria were applied retrospectively to patients transplanted in 2020 to construct a pre-intervention short-course eligible cohort. RESULTS During the intervention period, 41 patients underwent allogeneic HCT with 17 (41%) eligible for short-course EA. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographics or HCT characteristics between patients eligible for short-course EA during the intervention and pre-intervention period (n=24). Short-course EA was adhered to in 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use significantly decreased in the short-course EA eligible patients compared to the pre-intervention cohort from a median of 17 days to 8 days and 20 days to 10 days respectively (p<0.01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who underwent short-course EA. CONCLUSIONS In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome and HCT outcomes.
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Role of fluoroquinolone prophylaxis in allogeneic hematopoietic cell transplantation in regions with a high prevalence of fluoroquinolone resistance
Nair, A., Kaundal, S., Kasudhan, K. S., Chopra, M., Singh, C., Jandial, A., Jain, A., Prakash, G., Khadwal, A., Angrup, A., et al
Blood cell therapy. 2023;6(2):61-65
Abstract
INTRODUCTION The role of fluoroquinolone (FQ) prophylaxis in preventing gram-negative bacilli (GNB) bacteremia, graft-versus-host disease (GVHD), and overall survival (OS) after allogeneic hematopoietic cell transplantation (allo-HCT) is debatable and may differ in settings with low and high prevalences of FQ resistance. In this study, we aimed to answer this question in regions with high FQ resistance. METHODS This single-center retrospective study included all consecutive allo-HCT recipients aged ≥12 years from 2012 to 2021. Allo-HCT recipients until 2016 were administered FQ prophylaxis (levofloxacin). After 2016, the institutional protocol was modified to no antibiotic prophylaxis. Data were retrieved from patient records for disease and transplant characteristics, the incidence of GNB bacteremia, duration of parenteral antibiotics, hospitalization duration, acute GVHD, and OS. RESULTS A total of 135 allo-HCT recipients (43 in the FQ-prophylaxis cohort and 92 in the no-antibiotic prophylaxis cohort) were analyzed in this study. The two cohorts were matched for age (median, 26 vs. 24.5 years; p = 0.8). The no-antibiotic prophylaxis cohort had a higher proportion of malignant diagnoses (80% vs. 58%, p = 0.01), haploidentical transplants (46% vs. 14%, p = 0.004), and posttransplant cyclophosphamide exposure (46% vs. 14%, p = 0.003) than did the FQ cohort. Despite this, the incidence of GNB bacteremia was not significantly different between the two cohorts (37% vs. 34%, p = 0.6). There were no differences in parenteral antibiotic use or hospitalization duration, as well as the incidence of acute GVHD (53% vs. 53%, p = 0.3). The 1-year OS was similar between the two cohorts (66% vs. 67%, p = 0.6). CONCLUSION This study shows that FQ prophylaxis did not affect the incidence of GNB bacteremia, parenteral antibiotic use, hospitalization duration, acute GVHD, and OS post-allo-HCT.
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A phase 3 randomized, double-blind, comparator-controlled study to evaluate safety, tolerability and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in allogeneic hematopoietic cell transplant recipients (PNEU-STEM)
Wilck, M., Cornely, O. A., Cordonnier, C., Velez, J. D., Ljungman, P., Maertens, J., Selleslag, D., Mullane, K. M., Nabhan, S., Chen, Q., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023
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Abstract
BACKGROUND Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk for pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE™), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS Participants received 3 doses of V114 or PCV13 in one-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAXTM 23 or a fourth dose of PCV (if they experienced chronic graft versus host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90. CONCLUSIONS V114 was well tolerated in allo-HCT recipients with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and higher for V114 serotypes 22F and 33F. Study results support use of V114 in allo-HCT recipients.
PICO Summary
Population
Adults and children who received allo-HCT 90 to 180 days prior to randomization, from 44 centres in 10 countries (n=274)
Intervention
3 doses of V114 pneumococcal conjugate vaccine in one-month intervals starting 3-6 months after transplant. For people who experienced chronic GvHD, a fourth dose of PNEUMOVAXTM 23 was given (n=139)
Comparison
Three doses of PCV13 in pneumococcal conjugate vaccine in one-month intervals starting 3-6 months after transplant. For people who experienced chronic GvHD, a fourth dose was given. (n=135)
Outcome
The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90.
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Stopping antibacterial prophylaxis in pediatric allogeneic hematopoietic cell transplantation: An internal audit
Wintjes, N., Krämer, K., Kolve, H., Mohring, D., Schaumburg, F., Rossig, C., Burkhardt, B., Groll, A. H.
Transplant infectious disease : an official journal of the Transplantation Society. 2023;:e14211
Abstract
BACKGROUND Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. METHODS The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. RESULTS A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3 vs. 94.1%; p = .57) and bacterial infections (34.6 vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39 vs. 34; p = .002). Detection rates of resistant organisms were overall low. CONCLUSION In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.
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Clinical impact and early prediction of carbapenem-resistant Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation recipients
Sakaguchi, M., Atsuta, Y., Sekiya, N., Najima, Y., Fukushima, K., Shingai, N., Toya, T., Kobayashi, T., Ohashi, K., Doki, N.
Journal of global antimicrobial resistance. 2023;32:187-194
Abstract
OBJECTIVE Although antipseudomonal agents are administered in high-risk patients, no reports have focused on the risk of carbapenem-resistant (CR) Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. METHODS We retrospectively studied a cohort of adult allo-HSCT recipients with P. aeruginosa bacteraemia, focusing on a comparison between carbapenem-sensitive (CS) and CR P. aeruginosa after initiating conditioning chemotherapy at our institute between January 2005 and December 2020. The incidence, all-cause 30-d mortality of P. aeruginosa bacteraemia, and risk factors for carbapenem resistance among patients with P. aeruginosa bacteraemia in allo-HSCT recipients were evaluated. RESULTS Forty-eight patients with P. aeruginosa bacteraemia were included, with an incidence of 3.84/100 recipients (CS = 1.92 vs. CR = 1.92). The all-cause 30-d mortality was significantly higher in CR P. aeruginosa bacteraemia (CS = 4.2% vs. CR = 39.1%; P = 0.003). The factor significantly associated with CR P. aeruginosa bacteraemia was carbapenem use for at least 3 d within 30 d before the onset of bacteraemia (odds ratio = 8.92; 95% confidence interval: 1.35-58.90). Inappropriate antimicrobial selection was significantly more frequent in CR P. aeruginosa bacteraemia (CS = 0% vs. CR = 29.2%; P ˂ 0.009). CONCLUSION Empirical combination therapy with reference to antimicrobial susceptibility profiles in each institution should be considered when CR P. aeruginosa bacteraemia is suspected in allo-HSCT recipients based on the risk of carbapenem exposure.
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Late-onset Pneumocystis jirovecii pneumonia post-allogeneic stem cell transplantation after time-dependent discontinuation of prophylaxis
Stavi, V., Desai, N., Michelis, F. V., Kim, D. D. H., Kumar, R., Lipton, J. H., Law, A. D.
European journal of haematology. 2023
Abstract
INTRODUCTION Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6-12 months post-HSCT is the standard approach. However, there is no consensus regarding the optimal duration of prophylaxis. METHODS We identified patients who developed PJP more than 1-year post-HSCT. All patients had previously received 12 months of PJP prophylaxis. PJP was diagnosed based on clinical findings and the detection of P. jirovecii in bronchoalveolar lavage (BAL) using polymerase chain reaction (PCR). The CD4(+) T-cell percentage was determined using flow cytometry. Data expressed as median (interquartile range). RESULTS Ten patients developed PJP at 17.5 months (16-24 months) post-HSCT. PJP diagnosis occurred 5.5 months (3-15 months) after discontinuing prophylaxis. Eight patients received anti-thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis. At diagnosis, only one patient had lymphopenia; all patients had CD4(+) T-lymphocyte counts ≥0.2 × 10(9) /L (median 0.337 × 10(9) /L). Three patients had concomitant bacterial infections. The clinical presentation was mild; only three required hospitalization, none of them required intensive care and there were no deaths. CONCLUSION There is a need to develop risk-adapted prophylactic strategies in the contemporary era using ATG-based GVHD prophylaxis.