Pseudomonas aeruginosa Bloodstream Infections Presenting with Septic Shock in Neutropenic Cancer Patients: Impact of Empirical Antibiotic Therapy.

This large, multicenter, retrospective cohort study including onco-hematological neutropenic patients with Pseudomonas aeruginosa bloodstream infection (PABSI) found that among 1213 episodes, 411 (33%) presented with septic shock. The presence of solid tumors (33.3% vs. 20.2%, p < 0.001), a high-risk Multinational Association for Supportive Care in Cancer (MASCC) index score (92.6% vs. 57.4%; p < 0.001), pneumonia (38% vs. 19.2% p < 0.001), and infection due to multidrug-resistant P. aeruginosa (MDRPA) (33.8% vs. 21.1%, p < 0.001) were statistically significantly higher in patients with septic shock compared to those without. Patients with septic shock were more likely to receive inadequate empirical antibiotic therapy (IEAT) (21.7% vs. 16.2%, p = 0.020) and to present poorer outcomes, including a need for ICU admission (74% vs. 10.5%; p < 0.001), mechanical ventilation (49.1% vs. 5.6%; p < 0.001), and higher 7-day and 30-day case fatality rates (58.2% vs. 12%, p < 0.001, and 74% vs. 23.1%, p < 0.001, respectively). Risk factors for 30-day case fatality rate in patients with septic shock were orotracheal intubation, IEAT, infection due to MDRPA, and persistent PABSI. Therapy with granulocyte colony-stimulating factor and BSI from the urinary tract were associated with improved survival. Carbapenems were the most frequent IEAT in patients with septic shock, and the use of empirical combination therapy showed a tendency towards improved survival. Our findings emphasize the need for tailored management strategies in this high-risk population.

Seroprevalence study prior and post vaccination in cancer patients in principality of Andorra (COVONCO study).

BACKGROUND: COVID-19 serologic response in patients with cancer may be lower than in the general population and may be influenced by the type of tumor or anticancer treatment. This study aims to analyze serological response prior and after vaccination of COVID-19 within the oncological population in Andorra. We set out to identify risk factors for a higher or lower serological response. PATIENTS AND METHODS: Observational, unicentric, prospective cohort study of oncologic patients in Andorra. We calculated the seroprevalence of antibodies against SARS-CoV-2 (May 2020-June 2021) and analyzed the main demographic, oncologic features and factors associated with being seropositive. RESULTS: A total of 373 patients were analyzed, mainly with solid tumours (n = 334, 89.5%). At baseline, seroprevalence was 13%, increasing during follow-up to 19%; lower seroprevalence was observed in patients with hematologic malignancies (2.6% vs 14.2%; p = 0.041) and patients receiving biological therapies (0% vs 15%, p = 0.005). In the overall seroprevalence analysis, women (23% vs 11.9%; p = 0.006) and tumour-free patients (p = 0.034) showed higher seroprevalence. The multivariable analysis showed that odds of being seropositive were higher among women (OR: 2.44, 95% CI 1.28-4.64), and patients who underwent surgery (OR: 3.35, 95% CI 1.10-10.20). About 80% of the cohort received at least one dose of COVID-19 vaccination, showing a higher seroprevalence of patients who received ChAdOx1-S than those who received BNT162b2 (24.4% vs 6.4%: p = 0.001). CONCLUSION: The seroprevalence of antibodies against SARS-COV-2 in oncologic patients in Andorra was higher among females and patients who received hormonal therapy and surgery while patients with hematologic malignancies and biologic therapies showed lower seropositivity without finding differences in the type of tumour or anticancer treatment.

Pseudomonas aeruginosa Bloodstream Infections in Patients with Cancer: Differences between Patients with Hematological Malignancies and Solid Tumors.

Objectives: To assess the clinical features and outcomes of Pseudomonas aeruginosa bloodstream infection (PA BSI) in neutropenic patients with hematological malignancies (HM) and with solid tumors (ST), and identify the risk factors for 30-day mortality. Methods: We performed a large multicenter, retrospective cohort study including onco-hematological neutropenic patients with PA BSI conducted across 34 centers in 12 countries (January 2006−May 2018). Episodes occurring in hematologic patients were compared to those developing in patients with ST. Risk factors associated with 30-day mortality were investigated in both groups. Results: Of 1217 episodes of PA BSI, 917 occurred in patients with HM and 300 in patients with ST. Hematological patients had more commonly profound neutropenia (0.1 × 109 cells/mm) (67% vs. 44.6%; p < 0.001), and a high risk Multinational Association for Supportive Care in Cancer (MASCC) index score (32.2% vs. 26.7%; p = 0.05). Catheter-infection (10.7% vs. 4.7%; p = 0.001), mucositis (2.4% vs. 0.7%; p = 0.042), and perianal infection (3.6% vs. 0.3%; p = 0.001) predominated as BSI sources in the hematological patients, whereas pneumonia (22.9% vs. 33.7%; p < 0.001) and other abdominal sites (2.8% vs. 6.3%; p = 0.006) were more common in patients with ST. Hematological patients had more frequent BSI due to multidrug-resistant P. aeruginosa (MDRPA) (23.2% vs. 7.7%; p < 0.001), and were more likely to receive inadequate initial antibiotic therapy (IEAT) (20.1% vs. 12%; p < 0.001). Patients with ST presented more frequently with septic shock (45.8% vs. 30%; p < 0.001), and presented worse outcomes, with increased 7-day (38% vs. 24.2%; p < 0.001) and 30-day (49% vs. 37.3%; p < 0.001) case-fatality rates. Risk factors for 30-day mortality in hematologic patients were high risk MASCC index score, IEAT, pneumonia, infection due to MDRPA, and septic shock. Risk factors for 30-day mortality in patients with ST were high risk MASCC index score, IEAT, persistent BSI, and septic shock. Therapy with granulocyte colony-stimulating factor was associated with survival in both groups. Conclusions: The clinical features and outcomes of PA BSI in neutropenic cancer patients showed some differences depending on the underlying malignancy. Considering these differences and the risk factors for mortality may be useful to optimize their therapeutic management. Among the risk factors associated with overall mortality, IEAT and the administration of granulocyte colony-stimulating factor were the only modifiable variables.

Mass SARS-CoV-2 serological screening, a population-based study in the Principality of Andorra.

BACKGROUND: Andorra is a small country located in the Pyrenees attracting millions of visitors for tourism, mostly associated with skiing, and nature-related activities. As its neighbouring countries, Spain and France, it has been heavily affected by the COVID-19 pandemic. We estimated SARS-CoV-2 seroprevalence in the entire country by universal serological testing under a lockdown environment. METHODS: A total of 77,543 inhabitants of Andorra were invited to participate in the study. From 4-28 May, 2020, two cross sectional serological surveys were conducted using a rapid serological test (nCOV IgG/IgM) on a finger prick blood sample in 59 drive-through or walk-through checkpoints, all over Andorra. We calculated seroprevalence of antibodies against SARS-CoV-2 and analysed the main sociodemographic factors associated with being seropositive. FINDINGS: 70,494 inhabitants (90.9% of the population) participated in at least one survey. Overall seroprevalence was 11.0%. The most affected age groups were those over 90 years old (15.2%) and 80-89 (13.8%), followed by adults 50-59 (13.6%) and adolescents 10-19 (13.7%). Most seropositive participants, 6,061 (95.1%), were asymptomatic before the surveys. The multivariable analysis showed that the odds of being seropositive was higher among seasonal workers (OR 2.41; 95% CI 1.07-5.45) or in the population living in La Massana region, a popular ski-related area (OR 2.66; 95% CI 2.44-2.89). A higher seroprevalence was observed in those familiar nuclei with greater numbers of cohabitants: 18% in families with 6 household members or more; 13% in medium size families (3/4/5 people) and 12% in small size (1 to 2 people) nuclei. INTERPRETATION: The prevalence of antibodies against SARS-CoV-2 in the population of Andorra was high during the first wave of the pandemic. Seasonal workers and inhabitants based in La Massana presented a higher seroprevalence. Mass antibody screening allows to identify infection hotspots and should contribute to the design of tailored interventions to prevent SARS-CoV-2 transmission in Andorra. FUNDING: Andorran Ministry of Health, Andorran Health Services.

A Randomized, Double-Blind, Placebo-Controlled Trial (TAURCAT Study) of Citrate Lock Solution for Prevention of Endoluminal Central Venous Catheter Infection in Neutropenic Hematological Patients.

Infection of long-term central venous catheters (CVCs) remains a challenge in the clinical management of cancer patients. We aimed to determine whether a lock solution with taurolidine-citrate-heparin would be more effective than placebo for preventing nontunneled CVC infection in high-risk neutropenic hematologic patients. We performed a prospective, multicenter, randomized (1:1), double-blind, parallel, superiority, placebo-controlled trial involving 150 hematological patients with neutropenia carrying nontunneled CVCs who were assigned to receive CVC lock solution with taurolidine-citrate-heparin or heparin alone. The primary endpoint was bacterial colonization of the CVC hubs. Secondary endpoints were the incidence of catheter-related bloodstream infection (CRBSI), CVC removal, adverse events related to the lock solution, and the 30-day case fatality rate. CVC lock solution with taurolidine-citrate-heparin was associated with less colonization of the CVC hubs than that with placebo, with no statistically significant differences: 4.1%, versus 10.1% (relative risk [RR] = 0.41, 95% confidence interval [CI] = 0.11 to 1.52), with a cumulative incidence of 4.17 (95% CI = 0.87 to 11.70) and 10.14 (95% CI = 4.18 to 19.79), respectively. There were no significant differences regarding the secondary endpoints. Only three episodes of CRBSI occurred during the study period. No adverse events related to the administration of the lock solution occurred. In this trial involving high-risk patients carrying nontunneled CVCs, the use of taurolidine-citrate-heparin did not show a benefit over the use of placebo. Nevertheless, the safety of this prevention strategy and the trend toward less hub colonization in the taurolidine-citrate-heparin group raise the interest in assessing its efficacy in centers with higher rates of CRBSI. (This study has been registered in ISRCTN under identifier ISRCTN47102251.).

Current etiology, clinical features and outcomes of bacteremia in older patients with solid tumors.

PURPOSE: To assess the etiology, clinical features and outcomes of bacteremia in older patients with solid tumors. METHODS: All episodes of bacteremia in hospitalized patients with solid tumors were prospectively collected. Patients aged ≥70 years were compared to patients aged <70 years. Risk factors for case-fatality rates in older patients were identified. RESULTS: We compared 217 episodes of bacteremia involving older patients and 525 occurring in younger patients. Older patients had more frequently other comorbidities, but were less commonly neutropenic and carried less frequently central venous catheters. Bacteremia from an abdominal source was more common in patients ≥70, whereas an endogenous source and catheter-related infection were less frequently observed. Streptococcus bovis group (3.7% vs. 0.8%, p = .01) and Listeria monocytogenes (4.6% vs. 1.9%, p = .04) were more common in older patients, whereas coagulase-negative staphylococci were less frequently found (1.4% vs. 5.3% p = .01). Infection due to multi-drug resistant (MDR) strains was significantly higher in older patients (17.1% vs. 10.9%, p = .02), who in addition, presented higher overall mortality (35.4% vs 27.7%, p = .04). In older patients, lung tumor, neutropenia, and low grade fever were associated with early mortality, whereas comorbidities, corticosteroids, septic shock and inadequate empirical antibiotic therapy were associated with overall mortality. CONCLUSIONS: We identified remarkable differences in the etiology and sources of bacteremia between older and younger cancer patients with bacteremia. Older patients had more frequent infection due to MDR organisms and presented a higher overall mortality. Corticosteroids and inadequate empirical antibiotic therapy are modifiable factors associated with mortality.

Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial.

BACKGROUND: Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy unnecessarily. We aimed to establish whether EAT discontinuation driven by a clinical approach regardless of neutrophil recovery would optimise the duration of therapy. METHODS: We did an investigator-driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six academic hospitals in Spain. Eligible patients were adults with haematological malignancies or haemopoietic stem-cell transplantation recipients, with high-risk febrile neutropenia without aetiological diagnosis. An independent, computer-generated randomisation sequence was used to randomly enrol patients (1:1) to the experimental or control group. Investigators were masked to assignment only before randomisation. EAT based on an antipseudomonal ß-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) or as combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) was started according to local protocols and following international guidelines and recommendations. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0·5 × 109 cells per L or higher. The primary efficacy endpoint was the number of EAT-free days. Primary analyses were done in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01581333. FINDINGS: Between April 10, 2012, and May 31, 2016, 157 episodes among 709 patients assessed for eligibility were included in analyses. 78 patients were randomly assigned to the experimental group and 79 to the control group. The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16·1 [SD 6·3] vs 13·6 [7·2], absolute difference -2·4 [95% CI -4·6 to -0·3]; p=0·026). 636 adverse events were reported (341 in the experimental group vs 295 in the control group; p=0·057) and most (580 [91%]; 323 in the experimental group vs 257 in the control group) were considered mild or moderate (grade 1-2). The most common adverse events in the experimental versus the control group were mucositis (28 [36%] of 78 patients vs 20 [25%] of 79 patients), diarrhoea (23 [29%] of 78 vs 24 [30%] of 79), and nausea and vomiting (20 [26%] of 78 vs 22 [28%] of 79). 56 severe adverse events were reported, 18 in the experimental group and 38 in the control group. One patient died in the experimental group (from hepatic veno-occlusive disease after an allogeneic haemopoietic stem-cell transplantation) and three died in the control group (one from multiorgan failure, one from invasive pulmonary aspergillosis, and one from a post-chemotherapy intestinal perforation). INTERPRETATION: In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe. FUNDING: Instituto de Salud Carlos III, Spanish Ministry of Economy (PI11/02674).

A fresh look at polymicrobial bloodstream infection in cancer patients.

OBJECTIVES: To assess the current incidence, clinical features, risk factors, aetiology, antimicrobial resistance and outcomes of polymicrobial bloodstream infection (PBSI) in patients with cancer. METHODS: All prospectively collected episodes of PBSI in hospitalised patients were compared with episodes of monomicrobial bloodstream infection (MBSI) between 2006 and 2015. RESULTS: We identified 194 (10.2%) episodes of PBSI and 1702 MBSI (89.8%). The presence of cholangitis, biliary stenting, neutropenia, corticosteroids, neutropenic enterocolitis and other abdominal infections were identified as risk factors for PBSI. Overall, Gram-negative organisms were the most frequent aetiology, but Enterococcus spp. were especially frequent causes of Gram-positive PBSI (30.8%). Multidrug-resistant (MDR) organisms were more commonly found in PBSI than in MBSI (20.6% vs 12.9%; p = 0.003). Compared to patients with MBSI, those with PBSI presented with higher early (15% vs 1.4%; p = 0.04) and overall (32% vs 20.9%; p<0.001) case-fatality rates. Risk factors for overall case-fatality were a high-risk MASCC (Multinational Association of Supportive Care in Cancer) index score, corticosteroid use, persistent bacteraemia and septic shock. CONCLUSIONS: PBSI is a frequent complication in patients with cancer and is responsible for high mortality rates. Physicians should identify patients at risk for PBSI and provide empiric antibiotic therapy that covers the most frequent pathogens involved in these infections, including MDR strains.

Efficacy of ß-Lactam/ß-Lactamase Inhibitor Combinations for the Treatment of Bloodstream Infection Due to Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae in Hematological Patients with Neutropenia.

ß-Lactam/ß-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-ß-lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients.

Clinical features, aetiology and outcome of bacteraemic pneumonia in neutropenic cancer patients.

BACKGROUND AND OBJECTIVE: We aimed to assess the clinical features, aetiology and outcomes of bacteraemic pneumonia in neutropenic cancer patients (NCP) in the current era of increasing antimicrobial resistance. METHODS: All episodes of bacteraemia occurring in hospitalized patients with cancer, including haematopoietic stem cell transplant recipients, from January 2006 to April 2015 were included. RESULTS: We identified 1723 episodes of bacteraemia, of which 795 occurred in neutropenic patients with cancer, and among them, 55 episodes were identified as bacteraemic pneumonia. The most frequent causative agents were Pseudomonas aeruginosa (39.6%), Streptococcus pneumoniae (20.6%) and Escherichia coli (8.6%). Among the Gram-negative organisms, 12.8% were multidrug resistant (MDR). Eleven patients (20%) required admission to intensive care, and eight (14.8%) underwent invasive mechanical ventilation. Nine patients (16.3%) received inadequate empirical antibiotic therapy, of whom six (66.6%) died; eight of these nine patients had pneumonia caused by resistant microorganisms. The early (48 h) case-fatality rate was 24% and the overall (30 day) case-fatality rate was 46.2%. CONCLUSION: Bacteraemic pneumonia is a frequent complication among NCP and is mainly caused by P. aeruginosa and S. pneumoniae. The emergence of MDR organisms is of special concern. Despite the improvement in the management of cancer patients, case-fatality rates of NCP with bacteraemic pneumonia remain high. Urgent assessment is needed to identify a better approach for the management and support of these patients.

Causes of death in a contemporary cohort of patients with invasive aspergillosis.

Information regarding the processes leading to death in patients with invasive aspergillosis (IA) is lacking. We sought to determine the causes of death in these patients, the role that IA played in the cause, and the timing of death. The factors associated with IA-related mortality are also analyzed. We conducted a multicenter study (2008-2011) of cases of proven and probable IA. The causes of death and whether mortality was judged to be IA-related or IA-unrelated were determined by consensus using a six-member review panel. A multivariate analysis was performed to determine risk factors for IA-related death. Of 152 patients with IA, 92 (60.5%) died. Mortality was judged to be IA-related in 62 cases and IA-unrelated in 30. The most common cause of IA-related death was respiratory failure (50/62 patients), caused primarily by Aspergillus infection, although also by concomitant infections or severe comorbidities. Progression of underlying disease and bacteremic shock were the most frequent causes of IA-unrelated death. IA-related mortality accounted for 98% and 87% of deaths within the first 14 and 21 days, respectively. Liver disease (HR 4.54; 95% CI, 1.69-12.23) was independently associated with IA-related mortality, whereas voriconazole treatment was associated with reduced risk of death (HR 0.43; 95% CI, 0.20-0.93). In conclusion, better management of lung injury after IA diagnosis is the main challenge for physicians to improve IA outcomes. There are significant differences in causes and timing between IA-related and IA-unrelated mortality and these should be considered in future research to assess the quality of IA care.