An Ocean between the Waves: Trends in Antimicrobial Consumption in Hospitalized Patients with COVID-19.

We assessed the antibiotic use in SARS-CoV-2-infected patients during four different waves of the COVID-19 pandemic, as well as its trends over the period and associated risk factors. We performed a cross-sectional retrospective analysis nested in a prospectively collected cohort of hospitalized adult patients with COVID-19 at a university hospital in Spain. A total of 2415 patients were included in this study, among whom 1120 corresponded to the first wave. The highest percentage of patients receiving some sort of antibiotic treatment was higher during the first wave (77.6%) than during the others; nevertheless, our calculation of the average DOT (days of antibiotic treatment) per 100 patient days of stay found that the highest antibiotic prescription rate corresponded to the second pandemic wave (61.61 DOT/100 patient days), which was associated with a higher ICU admission rate and a lower SpO2/FiO2 ratio at admission. After the second wave, the prescription rates presented a steady downward trend. With regard to the use of specific antibiotic families, amoxicillin/clavulanate was the most used antibiotic in our cohort (14.20 DOT/100 patient days) due to a high prescription rate during the first wave. According to the "AWaRe" WHO classification, antibiotics corresponding to the "Watch" group were the most prescribed (27.92 DOT/100 patient days). The antibiotic use rate fell progressively, but it remained high during all four waves analyzed. In conclusion, antibiotic use was high throughout all the waves that were analyzed, despite a relatively low incidence of bacterial coinfection and superinfection. Efforts should be made to keep antimicrobial stewardship programs active, especially in complicated epidemiological situations, such as the SARS-CoV-2 pandemic.

The Etiology, Antibiotic Therapy and Outcomes of Bacteremic Skin and Soft-Tissue Infections in Onco-Hematological Patients.

OBJECTIVES: to assess the current epidemiology, antibiotic therapy and outcomes of onco- hematological patients with bacteremic skin and soft-tissue infections (SSTIs), and to identify the risk factors for Gram-negative bacilli (GNB) infection and for early and overall mortality. METHODS: episodes of bacteremic SSTIs occurring in cancer patients at two hospitals were prospectively recorded and retrospectively analyzed. RESULTS: Of 164 episodes of bacteremic SSTIs, 53% occurred in patients with solid tumors and 47% with hematological malignancies. GNB represented 45.5% of all episodes, led by Pseudomonas aeruginosa (37.8%). Multidrug resistance rate was 16%. Inadequate empirical antibiotic therapy (IEAT) occurred in 17.7% of episodes, rising to 34.6% in those due to resistant bacteria. Independent risk factors for GNB infection were corticosteroid therapy and skin necrosis. Early and overall case-fatality rates were 12% and 21%, respectively. Risk factors for early mortality were older age, septic shock, and IEAT, and for overall mortality were older age, septic shock and resistant bacteria. CONCLUSIONS: GNB bacteremic SSTI was common, particularly if corticosteroid therapy or skin necrosis. IEAT was frequent in resistant bacteria infections. Mortality occurred mainly in older patients with septic shock, resistant bacteria and IEAT. These results might guide empirical antibiotic therapy in this high-risk population.

Increasing Gram-Negative Catheter-Related Bloodstream Infection in Cancer Patients.

Background: We aimed to assess the incidence, etiology and outcomes of catheter-related bloodstream infection (CRBSI) in onco-hematological patients, to assess the differences between patients with hematological malignancies (HMs) and solid tumors (STs) and to identify the risk factors for Gram-negative (GN) CRBSI. Methods: All consecutive episodes of BSI in adult cancer patients were prospectively collected (2006-2020). The etiology of CRBSI was analyzed in three different 5-year periods. Risk factors for GN CRBSI were assessed in the whole cohort and separately in patients with HMs and STs. Results: Among 467 episodes of monomicrobial CRBSI, 407 were Gram-positive (GP) (87.1%), 49 GN (10.5%) and 11 fungal (2.4%). Hematological patients (369 episodes) were more frequently neutropenic and were more likely to carry central venous catheters and develop GP CRBSI. Patients with STs (98 episodes) had more comorbidities, more frequently carried port reservoirs and commonly presented more GN CRBSI. GN CRBSI significantly increased over the study period, from 5.2% to 23% (p < 0.001), whereas GP CRBSI decreased from 93.4% to 73.3% (p < 0.001). CRBSI episodes involving port reservoirs and peripherally-inserted central catheters were significantly increased (p < 0.001). The most frequent GPs were coagulase-negative staphylococci (CoNS) (57.8%) and Pseudomonas aeruginosa was the most common GN (3%). Multidrug-resistant (MDR) GN represented 32.7% of all GN CRBSIs and increased over time (p = 0.008). The independent risk factors for GN CRBSI in the whole cohort were solid tumor, chronic kidney disease and carrying a port reservoir. Carrying a port reservoir was also a risk factor in patients with STs. Health-care acquisition was identified as a risk factor for GN CRBSI in the whole cohort, as well as in patients with STs and HMs. Inadequate empirical antibiotic treatment (IEAT) occurred regardless of the etiology: 49% for GNs and 48.6% for GPs (p = 0.96). In GP CRBSI, IEAT was mainly due to inadequate coverage against CoNS (87%), whereas in GN CRBSI, IEAT was associated with multidrug resistance (54.2%). Early (48 h and 7-day) and 30-day case-fatality rates were similar when analyzed according to the type of underlying disease and etiology, except for the 30-day case-fatality rate, which was higher in the group of patients with STs compared to those with HMs (21.5% vs. 12.5%, p = 0.027). The 48 h case-fatality rate was significantly higher in patients in whom the catheter had not been removed (5.6% vs. 1%; p = 0.011), and it remained significant for GP CRBSI (6% vs. 1.3%, p = 0.023). Conclusions: GNs are an increasing cause of CRBSI in cancer patients, particularly in solid tumor patients carrying port reservoirs. Multidrug resistance among GNs is also increasing and is associated with higher rates of IEAT. Decreased 48 h survival was associated with the non-removal of the catheter. These findings should be considered when deciding on early therapeutic management for cancer patients with suspected CRBSI.

Effect of Combination Antibiotic Empirical Therapy on Mortality in Neutropenic Cancer Patients with Pseudomonas aeruginosa Pneumonia.

To assess the effect of combination antibiotic empirical therapy on 30-day case-fatality rate in neutropenic cancer patients with Pseudomonas aeruginosa (PA) bacteremic pneumonia. This was a multinational, retrospective cohort study of neutropenic onco-hematological patients with PA bloodstream infection (BSI) (2006−2018). The effect of appropriate empirical combination therapy, appropriate monotherapy and inappropriate empirical antibiotic therapy [IEAT] on 30-day case-fatality was assessed only in patients with PA bacteremic pneumonia. Among 1017 PA BSI episodes, pneumonia was the source of BSI in 294 (28.9%). Among those, 52 (17.7%) were caused by a multidrug-resistant (MDR) strain and 68 (23.1%) received IEAT, mainly when the infection was caused by an MDR strain [38/52 (73.1%) vs. 30/242 (12.4%); p < 0.001]. The 30-day case-fatality rate was higher in patients with PA bacteremic pneumonia than in those with PA BSI from other sources (55.1% vs. 31.4%; p < 0.001). IEAT was associated with increased 30-day case-fatality (aHR 1.44 [95%CI 1.01−2.03]; p = 0.042), whereas the use of appropriate combination empirical treatment was independently associated with improved survival (aHR 0.46 [95%CI 0.27−0.78]; p = 0.004). Appropriate empirical monotherapy was not associated with improved overall survival (aHR 1.25 [95%CI 0.76−2.05]; p = 0.39). Combination antibiotic empirical therapy should be administered promptly in febrile neutropenic patients with suspected pneumonia as the source of infection.

Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: a Matched Control Study (ZENITH Study).

We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T.

Impact of Empirical Antibiotic Regimens on Mortality in Neutropenic Patients with Bloodstream Infection Presenting with Septic Shock.

We analyzed risk factors for mortality in febrile neutropenic patients with bloodstream infections (BSI) presenting with septic shock and assessed the impact of empirical antibiotic regimens. A multicenter retrospective study (2010 to 2019) of two prospective cohorts compared BSI episodes in patients with or without septic shock. Multivariate analysis was performed to identify independent risk factors for mortality in episodes with septic shock. Of 1,563 patients with BSI, 257 (16%) presented with septic shock. Those patients with septic shock had higher mortality than those without septic shock (55% versus 15%, P < 0.001). Gram-negative bacilli caused 81% of episodes with septic shock, Gram-positive cocci caused 22%, and Candida species caused 5%. Inappropriate empirical antibiotic treatment (IEAT) was administered in 17.5% of septic shock episodes. Empirical ß-lactam combined with other active antibiotics was associated with the lowest mortality observed. When amikacin was the only active antibiotic, mortality was 90%. Addition of empirical specific Gram-positive coverage had no impact on mortality. Mortality was higher when IEAT was administered (76% versus 51%, P = 0.002). Age of >70 years (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2 to 4.7), IEAT for Candida spp. or Gram-negative bacilli (OR, 3.8; 95% CI, 1.3 to 11.1), acute kidney injury (OR, 2.6; 95% CI, 1.4 to 4.9), and amikacin as the only active antibiotic (OR, 15.2; 95% CI, 1.7 to 134.5) were independent risk factors for mortality, while the combination of ß-lactam and amikacin was protective (OR, 0.32; 95% CI, 0.18 to 0.57). Septic shock in febrile neutropenic patients with BSI is associated with extremely high mortality, especially when IEAT is administered. Combination therapy including an active ß-lactam and amikacin results in the best outcomes.

Immunomodulatory therapy, risk factors and outcomes of hospital-acquired bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish case-control matched multicentre study (BACTCOVID).

OBJECTIVES: The effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia. METHODS: We performed a severity matched case-control study (1:1 ratio) nested in a large multicentre prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed. RESULTS: Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9-20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59; 1.65-4.07; p < 0.001). DISCUSSION: Hospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.

Relapsing Haemothorax as an Unusual Presentation of Primary Angiosarcoma of the Spleen.

Spontaneous haemothorax (SH) is a rare subcategory of haemothorax that involves the accumulation of blood within the pleural space in the absence of trauma. SH especially occurs in middle-aged or elderly patients, but data are usually limited to case reports and case series. Coagulopathy, aneurysm or aortic dissection, Rendu-Osler-Weber syndrome and malignancy have to be considered among the causes of SH. AIM: We describe a case of primary angiosarcoma of the spleen presenting as relapsing haemothorax. RESULTS: An 81-year-old woman was referred to our hospital because of a 2-month history of relapsing haemothorax after the performance of urgent splenectomy due to active bleeding from large spleen cysts. No evidence of neoplasm was seen after pathological examination of the spleen. On admission, left haemothorax and 2 new cystic masses in the thoracic wall were documented, both in close relation to the scars of previous surgery and chest tubes. After excision of 1 mass, histological examination revealed angiosarcoma, and a final diagnosis of primary angiosarcoma of the spleen with postsurgical metastatic dissemination to the thorax and pleura was made. CONCLUSION: Primary angiosarcoma should be included in the differential diagnosis of haemorrhagic spleen cysts. Clinical diagnosis and management usually requires splenectomy, but it should be carefully planned in order to avoid local metastatic dissemination or haematogenous spread of the tumour. LEARNING POINTS: The differential diagnosis of spleen cysts must include malignant conditions.Despite its absolute rarity, angiosarcoma is considered the most common primary non-haematolymphoid splenic malignancy and has a poor prognosis.Splenectomy is usually required for a prompt diagnosis of primary angiosarcoma of the spleen, but it needs to be performed with extreme caution to avoid metastatic dissemination.