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BACKGROUND: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI. METHODS: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200â mg twice daily) or vancomycin (125â mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs. RESULTS: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (â¼3.5-fold), and increased the resistome. CONCLUSIONS: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.
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Antibacterianos , Clostridioides difficile , Infecciones por Clostridium , Microbioma Gastrointestinal , Vancomicina , Humanos , Vancomicina/uso terapéutico , Vancomicina/efectos adversos , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/microbiología , Masculino , Femenino , Persona de Mediana Edad , Método Doble Ciego , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Anciano , Clostridioides difficile/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Adulto , Resultado del Tratamiento , Metaboloma/efectos de los fármacos , Oxadiazoles/uso terapéutico , Oxadiazoles/efectos adversos , Disbiosis/inducido químicamente , Bencimidazoles , PiridinasRESUMEN
Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P = .03) and history of pneumonia (aOR, 48.7; P = .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P = .01), systemic antibiotic usage (aOR, 5.03; P = .04), and antimold prophylaxis (aOR, 11.9; P = .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ratio [aHR], 86.9; P < .001), intensive care unit stay (aHR, 3.67; P = .02), disseminated IA (aHR, 8.98; P < .001), and dialysis (aHR, 2.93; P = .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P = .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA.
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BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) are a major threat to patients. To date, data on risk factors have been limited, with low internal and external validity. In this multicentre study, risk factors for CRE BSI were determined by comparison with two control groups: patients with carbapenem-susceptible Enterobacterales (CSE) BSI, and patients without Enterobacterales infection (uninfected patients). METHODS: A multicentre, case-control-control study was nested in a European prospective cohort study on CRE (EURECA). CRE BSI:CSE BSI matching was 1:1, CRE BSI:Uninfected patients matching was 1:3, based on hospital, ward and length of stay. Conditional logistic regression was applied. RESULTS: From March 2016 to November 2018, 73 CRE BSIs, 73 CSE BSIs and 219 uninfected patients were included from 18 European hospitals. For CRE versus CSE BSI, previous CRE colonization/infection [incidence rate ratio (IRR) 7.32; 95% CI 1.65-32.38) increased the risk. For CRE versus uninfected controls, independent risk factors included: older age (IRR 1.03; 95% CI 1.01-1.06), patient referral (long-term care facility: IRR 7.19; 95% CI 1.51-34.24; acute care hospital: IRR 5.26; 95% CI 1.61-17.11), previous colonization/infection with other MDR organisms (MDROs) (IRR 9.71; 95% CI 2.33-40.56), haemodialysis (IRR 8.59; 95% CI 1.82-40.53), invasive procedures (IRR 5.66; 95% CI 2.11-15.16), and ß-lactam/ß-lactamase inhibitor combinations (IRR 3.92; 95% CI 1.68-9.13) or third/fourth generation cephalosporin (IRR 2.75; 95% CI 1.06-7.11) exposure within 3â months before enrolment. CONCLUSIONS: Evidence of previous CRE colonization/infection was a major risk factor for carbapenem resistance among Enterobacterales BSI. Compared with uninfected patients, evidence of previous MDRO colonization/infection and healthcare exposure were important risk factors for CRE BSI. Targeted screening, infection prevention and antimicrobial stewardship should focus on these high-risk patients.
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The 2023 International CMV Symposium took place in Barcelona in May 2023. During the 2-day meeting, delegates and faculty discussed the ongoing challenge of managing the risk of cytomegalovirus infection (the Troll of Transplantation) after solid organ or hematopoietic cell transplantation. Opportunities to improve outcomes of transplant recipients by applying advances in antiviral prophylaxis or pre-emptive therapy, immunotherapy, and monitoring of cell-mediated immunity to routine clinical practice were debated and relevant educational clinical cases presented. This review summarizes the presentations, cases, and discussions from the meeting and describes how further advances are needed before the Troll of Transplantation is slain.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Trasplante de Órganos , Humanos , Citomegalovirus , Antivirales/uso terapéutico , Trasplante de Órganos/efectos adversos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
We aimed to compare the efficacy of ceftazidime-avibactam (CAZ-AVI) versus the best available therapy (BAT) in solid organ transplant (SOT) recipients with bloodstream infection caused by carbapenemase-producing Klebsiella pneumoniae (CPKP-BSI). A retrospective (2016-2021) observational cohort study was performed in 14 INCREMENT-SOT centers (ClinicalTrials.gov identifier: NCT02852902; Impact of Specific Antimicrobials and MIC Values on the Outcome of Bloodstream Infections Due to ESBL- or Carbapenemase-producing Enterobacterales in Solid Organ Transplantation: an Observational Multinational Study). Outcomes were 14-day and 30-day clinical success (complete resolution of attributable manifestations, adequate source control, and negative follow-up blood cultures) and 30-day all-cause mortality. Multivariable logistic and Cox regression analyses adjusted for the propensity score to receive CAZ-AVI were constructed. Among 210 SOT recipients with CPKP-BSI, 149 received active primary therapy with CAZ-AVI (66/149) or BAT (83/149). Patients treated with CAZ-AVI had higher 14-day (80.7% vs 60.6%, P = .011) and 30-day (83.1% vs 60.6%, P = .004) clinical success and lower 30-day mortality (13.25% vs 27.3%, P = .053) than those receiving BAT. In the adjusted analysis, CAZ-AVI increased the probability of 14-day (adjusted odds ratio [aOR], 2.65; 95% confidence interval [CI], 1.03-6.84; P = .044) and 30-day clinical success (aOR, 3.14; 95% CI, 1.17-8.40; P = .023). In contrast, CAZ-AVI therapy was not independently associated with 30-day mortality. In the CAZ-AVI group, combination therapy was not associated with better outcomes. In conclusion, CAZ-AVI may be considered a first-line treatment in SOT recipients with CPKP-BSI.
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Enterobacteriaceae Resistentes a los Carbapenémicos , Infecciones por Klebsiella , Sepsis , Humanos , Antibacterianos/uso terapéutico , Klebsiella pneumoniae , Estudios Retrospectivos , Combinación de Medicamentos , Pruebas de Sensibilidad Microbiana , Infecciones por Klebsiella/tratamiento farmacológicoRESUMEN
BACKGROUND: Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. METHODS: In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis until CMV-CMI recovery or to receive fixed-duration prophylaxis until day 90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed 2 deleterious events (CMV disease/replication and neutropenia). RESULTS: A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs 2.7%; P = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. CONCLUSIONS: Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed. CLINICAL TRIALS REGISTRATION: NCT03123627.
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Infecciones por Citomegalovirus , Trasplante de Riñón , Suero Antilinfocítico/uso terapéutico , Antivirales/uso terapéutico , Citomegalovirus , Ganciclovir/uso terapéutico , Humanos , Trasplante de Riñón/efectos adversos , Receptores de TrasplantesRESUMEN
The objective of this study was to investigate the efficacy and safety of early treatment with sarilumab, added to standard of care (SOC), in hospitalized adults with COVID-19. Methods included phase II, open-label, randomized, controlled clinical trial of hospitalized patients with COVID-19 pneumonia and interleukin (IL)-6 levels ≥ 40 pg/mL and/or d-dimer > 1,500 ng/mL. Participants were randomized (1:1:1) to receive SOC (control group), SOC plus a single subcutaneous dose of sarilumab 200 mg (sarilumab-200 group), or SOC plus a single subcutaneous dose of sarilumab 400 mg (sarilumab-400 group). The primary outcome variable was the development of acute respiratory distress syndrome (ARDS) requiring high-flow nasal oxygenation (HFNO), non-invasive mechanical ventilation (NIMV) or invasive mechanical ventilation (IMV) at day 28. One-hundred and 15 participants (control group, n = 39; sarilumab-200, n = 37; sarilumab-400, n = 39) were included. At randomization, 104 (90%) patients had supplemental oxygen and 103 (90%) received corticosteroids. Eleven (28%) patients in the control group, 10 (27%) in sarilumab-200, and five (13%) in sarilumab-400 developed the primary outcome (hazard ratio [95% CI] of sarilumab-400 vs control group: 0.41 [0.14, 1.18]; P = 0.09). Seven (6%) patients died: three in the control group and four in sarilumab-200. There were no deaths in sarilumab-400 (P = 0.079, log-rank test for comparisons with the control group). In patients recently hospitalized with COVID-19 pneumonia and features of systemic inflammation, early IL-6 blockade with a single dose of sarilumab 400 mg was safe and associated with a trend for better outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT04357860.).
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Adulto , Humanos , Inflamación , SARS-CoV-2 , Resultado del TratamientoRESUMEN
BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. METHODS: We conducted a multicentre retrospective observational study of patients who received ≥48â h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30â day crude mortality. Secondary outcomes were 21â day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30â day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. RESULTS: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2â days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20-0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18-1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08-1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21â day clinical response (OR 2.43, 95% CI 1.16-5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18-0.85; P = 0.02). CONCLUSIONS: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.
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Antibacterianos , Ceftazidima , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Proteínas Bacterianas , Ceftazidima/uso terapéutico , Combinación de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , beta-LactamasasRESUMEN
BACKGROUND: Both fidaxomicin and bezlotoxumab (used in combination with an antibiotic against Clostridioides difficile) achieve reductions in recurrence rates of C. difficile infection (CDI). However, the two strategies have never been compared. METHODS: Data from two retrospective cohorts of 'real-life' use of fidaxomicin and bezlotoxumab in combination with a standard anti-C. difficile antibiotic were used to compare the rates of recurrence of both strategies. Since the two cohorts were not identical, we used a propensity score analysis. RESULTS: Three hundred and two patients were included: 244 in the fidaxomicin cohort and 78 in the bezlotoxumab cohort. A history of renal failure or immunosuppression was more frequent in patients receiving bezlotoxumab (39.7% and 66.7% versus 26.6% and 38.9%; Pâ=â0.03 and Pâ<â0.001, respectively), but the severity and number of previous CDI episodes were similar in both cohorts. We observed that 19.3% of the patients in the fidaxomicin cohort experienced recurrence, compared with 14.1% in the bezlotoxumab cohort (OR 1.45; 95% CI 0.71-2.96; Pâ=â0.29) but the difference remained non-significant after propensity score matching using previously defined variables (OR 1.24; 95% CI 0.50-3.07; Pâ=â0.64). Moreover, the multivariate analysis did not show differences depending on the drug used. CONCLUSIONS: We observed that fidaxomicin and bezlotoxumab are prescribed in similar clinical scenarios, although those treated with bezlotoxumab have greater comorbidity. The proportion of recurrences was numerically lower in those treated with bezlotoxumab, although the propensity analysis did not find significant differences between the two drugs.
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Infecciones por Clostridium , Vancomicina , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales , Anticuerpos ampliamente neutralizantes , Infecciones por Clostridium/tratamiento farmacológico , Estudios de Cohortes , Fidaxomicina/uso terapéutico , Humanos , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento , Vancomicina/uso terapéuticoRESUMEN
This article gives a personal, historical, account of the impact of the COVID-19 pandemic on transplantation services. The content is based on discussions held at two webinars in November 2020, at which kidney transplantation experts from prestigious institutions in Europe and the United States reflected on how the pandemic affected working practices. The group discussed adaptations to clinical care (i.e., ceasing, maintaining and re-starting kidney transplantations, and cytomegalovirus infection management) across the early course of the pandemic. Discussants were re-contacted in October 2021 and asked to comment on how transplantation services had evolved, given the widespread access to COVID-19 testing and the roll-out of vaccination and booster programs. By October 2021, near-normal life and service delivery was resuming, despite substantial ongoing cases of COVID-19 infection. However, transplant recipients remained at heightened risk of COVID-19 infection despite vaccination, given their limited response to mRNA vaccines and booster dosing: further risk-reduction strategies required exploration. This article provides a contemporaneous account of these different phases of the pandemic from the transplant clinician's perspective, and provides constructive suggestions for clinical practice and research.
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COVID-19 , Trasplante de Riñón , COVID-19/epidemiología , Prueba de COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Infections caused by multidrug-resistant gram-negative bacilli (MDR GNB), in particular extended-spectrum ß-lactamase-producing (ESBL-E) and carbapenem-resistant Enterobacterales (CRE), pose a major threat in solid organ transplantation (SOT). Outcome prediction and therapy are challenging due to the scarcity of randomized clinical trials (RCTs) or well-designed observational studies focused on this population. METHODS: Narrative review with a focus on the contributions provided by the ongoing multinational INCREMENT-SOT consortium (ClinicalTrials identifier NCT02852902) in the fields of epidemiology and clinical management. RESULTS: The Spanish Society of Transplantation (SET), the Group for Study of Infection in Transplantation of the Spanish Society of Infectious Diseases and Clinical Microbiology (GESITRA-SEIMC), and the Spanish Network for Research in Infectious Diseases (REIPI) recently published their recommendations for the management of MDR GNB infections in SOT recipients. We revisit the SET/GESITRA-SEIMC/REIPI document taking into consideration new evidence that emerged on the molecular epidemiology, prognostic stratification, and treatment of post-transplant ESBL-E and CRE infections. Results derived from the INCREMENT-SOT consortium may support the therapeutic approach to post-transplant bloodstream infection (BSI). The initiatives devoted to sparing the use of carbapenems in low-risk ESBL-E BSI or to repurposing existing non-ß-lactam antibiotics for CRE in both non-transplant and transplant patients are reviewed, as well as the eventual positioning in the specific SOT setting of recently approved antibiotics. CONCLUSION: Due to the clinical complexity and relative rarity of ESBL-E and CRE infections in SOT recipients, multinational cooperative efforts such as the INCREMENT-SOT Project should be encouraged. In addition, RCTs focused on post-transplant serious infection remain urgently needed.
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Enfermedades Transmisibles , Trasplante de Órganos , Sepsis , Antibacterianos/uso terapéutico , Carbapenémicos/uso terapéutico , Bacterias Gramnegativas , Humanos , Trasplante de Órganos/efectos adversos , Sepsis/tratamiento farmacológico , beta-LactamasasRESUMEN
The CMV Symposium in September 2021 was an international conference dedicated to cytomegalovirus (CMV) infection after solid organ or hematopoietic stem cell transplantation. This review provides an overview of the presentations given by the expert faculty, supplemented with educational clinical cases. Topics discussed include CMV epidemiology and diagnosis, the burden of CMV infection and disease, CMV-specific immunity and management of CMV in transplant settings. Major advances in the prevention and treatment of CMV in the past decade and increased understanding of CMV immunity have led to improved patient outcomes. In the future, management algorithms may be individualized based on the transplant recipient's immune profile, which will mark the start of a new era for patients with CMV.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Trasplante de Pulmón , Trasplante de Órganos , Humanos , Citomegalovirus , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/prevención & control , Trasplante de Órganos/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antivirales/uso terapéuticoRESUMEN
BACKGROUND: This is a prospective, multicenter, observational study in cytomegalovirus (CMV)-seropositive kidney transplant recipients with pretransplant CMV-specific cell-mediated immunity (CMV-CMI) receiving antithymocyte globulin (ATG). We aimed to investigate posttransplant CMV-CMI over time and the impact of the dose-dependent ATG. METHODS: CMV-CMI was assessed at days +30, +45, +60, and +90 after transplantation with the QuantiFERON-CMV assay. A reactive result (interferon-γ [IFN-γ]â ≥â 0.2 IU/mL) indicated a positive CMV-CMI. RESULTS: A total of 78 positive CMV-CMI patients were enrolled in the study, of which 59.5% had a positive CMV-CMI at day +30 and 82.7% at day +90. Multivariate logistic regression analysis showed that ATG dose was not associated with positive CMV-CMI at any point. However, pretransplant IFN-γ level (>12 IU/mL vs ≤12 IU/mL) was associated with positive CMV-CMI at day +30 (odds ratio, 12.9; 95% confidence interval, 3.1-53.3; Pâ <â .001). In addition, all the patients who did not recover CMV-CMI at day +90 had a pretransplant IFN-γ level ≤12 IU/mL. CONCLUSIONS: More than half of CMV-seropositive kidney transplant recipients receiving ATG recover (or maintain) CMV-CMI by the first month after transplantation. The pretransplant IFN-γ level, but not the ATG dose, shows a strong association with the kinetics of this recovery.
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Suero Antilinfocítico/uso terapéutico , Antivirales , Infecciones por Citomegalovirus , Inmunidad Celular , Trasplante de Riñón , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Humanos , Interferón gamma/análisis , Estudios Prospectivos , Linfocitos TRESUMEN
Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000-2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000-2009 to 0.22 cases per 100,000 admissions in 2010-2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy.
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Fusariosis , Fusarium , Neutropenia , Antifúngicos/uso terapéutico , Fusariosis/tratamiento farmacológico , Fusariosis/epidemiología , Humanos , Neutropenia/tratamiento farmacológico , Neutropenia/epidemiología , Estudios Observacionales como Asunto , España/epidemiologíaRESUMEN
There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.
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Bacteriemia , Trasplante de Riñón , Infecciones Urinarias , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Estudios de Cohortes , Ertapenem , Humanos , Puntaje de Propensión , Estudios Retrospectivos , Infecciones Urinarias/tratamiento farmacológico , beta-LactamasasRESUMEN
HCMV-encoded microRNAs (hcmv-miRNAs) are non-coding and non-immunogenic molecules that target numerous cellular genes and allow the virus to modulate the host's signalling pathways, thus favouring viral survival and replication. Given their capacity to silence the human genes involved in various physiological processes, these hcmv-miRNAs have now emerged as a potential clinical biomarker in many human diseases. In this review, we summarize the evidence published on the diagnostic and prognostic value of hcmv-miRNAs in several human diseases and their clinical implications. Specifically, we discuss the role of hcmv-miRNAs in the development of cardiovascular diseases and cancer by silencing tumour suppressors. We also examine the current knowledge on the utility of some hcmv-miRNAs in predicting HCMV viraemia recurrence in transplant patients, as well as the interference of hcmv-miRNAs in the development of an appropriate immune response against other viral infections, which might have therapeutic implications.Abbreviations: HCMV, human cytomegalovirus; hcmv-miRNA, HCMV-encoded microRNAs.
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Enfermedades Cardiovasculares/virología , Infecciones por Citomegalovirus/genética , Citomegalovirus/genética , MicroARNs/genética , Neoplasias/virología , Enfermedades Cardiovasculares/genética , Citomegalovirus/patogenicidad , Diagnóstico Precoz , Marcadores Genéticos , Interacciones Huésped-Patógeno , Humanos , Neoplasias/genética , Pronóstico , ARN Viral/genética , Transducción de SeñalRESUMEN
BACKGROUND: Whether active therapy with ß-lactam/ß-lactamase inhibitors (BLBLI) is as affective as carbapenems for extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) bloodstream infection (BSI) secondary to urinary tract infection (UTI) in kidney transplant recipients (KTRs) remains unclear. METHODS: We retrospectively evaluated 306 KTR admitted to 30 centers from January 2014 to October 2016. Therapeutic failure (lack of cure or clinical improvement and/or death from any cause) at days 7 and 30 from ESBL-E BSI onset was the primary and secondary study outcomes, respectively. RESULTS: Therapeutic failure at days 7 and 30 occurred in 8.2% (25/306) and 13.4% (41/306) of patients. Hospital-acquired BSI (adjusted OR [aOR]: 4.10; 95% confidence interval [CI]: 1.50-11.20) and Pitt score (aOR: 1.47; 95% CI: 1.21-1.77) were independently associated with therapeutic failure at day 7. Age-adjusted Charlson Index (aOR: 1.25; 95% CI: 1.05-1.48), Pitt score (aOR: 1.72; 95% CI: 1.35-2.17), and lymphocyte count ≤500 cells/µL at presentation (aOR: 3.16; 95% CI: 1.42-7.06) predicted therapeutic failure at day 30. Carbapenem monotherapy (68.6%, primarily meropenem) was the most frequent active therapy, followed by BLBLI monotherapy (10.8%, mostly piperacillin-tazobactam). Propensity score (PS)-adjusted models revealed no significant impact of the choice of active therapy (carbapenem-containing vs any other regimen, BLBLI- vs carbapenem-based monotherapy) within the first 72 hours on any of the study outcomes. CONCLUSIONS: Our data suggest that active therapy based on BLBLI may be as effective as carbapenem-containing regimens for ESBL-E BSI secondary to UTI in the specific population of KTR. Potential residual confounding and unpowered sample size cannot be excluded (ClinicalTrials.gov identifier: NCT02852902).
Asunto(s)
Bacteriemia , Trasplante de Riñón , Infecciones Urinarias , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Carbapenémicos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Humanos , Lactamas , Estudios Retrospectivos , Infecciones Urinarias/tratamiento farmacológico , Inhibidores de beta-Lactamasas/uso terapéutico , beta-LactamasasRESUMEN
BACKGROUND: The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. PATIENTS AND METHODS: The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10 years. Proven and probable/putative IA was included. RESULTS: We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3 months was significantly lower (p < 0.001) in lung transplant recipients (14.8%) than in all other transplants [globally: 48.6%; kidney 52.0%, liver 58.3%, heart 31.2%, and combined 42.9%]. Fifty-four percent of episodes occurred despite the receipt of antifungal prophylaxis, and in 10%, IA occurred during prophylaxis (breakthrough infection), with both nebulised amphotericin (in lung transplant recipients) and candins (in the rest). CONCLUSIONS: Invasive aspergillosis diagnostic criteria, applied to SOT patients, may differ from those established for haematological patients. IA in lung transplants has a higher incidence, but is associated with a better prognosis than other transplants. Combination therapy is frequently used for IA in SOT. Prophylactic measures require optimisation of its use within this population.
Asunto(s)
Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/terapia , Trasplante de Órganos , Adulto , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Causalidad , Estudios de Cohortes , Femenino , Humanos , Aspergilosis Pulmonar Invasiva/epidemiología , Aspergilosis Pulmonar Invasiva/etiología , Masculino , Estudios Retrospectivos , Sensibilidad y Especificidad , España/epidemiología , Voriconazol/efectos adversos , Voriconazol/uso terapéutico , Adulto JovenRESUMEN
Carbapenemase-producing Enterobacterales and specifically Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-Kp is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than that caused by carbapenem-susceptible isolates. This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent intensive care unit in a university hospital (>40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression). We analyze 69 cases of K. pneumoniae VAP, of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC > 16 mg/ml). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.46 to 3.41). Adequate targeted therapy (HR, 0.03; 95% CI, <0.01 to 0.23) was associated with all-cause mortality. Assuming the limitations due to the available sample size, the prognosis of VAP caused by KPC-Kp is similar to VAPs caused by carbapenem-susceptible K. pneumoniae when appropriate treatment is used.
Asunto(s)
Infecciones por Klebsiella , Neumonía Asociada al Ventilador , Antibacterianos/uso terapéutico , Proteínas Bacterianas/genética , Humanos , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae , Meropenem/uso terapéutico , Neumonía Asociada al Ventilador/tratamiento farmacológico , Estudios Retrospectivos , beta-Lactamasas/genéticaRESUMEN
OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2â+â3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2â+â3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2â+â3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.