Clinical aspects of visceral leishmaniasis caused by L. infantum in adults. Ten years of experience of the largest outbreak in Europe: what have we learned?

BACKGROUND: An outbreak of leishmaniasis caused by Leishmania infantum was declared in the southwest of the Madrid region (Spain) in June 2009. This provided a unique opportunity to compare the management of visceral leishmaniasis (VL) in immunocompetent adults (IC-VL), patients with HIV (HIV-VL) and patients receiving immunosuppressants (IS-VL). METHODS: A cohort of adults with VL, all admitted to the Hospital Universitario de Fuenlabrada between June 2009 and June 2018, were monitored in this observational study, recording their personal, epidemiological, analytical, diagnostic, treatment and outcome variables. RESULTS: The study population was made up of 111 patients with VL (10% HIV-VL, 14% IS-VL, 76% IC-VL). Seventy-one percent of the patients were male; the mean age was 45 years (55 years for the IS-VL patients, P = 0.017). Fifty-four percent of the IC-VL patients were of sub-Saharan origin (P = 0.001). Fever was experienced by 98% of the IC-VL patients vs 73% of the LV-HIV patients (P = 0.003). Plasma ferritin was > 1000 ng/ml in 77% of the IC-VL patients vs 17% of the LV-HIV patients (P = 0.007). Forty-two percent of patients fulfilled the criteria for haemophagocytic lymphohistiocytosis. RDT (rK39-ICT) serological analysis returned sensitivity and specificity values of 45% and 99%, respectively, and ELISA/iIFAT returned 96% and 89%, respectively, with no differences in this respect between patient groups. Fourteen (13.0%) patients with VL experienced treatment failure, eight of whom were in the IC-VL group. Treatment with < 21 mg/kg (total) liposomal amphotericin B (LAB) was associated with treatment failure in the IC-VL patients [P = 0.002 (OR: 14.7; 95% CI: 2.6-83.3)]. CONCLUSIONS: IS-VL was more common than HIV-VL; the lack of experience in dealing with IS-VL is a challenge that needs to be met. The clinical features of the patients in all groups were similar, although the HIV-VL patients experienced less fever and had lower plasma ferritin concentrations. RDT (rK39-ICT) analysis returned a good specificity value but a much poorer sensitivity value than reported in other scenarios. The patients with HIV-VL, IS-VL and IC-VL returned similar serological results. Current guidelines for treatment seem appropriate, but the doses of LAB required to treat patients with HIV-VL and IS-VL are poorly defined.This work received financial support from the Red de Investigación Cooperativa en Enfermedades Tropicales (RICET) (RD12/0018/0008; RD16/0027/0017) (ISCIII) and the FEDER.S

Cellular Markers of Active Disease and Cure in Different Forms of Leishmania infantum-Induced Disease

Increased numbers of peripheral blood mononucleocytes (PBMC) and increased IFN-γ secretion following in vitro challenge of blood samples with soluble Leishmania antigen (SLA), have been proposed as biomarkers of specific cell-mediated immunity, indicating that treatment of visceral leishmaniasis (VL) has been successful. However, Leishmania infantum infection may manifest as cutaneous leishmaniasis (CL), and less commonly as localized leishmanial lymphadenopathy (LLL) or mucosal leishmaniasis (ML). The present work examines the value of these biomarkers as indicators of cured leishmaniasis presenting in these different forms. Blood samples were collected before and after treatment from patients living in Fuenlabrada (Madrid, Spain), an L. infantum-endemic area recently the center of a leishmaniasis outbreak. All samples were subjected to Leishmania-specific PCR, serological tests (IFAT and rK39-ICT), and the SLA-cell proliferation assay (SLA-CPA), recording PBMC proliferation and the associated changes in IFN-γ production. Differences in the results recorded for the active and cured conditions were only significant for VL. PCR returned positive results in 67% of patients with active VL and in 3% of those with cured leishmaniasis. Similarly, rK39-ICT returned a positive result in 77% of active VL samples vs. 52% in cured VL samples, and IFAT in 90% vs. 56%; in the SLA-CPA, PBMC proliferation was seen in 16% vs. 90%, and an associated increase in IFN-γ production of 14 and 84%, respectively. The present findings reinforce the idea that PBMC proliferation and increased IFN-γ production in SLA-stimulated PBMC provide biomarkers of clinical cure in VL. Other tests are urgently needed to distinguish between the cured and active forms of the other types of clinical leishmaniasis caused by L. infantum

Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project)

REIPI/INCREMENT-SOT Group.[Background] Whether active therapy with β-lactam/β-lactamase inhibitors (BLBLI) is as affective as carbapenems for extended-spectrum β-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).This work was supported by: (1) Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III (ISCIII), Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0002, REIPI RD16/0016/0008; RD16/0016/00010], co-financed by European Development Regional Fund “A way to achieve Europe”, Operative Program Intelligent Growth 2014-2020; (2) European Society of Clinical Microbiology and Infectious diseases Study Group for Infections in Compromised Hosts (ESGICH, grant to J.M.A.); (3) Sociedad Andaluza de Trasplante de Órgano Sólido (SATOT, grant to L.M.M.); (4) Research project PI16/01631 integrated into the Plan Estatal de I+D+I 2013-2016 and co-financed by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación and the Fondo Europeo de Desarrollo Regional (FEDER); (5) M.F.R. holds a research contract “Miguel Servet” (CP 18/00073) from ISCIII, Ministerio de Ciencia, Innovación y Universidades. The work was also supported by the following European Society of Clinical Microbiology and Infectious diseases (ESCMID) study groups: Infections in Compromised Hosts (ESGICH), Bloodstream Infections and Sepsis (ESGBIS) and Antimicrobial Resistance Surveillance (ESGARS).Peer reviewe

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients—Results of a Spanish multicenter cohort

Preliminary results of this study were presented at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), held in Amsterdam, The Netherlands, from 13 to 16 April, 2019 (oral communication O‐0699).Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram‐negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended‐spectrum β‐lactamase‐producing Enterobacteriaceae [14%] or carbapenem‐resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5‐2) was administered for a median of 7 days (IQR: 3‐10). Clinical cure (remission of UTI‐attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow‐up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98‐112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.This study was supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016)—cofinanced by the European Development Regional Fund “A way to achieve Europe”; the Group for Study of Infection in Transplantation and the Immunocompromised Host (GESITRA‐IC) of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC); and the Spanish Network for Research in Renal Diseases (REDInREN RD16/0009). MFR holds a research contract “Miguel Servet” (CP 18/00073) from the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III

Efficacy and Safety of Oral Fosfomycin for Asymptomatic Bacteriuria in Kidney Transplant Recipients: Results from a Spanish Multicenter Cohort

Current guidelines recommend against systematic screening for or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of posttransplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR], 1.1 to 10.5). Most episodes (96.4% [132/137]) were caused by Gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended‐spectrum β‐lactamase‐producing Enterobacterales [20.4%] and carbapenem‐resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [CI], 31.9% to 48.9%) for the whole cohort and 42.3% (95% CI, 31.2% to 54.0%) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR], 2.42; 95% CI, 1.11 to 5.29; P value = 0.027) and use of fosfomycin as salvage therapy (OR, 8.31; 95% CI, 1.67 to 41.35; P value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse events were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens.This study was supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III (ISCIII), Subdirección General de Redes y Centros de Investigación Cooperativa, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016), and Spanish Network for Research in Renal Diseases (REDInREN RD16/0009) and cofinanced by the European Development Regional Fund entitled A way to achieve Europe. M.F.-R. holds a research contract (Miguel Servet, CP18/00073), from the Spanish Ministry of Science and Innovation, ISCIII.Peer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Lymphoproliferative response after stimulation with soluble leishmania antigen (SLA) as a predictor of visceral leishmaniasis (VL) relapse in HIV+ patients.

The introduction of HAART resulted in the decrease of Leishmania/HIV co-infection cases; nevertheless, the number of relapses remains high and secondary prophylaxis is recommended. However, secondary prophylaxis is not necessary in all patients, and presents a high risk of toxicity and an elevated cost. Our aim was to study whether specific cellular response to Leishmania infantum (measured by cell proliferation response after stimulation with soluble Leishmania antigen (SLA)), could be a useful tool to attempt a secondary prophylaxis withdrawal. In June 2009 an outbreak of leishmaniasis by Leishmania infantum was declared in the southeast of Madrid, and since January 2013, we recruited 10 HIV+ patients that had been treated for visceral leishmaniasis. 6 patients had positive SLA-cell proliferation test. The mean CD4 cell counts of those patients with positive SLA were 140 cel/mm3 and 40 cel/mm3 in those with negative SLA test. 3 patients with positive SLA-cell proliferation test (CD4 count: 336, 307, 625) were not on prophylaxis, and the other 3 patients (CD4 count: 152, 189, 359) were on secondary prophylaxis that was withdrawn after the positive SLA-cell proliferation test with no posterior relapses (mean follow up 60 weeks). From the 4 patients, which had negative SLA-cell proliferation test and continued on prophylaxis, 3 had positive PCR for Leishmania at the end of the follow-up and 2 presented clinical relapses. The performance of SLA-cell proliferation test can be a useful tool that can permit us to try withdrawal of the prophylaxis in Leishmania/HIV co-infected patients with low CD4+ counts under clinical supervision, diminishing risk of toxicity and cost.This study received financial support from the ‘Red de Investigación Cooperativa en Enfermedades Tropicales (RICET + RD12/0018/0008), VI PN de I + D + I 2008–2011, ISCIII— Subdirección General de Redes y Centros de Investigación Cooperativa; y fondos FEDER, and from ISCIII-AES project Impact of leishmaniasis outbreak in the southwest of Madrid in the immunosuppressed population (PI13/00440). EC was supported by a research contract funded via VII PN I + D + I 2013–2016 and FEDER Funds (RICET RD12/0018/0003).S