Diagnostic and therapeutic approach to pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitors.

The advent of immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death (PD-1)/PD-1 ligand 1 (PD-L1) axis has transformed the treatment paradigm for multiple cancer types. ICIs are able to restore T-cell-mediated antitumor responses and do not entail an increased risk of infection per se. However, immunotherapy is associated to a unique form of toxicity due to the off-target effects on healthy tissues of the excessively enhanced immune response in form of immune-related adverse events (irAEs). Although ICI-induced pneumonitis ranks the fifth of all irAEs in terms of frequency of occurrence, it is associated with a relevant attributable mortality. This review summarizes the incidence, risk factors, clinical and radiological presentation, and therapeutic approach of ICI-induced pneumonitis. Particular focus is on the differential diagnosis of new or worsening pulmonary infiltrates in cancer patients receiving ICI therapy. Finally, the impact on the risk of opportunistic infection of ICIs and immunosuppressive therapy used to treat associated irAEs is reviewed. The diagnosis and management of suspected ICI-induced pneumonitis remains clinically challenging Current management of CMV infection in cancer patients (solid tumors). Epidemiology and therapeutic strategies.

Correction to: Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies.

[This corrects the article DOI: 10.1093/ofid/ofab250.].

Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies.

BACKGROUND: There are no clear criteria for antifungal de-escalation after initial empirical treatments. We hypothesized that early de-escalation (ED) (within 5 days) to fluconazole is safe in fluconazole-susceptible candidemia with controlled source of infection. METHODS: This is a multicenter post hoc study that included consecutive patients from 3 prospective candidemia cohorts (2007-2016). The impact of ED and factors associated with mortality were assessed. RESULTS: Of 1023 candidemia episodes, 235 met inclusion criteria. Of these, 54 (23%) were classified as the ED group and 181 (77%) were classified as the non-ED group. ED was more common in catheter-related candidemia (51.9% vs 31.5%; P = .006) and episodes caused by Candida parapsilosis, yet it was less frequent in patients in the intensive care unit (24.1% vs 39.2%; P = .043), infections caused by Nakaseomyces glabrata (0% vs 9.9%; P = .016), and candidemia from an unknown source (24.1% vs 47%; P = .003). In the ED and non-ED groups, 30-day mortality was 11.1% and 29.8% (P = .006), respectively. Chronic obstructive pulmonary disease (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.48-10.61), Pitt score > 2 (OR, 4.39; 95% CI, 1.94-9.20), unknown source of candidemia (OR, 2.59; 95% CI, 1.14-5.86), candidemia caused by Candida albicans (OR, 3.92; 95% CI, 1.48-10.61), and prior surgery (OR, 0.29; 95% CI, 0.08-0.97) were independent predictors of mortality. Similar results were found when a propensity score for receiving ED was incorporated into the model. ED had no significant impact on mortality (OR, 0.50; 95% CI, 0.16-1.53). CONCLUSIONS: Early de-escalation is a safe strategy in patients with candidemia caused by fluconazole-susceptible strains with controlled source of bloodstream infection and hemodynamic stability. These results are important to apply antifungal stewardship strategies.

Assessment of latent infections in patients receiving biological therapies.

The use of biological (or targeted) therapies constitutes a major advance in the management of autoinflammatory and malignant diseases. However, due to the selective effect of these agents on the host's immune response, reactivation of certain pathogens that cause latent infection is to be expected. The most relevant concern is the risk of reactivation of latent tuberculosis infection (LTBI) and progression to active tuberculosis among patients treated with agents targeting tumor necrosis factor (TNF)-α. Systematic screening for LTBI at base-line with appropriate initiation of antituberculous treatment, if needed, is mandatory in this patient population as risk minimization strategy. In addition, reactivation of hepatitis B virus induced by B-cell-depleting (anti-CD20) and anti-TNF-α agents should be also prevented among HBsAg-positive patients and those with isolated anti-HBc IgG positivity (risk of "occult HBV infection"). The present review summarizes available evidence regarding the risk of reactivation of these latent infections induced by newer biological agents, as well as the recommendations included in the most recent guidelines.

Regular monitoring of cytomegalovirus-specific cell-mediated immunity in intermediate-risk kidney transplant recipients: predictive value of the immediate post-transplant assessment.

OBJECTIVE: Previous studies on monitoring of post-transplant cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) are limited by single-centre designs and disparate risk categories. We aimed to assess the clinical value of a regular monitoring strategy in a large multicentre cohort of intermediate-risk kidney transplant (KT) recipients. METHODS: We recruited 124 CMV-seropositive KT recipients with no T-cell-depleting induction pre-emptively managed at four Spanish institutions. CMV-specific interferon-γ-producing CD4+ and CD8+ T cells were counted through the first post-transplant year by intracellular cytokine staining after stimulation with pp65 and immediate early-1 peptides (mean of six measurements per patient). The primary outcome was the occurrence of any CMV event (asymptomatic infection and/or disease). Optimal cut-off values for CMV-specific T cells were calculated at baseline and day 15. RESULTS: Twelve-month cumulative incidence of CMV infection and/or disease was 47.6%. Patients with pre-transplant CMV-specific CD8+ T-cell count <1.0 cells/µL had greater risk of CMV events (adjusted hazard ratio (aHR) 2.84; p 0.054). When the CMI assessment was performed in the immediate post-transplant period (day 15), the presence of <2.0 CD8+ T cells/µL (aHR 2.18; p 0.034) or <1.0 CD4+ T cells/µL (aHR 2.43; p 0.016) also predicted the subsequent development of a CMV event. In addition, lower counts of CMV-specific CD4+ (but not CD8+) T cells at days 60 and 180 were associated with a higher incidence of late-onset events. CONCLUSIONS: Monitoring for CMV-specific CMI in intermediate-risk KT recipients must be regular to reflect dynamic changes in overall immunosuppression and individual susceptibility. The early assessment at post-transplant day 15 remains particularly informative.

Achromobacter xylosoxidans bacteremia: clinical and microbiological features in a 10-year case series.

OBJECTIVE: The treatment of Achromobacter xylosoxidans bacteremia is challenged by antimicrobial resistance and the paucity of data. We aimed at offering a contemporary description of this uncommon entity. METHODS: Retrospective case series of 13 episodes of A. xylosoxidans bacteremia diagnosed over a 10-year period (November 2007 to May 2017) in our tertiary care center. RESULTS: Solid organ cancer and heart failure were the most common comorbidities (4/13 [30.7%]). All but one episodes were hospital-acquired. Most patients had received previous antibiotic therapy (7/13 [53.8%]) and had a central venous catheter in place (6/13 [46.1%]). Primary and intravascular catheter were the most common sources (4/13 [30.7%] each). Meropenem was the agent with best in vitro activity (92.3% [12/13] of susceptible isolates). All-cause 30-day mortality (overall 23.1%) was higher in patients with primary bacteremia (50.0% vs. 11.1%; P-value=0.203) and prior chemotherapy (66.7% vs. 10.0%; P-value=0.108). CONCLUSIONS: Bacteremia due to A. xylosoxidans constitutes a serious infection among immunocompromised hosts. Carbapenem-based therapy may be appropriate in most cases.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2-4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection. IMPLICATIONS: Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD19, CD20 and CD52 and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Although CD19-targeted agents (blinatumomab or inebilizumab) are not associated with an increased risk of infection, they may cause IgG hypogammaglobulinaemia and neutropenia. The requirement for prolonged intravenous infusion of blinatumomab may increase the risk of catheter-associated bloodstream infections. Infection remains the most common non-haematological adverse effect of anti-CD20 monoclonal antibodies, including severe respiratory tract infection, hepatitis B virus (HBV) reactivation and varicella-zoster virus infection. Screening for chronic or resolved HBV infection is recommended for patients receiving anti-CD20 monoclonal antibodies. Antiviral prophylaxis should be offered for 12-18 months to hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/anti-hepatitis B core antibody (HBc)-positive patients. Anti-Pneumocystis prophylaxis should be considered in patients receiving concomitant chemotherapy, particularly steroids. Alemtuzumab (anti-CD52) increases the risk of infections, in particular among leukaemia and solid organ transplant patients. These populations benefit from anti-Pneumocystis prophylaxis, prevention strategies for cytomegalovirus infection, and screening for HBV, hepatitis C virus and tuberculosis. Antiviral prophylaxis for at least 6-12 months should be provided for HBsAg-positive patients. IMPLICATIONS: As there are limited clinical data for many of the reviewed agents, special attention must be given to promptly detect and report emerging infectious complications.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Cell surface receptors and associated signaling pathways).

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia. IMPLICATIONS: With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Introduction).

BACKGROUND: The field of new biological agents is increasing exponentially over the past years, thus making prevention and management of associated infectious complications a challenge for nonspecialized clinicians. AIMS: The present consensus document is an initiative of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) aimed at analysing, from an infectious diseases perspective, the safety of targeted and biological therapies. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The document is structured in sections according to the targeted site of action of each drug class: proinflammatory cytokines; interleukins, immunoglobulins and other soluble immune mediators; cell surface receptors and associated signaling pathways; intracellular signaling pathways; lymphoma and leukaemia cells surface antigens; and other targeted therapies. A common outline is followed for each agent: summary of mechanism of action, approved indications and common off-label uses; expected impact on the host's susceptibility to infection; available clinical evidence (i.e. pivotal clinical trials, postmarketing studies, case series and case reports); and suggested prevention and risk minimization strategies. The methodologic and practical difficulties of assessing the specific risk posed by a given agent are also discussed. IMPLICATIONS: This ESGICH consensus document constitutes not only a comprehensive overview of the molecular rationale and clinical experience on the risk of infection associated with approved targeted therapies but also an attempt to propose a series of recommendations with the purpose of guiding physicians from different disciplines into this emerging framework.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors).

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of immune checkpoint inhibitors, LFA-3-targeted agents, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors, and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death (PD)-1/PD-1 ligand 1 (PD-L1)-targeted agents do not appear to intrinsically increase the risk of infection but can induce immune-related adverse effects requiring additional immunosuppression. Although CD4+ T-cell lymphopenia is associated with alefacept, no opportunistic infections have been observed. Progressive multifocal leukoencephalopathy (PML) may occur during therapy with natalizumab (anti-α4-integrin monoclonal antibody (mAb)) and efalizumab (anti-CD11a mAb), but no cases have been reported to date with vedolizumab (anti-α4ß7 mAb). In patients at high risk for PML (positive anti-JC polyomavirus serology with serum antibody index >1.5 and duration of therapy ≥48 months), the benefit-risk ratio of continuing natalizumab should be carefully considered. Fingolimod induces profound peripheral blood lymphopenia and increases the risk of varicella zoster virus (VZV) infection. Prophylaxis with (val)acyclovir and VZV vaccination should be considered. Proteasome inhibitors also increase the risk of VZV infection, and antiviral prophylaxis with (val)acyclovir is recommended. Anti-Pneumocystis prophylaxis may be considered in myeloma multiple patients with additional risk factors (i.e. high-dose corticosteroids). IMPLICATIONS: Clinicians should be aware of the risk of immune-related adverse effects and PML in patients receiving immune checkpoint and cell adhesion inhibitors respectively.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti-Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles-mumps-rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made. IMPLICATIONS: Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors).

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biologic therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Although BCR-ABL tyrosine kinase inhibitors modestly increase the overall risk of infection, dasatinib has been associated with cytomegalovirus and hepatitis B virus reactivation. BRAF/MEK kinase inhibitors do not significantly affect infection susceptibility. The effect of Bruton tyrosine kinase inhibitors (ibrutinib) among patients with B-cell malignancies is difficult to distinguish from that of previous immunosuppression. However, cases of Pneumocystis jirovecii pneumonia (PCP), invasive fungal infection and progressive multifocal leukoencephalopathy have been occasionally reported. Because phosphatidylinositol-3-kinase inhibitors (idelalisib) may predispose to opportunistic infections, anti-Pneumocystis prophylaxis and prevention strategies for cytomegalovirus are recommended. No increased rates of infection have been observed with venetoclax (antiapoptotic protein Bcl-2 inhibitor). Therapy with Janus kinase inhibitors markedly increases the incidence of infection. Pretreatment screening for chronic hepatitis B virus and latent tuberculosis infection must be performed, and anti-Pneumocystis prophylaxis should be considered for patients with additional risk factors. Cancer patients receiving mTOR inhibitors face an increased incidence of overall infection, especially those with additional risk factors (prior therapies or delayed wound healing). IMPLICATIONS: Specific preventive approaches are warranted in view of the increased risk of infection associated with some of the reviewed agents.

Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation.

OBJECTIVES: To assess the risk factors for development of late-onset invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT). METHODS: We performed a multinational case-control study that retrospectively recruited 112 KT recipients diagnosed with IPA between 2000 and 2013. Controls were matched (1:1 ratio) by centre and date of transplantation. Immunosuppression-related events (IREs) included the occurrence of non-ventilator-associated pneumonia, tuberculosis, cytomegalovirus disease, and/or de novo malignancy. RESULTS: We identified 61 cases of late (>180 days after transplantation) IPA from 24 participating centres (accounting for 54.5% (61/112) of all cases included in the overall study). Most diagnoses (54.1% (33/61)) were established within the first 36 post-transplant months, although five cases occurred more than 10 years after transplantation. Overall mortality among cases was 47.5% (29/61). Compared with controls, cases were significantly older (p 0.010) and more likely to have pre-transplant chronic obstructive pulmonary disease (p 0.001) and a diagnosis of bloodstream infection (p 0.016) and IRE (p <0.001) within the 6 months prior to the onset of late IPA. After multivariate adjustment, previous occurrence of IRE (OR 19.26; 95% CI 2.07-179.46; p 0.009) was identified as an independent risk factor for late IPA. CONCLUSION: More than half of IPA cases after KT occur beyond the sixth month, with some of them presenting very late. Late IPA entails a poor prognosis. We identified some risk factors that could help the clinician to delimit the subgroup of KT recipients at the highest risk for late IPA.

Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.

Comparison of the clinical course of Clostridium difficile infection in glutamate dehydrogenase-positive toxin-negative patients diagnosed by PCR to those with a positive toxin test.

OBJECTIVES: To evaluate the potential role of PCR-based assays in the over-diagnosis of Clostridium difficile infection (CDI) by using a validated diagnostic algorithm in daily clinical practice. METHODS: We performed a retrospective cohort study evaluating all C. difficile-positive stool samples identified at our institution during a 12-month period, to compare outcomes and recurrence rates between patients with a positive enzyme immunoassay (EIA) for both glutamate dehydrogenase (GDH) and toxin A/B ('toxin-positive group'), with those with GDH-positive, toxin-negative samples in whom the diagnosis was made by a positive PCR-based assay ('toxin-/PCR+ group'). Medical records were reviewed by two independent investigators blinded to the mode of diagnosis. RESULTS: We analysed 231 first CDI episodes (106 (45.8 %) in the 'toxin-positive group' and 125 (54.1%) in the 'toxin-/PCR+ group'). Both groups had similar baseline characteristics. Patients in the 'toxin-positive group' presented more frequently with a severe/severe complicated form than those in the 'toxin-/PCR+ group' (36 (33.9%) versus 24 (19.2%); p 0.011) and had more recurrences (27 (25.5%) versus 9 (7.2%); p 0.001). Diagnosis of CDI based on a GDH/toxin-positive EIA independently predicted severe/severe-complicated course (adjusted OR 2.11; 95% CI 1.06-4.22; p 0.033) and recurrence (adjusted OR 3.79; 95% CI 1.65-8.69; p 0.002). There were no differences in all-cause mortality (12.3% versus 12.0%; p 0.95) or CDI-attributable mortality (4.7% versus 4.8%; p 0.93). CONCLUSIONS: Toxin-positive patients were more likely to have severe-complicated forms of CDI and recurrences. Nevertheless, CDI-related complications may still occasionally occur among toxin-negative patients diagnosed by PCR, which stresses the need for individualized clinical evaluation.

Pathogen-related factors affecting outcome of catheter-related bacteremia due to methicillin-susceptible Staphylococcus aureus in a Spanish multicenter study.

Even with appropriate clinical management, complicated methicillin-susceptible Staphylococcus aureus (MSSA) catheter-related bacteremia (CRB) is frequent. We investigated the influence of molecular characteristics of MSSA strains on the risk of complicated bacteremia (CB) in MSSA-CRB. A multicenter prospective study was conducted in Spain between 2011 and 2014 on MSSA-CRB. Optimized protocol-guided clinical management was required. CB included endocarditis, septic thrombophlebitis, persistent bacteremia and/or end-organ hematogenous spread. Molecular typing, agr functionality and DNA microarray analysis of virulence factors were performed in all MSSA isolates. Out of 83 MSSA-CRB episodes included, 26 (31.3%) developed CB. MSSA isolates belonged to 16 clonal complexes (CCs), with CC30 (32.5%), CC5 (15.7%) and CC45 (13.3) being the most common. Comparison between MSSA isolates in episodes with or without CB revealed no differences regarding agr type and functionality. However, our results showed that CC15 and the presence of genes like cna, chp and cap8 were associated with the development of CB. The multivariate analysis highlighted that the presence of cna (Hazard ratio 2.9; 95% CI 1.14-7.6) was associated with the development of CB. Our results suggest that particular CCs and specific genes may influence the outcome of MSSA-CRB.

No evidence of increased ocular involvement in candidemic patients initially treated with echinocandins.

Candins are commonly used as initial therapy in patients with candidemia and are known to diffuse poorly into ocular tissue. The aim of our multicenter study was to assess whether eye involvement was more common in patients initially treated with echinocandins. We performed a post hoc analysis of a prospective, multicenter, population-based candidemic surveillance program implemented in Spain during 2010-2011 (CANDIPOP project). Eye involvement was detected in 13 of 168 patients with candidemia (7.7%) who underwent ophthalmoscopy. Two patients had endophthalmitis, while the remaining patients had chorioretinitis. The frequency of ocular candidiasis was similar in patients receiving initial therapy with candins (3/56; 5.4%) or with other regimens (10/112; 8.9%). At multivariate analysis, risk conditions for eye involvement were dialysis after candidemia (OR, 19.4; 95% CI, 1.7-218.4) and involvement of organs other than the eye (OR, 5.4; 95% CI, 1.1-25.7). In conclusion, eye involvement was not found to be more frequent in patients receiving initial therapy with echinocandins than in patients receiving other drugs.

Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance.

OBJECTIVES: The clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration-time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients. METHODS: We included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3-7 days) and late (3-30 days) mortality. RESULTS: Rates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48-5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04-0.98; p 0.026). CONCLUSIONS: High fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found.

Significance of the isolation of Staphylococcus aureus from a central venous catheter tip in the absence of concomitant bacteremia: a clinical approach.

The optimal approach following the isolation of Staphylococcus aureus from an intravascular catheter tip in the absence of concomitant bacteremia remains unclear. We aimed to determine the rate of delayed complications in these patients. We performed a retrospective observational study (during the period 2002-2012) including patients with a catheter tip culture yielding S. aureus. Patients were followed up for ≥6 months. The primary endpoint was the occurrence of delayed staphylococcal complications (either bacteremia and/or metastatic distant infections). A total of 113 patients were included (75 % male, median age 61 years): 46 and 67 with negative and positive blood cultures, respectively. We found a lower rate of delayed staphylococcal complications in cases with no bacteremia within 48 h since catheter removal than in cases of confirmed S. aureus catheter-related bacteremia (0.0 % vs. 25.4 %; p-value < 0.001). In the group without bacteremia, there was a subgroup of 15 patients (32.6 %) who did not receive antimicrobial treatment. Again, delayed complications occurred less commonly in this subgroup of patients without bacteremia (0.0 % vs. 25.4 %; p-value = 0.033). In contrast to patients with S. aureus catheter-related bacteremia, no delayed infectious complications were observed in patients with an isolated catheter tip culture yielding S. aureus and negative blood cultures within 48 h of catheter removal. Futures studies are needed to assess if the therapeutic approach could be different for this group of patients.