Present and future of resistance in Pseudomonas aeruginosa: implications for treatment.

Pseudomonas aeruginosa is a pathogen that has a high propensity to develop antibiotic resistance, and the emergence of multidrug-resistant strains is a major concern for global health. The mortality rate associated with infections caused by this microorganism is significant, especially those caused by multidrug-resistant strains. The antibiotics used to treat these infections include quinolones, aminoglycosides, colistin, and ß-lactams. However, novel combinations of ß-lactams-ß-lactamase inhibitors and cefiderocol offer advantages over other members of their family due to their better activity against certain resistance mechanisms. Selecting the appropriate empiric antibiotic treatment requires consideration of the patient's clinical entity, comorbidities, and risk factors for multidrug-resistant pathogen infections, and local epidemiological data. Optimizing antibiotic pharmacokinetics, controlling the source of infection, and appropriate collection of samples are crucial for successful treatment. In the future, the development of alternative treatments and strategies, such as antimicrobial peptides, new antibiotics, phage therapy, vaccines, and colonization control, holds great promise for the management of P. aeruginosa infections.

Impact of the COVID-19 pandemic on the diagnosis and treatment of onco-hematologic patients: a discussion paper.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.

Treatment of infections caused by carbapenemase-producing Enterobacterales.

Antibiotic resistance is one of the main menaces to public and individual health worldwide. In the last two decades, an increase in the detection of carbapenem-resistant Enterobacterales has been reported. The treatment of infections caused by these strains is a therapeutic challenge. The use of carbapenems may be beneficial depending on MIC value and source of infection. New drugs, with different activity against the different classes of carbapenemases, are developed showing significant benefits.

A systematic literature review and expert consensus on risk factors associated to infection progression in adult patients with respiratory tract or rectal colonisation by carbapenem-resistant Gram-negative bacteria.

OBJECTIVE: Risk factors (RFs) associated with infection progression in patients already colonised by carbapenem-resistant Gram-negative bacteria (CRGNB) have been addressed in few and disperse works. The aim of this study is to identify the relevant RFs associated to infection progression in patients with respiratory tract or rectal colonisation. METHODS: A systematic literature review was developed to identify RFs associated with infection progression in patients with CRGNB respiratory tract or rectal colonisation. Identified RFs were then evaluated and discussed by the expert panel to identify those that are relevant according to the evidence and expert's experience. RESULTS: A total of 8 articles were included for the CRGNB respiratory tract colonisation and 21 for CRGNB rectal colonisation, identifying 19 RFs associated with pneumonia development and 44 RFs associated with infection progression, respectively. After discussion, the experts agreed on 13 RFs to be associated with pneumonia development after respiratory tract CRGNB colonisation and 33 RFs to be associated with infection progression after rectal CRGNB colonisation. Respiratory tract and rectal colonisation, previous stay in the ICU and longer stay in the ICU were classified as relevant RF independently of the pathogen and site of colonisation. Previous exposure to antibiotic therapy or previous carbapenem use were also common relevant RF for patients with CRGNB respiratory tract and rectal colonisation. CONCLUSIONS: The results of this study may contribute to the early identification of CRGNB colonized patients at higher risk of infection development, favouring time-to-effective therapy and improving health outcomes.

Respiratory infections in Coronavirus disease 2019.

In the last two years, the capacity of our hospitals has clearly been overwhelmed due to the COVID-19 pandemic The patient who comes to the hospital with a respiratory coinfection does not have the same characteristics as the patient who suffers a superinfection while hospitalized. The number of secondary infections increase proportionally to the severity of the patient's disease. Besides, pathogens that cause a coinfection are clearly differentiated from the pathogens that cause a superinfection. However, in patients subjected to airway manipulation, superinfections by distinct pathogens can occur. Seventy five percent of patients admitted worldwide with COVID-19 (especially during the first two waves of the pandemic) received some form of antibiotic treatment during admission. In this context, it is essential to develop and implement algorithms that allow us to define the predictors in each individual case for the development of a superinfection.

Respiratory co-and superinfections in COVID-19.

There are few publications on the impact of coinfection and superinfection in patients with COVID-19. Patients with higher severity are much more prone to secondary bacterial, fungal or viral infections. The overuse of antimicrobials in many viral infections (including SARS-CoV-2 infections) undoubtedly contributes to the current antimicrobial resistance crisis. In the context of COVID-19, we are witnessing an increase in multidrug-resistant bacterial infections in our hospitals. The heterogeneity of published studies makes it critical to perform more large-scale studies to better understand the pathogenesis of coinfections or superinfections in the COVID-19 patient.

In vitro activity of imipenem/relebactam against Gram-negative clinical isolates in two Spanish tertiary hospitals.

OBJECTIVE: The aim of this study was to analyze the activity of the imipenem-relebactam combination (IMI/REL) against a collection of multidrug-resist Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii clinical isolates. METHODS: The study was conducted in two tertiary hospitals in Spain and included 192 clinical isolates of these 3 genera (139 resistant and 53 susceptible to IMI). The MICs for IMI with and without REL (at a fixed concentration of 4 mg/L) were determined by a standard broth microdilution method according to international recommendations. RESULTS: All IMI-susceptible E. coli strains were also susceptible to IMI/REL. Enterobacterales resistant to IMI due to the production of carbapenemases, the MIC50 and MIC90 decreased from 64/256 with IMI to 8/64 mg/L with IMI/REL. This high activity was principally detected among isolates with KPC enzymes. Enterobacterales with class B carbapenemases, P. aeruginosa carrying VIM carbapenemase and A. baumannii strains showed no changes on IMI MIC50 or MIC90 after adding REL. Among P. aeruginosa strains without carbapenemase the MIC for IMI/REL was reduced between 1 to 5 dilutions. CONCLUSIONS: IMI/REL showed high activity against the strains that carry Klebsiella pneumoniae carbapenemase (KPC) and against carbapenem-resistant P. aeruginosa unrelated to the VIM enzyme, mainly AmpC beta lactamase associated with impermeability. Against strains carrying oxacillinase 48 (OXA-48) associated with extended-spectrum beta-lactamase (ESBL), IMI/REL presented activity only slightly better than IMI and had no beneficial effect superior to IMI against A. baumannii.

[A systematic review and expert's analysis of risk factors of infections in adults due to carbapenem-resistant Pseudomonas aeruginosa or Acinetobacter baumannii in Spain]. / Revisión sistemática de la literatura y análisis de expertos sobre los factores de riesgo asociados a infecciones causadas por Pseudomonas aeruginosa o Acinetobacter baumannii resistentes a carbapenémicos en pacientes adultos en España.

OBJECTIVE: The aim of the study is to identify risk factors associated to infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Acinetobacter baumannii (CRAB) in adult patients through a systematic literature review, classify them according to their importance and provide recommendations by experts in the Spanish context. METHODS: We developed a systematic literature review to identify risk factors associated to CRPA or CRAB infections and they were evaluated and discussed by a multidisciplinary panel of experts. RESULTS: There were included 29 studies for P. aeruginosa and 23 for A. baumannii out of 593 identified through systematic literature review. We identified 38 risk factors for P. aeruginosa and 36 for A. baumannii. After risk factor evaluation by the panel of experts, results for CRPA were: 11 important, 10 slightly important and 15 unimportant risk factors; and for CRAB were: 9 important, 5 slightly important and 19 unimportant risk factors. For both pathogens, previous use of antibiotics and hospitalization were important risk factors. CONCLUSIONS: We could identify the main risk factors associated to CRPA and CRAB through literature review. There is a need for developing additional studies with higher levels of evidence to identify sooner and better infected patients through associated risk factors.

Efficacy of extended infusion of ß-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE).

BACKGROUND: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal ß-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. METHODS: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. DISCUSSION: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT 2018-001476-37. ClinicalTrials.gov, ID: NCT04233996.

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.

Suppressive antibiotic therapy in prosthetic joint infections: a multicentre cohort study.

OBJECTIVES: The aim was to describe the effectiveness of suppressive antibiotic treatment (SAT) in routine clinical practice when used in situations in which removal of a prosthetic implant is considered essential for the eradication of an infection, and it cannot be performed. METHODS: This was a descriptive retrospective and multicentre cohort study of prosthetic joint infection (PJI) cases managed with SAT. SAT was considered to have failed if a fistula appeared or persisted, if debridement was necessary, if the prosthesis was removed due to persistence of the infection or if uncontrolled symptoms were present. RESULTS: In total, 302 patients were analysed. Two hundred and three of these patients (67.2%) received monotherapy. The most commonly used drugs were tetracyclines (39.7% of patients) (120/302) and cotrimoxazole (35.4% of patients) (107/302). SAT was considered successful in 58.6% (177/302) of the patients (median time administered, 36.5 months; IQR 20.75-59.25). Infection was controlled in 50% of patients at 5 years according to Kaplan-Meier analysis. Resistance development was documented in 15 of 65 (23.1%) of the microbiologically documented cases. SAT failure was associated with age <70 years (sub-hazard ratio (SHR) 1.61, 95% CI 1.1-2.33), aetiology other than Gram-positive cocci (SHR 1.56, 95% CI 1.09-2.27) and location of the prosthesis in the upper limb (SHR 2.4, 95% CI 1.5-3.84). SAT suspension was necessary due to adverse effects in 17 of 302 patients (5.6%). CONCLUSIONS: SAT offers acceptable results for patients with PJI when surgical treatment is not performed or when it fails to eradicate the infection.

Stewardship in sepsis.

Sepsis is the major cause of mortality from any infectious disease worldwide. The goals of antimicrobial stewardship are to achieve optimum clinical outcomes and to ensure cost effectiveness and minimum unintended consequences, including toxic effects, selection of pathogenic organisms, and resistance. The combination of inadequate diagnostic criteria for sepsis with the extraordinary time pressure to provide broad-spectrum antimicrobial therapy is troubling from a stewardship perspective. Use of empirical therapy according to guidelines, de-escalation of therapy, switch from intravenous to oral therapy, therapeutic drug monitoring, use of a list of restricted antibiotics, and bedside consultation can lead to significant benefits for clinical outcomes, adverse events, and costs.

Fungal biofilms: From bench to bedside.

Biofilms cause recurrent invasive infections that are difficult to eradicate because of their high resistance to antimicrobials and host defence mechanisms. Fungal biofilm-related infections are associated with high mortality rates. Although current guidelines recommend catheter removal for catheter-related bloodstream infections due to Candida species, several studies have shown that the efficacy of the antifungal lock technique. The use of combinations of antifungal agents may improve the management of biofilm-related fungal infections and prevent the emergence of resistance associated with monotherapy. Since the presence of mixed bacterial-fungal biofilm infections is very prevalent, a combination of antibacterial and antifungal agents should be considered.

Current aspects in sepsis approach. Turning things around.

The incidence and prevalence of sepsis depend on the definitions and records that we use and we may be underestimating their impact. Up to 60% of the cases come from the community and in 30-60% we obtain microbiological information. Sometimes its presentation is ambiguous and there may be a delay in its detection, especially in the fragile population. Procalcitonin is the most validated biomarker for bacterial sepsis and the one that best discriminates the non-infectious cause. Presepsin and pro-adrenomedullin are useful for early diagnosis, risk stratification and prognosis in septic patients. The combination of biomarkers is even more useful to clarify an infectious cause than any isolated biomarker. Resuscitation with artificial colloids has worse results than crystalloids, especially in patients with renal insufficiency. The combination of saline solution and balanced crystalloids is associated with a better prognosis. Albumin is only recommended in patients who require a large volume of fluids. The modern molecular methods on the direct sample or the identification by MALDI-TOF on positive blood culture have helped to shorten the response times in diagnosis, to optimize the antibiotic treatment and to facilitate stewardship programs. The hemodynamic response in neonates and children is different from that in adults. In neonatal sepsis, persistent pulmonary hypertension leads to an increase in right ventricular afterload and heart failure with hepatomegaly. Hypotension, poor cardiac output with elevated systemic vascular resistance (cold shock) is often a terminal sign in septic shock. Developing ultra-fast Point-of-Care tests (less than 30 minutes), implementing technologies based on omics, big data or massive sequencing or restoring "healthy" microbiomes in critical patients after treatment are the main focuses of research in sepsis. The main benefits of establishing a sepsis code are to decrease the time to achieve diagnosis and treatment, improve organization, unify criteria, promote teamwork to achieve common goals, increase participation, motivation and satisfaction among team members, and reduce costs.

Diagnosis and treatment of catheter-related bloodstream infection: Clinical guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology and (SEIMC) and the Spanish Society of Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC).

Catheter-related bloodstream infections (CRBSI) constitute an important cause of hospital-acquired infection associated with morbidity, mortality, and cost. The aim of these guidelines is to provide updated recommendations for the diagnosis and management of CRBSI in adults. Prevention of CRBSI is excluded. Experts in the field were designated by the two participating Societies (the Spanish Society of Infectious Diseases and Clinical Microbiology and [SEIMC] and the Spanish Society of Spanish Society of Intensive and Critical Care Medicine and Coronary Units [SEMICYUC]). Short-term peripheral venous catheters, non-tunneled and long-term central venous catheters, tunneled catheters and hemodialysis catheters are covered by these guidelines. The panel identified 39 key topics that were formulated in accordance with the PICO format. The strength of the recommendations and quality of the evidence were graded in accordance with ESCMID guidelines. Recommendations are made for the diagnosis of CRBSI with and without catheter removal and of tunnel infection. The document establishes the clinical situations in which a conservative diagnosis of CRBSI (diagnosis without catheter removal) is feasible. Recommendations are also made regarding empirical therapy, pathogen-specific treatment (coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus spp., Gram-negative bacilli, and Candida spp.), antibiotic lock therapy, diagnosis and management of suppurative thrombophlebitis and local complications.

[Therapeutic protocol for the empirical treatment of oral and pharyngeal infections]. / Protocolo terapéutico empírico de las infecciones bucales y faríngeas.

INTRODUCTION: Most oral cavity infections are odontogenic, although they can also affect extradental structures (non-odontogenic infections). Pharyngitis is inflammation and/or infection of the pharynx and /or the peri-tonsillar area. TREATMENT: Both infections are highly prevalent in the population, and one of the most common reasons for consultation and the prescription of antibiotics in primary care clinics. Both infections are usually treated empirically, based on clinical diagnosis and the prevalence and antibiotic sensitivity of the most commonly implicated microorganisms.

Guía clínica española del acceso vascular para hemodiálisis / Spanish clinical guidelines on vascular access for haemodialysis

El acceso vascular para hemodiálisis es esencial para el enfermo renal tanto por su morbimortalidad asociada como por su repercusión en la calidad de vida. El proceso que va desde la creación y mantenimiento del acceso vascular hasta el tratamiento de sus complicaciones constituye un reto para la toma de decisiones debido a la complejidad de la patología existente y a la diversidad de especialidades involucradas. Con el fin de conseguir un abordaje consensuado, el Grupo Español Multidisciplinar del Acceso Vascular (GEMAV), que incluye expertos de las cinco sociedades científicas implicadas (nefrología [S.E.N.], cirugía vascular [SEACV], radiología vascular e intervencionista [SERAM-SERVEI], enfermedades infecciosas [SEIMC] y enfermería nefrológica [SEDEN]), con el soporte metodológico del Centro Cochrane Iberoamericano, ha realizado una actualización de la Guía del Acceso Vascular para Hemodiálisis publicada en 2005. Esta guía mantiene una estructura similar, revisando la evidencia sin renunciar a la vertiente docente, pero se aportan como novedades, por un lado, la metodología en su elaboración, siguiendo las directrices del sistema GRADE con el objetivo de traducir esta revisión sistemática de la evidencia en recomendaciones que faciliten la toma de decisiones en la práctica clínica habitual y, por otro, el establecimiento de indicadores de calidad que permitan monitorizar la calidad asistencial.

Vascular access for haemodialysis is key in renal patients both due to its associated morbidity and mortality and due to its impact on quality of life. The process, from the creation and maintenance of vascular access to the treatment of its complications, represents a challenge when it comes to decision-making, due to the complexity of the existing disease and the diversity of the specialities involved. With a view to finding a common approach, the Spanish Multidisciplinary Group on Vascular Access (GEMAV), which includes experts from the five scientific societies involved (nephrology [S.E.N.], vascular surgery [SEACV], vascular and interventional radiology [SERAM-SERVEI], infectious diseases [SEIMC] and nephrology nursing [SEDEN]), along with the methodological support.

Non-valvular intravascular device and endovascular graft-related infection.

In the last few years there has been an increase of implantable cardiac electronic device and vascular graft related infections. This is due in part to a higher complexity of some of these procedures and an increase in patient's comorbidities. Despite wide diagnosis methods availability, early stage diagnosis usually constitutes a challenge as often patients only denote insidious symptoms. In most confirmed cases, removal of the infected device is required to resolve the infection. This is mostly explainable because of bacterial ability to grow as biofilms on biomaterial surfaces, conferring them antimicrobial resistance. If removal is not possible, chronic suppressive antimicrobial therapy could be an option.

[Directed therapeutic approach to Staphylococcus aureus infections. Clinical aspects of prescription]. / Aproximación terapéutica dirigida de las infecciones por Staphylococcus aureus. Aspectos clínicos de la prescripción.

Infections caused by Staphylococcus aureus have had classically an important impact in morbidity and mortality in the nosocomial and community scene. The description of methicillin resistance among nosocomial isolates of S. aureus and his widespread diffusion has become methicillin-resistant S. aureus (MRSA) in one of the most common causes of bacterial nosocomial infections. In the last years MRSA strains have also emergence in the community. This together with a progressive increase in resistance to antibiotics used classically has become vancomycin in the treatment of choice in most cases according to clinical guidelines. As a result, a progressive rise in the minimum inhibitory concentration (MIC) to vancomycin has been reported. In this context strains with intermediate susceptibility to vancomycin (MIC 8-4 mg/L) and heteroresistance have been noted. These strains are associated with a higher risk of treatment failure when using vancomycin. Among isolates of S. aureus susceptible to vancomycin there has been described stains with elevated MICs (≥1.5 mg/L). It is controversial if the presence of these strains has an impact on clinical outcome if treatment with vancomycin or ß-lactams is prescribed. The development of new antibiotics with activity against MRSA and exploring synergies offer a promising alternative to treatment with vancomycin.

Enterococcal bloodstream infection. Design and validation of a mortality prediction rule.

BACKGROUND: To develop a prediction rule to describe the risk of death as a result of enterococcal bloodstream infection. METHODS: A prediction rule was developed by analysing data collected from 122 patients diagnosed with enterococcal BSI admitted to the Clínica Universidad de Navarra (Pamplona, Spain); and validated by confirming its accuracy with the data of an external population (Hospital del Mar, Barcelona). RESULTS: According to this model, independent significant predictors for the risk of death were being diabetic, have received appropriate treatment, severe prognosis of the underlying diseases, have renal failure, received solid organ transplant, malignancy, source of the bloodstream infection and be immunosuppressed. The prediction rule showed a very good calibration (Hosmer-Lemeshow statistic, P = 0.93) and discrimination for both training and testing sets (area under ROC curve = 0.84 and 0.83 respectively). CONCLUSIONS: The predictive rule was able to predict risk of death as a result of enterococcal bloodstream infection as well as to identify patients, who being below the threshold value, will have a low risk of death with a negative predictive value of 96%.