Human intestinal microbiome: Role in health and disease.

The study of the microbiota and the microbiome, and specifically the intestinal one, has determined great interest due to the possible association of their alterations with numerous diseases. These include entities as diverse as Crohn's disease, autism, diabetes, cancer or situations as prevalent today as obesity. In view of this situation, different recommendations have been performed regarding the use of probiotics, prebiotics, and postbiotics as modulators of the microbiota and the microbiome, seeking both preventive and therapeutic effects, and faecal material transfer (FMT) is proposed as an alternative. The latter has emerged as the only proven beneficial intervention on the intestinal microbiome, specifically in the treatment of recurrent colitis associated with Clostridioides difficile (R-CDI). In the rest of the entities, the lowering of laboratory costs has favored the study of the microbiome, which is resolved by delivering reports with catalogs of microorganisms, metabolites or supposed biomarkers without consensus on their composition associated with healthy or diseased microbiota and the disease. There is still insufficient evidence in any disease for interventions on the microbiome beyond FMT and R-CDI. Multi- and multi-disciplinary work with extensive research and the application of artificial intelligence in this field may shed light on the questions raised currently. Ethical issues must also be resolved in light of possible interventions within the umbrella of personalized medicine.

A multisite validation of a two hours antibiotic susceptibility flow cytometry assay directly from positive blood cultures.

BACKGROUND: Rapid antimicrobial susceptibility testing (AST) is urgently needed to provide safer treatment to counteract antimicrobial resistance. This is critical in septic patients, because resistance increases empiric therapy uncertainty and the risk of a poor outcome. We validate a novel 2h flow cytometry AST assay directly from positive blood cultures (PBC) by using a room temperature stable FASTgramneg and FASTgrampos kits (FASTinov® Porto, Portugal) in three sites: FASTinov (site-1), Hospital Ramon y Cajal, Madrid, Spain (site-2) and Centro Hospitalar S. João, Porto, Portugal (site-3). A total of 670 PBC were included: 333 spiked (site-1) and 337 clinical PBC (151 site-2 and 186 site-3): 367 gram-negative and 303 gram-positive. Manufacturer instructions were followed for sample preparation, panel inoculation, incubation (1h/37ºC) and flow cytometry analysis using CytoFlex (Site-1 and -2) or DxFlex (site-3) both instruments from Beckman-Coulter, USA. RESULTS: A proprietary software (bioFAST) was used to immediately generate a susceptibility report in less than 2 h. In parallel, samples were processed according to reference AST methods (disk diffusion and/or microdilution) and interpreted with EUCAST and CLSI criteria. Additionally, ten samples were spiked in all sites for inter-laboratory reproducibility. Sensitivity and specificity were >95% for all antimicrobials. Reproducibility was 96.8%/95.0% for FASTgramneg and 95.1%/95.1% for FASTgrampos regarding EUCAST/CLSI criteria, respectively. CONCLUSION: FASTinov® kits consistently provide ultra-rapid AST in 2h with high accuracy and reproducibility on both Gram-negative and Gram-positive bacteria. This technology creates a new paradigm in bacterial infection management and holds the potential to significantly impact septic patient outcomes and antimicrobial stewardship.

Meningococcal meningitis in Spain in the Horizon 2030: A position paper.

Meningococcal meningitis (MM) and invasive meningococcal disease remain a major public health problem that generates enormous public alarm. It is caused by Neisseria meningitidis, a Gram-negative diplococcus with an enormous capacity for acute and rapidly progressive disease, both episodic and epidemic in nature, with early diagnosis and treatment playing a major role. It occurs at any age, but is most common in children under 5 years of age followed by adolescents. Although most cases occur in healthy people, the incidence is higher in certain risk groups. Despite advances in reducing the incidence, it is estimated that in 2017 there were around 5 million new cases of MM worldwide, causing approximately 290,000 deaths and a cumulative loss of about 20,000,000 years of healthy life. In Spain, in the 2021/22 season, 108 microbiologically confirmed cases of MM were reported, corresponding to an incidence rate of 0.23 cases per 100,000 inhabitants. This is a curable and, above all, vaccine-preventable disease, for which the World Health Organisation has drawn up a roadmap with the aim of reducing mortality and sequelae by 2030. For all these reasons, the Illustrious Official College of Physicians of Madrid (ICOMEM) and the Medical Associations of 8 other provinces of Spain, have prepared this opinion document on the situation of MM in Spain and the resources and preparation for the fight against it in our country. The COVID-19 and Emerging Pathogens Committee of ICOMEM has invited experts in the field to participate in the elaboration of this document.

Respiratory syncytial virus: A new era.

Respiratory syncytial virus (RSV) is a major public health problem that has undergone significant changes in recent years. First of all, it has become easier to diagnose with highly reliable and rapidly available confirmatory tests. This has led to a better understanding of its epidemiology and RSV has gone from being a disease of the pediatric age group, severe only in infants and immunosuppressed children, to being a common disease in people of all ages, particularly important in patients of advanced age or with immunosuppressive diseases. Recent therapeutic and prophylactic advances, both with long-lasting monoclonal antibodies and vaccines, are another reason for satisfaction. For these reasons, the COVID and Emerging Pathogens Committee of the Illustrious Official College of Physicians of Madrid (ICOMEM) has considered it pertinent to review this subject in the light of new knowledge and new resources for dealing with this infection. We have formulated a series of questions that we believe will be of interest not only to members of the College but also to any non-expert in this subject, with a particular focus on the situation of RSV infection in Spain.

Unresolved issues in the diagnosis of catheter related candidemia: A position paper.

The incidence and recent trends of candidemia and the contribution of the COVID-19 pandemic to its evolution are not well documented. The catheter is a major focus of Candida spp. infections, but the methods used to confirm the origin of candidemia are still based on the data generated for bacterial infection. The presence of Candida spp. on the tip of a removed catheter is the gold standard for confirmation but it is not always possible to remove it. Conservative methods, without catheter removal, have not been specifically studied for microorganisms whose times of growth are different from those of bacteria and therefore these results are not applicable to candidemia. The different Candida species do not have a particular tropism for catheter colonization and fungal biomarkers have not yet been able to contribute to the determination of the origin of candidemia. Techniques such Candida T2 Magnetic Resonance (T2MR) has not yet been applied for this purpose. Finally, there is not yet a consensus of how to proceed when Candida spp. is isolated from an extracted catheter and blood cultures obtained from simultaneous peripheral veins are negative. In this lack of firm data, a group of experts has formulated a series of questions trying to answer them based on the literature, indicating the current deficiencies and offering their own opinion. All authors agree with the conclusions of the manuscript and offer it as a position and discussion paper.

In vitro activity of cefiderocol and other newly approved antimicrobials against multi-drug resistant Gram-negative pathogens recovered in intensive care units in Spain and Portugal.

OBJECTIVE: The antimicrobial resistance is a significant public health threat, particularly for healthcare-associated infections caused by carbapenem-resistant Gram-negative pathogens which are increasingly reported worldwide. The aim of this study was to provide data on the in vitro antimicrobial activity of cefiderocol and that of commercially available comparator antibiotics against a defined collection of recent clinical multi-drug resistant (MDR) microorganisms, including carbapenem resistant Gram-negative bacteria collected from different regions in Spain and Portugal. METHODS: A total of 477 clinical isolates of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia were prospectively (n=265) and retrospectively (n=212) included (2016-2019). Susceptibility testing was performed using standard broad microdilution and results were interpreted using CLSI-2021 and EUCAST-2021 criteria. RESULTS: Overall, cefiderocol showed a good activity against Enterobacterales isolates, being 99.5% susceptible by CLSI and 94.5% by EUCAST criteria. It also demonstrated excellent activity against P. aeruginosa and S. maltophilia isolates, all being susceptible to this compound considering CLSI breakpoints. Regarding A. baumannii (n=64), only one isolate was resistant to cefiderocol. CONCLUSIONS: Our results are in agreement with other studies performed outside Spain and Portugal highlighting its excellent activity against MDR gram-negative bacteria. Cefiderocol is a therapeutic alternative to those available for the treatment of infections caused by these MDR bacteria.

COVID-19: On the threshold of the fifth year. The situation in Spain.

Despite having emerged from pandemic status, the incidence of COVID-19 episodes has recently increased in Spain, including pediatric cases and admissions to Intensive Care Units. Several recombinant variants are circulating among us, particularly XBB arising from two Omicron BA.2 sublineages with mutations in the genes encoding the spicule proteins that could increase binding to the ACE2 receptor and be more prone to immune escape. Faced with these, 3 pharmaceutical companies have developed vaccines adapted to the XBB.1.5 sublineage that are already available for administration in our setting with risks that should not be different from those of previous mRNA vaccines and with clearly favorable benefit/risk ratios. They should be applied to patients with potential for poor COVID-19 evolution and to collectives that have a particular relationship of proximity with them. Their application should be understood not only from a perspective of individual convenience but also from that of collective responsibility. The most convenient seems to be a simultaneous immunization of COVID-19 and influenza in our environment. In the therapeutic aspect, there is little to expect right now from antisera, but the already known antiviral drugs are still available and indicated, although their efficacy will have to be reevaluated due to their impact on populations that are mostly immunized and with a better prognosis than in the past. In our opinion, it is necessary to continue to make a reasonable and timely use of masks and other non-pharmacological means of protection.

Tuberculosis in Spain: An opinion paper.

This document is the result of the deliberations of the Committee on Emerging Pathogens and COVID-19 of the Illustrious Official College of Physicians of Madrid (ICOMEM) regarding the current situation of tuberculosis, particularly in Spain. We have reviewed aspects such as the evolution of its incidence, the populations currently most exposed and the health care circuits for the care of these patients in Spain. We have also discussed latent tuberculosis, the reality of extrapulmonary disease in the XXI century and the means available in daily practice for the diagnosis of both latent and active forms. The contribution of molecular biology, which has changed the perspective of this disease, was another topic of discussion. The paper tries to put into perspective both the classical drugs and their resistance figures and the availability and indications of the new ones. In addition, the reality of direct observation in the administration of antituberculosis drugs has been discussed. All this revolution is making it possible to shorten the treatment time for tuberculosis, a subject that has also been reviewed. If everything is done well, the risk of relapse of tuberculosis is small but it exists. On the other hand, many special situations have been discussed in this paper, such as tuberculosis in pediatric age and tuberculosis as a cause for concern in surgery and intensive care. The status of the BCG vaccine and its present indications as well as the future of new vaccines to achieve the old dream of eradicating this disease have been discussed. Finally, the ethical and medicolegal implications of this disease are not a minor issue and our situation in this regard has been reviewed.

Treatment guidelines for multidrug-resistant Gram-negative microorganisms.

In recent years, new antimicrobials have been introduced in therapeutics, including new beta-lactam-beta-lactamase inhibitor combinations and cefiderocol in response to therapeutic needs in the face of increasing resistance. There are also different treatment guidelines for infections caused by these microorganisms that have been approved by different professional societies, including those of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Disease Society of America (IDSA) and the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). All of them are based on scientific evidence, but with differences in the weight of expert opinion in their recommendations. Both ESCMID and IDSA include recommendations for the treatment of extended-spectrum beta-lactamase-producing microorganisms. The IDSA is the only one including AmpC producers, all address the treatment of infections caused by carbapenem-resistant Enterobacterales and Acinetobacter baumannii and multidrug-resistant or difficult-to-treat Pseudomonas aeruginosa, and the IDSA and SEIMC include recommendations on the treatment of Stenotrophomonas maltophilia. Future guidelines should integrate new antimicrobials and new innovative management options not covered by current guidelines.

Sexually transmitted infections in Spain: Current status.

Sexually Transmitted Infections (STI) are a major public health problem. The problems inherent to their diagnosis, treatment and prevention have to do not only with their nature, but also with organizational issues and overlapping competencies of the different health authorities in Spain. The real situation of STI in Spain, at present, is poorly known. For this reason, the Scientific Committee on COVID and Emerging Pathogens of the Illustrious Official College of Physicians of Madrid (ICOMEM) has formulated a series of questions on this subject which were distributed, not only among the members of the Committee, but also among experts outside it. The central health authorities provide very high and increasing figures for gonococcal infection, syphilis, Chlamydia trachomatis infection and lymphogranuloma venereum (LGV). Both HIV infection and Monkeypox are two important STI caused by viruses in our environment, to which it should be added, mainly, Herpes simplex virus (HSV) and Human papillomavirus (HPV) infections. Emerging microorganisms such as Mycoplasma genitalium pose not only pathogenic challenges but also therapeutic problems, as in the case of N. gonohrroeae. The pathways that patients with suspected STI follow until they are adequately diagnosed and treated are not well known in Spain. Experts understand that this problem is fundamentally managed in public health institutions, and that Primary Care and Hospital Emergency Services, together with some institutions that deal monographically with this problem, are the recipients of most of these patients. One of the most serious difficulties of STI lies in the availability of the microbiological tests necessary for their diagnosis, particularly in this era of outsourcing of microbiology services. Added to this is the increased cost of implementing the latest generation of molecular techniques and the difficulties of transporting samples. It is clear that STI are not diseases to which the entire population is equally exposed and it is necessary to have a better knowledge of the risk groups where to focus the necessary interventions adapted to their characteristics. It should not be forgotten that STI are also a problem in the pediatric age group and that their presence can be a marker of sexual abuse with all that this implies in terms of health care and medicolegal activity. Finally, STI are infections that are associated with a high cost of care for which we have very little information. The possibility of expanding the automatic performance of laboratory tests for STI surveillance through laboratory routines is encountering ethical and legal problems that are not always easy to solve. Spain has created a ministerial area of specific attention to STI and there are plans to improve the diagnosis, treatment and prevention of these problems, but we still lack the necessary evidence on their impact. We cannot forget that these are diseases that transcend the individual and constitute a Public Health problem.

Advantages and disadvantages of maintaining the mandatory use of masks in health centers and nursing homes in Spain. How and when is it justified to maintain it?

We address the advantages and disadvantages of maintaining the mandatory use of masks in health centers and nursing homes in the current epidemiological situation in Spain and after the declaration of the World Health Organization on May 5, 2023 of the end of COVID-19 as public health emergency. We advocate for prudence and flexibility, respecting the individual decision to wear a mask and emphasizing the need for its use when symptoms suggestive of a respiratory infection appear, in situations of special vulnerability (such as immunosuppression), or when caring for patients with those infections. At present, given the observed low risk of severe COVID-19 and the low transmission of other respiratory infections, we believe that it is disproportionate to maintain the mandatory use of masks in a general way in health centers and nursing homes. However, this could change depending on the results of epidemiological surveillance and it would be necessary to reconsider returning to the obligation in periods with a high incidence of respiratory infections.

Phenotypic and Molecular Characterization of an Enterobacter ludwigii Clinical Isolate Carrying a Plasmid-Mediated blaIMI-6 Gene.

We report a plasmid-encoded IMI-6 carbapenemase in a clinical isolate of Enterobacter ludwigii from Spain. The isolate belongs to ST641 and was susceptible to expanded-spectrum cephalosporins and resistant to carbapenems. The modified carbapenem inactivation method (mCIM) test was positive, but ß-Carba was negative. Whole-genome sequencing identified the blaIMI-6 gene located in a conjugative IncFIIY plasmid and associated with the LysR-like regulator imiR. Both genes were bracketed by an ISEclI-like insertion sequence and a putatively defective ISEc36 insertion sequence. IMPORTANCE IMI carbapenemases confer an unusual resistance pattern of susceptibility to broad-spectrum cephalosporins and piperacillin-tazobactam but decreased susceptibility to carbapenems, which may make them difficult to detect in routine practice. Commercially available molecular methods for the detection of carbapenemases in clinical laboratories do not usually include blaIMI genes, which could contribute to the hidden dissemination of bacteria producing these enzymes. Techniques should be implemented to detect minor carbapenemases that are not very frequent in our environment and control their dissemination.

Activity of imipenem/relebactam against Enterobacterales and Pseudomonas aeruginosa in Spain. SMART 2016-2020.

OBJECTIVE: To determine susceptibility to the novel ß-lactam/ß-lactamase inhibitor combination imipenem/relebactam in clinical isolates recovered from intra-abdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream (BSI) infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study in SPAIN during 2016 - 2020. METHODS: Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of Enterobacterales and Pseudomonas aeruginosa. MICs were interpreted using EUCAST-2021 breakpoints. RESULTS: In total, 5,210 Enterobacterales and 1,418 P. aeruginosa clinical isolates were analyzed. Imipenem/relebactam inhibited 98.8% of Enterobacterales. Distinguishing by source of infection susceptibility was 99.1% in BSI, 99.2% in IAI, 97.9% in RTI, and 99.2% in UTI. Of intensive care unit isolates (ICU) 97.4% were susceptible and of non-ICU isolates 99.2% were susceptible. In Enterobacterales, activity against Class A, Class B and Class D carbapenemases was 96.2%, 15.4% and 73.2%, respectively. In P. aeruginosa, imipenem/relebactam was active in 92.2% of isolates. By source of infection it was 94.8% in BSI, 92.9% in IAI, 91.7% in RTI, and 93.1% in UTI. An 88.7% of ICU isolates and 93.6% of non-ICU isolates were susceptible to imipenem/relebactam. Imipenem/relebactam remained active against P. aeruginosa ceftazidime-resistant (76.3%), cefepime-resistant (73.6%), imipenem-resistant (71.5%) and piperacillin-resistant (78.7%) isolates. Of all multidrug-resistant or difficult-to-treat resistance P. aeruginosa isolates, 75.1% and 46.2%, respectively, were susceptible to imipenem/relebactam. CONCLUSIONS: Imipenem/relebactam showed high rates of susceptibility in Enterobacterales and P. aeruginosa isolates from different sources of infection as well as depending on patients' location (ICU or non-ICU scenarios).

Status of Herpes Zoster and Herpes Zoster Vaccines in 2023: A position paper.

Herpes zoster infection (HZ) is an important public health problem due to its high incidence and frequent complications, especially post-herpetic neuropathy . The incidence of HZ increases with age and is more frequent in immunocompromised patients. It is estimated that at least 60,000 people develop HZ each year in Spain. The usual forms of HZ are so clinically characteristic that they do not usually require microbiological confirmation, which is reserved for cases without cutaneous manifestations or with atypical presentation. There are currently two vaccines approved by the regulatory agencies and marketed in Spain to prevent the onset of HZ and its complications. The first (Zostavax®) was marketed by the company MSD and licensed in Europe in 2006 and is a live attenuated virus vaccine that is administered in a single dose, while the second (Shingrix®) is a recombinant vaccine, marketed in 2017 and requires two doses. While the former cannot be administered to immunocompromised persons, the latter can be prescribed to any group of adults. The criteria for the indication and financing of these vaccines have not been uniform in the various autonomous communities of Spain. These and other aspects of HZ have been discussed by a group of experts from the Illustrious Official College of Physicians of Madrid (ICOMEM) whose criteria and opinions are included in this paper.

Usefulness of EUCAST rapid antibiotic susceptibility breakpoints and screening cut-off values directly from blood cultures for the inference of ß-lactam resistance mechanisms in Enterobacterales.

Background: Reducing the turnaround time for reporting antimicrobial susceptibility testing (AST) results is important for adjusting empirical treatments and may impact clinical outcomes of septic patients, particularly in settings with high antimicrobial resistance. Disc diffusion could be useful for inferring ß-lactam resistance mechanisms. Objectives: To evaluate the usefulness of EUCAST rapid AST (RAST) disc diffusion breakpoints for the screening of resistance mechanisms (sRAST) and interpretive reading of resistance phenotypes to infer ESBL and carbapenemases production in Enterobacterales. Methods: Blood cultures were artificially spiked with Enterobacterales clinical isolates with well-characterized ß-lactam resistance mechanisms (n = 93), WT phenotypes (n = 26) and ATCC strains (n = 8). AST was performed by disc diffusion directly from blood cultures and inhibition zones were manually measured at 4, 6 and 8 h. To infer the presence of resistance mechanisms, EUCAST RAST breakpoints and screening cut-off values (sRAST) combined with the double-disc synergy test (DDS) for ESBLs or aztreonam susceptibility for carbapenemases detection were used. Results: DDS together with sRAST detected all ESBL producers as early as at 4 h incubation. Cefotaxime was the antibiotic with the highest discriminatory power. The suspicion of carbapenemase production by sRAST at 8 h was possible in 73% of Klebsiella pneumoniae and in 100% of Escherichia coli carbapenemase-producing isolates. Phenotypic analysis improves the detection of some low hydrolytic carbapenemases (OXA-48 or KPC-3 mutants). Conclusions: Early detection of ß-lactam resistance mechanisms directly from positive blood cultures was possible using sRAST together with the interpretive reading of antibiotic resistance phenotypes. Some carbapenemase types such as OXA-48 might be difficult to infer. Screening-positive isolates should be confirmed using an alternative technique.

Insights for COVID-19 in 2023.

Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution. Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron). However, its efficacy is high against severe symptomatic infection, hospitalization and death. The new vaccines being introduced are bivalent and active against the Omicron variants. Potential new vaccines to be introduced in the coming year include a vaccine based on a recombinant protein that emulates the receptor binding domain of the Spike protein under development by the Spanish company Hipra, as well as vaccines for nasal or oral administration. Available information suggests that vaccines against COVID-19 can be administered in association with influenza vaccination without particular complications. New drugs against COVID-19, both antiviral and anti-inflammatory, are under investigation, but this does not seem to be the case with monoclonal antibodies. The indication to use masks in some circumstances will be maintained next year in view of the accumulation of scientific data on their efficacy. Finally, the long COVID or Post-COVID syndrome may continue to affect a very high proportion of patients who have had the disease, requiring combined diagnostic and therapeutic resources.

Antimicrobial resistance in Gram-negative bacilli in Spain: an experts' view.

BACKGROUND: Antibiotic resistance in Gram-negative bacilli poses a serious problem for public health. In hospitals, in addition to high mortality rates, the emergence and spread of resistance to practically all antibiotics restricts therapeutic options against serious and frequent infections. OBJECTIVE: The aim of this work is to present the views of a group of experts on the following aspects regarding resistance to antimicrobial agents in Gram-negative bacilli: 1) the current epidemiology in Spain, 2) how it is related to local clinical practice and 3) new therapies in this area, based on currently available evidence. METHODS: After reviewing the most noteworthy evidence, the most relevant data on these three aspects were presented at a national meeting to 99 experts in infectious diseases, clinical microbiology, internal medicine, intensive care medicine, anaesthesiology and hospital pharmacy. RESULTS AND CONCLUSIONS: Subsequent local debates among these experts led to conclusions in this matter, including the opinion that the approval of new antibiotics makes it necessary to train the specialists involved in order to optimise how they use them and improve health outcomes; microbiology laboratories in hospitals must be available throughout a continuous timetable; all antibiotics must be available when needed and it is necessary to learn to use them correctly; and the Antimicrobial Stewardship Programs (ASP) play a key role in quickly allocating the new antibiotics within the guidelines and ensure appropriate use of them.

Antibacterial spectrum of cefiderocol.

Cefiderocol, a siderophore catechol cephalosporin, recently introduced in the market has been developed to enhance the in vitro activity of extended spectrum cephalosporins and to avoid resistance mechanisms affecting cephalosporins and carbapenems. The in vitro study of cefiderocol in the laboratory requires iron depleted media when MIC values are determined by broth microdilution. Disk diffusion presents good correlation with MIC values. In surveillance studies and in clinical trials it has been demonstrated excellent activity against Gram-negatives, including carbapenemase producers and non-fermenters such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Few cefiderocol resistant isolates have been found in surveillance studies. Resistance mechanisms are not directly associated with porin deficiency and or efflux pumps. On the contrary, they are related with gene mutations affecting iron transporters, AmpC mutations in the omega loop and with certain beta-lactamases such us KPC-variants determining also ceftazidime-avibactam resistance, certain infrequent extended-spectrum betalactamases (PER, BEL) and metallo-beta-lactamases (certain NDM variants and SPM enzyme).

Monkeypox in humans: a new outbreak.

Infection caused by Monkeypox Virus (MPVX) has small rodents as its natural reservoir and both monkeys and humans are occasional hosts. The causative agent is an Orthopoxvirus (MPVX) that was isolated in monkeys in 1958 and proved capable of passing to humans in 1970. It remained contained in Africa, causing isolated episodes of infection, until 2003 when an outbreak occurred in the United States following importation of animals from that continent. Since then, anecdotal cases have continued to be reported outside Africa, usually very clearly linked to travelers to those countries, but in May 2022, a broad outbreak of this disease has begun, now affecting several continents, with the emergence of human cases of MPVX (H-MPVX) infection mainly among Men that have Sex with Men (MSM). The disease has an incubation time ranging from 5 to 15 days and is characterized by the presence of pustules, fever, malaise and headache. The presence of significant regional lymphadenopathy is a differential feature with episodes of classical smallpox. Proctitis and pharyngitis, with minimal skin lesions, may be another form of presentation. Diagnosis can be confirmed by PCR testing of lesions or by demonstration of MPVX in other body fluids or tissues, although in the appropriate epidemiologic setting the clinical picture is highly suggestive of the disease. Effective drug treatment has been developed as part of programs to protect against potential bioterrorist agents and smallpox vaccinees are known to have high protection against monkeypox. New vaccines are available, but neither the drugs nor the vaccines are yet freely available on the market. The prognosis of the disease appears, at least in adults in developed countries, to be good, with very low mortality figures and much less aggressive behavior than that described in classical smallpox. Isolation measures, essential for the control of the outbreak, have been published by the health authorities.

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.