Community-Acquired Pneumonia Due to Multidrug- and Non–Multidrug-Resistant Pseudomonas aeruginosa

Background: Pseudomonas aeruginosa is not a frequent pathogen in community-acquired pneumonia (CAP). However, in patients with severe CAP, P aeruginosa can be the etiology in 1.8% to 8.3% of patients, with a case-fatality rate of 50% to 100%. We describe the prevalence, clinical characteristics, outcomes, and risk factors associated with CAP resulting from multidrug-resistant (MDR) and non-MDR P aeruginosa. Methods: Prospective observational study of 2,023 consecutive adult patients with CAP with definitive etiology. Results: P aeruginosa was found in 77 (4%) of the 2,023 cases with microbial etiology. In 22 (32%) of the 68 cases of P aeruginosa with antibiogram data, the isolates were MDR. Inappropriate therapy was present in 49 (64%) cases of P aeruginosa CAP, including 17/22 (77%) cases of MDR P aeruginosa CAP. Male sex, chronic respiratory disease, C-reactive protein <12.35 mg/dL, and pneumonia severity index risk class IV to V were independently associated with P aeruginosa CAP. Prior antibiotic treatment was more frequent in MDR P aeruginosa CAP compared with non-MDR P aeruginosa (58% vs 29%, P = .029), and was the only risk factor associated with CAP resulting from MDR P aeruginosa. In the multivariate analysis, age ≥65 years, CAP resulting from P aeruginosa, chronic liver disease, neurologic disease, nursing home, criteria of ARDS, acute renal failure, ICU admission, and inappropriate empiric treatment were the factors associated with 30-day mortality. Conclusions: P aeruginosa is an individual risk factor associated with mortality in CAP. The risk factors described can help clinicians to suspect P aeruginosa and MDR P aeruginosa

Cutaneous infection by Phaeoacremonium parasiticum

Background: Phaeoacremonium parasiticum is considered a rare infectious agent that is part of a heterogeneous group of fungi causing phaeohyphomycosis. This organism is capable of producing subcutaneous infections, eumycetomas, osteomyelitis, arthritis, myositis and also disseminated diseases, such as fungemia and endocarditis. Case report: We describe a case of cutaneous infection by P. parasiticum in a kidney transplant patient. The identification of this microorganism was performed by microbiological and histopathological studies and confirmed with the sequence of the gene encoding β-tubulin and a real time panfungal PCR targeting 18S ribosomal RNA gene. The microorganism was correctly identified by phenotypic and molecular methods. The patient was treated with oral antifungal therapy and a debulking surgery and evolved without any complication. Conclusions: The diagnosis of this infection is difficult and usually affects kidney transplant patients, but the reasons of this association are still unknown

A captured room temperature stable Wheland intermediate as a key structure for the orthogonal decoration of 4-amino-pyrido[2,3-d]pyrimidin-7 (8H)-ones

Wheland intermediates are usually unstable compounds and only a few have been isolated at very low temperatures. During our work on tyrosine kinase inhibitors, we studied the bromination of 7 in order to obtain a dibromo substituted pyrido[2,3-d]pyrimidin-7(8H)-one which could be orthogonally decorated. Surprisingly, treatment of 7 with 3 equiv. of Br2 in acetic acid (AcOH) afforded 12, a captured room temperature stable Wheland bromination intermediate stabilized by the bromination of the imino tautomer of the amino group at C4 of the pyridopyrimidine skeleton. The structure was confirmed by crystal structure determination from powder X-ray diffraction data. Treatment of 12 with DMSO afforded the dibromo substituted compound 13 presenting a bromine atom at C6 and C5-C6 unsaturation. 13 was directly accessed by treating 7 with N-bromosuccinimide (NBS), a protocol extended to other compounds using NBS or N-iodosuccinimide (NIS) to afford 6-halo substituted systems. 26, bearing an iodine at C6 and a p-bromophenylamino at C2, allows the orthogonal decoration of pyridopyrimidines

Causes of death in a contemporary cohort of patients with invasive aspergillosis

Information regarding the processes leading to death in patients with invasive aspergillosis (IA) is lacking. We sought to determine the causes of death in these patients, the role that IA played in the cause, and the timing of death. The factors associated with IA-related mortality are also analyzed. We conducted a multicenter study (2008-2011) of cases of proven and probable IA. The causes of death and whether mortality was judged to be IA-related or IA-unrelated were determined by consensus using a six-member review panel. A multivariate analysis was performed to determine risk factors for IA-related death. Of 152 patients with IA, 92 (60.5%) died. Mortality was judged to be IA-related in 62 cases and IA-unrelated in 30. The most common cause of IA-related death was respiratory failure (50/62 patients), caused primarily by Aspergillus infection, although also by concomitant infections or severe comorbidities. Progression of underlying disease and bacteremic shock were the most frequent causes of IA-unrelated death. IA-related mortality accounted for 98% and 87% of deaths within the first 14 and 21 days, respectively. Liver disease (HR 4.54; 95% CI, 1.69-12.23) was independently associated with IA-related mortality, whereas voriconazole treatment was associated with reduced risk of death (HR 0.43; 95% CI, 0.20-0.93). In conclusion, better management of lung injury after IA diagnosis is the main challenge for physicians to improve IA outcomes. There are significant differences in causes and timing between IA-related and IA-unrelated mortality and these should be considered in future research to assess the quality of IA car

Microbiology and outcomes of community acquired pneumonia in non cystic-fibrosis bronchiectasis patients

Background: It is general belief that Non-cystic fibrosis bronchiectasis (NCFB) is characterized by frequent community-acquired pneumonia. Nonetheless, the knowledge on clinical characteristics of CAP in NCFBE is poor and no specific recommendations are available. We aim to investigate clinical and microbiological characteristics of NCFBE patients with CAP. Methods: Prospective observational study of 3495 CAP patients (2000-2011). Results: We found 90 (2.0%) NCFBE-CAP that in comparison with non-bronchiectatic CAP (n, 3405) showed older age (mean ± [SD], NCFBE-CAP 73 ± 14 vs. CAP 65 ± 19yrs), more vaccinations (pneumococcal: 35% vs. 14%; influenza: 60% vs. 42%), comorbidities (n ≥ 2: 43% vs. 25%), previous antibiotics (38% vs. 22%), and inhaled steroids (53% vs. 16%) (p < 0.05 each). Streptococcus pneumoniae was the most frequent isolate in both groups (NCFBE-CAP 44.4% vs. CAP 42.7%; p = 0.821) followed by respiratory virus, mixed infections and atypical bacteria. Considering overall frequencies of the main pathogens (including monomicrobial and mixed infections) Pseudomonas aeruginosa (15.5% vs. 2.9%; p < 0.001) and Enterobacteriaceae (8.8% vs. 2.4%; p = 0.025) were more prevalent in NCFBE-CAP patients than in CAP. Despite these clinical and microbiological differences, NCFBE-CAP showed similar outcomes to CAP patients (mortality, length of hospital stay, etc.). Conclusions: NCFBE-CAP patients are usually older and have more comorbidities but similar outcomes than general CAP population. Usual CAP pathogens, such as S. pneumoniae, are also involved in NCFBE-CAP but P. aeruginosa and other Enterobacteriaceae were globally more frequent than in CAP. Therefore, a wide microbiological investigation should be recommended in all NCFBE-CAP cases as well as routine pneumococcal vaccination for prevention of pneumonia

Community-Acquired Pneumococcal Pneumonia in Virologically Suppressed HIV-Infected Adult Patients: A Matched Case-Control Study

Background: The study aimed to investigate whether the clinical presentations and outcomes (length of stay, ICU admission, and 30-day mortality) of pneumococcal pneumonia in virologically suppressed patients who were HIV-infected on ART with a CD4+ T-cell count > 350 cells/mm3 are comparable to those seen in patients with HIV, using a case-control design. Methods: A case-control study was carried out in Hospital Clinic, Barcelona, Spain (2001-2016). Control patients were matched by age (±10 years), sex, comorbidities, and pneumonia diagnosis in the same calendar period. Clinical presentation and outcomes of pneumococcal pneumonia in patients who were and were not infected with HIV were compared. Results: Pneumococcal pneumonia was studied in 50 cases (HIV infection) and 100 control patients (non-HIV infection). Compared with the control patients, case patients had higher rates of influenza (14% vs 2%, P = .007) and pneumococcal vaccination (10% vs 1%, P = .016). The group of cases also presented a higher rate of coinfection with hepatitis B virus (6% vs 0%, P = .036). Both groups presented similar ICU admission (18% vs 27%, P = .22), need for mechanical ventilation (12% vs 8%; P = .43), length of stay (7 days vs 7 days, P = .76), and 0% of 30-day mortality. No evidence was found of a more severe presentation or a worse clinical outcome in cases than in control patients. Conclusions: Pneumococcal pneumonia episodes requiring hospitalization in virologically suppressed patients with HIV with > 350 CD4+ T-cell count/mm3 were neither more severe nor had worse prognosis compared with uninfected patients. These results support the fact that such patients do not need treatment, admission, or care sites different to the general population

An Unequivocal Synthesis of 2-Aryl Substituted 3-Amino-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-ones

The reaction between pyridones (1) and substituted hydrazines 4 can afford two different regioisomeric pyrazolo[3,4-b]pyridin - 6-ones 2 and 3 depending on the initial substitution of the methoxy group and the direction of the cyclization. In the case of phenylhydrazine 4 (R3 = Ph), we have clearly shown that the treatment of pyridones 1a-d with 4 (R3 = Ph) in MeOH at temperatures below 1408C yields, independently of the nature and position of the substituents present in the pyridone ring, the open intermediates 7a-d. When the reaction is carried at 1408C under microwave irradiation, the corresponding 2-aryl substituted pyrazolo[3,4-b]pyridines 3a-d are always formed. We have experimentally determined, using DSC techniques, the activation energies of the two steps involved in the formation of 3: a) substitution of the methoxy group present in pyridones 1 with phenylhydrazine 4 (R3 = Ph) to afford intermediates 7 and b) cyclization of intermediates 7 to yield pyrazolopyridines 3. The results obtained, 15 and 42 kcal·mol 1 respectively, are in agreement with the experimental findings

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds

Autocatalytic photoinduced oxidative dehydrogenation of pyrido[2,3-d]pyrimidin-7(8H)-ones: synthesis of C5-C6 unsaturated systems with concomitant formation of a long-lived radical

5,6-Dihydropyrido[2,3-d]pyrimidin-7(8H)-ones are readily accessed by a variety of methods and are a good scaffold for the development of biologically active compounds. However, they are very reluctant to dehydrogenate to give C5-C6 unsaturated compounds, usually with higher activity. A serendipitous discovery has allowed us to develop an autocatalytic photochemical dehydrogenation process by irradiating at 450 or 365 nm in DMSO, in the presence of air, and at room temperature the corresponding 5,6-dihydro derivative (with a variety of substituents at C2, C4, C5, C6, and N8) without adding any external photosensitizer. A complete study including reactions in DMSO-d6 followed by NMR spectroscopy, EPR experiments, the use of radical quenchers, spin-trapping techniques, and reaction with methyl viologen, complemented with ab initio calculations has allowed us to propose a mechanistic rationalization for such a process.This research was funded by Ministerio de Ciencia, Innovación y Universidades, Proyectos de I + D + I “Retos Investigación” del Programa Estatal de I + D + I orientada a los Retos de la Sociedad, grant number RTI2018-096455-B-I00. We thank Dr Alexandr Shafir of the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) and Dr Ana Belén Cuenca of Institut Químic de Sarrià, Universitat Ramon Llull for giving us the possibility of carrying out the first experiment using Penn PhD Photoreactor M2. We thank one of the referees for very interesting and fruitful suggestions and discussion about the mechanistic proposal.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

Pyrazolo[3,4-b]pyridines are a group of heterocyclic compounds presenting two possible tautomeric forms: the 1H- and 2H-isomers. More than 300,000 1H-pyrazolo[3,4-b]pyridines have been described which are included in more than 5500 references (2400 patents) up to date. This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, and C6, the synthetic methods used for their synthesis, starting from both a preformed pyrazole or pyridine, and the biomedical applications of such compounds