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Objectives: To characterize the mechanisms of antimicrobial resistance and the prevalence of the polysaccharide capsule among urogenital and respiratory Haemophilus parainfluenzae isolates. Methods: Antimicrobial susceptibility was tested by microdilution. Fifty-five MDR strains were subjected to WGS and were phylogenetically compared with all the available H. parainfluenzae genomes from the NCBI database. The identification of the capsular bexA gene was performed by PCR in 266 non-MDR strains. Results: In 31 of the 42 ampicillin-resistant strains, blaTEM-1 located within Tn3 was identified. β-Lactamase-negative cefuroxime-resistant strains (n=12) presented PBP3 substitutions. The catS gene (n=14), the tet(M)-MEGA element (n=18) and FolA substitutions (I95L and F154V/S) (n=41) were associated with resistance to chloramphenicol, tetracycline plus macrolides, and co-trimoxazole, respectively. Thirty-seven isolates had a Tn10 harbouring tet(B)/(C)/(D)/(R) genes with (n=15) or without (n=22) catA2. Putative transposons (Tn7076-Tn7079), including aminoglycoside and co-trimoxazole resistance genes, were identified in 10 strains (18.2%). These transposons were integrated into three new integrative and conjugative elements (ICEs), which also included the resistance-associated transposons Tn3 and Tn10. The capsular operon was found only in the urogenital isolates (18/154, 11.7%), but no phylogenetic clustering was observed. The capsular operons identified were similar to those of Haemophilus influenzae serotype c and Haemophilus sputorum type 2. Conclusions: The identification of ICEs with up to three resistance-associated transposons suggests that these transferable elements play an important role in the acquisition of multidrug resistance in H. parainfluenzae. Moreover, the presence of polysaccharide capsules in some of these urogenital isolates is a cause for concern., This study was funded by the Fundación Española del Pulmón SEPAR (418/2017); the Instituto de Salud Carlos III through the Projects from the Fondo de Investigaciones Sanitarias (PI16/00977); CIBER de Enfermedades Respiratorias (CIBERES—CB06/06/0037; CB06/06/1102), co-funded by the European Regional Development Fund/European Social Fund (ERDF/ESF, ‘Investing in your future’) and CERCA Programme/Generalitat de Catalunya for institutional support; and the RTI2018-096369-B-100 grant. Bioinformatic analysis was supported by an Amazon Web Services (AWS) research grant to S.M.A.C. was supported by an FPU grant (Formación de Profesorado Universitario, FPU16/02202) from the Ministerio de Educación and S.M. was supported by a ‘Miguel Servet’ contract (CP19/00096) from the Instituto de Salud Carlos III.

[Background] We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis., [Methods] A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy., [Results] Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93–1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018)., [Conclusions] Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events., [Clinical Trials Registration] NCT01898338., This work was supported by the Spanish Ministry of Science, Innovation and Universities (PI12/01907); Spanish Network for Research in Infectious Diseases (RD16/0016/0005); Instituto de Salud Carlos III (ISCIII); and Spanish Ministry of Economy, Industry and Competitiveness. This work was also supported by the European Development Regional Fund “A way to achieve Europe,” Operational Programme Intelligent Growth 2014–2020; Spanish Clinical Research Network (SCReN), co-financed by the Plan Nacional de I+D and ISCIII, Subdirección General de Evaluación y Fomento de la Investigación (PT13/0002/0007); and the Grupo de Estudio de la Infección Relacionada con la Asistencia Sanitaria. J. M.-M. received a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques Agust Pi i Sunyer, Barcelona, Spain, during 2017–2021.