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Objectives: To analyse the clonal dynamics and clinical characteristics of adult invasive pneumococcal disease (IPD) caused by MDR and penicillin-non-susceptible (PNS) pneumococci in Spain., Methods: All adult IPD episodes were prospectively collected (1994-2018). Streptococcus pneumoniae isolates were serotyped, genotyped and tested for antimicrobial susceptibility. Changes in the incidence of IPD were analysed and risk factors contributing to MDR were assessed by logistic regression., Results: Of 2095 IPD episodes, 635 (30.3%) were caused by MDR/PNS isolates. Over the study period, the incidence of MDR/PNS-IPD decreased (IRR 0.70; 95% CI 0.53-0.93) whereas that of susceptible isolates remained stable (IRR 0.96; 95% CI 0.80-1.16). A reduction of resistance rates to penicillin (-19.5%; 95% CI -37% to 2%) and cefotaxime (-44.5%; 95% CI -64% to -15%) was observed. Two clones, Spain9V-ST156 and Denmark14-ST230, accounted for 50% of current resistant disease. Among current MDR/PNS isolates, 45.8% expressed serotypes not covered by the upcoming PCV15/PCV20 vaccines. MDR/PNS episodes were associated with older patients with comorbidities, nosocomial acquisition and higher 30 day mortality. MDR/PNS pneumococci were not independently associated with 30 day mortality in multivariate analysis [OR 0.826 (0.648-1.054)]., Conclusions: Our study shows an overall reduction of MDR/PNS isolates in adults after the introduction of pneumococcal conjugate vaccines. However, a significant proportion of current resistant isolates are not covered by any of the upcoming PCV15/PCV20 vaccines. The burden of resistant disease is related to older patients with underlying conditions and caused by two major clones. Our data show that MDR is not a statistically significant factor related to increased mortality., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The objectives of this study were to establish the frequency of Haemophilus haemolyticus in clinical samples, to determine the antimicrobial resistance rate and to identify the mechanisms of resistance to β-lactams and quinolones., Methods: An updated database was used to differentiate between MALDI-TOF MS results for Haemophilus influenzae and H. haemolyticus. Antimicrobial susceptibility was studied by microdilution, following EUCAST criteria. The β-lactamase types were identified by PCR analysis of isolates that tested positive for nitrocefin hydrolysis. Mutations in the ftsI gene were identified in isolates with ampicillin MICs ≥0.25 mg/L. Mutations in the quinolone resistance-determining region (QRDR) were identified in isolates with ciprofloxacin MICs ≥0.5 mg/L., Results: Overall, we identified 69 H. haemolyticus isolates from 1706 clinical isolates of Haemophilus spp. from respiratory, genital, invasive, and other infection sources. The frequency of H. haemolyticus was low in respiratory samples compared with that of H. influenzae, but in genital-related samples, the frequency was similar to that of H. influenzae. We found low antimicrobial resistance rates among H. haemolyticus isolates, with 8.7% for ampicillin, 8.7% for co-trimoxazole, 7.2% for tetracycline and 4.3% for ciprofloxacin. Mutations in the ftsI gene classified the isolates into four groups, including the newly described Group Hhae IV, which presents mutations in the ftsI gene not identified in H. influenzae and H. haemolyticus type strains. Three ciprofloxacin-resistant H. haemolyticus isolates with mutations affecting GyrA and ParC were identified., Conclusions: The frequency of H. haemolyticus was low, especially in respiratory samples, where H. influenzae is the main pathogen of this genus. Although antimicrobial resistance rates were low, three ciprofloxacin-resistant H. haemolyticus clinical isolates have been identified for the first time., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We aimed to analyse the clinical epidemiology and genetic diversity of invasive pneumococcal disease (IPD) episodes attributed to the Spain(23F)-ST81 (PMEN1) clone., Methods: Fifty-eight (2.7%) of 2117 invasive pneumococci isolated from adult patients during the 1990-2012 period shared a PFGE pattern related to the PMEN1 clone. The genotype was confirmed by multilocus sequence typing. The pbp2x, pbp1a, pbp2b and pspA genes were PCR-amplified and sequenced. Polymorphisms in the pspC gene were identified by PCR restriction fragment length polymorphism. The presence of transposons with erythromycin and tetracycline resistance determinants was detected by PCR., Results: The prevalence of the PMEN1 clone increased from 0.8% in 1991 to 6.2% in 2001, and decreased to 0% in 2010-12, concomitant with the introduction of the seven-valent pneumococcal conjugate vaccine for children. A total of 93.1% of patients had pneumonia, meningitis or peritonitis; 87.9% of patients had associated underlying diseases, mainly cancer, chronic obstructive pulmonary disease and diabetes. Two closely related sequence types (STs) (ST81, n = 52; ST85, n = 6) were detected, with different serotypes: 23F (n = 42), 19A (n = 9) and 19F (n = 6). All the isolates were resistant to penicillin, co-trimoxazole and chloramphenicol. All the isolates also shared the same pbp1a allele, whereas multiple alleles of pbp2b, pbp2x, pspA and pspC were detected. Of the isolates, 89.7% were tetracycline resistant and 60.3% (n = 35) were macrolide resistant, and resistance was associated with different Tn916-like transposons., Conclusions: Adult IPD caused by this clone was mainly detected in patients with underlying conditions, and genetic variability was observed among PMEN1 isolates collected in our area over the past 20 years.

The rapid spread of the new influenza virus A(H1N1)v in young age groups in 2009 has been partly attributed to a high transmission intensity in schools. However, detailed characterization of the spread of influenza in school populations has been difficult to obtain, simply because it is very hard to identify who infected whom in a large outbreak. Data collected in large outbreak investigations typically miss many transmission events, and some reported transmission events will be incorrect. Here the authors present robust likelihood-based methods that can be used to analyze outbreak data while explicitly accounting for both missing data and erroneous data. They apply this method to a school-based outbreak of pandemic influenza A(H1N1)v that occurred in London, United Kingdom, in April 2009. The authors show that the generation interval in this school-based population was 2.20 days and that the reproduction number declined coincident with school closure, from 1.33 secondary cases per primary case to 0.43 secondary cases per primary case. These results provide quantitative evidence for the change in influenza transmission that is to be expected from school closure.

Objectives: To analyse the epidemiology of isolates of serotype 6C among invasive pneumococci isolated from children and adults in Spain between 1997 and 2009, and to characterize serotype 6C clones and macrolide and quinolone resistance mechanisms., Methods: Antimicrobial susceptibility was determined following CLSI guidelines. Phenotypic characterization of macrolide-resistant isolates was performed by the double disc diffusion method. Genes associated with resistance to erythromycin and tetracycline were sought by PCR, while quinolone resistance was analysed by restriction fragment length polymorphism of the quinolone resistance-determining region. Isolates were typed by multilocus sequence typing., Results: Seven hundred and eighty-nine of 866 serotype 6A pneumococci collected from 1997 to 2009 were available. Of these, 213 (27.0%) were serotype 6C; 16/163 (9.8%) in the 1997-2001 (pre-PCV7) period, 37/322 (11.5%) in the 2002-05 (early-PCV7) period and 160/381 (42.0%) in the 2006-09 (late-PCV7) period. The overall proportions of serotype 6C increased from 0.1% (pre-PCV7) to 1% (late-PCV7) for paediatric isolates and from 0.3% to 1.7% among adult isolates. A major serotype 6C lineage (ST224/ST1150/ST4821), accounting for 66.7% of the isolates, was identified across the whole period. In the late-PCV7 period the antimicrobial non-susceptibility of serotype 6C increased in association with the emergence of the ST386/ST4310/ST4825 lineage, which carried a Tn6002 transposon [erm(B) and tet(M) genes]., Conclusions: Serotype 6C pneumococci were identified in Spain during the period 1997-2009. The increase in serotype 6C in the late-PCV7 period was associated with the spread of the ST224/ST1150/ST4821 lineage and the emergence of the ST386/ST4310/ST4825 lineage.

Objectives: To assess the risk factors, antibiotic therapy and outcomes of multidrug-resistant Gram-negative bacilli (MDRGNB) bacteraemia in hospitalized patients with cancer., Methods: Episodes of MDRGNB bacteraemia were compared with a susceptible control group in a 4 year prospective study., Results: Of 747 bacteraemias, 372 (49.7%) were caused by a Gram-negative bacilli (GNB). Fifty-one of these (13.7%) were caused by a multidrug-resistant (MDR) strain. Previous antibiotics [odds ratio (OR) 3.57; 95% confidence interval (CI) 1.63-7.80] and urinary catheter (OR 2.41; 95% CI 1.01-5.74) were identified as independent risk factors for MDRGNB acquisition. The most frequent mechanism of resistance was extended-spectrum β-lactamase (ESBL) production (45%), mainly by Escherichia coli, followed by Amp-C cephalosporinase hyperproduction (24%). Patients with MDRGNB bacteraemia more frequently received inadequate initial antibiotic therapy (69% versus 9%; P < 0.001) and time to adequate therapy was longer in this group (41% versus 4%; P < 0.001). Patients in the resistant group more frequently required intensive care unit (ICU) admission (14% versus 5%; P = 0.023), had greater need for mechanical ventilation (14% versus 3%; P = 0.005) and had a higher overall case-fatality rate (41% versus 21%; P = 0.003). Risk factors for mortality were solid tumour (OR 5.04; 95% CI 2.49-10.19), current corticosteroid use (OR 4.38; 95% CI 2.39-8.05), ICU admission (OR 11.40; 95% CI 3.19-40.74) and MDRGNB bacteraemia (OR 3.52; 95% CI 1.36-9.09)., Conclusions: MDRGNB bacteraemia was common among cancer patients, especially in those exposed to antibiotics and urinary catheter. The most frequent mechanism of resistance was ESBL production. Patients with MDRGNB more frequently received inadequate empirical antibiotic therapy and presented poorer outcomes with a higher overall case-fatality rate (within 30 days).

Objectives: This study aimed to compare the antibiotic susceptibilities, serotypes and genotypes of pneumococci causing pneumonia or acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in patients with COPD., Methods: A total of 611 pneumococci collected from 487 COPD patients with pneumonia (n = 255, 94 bacteraemic pneumonia) or AECOPD episodes (n = 356), from 2001 to 2008, were analysed. Antibiotic susceptibility was studied by microdilution. Serotypes (PCR or Quellung) and genotypes (PFGE and multilocus sequence typing) were determined., Results: Pneumococci isolated from AECOPD episodes were significantly more resistant to co-trimoxazole and chloramphenicol than those isolated from pneumonia episodes (39.0% versus 29.7% and 13.8% versus 8.2%, respectively, P < 0.05). Comparing serotypes of isolates causing bacteraemic pneumonia, non-bacteraemic pneumonia and AECOPD, serotypes 4, 5 and 8 were associated with bacteraemic pneumonia (P < 0.05), serotypes 1 and 3 were associated with bacteraemic and non-bacteraemic pneumonia (P < 0.05) and serotypes 16F and 11A and non-typeable pneumococci were associated with AECOPD episodes (P < 0.05). The genotypes related to serotypes 3 (Netherlands(3)-ST180 and ST260(3)), 1 (Sweden(1)-ST306), 5 (Colombia(5)-ST289) and 8 (Netherlands(8)-ST53) were isolated more frequently in pneumonia episodes (P < 0.05), whereas genotype ST30(16F) (serotype 16F) was more frequently recovered from AECOPD episodes., Conclusions: In our experience, serotype 3 pneumococci (Netherlands(3)-ST180 and ST260(3) genotypes) commonly cause pneumonia and acute exacerbations in COPD patients. Pneumococci of serotypes 1 (Sweden(1)-ST306), 4 (ST247(4)), 5 (Colombia(5)-ST289) and 8 (Netherlands(8)-ST53) were more often associated with pneumonia. Non-typeable pneumococci may play an important role in acute exacerbations.

Objectives: The increase in erythromycin resistance among Streptococcus pyogenes isolates is a cause for concern. We analysed trends in macrolide resistance, phenotypes, genotypes, resistance determinants and transposons among erythromycin-resistant S. pyogenes isolates collected from adults in a Barcelona hospital (1993-2008)., Methods: Antibiotic susceptibility was studied by microdilution. Molecular typing was performed by PFGE, emm typing and multilocus sequence typing (MLST). Macrolide resistance genes and those related to the Tn916 family of transposons were detected by PCR., Results: Ninety-nine (18.3%) of 541 isolates were erythromycin resistant. Erythromycin resistance rates progressively increased from 0% (0/24) in 1993-1994 to 34.2% (50/146, P < 0.001) in 2001-2004, then falling to 7.4% (8/108, P = 0.02) in 2007-2008. Sixty-six erythromycin-resistant isolates were available for molecular studies. Of these, 26 had an M phenotype [mef(A)] and 40 had an MLS(B) phenotype [erm(B), n = 33; and erm(TR), n = 7]. Among M-phenotype isolates, the most frequent genotypes (88.5%) were emm4-ST39, emm6-ST382 and emm75-ST49, whereas genotypes emm11-ST403, emm28-ST52 and emm25-ST350 accounted for 72.5% of MLS(B)-phenotype isolates. Twenty-five isolates harboured both erm(B) and tet(M) genes related to the Tn916 family of transposons, Tn6002 being the most frequent. Ten isolates (10.1%) were ciprofloxacin non-susceptible, related to the emm6-ST382 clone with a ParC S79A change., Conclusions: The peak of macrolide resistance rates among S. pyogenes observed in the 2001-2004 period was associated with an increase in the MLS(B) phenotype caused by the spread of emm11-ST403 and emm28-ST52 clones harbouring transposons of the Tn916 family. However, erythromycin resistance rates decreased significantly in the 2007-2008 period.

Objectives: To assess the clinical features, risk factors, molecular epidemiology and outcome of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) bacteraemia in hospitalized cancer patients., Methods: Episodes of ESBL-EC bacteraemia were compared with a susceptible control group in a 3 year prospective study. ESBL-EC strains were studied by PCR and isoelectric focusing, and molecular typing was performed by PFGE., Results: Out of 531 episodes of bacteraemia, 135 were caused by E. coli. Seventeen of these cases involved ESBL-EC-producing strains (12.6%). In the multivariate analysis, female gender [odds ratio (OR) 3.43; 95% confidence interval (CI) 1.03-11.4] and previous antibiotic therapy (OR 3.22; 95% CI 1.00-10.3) were found to be independent risk factors for ESBL acquisition. An analysis of ESBL-EC isolates revealed a polyclonal distribution with CTX-M predominance (59%). Patients with ESBL-EC bacteraemia were more likely to have received an inadequate empirical antibiotic therapy (65% versus 6%; P = 0.000), and the time to adequate therapy was longer in this group (0 versus 1.50 days; P = 0.000). The overall mortality rate was 22%, ranging from 20% to 35% (P = 0.20). Risk factors for mortality were solid tumour (OR 19.41; 95% CI 4.66-80.83), corticosteroid therapy (OR 3.04 95% CI 1.05-8.81) and intensive care unit admission (OR 248.24, 95% CI 18.49-3332.14). In neutropenic patients, ESBL-EC bacteraemia was associated with poorer outcome and a higher overall mortality rate (37.5% versus 6.5%; P = 0.01)., Conclusions: In our centre, ESBL-EC bacteraemia is frequent among cancer patients, especially in those exposed to antibiotic pressure. All ESBL-EC strains were unrelated and most of them carried a CTX-M group enzyme. Patients with ESBL-EC bacteraemia received inadequate empirical antibiotic therapy more frequently than patients carrying a susceptible strain, but significant differences in mortality could not be demonstrated.

Objectives: Multidrug-resistant Streptococcus pneumoniae isolates of serotype 19A have emerged all over the world in recent years. The aim of this study was to characterize highly penicillin-resistant pneumococcal strains of the 19A serotype, collected in Spain from 1997 to 2007 from patients with invasive disease., Methods: Antibiotic susceptibility was studied by microdilution. All penicillin-resistant pneumococci were typed by PFGE and selected strains were studied by multilocus sequence typing (MLST). The presence of genes related to the Tn916 family of transposons was investigated by PCR., Results: From a total of 1197 invasive pneumococcal isolates of serotype 19A received at the Spanish Reference Laboratory between 1997 and 2007, 51 (4.3%) strains showed high-level resistance to penicillin (MICs of 2-4 mg/L). These 51 isolates belonged to three multiresistant clones related to sequence type (ST)81 (n = 21), ST320 (n = 19) and ST276 (n = 11). All 51 serotype 19A pneumococci were tetracycline-resistant and had the tet(M) gene, and 41 strains were macrolide-resistant, harbouring the erm(B) gene. The presence of int and xis genes was detected in all strains associated with other genes of the Tn916 family., Conclusions: The rise in penicillin-resistant serotype 19A invasive pneumococci in Spain was associated with the emergence and clonal spread of two worldwide-disseminated multiresistant clones (ST276 and ST320). The Spain(23F)-1-19A (ST81) clone remained stable throughout the study period. Multidrug resistance was associated with transposons of the Tn916 family.

Background: A dramatic decrease in the incidence of invasive pneumococcal disease (IPD) was observed among children and adults in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). Little is known about the incidence of IPD after PCV7 licensure in Europe. The objective of this study was to examine changes in the prevalence of IPD among adults in the PCV7 era., Methods: We undertook a prospective study involving adults with IPD who required hospital admission in the southern area of Barcelona, Spain. Three periods were studied: the pre-PCV7 period (1997-2001), the early PCV7 period (2002-2004), and the late PCV7 period (2005-2007)., Results: A total of 1007 episodes of IPD were observed. Rates of IPD among adults increased from 13.9 to 14.6 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .6) and then to 19.55 episodes per 100,000 population in the late PCV7 period (P < .001). The rates of IPD among adults due to non-PCV7 serotypes increased from 8.4 to 9.7 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .15) and then to 15.3 episodes per 100,000 population in the late PCV7 period (P < .001); IPD due to PCV7 serotypes decreased from 5.6 to 4.9 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .3), then to 4.3 episodes per 100,000 population in the late PCV7 period (P = .056). Among people aged > or = 65 years, IPD due to PCV7 serotypes decreased from 19.5 to 14.6 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .13), then to 12.3 episodes per 100,000 population in the late PCV7 period (P = .02). A decrease in the prevalence of antibioticresistant pneumococci in the late PCV7 period was associated with a decrease in the prevalence of multidrugresistant PCV7 clones (Spain(23F)-ST81, Spain(6B)-ST90, and ST88(19F)) and an increase in the prevalence of non-PCV7 antibiotic-susceptible clones (ST306(1), ST191(7F), ST989(12F), and ST433(22F))., Conclusions: Rates of IPD among adults increased in Barcelona in the late PCV7 period, coinciding with a clonal expansion of non-PCV7 serotypes. In contrast, rates of IPD caused by PCV7 serotypes decreased among people aged > or = 65 years, which suggests the development of a herd immunity.