The spread and clinical impact of ST14CC-PBP3 type IIb/A, a clonal group of non-typeable Haemophilus influenzae with chromosomally mediated ß-lactam resistance-a prospective observational study.

OBJECTIVES: Increasing incidences of non-typeable Haemophilus influenzae (NTHi) with ß-lactam resistance mediated through mutations in penicillin-binding protein 3 (BLNAR or rPBP3) have been observed in the past decades. Recently, an rPBP3 NTHi sequence type (ST) 14 with PBP3 type IIb/A caused a disease outbreak in a nursing home in Sweden with severe outcomes, indicating increased bacterial virulence. In this prospective observational study, the epidemiology and clinical significance of the corresponding clonal group (ST14CC-PBP3IIb/A) in Skåne, Sweden was investigated. METHODS: ST14CC-PBP3IIb/A isolates were identified through partial multilocus sequence typing and ftsI(PBP3 gene)-sequencing of prospectively collected H. influenzae from patients with respiratory tract or invasive infections (n=3262) in 2010-2012. Data on type of infection, hospitalization and outcomes were analysed, and the geographical distribution of isolates from different groups was investigated. RESULTS: Isolates belonging to ST14CC-PBP3IIb/A constituted 26% (n=94/360) of respiratory tract rPBP3 NTHi. From mapping of patient addresses, a dynamic geographical spread was apparent during the study period. Furthermore, patients with infections by ST14CC-PBP3IIb/A isolates had higher hospitalization rates compared with patients infected with other rPBP3 NTHi (14/83 versus 21/255, p 0.025) and to a group of patients infected with susceptible NTHi (14/83 versus 13/191, p 0.010). ST14CC-PBP3IIb/A isolates constituted 25% (n=2/8) of invasive rPBP3 NTHi during the study period. CONCLUSIONS: Our investigation suggests that the ST14CC-PBP3IIb/A clonal group is associated with increased clinical virulence, resistance to several antimicrobial agents, and is persistent over time. We conclude that virulence varies between different NTHi, and that NTHi disease may be more dependent on bacterial factors than previously recognized.

Twenty-two years of candidaemia surveillance: results from a Norwegian national study.

Several studies have reported an increased incidence of candidaemia and a redistribution of species, with a decrease in the number of Candida albicans isolates. In Norway, a prospective, national surveillance study of candidaemia has been ongoing since 1991. Data from the period 1991-2003 have been published previously. The aim of this study was to follow up the incidence, species distribution and antifungal susceptibility of Candida species isolates from blood cultures in the period 2004-2012, and compare them with the corresponding findings from the period 1991-2003. Blood culture isolates of Candida species from all medical microbiological laboratories in Norway were identified and susceptibility tested at the Norwegian Mycological Reference Laboratory. A total of 1724 isolates were recovered from 1653 patients in the period 2004-2012. Comparison of the two periods showed that the average incidence of candidaemia episodes per 100 000 inhabitants increased from 2.4 (1991-2003) to 3.9 (2004-2012). The increase in incidence in the latter period was significantly higher in patients aged >40 years (p 0.001), and a marked increase was observed in patients aged >60 years (p < 0.001). In conclusion, the average incidence in Norway over a period of 22 years modestly increased from 2.4 to 3.9 per 100,000 inhabitants, this being mainly accounted for by candidaemia in the elderly. The species distribution was stable, and the rate of acquired resistance was low.

Symptomatic and asymptomatic secondary transmission of Cryptosporidium parvum following two related outbreaks in schoolchildren.

Two related outbreaks (in 2009 and 2012) of cryptosporidiosis in Norwegian schoolchildren during a stay at a remote holiday farm provided us with a natural experiment to investigate possible secondary transmission of Cryptosporidium parvum IIa A19G1R1. After the children had returned home, clinical data and stool samples were obtained from their household contacts. Samples were investigated for the presence of Cryptosporidium oocysts by immunofluorescence antibody test. We found both asymptomatic and symptomatic infections, which are likely to have been secondary transmission. Laboratory-confirmed transmission rate was 17% [4/23, 95% confidence interval (CI) 7·0-37·1] in the 2009 outbreak, and 0% (95% CI 0-16·8) in the 2012 outbreak. Using a clinical definition, the probable secondary transmission rate in the 2012 outbreak was 8% (7/83, 95% CI 4·1-16·4). These findings highlight the importance of hygienic and public health measures during outbreaks or individual cases of cryptosporidiosis. We discuss our findings in light of previous studies reporting varying secondary transmission rates of Cryptosporidium spp.

Antibiotic prescriptions and cycles of Mycoplasma pneumoniae infections in Norway: can a nationwide prescription register be used for surveillance?

Mycoplasma pneumoniae outbreaks cause increased use of macrolides and tetracyclines. We aimed to investigate whether drug use data, in addition to laboratory data, could improve understanding of the spread of M. pneumoniae epidemics. Number of users of Mycoplasma antibiotics (erythromycin, doxycycline, clarithromycin) per week and county of residence in an indicator age group (6-12 years) was retrieved from the Norwegian prescription database for the epidemic season 2011-2012 and compared to non-epidemic seasons. In 2011, increased use of Mycoplasma antibiotics was first observed in September on the west coast of Norway. The Norwegian laboratory-based surveillance system showed the first increase in positive tests in August 2011 and an epidemic was announced on 25 October 2011. At that time the use of Mycoplasma antibiotics had already exceeded three times the use in non-epidemic periods. Data for three counties from the regional microbiological laboratories showed that the increase in number of positive samples coincided in time with the increase in prescription data. Laboratory data cannot accurately determine the extent of an epidemic, and drug use data cannot identify the cause. Establishing a systematic interaction between the two monitoring systems will enhance surveillance and probably contribute to improved infection control and prudent antibiotic prescribing.

Emergence of clonally related multidrug resistant Haemophilus influenzae with penicillin-binding protein 3-mediated resistance to extended-spectrum cephalosporins, Norway, 2006 to 2013.

Resistance to cephalosporins in Haemophilus influenzae is usually caused by characteristic alterations in penicillin-binding protein 3 (PBP3), encoded by the ftsI gene. Resistance to extended-spectrum cephalosporins is associated with high-level PBP3-mediated resistance (high-rPBP3), defined by the second stage S385T substitution in addition to a first stage substitution (R517H or N526K). The third stage L389F substitution is present in some high-rPBP3 strains. High-rPBP3 H. influenzae are considered rare outside Japan and Korea. In this study, 30 high-rPBP3 isolates from Norway, collected between 2006 and 2013, were examined by serotyping, multilocus sequence typing (MLST), ftsI sequencing, detection of beta-lactamase genes and minimum inhibitory concentration (MIC) determination. MICs were interpreted according to clinical breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Respiratory isolates predominated (proportion: 24/30). The 30 isolates included one serotype f isolate, while the remaining 29 lacked polysaccharide capsule genes. Resistance to extended-spectrum cephalosporins (cefixime, 29 isolates/30 isolates; cefepime, 28/30; cefotaxime, 26 /30; ceftaroline, 26/30; ceftriaxone, 14/30), beta-lactamase production (11/30) and co-resistance to non-beta-lactams (trimethoprim-sulfamethoxazole, 13/30; tetracycline, 4/30; chloramphenicol, 4/30; ciprofloxacin, 3/30) was frequent. The N526K substitution in PBP3 was present in 23 of 30 isolates; these included a blood isolate which represents the first invasive S385T + N526K isolate reported from Europe. The L389F substitution, present in 16 of 30 isolates, coincided with higher beta-lactam MICs. Non-susceptibility to meropenem was frequent in S385T + L389F + N526K isolates (8/12). All 11 beta-lactamase positive isolates were TEM-1. Five clonal groups of two to 10 isolates with identical MLST-ftsI allelic profiles were observed, including the first reported high-rPBP3 clone with TEM-1 beta-lactamase and co-resistance to ciprofloxacin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole. Prior to this study, no multidrug resistant high-rPBP3 H. influenzae had been reported in Norway. Intensified surveillance of antimicrobial resistance is needed to guide empiric therapy.

Mutant ftsI genes in the emergence of penicillin-binding protein-mediated beta-lactam resistance in Haemophilus influenzae in Norway.

The most important mechanism for beta-lactam resistance in beta-lactamase-negative ampicillin-resistant (BLNAR) isolates of Haemophilus influenzae is the alteration of penicillin-binding protein 3 (PBP3) as a result of ftsI gene mutations. The present study aimed to map PBP3 alterations and to determine the correlation to beta-lactam resistance in respiratory tract isolates of H. influenzae in Norway, as well as assess the contribution of clonal spread to the emergence of PBP3-mediated resistance. Twenty-three beta-lactamase negative respiratory tract isolates with resistance to penicillins and 23 susceptible control isolates were examined by determination of beta-lactam MICs, ftsI sequencing and molecular typing by pulsed-field gel electrophoresis (PFGE). Ampicillin MIC ranges in the resistant group and the control group were 1-2 mg/L and 0.125-0.5 mg/L, respectively. All isolates in the resistant group had the PBP3 substitution Asn526-->Lys and were thus categorized as group II low-BLNAR. No control isolate met the genetic BLNAR (gBLNAR) criteria. The PBP3 substitution patterns corresponded well to those observed in previous European studies. Eighty-three percent (19/23) of the resistant isolates belonged to two clones, demonstrating the capability of low-BLNAR strains of clonal dissemination. Combined analysis of ftsI DNA sequences and PFGE patterns revealed distinctly different ftsI alleles in genetically indistinguishable isolates and identical copies of the same ftsI allele in unrelated isolates. A possible explanation of this observation is the recombinational exchange of ftsI alleles. This phenomenon, as well as the possibility of endemic European gBLNAR strains, should be further investigated.

[Physicians pilloried? On physicians' blunders and blundering physicians in Norwegian tabloids]. / Leger i gapestokk? Om legetabber og tabbeleger i norsk tabloidpresse.

Doctors frequently claim that the tabloid press focuses too much on malpractice cases and that the identity of the individual physicians is also revealed. A systematic review of two Norwegian tabloids over six months in 1994 showed that articles on malpractice occurred less often than expected. We found 1.6 articles each week, on average. In addition, the doctors were identified in only three of 42 articles. The situation leading to the complaint was commented by the doctor involved in one article, while criticism from a colleague who was not directly involved was included in two of 42 articles. The results indicate that doctors need to be trained to handle the press.