The in vitro susceptibilities of 184 erythromycin-resistant streptococci to a novel ketolide, telithromycin (HMR 3647), were tested. These clinical isolates included 111 Streptococcus pyogenes, 18 group C streptococcus, 18 group G streptococcus, and 37 Streptococcus pneumoniae strains. The MICs for all but eight S. pyogenes strains were <0.5 g/ml, indicating that telithromycin is active in vitro against erythromycin-resistant Streptococcus strains. All strains for which MICs were >1 g/ml had an erm(B) resistance gene and six strains for which MICs were >4 g/ml had a constitutive erm(B) gene (MIC range, 4 to 64 g/ml). Interestingly, for S. pneumoniae strains with a constitutive erm(B) gene, MICs were <0.25 g/ml (MIC range, <0.008 to 0.25 g/ ml). Our in vitro data show that for S. pyogenes strains which constitutively express the erm(B) methylase gene, MICs are so high that the strains might be clinically resistant to telithromycin.Ketolides represent a new generation of macrolides, in which a 3-keto group replaces L-cladinose in the lactone ring. Ketolides have shown to be more active in vitro than other macrolides against various gram-positive bacteria such as Enterococcus species (6, 24), Staphylococcus aureus (6, 13), and Streptococcus species, including erythromycin-resistant Streptococcus pneumoniae and Streptococcus pyogenes strains (6,16,18). On the other hand, methicillin-resistant and some erythromycin-resistant S. aureus strains, as well as some Staphylococcus epidermidis strains (1, 18), seem to be resistant to ketolides (1, 6, 13).In streptococci, there are two well-characterized macrolide resistance mechanisms: target site modification and active drug efflux. Target site modification is mediated by methylases encoded by the erm (erythromycin ribosome methylation) genes (21, 26). Methylation of A2058 of the peptidyl transferase loop of 23S rRNA causes resistance to macrolides as well as to lincosamides and streptogramin B antibiotics (the MLS B resistance phenotype) (26). The expression of the erm genes can be either constitutive or inducible (27). In streptococci, erm genes are carried on both the chromosome and plasmids (2, 21) and are associated with conjugative transposons (25). The activeefflux mechanism, encoded by the mef (macrolide efflux) genes, is more specific and causes resistance only to 14-and 15-member-ring macrolides (the M resistance phenotype) (3,22). Expression of mef genes is constitutive (C. Arpin, M. H. Canron, P. Noury, and C. Quentin, Letter, J. Antimicrob. Chemother. 44:133-134, 1999). The mef genes are chromosomal (11,17) and, at least in the case of S. pyogenes, can be transferred by conjugation (11).The present work was carried out to study the activity of a novel ketolide, telithromycin (HMR 3647), against Streptococcus species with known macrolide resistance determinants. In addition, its activity against nine S. pneumoniae strains with an unknown macrolide resistance mechanism was tested. MATERIALS AND METHODSBacterial strains. Altogether 184 erythromycin-resistant strep...

Objective To measure quantitatively and objectively the maternal and fetal tobacco exposure during pregnancy and its neonatal effects. Design Tobacco exposure was assessed from maternal serum samples, obtained during the first half of pregnancy and from umbilical serum samples obtained at delivery, by measuring the concentration of nicotine metabolite, cotinine. Data on the respective pregnancies and neonates were collected from the Finnish Medical Birth Registry. Setting Finland. Subjects One thousand two hundred and thirty‐seven pregnancies and newborns, representing all pregnancies resulting in a liveborn infant during one week in one country. Main outcome measures Gestational age, birthweight and crown‐heel length of newborns. Results Cotinine (>6 μg/l) was detected in either maternal or umbilical serum in 300 pregnancies, and these mothers and newborns were classified as exposed. Important differences occurred between measured exposure and reported smoking behaviour. Of the exposed mothers, 38% were nonsmokers and 3.4% of the nonexposed mothers were smokers. Tobacco exposure was associated with shorter gestational age, reduced birthweight and shorter crown‐heel length of the newborns. After correction for parity, gender, and gestational age, the exposed newborns were on average 188 g (95% confidence interval (CI) 123–253 g) lighter and 10 mm (95% CI7–13 mm) shorter than the nonexposed newborns. One μg/ml of cotinine in maternal serum resulted in a mean decrease of 1.29 g (95% CI 0.55–2.02 g) in birthweight and in a mean decrease of 0.059 mm (95% CI 0.035–0.083 mm) in birth length. Maternal cotinine concentrations better explained the neonatal findings than the reported smoking habits. Conclusions There is a quantitative dose and effect relation between tobacco exposure and a decrease in the gestational age at birth and size of the neonate. The smoking habit reported by mothers themselves is not an accurate measure of fetal tobacco exposure.

Eleven clinical isolates of Streptococcus pneumoniae, isolated in Finland during 1996 to 2000, had an unusual macrolide resistance phenotype. They were resistant to macrolides and streptogramin B but susceptible, intermediate, or low-level resistant to lincosamides. No acquired macrolide resistance genes were detected from the strains. The isolates were found to have mutations in domain V of the 23S rRNA or ribosomal protein L4. Seven isolates had an A2059C mutation in two to four out of the four alleles encoding the 23S rRNA, two isolates had an A2059G mutation in two alleles, one isolate had a C2611G mutation in all four alleles, and one isolate had a 69 GTG 71 -to-69 TPS 71 substitution in ribosomal protein L4.Streptococcus pneumoniae (pneumococcus) is an important pathogen in respiratory tract infections, meningitis, and septicemia both in children and adults. There has been an increase in the prevalence of macrolide-resistant pneumococci over the last decade. In Finland, the prevalence has increased from 0.6% in 1988 to 1990 to 11.2% in 2000 according to the Finnish Study Group for Antimicrobial Resistance (unpublished data [http://www.mmm.fi/elintarvikkeet_elaimet/julkaisut_tiedotteet /finres99en.htm]).In streptococci, there are two well-characterized macrolide resistance mechanisms: target site modification and active drug efflux. Target site modification is mediated by the methylases encoded by the erm (erythromycin ribosome methylation) genes (22,30). Methylation of A2058 of the peptidyl transferase loop of 23S rRNA causes resistance to 14-, 15-, and 16-membered ring macrolides; lincosamides; and streptogramin B: the macrolide-lincosamide-streptogramin B (MLS B ) phenotype (30). The expression of the erm genes can be either constitutive or inducible (31). The active efflux mechanism, encoded by the mef (macrolide efflux) genes, is more specific and causes resistance only to 14-and 15-membered ring macrolides: the M phenotype (3,25).Among Finnish clinical isolates of pneumococci, we found a novel type of macrolide resistance, which did not fit into the two phenotypes described above. These strains were resistant to 14-, 15-, and 16-membered ring macrolides and to streptogramin B and were susceptible, intermediate, or low-level resistant to clindamycin (a lincosamide). Also, these strains did not carry mef(A) or erm(B) resistance genes (9). Tait-Kamradt et al. (26, 27) described mutations in the peptidyl transferase loop of the 23S rRNA and ribosomal protein L4 as a cause of a new resistance type in pneumococci with a similar phenotype. The mutations were obtained first in vitro after subsequent passages in azithromycin-containing broth, and later such mutations were found in clinical isolates. The number of alleles encoding 23S rRNA was confirmed to be four. Mutations in 23S rRNA causing macrolide resistance have been described also in other bacteria such as Propionibacterium and Mycobacterium species (13,18).In this study, we describe a new point mutation in a pneumococcal 23S rRNA-encoding gene as a ca...

Streptococcus pyogenes isolates (group A streptococcus) of different erythromycin resistance phenotypes were collected from all over Finland in 1994 and 1995 and studied; they were evaluated for their susceptibilities to 14 antimicrobial agents (396 isolates) and the presence of different erythromycin resistance genes (45 isolates). The erythromycin-resistant isolates with the macrolide-resistant but lincosamide- and streptogramin B-susceptible phenotype (M phenotype) were further studied for their plasmid contents and the transferability of resistance genes. Resistance to antimicrobial agents other than macrolides, clindamycin, tetracycline, and chloramphenicol was not found. When compared to our previous study performed in 1990, the rate of resistance to tetracycline increased from 10 to 93% among isolates with the inducible resistance (IR) phenotype of macrolide, lincosamide, and streptogramin B (MLSB) resistance. Tetracycline resistance was also found among 75% of the MLSB-resistant isolates with the constitutive resistance (CR) phenotype. Resistance to chloramphenicol was found for the first time in S. pyogenes in Finland; 3% of the isolates with the IR phenotype were resistant. All the chloramphenicol-resistant isolates were also resistant to tetracycline. Detection of erythromycin resistance genes by PCR indicated that, with the exception of one isolate with the CR phenotype, all M-phenotype isolates had the macrolide efflux (mefA) gene and all the MLSB-resistant isolates had the erythromycin resistance methylase (ermTR) gene; the isolate with the CR phenotype contained the ermB gene. No plasmid DNA could be isolated from the M-phenotype isolates, but the mefA gene was transferred by conjugation.

Background Hemolytic uremic syndrome (HUS) is a multisystemic disease. In a nationwide study, we characterized the incidence, clinical course, and prognosis of HUS caused by Shiga toxin (Stx)-producing Escherichia coli (STEC) strains with emphasis on risk factors, disease severity, and long-term outcome. Methods The data on pediatric HUS patients from 2000 to 2016 were collected from the medical records. STEC isolates from fecal cultures of HUS and non-HUS patients were collected from the same time period and characterized by whole genome sequencing analysis. Results Fifty-eight out of 262 culture-positive cases developed verified (n = 58, 22%) STEC-HUS. Another 29 cases had probable STEC-HUS, the annual incidence of STEC-HUS being 0.5 per 100,000 children. Eleven different serogroups were detected, O157 being the most common (n = 37, 66%). Age under 3 years (OR 2.4), stx2 (OR 9.7), and stx2a (OR 16.6) were found to be risk factors for HUS. Fifty-five patients (63%) needed dialysis. Twenty-nine patients (33%) developed major neurological symptoms. Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up. Age under 3 years, leukocyte count over 20 × 10 9 /L, and need for dialysis were predictive factors for poor renal outcome. Conclusions Age under 3 years, stx2, and stx2a were risk factors for HUS in STEC-positive children. However, serogroup or stx types did not predict the renal outcome or major CNS symptoms.

A total of 238 erythromycin-resistant Streptococcus pyogenes isolates were collected in 1986-1997 from eight different countries in Europe and North and South America. The antibiotic susceptibility patterns of all isolates and the resistance genes of 92 isolates of known clonal origin were studied. The mefA gene was detected in all 54 isolates with the M-phenotype and was found in every country. The ermTR and the ermB genes were detected in 27 and 11, respectively, of the 38 isolates with the macrolide-lincosamide-streptogramin B resistance phenotypes. In addition to the mefA gene, the recently sequenced ermTR gene was also widely distributed among isolates of different clonal origin.

In 1990, a new type of erythromycin resistance phenotype, designated NR, was found in group A streptococcus (GAS) in Finland. In the present study, the distribution of GAS isolates with this and other erythromycin-resistance phenotypes was surveyed in Finland, and the clonality of the isolates was explored. Of 4179 GAS isolates collected from all over Finland, 695 (17%) were resistant to erythromycin, and 82% of these had the NR phenotype. Of a group of 96 isolates with the NR phenotype from different areas, 91% was T4 serotype, opacity factor-positive. The majority of these isolates were studied further: All were M4 serotype and 88% were of one clonal origin in genetic analyses. Thus, one single clone predominates among erythromycin-resistant GAS in Finland. This clone is of T4M4 serotype and mediates the new type of erythromycin resistance, characterized by the NR phenotype.

Acute idiopathic tubulointerstitial nephritis (TIN) is considered a condition with a good long-term prognosis. However, there is evidence that some patients develop permanent renal impairment. The aim of this study was to evaluate the clinical characteristics of TIN at the time of diagnosis in children and determine whether the findings upon presentation predict renal outcome. The clinical data and biopsy findings from 26 children with idiopathic TIN admitted to four Finnish university hospitals were analyzed retrospectively. Twenty-five patients (96%) manifested renal insufficiency. After the mean follow-up time of 2.75 years (SD 2.5; 0.9-13.5), 4 patients (15%) had permanent renal insufficiency and 8 patients (31%) had persistent low-molecular weight proteinuria. Uveitis was found in 12 patients (46%). Four of these patients (33%) developed chronic uveitis. Our analysis showed that none of the laboratory or biopsy findings upon presentation prognosticated renal outcome. No correlation between renal disease and uveitis could be found either. The occurrence of uveitis among TIN patients was higher than previously reported. Uveitis may develop late and without recurrence of renal dysfunction. Therefore, follow-up by a pediatrician and by an ophthalmologist is warranted in children with acute TIN for at least 12 months from diagnosis.