Yngvar Tveten

Uncomplicated urinary tract infections Bacterial findings and efficacy of empirical antibacterial treatment

Objective . To assess bacterial aetiology, antimicrobial susceptibility and efficacy of empirical treatment in uncomplicated urinary tract infections and to evaluate the dipstick as a diagnostic tool. Design . Prospective study. Setting . Clinical microbiology laboratory and 17 general practice clinics in Telemark County, Norway. Subjects . A total of 184 female patients between 15 and 65 years of age with symptoms of uncomplicated urinary tract infection. Main outcome measures . Results from dipstick testing (leucocyte esterase and nitrite), bacterial culture, susceptibility patterns and efficacy of empirical antibacterial therapy on symptoms. Results. Significant bacteruria was detected in 140 (76%) of the 184 urines. The leukocyte esterase test was of little help in predicting culture-positive UTI. A positive nitrite test accurately predicted culture-positivity, while a negative result was ambiguous. The most common bacterium, E. coli, was found in 112 (80%) of the 140 positive urines and was predominantly sensitive to ciprofloxacin (100%), mecillinam (94%), nitrofurantoin (97%), trimethoprim (88%), and sulphonamide (81%), and to a lesser extent to ampicillin (72%). In 18 patients the causative bacterium was resistant to the therapeutic agent used; 7 of these returned to their GP with persisting symptoms while in 11 symptoms resolved without further treatment. Conclusion . The study confirms E. coli as the predominant cause of uncomplicated UTI. Since in the majority of cases the bacterium found was susceptible to the locally preferred antimicrobials and the patients’ symptoms were cured, empiric therapy is found to be an effective practice in the study area and, by inference, in others with similar antimicrobial susceptibility patterns.

Multilocus sequence typing and ftsI sequencing: a powerful tool for surveillance of penicillin-binding protein 3-mediated beta-lactam resistance in nontypeable Haemophilus influenzae

BackgroundBeta-lactam resistance in Haemophilus influenzae due to ftsI mutations causing altered penicillin-binding protein 3 (PBP3) is increasing worldwide. Low-level resistant isolates with the N526K substitution (group II low-rPBP3) predominate in most geographical regions, while high-level resistant isolates with the additional S385T substitution (group III high-rPBP3) are common in Japan and South Korea.Knowledge about the molecular epidemiology of rPBP3 strains is limited. We combined multilocus sequence typing (MLST) and ftsI/PBP3 typing to study the emergence and spread of rPBP3 in nontypeable H. influenzae (NTHi) in Norway.ResultsThe prevalence of rPBP3 in a population of 795 eye, ear and respiratory isolates (99% NTHi) from 2007 was 15%. The prevalence of clinical PBP3-mediated resistance to ampicillin was 9%, compared to 2.5% three years earlier. Group II low-rPBP3 predominated (96%), with significant proportions of isolates non-susceptible to cefotaxime (6%) and meropenem (20%). Group III high-rPBP3 was identified for the first time in Northern Europe.Four MLST sequence types (ST) with characteristic, highly diverging ftsI alleles accounted for 61% of the rPBP3 isolates. The most prevalent substitution pattern (PBP3 type A) was present in 41% of rPBP3 isolates, mainly carried by ST367 and ST14. Several unrelated STs possessed identical copies of the ftsI allele encoding PBP3 type A.Infection sites, age groups, hospitalization rates and rPBP3 frequencies differed between STs and phylogenetic groups.ConclusionsThis study is the first to link ftsI alleles to STs in H. influenzae. The results indicate that horizontal gene transfer contributes to the emergence of rPBP3 by phylogeny restricted transformation.Clonally related virulent rPBP3 strains are widely disseminated and high-level resistant isolates emerge in new geographical regions, threatening current empiric antibiotic treatment. The need of continuous monitoring of beta-lactam susceptibility and a global system for molecular surveillance of rPBP3 strains is underlined. Combining MLST and ftsI/PBP3 typing is a powerful tool for this purpose.

Mutant ftsI genes in the emergence of penicillin-binding proteinmediated β-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.

Preventing Secondary Cases of Meningococcal Disease by Identifying and Eradicating Disease-Causing Strains in Close Contacts of Patients

In Norway, the use of chemoprophylaxis after cases of meningococcal disease is not recommended. Instead, household members less than 15 years are treated with penicillin for 7 days. Failures of this treatment have been reported. We therefore used DNA fingerprinting to identify the disease-causing strain in healthy contacts combined with selective rifampicin prophylaxis to these carriers to prevent secondary cases. During a 2-year period (1987-89) there were 13 cases of meningococcal disease in the County of Telemark (165000 inhabitants). 65 (14.7%) out of 441 contacts to these 13 patients harbored meningococci in their throat; 16 (3.6%) carried the disease-causing strain. Only 1 carrier fulfilled the criteria for being treated with penicillin; 8 were adults and the remaining 7 were not household members. No secondary cases of meningococcal disease occurred during the study period or the following 12 months. During the 4-year period (1984-87) preceding the study period there were 39 cases of meningococcal disease in Telemark; 7 of them were index cases for 12 bacteriologically verified and 4 clinically suspected secondary cases of meningococcal disease. We conclude that selective prophylaxis with rifampicin seems to be more efficient that penicillin treatment of household members less than 15 to prevent secondary cases of meningococcal disease.

Aetiology and risk factors of community-acquired pneumonia in hospitalized patients in Norway.

In Norway, data on the aetiology of community‐acquired pneumonia (CAP) in hospitalized patients are limited. The aims of this study were to investigate the bacterial aetiology of CAP in hospitalized patients in Norway, risk factors for CAP and possible differences in risk factors between patients with Legionnaires disease and pneumonia because of other causes.

Haemophilus influenzae with Non-Beta-Lactamase-Mediated Beta-Lactam Resistance: Easy To Find but Hard To Categorize

ABSTRACT Haemophilus influenzae is a major pathogen, and beta-lactams are first-line drugs. Resistance due to altered penicillin-binding protein 3 (rPBP3) is frequent, and susceptibility testing of such strains is challenging. A collection of 154 beta-lactamase-negative isolates with a large proportion of rPBP3 (67.5%) was used to evaluate and compare Etest (Haemophilus test medium [HTM]) and disk diffusion (EUCAST method) for categorization of susceptibility to aminopenicillins and cefuroxime, using MICs generated with broth (HTM) microdilution and clinical breakpoints from CLSI and EUCAST as the gold standards. In addition, the proficiency of nine disks in screening for the rPBP3 genotype (N526K positive) was evaluated. By Etest, both essential and categorical agreement were generally poor (<70%), with high very major errors (VME) (CLSI, 13.0%; EUCAST, 34.3%) and falsely susceptible rates (FSR) (CLSI, 87.0%; EUCAST, 88.3%) for ampicillin. Ampicillin (2 μg) with adjusted (+2 mm) zone breakpoints was superior to Etest for categorization of susceptibility to ampicillin (agreement, 74.0%; VME, 11.0%; FSR, 28.3%). Conversely, Etest was superior to 30 μg cefuroxime for categorization of susceptibility to cefuroxime (agreement, 57.1% versus 60.4%; VME, 2.6% versus 9.7%; FSR, 7.1% versus 26.8%). Benzylpenicillin (1 unit) (EUCAST screening disk) and cefuroxime (5 μg) identified rPBP3 isolates with highest accuracies (95.5% and 92.2%, respectively). In conclusion, disk screening reliably detects rPBP3 H. influenzae, but false ampicillin susceptibility is frequent with routine methods. We suggest adding a comment recommending high-dose aminopenicillin therapy or the use of other agents for severe infections with screening-positive isolates that are susceptible to aminopenicillins by gradient or disk diffusion.

Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study

Objectives To compare the clinical and bacteriological outcomes of pivmecillinam treatment for community-acquired urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli versus non-ESBL-producing E. coli in an outpatient setting. Methods A prospective, multicentre, observational cohort study of women aged ≥16 years, with pivmecillinam-treated community-acquired UTIs caused by E. coli with or without ESBL production, recruited from primary care, was conducted in the period from April 2013 to August 2016. Eighty-eight women (mean age 49.4 years) with community-acquired UTIs caused by ESBL-producing E. coli were compared with a control group of 74 women (mean age 50.1 years). Trial registration Regional Committees for Medical and Health Research Ethics (REC) in Norway, ID 2011/2214, and ClinicalTrials.gov, ID NCT01531023. Results The median time until symptom resolution after treatment initiation was 5 days for the ESBL cases and 3 days for the non-ESBL controls (P < 0.01). The proportion of women warranting a second antibiotic prescription in the follow-up period was higher for the ESBL cases [30/88 (34.1%) versus 10/72 (13.9%), P < 0.01]. Persistent bacteriuria was non-significantly more common among ESBL cases than in the control group [15/81 (18.5%) versus 6/67 (9.0%), P = 0.10]. A pivmecillinam dosage of 200 mg given three times daily for ≤5 days was associated with treatment failure (OR 4.77, 95% CI 1.40-19.44, P = 0.03) for the ESBL E. coli group. For the subgroup treated with 400 mg of pivmecillinam given three times daily there was no significantly increased OR for treatment failure between ESBL cases and the control group irrespective of treatment duration. Conclusions Pivmecillinam given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production.