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Introduction Trimethoprim is structurally similar to potassium-sparing diuretics and may induce hyperkalaemia. The prevalence and the factors that predispose to trimethoprim-associated hyperkalaemia have never been extensively addressed. Methods A literature search with no date or language limits was carried out using the National Library of Medicine, Embase and Web of Science in March and repeated during August 2021. The principles underlying the Economic and Social Research Council guidance on the conduct of synthesis and the PRISMA guidelines were employed. For the analysis, we retained reports including ≥10 subjects on treatment with trimethoprim, which addressed the possible occurrence of hyperkalaemia. Results Eighteen reports were retained for the final analysis. The pooled prevalence of potassium value >5.0 mmol/L, >5.5 mmol/L and >6.0 mmol/L or symptomatic, was, respectively, 22%, 10% and 0.2%. The analysis disclosed that the risk of trimethoprim-associated hyperkalaemia is dose-related and enhanced by drugs with known hyperkalaemic potential including potassium-sparing diuretics, renin–angiotensin–aldosterone system inhibitors, β-blockers and non-steroidal anti-inflammatory agents. Poor kidney function also increased the tendency towards hyperkalaemia. The time to onset of hyperkalaemia was generally 1 week or less after starting trimethoprim. Conclusions The present analysis documents the hyperkalaemic potential of trimethoprim, a widely prescribed drug that was introduced more than 50 years ago. Clinicians must recognize patients at risk of trimethoprim-associated hyperkalaemia.

Objectives Increasing spread of resistance could jeopardize the use of antifolates against MRSA infections. Methods We compared the prevalence of phenotypic trimethoprim/sulfamethoxazole resistance in 20 534 clinical Staphylococcus aureus isolates (19 096 MSSA and 1438 MRSA) of non-redundant patients at Heidelberg University Hospital over 8 years and performed WGS on trimethoprim/sulfamethoxazole-resistant MRSA. Results From 2012 to 2019, trimethoprim/sulfamethoxazole resistance in MSSA (674/19 096; 3.5%) ranged between 1.5% and 7.2% and in MRSA (135/1438; 9.4%) between 0.5% and 20.2%, reaching a peak in 2016 and 2018, respectively (Ptrend Conclusions The presented results support that trimethoprim/sulfamethoxazole-resistant S. aureus, formerly associated with SSTI from outpatients and S. aureus in the (sub)tropics, is on the rise in the temperate zone, potentially due to migration. Closer monitoring of trimethoprim/sulfamethoxazole resistance in S. aureus is recommended to safeguard the effectiveness of antifolate compounds.

Objectives We aimed to determine susceptibilities of Elizabethkingia spp. to 25 commonly tested and 8 novel antibiotics, and to compare the performance of different susceptibility testing methods. Methods Clinical isolates of Elizabethkingia spp., Chryseobacterium spp. and Flavobacterium spp. collected during 2002–18 (n = 210) in a nationwide surveillance programme in Taiwan were speciated by 16S rRNA sequencing. MICs were determined by broth microdilution. The broth microdilution results of 18 common antibiotics were compared with those obtained by the VITEK 2 automated system. Results Among the Elizabethkingia spp. identified (n = 108), Elizabethkingia anophelis was the most prevalent (n = 90), followed by Elizabethkingia meningoseptica (n = 7) and Elizabethkingia miricola cluster [E. miricola (n = 6), Elizabethkingia bruuniana (n = 3) and Elizabethkingia ursingii (n = 2)]. Most isolates were recovered from respiratory or blood specimens from hospitalized, elderly patients. PFGE showed two major and several minor E. anophelis clones. All isolates were resistant to nearly all the tested β-lactams. Doxycycline, minocycline and trimethoprim/sulfamethoxazole inhibited >90% of Elizabethkingia spp. Rifampin inhibited E. meningoseptica (100%) and E. anophelis (81.1%). Fluoroquinolones and tigecycline were active against E. meningoseptica and E. miricola cluster isolates. Novel antibiotics, including imipenem/relebactam, meropenem/vaborbactam, ceftazidime/avibactam, cefepime/zidebactam, delafloxacin, eravacycline and omadacycline were ineffective but lascufloxacin inhibited half of Elizabethkingia spp. The very major discrepancy rates of VITEK 2 were >1.5% for ciprofloxacin, moxifloxacin and vancomycin. Major discrepancy rates were >3% for amikacin, tigecycline, piperacillin/tazobactam and trimethoprim/sulfamethoxazole. Conclusions MDR, absence of standard interpretation criteria and poor intermethod concordance necessitate working guidelines to facilitate future research of emerging Elizabethkingia spp.

Background In Vietnam, Streptococcus pneumoniae is a leading cause of disease, including meningitis. Antibiotics are available without physician prescription at community pharmacies and rates of antibiotic non-susceptibility are high. Appropriate treatment and antibiotic stewardship need to be informed by surveillance data. Objectives To report community-based pneumococcal antibiotic susceptibility testing data from children enrolled in a pneumococcal conjugate vaccine trial in Ho Chi Minh City [the Vietnam Pneumococcal Project (ViPP)] and compare these with published hospital-based data from the nationwide Survey of Antibiotic Resistance (SOAR) to determine whether hospital surveillance data provide an informative estimate of circulating pneumococcal resistance. Methods Pneumococcal isolates from 234 nasopharyngeal swabs collected from ViPP participants at 12 months of age underwent antibiotic susceptibility testing using CLSI methods and the data were compared with SOAR data. Results Antibiotic susceptibility testing identified penicillin-non-susceptible pneumococci in 93.6% of pneumococcus-positive ViPP swabs (oral, non-meningitis breakpoints). Non-susceptibility to erythromycin, trimethoprim/sulfamethoxazole, clindamycin and tetracycline also exceeded 79%. MDR, defined as non-susceptibility to three or more classes of antibiotic, was common (94.4% of swabs). Low or no resistance was detected for ceftriaxone (non-meningitis breakpoints), ofloxacin and vancomycin. Antibiotic non-susceptibility rates in ViPP and SOAR were similar for several antibiotics tested. Conclusions A very high proportion of pneumococci carried in the community are MDR. Despite wide disparities in population demographics between ViPP and SOAR, the non-susceptibility rates for several antibiotics were comparable. Thus, with some qualification, hospital antibiotic susceptibility testing data in Vietnam can inform circulating pneumococcal antibiotic non-susceptibility in young children, the group at highest risk of pneumococcal disease, to guide antibiotic prescribing and support surveillance strategies.

Background In the pre-pneumococcal conjugated vaccines (PCVs) era, serotypes included in the 7/13-valent PCVs (PCV7/PCV13) caused most pneumococcal otitis media (OM) and antibiotic-non-susceptible pneumococcal OM (ANSP-OM) episodes. In southern Israel, sequential PCV7/PCV13 introduction resulted in >90% reduction of vaccine-serotype OM. Objectives We assessed the dynamics of ANSP-OM necessitating middle ear fluid culture following PCV7/PCV13 sequential introduction in young children. Methods This was a prospective, population-based, active surveillance. All episodes in children Results Overall, 2270 pneumococcal OM episodes were identified. Annual overall pneumococcal, PCV13 and non-PCV13 serotype OM incidence declined by 86%, 97% and 33%, respectively, comparing pre-PCV with the PCV13 period. During 2004–08, 95% of ANSP was observed in vaccine serotypes. Incidence of penicillin (MIC ≥0.1 mg/L and ≥1.0 mg/L), macrolide, tetracycline, clindamycin, ceftriaxone and multidrug ANSP-OM declined by >90% in the PCV13 period. Rates of trimethoprim/sulfamethoxazole and chloramphenicol ANSP-OM declined by 85% and 79%, respectively. The proportions of ANSP of all pneumococcal isolates declined by ∼70% for penicillin, ceftriaxone and erythromycin; 53% for tetracycline; and 55% for MDR, versus no significant reductions observed for chloramphenicol, trimethoprim/sulfamethoxazole and clindamycin. Conclusions PCV7/PCV13 sequential introduction resulted in rapid and substantial ANSP-OM reduction, in parallel with the near disappearance of PCV13-serotype OM and no increase in replacement disease.

Objectives To determine antibiotic susceptibility of Streptococcus pneumoniae and Haemophilus influenzae isolates collected from community-acquired respiratory tract infections (CA-RTIs) in 2016–18 in four Asian countries. Methods MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST (dose-specific) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. Results In total, 260 S. pneumoniae and 258 H. influenzae isolates were tested. Pneumococci from Vietnam (n = 161) were the least susceptible, with rates of susceptibility >90% for fluoroquinolones by CLSI breakpoints, ∼60% for amoxicillin, amoxicillin/clavulanic acid and ceftriaxone but 90% for amoxicillin/clavulanic acid, cephalosporins [except cefaclor in Singapore (77.5%)], macrolides and fluoroquinolones; for isolates from Vietnam (n = 89) the rates of susceptibility were >85% only for amoxicillin/clavulanic acid (95.5%), ceftriaxone (100%) and macrolides (87.6%–89.9%). Susceptibility to other antibiotics ranged from 7.9% (trimethoprim/sulfamethoxazole) to 57.3%–59.6% (fluoroquinolones) and 70.8% (cefixime). The application of different EUCAST breakpoints for low and higher doses for some of the antibiotics (amoxicillin, amoxicillin/clavulanic acid, ampicillin, penicillin, ceftriaxone, clarithromycin, erythromycin, levofloxacin and trimethoprim/sulfamethoxazole) allowed, for the first time in a SOAR study, the effect of raising the dosage on susceptibility to be quantified. A limitation of the study was the small sample sizes and only one or two sites participating per country; however, since susceptibility data are scarce in some of the participating countries any information concerning antibiotic susceptibility is of value. Conclusions Antibiotic susceptibility varied across countries and species, with isolates from Vietnam demonstrating the lowest susceptibility. Knowledge of resistance patterns can be helpful for clinicians when choosing empirical therapy options for CA-RTIs.

ObjectivesThis study assessed the demographic and molecular characteristics of community-associated (CA) and healthcare-associated (HA) MRSA genotypes in Canadian hospitals between 2007 and 2016.MethodsA total of 1963 MRSA were identified among 9103 Staphylococcus aureus isolates collected from inpatients and outpatients presenting to tertiary-care medical centres across Canada. Antimicrobial susceptibility testing was performed by broth microdilution in accordance with CLSI standards (M7 11th edition, 2018). PCR was performed to detect the Panton–Valentine leucocidin (PVL) genes and molecular analysis was performed by spa typing.ResultsBetween 2007 and 2016, the annual proportion of S. aureus that were MRSA decreased from 26.1% to 16.9% (P ConclusionsThe proportion of MRSA in Canada declined between 2007 and 2016. In contrast, the proportion of CA-MRSA strain types, particularly CMRSA10 (USA300), continues to increase. In 2016, CA-MRSA genotypes surpassed HA-MRSA as the most common cause of MRSA infections in Canadian hospitals.

OBJECTIVES:In 2012, a stratified random survey, using mystery shoppers, was conducted to investigate the availability and quality of antibiotics sold to patients in the private sector in five southern provinces of the Lao People's Democratic Republic (Laos). METHODS:A total of 147 outlets were sampled in 10 districts. The active pharmaceutical ingredient (API) content measurements for 909 samples, including nine APIs (amoxicillin, ampicillin, ceftriaxone, ciprofloxacin, doxycycline, ofloxacin, sulfamethoxazole, tetracycline and trimethoprim), were determined using HPLC. RESULTS:All the analysed samples contained the stated API and we found no evidence for falsification. All except one sample had all the units tested with %API values between 75% and 125% of the content stated on the label. However, we identified the presence of substandard antibiotics: 19.6% (201/1025) of samples had their units outside the 90%-110% content of the label claim and 60.2% (617/1025) of the samples had units outside of the International Pharmacopoeia uniformity of content limit range. Amoxicillin had a high number of samples [67.1% (151)] with units above the limit range, followed by ciprofloxacin [58.8% (10)] and ofloxacin [57.4% (39)]. Ceftriaxone, trimethoprim and sulfamethoxazole had the highest number of samples with low API content: 57.1% (4), 51.6% (64) and 34.7% (43), respectively. Significant differences in %API were found between stated countries of manufacture and stated manufacturers. CONCLUSIONS:With the global threat of antimicrobial resistance to patient outcomes, greater understanding of the role of poor-quality antibiotics is needed. Substandard antibiotics will have reduced therapeutic efficacy, impacting public health and control of bacterial infections.

Objectives Most studies addressing community-acquired urinary tract infections (UTIs) pertain to mixed cohorts, in which young healthy adults are under-represented. We aimed to dissect the intricate interrelation between exposures and subsequent antimicrobial resistance (AMR) patterns in a unique setting of young healthy adults, allowing further guidance in this group. Methods We carried out a retrospective cross-sectional study of all Enterobacteriaceae-associated outpatient UTIs during 2014-16 in soldiers, representing the young fit population in Israel. Electronic medical records were reviewed for demographic and clinical data, antimicrobial exposures and prescriptions. Risk factors for AMR were analysed by multivariate logistic regression. Results Of 1207 cases, 1144 (94.8%) were females, with a median age of 20.2 years. Escherichia coli was the predominant species (83.2%). Only 686 (56.8%) isolates were fully susceptible. AMR rates were as follows: trimethoprim/sulfamethoxazole, 19.6%; oral cephalosporins, 9.7%-16.7%; amoxicillin/clavulanate, 12.1%; ciprofloxacin, 11.1%; and nitrofurantoin, 12.6%. Predictors of AMR were recurrent UTIs, past-year hospitalization, male gender and non E. coli strains. Antimicrobials prescribed >6 months preceding the culprit infection were not related to AMR. Fluoroquinolone and cephalosporin exposures were highly predictive of further AMR, yet nitrofurantoin and, to a lesser extent, amoxicillin/clavulanate had fewer associations with AMR induction and resistance to these antimicrobials was less associated with any exposure. Conclusions This nationwide study of community-related UTIs shows significant AMR rates for commonly used oral antimicrobials even in young fit adults. Nitrofurantoin proved once more to be an adequate empirical choice regardless of previous exposures, having a less detrimental effect on future AMR. Conversely, both resistance to fluoroquinolones following previous exposures and the associated heavy ecological burden should deter their common use as first-line agents for UTIs.

Objectives To determine the antibiotic susceptibility of isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2014-16 from patients with community-acquired respiratory infections in the Czech Republic. Methods MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. Results S. pneumoniae isolates (n = 200) showed high rates of susceptibility (>95%) to amoxicillin, amoxicillin/clavulanic acid, penicillin [intravenous (iv) non-meningitis], ceftriaxone, cefuroxime and the fluoroquinolones using CLSI breakpoints. Susceptibility to cefaclor and trimethoprim/sulfamethoxazole was 94%-94.5%, to penicillin (oral) 91.5% and to the macrolides 89.5%. Susceptibility of H. influenzae (n = 197) to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime, azithromycin and the fluoroquinolones was ≥98% by CLSI criteria. Rates of susceptibility to the remaining agents were ≥75% except for clarithromycin at 37.1%. Great variability was seen across breakpoints, especially for the macrolides, cefaclor and cefuroxime (oral), 98.0% of H. influenzae showing susceptibility to the latter by CLSI criteria, 69.5% by PK/PD and 1.5% by EUCAST standards. The β-lactamase rate was 13.7% with no β-lactamase-negative-ampicillin-resistant (BLNAR) isolates by CLSI criteria. Conclusions Antibiotic resistance among the two major respiratory pathogens remained low in the Czech Republic. These findings support local clinicians in continuing the historically restrictive use of antibiotics in the Czech Republic, with selection of narrower-spectrum agents for the empirical therapy of community-acquired respiratory tract infections. This highlights one of the great benefits of continuous surveillance of antimicrobial resistance: knowledge of current local resistance patterns reduces the need to choose broad-spectrum agents that contribute to increasing resistance worldwide.

Objective: To describe the patterns of dispensed non-medical prescriber prescriptions for antibiotics in primary care across England between 2011 and 2015.\ud Methods: A retrospective analysis of dispensed antibiotic prescriptions, written by non-medical prescribers and medical prescribers between 2011 and 2015 in primary care in England, obtained from the National Health Service Business Services Authority.\ud Results: Between 2011 and 2015, the numbers of non-medical prescribers (mainly nurses but also pharmacists and small numbers of allied health professionals) in England, who have independent prescribing capability, has risen by over a third to nearly 30,000. Most of these prescribers provide a broad range of services in primary care. The rate of dispensed non-medical prescriber prescriptions for antibiotics over this period has increased, as has the percentage of all primary care antibiotics dispensed that were prescribed by non-medical prescribers, which is currently nearly 8%. The most commonly dispensed NMP antibiotic prescriptions were penicillin, sulfonamides, trimethoprim, macrolides, tetracyclines, and nitrofurantoin.\ud Conclusion: Increasing numbers of non-medical prescribers are working in primary care in England and managing infections. Antibiotics prescribed by this group align with surveillance reports of antibiotic use in primary care. With the numbers of non-medical prescribers being set to rise further, they form an important group to involve in antimicrobial stewardship efforts.

Background Mycobacterium abscessus complex (MABC) is the most common non-tuberculous mycobacterium that causes complicated skin and soft tissue infections (cSSTIs). The selection of antimycobacterial agents for successful treatment of such infections is a critical issue. Objectives To investigate the antimicrobial susceptibility patterns of MABC isolates from skin and soft tissue to a variety of antimycobacterial agents. Methods Sixty-seven MABC isolates were collected and partial gene sequencing of secA1, rpoB and hsp65 was used to classify them into three subspecies: M. abscessus subsp. abscessus (MAB), M. abscessus subsp. massiliense (MMA) and M. abscessus subsp. bolletii (MBO). The MICs of 11 antimycobacterial agents for these 67 isolates were determined using a broth microdilution method and commercial Sensititre RAPMYCOI MIC plates, as recommended by CLSI. Results In total, 28 MAB, 38 MMA and 1 MBO were isolated from patients with cSSTIs at our hospital. Most MABC strains were resistant to ciprofloxacin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin and trimethoprim/sulfamethoxazole. In addition, most MABC strains were intermediately susceptible or resistant to cefoxitin. Eighteen of the 28 MABs and 1 MBO isolate harboured the T28 polymorphism in the erm(41) gene. Two of the 38 MMA isolates had an rrl A2059G point mutation. Most of the MABC strains were susceptible to amikacin and tigecycline. Conclusions In Taiwan, amikacin, clarithromycin and tigecycline have good activity against MMA and MAB erm(41) C28 sequevar isolates, whereas amikacin and tigecycline, rather than clarithromycin, have good activity against both MBO and MAB erm(41) T28 sequevar isolates. Clinical trials are warranted to correlate these data with clinical outcomes.

Objectives Shiga toxin-producing Escherichia coli (STEC) are zoonotic and transmission to humans occurs via contaminated food or contact with infected animals. In this study, WGS data were used to predict antimicrobial resistance (AMR) in STEC from symptomatic human cases to assess the extent of transmission of antibiotic-resistant E. coli from animals to humans. Methods WGS data from 430 isolates of STEC were mapped to genes known to be associated with phenotypic AMR. Susceptibility testing was performed by a breakpoint method on all viable isolates exhibiting resistance to at least one antimicrobial. Results 327/396 (82.6%) of STEC O157 and 22/34 (64.7%) of STEC O26 lacked identifiable resistance genes and were predicted to be fully susceptible to 11 diverse classes of antimicrobials. For the remaining 81 isolates, 74 were phenotypically tested and there was concordance between WGS-predicted resistance and expression of phenotypic resistance. The most common resistance profile was ampicillin, streptomycin, trimethoprim/sulphonamide and tetracycline occurring in 25 (5.8%) isolates. Resistance to other antimicrobials, including resistance to chloramphenicol (2.1%), resistance to azithromycin (0.2%) and reduced susceptibility to ciprofloxacin (2.6%), was less frequent. Three isolates were identified as ESBL producers. Conclusions β-Lactams, trimethoprim/sulphonamides and tetracyclines account for the majority of therapeutic antimicrobials sold for veterinary use and this may be a risk factor for the presence of AMR in domestically acquired human clinical isolates of STEC. Isolates that were resistant to ampicillin, streptomycin, sulphonamide, tetracycline and azithromycin and had reduced susceptibility to ciprofloxacin were associated with cases who reported recent travel abroad.

Background Trimethoprim/sulfamethoxazole is a synthetic antibiotic combination recommended for the treatment of complicated non-typhoidal Salmonella infections in humans. Resistance to trimethoprim/sulfamethoxazole is mediated by the acquisition of mobile genes, requiring both a dfr gene (trimethoprim resistance) and a sul gene (sulfamethoxazole resistance) for a clinical resistance phenotype (MIC ≥4/76 mg/L). In 2017, the CDC investigated a multistate outbreak caused by a Salmonella enterica serotype Heidelberg strain with trimethoprim/sulfamethoxazole resistance, in which sul genes but no known dfr genes were detected. Objectives To characterize and describe the molecular mechanism of trimethoprim resistance in a Salmonella Heidelberg outbreak isolate. Methods Illumina sequencing data for one outbreak isolate revealed a 588 bp ORF encoding a putative dfr gene. This gene was cloned into Escherichia coli and resistance to trimethoprim was measured by broth dilution and Etest. Phylogenetic analysis of previously reported dfrA genes was performed using MEGA. Long-read sequencing was conducted to determine the context of the novel dfr gene. Results and conclusions The novel dfr gene, named dfrA34, conferred trimethoprim resistance (MIC ≥32 mg/L) when cloned into E. coli. Based on predicted amino acid sequences, dfrA34 shares less than 50% identity with other known dfrA genes. The dfrA34 gene is located in a class 1 integron in a multiresistance region of an IncC plasmid, adjacent to a sul gene, thus conferring clinical trimethoprim/sulfamethoxazole resistance. Additionally, dfrA34 is associated with ISCR1, enabling easy transmission between other plasmids and bacterial strains.

Objectives To determine whether local trainer-led TARGET antibiotic interactive workshops improve antibiotic dispensing in general practice. Methods Using a McNulty–Zelen-design randomized controlled trial within three regions of England, 152 general practices were stratified by clinical commissioning group, antibiotic dispensing rate and practice patient list size, then randomly allocated to intervention (offered TARGET workshop that incorporated a presentation, reflection on antibiotic data, promotion of patient and general practice (GP) staff resources, clinical scenarios and action planning, 73 practices) or control (usual practice, 79 practices). The primary outcome measure was total oral antibiotic items dispensed/1000 patients for the year after the workshop (or pseudoworkshop date for controls), adjusted for the previous year’s dispensing. Results Thirty-six (51%) intervention practices (166 GPs, 51 nurses and 101 other staff) accepted a TARGET workshop invitation. In the ITT analysis total antibiotic dispensing was 2.7% lower in intervention practices (95% CI#5.5%to 1%, P"0.06) compared with controls. Dispensing in intervention practices was 4.4% lower for amoxicillin/ampicillin (95% CI 0.6%–8%, P"0.02); 5.6% lower for trimethoprim (95% CI 0.7%–10.2%, P"0.03); and a non-significant 7.1% higher for nitrofurantoin (95% CI#0.03 to 15%, P"0.06). The Complier Average Causal Effect (CACE) analysis, which estimates impact in those that comply with assigned intervention, indicated 6.1% (95% CI 0.2%–11.7%, P"0.04) lower total antibiotic dispensing in intervention practices and 11% (95% CI 1.6%–19.5%, P"0.02) lower trimethoprim dispensing. Conclusions This study within usual service provision found that TARGET antibiotic workshops can help improve antibiotic use, and therefore should be considered as part of any national antimicrobial stewardship initiatives. Additional local facilitation will be needed to encourage all general practices to participate.

OBJECTIVES: The objective of this study was to measure the associations between domains of deprivation and antibiotic resistance of Escherichia coli. METHODS: Routine surveillance data for antibiotic susceptibility of E. coli isolates were obtained from urine specimens taken from patients presenting with suspected urinary tract infection in 2010-12 to healthcare practitioners based in the community in Leeds and Bradford. Eight antibiotics were included in the analyses. Postcodes were linked to lower super output areas (average populations of 1500). The 2010 Indices of Deprivation were used as neighbourhood characteristics for each lower super output area. Multilevel logistic regression models were used to estimate the independent effect of structural components on the odds of resistance to each antibiotic. RESULTS: With respect to living conditions, residence in the most-deprived areas compared with the least-deprived areas was associated with increased odds of antibiotic resistance for all eight antibiotics analysed. The magnitude of these associations included an OR of 2.04 (95% CI 1.03-3.07) for cefalexin, 2.16 (95% CI 1.16-4.05) for ciprofloxacin, 2.47 (95% CI 1.08-5.66) for nitrofurantoin and 1.33 (95% CI 1.07-1.75) for trimethoprim. CONCLUSIONS: Social deprivation in the form of living conditions is associated with increased antibiotic resistance for E. coli. This evidence suggests there is a need for further individual-level studies to explore the potential mechanism for these associations.

Objectives The goal of this study was to characterize Streptococcus pneumoniae demonstrating MDR (resistant to three or more antimicrobial classes) or XDR (resistant to five or more classes) phenotypes, collected from Canada during the CANWARD 2007–13 study. Methods From 2007 to 2013 inclusive, S. pneumoniae isolates were collected as a part of the CANWARD surveillance study. MDR and XDR isolates were subjected to PFGE, MLST, molecular detection of pneumococcal pili and macrolide resistance determinants mef(A/E) and erm(B), sequencing of PBPs 1A, 2B and 2X and comparison with Pneumococcal Molecular Epidemiology Network (PMEN) clones. Results Of 2129 S. pneumoniae isolates collected during the CANWARD 2007–13 study, 61 (2.9%) were found to be MDR. Of these MDR isolates, 43 (70.5%) were XDR. The most common serotypes for both MDR and XDR S. pneumoniae were 19A and 19F. Twenty-nine of 61 isolates (48%) demonstrated resistance to clarithromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulfamethoxazole. All isolates possessed at least one macrolide resistance determinant and mutations in PBPs 1A, 2B and 2X. The most common clone was piliated, XDR ST320, an internationally circulating double-locus variant of Taiwan19F-14 (ST236). Conclusions Though the rate of MDR S. pneumoniae has remained relatively stable since 2007, XDR strains have emerged in Canada. These strains are virulent, possess resistance determinants and are related to international clones.

Objectives The objective of this study was to evaluate the in vitro antimicrobial activity of ceftaroline and comparator agents tested against Staphylococcus aureus isolates causing bloodstream infection (BSI). Methods A total of 4426 S. aureus isolates from patients with BSI were collected in 150 medical centres in the USA in 2009–13 and tested for susceptibility to ceftaroline and comparators by the CLSI broth microdilution method. Results Overall, 45.5% of isolates were MRSA. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.9% of S. aureus isolates at ≤1 mg/L (highest MIC, 2 mg/L). Daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L) were active against ≥99.8% of isolates at the respective susceptible breakpoints. Susceptibility rates for clindamycin (MIC50/90, ≤0.25/>2 mg/L) and levofloxacin (MIC50/90, ≤0.5/>4 mg/L) were 80.8% and 59.2%, respectively. Against MSSA, ceftaroline (MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible) was 16-, 4–8- and 4-fold more active in vitro (based on MIC50/90) than ceftriaxone (MIC50/90, 4/4 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L), respectively, and slightly more potent than daptomycin (MIC50/90, 0.25/0.5 mg/L). When tested against MRSA, ceftaroline was active against 95.4% and 100.0% of isolates at ≤1 and ≤2 mg/L, respectively. Moreover, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole. Conclusions Ceftaroline demonstrated potent in vitro activity when tested against a large collection of contemporary (2009–13) S. aureus isolates causing BSI in US hospitals.

Objectives: The therapeutic arsenal for MRSA infections is limited. The aim of this study was to assess the noninferiority of a combination of trimethoprim/sulfamethoxazole plus rifampicin versus linezolid alone for the treatment of MRSA infection. Methods: We conducted a randomized, open-label, single-centre, non-inferiority trial comparing trimethoprim/ sulfamethoxazole (160 mg/800 mg three times daily) plus rifampicin (600 mg once a day) versus linezolid (600 mg twice a day) alone in adult patients with various types of MRSA infection. Patients were allocated 1:1 to either regimen. The primary outcome was clinical cure at 6 weeks after the end of treatment (non-inferiority margin 20%) assessed by both ITT and PP analyses. Secondary outcomes included the microbiologically documented persistence of MRSA in clinical cultures, mortality and adverse events. The study protocol has been registered with ClinicalTrials.gov (NCT00711854). Results: Overall, 150 patients were randomized to one of the two treatment arms between January 2009 and December 2013 and were included in the ITT analysis. Of these 56/75 (74.7%) in the linezolid group and 59/75 (78.7%) in the trimethoprim/sulfamethoxazole and rifampicin group experienced clinical success (risk difference 4%, 95% CI 29.7% to 17.6%). The results were confirmed by the PP analysis, with 54/66 (81.8%) cured patients in the linezolid group versus 52/59 (88.1%) in the trimethoprim/sulfamethoxazole and rifampicin group (risk difference 6.3%, 95% CI 26.8% to 19.2%). There were no statistically significant differences between the two groups in any of the secondary outcomes, including microbiologically documented failure. Four adverse drug reactions attributed to the study medication occurred in the linezolid group versus nine in the trimethoprim/ sulfamethoxazole and rifampicin group. Conclusions: Compared with linezolid, trimethoprim/sulfamethoxazole and rifampicin seems to be non-inferior in the treatment of MRSA infection.

To measure trends in antibiotic prescribing in UK primary care in relation to nationally recommended best practice.A descriptive study linking individual patient data on diagnosis and prescription in a large primary care database, covering 537 UK general practices during 1995-2011.The proportion of cough/cold episodes for which antibiotics were prescribed decreased from 47% in 1995 to 36% in 1999, before increasing to 51% in 2011. There was marked variation by primary care practice in 2011 [10th-90th percentile range (TNPR) 32%-65%]. Antibiotic prescribing for sore throats fell from 77% in 1995 to 62% in 1999 and then stayed broadly stable (TNPR 45%-78%). Where antibiotics were prescribed for sore throat, recommended antibiotics were used in 69% of cases in 2011 (64% in 1995). The use of recommended short-course trimethoprim for urinary tract infection (UTI) in women aged 16-74 years increased from 8% in 1995 to 50% in 2011; however, a quarter of practices prescribed short courses in ≤16% of episodes in 2011. For otitis media, 85% of prescriptions were for recommended antibiotics in 2011, increasing from 77% in 1995. All these changes in annual prescribing were highly statistically significant (P0.001).The implementation of national guidelines in UK primary care has had mixed success, with prescribing for coughs/colds, both in total and as a proportion of consultations, now being greater than before recommendations were made to reduce it. Extensive variation by practice suggests that there is significant scope to improve prescribing, particularly for coughs/colds and for UTIs.

OBJECTIVES To examine the prevalence of multidrug-resistant (MDR) urinary Escherichia coli among US outpatients and to assess the antimicrobial activity of oral antibiotics commonly used to treat urinary tract infections (UTIs) against MDR isolates. METHODS Antimicrobial susceptibility testing data from outpatient urine cultures in The Surveillance Network (TSN) Database USA were analysed. Six antimicrobial agents from six separate drug classes were included: ampicillin, cefalotin, ciprofloxacin, nitrofurantoin, trimethoprim/sulfamethoxazole and amoxicillin/clavulanate. Isolates were categorized as resistant to one, two, three, four, five and six agents and compared for the years 2001 and 2010. Phenotypes of MDR isolates were assessed to determine antimicrobial activity of recommended therapy for UTIs. RESULTS Prevalence of MDR E. coli increased from 9.1% in 2001 (n = 29,198) to 17.0% in 2010 (n = 32,742) (P < 0.0001). In isolates that demonstrated resistance to three, four or five antimicrobial agents in 2010, resistance to nitrofurantoin was observed in only 2.1%, 7.5% and 24.1% of isolates, respectively. Conversely, widespread resistance was observed for trimethoprim/sulfamethoxazole (62.6%, 88.6% and 97.9% for isolates resistant to three, four and five agents, respectively) and ciprofloxacin (48.9%, 84.3% and 98.2% for isolates resistant to three, four and five agents, respectively). CONCLUSIONS Because of its consistent antimicrobial activity against MDR E. coli, nitrofurantoin remains a reliable first-line agent for the empirical treatment of acute uncomplicated cystitis.

Objective Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has become an important cause of community-onset urinary tract infections. We aimed to evaluate the efficacy of non-carbapenem antibiotics for acute pyelonephritis (APN) due to ESBL-producing E. coli. Methods We conducted a retrospective cohort study of patients with community-onset APN due to ESBL-producing E. coli at a single centre in Korea from 2007 to 2013. Outcomes included both microbiological and clinical failure. To adjust for non-random assignment of antibiotics, the propensity score method of inverse probability of treatment weighting and a multivariable analysis using Cox proportional hazards modelling were employed to estimate the efficacy of non-carbapenem antibiotics as compared with carbapenems. Results Of 152 eligible patients, 85 (55.9%) received carbapenems and 67 (44.1%) received non-carbapenems. Non-carbapenem antibiotics used in this cohort included aminoglycosides (n = 30), β-lactam/β-lactamase inhibitors (n = 13), fluoroquinolones (n = 12) and trimethoprim/sulfamethoxazole (n = 5). Microbiological failure was observed in 16 patients receiving carbapenems (16/83, 19.3%) versus 4 patients receiving non-carbapenem (4/67, 6.0%). After weighting, the risk of microbiological failure was similar between the two groups [weighted hazard ratio (HR) 0.99; 95% CI 0.31-3.19]. In a multivariable regression analysis combined with weights, the estimate did not change (weighted adjusted HR 0.96; 95% CI 0.41-2.27). The clinical failure rate was also similar in the two groups (weighted HR 1.05; 95% CI 0.24-4.62). Conclusions These results suggest that non-carbapenem antibiotics were as effective as carbapenems as definitive therapy for treating community-onset APN caused by ESBL-producing E. coli if they are active in vitro.

Background:Littleisknownabouttheprevalenceofantimicrobialresistance(AMR)amongstbacterialpathogensin sub-Saharan Africa (sSA), despite calls for continent-wide surveillance to inform empirical treatment guidelines. Methods: We searched PubMed and additional databases for susceptibility data of key pathogens for surveillance, published between 1990 and 2013. Extracted data were standardized to a prevalence of resistance in populations of isolates and reported by clinical syndrome, microorganism, relevant antimicrobial drugs and region. Results: We identified 2005 publications, of which 190 were analysed. Studies predominantly originated from east sSA (61%), were hospital based (60%), were from an urban setting (73%) and reported on isolates from patients with a febrile illness (42%). Quality procedures for susceptibility testing were described in ,50% of studies. Median prevalence(MP)ofresistancetochloramphenicolinEnterobacteriaceae,isolatedfrompatientswithafebrileillness, ranged between 31.0% and 94.2%, whilst MP of resistance to third-generation cephalosporins ranged between 0.0% and 46.5%. MP of resistance to nalidixic acid in Salmonella enterica Typhi ranged between 15.4% and 43.2%. The limited number of studies providing prevalence data on AMR in Gram-positive pathogens or in pathogensisolated frompatientswitha respiratory tract infection,meningitis, urinary tract infection or hospital-acquired infection suggested high prevalence of resistance to chloramphenicol, trimethoprim/sulfamethoxazole and tetracycline and low prevalence to third-generation cephalosporins and fluoroquinolones. Conclusions: Our results indicate high prevalence of AMR in clinical bacterial isolates to antimicrobial drugs commonly used in sSA. Enhanced approaches for AMR surveillance are needed to support empirical therapy in sSA.

OBJECTIVES: Sulfamethoxazole and trimethoprim have been used for decades, yet high dosages are rarely reported. We aimed to measure blood concentrations of both molecules in this situation. METHODS: Between 2002 and 2010, 22 patients received two tablets of co-trimoxazole three times a day, equivalent to a daily dosage of 2400 mg of sulfamethoxazole and 480 mg of trimethoprim. The trimethoprim and sulfamethoxazole concentrations were determined 3 h after administration using ion-paired HPLC. RESULTS: In the presence of a negative control, which yielded no peaks at the retention times for trimethoprim and sulfamethoxazole, the mean ± SD value for sulfamethoxazole concentration was 161.01 ± 69.154 mg/L and the mean ± SD value for trimethoprim was 5.788 ± 2.74 mg/L. CONCLUSIONS: These concentrations are largely above the trimethoprim and sulfamethoxazole MIC distributions as well as the trimethoprim resistance clinical breakpoint (4 mg/L) reported by EUCAST in 2012 for most bacterial pathogens, including Gram-positive species such as Staphylococcus aureus. Our results support proposing a high-dosage regimen of co-trimoxazole as a suitable alternative for methicillin-resistant S. aureus infections.

Objectives This study aimed to define the molecular basis of co-trimoxazole resistance in Malawian pneumococci under the dual selective pressure of widespread co-trimoxazole and sulfadoxine/pyrimethamine use. Methods We measured the trimethoprim and sulfamethoxazole MICs and analysed folA and folP nucleotide and translated amino acid sequences for 143 pneumococci isolated from carriage and invasive disease in Malawi (2002–08). Results Pneumococci were highly resistant to both trimethoprim and sulfamethoxazole (96%, 137/143). Sulfamethoxazole-resistant isolates showed a 3 or 6 bp insertion in the sulphonamide-binding site of folP. The trimethoprim-resistant isolates fell into three genotypic groups based on dihydrofolate reductase (encoded by folA) mutations: Ile-100-Leu (10%), the Ile-100-Leu substitution together with a residue 92 substitution (56%) and those with a novel uncharacterized resistance genotype (34%). The nucleotide sequence divergence and dN/dS of folA and folP remained stable from 2004 onwards. Conclusions S. pneumoniae exhibit almost universal co-trimoxazole resistance in vitro and in silico that we believe is driven by extensive co-trimoxazole and sulfadoxine/pyrimethamine use. More than one-third of pneumococci employ a novel mechanism of co-trimoxazole resistance. Resistance has now reached a point of stabilizing evolution. The use of co-trimoxazole to prevent pneumococcal infection in HIV/AIDS patients in sub-Saharan Africa should be re-evaluated.

The continuing spread of resistant Gram-negative bacteria is a therapeutic challenge and prudent use of antimicrobials is therefore essential. Urinary tract infections (UTIs), usually due to Gram-negative bacteria, are among the most common infections seen in the community. Moreover, bacterial strains producing extended-spectrum β-lactamases (ESBLs) that are resistant not only to cephalosporins and penicillins, but also to fluoroquinolones and trimethoprim, are becoming more prevalent in the community. This means that oral antibiotic options to treat these infections are limited. The discovery of new drugs to tackle these problems has been difficult and slow paced; it is therefore timely to 'rediscover' the current antibiotics we have available in our clinical formulary, to determine how best they can be used. Pivmecillinam is an oral antibiotic with excellent clinical efficacy in the treatment of uncomplicated UTIs. It has been used extensively in Nordic countries with few problems, but, despite this, it is not widely used in other countries. There is emerging in vitro and in vivo evidence of its activity against ESBL-producing organisms and its synergistic potential with β-lactamase inhibitors. Pivmecillinam is well tolerated with a low side-effect profile. Pivmecillinam also has a minimal effect on the intestinal and vaginal flora of the host; thus, there is a lower rate of selection of resistant bacteria, vaginal candidiasis and, of note, Clostridium difficile.

Objectives To determine the prevalence of antibiotic resistance and the epidemiology of Escherichia coli bacteraemia isolates across the Yorkshire and Humber National Health Service region over 2 years. Methods Ten percent of all E. coli blood culture isolates were collected per month from 14 laboratories across the Yorkshire and Humber region. Individual laboratories submitted antibiotic susceptibility data and isolates were re-tested centrally using the VITEK2(®) system (bioMerieux, France). Isolates were also characterized using PCR to test for the presence of sequences encoding extended-spectrum β-lactamases (ESBLs) and genotyped using amplified fragment length polymorphism (AFLP). Selected isolates were further characterized using multilocus sequence typing. Results Between July 2010 and June 2012, 770 isolates were examined: 63%, 40%, 14% and 7% of isolates were non-susceptible to ampicillin, trimethoprim, ciprofloxacin and gentamicin, respectively. Eight percent of isolates (n = 63) were ESBL positive; CTX-M group 1 enzymes were the most common (68%). There was a fluctuating trend in the prevalence of resistance to amoxicillin/clavulanic acid (MIC >8 mg/L): July-September 2010, 16%; July-September 2011, 38%; and April-June 2012, 22%. AFLP identified 106 types. The majority of isolates belonged to one of two AFLP types: AFLP 1 [sequence type (ST) 131; 17%] and AFLP 2 (ST73; 18%). ST131 and ST73 were both associated with hospital- and community-onset bacteraemia, and with urinary, hepatobiliary and gastrointestinal sources of infection. ESBL-positive isolates were predominantly ST131 (60%). Conclusions Continued surveillance of antibiotic resistance among E. coli bacteraemia isolates is necessary to enhance these early baseline data. The variable prevalence of resistance to amoxicillin/clavulanic acid raises concerns, as both E. coli bacteraemia and empirical use of this antibiotic are common.

OBJECTIVES Patients with classic Whipple's disease have a lifetime defect in immunity to Tropheryma whipplei and frequently develop treatment failures, relapses or reinfections. Empirical treatments were tested before culture was possible, but the only in vitro bactericidal treatment consists of a combination of doxycycline and hydroxychloroquine. METHODS Our laboratory has been a reference centre since the first culturing of Tropheryma whipplei, and we have tested 27,000 samples by PCR and diagnosed 250 cases of classic Whipple's disease. We report here the clinical course of patients who were followed by one of our group. RESULTS Of 29 patients, 22 (76%) were previously treated with immunosuppressive drugs, 26 (90%) suffered from arthralgias and 22 (76%) exhibited weight loss. Intravenous initial treatment was paradoxically associated with an increased risk of failure (P = 0.0282). Treatment with doxycycline and hydroxychloroquine (± sulfadiazine or trimethoprim/sulfamethoxazole) was associated with a better outcome (0/13 failures), whereas all 14 patients who were first treated with trimethoprim/sulfamethoxazole and referred to us (P < 0.0001) experienced failure. Among the patients treated with doxycycline and hydroxychloroquine after previous antibiotic treatments, two presented with a reinfection caused by different T. whipplei strains. Finally, serum therapeutic drug monitoring allowed us to detect a lack of compliance in the only patient with failure among the 22 patients treated with lifetime doxycycline. CONCLUSIONS In vitro results were confirmed by clinical outcomes and trimethoprim/sulfamethoxazole was associated with failures. The recommended management is a combination of doxycycline and hydroxychloroquine for 1 year, followed by doxycycline for the patient's lifetime along with stringent therapeutic drug monitoring.

The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs).Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time-kill assays against two strains of Staphylococcus aureus and three strains of β-haemolytic streptococci.The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18-0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3-4.5) for both standard and high doses, and 0.23 (range, 0.1-0.46) and 0.36 (range, 0.14-1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time-kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and β-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole.This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and β-haemolytic streptococci.

Received 23 December 2012; returned 15 January 2013; revised 04 March 2013; accepted 15 March 2013 Objectives: Antibiotic exposure is the most important risk factor for Clostridium difficile infection (CDI). Most evaluations of antimicrobial risk factors have been conducted in healthcare settings. The objective of this meta-analysis was to evaluate the association between antibiotic exposure and community-associated CDI (CA-CDI) (i.e. symptom onset in the community with no healthcare facility admission within 12 weeks) and to determine the classes of antibiotics posing the greatest risk. Methods: We searched four electronic databases for subject headings and text words related to CA-CDI and antibiotics. Studies that investigated the risk of CA-CDI associated with antibiotic usage were considered eligible. Data from the identified studies were combined using a random-effects model and ORs were calculated. Results: Of 910 citations identified, eight studies (n¼ 30 184 patients) met our inclusion criteria. Antibiotic exposure was associated with an increased risk of CA-CDI (OR 6.91, 95% CI 4.17–11.44, I 2 ¼ 95%). The risk was greatest with clindamycin (OR 20.43, 95% CI 8.50 –49.09) followed by fluoroquinolones (OR 5.65, 95% CI 4.38– 7.28), cephalosporins (OR 4.47, 95% CI 1.60 –12.50), penicillins (OR 3.25, 95% CI 1.89–5.57), macrolides (OR 2.55, 95% CI 1.91–3.39) and sulphonamides/trimethoprim (OR 1.84, 95% CI 1.48 –2.29). Tetracyclines were not associated with an increased CDI risk (OR 0.91, 95% CI 0.57–1.45). Conclusions: Antibiotic exposure was an important risk factor for CA-CDI, but the risk was different amongst different antibiotic classes. The risk was greatest with clindamycin followed by fluoroquinolones and cephalosporins, whereas tetracyclines were not associated with an increased risk.

To investigate the effect of trimethoprim/sulfamethoxazole on the survival of Mycobacterium tuberculosis and trimethoprim and sulfamethoxazole individually and combined with the first-line tuberculosis drugs (isoniazid, rifampicin and ethambutol).M. tuberculosis strains were exposed to either trimethoprim/sulfamethoxazole combination or sulfamethoxazole and trimethoprim alone at various concentrations. The strains were also exposed to sulfamethoxazole in combination with existing antibiotics to assess the combined effect on the growth of M. tuberculosis in the BACTEC 460TB system. The effect of the drugs was compared with vehicle-treated controls. Drug interactions were interpreted using quotient values obtained from the growth index of cultures treated with a single drug or the combination.Trimethoprim showed a negligible effect on the growth of M. tuberculosis while sulfamethoxazole inhibited 80% of the growth of M. tuberculosis at 4.75 mg/L. There was no synergistic activity between sulfamethoxazole and trimethoprim, although an additive effect was observed. A statistically significant synergistic effect was observed between sulfamethoxazole and rifampicin. Sulfamethoxazole also had an additive effect with ethambutol, but there was no interaction with isoniazid.Sulfamethoxazole is the main active compound against M. tuberculosis in the combination trimethoprim/sulfamethoxazole and has a synergistic effect with rifampicin. These findings suggest that sulfamethoxazole has potential in the multidrug regimen against M. tuberculosis.

A recent study reported that trimethoprim/sulfamethoxazole caused acute psychosis in four renal transplant patients with Pneumocystis jirovecii pneumonia. We aimed to investigate the incidence of and factors associated with trimethoprim/sulfamethoxazole-related acute psychosis in HIV-infected patients with P. jirovecii pneumonia.We reviewed the medical records of HIV-infected patients who presented with P. jirovecii pneumonia and received trimethoprim/sulfamethoxazole at six major hospitals in Taiwan from July 2009 to May 2011. Acute psychosis was defined as the occurrence of hallucinations or delusions following the initiation of trimethoprim/sulfamethoxazole during hospitalization.During the study period, 135 patients receiving trimethoprim/sulfamethoxazole for P. jirovecii pneumonia were enrolled and 16 (11.9%; 95% CI, 6.3%-17.4%) developed acute psychosis after a median duration of 5 days of trimethoprim/sulfamethoxazole treatment (range, 3-11 days). The incidence increased from 0% (0/16) in patients who received a daily trimethoprim dose of ≤12 mg/kg to 23.5% (4/17) in those who received a daily trimethoprim dose of18 mg/kg. In multivariate logistic regression analysis, a higher daily dose of trimethoprim/sulfamethoxazole (OR, per 1 mg increase of trimethoprim, 1.40; 95% CI, 1.12-1.76; P = 0.0035) and use of adjunctive steroids (OR, 4.43; 95% CI, 1.14-17.15; P = 0.031) were associated with acute psychosis.In this case series, 11.9% of HIV-infected patients developed acute psychosis while receiving trimethoprim/sulfamethoxazole for P. jirovecii pneumonia. While the study was limited by its retrospective design, the risk appeared to increase with increasing daily dose of trimethoprim/sulfamethoxazole in those vulnerable patients with multiple risks for acute psychosis.

Objectives Research in residential homes has been limited to date and the extent of systemic and topical antimicrobial prescribing is largely unknown. The aim of this study was to investigate antimicrobial prescribing in residential homes in Northern Ireland (NI). Methods Point prevalence studies (PPSs) were completed in November 2010 (PPS1) and April 2011 (PPS2) in 30 residential homes. Data were obtained from care plans, medication administration records and staff in relation to antimicrobial prescribing and facility and resident characteristics, and analysed descriptively. Results The point prevalence of systemic antimicrobial prescribing was 9.4% in PPS1 and 9.2% in PPS2 (range 0.0%-33.3% during both PPSs). Trimethoprim was the most commonly prescribed systemic antimicrobial and the main indication was the prevention of urinary tract infections. Almost 25% of systemic antimicrobials were prescribed at inappropriate doses. The point prevalence of topical antimicrobial prescribing was 6.4% (range 0.0%-22.2%) in PPS1 and 5.9% (range 0.0%-21.1%) in PPS2. The most commonly prescribed topical antimicrobials were chloramphenicol eye preparations in PPS1 and fusidic acid skin preparations in PPS2; treatment with these topical antimicrobials was generally prolonged. More than 25% of all systemic and 55% of all topical antimicrobials were initiated following telephone consultations as opposed to face-to-face consultations. Conclusions The prevalence of systemic antimicrobial prescribing in residential homes in NI is relatively high compared with care homes (particularly nursing homes) in other countries. Systemic and topical antimicrobial prescribing is not always appropriate in terms of the doses prescribed and the duration of use. It is apparent that current strategies employed in NI are insufficient to ensure prudent antimicrobial prescribing within this environment.

OBJECTIVES Direct SOS-dependent regulation of qnrB genes by fluoroquinolones mediated by LexA was reported. The smaqnr gene, on the Serratia marcescens chromosome, and qnrD both contain a putative LexA box. The aim of this study was to evaluate whether smaqnr or qnrD genes are induced via SOS-dependent mechanisms, and to investigate whether other antimicrobial agents induce qnrB, qnrD and smaqnr expression. METHODS RT-PCR was used to evaluate qnrB1, qnrD and smaqnr expression. Different concentrations of ciprofloxacin, levofloxacin, moxifloxacin and ceftazidime were evaluated as inducers. Additionally, the promoter regions of qnrB1, qnrD and smaqnr were fused transcriptionally to green fluorescent protein and used in reporter gene assays. Disc diffusion assays with different antimicrobial agents were used to detect induction. Measurements of transcriptional induction by ciprofloxacin were carried out using a plate reader. RESULTS RT-PCR assays showed that qnrB1, qnrD and smaqnr were induced at different concentrations of ciprofloxacin, moxifloxacin, levofloxacin and ceftazidime, increasing transcription 1.5- to 16.3-fold compared with basal expression, and depending on the antimicrobial agent and promoter analysed. The reporter gene assays showed that the qnrB1, qnrD and smaqnr genes were induced by ciprofloxacin, as expected, but also by ceftazidime, ampicillin and trimethoprim in Escherichia coli wild-type strains, but not in the recA-deficient E. coli HB101. Induction was not evident for imipenem or gentamicin. CONCLUSIONS β-Lactams and trimethoprim, along with fluoroquinolones, induce transcription of qnrB, qnrD and smaqnr genes using SOS-dependent regulation. These results show the direct SOS-dependent regulation of a low-level fluoroquinolone resistance mechanism in response to other antimicrobials.

Background: Data on more than a decade of outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe were collected from 33 countries as part of the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC). Methods: For the period 1997–2009, data on outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials aggregated at the level of the active substance were collected and expressed in defined daily doses (DDD; WHO, version 2011) per 1000 inhabitants per day (DID). Using the Anatomical Therapeutic Chemical (ATC) classification, trends in the use of tetracyclines (J01A), sulphonamides and trimethoprim (J01E) and other antibacterials (J01X) over time, seasonal variation and composition of use were analysed. Results: In 2009, the variations in outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials between countries, and also in the composition of use over time, were huge. For tetracyclines a significant and for sulphonamides and trimethoprim a non-significant decrease in use was observed between 1997 and 2009 in Europe. The seasonal variation in their use significantly decreased over time. For the other antibacterials, no significant changes in the volume of use or its seasonal variation were seen. Conclusions: As for all other major antibiotic subgroups, a striking variation in use and composition of use between countries in Europe was observed for outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials. In combination with the decreasing use, especially of recommended substances, this represents an opportunity not only to reduce antibiotic use but also to improve its quality., peer-reviewed

Objectives This study was designed to determine the susceptibility of clinical isolates of multidrug-resistant (MDR) and non-MDR Mycobacterium tuberculosis to sulfamethoxazole, trimethoprim and trimethoprim/sulfamethoxazole over a 12 year period in Taiwan. Patients and methods We examined a total of 117 clinical isolates of M. tuberculosis collected from Southern Taiwan, 116 from 1995 to 2006 and an extensively drug-resistant (XDR) isolate in 2009. These included 28 isolates susceptible to all four first-line agents, 52 MDR isolates and 36 isolates with a mixed combination of drug resistance patterns other than MDR and 1 XDR isolate. Results Sulfamethoxazole inhibited 80% growth of all 117 isolates regardless of their susceptibility to the first-line agents at an MIC(90) of 9.5 mg/L. The concentration required to inhibit 99% growth was 38 mg/L. There were no significant changes in the MIC(50) or MIC(90) of sulfamethoxazole over a 12 year period. All 117 isolates were resistant to trimethoprim at >8 mg/L. The combination of trimethoprim/sulfamethoxazole at a ratio of 1:19 had no additive or synergistic effects. Conclusions Sulfamethoxazole inhibited the growth of clinical isolates of M. tuberculosis at achievable concentrations in plasma after oral administration. Susceptibility to sulfamethoxazole remained constant over a 12 year period. Trimethoprim was inactive against M. tuberculosis and trimethoprim/sulfamethoxazole provided no additional activity. Although the current and prior studies demonstrate that sulfamethoxazole is active against M. tuberculosis the search needs to continue for more active, lipid-soluble sulphonamides that are better absorbed into tissues and have improved therapeutic efficacy.

Background Toxins contribute to the pathogenicity of Staphylococcus aureus infections by inducing a dysregulated inflammatory response. This study evaluated the impact of anti-staphylococcal antibiotic exposures over an increasing concentration range on cytokine production from peripheral blood mononuclear cells (PBMCs) after S. aureus toxin exposures. Methods Human PBMCs were suspended in complete Roswell Park Memorial Institute (RPMI) 1640 medium with 10% fetal bovine serum at 10(6) cells/mL with 100 ng/mL S. aureus toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin A (SEA), α-toxin or Panton-Valentine leucocidin (PVL). Vancomycin, trimethoprim/sulfamethoxazole, tigecycline, daptomycin, linezolid, clindamycin and azithromycin were added at a concentration range of 0.5-100 mg/L. Cytokine [interleukin-1β (IL-1β), IL-6, IL-8, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α)] concentrations were measured in duplicate by ELISA following exposure and were compared with response with toxin alone. Results At concentrations approximating serum C(max), tigecycline decreased IL-6 by 52%-57% and IFN-γ production by 43%-53% compared with toxin alone (P ≤ 0.05) and linezolid inhibited TNF-α by 12%-35% and IL-8 by 25%-42% (P ≤ 0.02). However, trimethoprim/sulfamethoxazole increased TNF-α and IL-8 production (P = 0.002). Clindamycin, daptomycin, vancomycin and azithromycin had no consistent significant effect at approximate serum C(max) concentrations. All antibiotics had a concentration-dependent effect on cytokine production, with tigecycline, clindamycin and trimethoprim/sulfamethoxazole being the most potent inhibitors of cytokine production at concentrations exceeding 25 mg/L. Conclusions S. aureus toxins stimulate production of inflammatory cytokines in PBMCs. Antimicrobials with high tissue penetration, including tigecycline, clindamycin, trimethoprim/sulfamethoxazole and linezolid, reduced cytokine production, which, along with their antimicrobial effects, may have importance in the therapeutic outcome of severe infections.

Evaluation and optimization of antibiotic use (antibiotic stewardship) is being increasingly promoted as a means to reduce antibiotic resistance, adverse events, treatment complications and costs within institutions. Our goal was to examine the prevalence of antibiotic use among long-term care facility residents and the extent of variability across these institutions.We conducted a population-based, point-prevalence study of antibiotic use among elderly individuals (n = 37,371) residing in long-term care facilities (n = 363 institutions) in Ontario between April and June 2009, using linked healthcare databases from Canada's largest province. Facilities were grouped into quintiles according to their mean antibiotic dispensing rates and variation was compared across quintiles.There were 2190 (5.9%) long-term care residents receiving antibiotic prescriptions on the study date. The three most prevalent antibiotics were agents most commonly used for the treatment of urinary tract infections, including nitrofurantoin (365, 15.4%), trimethoprim/sulfamethoxazole (338, 14.3%) and ciprofloxacin (304, 12.8%). The majority of treatment courses were at least 10 days in duration (1482, 62.6%), and many exceeded 90 days (495, 20.9%), suggesting chronic prophylaxis. There was substantial variability in antibiotic use across facilities, with a 5-fold variation from the highest-use quintile (10.8%) to the lowest-use quintile (2.2%). This variation persisted after adjustment for multiple facility-level and resident-level factors, including demographic characteristics, healthcare utilization statistics, co-morbidity prevalence, functional status and device dependence.Antibiotic use is common among long-term care residents, variable across institutions, and may benefit from focused antimicrobial stewardship interventions to standardize treatment indications and duration.

To explore the role of topoisomerase I in gene activation and increased RecA levels during the bacterial SOS response, as well as the effect of antibiotic treatment and stress challenge on cell killing initiated by trapped topoisomerase I cleavage complex.A mutant Escherichia coli strain with a ΔtopA mutation was used to investigate the role of topoisomerase I function in the SOS response to trimethoprim and mitomycin C. Induction of the recA and dinD1 promoters was measured using luciferase reporters of these promoters fused to luxCDABE. An increase in the RecA level following trimethoprim treatment was quantified directly by western blotting. The effect of stress challenge from trimethoprim and acidified nitrite treatments on cell killing by topoisomerase I cleavage complex accumulation was measured by the decrease in viability following induction of recombinant mutant topoisomerase I that forms a stabilized cleavage complex.Topoisomerase I function was found to be required for efficient transcriptional activation of the recA and dinD1 promoters during the E. coli SOS response to trimethoprim and mitomycin C. The role of topoisomerase I in the SOS response was confirmed with quantitative western blot analysis of RecA following trimethoprim treatment. The bactericidal effect from topoisomerase I cleavage complex accumulation was shown to be enhanced by stress challenge from trimethoprim and acidified nitrite.Bacterial topoisomerase I function is actively involved in the SOS response to antibiotics and stress challenge. Cell killing initiated by the topoisomerase I cleavage complex would be enhanced by antibiotics and the host response. These findings provide further support for bacterial topoisomerase I as a therapeutic target.

Item does not contain fulltext OBJECTIVES: We evaluated the changes in antibiotic resistance from 1998 to 2009 of Klebsiella pneumoniae isolated from the intensive care units (ICUs) and urology services of 14 Dutch hospitals and the consequences for empirical therapy. METHODS: Quantitative antibiotic susceptibility testing of K. pneumoniae was performed in a central laboratory using a microbroth dilution method. Breakpoints were as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The prevalence of extended-spectrum beta-lactamase (ESBL)- and carbapenemase-producing isolates was determined. RESULTS: A significant increase in resistance among ICU isolates was observed for ceftazidime (4.2%-10.8%), ciprofloxacin (5.8%-18.5%) and trimethoprim/sulfamethoxazole (11.9%-23.1%), and for cefuroxime (2.8%-7.9%) and trimethoprim/sulfamethoxazole (13.5%-27.8%) among urology isolates. Among ICU isolates the prevalence of ESBLs increased significantly from 2% to 8%. Carbapenemase production was not demonstrated. Among ICU isolates the prevalence of multidrug resistance increased and has been >/=12% since 2004. Among urology isolates multidrug resistance was highest in 2009 at 7.4%. Overall, resistance was significantly higher among ICU isolates. CONCLUSIONS: We observed an increase in resistance among ICU and urology isolates and an increased prevalence of ESBLs among ICU isolates. Carbapenemase production was not demonstrated. A regular update of empirical treatment protocols based on actual surveillance data is justified. 01 april 2011

Objectives To determine the temporal relationship between antibiotic use and incidence of antibiotic-resistant Escherichia coli in both the inpatient and outpatient setting of a large urban area. Methods A retrospective observational time-series analysis was performed to evaluate the incidence of non-duplicate clinical isolates of E. coli resistant to ciprofloxacin, trimethoprim/sulfamethoxazole and cefepime from January 2000 through December 2007, combined with a transfer function model of aggregated data on antibiotic use in both settings obtained from the hospital's pharmacy and outpatient billing offices. Results Ciprofloxacin resistance increased from 6.0% (2000) to 15.4% (2007; P

Objectives Low concentrations of some antibiotics have been reported to stimulate mutagenesis and recombination, which may facilitate bacterial adaptation to different types of stress, including antibiotic pressure. However, the mutagenic effect of most of the currently used antibiotics remains untested. Furthermore, it is known that in many bacteria, including Escherichia coli, stimulation of mutagenesis is mediated by the SOS response. Thus, blockage or attenuation of this response through the inhibition of RecA has been proposed as a possible therapeutic adjuvant in combined therapy to reduce the ability to generate antibiotic-resistant mutants. The aim of this work was to study the capacity of sublethal concentrations of antimicrobials of different families with different molecular targets to increase the mutant frequency of E. coli, and the effect that inactivation of recA would have on antibiotic-mediated mutagenesis. Methods We tested the mutagenicity of the following antimicrobials: ampicillin; ceftazidime; imipenem; fosfomycin; ciprofloxacin; trimethoprim; sulfamethoxazole; trimethoprim/sulfamethoxazole; colistin; tetracycline; gentamicin; rifampicin; and chloramphenicol. Results Eight out of the 13 antimicrobials tested stimulate E. coli mutagenesis (slightly in most cases), with trimethoprim, alone or in combination with sulfamethoxazole, producing the highest effect. Inactivation of recA abolishes the mutagenic effect and also produces increased susceptibility to some of the tested antimicrobials. Conclusions The fact that inactivation of recA reduces mutagenicity and/or increases the activity of a large number of antimicrobials supports the hypothesis that RecA inhibition might have favourable effects on antibiotic therapy.

Sir, Fluoroquinolones are among the most widely prescribed antibiotics. Recent reports show that quinolones are prescribed in nearly half of all outpatient urinary tract infection (UTI) visits in the USA, although current guidelines recommend against their use as first-line treatment for uncomplicated UTIs. As a result, the prevalence of quinolone-resistant pathogens, particularly Gram-negative bacteria, is on the rise globally. Horizontally transferable genes (qnr) borne by plasmids encode low-level quinolone resistance in Escherichia coli. Previous studies have found that plasmid-mediated resistance to low concentrations of ciprofloxacin increases the selection of higher ciprofloxacin resistance, by allowing the bacterial population to survive and grow to a level at which secondary mutations to higher resistance can occur. This low-level resistance, conferred by multiresistance plasmids, would not be detected by the usual breakpoints for susceptibility used in microbiology laboratories. By prescribing a quinolone to patients infected with these apparently susceptible isolates, physicians may inadvertently facilitate the selection of higher-level resistance. There are important clinical and public health implications. First, the treatment of infections caused by Gram-negative bacteria containing these resistance elements may be less effective than the treatment of infections caused by bacteria lacking these genes. Second, the biological linking of quinolone resistance with other resistance types that can be carried by plasmids means that overprescribing of quinolones and other antibiotics is likely to further fuel the dissemination of multidrug-resistant bacteria, for which there are limited available treatment options. To inform the practice of evidence-based prescribing, we aimed in the present study to ascertain whether there was an association between fluoroquinolone resistance among urinary E. coli isolates and resistance to other antimicrobial agents. We conducted a cross-sectional analysis of antimicrobial surveillance data from a nationally representative network of microbiological laboratories (The Surveillance Network Database—USA) described in detail elsewhere. The results of all routine susceptibility tests were reported based on CLSI criteria adopted by the facility at the time of testing. Aminoglycoside (gentamicin) susceptibility was chosen as a marker because resistance to it in E. coli is almost always plasmid mediated and plasmids containing qnr and other quinolone resistance genes (such as qepA) commonly contain genes for aminoglycoside resistance. Since clinicians may be more likely to prescribe a quinolone if an isolate is non-susceptible to other treatment options, we included only isolates that were also susceptible to at least trimethoprim/sulfamethoxazole, ampicillin or nitrofurantoin, which are commonly used for treatment of UTIs. Multivariable Poisson regression with robust error variances was used to estimate the relative risk (RR) of fluoroquinolone non-susceptibility. Statistical analyses were performed using Stata v.12.0, with P values ,0.05 considered significant. The study was exempt from Institutional Review Board review at Harvard University. The study included 1651506 outpatient urine E. coli isolates tested for fluoroquinolone (ciprofloxacin or levofloxacin) and aminoglycoside (gentamicin) susceptibility between 2000 and 2010 (Table S1, available as Supplementary data at JAC Online). The majority of isolates in the sample were from female patients (89.5%) and the mean age was 46 years. Fluoroquinolone and gentamicin resistance increased significantly over the sample period, from 3.2% in 2000 to 18.2% in 2010 (P,0.001) and from 2.3% to 7.4% (P,0.001), respectively. After controlling for age, sex, region and year, isolates that were non-susceptible to gentamicin were seven times more likely to be fluoroquinolone resistant than gentamicin-susceptible isolates (adjusted RR: 7.0; 95% CI: 6.5–7.5; P,0.001) (Table 1) that were also susceptible to ampicillin, nitrofurantoin and trimethoprim/sulfamethoxazole. The risk of fluoroquinolone resistance was higher for isolates susceptible to only ampicillin (adjusted RR: 7.8; 95% CI: 7.5–8.1) or trimethoprim/sulfamethoxazole (adjusted RR: 8.6; 95% CI: 8.5 –8.8). Across all five models, age, isolates tested in the south and year were positively associated with fluoroquinolone resistance. Our findings show that the risk of fluoroquinolone-resistant E. coli infection in the outpatient setting is heightened by nonsusceptibility to an aminoglycoside, even amongst isolates that were susceptible to three other antibiotics commonly used to treat UTIs. We also found that there was some geographic variation in risk, with a nearly 50% increased risk of quinolone resistance among isolates from the south, holding other factors constant. There are a number of limitations, including the lack of patient-level data on antimicrobial use. However, our results correspond favourably with similar associations of fluoroquinolone resistance with other resistances reported previously in intensive care patients. One explanation for this association is the widespread circulation of plasmid-encoded quinolone resistance genes. To our knowledge, these findings are the first national-level

Resistance in Gram-negative bacteria has been increasing, particularly over the last 6 years. This is mainly due to the spread of strains producing extended-spectrum β-lactamases (ESBLs) such as CTX-M enzymes or AmpC β-lactamases. Many of the isolates producing these enzymes are also resistant to trimethoprim, quinolones and aminoglycosides, often due to plasmid co-expression of other resistance mechanisms. CTX-M-producing Escherichia coli often occurs in the community and as E. coli is one of the commonest organisms causing urinary tract infections (UTIs) the choice of agents to treat these infections is diminishing. Novel combinations of antibiotics are being used in the community and broad-spectrum agents such as carbapenems are being used increasingly as empirical treatment for severe infections. Of particular concern therefore are reports in the UK of organisms that produce carbapenemases. As resistance is becoming more widespread, prudent use of antimicrobials is imperative and, as asymptomatic bacteriuria is typically benign in the elderly, antibiotics should not be prescribed without clinical signs of UTI. The use of antibiotics as suppressive therapy or long-term prophylaxis may no longer be defensible.

Background: To optimize empirical treatment of urinary tract infections (UTIs), regular evaluation of the antibiotic susceptibility of the most common uropathogen, Escherichia coli, is necessary. We compared the antibiotic prescription rate for UTIs in women and E. coli antibiotic susceptibility results, including the prevalence of extended-spectrum beta-lactamase (ESBL) producing strains, in 2009 with data collected 5 years ago. Methods: Urinary samples of female patients with symptoms of uncomplicated UTI in 42 general practices, all participating in the Sentinel Stations network of NIVEL, were collected during a 6-month period. Uropathogens were identified and the antibiotic susceptibility of E. coli was determined. Results: We analysed 970 urine cultures, of which 785 (81%) were considered positive (103 cfu/ml). Escherichia coli accounted for 72% of the isolates. ESBLs showed an increase between both surveys (0.1 versus 1%, P < 0.05), while no difference in antibiotic susceptibility of the commonly used antimicrobial agents for UTIs was observed. A significantly lower susceptibility rate to co-amoxiclav was observed in the eastern region compared with the northern part of the country (80 versus 92%, P < 0.05). Consistent with national guidelines, the prescription rate of trimethoprim decreased over time (19 versus 5%, P < 0.05) whereas nitrofurantoin and fosfomycin rates showed an increase (58 versus 66% and 0 versus 5% respectively, both P < 0.05). Conclusions: The antibiotic susceptibility of uropathogenic E. coli did not change over a 5-year period in female patients with uncomplicated UTI in The Netherlands, but ESBL-prevalence increased. With respect to the prescription of antimicrobial agents a good compliance to national UTI guidelines was observed.