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Preview: Journal of Antimicrobial Chemotherapy - current issue

Journal of Antimicrobial Chemotherapy Current Issue





Published: Thu, 18 Jan 2018 00:00:00 GMT

Last Build Date: Fri, 16 Feb 2018 03:49:21 GMT

 






We can do better: a fresh look at echinocandin dosing

Thu, 11 Jan 2018 00:00:00 GMT

J Antimicrob Chemother 2018; 73: Suppl 1: i44–i50



Intestinal carriage of ampicillin- and vancomycin-resistant Enterococcus faecium in humans, dogs and cats in the Netherlands

Mon, 25 Dec 2017 00:00:00 GMT

Abstract
Background
The prevalence of ampicillin- and/or vancomycin-resistant Enterococcus faecium (AREf and VREf) has increased in hospitalized patients in the Netherlands.
Objectives
To quantify the prevalence, risk factors and co-carriage of AREf and VREf in humans, cats and dogs in the Dutch population.
Methods
From 2014 to 2015, ∼2000 inhabitants of the Netherlands each month were randomly invited to complete a questionnaire and provide a faecal sample. Subjects owning pets were also asked to submit one dog or cat sample. Faecal samples were screened for AREf and VREf. The genetic relatedness of isolates was determined using core genome MLST. Logistic regression analysis was used to determine risk factors.
Results
Of 25 365 subjects, 4721 (18.6%) completed the questionnaire and 1992 (42.2%) human, 277 dog and 118 cat samples were submitted. AREf was detected in 29 human (1.5%), 71 dog (25.6%) and 6 cat (5.1%) samples. VREf (vanA) was detected in one human and one dog. AREf/VREf co-carriage was not detected in 388 paired samples. The use of antibiotics (OR 4.2, 95% CI 1.7–11.2) and proton pump inhibitors (OR 2.7, 95% CI 1.1–6.3) were risk factors for AREf carriage in humans. In dogs, these were the use of antibiotics (OR 2.3, 95% CI 1.1–4.6) and eating raw meat (OR 3.2, 95% CI 1.4–6.6). Core genome MLST-based phylogenetic linkage indicated clonal relatedness for a minority of human (16.7%) and pet AREf isolates (23.8%) in three clusters.
Conclusions
Intestinal carriage with AREf or VREf is rare in the Dutch general population. Although AREf carriage is high in dogs, phylogenetic linkage between human and pet AREf isolates was limited.



Effect of general practice characteristics and antibiotic prescribing on Escherichia coli antibiotic non-susceptibility in the West Midlands region of England: a 4 year ecological study

Thu, 21 Dec 2017 00:00:00 GMT

Abstract
Objectives
To assess the effect of general practice characteristics and antibiotic prescribing on the number of non-susceptible Escherichia coli isolated from urine specimens submitted from community settings, we undertook an ecological study of the general practice population in the West Midlands.
Methods
Descriptive analysis and multilevel modelling of temporal trends in antibiotic prescribing and non-susceptibility of E. coli urine isolates to a range of antibiotics prescribed in the community over a 4 year period.
Results
Nine of the 16 antibiotic prescribing/non-susceptibility combinations demonstrated a significant statistical linear correlation with non-susceptibility either for prescribing in a quarter or for prescribing within the previous 12 months. The magnitude of the effect varied, from a 0.3% increase in the odds of non-susceptibility to ampicillin/amoxicillin (when prescribing ampicillin/amoxicillin) to a 6.3% increase in the odds of non-susceptibility to nitrofurantoin (when prescribing nitrofurantoin) for an increase of 50 DDDs per 1000 practice population within a quarter (equivalent to ∼10 courses of antibiotics). In all 16 models, single-handed general practices were shown to have a significant association with increased numbers of non-susceptible E. coli urine isolates (adjusted ORs 1.083–1.657). Increased prescribing of ampicillin/amoxicillin in winter periods was associated with increased non-susceptibility of E. coli isolated from urine specimens.
Conclusions
Small increases in antibiotic prescribing in individual general practices reduce the number of susceptible bacteria in the practice population. To maintain the effectiveness of available treatment, antibiotic stewardship should be encouraged and supported within each practice.



Characterization of OXA-48-like carbapenemase producers in Canada, 2011–14

Mon, 18 Dec 2017 00:00:00 GMT

Abstract
Objectives
Since the first identification of the OXA-48 carbapenemase in 2001, Enterobacteriaceae harbouring OXA-48-like enzymes have been reported globally. Here, we applied WGS to characterize the molecular epidemiology of these bacterial isolates.
Methods
Enterobacteriaceae non-susceptible to carbapenems isolated from patients between 2011 and 2014 were voluntarily submitted to the Canadian National Microbiology Laboratory where they were screened for carbapenemase genes. WGS was conducted on OXA-48-like producers using the Illumina MiSeq platform. WGS data were used for single nucleotide variant (SNV) analysis, MLST analysis, detection of resistance genes and partial plasmid characterization. Susceptibilities were determined using Vitek2 and Etest. Patient data provided from sites were reviewed.
Results
Sixty-seven non-duplicated cases were identified among Escherichia coli (n =21) and Klebsiella pneumoniae (n =46). Recent international travel was observed in 40.4% of cases. OXA-181 (52.2%) and OXA-48 (31.3%) were the most common variants, one E. coli OXA-48 producer was found to harbour the acquired colistin resistance gene mcr-1. The dominant STs were ST38 and ST410 in E. coli and ST14 in K. pneumoniae. Three common plasmid types were observed among isolates: IncL/M associated with OXA-48 producers, and ColKP3 and IncX3 associated with OXA-181/232 producers.
Conclusions
Enterobacteriaceae with OXA-48-like carbapenemases are emerging in Canada. This study highlights the complexity of OXA-48-types identified in Canada owing to travel and the successful clones and plasmids harbouring the OXA-48-like enzyme.



Antibiotic consumption in Shandong Province, China: an analysis of provincial pharmaceutical centralized bidding procurement data at public healthcare institutions, 2012–16

Mon, 18 Dec 2017 00:00:00 GMT

Abstract
Objectives
To explore the trends of antibiotic consumption in public healthcare institutions through analysing the provincial centralized bidding procurement (CBP) data in Shandong, China.
Methods
The Shandong CBP system has been established since 2011, covering public healthcare institutions of 500 secondary and tertiary hospitals, 600 urban primary healthcare centres (PHCs) and 1600 rural PHCs. We collected all the antibiotic procurement records from the CBP system between 2012 and 2016. Antibiotic consumption data were calculated using Anatomical Therapeutic Chemical (ATC)/DDD methodology and normalized using DDD per 1000 inhabitants per day (DID).
Results
Overall antibiotic consumption increased from 12.859 DID in 2012 to 15.802 DID in 2014, then decreased to 13.802 DID in 2016. The top three antibiotics consumed in 2016 were penicillins (4.251 DID), quinolones (2.957 DID) and macrolides (2.057 DID). PHCs consumed 80% of the total antibiotics, of which rural PHCs accounted for 88%. Antibiotic consumption peaked in 2014 for rural PHCs and in 2015 for hospitals, and declined thereafter. In urban PHCs, the consumption steadily increased from 2012 to 2016.
Conclusions
Zero mark-up drug policies and national policies to improve rational use of antibiotic were associated with the reduction of antibiotic consumption in public healthcare institutions in Shandong Province. Regulations for antibiotic use in PHCs should be strengthened.



Prevalence of carbapenem resistance and carbapenemase production among Enterobacteriaceae isolated from urine in the UK: results of the UK infection-Carbapenem Resistance Evaluation Surveillance Trial (iCREST-UK)

Fri, 15 Dec 2017 00:00:00 GMT

Abstract
Objectives
Although carbapenem susceptibility testing has been recommended for all Enterobacteriaceae from clinical specimens, for practical reasons a carbapenem is not included in many primary antibiotic panels for urine specimens. The ‘iCREST’ study sought carbapenemase-producing Enterobacteriaceae (CPE) in routine urine specimens yielding Gram-negative growth in five diagnostic laboratories in the UK. We sought also to compare locally and centrally determined MICs of meropenem and ceftazidime/avibactam.
Methods
Positive growth from up to 2000 urine specimens per laboratory was plated onto chromID® CARBA SMART agar. Suspected CPE colonies were tested locally by Etest for susceptibility to meropenem and ceftazidime/avibactam, and referred to central laboratories for PCR confirmation of CPE status and microbroth MIC determination.
Results
Twenty-two suspected CPE were identified from 7504 urine specimens. Ten were confirmed by PCR to have NDM (5), IMP (2), KPC (2) or OXA-48-like (1) carbapenemases. Locally determined ceftazidime/avibactam MICs showed complete categorical agreement with those determined centrally by microbroth methodology. The seven ceftazidime/avibactam-resistant isolates (MICs ≥256 mg/L) had NDM or IMP metallo-carbapenemases.
Conclusions
The frequency of confirmed CPE among Gram-negative urinary isolates was low, at 0.13% (10/7504), but CPE were found in urines at all five participating sites and the diversity of carbapenemase genes detected reflected the complex epidemiology of CPE in the UK. These data can inform local policies about the cost-effectiveness and clinical value of testing Gram-negative bacteria from urine specimens routinely against a carbapenem as part of patient management and/or infection prevention and control strategies.



Whole genome analysis of cephalosporin-resistant Escherichia coli from bloodstream infections in Australia, New Zealand and Singapore: high prevalence of CMY-2 producers and ST131 carrying blaCTX-M-15 and blaCTX-M-27

Thu, 14 Dec 2017 00:00:00 GMT

Abstract
Objectives
To characterize MDR Escherichia coli from bloodstream infections (BSIs) in Australia, New Zealand and Singapore.
Methods
We collected third-generation cephalosporin-resistant (3GC-R) E. coli from blood cultures in patients enrolled in a randomized controlled trial from February 2014 to August 2015. WGS was used to characterize antibiotic resistance genes, MLST, plasmids and phylogenetic relationships. Antibiotic susceptibility was determined using disc diffusion and Etest.
Results
A total of 70 3GC-R E. coli were included, of which the majority were ST131 (61.4%). BSI was most frequently from a urinary source (69.6%), community associated (62.9%) and in older patients (median age 71 years). The median Pitt score was 1 and ICU admission was infrequent (3.1%). ST131 possessed more acquired resistance genes than non-ST131 (P =0.003). Clade C1/C2 ST131 predominated (30.2% and 53.5% of ST131, respectively) and these were all ciprofloxacin resistant. All clade A ST131 (n =6) were community associated. The predominant ESBL types were blaCTX-M (80.0%) and were strongly associated with ST131 (95% carried blaCTX-M), with the majority blaCTX-M-15. Clade C1 was associated with blaCTX-M-14 and blaCTX-M-27, whereas blaCTX-M-15 predominated in clade C2. Plasmid-mediated AmpC genes (mainly blaCMY-2) were frequent (17.1%) but were more common in non-ST131 (P <0.001) isolates from Singapore and Brisbane. Two strains carried both blaCMY-2 and blaCTX-M. The majority of plasmid replicon types were IncF.
Conclusions
In a prospective collection of 3GC-R E. coli causing BSI, community-associated Clade C1/C2 ST131 predominate in association with blaCTX-M ESBLs, although a significant proportion of non-ST131 strains carried blaCMY-2.



Antibiotic susceptibility of Francisella tularensis subsp. holarctica strains isolated from tularaemia patients in France between 2006 and 2016

Thu, 14 Dec 2017 00:00:00 GMT

Abstract
Objectives
To determine the in vitro susceptibility to 18 antibiotics of human strains of Francisella tularensis isolated in France between 2006 and 2016, to check the absence of acquired resistance and to evaluate potential therapeutic alternatives.
Methods
Fifty-nine clinically unrelated F. tularensis subsp. holarctica strains identified at the French National Reference Centre for Francisella as belonging to the phylogenetic subclade B.FTNF002-00 were used. MICs were determined in CAMHB medium supplemented with 2% PolyViteX®, using the CLSI broth microdilution method.
Results
All strains were susceptible to fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin and moxifloxacin; MIC range: 0.016–0.25 mg/L), aminoglycosides (gentamicin and tobramycin; MIC range: ≤0.03–0.25 mg/L), doxycycline (MIC range: 0.125–0.25 mg/L) and chloramphenicol (MIC range: 0.5–2 mg/L). The erythromycin MIC range (0.5–2 mg/L) confirmed that all isolates belonged to biovar I of F. tularensis subsp. holarctica. Azithromycin and telithromycin displayed lower MIC ranges (0.25–1 and 0.03–0.5 mg/L, respectively). The tigecycline MIC range (0.25–1 mg/L) was slightly higher than that of doxycycline. All strains were resistant to ampicillin, meropenem, daptomycin, clindamycin and linezolid.
Conclusions
F. tularensis strains isolated in France remain susceptible to antibiotic classes recommended for tularaemia treatment. Because fluoroquinolones display the lowest MIC90, have bactericidal activity and have lower therapeutic failure rates compared with doxycycline, they may be advocated as first-line treatment of mild cases of tularaemia, predominant in Europe. MIC data also indicate that azithromycin or telithromycin may be possible therapeutic options against biovar I strains from Western Europe in case of contraindication to first-line antibiotics.



Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model

Thu, 14 Dec 2017 00:00:00 GMT

Abstract
Background
Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen.
Methods
A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25–64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h.
Results
Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8 ± 0.5 h; Cmax 2630.1 ± 245.7 mg/L; AUC0-24 33 932.5 ± 1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to > 1024 mg/L, P =0.0039; resistant subpopulation MIC50 128 to > 1024 mg/L, MIC90 >1024 mg/L, P =0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed.
Conclusions
Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.



Emergence and genomic analysis of MDR Laribacter hongkongensis strain HLGZ1 from Guangzhou, China

Wed, 13 Dec 2017 00:00:00 GMT

Abstract
Background
Laribacter hongkongensis is a facultative anaerobic, non-fermentative, Gram-negative bacillus associated with community-acquired gastroenteritis and traveller’s diarrhoea. No clinical MDR L. hongkongensis isolate has been reported yet.
Methods
We performed WGS (PacBio and Illumina) on a clinical L. hongkongensis strain HLGZ1 with an MDR phenotype.
Results
HLGZ1 was resistant to eight classes of commonly used antibiotics. Its complete genome was a single circular chromosome of 3 424 272 bp with a G + C content of 62.29%. In comparison with the reference strain HLHK9, HLGZ1 had a higher abundance of genes associated with DNA metabolism and recombination. Several inserts including two acquired resistance gene clusters (RC1 and RC2) were also identified. RC1 carried two resistance gene cassette arrays, aac(6′)-Ib-cr-aadA2-Δqac-Δsul1-floR-tetR-tetG and arr-3-dfrA32-ereA2-Δqac-sul1, which shared significant nucleotide sequence identities with the MDR region of Salmonella Genomic Island 1 from Salmonella enterica serovar Typhimurium DT104. There was also an integron-like structure, intl1-arr3-dfrA27-Δqac-sul1-aph(3′)-Ic, and a tetR-tetA operon located on RC2. MLST analysis identified HLGZ1 as ST167, a novel ST clustered with two strains previously isolated from frogs.
Conclusions
This study provides insight into the genomic characteristics of MDR L. hongkongensis and highlights the possibilities of horizontal resistance gene transfer in this bacterium with other pathogens.



Reporting antimicrobial susceptibilities and resistance phenotypes in Acinetobacter spp: a nationwide proficiency study

Wed, 13 Dec 2017 00:00:00 GMT

Abstract
Objectives
To evaluate the proficiency of Spanish microbiology laboratories with respect to the antimicrobial susceptibility testing (AST) of Acinetobacter spp.
Methods
Eight Acinetobacter spp. with different resistance mechanisms were sent to 48 Spanish centres which were asked to report: (i) the AST system used; (ii) MICs; (iii) breakpoints used (CLSI versus EUCAST); (iv) clinical category; and (v) resistance mechanisms inferred. Minor, major and very major errors (mE, ME and VME, respectively) were determined.
Results
The greatest percentages of discrepancies were: (i) by AST method: 18.5% Etest, 14.3% Vitek 2 and Sensititre; (ii) by breakpoints: 20.5% (CLSI) and 10.8% (EUCAST); and (iii) by antimicrobial agent: ampicillin/sulbactam (56.2% CLSI), minocycline (40.7% CLSI), tobramycin (38.7% CLSI, 16.8% EUCAST), imipenem (27.8% CLSI, 30.0% EUCAST) and meropenem (25.4% CLSI, 20.8% EUCAST). Categorical error rates: (i) by AST method ranged from 30.0% (Phoenix) to 100% (Sensititre and disc diffusion) for mE, 0.0% (Etest, Sensititre, disc diffusion) to 40% (Phoenix) for ME, and 0.0% (Sensititre and disc diffusion) to 30% (Phoenix) for VME; (ii) by breakpoints: mE (80.1% CLSI, 58.4% EUCAST), ME (3.5% CLSI, 12.4% EUCAST) and VME (16.4% CLSI, 29.2% EUCAST); and (iii) by antimicrobial agent: mE (100% levofloxacin/CLSI, 100% levofloxacin and meropenem/EUCAST), ME (35.3% colistin/CLSI, 25.0% colistin/EUCAST) and VME (64.7% colistin/CLSI, 86.7% gentamicin/EUCAST).
Conclusions
Clinical microbiology laboratories must improve their ability to determine antimicrobial susceptibilities of Acinetobacter spp. isolates. Higher discrepancies using CLSI when compared with EUCAST are mainly due to mE and to a much lesser extent to ME or VME.



Telavancin for refractory MRSA bacteraemia in intermittent haemodialysis recipients

Wed, 13 Dec 2017 00:00:00 GMT

Abstract
Background
Patients with end-stage renal disease (ESRD) requiring intermittent haemodialysis (IHD) are at high risk of MRSA bacteraemia (MRSA-B) and often fail first-line therapy. The safety, effectiveness and optimal dosing of telavancin for MRSA-B in this patient population are unclear.
Objectives
We aimed to describe clinical outcomes of telavancin in the treatment of refractory MRSA-B in patients with ESRD requiring IHD.
Patients and methods
This was a retrospective study of hospitalized patients at two tertiary care academic medical centres with recurrent or persistent (≥3 days) MRSA-B treated with telavancin monotherapy. Outcomes included duration of MRSA-B (pre-telavancin versus post-telavancin) and microbiological failure (duration of MRSA-B ≥3 days after initiation of telavancin).
Results
Telavancin dosed 10 mg/kg three times weekly post-IHD or 10 mg/kg every 48 h resulted in microbiological cure in 7/8 (87.5%) refractory MRSA-B cases. Telavancin monotherapy was associated with a significant reduction in median duration of bacteraemia [16 days pre-telavancin (IQR 8–19 days) versus 1 day post-telavancin (IQR 0–2 days); P =0.018]. Telavancin was well tolerated by all patients and no adverse events were reported.
Conclusions
Telavancin was very safe and highly effective in the treatment of refractory MRSA-B in a cohort of patients with ESRD requiring IHD. These data support the utility of telavancin in the armamentarium against refractory MRSA-B, particularly in the high-risk IHD-dependent population.






In vitro activity of ceftolozane/tazobactam versus antimicrobial non-susceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008–16

Tue, 12 Dec 2017 00:00:00 GMT

Abstract
Objectives
Ceftolozane/tazobactam is a novel β-lactam β-lactamase inhibitor combination with a broad spectrum of activity that includes Pseudomonas aeruginosa. The purpose of this study was to evaluate the in vitro activity of ceftolozane/tazobactam and relevant comparators versus a large collection of antimicrobial non-susceptible P. aeruginosa clinical isolates recovered from patients across Canada (CANWARD, 2008–16).
Methods
Susceptibility testing was performed on P. aeruginosa clinical isolates obtained from sentinel hospitals across Canada between January 2008 and December 2016 using broth microdilution, as described by the CLSI. MDR P. aeruginosa were defined as isolates that tested non-susceptible to at least one antimicrobial from ≥3 classes. XDR P. aeruginosa were defined as isolates that tested non-susceptible to at least one antimicrobial from ≥5 classes.
Results
In total, 3229 P. aeruginosa isolates were obtained as a part of CANWARD. Ceftolozane/tazobactam was the most active antimicrobial evaluated, with 98.3% of isolates testing susceptible. The percentage of antimicrobial non-susceptible isolates that remained susceptible to ceftolozane/tazobactam ranged from 85.3% (amikacin non-susceptible subset) to 95.0% (ciprofloxacin non-susceptible subset). Four-hundred and sixty-two P. aeruginosa isolates were MDR (14.3% of all isolates tested) and 84 were XDR (2.6% of all isolates tested). Ceftolozane/tazobactam demonstrated excellent in vitro activity versus the MDR and XDR isolates, with 90.5% and 78.6% remaining susceptible, respectively.
Conclusions
Ceftolozane/tazobactam demonstrated excellent in vitro activity against antimicrobial non-susceptible P. aeruginosa clinical isolates, including MDR and XDR subsets. It may prove useful in the treatment of infections caused by these organisms.



Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria

Tue, 12 Dec 2017 00:00:00 GMT

Abstract
Objectives
Although high-dose rifampicin holds promise for improving tuberculosis disease control by eradication of persistent bacteria, the optimal dose of rifampicin that kills persistent bacteria and shortens the treatment duration is unknown.
Methods
The Cornell mouse model was used to test the efficacy of rifampicin at elevated doses combined with isoniazid and pyrazinamide to kill actively growing and persistent bacilli and to measure relapse rate. Persistent bacteria were evaluated using Mycobacterium tuberculosis culture supernatant containing resuscitation-promoting factors. Pharmacokinetic parameters and dose-dependent activity for cultivable and persistent bacilli were determined.
Results
Increasing doses of rifampicin in combination with isoniazid and pyrazinamide resulted in dose-dependent faster bacterial clearance. Evaluated both on solid media and in culture filtrate containing resuscitation-promoting factors, a regimen containing a standard dose of rifampicin at 10 mg/kg over 14 weeks failed to achieve organ sterility. In contrast, higher doses of rifampicin achieved organ sterility in a much shorter time of 8–11 weeks. Disease relapse, which occurred in 86% of mice treated with the standard regimen for 14 weeks, was completely prevented by rifampicin doses of ≥ 30 mg/kg.
Conclusions
In the treatment of murine tuberculosis, a rifampicin dose of 30 mg/kg was sufficient to eradicate persistent M. tuberculosis, allowing shorter treatment duration without disease relapse.



Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis

Mon, 11 Dec 2017 00:00:00 GMT

Abstract
Background
Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance.
Methods
This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information.
Results
Data suggest that atovaquone/proguanil treatment efficacy is 89%–98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%–26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent.
Conclusions
Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.



Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients

Mon, 11 Dec 2017 00:00:00 GMT

Abstract
Objectives
To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated.
Methods
Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n =15) or etravirine 400 mg once daily (ETR cohort; n =15). Etravirine or darunavir/cobicistat were added on days 1–14 and 1–7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0–24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored.
Results
Etravirine co-administration decreased cobicistat AUC0–24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0–24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants.
Conclusions
Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice.



Enterobacteriaceae producing OXA-48-like carbapenemases in Poland, 2013–January 2017

Sat, 09 Dec 2017 00:00:00 GMT

Abstract
Objectives
To analyse OXA-48 (OXA-48/181)-type carbapenemase-producing Enterobacteriaceae reported in Poland from 2013 until January 2017.
Methods
Bacterial isolates were typed by PFGE and MLST. Genes coding for OXA-48/181 types and other β-lactamases were amplified and sequenced. Mobile elements with blaOXA-48/181-like genes were PCR mapped. blaOXA-48/181-carrying plasmids were characterized by nuclease S1-hybridization profiling, transfer assays and PCR-based replicon typing, while the chromosomal location of the genes was confirmed by the I-CeuI analysis.
Results
Fifty-four isolates from 52 patients in 20 hospitals (14 cities) were included, in 14 cases having probable foreign origins indicated. The organisms were genetically diverse and represented numerous pandemic clones, including Klebsiella pneumoniae ST395 (n =23), ST11, ST15 and ST101, Escherichia coli ST38, ST410 and ST648, and Enterobacter cloacae complex ST78. These produced OXA-48 (n =49), OXA-181 (n =4) or OXA-232 (n =1). One of five K. pneumoniae ST395 pulsotypes caused a multicentre outbreak with 18 cases, which significantly contributed to the total number of patients. Depending on the variant, the blaOXA-48/181-like genes were parts of the Tn1999-, Tn2013- or Tn2016-like transposons, with blaOXA-48 found in an ISEcp1-associated module (Tn2016-like) for the first time. Three genotypes, including E. coli ST38, had chromosomal blaOXA-48 genes, while others carried transmissible IncL (∼60 kb; blaOXA-48; n =30), IncM (∼80–95 kb; blaOXA-48; n =4), IncX3 (∼50 kb; blaOXA-181; n =4) or non-typeable (∼90–160 kb; blaOXA-48 or blaOXA-232) plasmids.
Conclusions
Even though OXA-48/181 producers seem to occur infrequently in Poland, their epidemiology has been marked by various phenomena, namely multiple imports, several limited transmissions plus one larger clonal outbreak, and possible plasmid transfers.



Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015–16

Fri, 08 Dec 2017 00:00:00 GMT

Abstract
Background
Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane β-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015.
Methods
Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance. Identification was by MALDI-TOF mass spectroscopy, and susceptibility testing by BSAC agar dilution. Carbapenemase genes were sought by PCR; other resistance mechanisms were inferred using genetic data and interpretive reading.
Results
Susceptibility rates to ceftazidime/avibactam exceeded 95% for: (i) Enterobacteriaceae with KPC, GES or other Class A carbapenemases; (ii) Enterobacteriaceae with OXA-48-like enzymes; and (iii) for ESBL or AmpC producers, even when these had impermeability-mediated ertapenem resistance. Almost all isolates with metallo-carbapenemases were resistant. Potentiation of ceftazidime by avibactam was seen for 87% of ceftazidime-resistant Enterobacteriaceae with ‘unassigned’ ceftazidime resistance mechanisms, including two widely referred groups of Klebsiella pneumoniae where no synergy was seen between cephalosporins and established β-lactamase inhibitors. Potentiation here may be a diazabicyclooctane/cephalosporin enhancer effect. Activity was seen against Pseudomonas aeruginosa with derepressed AmpC, but not for those with efflux-mediated resistance.
Conclusions
Of the available β-lactams or inhibitor combinations, ceftazidime/avibactam has the widest activity spectrum against problem Enterobacteriaceae, covering all major types except metallo-carbapenemase producers; against P. aeruginosa it has a slightly narrower spectrum than ceftolozane/tazobactam, which also covers efflux-type resistance.



Illumina short-read and MinION long-read WGS to characterize the molecular epidemiology of an NDM-1 Serratia marcescens outbreak in Romania

Fri, 08 Dec 2017 00:00:00 GMT

Abstract
Background and Objectives
Serratia marcescens is an emerging nosocomial pathogen, and the carbapenemase blaNDM has been reported in several surveys in Romania. We aimed to investigate the molecular epidemiology of S. marcescens in two Romanian hospitals over 2010–15, including a neonatal NDM-1 S. marcescens outbreak.
Methods
Isolates were sequenced using Illumina technology together with carbapenem-non-susceptible NDM-1-positive and NDM-1-negative Klebsiella pneumoniae and Enterobacter cloacae to provide genomic context. A subset was sequenced with MinION to fully resolve NDM-1 plasmid structures. Resistance genes, plasmid replicons and ISs were identified in silico for all isolates; an annotated phylogeny was reconstructed for S. marcescens. Fully resolved study NDM-1 plasmid sequences were compared with the most closely related publicly available NDM-1 plasmid reference.
Results
44/45 isolates were successfully sequenced (S. marcescens, n =33; K. pneumoniae, n =7; E. cloacae, n =4); 10 with MinION. The S. marcescens phylogeny demonstrated several discrete clusters of NDM-1-positive and -negative isolates. All NDM-1-positive isolates across species harboured a pKOX_NDM1-like plasmid; more detailed comparisons of the plasmid structures demonstrated a number of differences, but highlighted the largely conserved plasmid backbones across species and hospital sites.
Conclusions
The molecular epidemiology is most consistent with the importation of a pKOX_NDM1-like plasmid into Romania and its dissemination amongst K. pneumoniae/E. cloacae and subsequently S. marcescens across hospitals. The data suggested multiple acquisitions of this plasmid by S. marcescens in the two hospitals studied; transmission events within centres, including a large outbreak on the Targu Mures neonatal unit; and sharing of the pKOX_NDM1-like plasmid between species within outbreaks.



Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass

Fri, 08 Dec 2017 00:00:00 GMT

Abstract
Objectives
Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations ≥40 mg/L.
Methods
Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied. Blood samples were collected after the preoperative cefazolin dose, prior to intraoperative cefazolin doses and at wound closure. Intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥ 40 mg/L (≥8 mg/L unbound, assuming 80% protein binding).
Results
Fifty-five subjects (64.9 ± 10.4 years, 89.7 ± 16.5 kg, CLCR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were <40 mg/L in 40% (12 of 30) of intraoperative trough samples and 9.8% (5 of 51) of closure samples. Below-target concentrations at some time during surgery were documented in 30.9% (17 of 55) of subjects. In multivariate analyses, lower body weight (P =0.027) and shorter duration of surgery (P =0.045) were significant predictors of closure concentrations <40 mg/L. A total cefazolin exposure (preoperative and intraoperative doses) of ≥ 7.6 mg/kgdosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations.
Conclusions
The standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. The findings supported a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery.



Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline

Fri, 08 Dec 2017 00:00:00 GMT

Abstract
Objectives
Ceftaroline is often used in durations greater than that studied in clinical trials. Several retrospective, non-comparative studies have suggested a higher than anticipated incidence of neutropenia in patients receiving prolonged treatment with ceftaroline. We sought to determine if ceftaroline was associated with neutropenia by comparing the incidence with ceftaroline treatment with treatment with several comparative antibiotics.
Methods
Patients receiving 14 or more consecutive days of treatment with ceftaroline were compared with patients receiving cefazolin, daptomycin, linezolid, nafcillin or vancomycin (control group). The primary outcome was the development of neutropenia. Multivariate logistic regression and propensity score weighting using inverse probability weights with regression adjustment were used to control for confounding variables.
Results
A total of 753 patients were included (53 that received ceftaroline and 700 that received a comparative antibiotic). Ceftaroline was associated with a greater incidence of neutropenia as compared with the control group (17.0% versus 3.9%, P < 0.001). Several covariates were also associated with neutropenia and included younger age, lower baseline absolute neutrophil count, liver disease and bone and joint infections. After controlling for these confounders, receipt of ceftaroline continued to be associated with the development of neutropenia (adjusted OR 3.97, P =0.003). Analysis after propensity score weighting confirmed this finding.
Conclusions
The results of this study suggest that prolonged treatment with ceftaroline is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. Careful monitoring of absolute neutrophil count is recommended in patients receiving >14 days of ceftaroline.



Effectiveness of live attenuated influenza vaccine in preventing amoxicillin prescribing in preschool children: a self-controlled case series study

Fri, 08 Dec 2017 00:00:00 GMT

Abstract
Objectives
To determine the effectiveness of live attenuated influenza vaccine (LAIV) in reducing amoxicillin prescribing in preschool children in primary care.
Patients and methods
We used The Health Improvement Network (THIN), a large primary care database from the United Kingdom. We included children aged 2 to 4 years old at the start of either the 2013/14 or the 2014/15 winter season, with at least one amoxicillin prescription between September and May, irrespective of LAIV vaccination status. We used the self-controlled case series method to estimate influenza vaccine effectiveness (VE).
Results
The total study sample included 33 137 children from 378 general practices during the two winter seasons. Of these children, 43.4% with at least one amoxicillin prescription had been vaccinated. The rate of amoxicillin prescribing was significantly reduced during periods of influenza vaccine immunity. The associated VE for amoxicillin prescribing was 12.8% (95% CI 6.9%, 18.3%) in 2013/14 and 14.5% (9.6%, 19.2%) in 2014/15. Given a VE of 14.5%, we estimated that amoxicillin prescribing could have been reduced by 5.6% if LAIV uptake in children aged 2–4 years increased to 50% in the 2014/15 winter season.
Conclusions
Influenza vaccination of young children may contribute to a reduction in the prescribing of amoxicillin, one of the most commonly prescribed antibiotics in primary care. Further studies are required to confirm the size of the effect.



Pharmacist participation in antimicrobial stewardship in Australian and French hospitals: a cross-sectional nationwide survey

Fri, 08 Dec 2017 00:00:00 GMT

Abstract
Background
Hospital pharmacists are an integral part of antimicrobial stewardship (AMS) programmes globally. Currently, little is known as to how hospital pharmacists see their role and involvement within the AMS framework.
Objectives
To assess the current level of involvement of Australian and French hospital pharmacists in AMS programmes and identify barriers limiting their involvement in AMS.
Methods
Hospital pharmacists throughout Australia and France were invited to participate in a nationwide online survey throughout March–May 2016. The survey was promoted through the national hospital pharmacists’ association in Australia, while a stratified sampling method was used in France to invite pharmacists working in a variety of hospital settings.
Results
Invitations to participate in this survey were sent to 334 Australian pharmacists and 482 French pharmacists. Responses from 133 Australian and 126 French pharmacists were included for analysis. A total of 78.4% (203/259) of pharmacists reported the presence of an AMS programme. Pharmacists were most likely to be involved in AMS through assessing total antibiotic consumption and participating in AMS committee meetings. Barriers to participating in AMS included a lack of time and substantial non-clinical activities limiting involvement in AMS. Differences in responses were found between the two countries.
Conclusions
While the majority of pharmacists reported the presence of an AMS programme, multiple barriers to participation were identified by pharmacists in both countries. Further research should consider how to overcome the identified barriers to optimize the involvement of pharmacists in AMS.






MIC-based dose adjustment: facts and fables

Tue, 05 Dec 2017 00:00:00 GMT

Abstract
Over recent decades, several publications have described optimization procedures for antibiotic therapy in the individual patient based on antimicrobial MIC values. Most methods include therapeutic drug monitoring and use a single MIC determination plus the relevant pharmacokinetics/pharmacodynamics to adjust the dose to optimize antimicrobial drug exposure and antibacterial effects. However, the use of an MIC obtained by a single MIC determination is inappropriate. First, routine clinical laboratories cannot determine MICs with sufficient accuracy to guide dosage owing to the inherent assay variation in the MIC test. Second, the variation in any MIC determination, whatever method is used, must be accounted for. If dose adjustments are made based on therapeutic drug monitoring and include MIC determinations, MIC variation must be considered to prevent potential underdosing of patients. We present the problems and some approaches that could be used in clinical practice.



Italian nationwide survey on Pseudomonas aeruginosa from invasive infections: activity of ceftolozane/tazobactam and comparators, and molecular epidemiology of carbapenemase producers

Tue, 05 Dec 2017 00:00:00 GMT

Abstract
Objectives
Pseudomonas aeruginosa is a major cause of severe healthcare-associated infections and often shows MDR phenotypes. Ceftolozane/tazobactam is a new cephalosporin/β-lactamase inhibitor combination with potent activity against P. aeruginosa. This survey was carried out to evaluate the susceptibility of P. aeruginosa, circulating in Italy, to ceftolozane/tazobactam and comparators and to investigate the molecular epidemiology of carbapenemase-producing strains.
Methods
Consecutive non-replicate P. aeruginosa clinical isolates (935) from bloodstream infections and lower respiratory tract infections were collected from 20 centres distributed across Italy from September 2013 to November 2014. Antimicrobial susceptibility testing was performed by broth microdilution and results were interpreted according to the EUCAST breakpoints. Isolates resistant to ceftolozane/tazobactam were investigated for carbapenemase genes by PCR, and for carbapenemase activity by spectrophotometric assay. WGS using an Illumina platform was performed on carbapenemase-producing isolates.
Results
Ceftolozane/tazobactam was the most active molecule, retaining activity against 90.9% of P. aeruginosa isolates, followed by amikacin (88.0% susceptibility) and colistin (84.7% susceptibility). Overall, 48 isolates (5.1%) were positive for carbapenemase genes, including blaVIM (n =32), blaIMP (n =12) and blaGES-5 (n =4), while the remaining ceftolozane/tazobactam-resistant isolates tested negative for carbapenemase production. Carbapenemase producers belonged to 10 different STs, with ST175 (n =12) and ST621 (n =11) being the most common lineages. Genome analysis revealed different trajectories of spread for the different carbapenemase genes.
Conclusions
Ceftolozane/tazobactam exhibited potent in vitro activity against P. aeruginosa causing invasive infections in Italy. Carbapenemase production was the most common mechanism of resistance to ceftolozane/tazobactam.



Effect of Staphylococcus aureus Tet38 native efflux pump on in vivo response to tetracycline in a murine subcutaneous abscess model

Tue, 05 Dec 2017 00:00:00 GMT

Abstract
Objectives
Staphylococcus aureus native efflux pump Tet38 confers resistance to tetracycline when overexpressed. tet38 expression is selectively upregulated in infection sites. This study evaluated the effect of Tet38 on tetracycline response in a murine subcutaneous abscess model.
Methods
S. aureus MW2 and its tet38 mutant were injected subcutaneously on the opposite flanks of each mouse. The infected mice were treated with tetracycline (10 mg/kg) or PBS (control) intraperitoneally every 12 h. The efficacy of tetracycline against S. aureus was measured by the relative change in viable bacteria in the abscesses 24 h after infection compared with the initial inoculum. Plasmid-based tet38-complemented strains were created and used to infect the mice followed by tetracycline or PBS treatment.
Results
The increased bacterial loads of S. aureus MW2 and its tet38 mutant in the abscess after 24 h were similar. Tetracycline produced significant decreases of both MW2 and the tet38 mutant compared with control. Although the tetracycline MICs for MW2 and the tet38 mutant did not differ in vitro, the antibacterial effect of tetracycline was significantly 2-fold greater in the tet38 mutant compared with the MW2 parental strain in vivo with a decrease of 0.67 ± 0.21 and 0.35 ± 0.19 log10 cfu/abscess, respectively (P <0.05). The increased tetracycline activity in the tet38 mutant was complemented by plasmid-encoded tet38.
Conclusions
This study demonstrated that selective increased expression of tet38 in an abscess can affect tetracycline efficacy against S. aureus in vivo, highlighting an effect of native efflux pumps on response to therapy not reflected by testing in vitro.



Bicarbonate induces high-level resistance to the human antimicrobial peptide LL-37 in Staphylococcus aureus small colony variants

Mon, 04 Dec 2017 00:00:00 GMT

Abstract
Objectives
Staphylococcus aureus small colony variants (SCVs) cause persistent infections and are resistant to cationic antibiotics. Antimicrobial peptides (AMPs) have been suggested as promising alternatives for treating antibiotic-resistant bacteria. We investigated the capacity of the human cationic AMP LL-37 to kill SCVs in the presence of physiological concentrations of bicarbonate, which are reported to alter bacterial membrane permeability and change resistance of bacteria to AMPs.
Methods
MBCs of LL-37 for S. aureus SCVs with mutations in different genes in the presence and absence of bicarbonate were determined.
Results
In the absence of bicarbonate, SCVs of S. aureus strains LS-1 and 8325-4 had the same level of resistance to LL-37 as the parental strain (8 mg/L). In the presence of bicarbonate, hemB, menD and aroD SCVs of LS-1 had high-level resistance to LL-37 (≥128 mg/L) compared with the parental strain (16 mg/L). However, only the aroD SCV of strain 8324-5 showed high-level resistance. 8325-4 harbours mutations in two genes, tcaR and rsbU, which are involved in antimicrobial sensing and the stress response, respectively. When rsbU was repaired in 8325-4 it displayed high-level resistance to LL-37 in the presence of bicarbonate. This phenotype was lost when tcaR was also repaired, demonstrating that RsbU and TcaR are involved in LL-37 resistance in the presence of bicarbonate
Conclusions
S. aureus SCVs would be resistant to high concentrations of LL-37 in niches where there are physiological concentrations of bicarbonate and therefore this AMP may not be effective in combating SCVs.



Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations

Sat, 02 Dec 2017 00:00:00 GMT

Abstract
Objectives
This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin).
Methods
A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016.
Results
Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97–2.13) mg/L versus 0.81 (0.48–1.15) mg/L, P <0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose–response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L.
Conclusions
The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets.



Phenotypic antimicrobial susceptibility testing of Chlamydia trachomatis isolates from patients with persistent or successfully treated infections

Thu, 30 Nov 2017 00:00:00 GMT

Abstract
Objectives
Antimicrobial susceptibility data for Chlamydia trachomatis are lacking. Methodologies for susceptibility testing in C. trachomatis are not well-defined, standardized or performed routinely owing to its intracellular growth requirements. We sought to develop an assay for the in vitro susceptibility testing of C. trachomatis isolates from two patient cohorts with different clinical outcomes.
Methods
Twenty-four clinical isolates (11 from persistently infected and 13 from successfully treated patients) were overlaid with media containing two-fold serial dilutions of azithromycin or doxycycline. After incubation, aliquots were removed from the stock inoculum (SI) and each antimicrobial concentration for total RNA extraction, complementary DNA generation and real-time PCR. The MIC was defined as the lowest antimicrobial concentration where a 95% reduction in transcription was evident in comparison with the SI for each isolate.
Results
MICs of azithromycin were comparable for isolates from the two patient groups (82% ≤ 0.25 mg/L for persistently infected and 100% ≤ 0.25 mg/L for successfully treated patients). Doxycycline MICs were at least two-fold lower for isolates from the successfully treated patients (53.9% ≤ 0.064 mg/L) than for the persistently infected patients (100% ≥ 0.125 mg/L) (P = 0.006, Fisher’s exact test). Overall, 96% of isolates gave reproducible MICs when re-tested.
Conclusions
A reproducible assay was developed for antimicrobial susceptibility testing of C. trachomatis. MICs of azithromycin were generally comparable for the two different patient groups. MICs of doxycycline were significantly higher in the persistently infected patients. However, interpretation of elevated MICs in C. trachomatis is extremely challenging in the absence of breakpoints, or wild-type and treatment failure MIC distribution data.






Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial

Wed, 29 Nov 2017 00:00:00 GMT

Abstract
Background
Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA.
Methods
A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count <0.5 × 109/L for >10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed.
Results
One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n =78, voriconazole n =64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P =0.031; day 42, P <0.001; EOT, P <0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P =0.002) and numerically higher at day 7 and EOT (P >0.05 for both).
Conclusions
Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes.



Comparative efficacy of drugs for treating giardiasis: a systematic update of the literature and network meta-analysis of randomized clinical trials

Mon, 27 Nov 2017 00:00:00 GMT

Abstract
Background
Giardiasis is the commonest intestinal protozoal infection worldwide. The current first-choice therapy is metronidazole. Recently, other drugs with potentially higher efficacy or with fewer and milder side effects have increased in popularity, but evidence is limited by a scarcity of randomized controlled trials (RCTs) comparing the many treatment options available. Network meta-analysis (NMA) is a useful tool to compare multiple treatments when there is limited or no direct evidence available.
Objectives
To compare the efficacy and side effects of all available drugs for the treatment of giardiasis.
Methods
We selected all RCTs included in systematic reviews and expert reviews of all treatments for giardiasis published until 2014, extended the systematic literature search until 2016, and identified new studies by scanning reference lists for relevant studies. We then conducted an NMA of all available treatments for giardiasis by comparing parasitological cure (efficacy) and side effects.
Results
We identified 60 RCTs from 58 reports (46 from published systematic reviews, 8 from reference lists and 4 from the updated systematic search). Data from 6714 patients, 18 treatments and 42 treatment comparisons were available. Tinidazole was associated with higher parasitological cure than metronidazole [relative risk (RR) 1.23, 95% CI 1.12–1.35] and albendazole (RR 1.35, 95% CI 1.21–1.50). Taking into consideration clinical efficacy, side effects and amount of the evidence, tinidazole was found to be the most effective drug.
Conclusions
We provide additional evidence that single-dose tinidazole is the best available treatment for giardiasis in symptomatic and asymptomatic children and adults.



General practitioner and nurse prescriber experiences of prescribing antibiotics for respiratory tract infections in UK primary care out-of-hours services (the UNITE study)

Mon, 27 Nov 2017 00:00:00 GMT

Abstract
Background
Interventions are needed to reduce unnecessary antibiotic prescribing for respiratory tract infections (RTIs). Although community antibiotic prescribing appears to be decreasing in the UK, figures for out-of-hours (OOH) prescribing have substantially increased. Understanding the factors influencing prescribing in OOH and any perceived differences between general practitioner (GP) and nurse prescriber (NP) prescribing habits may enable the development of tailored interventions promoting optimal prescribing in this setting.
Objectives
To explore UK GP and NP views on and experiences of prescribing antibiotics for RTIs in primary care OOH services.
Methods
Thirty semi-structured interviews were conducted with GPs and NPs working in primary care OOH services. Inductive thematic analysis was used to analyse data.
Results
The research shows that factors particular to OOH influence antibiotic prescribing, including a lack of patient follow-up, access to patient GP records, consultation time, working contracts and implementation of feedback, audit and supervision. NPs reported perceptions of greater accountability for their prescribing compared with GPs and reported they had longer consultations during which they were able to discuss decisions with patients. Participants agreed that more complex cases should be seen by GPs and highlighted the importance of consistency of decision making, illness explanations to patients as well as a perception that differences in clinical training influence communication with patients and antibiotic prescribing decisions.
Conclusions
Environmental and social factors in OOH services and a mixed healthcare workforce provide unique influences on antibiotic prescribing for RTIs, which would need to be considered in tailoring interventions that promote prudent antibiotic prescribing in OOH services.



Four-days-a-week antiretroviral maintenance therapy in virologically controlled HIV-1-infected adults: the ANRS 162-4D trial

Sat, 25 Nov 2017 00:00:00 GMT

Abstract
Background
Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients’ quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL).
Methods
Eligible patients were adults with VL < 50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL < 50 copies/mL up to week 48. The study was designed to show an observed success rate of > 90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29).
Results
One hundred patients (82 men), median age 47 years (IQR 40–53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9–9.3) years and had a median CD4 cell count of 665 (IQR 543–829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%–98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred.
Conclusions
Antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving.



Antibiotic therapy in neonates and impact on gut microbiota and antibiotic resistance development: a systematic review

Wed, 22 Nov 2017 00:00:00 GMT

Abstract
Objectives
To systematically review the impact of antibiotic therapy in the neonatal period on changes in the gut microbiota and/or antibiotic resistance development.
Methods
Data sources were PubMed, Embase, Medline and the Cochrane Database, supplemented by manual searches of reference lists. Randomized controlled trials (RCTs) and observational studies were included if they provided data on different categories of antibiotic treatment (yes versus no, long versus short duration and/or broad- versus narrow-spectrum regimens) and subsequent changes in the gut microbiota and/or antibiotic resistance development. We evaluated risk of bias using the Cochrane Handbook, adapted to include observational studies. When appropriate, we used the vote-counting method to perform semi-quantitative meta-analyses. We applied the Grades of Recommendation, Assessment, Development and Evaluation approach to rate the quality of evidence (QoE). Study protocol registration: PROSPERO CRD42015026743.
Results
We included 48 studies, comprising 3 RCTs and 45 observational studies. Prolonged antibiotic treatment was associated with reduced gut microbial diversity in all three studies investigating this outcome (very low QoE). Antibiotic treatment was associated with reduced colonization rates of protective commensal anaerobic bacteria in four of five studies (very low QoE). However, all three categories of antibiotic treatment were associated with an increased risk of antibiotic resistance development, in particular MDR in Gram-negative bacteria, and we graded the QoE for these outcomes as moderate.
Conclusions
We are moderately confident that antibiotic treatment leads to antibiotic resistance development in neonates and it may also induce potentially disease-promoting gut microbiota alterations. Our findings emphasize the need to reduce unnecessary antibiotic treatment in neonates.



Doxycycline in the management of sexually transmitted infections

Wed, 22 Nov 2017 00:00:00 GMT

Abstract
Doxycycline is a second-generation tetracycline, available worldwide for half a century. It is an inexpensive broad-spectrum antimicrobial agent largely used in the management of several bacterial infections, particularly involving intracellular pathogens, as well as in the treatment of acne or for the prophylaxis of malaria. Physicochemical characteristics of doxycycline (liposolubility) allow a high diffusion in the tissues and organs. It has high bioavailability and a long elimination half-life allowing oral administration of one or two daily doses. Over the last decade, the prevalence of bacterial sexually transmitted infections (STIs) (syphilis, chlamydiosis, gonorrhoea and Mycoplasma genitalium infections) has increased in most countries, mainly in MSM, many of whom are infected with HIV. In light of increasing prevalence of resistance towards first-line regimens of some STI agents and recently updated recommendations for STI management, doxycycline appears to be an attractive option compared with other available antibiotics for the treatment of some STIs due to its efficacy, good tolerability and oral administration. More recently, indications for doxycycline in STI prophylaxis have been evaluated. Considering the renewed interest of doxycycline in STI management, this review aims to update the pharmacology of, efficacy of, safety of and resistance to doxycycline in this context of use.



Mechanisms leading to in vivo ceftolozane/tazobactam resistance development during the treatment of infections caused by MDR Pseudomonas aeruginosa

Tue, 14 Nov 2017 00:00:00 GMT

Abstract
Objectives
Characterization of the mechanisms driving ceftolozane/tazobactam resistance development in 5 of 47 (10.6%) patients treated for MDR Pseudomonas aeruginosa infections in a Spanish hospital.
Methods
Five pairs of ceftolozane/tazobactam-susceptible/resistant P. aeruginosa isolates were studied. MICs were determined by broth microdilution, clonal relatedness was assessed by MLST and resistance mechanisms were investigated by phenotypic and genotypic methods, including WGS. ampC variants were cloned to assess their impact on resistance.
Results
In all five cases, the same clone was detected for the susceptible/resistant pairs; the widespread ST175 high-risk clone in four of the cases and ST179 in the remaining case. Genomic analysis of the four initial ST175 isolates revealed the characteristic OprD mutation (Q142X) responsible for carbapenem resistance and the AmpR mutation (G154R) responsible for AmpC overexpression and β-lactam resistance. The final isolates had developed ceftolozane/tazobactam and ceftazidime/avibactam resistance, and each additionally showed a mutation in AmpC: E247K in one of the isolates, T96I in two isolates and a deletion of 19 amino acids (G229–E247) in the remaining isolate. The cloned AmpC variants showed greatly increased ceftolozane/tazobactam and ceftazidime/avibactam MICs compared with WT AmpC, but, in contrast, yielded lower MICs of imipenem, cefepime and particularly piperacillin/tazobactam. On the other hand, ceftolozane/tazobactam resistance development in ST179 was shown to be driven by the emergence of the extended-spectrum OXA β-lactamase OXA-14, through the selection of an N146S mutation from OXA-10.
Conclusions
Modification of intrinsic (AmpC) and horizontally acquired β-lactamases appears to be the main mechanism leading to ceftolozane/tazobactam resistance in MDR P. aeruginosa.