In this brief article, we focus on Oxford University Press's role as the publisher of the JAC and how it supports authors and readers. The article defines the role of the publisher, as opposed to the Editorial team, Editorial Office or Society owner. It reviews three key functions at the publisher, namely, editorial, production and marketing.
In the past 40 years, medical mycology has gone from a curiosity in the basements of medical schools to a mainstream branch of clinical microbiology and infectious diseases. Long gone are the days of carefully curated collections of organisms identified purely based on morphology and skill, the lack of therapeutic interventions beyond amphotericin B and the occasional strange case in the ward of a diabetic patient with mucormycosis. We highlight advances in medical mycology as reflected in the past 40 years of JAC.
Since the Journal of Antimicrobial Chemotherapy was first published in 1975, papers addressing therapeutic drug monitoring (TDM) have been a regular feature. Initially they focused on laboratory aspects of drug concentration measurement then they changed more to the application of TDM in a clinical setting. Over its history, the Journal has provided its readership with the latest technological and scientific advances in TDM and has helped to drive changes in TDM that have directly impacted on patient care. These have varied from improvement in the quality of antimicrobial measurements through better identification of dosage regimens and TDM targets that help predict outcome and adverse events. Despite these advances in our understanding of the science and practice of TDM, there remain many areas of uncertainty. As we move into the next 40 years, it is clear that the Journal will continue to provide the readership with the latest science and opinion in this important area.
First reported in 2003, mosaic tetracycline resistance genes are a subgroup of the genes encoding ribosomal protection proteins (RPPs). They are formed when two or more RPP-encoding genes recombine resulting in a functional chimera. To date, the majority of mosaic genes are derived from sections of three RPP genes, tet(O), tet(W) and tet(32), with others comprising tet(M) and tet(S). In this first review of mosaic genes, we report on their structure, diversity and prevalence, and suggest that these genes may be responsible for an under-reported contribution to tetracycline resistance in bacteria.
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been a focus of international attention since its identification in 2012. Epidemiologically it is characterized by sporadic community cases, which are amplified by hospital-based outbreaks. Healthcare facilities in 27 countries from most continents have experienced imported cases, with the most significant outbreak involving 186 cases in Korea. The mortality internationally is 36% and guidance for clinical management has yet to be developed. Most facilities and healthcare providers outside of the Middle East receiving patients have no or little experience in the clinical management of MERS. When a case does occur there is likely little time for a critical appraisal of the literature and putative pharmacological options. We identified published literature on the management of both MERS-CoV and the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) through searches of PubMed and WHO and the US CDC websites up to 30 April 2016. A total of 101 publications were retrieved for critical appraisal. Most published literature on therapeutics for MERS are in vitro experiments, animal studies and case reports. Current treatment options for MERS can be categorized as: immunotherapy with virus-specific antibodies in convalescent plasma; polyclonal and monoclonal antibodies produced in vitro or in genetically modified animals; and antiviral agents. The use of any therapeutics in MERS-CoV remains investigational. The therapeutic agents with potential benefits and warranting further investigation include convalescent plasma, interferon-β/ribavirin combination therapy and lopinavir. Corticosteroids, ribavirin monotherapy and mycophenolic acid likely have toxicities that exceed potential benefits.
Vancomycin-resistant Enterococcus faecium (VREfm) have been increasingly reported since the 1980s. Despite the high number of published studies about VRE epidemiology, the dynamics and evolvability of these microorganisms are still not fully understood. A multilevel population genetic analysis of VREfm outbreak strains since 1986, representing the first comprehensive characterization of plasmid content in E. faecium, was performed to provide a detailed view of potential transmissible units.
From a comprehensive MeSH search, we identified VREfm strains causing hospital outbreaks (1986–2012). In total, 53 VanA and 18 VanB isolates (27 countries, 5 continents) were analysed and 82 vancomycin-susceptible E. faecium (VSEfm) were included for comparison. Clonal relatedness was established by PFGE and MLST (goeBURST/Bayesian Analysis of Population Structure, BAPS). Characterization of van transposons (PCR mapping, RFLP, sequencing), plasmids (transfer, ClaI-RFLP, PCR typing of relaxases, replication-initiation proteins and toxin–antitoxin systems, hybridization, sequencing), bacteriocins and virulence determinants (PCR, hybridization, sequencing) was performed.
VREfm were mainly associated with major human lineages ST17, ST18 and ST78. VREfm and VSEfm harboured plasmids of different families [RCR, small theta plasmids, RepA_N (pRUM/pLG1) and Inc18] able to yield mosaic elements. Tn1546-vanA was mainly located on pRUM/Axe-Txe (USA) and Inc18-pIP186 (Europe) plasmids. The VanB2 type (Tn5382/Tn1549) was predominant among VanB strains (chromosome and plasmids).
Both strains and plasmids contributed to the spread and persistence of vancomycin resistance among E. faecium. Horizontal gene transfer events among genetic elements from different clonal lineages (same or different species) result in chimeras with different stability and host range, complicating the surveillance of epidemic plasmids.
Enterococcus faecium is a major nosocomial pathogen causing significant morbidity and mortality worldwide. Assessment of E. faecium using MLST to understand the spread of this organism is an important component of hospital infection control measures. Recent studies, however, suggest that MLST might be inadequate for E. faecium surveillance.
To use WGS to characterize recently identified vancomycin-resistant E. faecium (VREfm) isolates non-typeable by MLST that appear to be causing a multi-jurisdictional outbreak in Australia.
Illumina NextSeq and Pacific Biosciences SMRT sequencing platforms were used to determine the genome sequences of 66 non-typeable E. faecium (NTEfm) isolates. Phylogenetic and bioinformatics analyses were subsequently performed using a number of in silico tools.
Sixty-six E. faecium isolates were identified by WGS from multiple health jurisdictions in Australia that could not be typed by MLST due to a missing pstS allele. SMRT sequencing and complete genome assembly revealed a large chromosomal rearrangement in representative strain DMG1500801, which likely facilitated the deletion of the pstS region. Phylogenomic analysis of this population suggests that deletion of pstS within E. faecium has arisen independently on at least three occasions. Importantly, the majority of these isolates displayed a vancomycin-resistant genotype.
We have identified NTEfm isolates that appear to be causing a multi-jurisdictional outbreak in Australia. Identification of these isolates has important implications for MLST-based typing activities designed to monitor the spread of VREfm and provides further evidence supporting the use of WGS for hospital surveillance of E. faecium.
In Western Australia (WA), clonal complex 5, ST835, community-associated (CA) MRSA is isolated almost exclusively from aged care facilities. In WA four different staphylococcal cassette chromosome (SCC) mec (SCCmec) elements have been identified in this ST, indicating high genetic activity in the SCCmec region.
To investigate the SCC region of ST835 CA-MRSA WA MRSA-40 and determine the distribution of an SCCsorbitol element found within the region.
The SCC region contained a composite island, SCCmecWA MRSA-40-CI, that was composed of three elements, SCCpls, SCCsorbitol and SCCmecVT (5C2&5). This is the first time that a sorbitol operon has been reported in an SCC element.
Generation of SCCmecWA MRSA-40-CI has involved multiple genetic events and recombination with CoNS has occurred during evolution of the SCC elements. While Staphylococcus aureus is renowned for its ability to utilize mobile genetic elements to disseminate antimicrobial resistance, the SCC region of WA MRSA-40 shows that this clone has also utilized SCC elements to acquire extra virulence and possibly adapt to a niche environment.
During a 27 month period, we detected four incidents of penicillin-resistant (PR) Streptococcus dysgalactiae subsp. equisimilis (SDSE) isolated from blood cultures of three patients.
The 4 PR-SDSE were compared phenotypically and molecularly (using WGS) with 36 penicillin-susceptible SDSE from blood cultures obtained in the same catchment area and time period.
Phylogenetic analysis showed that the four PR-SDSE belonged to a single clone and a possible epidemiological link between the three patients was identified to be a dermatology department. MICs of penicillin were determined to be 0.5–2 mg/L using Etest and 0.5 mg/L when tested by a broth microdilution method. The four PR-SDSE were unrelated to the 36 penicillin-susceptible isolates, which could suggest that they did not evolve locally from a susceptible clone, but have been introduced into the region. In silico genome-based resistome analysis revealed identical PBP mutations in all four isolates. We detected mutations in multiple PBPs, including two amino acid substitutions within the active sites of the transpeptidase domain of PBP2x (T341P and Q555E), which have also been detected in other PR streptococci. The remaining mutations were, however, all located outside the active-site motifs of the transpeptidase domain.
To the best of our knowledge, this is the first description and characterization of invasive PR-SDSE. The resistant isolates had several amino acid changes in various PBPs compared with penicillin-susceptible SDSE. The observation that SDSE also can become PR emphasizes the importance of performing antimicrobial susceptibility testing.
To investigate the copy number of blaOXA-23 and its correlation with carbapenem resistance in carbapenem-resistant Acinetobacter baumannii (CRAB).
A total of 113 blaOXA-23-positive clinical CRAB isolates were collected from two hospitals in Zhejiang province, China. Their genetic relatedness was determined by MLST. The MIC of imipenem was determined using the agar diffusion method and the copy number of blaOXA-23 was measured using quantitative real-time PCR (qRT-PCR). The complete genomes of five clinical CRAB strains were sequenced using PacBio technology to investigate the multiplication mechanism of blaOXA-23.
Most of the isolates (100/113) belonged to global clone II and the MIC of imipenem ranged from 16 to 96 mg/L. The gene blaOXA-23 resided exclusively in Tn2006 or Tn2009. Approximately 38% of the isolates carried two or more copies of blaOXA-23. The copy number of blaOXA-23 was not correlated with the MIC of imipenem. Within the five sequenced strains, multiple copies of blaOXA-23 were either tandemly clustered or independently inserted at different genomic sites.
Multiplication of blaOXA-23 is common in CRAB, but does not enhance carbapenem resistance. Multiplication can be present in the form of either tandem amplifications or independent insertions at different sites.
The spread of carbapenem-resistant Enterobacteriaceae (CRE) represents one of the most worrisome problems for clinical medicine worldwide. In Italy, the Antibiotic-Resistance-Istituto Superiore di Sanità surveillance network, in collaboration with the Committee for Antimicrobial Agents of the Italian Society of Clinical Microbiologists, promoted a study to investigate the carbapenem-resistance mechanisms, clonal relatedness and capsular typing of a recent collection of carbapenem-resistant Klebsiella pneumoniae (CR-KP).
A total of 17 laboratories distributed across Italy collected all consecutive non-replicate CR-KP isolated from invasive infections during two different study periods (2011–12 and 2013). Carbapenemase genes were searched for by filter hybridization and confirmed by PCR and sequencing. KPC-producing K. pneumoniae (KPC-KP) were typed by PFGE and MLST. Capsular types were identified by wzi gene typing.
Of the collected K. pneumoniae isolates (n = 461), the overall proportion of CR-KP was 36.2% (n = 167). The majority (97%) of the CR-KP were positive for the blaKPC gene. Among the KPC-KP population, nine different STs were detected with the majority of isolates (94%) belonging to the clonal group (CG) 258. A subpopulation that belonged to ST512 and showed an identical PFGE profile represented the majority (57%) of KPC-KP strains, with a countrywide distribution. Capsular characterization showed the predominance of the wzi154, cps-2 capsular type (88.8% of all CG258 strains). ST258 strains were associated with both cps-1 and cps-2 capsular types, while ST512 was associated with cps-2 only.
Although a trend to a polyclonal evolution of the Italian KPC-KP was noted, this study showed that the KPC-KP population remained largely oligoclonal with the wide diffusion of an ST512 lineage carrying cps-2 capsular type and producing the KPC-3 enzyme.
We analysed the microbiological traits and population structure of KPC-producing Enterobacteriaceae isolates collected in Spain between 2012 and 2014. We also performed a comparative WGS analysis of the three major KPC-producing Klebsiella pneumoniae clones detected.
Carbapenemase and ESBL genes were sequenced. The Institut Pasteur MLST scheme was used. WGS data were used to construct phylogenetic trees, to identify the determinants of resistance and to de novo assemble the genome of one representative isolate of each of the three major K. pneumoniae clones.
Of the 2443 carbapenemase-producing Enterobacteriaceae isolates identified during the study period, 111 (4.5%) produced KPC. Of these, 81 (73.0%) were K. pneumoniae and 13 (11.7%) were Enterobacter cloacae. Three major epidemic clones of K. pneumoniae were identified: ST11/KPC-2, ST101/KPC-2 and ST512/KPC-3. ST11/KPC-2 differed from ST101/KPC-2 and ST512/KPC-3 by 27 819 and 6924 SNPs, respectively. ST101/KPC-2 differed from ST512/KPC-3 by 28 345 SNPs. Nine acquired resistance genes were found in ST11/KPC-2, 11 in ST512/KPC-3 and 13 in ST101/KPC-2. ST101/KPC-2 had the highest number of virulence genes (20). An 11 bp deletion at the end of the mgrB sequence was the cause of colistin resistance in ST512/KPC-3.
KPC-producing Enterobacteriaceae are increasing in Spain. Most KPC-producing K. pneumoniae isolates belonged to only five clones: ST11 and ST512 caused interregional spread, ST101 caused regional spread and ST1961 and ST678 produced independent hospital outbreaks. ST101/KPC-2 had the highest number of resistance and virulence genes. ST101/KPC-2 and ST512/KPC-3 were recently implicated in the spread of KPC in Italy.
WGS and phenotypic methods were used to determine the prevalence of azithromycin resistance in Salmonella enterica isolates from the UK and to identify the underlying mechanisms of resistance.
WGS by Illumina HiSeq was carried out on 683 Salmonella spp. isolates. Known genes associated with azithromycin resistance were detected by WGS using a mapping-based approach. Macrolide resistance determinants were identified and the genomic context of these elements was assessed by various bioinformatics tools. Susceptibility testing was in accordance with EUCAST methodology (MIC ≤16 mg/L).
Fifteen isolates of non-typhoidal Salmonella enterica belonging to serovars Salmonella Blockley, Salmonella Typhimurium, Salmonella Thompson, Salmonella Ridge and Salmonella Kentucky showed resistance or decreased susceptibility to azithromycin (from 6 to >16 mg/L) due to the presence of macrolide resistance genes mphA, mphB or mefB. These genes were either plasmid or chromosomally mediated. Azithromycin-resistant Salmonella Blockley isolates harboured a macrolide inactivation gene cluster, mphA-mrx-mphr(A), within a novel Salmonella azithromycin resistance genomic island (SARGI) determined by MinION sequencing. This is the first known chromosomally mediated mphA gene cluster described in salmonellae. Phylogenetic analysis and epidemiological information showed that mphA Salmonella Blockley isolates were not derived from a single epidemiologically related event. The azithromycin MICs of the 15 Salmonella spp. isolates showed that the presence of the mphA gene was associated with MIC ≥16 mg/L, while the presence of mefB or mphB was not.
Azithromycin resistance due to acquisition of known macrolide resistance genes was seen in four different Salmonella serovars and can be either plasmid-encoded or chromosomally encoded.
To evaluate the contribution of cysK and cysM to the fluoroquinolone (ofloxacin) antibiotic resistance in Salmonella Typhimurium, and their impact on H2S and cysteine production through targeted mutagenesis.
Salmonella Typhimurium 14028s and its cysK and cysM mutants were tested for their susceptibility to ofloxacin, as determined by a broth microdilution test (to determine the MIC) and survival curves. H2S levels were measured by the Pb(AC)2 method and cysteine levels were determined using 5,5-dithio-bis-2-nitrobenzoic acid. DNA damage induced by antibiotic treatment was determined by PFGE. Finally, expression of cysK and cysM genes under antibiotic treatment was determined by real-time reverse transcription PCR.
As determined by MIC, the cysK strain was more resistant to ofloxacin, a reactive oxygen species (ROS)-producing fluoroquinolone, than the WT and cysM strains, which correlates with survival curves. Moreover, the cysK strain exhibited higher H2S levels and lower cysteine levels than the WT strain. Finally, the cysK strain exhibited lower DNA damage upon challenge with ofloxacin than the WT and cysM strains. These results are in accordance with lower expression of cysK under ofloxacin treatment in the WT strain.
This work demonstrated that cysteine metabolism in Salmonella Typhimurium modulated H2S levels, conferring resistance to second-generation fluoroquinolones.
Recently, the first plasmid-mediated colistin-resistance gene, mcr-1, was reported. Colistin is increasingly used as an antibiotic of last resort for the treatment of infections caused by carbapenem-resistant bacteria, which have been rapidly disseminating worldwide in recent years.
The reported carriage rate of mcr-1 in humans remains sporadic thus far, except for those reported in Chinese populations. We aimed to determine its presence in the faecal metagenomes of healthy Dutch travellers between 2010 and 2012.
Faecal metagenomic DNA of pre- and post-travel samples from 122 healthy Dutch long-distance travellers was screened for the presence of mcr-1 using a TaqMan quantitative PCR assay, which was designed in this study. All positive samples were confirmed by sequencing of the amplicons.
The mcr-1 gene was detected in 6 (4.9%, 95% CI = 2.1%–10.5%) of 122 healthy Dutch long-distance travellers after they had visited destinations in South(-east) Asia or southern Africa between 2011 and 2012. One of these participants was already found to be positive before travel.
Our study highlights the potential of PCR-based targeted metagenomics as an unbiased and sensitive method to screen for the carriage of the mcr-1 gene and suggests that mcr-1 is widespread in various parts of the world. The observation that one participant was found to be positive before travel suggests that mcr-1 may already have disseminated to the microbiomes of Dutch residents at a low prevalence, warranting a more extensive investigation of its prevalence in the general population and possible sources.
Evaluation of the LightMix® modular carbapenemase kits for the rapid detection of carbapenemase-producing Enterobacteriaceae (CPE) and the application of these kits to the direct detection of colonized patients and bacteraemias.
The modular multiplex PCR kits targeting blaKPC, blaNDM, blaVIM, blaIMP and blaOXA-48-like carbapenem resistance genes were evaluated in terms of sensitivity and specificity for carbapenemase resistance in a set of 118 labelled clinical isolates. Among these, 96 were CPE genotypically characterized by PCR and sequencing. The limits of detection were calculated for the different carbapenem resistance genes in terms of cfu/mL. In addition, the kits were used to evaluate colonization of patients by CPE by comparing this assay with the Xpert® Carba-R Kit on 127 rectal, perirectal and pharyngeal samples. Blood cultures from bacteraemias (4) and spiked blood cultures (23) with genotypically characterized isolates were also evaluated.
The overall sensitivity and specificity of the multiplex PCR assay was 99% and 100%, respectively. The limit of detection for blaKPC, blaVIM, blaIMP and blaOXA-48-like is 60 cfu/mL and for blaNDM 500 cfu/mL. The colonization and bacteraemia studies revealed a 100% agreement between the results obtained by this assay and the ones obtained by GeneXpert®.
The LightMix® modular carbapenemase kits are highly reliable and utilizable assays for both colonized and septic patients, and can help in the improvement of infection control. Their modular design facilitates cost-effective detection of CPE in hospital settings.
In clinical microbiology, some instruments are able to automatically read inhibition zone diameters for antibiotic susceptibility testing (AST) performed by the disc diffusion (DD) method. The actual resolution of commercial reader systems is low and high-resolution scanners have been developed for microbiology. Here, we evaluated and compared the reading and interpretation of AST by the DD method using the Scan® 1200 instrument as compared with the Sirscan® system on 211 clinical strains and the possibility to read AST after 6 or 8 h of incubation as compared with 24 h on 121 additional Gram-negative strains and 76 non-fermenter Gram-negative and Gram-positive strains.
Validation of the technique was assessed on three reference strains as requested by EUCAST for analysis of the repeatability and reproducibility of the method.
Correlation between the two methods, assessed using 211 clinical isolates (n = 2439 zones of growth inhibition measured), was excellent with a correlation coefficient of 0.97. For the earlier reading experiments, preliminary results demonstrate the possibility of reading AST for drug–species combinations after 6 and 8 h for Gram-negative bacteria with rapid growth (correlation coefficient at 6 h = 0.96 and at 8 h = 0.98) and at 8 or 10 h for Gram-positive bacteria.
The Scan® 1200 has many advantages thanks to its small size, rapidity of use and high-resolution imaging allowing the possibility to improve AST results after only 6–8 h of incubation. This AST reader system represents a robust alternative tool for routine use in clinical microbiology laboratories.
The increasing threat of drug-resistant bacteria establishes a continuing need for the development of new strategies to fight infection. We examine the inhibition of the essential single-stranded DNA-binding proteins (SSBs) SSBA and SSBB as a potential antimicrobial therapy due to their importance in DNA replication, activating the SOS response and promoting competence-based mechanisms of resistance by incorporating new DNA.
Purified recombinant SSBs from Gram-positive (Staphylococcus aureus and Bacillus anthracis) and Gram-negative (Escherichia coli and Francisella tularensis) bacteria were assessed in a high-throughput screen for inhibition of duplex DNA unwinding by small molecule inhibitors. Secondary electrophoretic mobility shift assays further validated the top hits that were then tested for MICs using in vitro assays.
We have identified compounds that show cross-reactivity in vitro, as well as inhibition of both F. tularensis and B. anthracis SSBA. Five compounds were moderately toxic to at least two of the four bacterial strains in vivo, including two compounds that were selectively non-toxic to human cells, 9-hydroxyphenylfluoron and purpurogallin. Three of the SSBA inhibitors also inhibited S. aureus SSBB in Gram-positive bacteria.
Results from our study support the potential for SSB inhibitors as broad-spectrum antibacterial agents, with dual targeting capabilities against Gram-positive bacteria.
According to our previous study, OXA-58 translocates to the periplasm via the Sec pathway in carbapenem-resistant Acinetobacter baumannii (CRAb). In the present study, carbapenem-hydrolysing class D β-lactamases (CHDLs) belonging to the OXA-23, OXA-40 and OXA-51 families were examined to determine whether they are also Sec-dependent. Additionally, the effects of SecA inhibitors combined with carbapenems against CHDL-producing CRAb were examined.
Cell fractionation and western blot analyses were performed to detect periplasmic His-tagged CHDLs. A chequerboard analysis with pairwise combinations of carbapenems (imipenem or meropenem) and SecA inhibitors (rose bengal, sodium azide or erythrosin B) was performed using six clinical CRAb isolates harbouring different CHDL genes. The fractional inhibitory concentration (FIC) index was determined. The combination with the lowest FIC index was subjected to a time–kill analysis to examine synergistic effects.
In an in silico analysis, the CHDLs OXA-23, OXA-40 and OXA-51 were preferentially translocated via the Sec system. The SecA inhibitor rose bengal decreased periplasmic translocation of His-tagged OXA-23 and OXA-83 (belonging to the OXA-51 family), but not OXA-72 (belonging to the OXA-40 family) from ATCC 15151 transformants. Imipenem or meropenem with rose bengal showed synergistic effects (FIC index, ≤0.5) for six and four clinical isolates, respectively. Imipenem or meropenem with sodium azide showed no interactions (FIC index, 0.5–4) against all clinical isolates. Imipenem and rose bengal had the lowest FIC index and showed synergy at 24 h in the time–kill assay.
Combinations of SecA inhibitors and carbapenems have synergistic effects against CHDL-producing CRAb.
To evaluate the in vitro activity of anidulafungin combined with amphotericin B or voriconazole against Candida spp. biofilms.
Four Candida albicans, four Candida tropicalis, four Candida glabrata, two Candida parapsilosis and two Candida orthopsilosis blood isolates were tested by the microdilution chequerboard method combined with the XTT metabolic assay. Biofilm MIC was defined as the lowest concentration producing 50% metabolic inhibition with respect to control (BMIC50). Concentrations in the combinations ranged from 1/8 x BMIC50 to 4 x BMIC50 found for each antifungal tested alone.
Anidulafungin plus amphotericin B acted synergistically against C. albicans and C. glabrata biofilms [fractional inhibitory concentration index (FICI): 0.082–0.387], but showed no interaction against C. tropicalis, C. parapsilosis and C. orthopsilosis (FICI: 0.516–2.099). The combination of these antifungals failed to completely remove biofilms of C. albicans and C. glabrata, decreasing the metabolic activity of the biofilms up to 80% and 95%, respectively, which did not occur when each antifungal was used alone. Anidulafungin plus voriconazole showed no interaction against all isolates. Using a less stringent criterion previously proposed to define synergism (FICI < 1) and antagonism (FICI > 1.25), antagonistic interactions were found against some isolates.
Anidulafungin with amphotericin B results in a synergistic effect against C. albicans and C. glabrata biofilms at serum concentrations of the drugs, but showed no interaction against C. tropicalis and C. parapsilosis complex. Anidulafungin plus voriconazole showed no interaction against the five Candida species assayed. Biofilms of C. tropicalis were found to be the most resistant towards the combinations assayed. The results presented may be of potential interest in the clinical setting.
The objective of this study was to evaluate the prevalence and in vitro susceptibility of enterococci and VRE among bloodstream infections in European and US hospitals over time.
Isolates recovered from the blood of infected patients in Europe (72 996) and the USA (67 725) between 2001 and 2014 were included in the prevalence analysis. A subset (2349) collected during 2011–13 was used for the in vitro activity analysis.
Enterococcus faecium rates increased in Europe (from 1.4% in 2001 to 4.3% in 2014). These rates also increased in the USA (from 3.0% in 2001 to 5.4% in 2010), with decreasing prevalence (4.6% in 2011 to 3.6% in 2014) in later years. Enterococcus faecalis rates remained stable in Europe, but rose in the USA from 6.9% in 2001 to 8.8% in 2009, declining later (from 7.4% to 5.0%). VRE rates among E. faecalis did not vary in either region, while VRE rates among E. faecium increased in Europe (from 4.7% to 20.3%). US VRE rates among E. faecium increased until 2010 (60.0% in 2001 to 80.7% in 2010), decreasing from 75.1% in 2011 to 68.4% in 2013. Oritavancin demonstrated activity against vancomycin-susceptible E. faecalis (MIC50/90, 0.015/0.06 mg/L; 99.5% susceptible) and vancomycin-resistant E. faecalis (MIC50/90, 0.25/0.5 mg/L). Oritavancin showed MIC50, MIC90 and MIC100 values of 0.03, 0.12 and 0.25 mg/L, respectively, for VanA E. faecium.
Rates of E. faecium and VRE increased in Europe. Although still elevated, VRE rates appeared to show a decreasing trend in the USA since 2010. Oritavancin demonstrated activity against enterococci, including VRE.
Ceftaroline fosamil is indicated for the treatment of community-acquired bacterial pneumonia and ceftriaxone has an indication for lower respiratory tract infections. This study was conducted to compare the relative in vitro activities of these two agents against bacterial species associated with community-associated respiratory tract infections.
In all, 13 005 isolates of Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were collected in 2012–14 from 39 countries in the Asia–Pacific region, Europe, Latin America and Africa–Middle East from respiratory tract specimens. The identification was confirmed centrally by MALDI-TOF and broth microdilution susceptibility testing and interpretation was done according to CLSI guidelines.
Ceftaroline was 16-fold more potent against MSSA (MIC90 0.25 versus 4 mg/L) than ceftriaxone and ≥16-fold more potent against MRSA (MIC90 2 versus >32 mg/L). Ceftaroline was 16-fold more potent against S. pneumoniae (MIC90 0.12–0.25 mg/L) compared with ceftriaxone (MIC90 1–2 mg/L), with higher MIC values observed among penicillin-non-susceptible isolates for both agents. Similar activity (MIC90 ≤0.03 mg/L) was observed for ceftaroline and ceftriaxone against H. influenzae, with higher MIC values observed in the Asia–Pacific region for both agents compared with other regions. Ceftaroline was 4- to 8-fold more active against M. catarrhalis (MIC90 0.12–0.25 mg/L) compared with ceftriaxone (MIC90 1 mg/L).
These global MIC data demonstrated that ceftaroline exhibited superior in vitro activity compared with ceftriaxone against bacterial species that commonly cause community-associated respiratory tract infections.
Heteroresistance, described both in terms of various point mutations resulting in different levels of resistance and in terms of a mixture of mutant and WT bacilli, is identified in up to one-third of fluoroquinolone (FQ)-resistant Mycobacterium tuberculosis isolates. Heteroresistance is a challenge for current phenotypic and genotypic susceptibility testing (DST) regimes. We aimed to compare the performances of different phenotypic and genotypic DST in the context of FQ heteroresistance by mimicking, in a murine model, the course of selection of FQ resistance during treatment.
The capacity of different phenotypic DST [Lowenstein–Jensen (LJ) medium containing either 2 mg/L ofloxacin or 0.5, 1 or 2 mg/L moxifloxacin] and genotypic DST (gyrA/B Sanger sequencing) to detect FQ resistance was analysed.
Ninety-seven percent of mice harboured a heterogeneous population. The proportion of mice in which FQ resistance was detected varied according to the medium used (97% for 0.5 mg/L moxifloxacin, 80% for 2 mg/L ofloxacin, 47% for 1 mg/L moxifloxacin and 25% for 2 mg/L moxifloxacin). Compared with phenotypic DST, genotypic DST had a low sensitivity for detection of resistance (33%).
Our study shows the in vivo complexity of FQ resistance emergence and the poor sensitivity of Sanger DNA sequencing for detection of heteroresistance. Our data support the use of 0.5 mg/L moxifloxacin in LJ for detection of FQ resistance, but not the recent increase in the ofloxacin critical concentration from 2 to 4 mg/L given in the WHO recommendations.
Biofilm formation and bacterial adherence are important requirements for persistence, multidrug resistance and infection. The
In vitro assays were carried out to analyse the effect of
Biofilm formation was inhibited in A. baumannii by
Antibiotic nebulization theoretically allows the delivery of high doses to the lungs together with limited systemic exposure and toxicity. This study aimed to describe amikacin pharmacokinetics, and especially its absorption, in patients treated with high-dose nebulized amikacin.
Twenty critically ill patients experiencing ventilator-associated pneumonia received a 20 mg/kg infusion of amikacin, followed by either three other infusions or three nebulizations of 60 mg/kg amikacin. An extensive sampling regimen allowed measurement of amikacin serum concentrations at 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 h after each administration. Amikacin pharmacokinetics was studied by population compartmental modelling.
Amikacin pharmacokinetics was best described using a two-compartment structural model with first-order distribution and elimination, in which lung absorption was described using a transit model. Estimated means (interindividual variability) of the main parameters were: bioavailability F = 2.65% (22.1%); transit compartments n = 1.58 (fixed); transit constant ktr = 1.38 h–1 (33.4%); central volume Vc = 10.2 L (10.5%); and elimination constant k10 = 0.488 h–1 (35.8%). The addition of interoccasion variability on F (44.0%) and k10 (41.7%) allowed the description of intraindividual variability of bioavailability and elimination. Amikacin clearance was positively correlated with baseline creatinine clearance.
Our pharmacokinetic model provided an accurate description of amikacin concentrations following nebulization. There was wide interindividual and interoccasion variability in the absorption and elimination of amikacin. Nevertheless, systemic exposure after nebulization was always much lower than after infusion, an observation suggesting that nebulized high doses are safe in this regard and may be used to treat ventilator-associated pneumonia.
Darunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings.
We examined darunavir DRMs emerging in clinical practice in the UK.
Baseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls.
Of 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group.
Our findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility.
Daclatasvir (DCV) is a pan-genotypic non-structural protein 5A (NS5A) inhibitor that is approved for treatment of hepatitis C virus (HCV) genotype (GT)1 and GT3 in the USA and GT1, GT3 and GT4 in Europe. We set out to examine the impact of daclatasvir-based regimens on the sustained virologic response (SVR) in patients with GT2 infection with respect to GT2 subtype and NS5A polymorphisms at amino acid positions associated with daclatasvir resistance.
Analyses were performed on 283 GT2 NS5A sequences from five daclatasvir regimen-based clinical trials (ClinicalTrials.gov: NCT-01257204, NCT-01359644, NCT-02032875, NCT-02032888 and NCT-01616524) and 143 NS5A sequences from the Los Alamos HCV database. Susceptibility analyses of substitutions at amino acid positions associated with daclatasvir resistance and patient-derived NS5A sequences were performed using an in vitro HCV replication assay.
Of 13 GT2 subtypes identified from 426 NS5A sequences, the most prevalent were GT2a (32%), GT2b (48%) and GT2c (10%). The most prevalent NS5A polymorphism was L31M (GT2a = 88%; GT2b = 59%; GT2c = 10%). Substitutions identified in 96% of GT2 NS5A sequences exhibited daclatasvir EC50 values ranging from 0.005 to 20 nM when tested in vitro. A similar range in daclatasvir EC50 values was observed for 16 diverse GT2 patient-derived NS5A sequences (EC50 = 0.005–60 nM). Depending on the daclatasvir-based regimen studied (daclatasvir/interferon-based or daclatasvir/sofosbuvir-based), SVR rates ranged from 90% to 100% in GT2 patients with the most prevalent baseline NS5A-L31M polymorphism, compared with from 96% to 100% without this polymorphism.
High SVR rates were achieved in patients infected with GT2 treated with daclatasvir-based regimens irrespective of GT2 subtype or baseline NS5A polymorphisms.
HIV patients exposed to abacavir have an increased risk of myocardial infarction, with contradictory results in the literature. The aim of our study was to determine whether abacavir has a direct effect on platelet activation and aggregation using platelets from healthy donors and from HIV-infected patients under therapy with an undetectable viral load.
Platelet-rich plasma (PRP) or whole blood from healthy donors was treated with abacavir (5 or 10 μg/mL) or its active metabolite carbovir diphosphate. Experiments were also performed using blood of HIV-infected patients (n = 10) with an undetectable viral load. Platelet aggregation was performed on PRP by turbidimetry and under high shear conditions at 4000 s–1. Platelet procoagulant potential was analysed by measuring thrombin generation by thrombinography.
Abacavir and carbovir diphosphate significantly increased the aggregation of platelets from healthy donors induced by collagen at 2 μg/mL (P = 0.002), but not at 0.5 μg/mL. No effect of abacavir or carbovir diphosphate was observed on platelet aggregation induced by other physiological agonists or by high shear stress, or on thrombin generation. Pretreatment of blood from HIV-infected patients with abacavir produced similar results.
Our results suggest that abacavir does not significantly influence platelet activation in vitro when incubated with platelets from healthy donors or from HIV-infected patients. It is, however, not excluded that a synergistic effect with other drugs could promote platelet activation and thereby play a role in the pathogenesis of myocardial infarction.
To describe the effectiveness and safety of an abacavir/lamivudine + rilpivirine regimen in naive HIV-1-infected patients, as there is a lack of data with this combination.
This was an observational, retrospective, multicentre study in eight Spanish hospitals. All antiretroviral-naive patients ≥18 years old and starting abacavir/lamivudine + rilpivirine were included. Effectiveness (ITT and on-treatment) and safety (adverse events and laboratory parameters) were assessed during follow-up. Values are expressed as n (%) or median (IQR). The Wilcoxon signed-rank test was used to compare baseline and 6 and 12 month values.
Eighty-four patients were included [93% males, age = 36 (30–45) years]. Time since HIV diagnosis was 12 (4–35) months. Fifty-one per cent of patients had comorbidities. Baseline CD4+ was 425 (340–519) cells/mm3 and baseline HIV-RNA was 19 000 (9500–42 000) copies/mL. Median follow-up was 18 (9–22) months; 100% and 68% patients with at least 6 and 12 months, respectively. At 6 and 12 months effectiveness was 94% and 86% by ITT analysis and 96% and 97% by on-treatment analysis. At 12 months, there were significant increases in CD4+ (+262 cell/mm3) and HDL cholesterol (+4 mg/dL) and a significant decrease in the total cholesterol/HDL cholesterol ratio (–0.2). There were two (2.4%) virological failures (HIV-RNA 50–100 copies/mL); one patient later achieving virological suppression without changing the treatment. Six patients (7.1%) changed treatment due to reasons other than virological failure or side effects. One patient discontinued treatment due to gastrointestinal complaints attributed to abacavir/lamivudine.
Abacavir/lamivudine + rilpivirine was an effective and safe option in a selected group of HIV-1-infected treatment-naive patients.
To assess the accuracy of risk prediction algorithms used in the general population and an HIV-specific algorithm to predict hard cardiovascular events.
We compared the pooled equation algorithm (PE) proposed by the American Heart Association with the Framingham risk score (FRS) and the HIV-specific DAD (Data Collection on Adverse Effects of Anti-HIV Drugs) algorithm in a cohort of 2550 HIV+ patients followed for 17 337 patient-years.
During follow-up we recorded 67 myocardial infarctions and 2 cardiovascular deaths. PE and FRS identified and missed the same number of events (44 of 69 identified by PE and 49 of 69 by FRS). Similarly, DAD and FRS predicted and missed the same number of events (38 of 64 and 44 of 64 identified, respectively). All algorithms showed moderate sensitivity, specificity and positive predictive values, but high negative predictive values. However, PE and DAD identified more patients with no events than FRS (13.8% and 9.3% net reclassification improvement, respectively).
All algorithms showed a modest predictive ability, although the PE and DAD algorithms identified more patients at low risk.
We investigated the association between persistent low-level viraemia, measured as viraemia copy-years (VCY), and all-cause mortality.
We included 3271 HIV-infected patients who initiated their first combined ART (cART) during 1998–2012 enrolled in the multicentre Italian MASTER cohort. VCY was defined as the area under the curve of plasma viral load (pVL) and expressed in log10 copies · years/mL. VCY was evaluated from cART initiation until the end of follow-up [VCY-overall (VCY-o)], and stratified into before [VCY-early (VCY-e)] and after [VCY-late (VCY-l)] the eighth month from starting cART, and as the ratio of VCY-l to follow-up duration (VCY-l/FUD).
The risk of death increased of about 40% for higher than the median levels of VCY-o and VCY-e. Compared with subjects with permanently suppressed pVL after the eighth month from starting cART, mortality increased by 70% for those with VCY-l ≥3 log10 copies·years/mL, and by about 20-fold for those with VCY-l/FUD ≥2.3 log10 copies/mL. Patients who maintained low levels of VCY-l (<3 log10 copies · years/mL) or VCY-l/FUD (<2.3 log10 copies/mL) had a risk of death similar to patients with permanently suppressed pVL. CD4 cell count at baseline was predictive of high risk of death only in subjects with VCY-l ≥3 log10 copies · years/mL.
The risk of death did not increase in HIV-infected patients with low levels of VCY-l compared with patients with permanent virological suppression.
In patients with invasive aspergillosis (IA), fungal cultures are mostly negative. Consequently, azole resistance often remains undetected. The AsperGenius® multiplex real-time PCR assay identifies clinically relevant Aspergillus species and four resistance-associated mutations (RAMs; TR34/L98H/T289A/Y121F) in the Cyp51A gene. This multicentre study evaluated the diagnostic performance of this assay on bronchoalveolar lavage (BAL) fluid and correlated the presence of RAMs with azole treatment failure and mortality.
Stored BAL samples from patients with haematological diseases with suspected IA were used. BAL samples that were galactomannan/culture positive were considered positive controls for the presence of Aspergillus. Azole treatment failure and 6 week mortality were compared in patients with and without RAMs that had received ≥5 days of voriconazole monotherapy.
Two hundred and one patients each contributed one BAL sample, of which 88 were positive controls and 113 were negative controls. The optimal cycle threshold cut-off value for the Aspergillus species PCR was <38. With this cut-off, the PCR was positive in 74/88 positive controls. The sensitivity, specificity, positive predictive value and negative predictive value were 84%, 80%, 76% and 87%, respectively. 32/74 BAL samples were culture negative. Azole treatment failure was observed in 6/8 patients with a RAM compared with 12/45 patients without RAMs (P = 0.01). Six week mortality was 2.7 times higher in patients with RAMs (50.0% versus 18.6%; P = 0.07).
The AsperGenius® assay had a good diagnostic performance on BAL and differentiated WT from Aspergillus fumigatus with RAMs, including in culture-negative BAL samples. Most importantly, detection of RAMs was associated with azole treatment failure.
A polymorphism in the gene encoding β-1,3-glucan synthase, the target of the echinocandin class of antifungals, results in increased in vitro MICs of the echinocandins. This has resulted in controversy surrounding use of the echinocandins for treatment of Candida parapsilosis candidaemia. We aimed to compare 30 day mortality in adults with C. parapsilosis candidaemia treated with echinocandins versus fluconazole.
This is a retrospective observational cohort study. We used the Premier Perspective Database to identify adult patients with C. parapsilosis candidaemia treated with only fluconazole or only an echinocandin as definitive therapy. The primary outcome was 30 day mortality. Propensity scores were derived to estimate the probability the patient would have received either an echinocandin or fluconazole. Inverse probability of treatment weighting (IPTW) was used in a weighted logistic regression to calculate odds of 30 day mortality.
There were 307 unique patients with C. parapsilosis candidaemia. One hundred and twenty-six (41%) received fluconazole and 181 (59%) received an echinocandin. Age, gender, race, year of admission, need for ICU resources in the week prior to candidaemia onset, and receipt of vasopressors on the day of candidaemia onset were included in the propensity score model used to calculate inverse probability of treatment weights. Weighted logistic regression demonstrated no difference in 30 day mortality between patients receiving an echinocandin as compared with fluconazole (OR 0.82, 95% CI 0.33–2.07).
Our result supports the 2016 IDSA invasive candidiasis guidelines, which no longer clearly favour treatment with fluconazole over an echinocandin for C. parapsilosis candidaemia.
This study describes the safety, clinical effectiveness and trough plasma concentration (Cmin) of intravenous (iv) posaconazole, provided as part of Merck Sharp and Dohme Australia's Named Patient Programme (NPP) in non-clinical trial settings.
A multicentre, retrospective study on the NPP use of iv posaconazole between July 2014 and March 2015 across seven Australian hospitals.
Seventy courses of iv posaconazole were prescribed and evaluated in 61 patients receiving treatment for haematological malignancy. Sixty-one courses were prescribed for prophylaxis against invasive fungal disease (IFD), the majority of which (59) were initiated in patients with gastrointestinal disturbances and/or intolerance to previous antifungals. The median (IQR) duration for prophylaxis was 10 (6–15) days. No breakthrough IFD was observed during or at cessation of iv posaconazole. Nine courses of iv posaconazole were prescribed for treatment of IFD with a median (IQR) duration of 19 (7–30) days. Improvement in signs and symptoms of IFD was observed in five cases at cessation of, and six cases at 30 days post-iv posaconazole. Cmin was measured in 39 courses of iv posaconazole, with the initial level taken [median (IQR)] 4 (3–7) days after commencing iv posaconazole. The median (IQR) of initial Cmin was 1.16 (0.69–2.06) mg/L. No severe adverse events specifically attributed to iv posaconazole were documented, although six courses were curtailed due to potential toxicity.
This non-clinical trial experience suggests that iv posaconazole appeared to be safe and clinically effective for prophylaxis or treatment of IFD in patients receiving treatment for haematological malignancies.
International travel is a risk factor for intestinal colonization with ESBL-producing Enterobacteriaceae (EPE). This prospective cohort study focuses on molecular features of and risk factors for travel-acquired EPE.
Rectal swabs and survey data were collected from 188 Swedes travelling to four regions of high EPE prevalence. Samples were plated onto selective agars. ESBL producers were determined using phenotypic methods. Molecular characterization regarding virulence factors and phylogenetic grouping of ESBL-producing Escherichia coli was done using PCR. Isolates were also screened for the plasmid-mediated colistin resistance gene mcr-1.
Among 175 pre-travel EPE-negative participants, 32% were positive upon return. No carbapenemase-producing Enterobacteriaceae were found, but one CTX-M-producing E. coli harboured mcr-1 (travel to Thailand). Most E. coli strains (43.1%) belonged to phylogroup A and were rarely associated with extraintestinal infections and a few (9.2%) expressed uropathogenicity pap genes. During 10–26 months of follow-up, no clinical infections were observed. Colonization rates varied by visited region: the Indian subcontinent, 49.2%; northern Africa, 44.0%; South-East Asia, 19.1%; and Turkey, 9.5%. Travellers' diarrhoea (OR 2.5, P = 0.04) or antimicrobial treatment during the trip (OR 5.9, P = 0.02) were both independent risk factors for EPE colonization.
EPE acquired during travel have seemingly low pathogenicity, possibly indicating a low risk of clinical infection. Pre-travel advice should emphasize avoiding unnecessary antibiotic treatment during travel.
Carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat for healthcare providers worldwide.
To determine CPE carriage rates and risk factors in an unselected hospital cohort at the time of admission.
We approached 4567 patients within 72 h of admission to provide a rectal swab and answer a questionnaire on risk factors for carriage. Rectal swabs were cultured for carbapenem-resistant organisms on chromogenic and non-chromogenic agar, and tested for carbapenemase production by PCR (Check-Direct CPE). The study was approved by the NHS Research Ethics Committee.
Only 6 CPE were cultured from 5 (0.1%) of 4006 patients who provided a rectal swab; only 1 was cultured using non-chromogenic media. An additional 76 culture-negative rectal swabs were initially PCR positive, but none grew a carbapenem-resistant organism despite enrichment culture and only two were positive when retested several months later by Check-Direct and a second PCR assay (Cepheid GeneXpert® Carba-R). A modified Ct cut-off of <35 would have resolved these apparent false-positives. 40% of patients had a risk factor that should prompt screening and pre-emptive isolation as defined by UK CPE guidelines but only 8.1% and 20.2% of these patients had been screened and pre-emptively isolated by clinical teams, respectively. Overseas hospitalization was the only significant risk factor for CPE carriage (P < 0.001, OR 64.3, 95% CI 7.3–488.5).
This study highlights a very low carriage rate of CPE. Hospitalization abroad is the most important risk factor to guide admission screening in this low-prevalence setting.
Empirical treatment of uncomplicated urinary tract infections (UTIs) in women should be based on local susceptibility data. We aimed to generate regional and provincial cumulative antibiograms combining data from different laboratory information systems and determine the impact of basic patient characteristics on susceptibility results.
All positive urine samples for Escherichia coli obtained from women aged 18–65 years old in outpatient settings between 1 April 2010 and 31 March 2015 from four hospitals in Quebec, Canada, were included. The cumulative antibiogram for ciprofloxacin, nitrofurantoin and trimethoprim/sulfamethoxazole was calculated. A clinically significant difference in susceptibility profile was defined as factor(s) that lowered the susceptibility proportion below 80%.
A total of 36 293 positive urine cultures were analysed. In the last year of the study, the proportion of susceptibility for ciprofloxacin, nitrofurantoin and trimethoprim/sulfamethoxazole was 90.3%, 95.4% and 81.9%, respectively. The susceptibility proportion was <80% for trimethoprim/sulfamethoxazole in the Montreal region (73.4%; 95% CI 71.1%–75.9%), whereas it remained >80% for the other regions. A significant decrease in susceptibility with time was identified for ciprofloxacin (92.1%–90.3%, P < 0.001) and nitrofurantoin (97.1%–95.4%, P < 0.001). Increasing age, recent hospitalization and site of collection were associated with an increase in resistance for certain antibiotics.
Overall, all first-line antimicrobials remain acceptable choices for empirical treatment of uncomplicated UTIs in women in Quebec. The regional variability in susceptibility data within a single province emphasizes the importance of local susceptibility data to inform the development of empirical treatment guidelines for UTIs.
There are few convenient intravenous options for long-term outpatient treatment of osteoarticular infection (OAI) and limited effectiveness and safety data exist for this off-label use of ceftaroline. The objective of this study was to describe the long-term effectiveness and safety of ceftaroline for the treatment of OAI.
This was a matched retrospective cohort study of patients receiving ceftaroline- or vancomycin-based therapy for OAI in the outpatient setting. Patients were matched according to infection subtype, anatomical site and microbiology. The primary endpoint was 180 day infection-related readmission (IRR). Secondary endpoints included all-cause readmission, time-to-IRR and adverse event incidence.
The final matched cohort consisted of 50 ceftaroline-treated patients and 50 vancomycin-treated patients. The IRR incidence was 22% for ceftaroline patients and 30% for vancomycin patients; OR = 0.66 (95% CI = 0.27–1.62; P = 0.362). There was no significant difference between groups in all-cause readmission or time-to-IRR. Attributable adverse event incidences were 24% and 18% for ceftaroline and vancomycin, respectively. Rash (10%) and nausea (6%) were the most common ceftaroline adverse events, while acute kidney injury (6%) and rash (4%) were the most common vancomycin adverse events.
Attributable readmission and adverse events were common among patients treated with outpatient intravenous antimicrobials for OAI. This study found no appreciable difference in effectiveness or tolerability between ceftaroline- or vancomycin-treated patients. Although further research will be important to delineate the role of ceftaroline in the management of OAI, data derived from this study may aid clinicians in determining therapy when limited options exist.
Increasing the ceftaroline fosamil dose beyond 600 mg every 12 h may provide additional benefit for patients with complicated skin and soft tissue infections (cSSTIs) with severe inflammation and/or reduced pathogen susceptibility. A Phase III multicentre, randomized trial evaluated the safety and efficacy of ceftaroline fosamil 600 mg every 8 h in this setting.
Adult patients with cSSTI and systemic inflammation or comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g every 8 h) for 5–14 days. Clinical cure was assessed at the test of cure (TOC) visit (8–15 days after the final dose) in the modified ITT (MITT) and clinically evaluable (CE) populations. Non-inferiority was defined as a lower limit of the 95% CI around the treatment difference greater than –10%. An MRSA-focused expansion period was initiated after completion of the main study. Clinicaltrials.gov registration numbers NCT01499277 and NCT02202135.
Clinical cure rates at TOC demonstrated non-inferiority of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in the MITT and CE populations: 396/506 (78.3%) versus 202/255 (79.2%) patients (difference –1.0%, 95% CI –6.9, 5.4) and 342/395 (86.6%) versus 180/211 (85.3%) patients (difference 1.3%, 95% CI –4.3, 7.5), respectively. In the expansion period, 3/4 (75%) patients treated with ceftaroline fosamil were cured at TOC. The frequency of adverse events was similar between groups.
Ceftaroline fosamil 600 mg every 8 h was effective for cSSTI patients with evidence of systemic inflammation and/or comorbidities. No new safety signals were identified.
With increasing rates of infections caused by MDR Gram-negative organisms, clinicians resort to older agents such as colistimethate sodium (CMS) despite a significant risk of nephrotoxicity. Several risk factors for CMS-associated nephrotoxicity have been reported, but they have yet to be validated. We compared the performance of published mathematical models in predicting the risk of CMS-associated nephrotoxicity.
In a multicentre, retrospective, cohort study, adult patients (≥18 years of age) were evaluated from five large academic medical centres in the USA. Patients with normal renal function (baseline serum creatinine ≤1.5 mg/dL) who received intravenous CMS for ≥72 h were followed for up to 30 days. The development of nephrotoxicity was as defined by the RIFLE criteria. Each published model was conditioned using patient-specific variables to predict the risk of nephrotoxicity. The predictive performance of the models was evaluated using the observed-to-expected (O/E) ratio. The most significant cut-off threshold for stratifying patients into high and low risk of nephrotoxicity was identified using classification and regression tree analysis.
A total of 106 patients were examined (mean age 53.3 ± 14.9 years, 66% male); the overall observed nephrotoxicity rate was 52.8%. We identified a simple model demonstrating reasonable overall nephrotoxicity risk assessment [O/E ratio of 1.07 (95% CI = 0.81–1.39)] and high sensitivity (92.9%) in predicting nephrotoxicity development in patients on CMS therapy.
We identified a model that could be incorporated into patient management strategies to reduce the risk of nephrotoxicity in patients requiring CMS therapy.
Obesity is on course to overtake being underweight as a global disease burden. Obesity alters antibacterial pharmacokinetics (PK) and pharmacodynamics (PD). Historically, drug PK/PD parameters have not been studied in obese populations. This means dose recommendations risk being sub-therapeutic in a population at increased risk of infection. Suboptimal antibacterial prescribing is widely associated with treatment failure, worse clinical outcomes, unnecessary escalation to broad-spectrum therapy and the emergence of antimicrobial resistance (AMR).
To analyse current information provided by pharmaceutical companies, for the most commonly prescribed antibacterial agents in the UK, for evidence of dosing guidance for obese adults.
We analysed the manufacturers' Summary of Product Characteristics (SPC) for 42 of the most clinically important and frequently prescribed antibacterial agents dispensed across both primary and secondary care. The manufacturer's SPC was reviewed, and cross-referenced with the online British National Formulary, to assess dosing guidance for obese adults.
No advice was provided to guide dosing for obese adults in 35 (83%) of 42 of the most clinically important and frequently prescribed antibacterial agents in the UK. Seven (17%) antibacterial agents (tigecycline, vancomycin, daptomycin, amikacin, gentamicin, tobramycin and teicoplanin) provided variable levels of advice.
There is a paucity of advice and evidence in the UK to guide dosing common antibacterial agents in the obese. The literature on antibacterial PK/PD studies in obese populations remains scarce. In the face of the increasing risks of AMR combined with the global rise of obesity there is an urgent need to address this significant research gap.
Knowledge of the patterns of antibiotic consumption within a population provides valuable information on when, where and to whom antibiotics are prescribed. Such knowledge is critical in informing possible public health interventions to reduce inappropriate antibiotic use. The aims of this study were to (i) determine national patterns of antibiotic consumption, including assessment of seasonal variation in prescribing, and (ii) explore potential associations between antibiotic consumption and patient characteristics, such as age, sex and ethnicity.
Data on all subsidized antibiotic dispensing in New Zealand between 1 January 2006 and 31 December 2014 were obtained and stratified according to age, sex and ethnicity. Antibiotic dispensing was expressed as the number of DDDs per 1000 population per day (DID).
Total antibiotic consumption in New Zealand increased by 49% from 17.3 DID in 2006 to 25.8 DID in 2014. The increase in antibiotic consumption occurred in all ages and amongst all ethnic groups. The use of extended-spectrum penicillins, which almost doubled in the study period, made a major contribution to the overall increase and was highest in young children and in Pacific peoples. Consumption of quinolones increased early in the study period and then declined from 2011 onwards.
Future work should focus on identifying the appropriateness of antibiotic prescribing, particularly for penicillin prescribing in Pacific peoples and children, and on both reducing unwarranted antibiotic use and improving antibiotic selection when therapy is indicated.
Antifungal therapy saves lives, if given early in life-threatening invasive infection, and also greatly reduces morbidity in hundreds of millions of patients worldwide.
We have partially mapped by country systemic generic antifungal drug registration, availability and daily cost for intravenous deoxycholate amphotericin B (50 mg), flucytosine (5 g), oral fluconazole (750–800 mg) and oral itraconazole (400 mg).
Multiple publically available resources and local country contacts provided data for 159 countries with populations >1 million.
Amphotericin B is not licensed in and unavailable in 22 of 155 (14.2%) and 42 of 155 (27.1%) countries, respectively, representing an unserved population of 481 million. The daily price of deoxycholate amphotericin B varied from <$1 to $171. Fluconazole was licensed in all 141 (88.6%) countries for which data were available although 2 countries appear wholly dependent on the Diflucan® Partnership Program, which is restricted to HIV/AIDS patients. The daily price of fluconazole varied from <$1 to $31. Itraconazole is not licensed in and unavailable in at least 3 of 123 (2.4%) and 5 of 125 (4.0%) countries, respectively, representing an unserved population of at least 78 million. The daily price of itraconazole varied from <$1 to $102. Flucytosine is not licensed in and is unavailable in 89 of 125 (71.2%) and 95 of 125 (76.0%) countries, respectively, representing an unserved population of 2898 million. The daily price of flucytosine varied from $4.60 to $1409.
National governments without access to antifungal drugs should address this health system deficiency urgently to improve clinical outcomes from serious fungal disease. The variability in the price of antifungals between countries is striking.
To quantify associations between antimicrobial use and acquired resistance in indicator Escherichia coli over a period of time which involved sector-wide antimicrobial use reductions in broilers and pigs (years 2004–14), veal calves (2007–14) and dairy cattle (2005–14). Prevalence estimates of resistance were predicted for a hypothetical further decrease in antimicrobial use.
Data reported annually for the resistance surveillance programme in the Netherlands were retrieved. Two multivariate random-effects logistic models per animal sector were used to relate total and class-specific antimicrobial use (as defined daily dosages per animal per year, DDDA/Y) with the probability of E. coli resistance to a panel of 10 antimicrobial agents.
Positive dose–response relationships (ORs) were obtained from all models. Specific resistance phenotypes were more often associated with total antimicrobial use than with class-specific use. The most robust associations were found in pigs and veal calves. Resistance to historically widely used antimicrobials (e.g. penicillins, tetracyclines) was, in relative terms, less influenced by drug use changes over time than resistance to newer or less prescribed antimicrobials (e.g. third-/fourth-generation cephalosporins, fluoroquinolones). In pigs and veal calves, prevalence estimates for the most common resistance phenotypes were projected to decline ~5%–25% during 2014–16 if total antimicrobial use reduction reached 80%; projections for poultry and dairy cows were more modest.
Epidemiological evidence indicated that drug use history and co-selection of resistance are key elements for perpetuation of resistance. Data suggest that recent Dutch policies aimed at reducing total use of antimicrobials have decreased E. coli resistance in the pig and veal calf production sectors while the impact on the dairy cattle and poultry sectors is less clear.