Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the ...heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored.
To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research.
A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed.
The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1).
A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways.
Rapid diagnostic tests (RDTs) for infectious diseases, with a turnaround time of less than 2 hours, are promising tools that could improve patient care, antimicrobial stewardship and infection ...prevention in the emergency department (ED) setting. Numerous RDTs have been developed, although not necessarily for the ED environment. Their successful implementation in the ED relies on their performance and impact on patient management.
The aim of this narrative review was to provide an overview of currently available RDTs for infectious diseases in the ED.
PubMed was searched through August 2019 for available studies on RDTs for infectious diseases. Inclusion criteria included: commercial tests approved by the US Food and Drug Administration (FDA) or Conformité Européenne (CE) in vitro diagnostic devices with data on clinical samples, ability to run on fully automated systems and result delivery within 2 hours.
A nonexhaustive list of representative commercially available FDA- or CE-approved assays was categorized by clinical syndrome: pharyngitis and upper respiratory tract infection, lower respiratory tract infection, gastrointestinal infection, meningitis and encephalitis, fever in returning travellers and sexually transmitted infection, including HIV. The performance of tests was described on the basis of clinical validation studies. Further, their impact on clinical outcomes and anti-infective use was discussed with a focus on ED-based studies.
Clinicians should be familiar with the distinctive features of each RDT and individual performance characteristics for each target. Their integration into ED work flow should be preplanned considering local constraints of given settings. Additional clinical studies are needed to further evaluate their clinical effectiveness and cost-effectiveness.
Currently, contact precautions are recommended for patients colonized or infected with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). Recent studies have challenged this ...strategy. This study aimed to assess the rate of ESBL-PE faecal carriage among hospitalized patients according to type of hospital ward, and to identify risk factors associated with carriage.
A point prevalence study was conducted in five different types of hospital ward medical, surgical, intensive care unit (ICU), after care and rehabilitation, and geriatric in eight French hospitals. All patients included in the study provided a fresh stool sample.
In total, 554 patients were included in the study, with a median age of 73 years (range 60–82 years). The overall faecal carriage rate of ESBL-PE was 17.7%. The most frequently encountered species among ESBL-PE was Escherichia coli (71.4%), followed by Klebsiella pneumoniae (14.3%). Risk factors associated with ESBL-PE faecal carriage on univariate analysis were: living in the Paris region (P<0.01) and hospitalization on a geriatric ward (P<0.01). Interestingly, the cumulative duration of hospital stay before screening was not associated with a significantly higher prevalence of ESBL-PE carriage, regardless of ward type. The ESBL-PE colonization rate was much higher for patients hospitalized on geriatric wards (28.1%) and ICUs (21.7%) compared with those for patients hospitalized on surgical wards (14.8%), medical wards (12.8%) or aftercare and rehabilitation (11.2%).
The overall prevalence of ESBL-PE faecal carriage was 17.7%, with only 21% of patients identified previously as carriers. The delay between admission and screening was not associated with an increase in ESBL-PE faecal carriage.
Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance ...is a major limitation. Our aim was to determine whether the association of temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections.
Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected.
Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P < 0.001) and inhibited growth of resistant mutants in all cases.
The combination of fosfomycin and temocillin demonstrated a benefit in vitro and in vivo against E. coli strains producing KPC-3 or OXA-48-type carbapenemases. This combination prevented the emergence of fosfomycin resistance and proved to be more bactericidal than fosfomycin alone.
Non-O1, non-O139
Vibrio cholerae
(NOVC) are increasingly frequently observed ubiquitous microorganisms occasionally responsible for intestinal and extra-intestinal infections. Most cases involve ...self-limiting gastroenteritis or ear and wound infections in immunocompetent patients. Bacteraemia, which have been described in patients with predisposing factors, are rare and poorly known, both on the clinical and therapeutic aspects. We describe a case of NOVC bacteraemia and a systematic literature review in PubMed conducted up to November 2014 using a combination of the following search terms: “
Vibrio cholerae
non-O1” and “bacter(a)emia”. The case was a 70 year-old healthy male subject returning from Senegal and suffering from NOVC bacteraemia associated with liver abscesses. Disease evolution was favourable after 2 months’ therapy (ceftriaxone then ciprofloxacin). Three hundred and fifty cases of NOVC bacteraemia have been identified in the literature. The majority of patients were male (77 %), with a median age of 56 years and presenting with predisposing conditions (96 %), such as cirrhosis (55 %) or malignant disease (20 %). Diarrhoea was inconstant (42 %). Mortality was 33 %. The source of infection, identified in only 25 % of cases, was seafood consumption (54 %) or contaminated water (30 %). Practitioners should be aware of these infections, in order to warn patients with predisposing conditions, on the risk of ingesting raw or undercooked seafood or bathing in potentially infected waters.
The objective of this study was to perform an inventory of the extended-spectrum-β-lactamase (ESBL)-producing
isolates responsible for infections in French hospitals and to assess the mechanisms ...associated with ESBL diffusion. A total of 200 nonredundant ESBL-producing
strains isolated from clinical samples were collected during a multicenter study performed in 18 representative French hospitals. Antibiotic resistance genes were identified by PCR and sequencing experiments. The clonal relatedness between isolates was investigated by the use of the DiversiLab system. ESBL-encoding plasmids were compared by PCR-based replicon typing and plasmid multilocus sequence typing. CTX-M-15, CTX-M-1, CTX-M-14, and SHV-12 were the most prevalent ESBLs (8% to 46.5%). The three CTX-M-type EBSLs were significantly observed in
(37.1%, 24.2%, and 21.8%, respectively), and CTX-M-15 was the predominant ESBL in
(81.1%). SHV-12 was associated with ESBL-encoding
strains (37.9%).
,
'
, and
genes were the main plasmid-mediated resistance genes, with prevalences ranging between 19.5% and 45% according to the ESBL results. Molecular typing did not identify wide clonal diffusion. Plasmid analysis suggested the diffusion of low numbers of ESBL-encoding plasmids, especially in
and
However, the ESBL-encoding genes were observed in different plasmid replicons according to the bacterial species. The prevalences of ESBL subtypes differ according to the
species. Plasmid spread is a key determinant of this epidemiology, and the link observed between the ESBL-encoding plasmids and the bacterial host explains the differences observed in the
species.
The detection of Mycobacterium tuberculosis using a new commercial real-time polymerase chain reaction (PCR) assay (Xpert™ MTB/RIF) was evaluated on 91 respiratory and 89 non-respiratory samples ...recovered from 132 patients suspected of tuberculosis (TB). Overall, 31 (17.2%) of the 180 samples, including 17 respiratory and 14 non-respiratory (respectively 17 and 12 PCR-positive), yielded M. tuberculosis on culture. The sensitivity and specificity of PCR were respectively 100% and 100%, and 85.7% and 97.3% for respiratory and non-respiratory samples. Although the test is validated only for respiratory samples, our findings suggest that it could be useful for the diagnosis of extra-pulmonary TB.
Although resistance to quinolones is commonly chromosomally-encoded in Enterobacteriaceae, the emergence of plasmid-mediated quinolone resistance (PMQR) has also been reported, with at least three ...known resistance mechanisms to date, i.e., Qnr, aminoglycoside acetyltransferase AAC(6′)-Ib-cr and QepA. Qnr proteins protect target enzymes (DNA gyrase and type IV topoisomerase) from quinolone inhibition, the AAC(6′)-Ib-cr enzyme acetylates norfloxacin and ciprofloxacin, and the QepA efflux pump extrudes hydrophilic fluoroquinolones. Although these PMQR determinants confer only low-level resistance to quinolones and/or fluoroquinolones, they may provide a favourable background in which the selection of additional chromosomally-encoded quinolone resistance mechanisms can occur.
Temocillin is a 6-α-methoxy derivative of ticarcillin that shows in vitro activity against Enterobacteriaceae producing Klebsiella pneumoniae carbapenemase (KPC). Our objective was to assess in vivo ...temocillin activity against KPC-producing Escherichia coli.
Isogenic derivatives of the WT E. coli CFT073 producing KPC-2, KPC-3 or OXA-48 were constructed. An experimental murine model of intra-abdominal infection with sepsis was used. Mice were treated subcutaneously with temocillin 200 mg/kg every 2 h for 24 h, reproducing the duration of time that the free serum concentration of temocillin exceeded the MIC in humans with a regimen of 2 g every 12 h or 2 g every 8 h. Blood, peritoneal fluid (PF) and spleen were collected; 24 h survival and sterility rates were assessed.
Temocillin MICs were 8, 16, 32, and 256 mg/L for the susceptible strain and KPC-2-, KPC-3-, and OXA-48-producing strains, respectively. In mice treated with temocillin, significant bacterial reduction was obtained in PF, blood, and spleen for the susceptible strain and KPC-2- and KPC-3-producing strains (P < 0.001) but not for the OXA-48-producing strain. Sterility rates in PF were 53%, 10%, 0% and 0% (P < 0.001) and sterility rates in blood were 77%, 40%, 3% and 0% (P < 0.001), while survival rates were 97%, 97%, 57%, 0% (P < 0.001) for mice infected with the susceptible strain and KPC-2-, KPC-3- and OXA-48-producing strains, respectively.
In a lethal-infection model with bacteraemia from intra-abdominal origin, temocillin retained significant activity in PF, blood and spleen and prevented death in mice by effectively working against KPC-producing E. coli with temocillin MICs ≤16 mg/L.
Although carbapenemase-producing Enterobacteriaceae (CPE) have become a serious public health issue, their detection remains challenging. The aim of this study was to implement a test based on ...imipenem hydrolysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS), using 65 strains producing or not a carbapenemase. Then, we compared its performance to that of the Rapidec Carba NP test using 20 additional strains. The MS-based test effectively discriminated between CPE and other non-carbapenem-susceptible strains compared to the Rapidec Carba NP test (sensitivity 100% and 92%, specificity 94% and 92%, respectively). The MS-based test gave less difficulty in interpretation than the colorimetric Rapidec Carba NP test. MALDI-ToF gave a result in less than one hour and limited the use of expensive molecular assays. In conclusion, the hydrolysis test based on MALDI-ToF MS can detect clinically relevant CPE isolates in routine practice. This technology, also described to screen for carbapenem resistance in
Pseudomonas aeruginosa
and
Acinetobacter baumannii
complex strains, also seems to be interesting in routine practice for these pathogens.
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