[Show abstract][Hide abstract] ABSTRACT: The lack of new antibiotic classes calls for a cautious use of existing agents. Yet, every 10 min, almost two tons of antibiotics are used around the world, all too often without any prescription or control. The use, overuse and misuse of antibiotics select for resistance in numerous species of bacteria which then renders antimicrobial treatment ineffective. Almost all countries face increased antimicrobial resistance (AMR), not only in humans but also in livestock and along the food chain. The spread of AMR is fueled by growing human and animal populations, uncontrolled contamination of fresh water supplies, and increases in international travel, migration and trade. In this context of global concern, 68 international experts attending the fifth edition of the World HAI Resistance Forum in June 2015 shared their successes and failures in the global fight against AMR. They underlined the need for a “One Health” approach requiring research, surveillance, and interventions across human, veterinary, agricultural and environmental sectors. This strategy involves concerted actions on several fronts. Improved education and increased public awareness are a well-understood priority. Surveillance systems monitoring infections need to be expanded to include antimicrobial use, as well as the emergence and spread of AMR within clinical and environmental samples. Adherence to practices to prevent and control the spread of infections is mandatory to reduce the requirement of antimicrobials in general care and agriculture. Antibiotics need to be banned as growth promoters for farm animals in countries where it has not yet been done. Antimicrobial stewardship programmes in animal husbandry have proved to be efficient for minimising AMR, without compromising productivity. Regarding the use of antibiotics in humans, new tools to provide highly specific diagnoses of pathogens can decrease diagnostic uncertainty and improve clinical management. Finally, infection prevention and control measures – some of them as simple as hand hygiene – are essential and should be extended beyond healthcare settings. Aside from regulatory actions, all people can assist in AMR reduction by limiting antibiotic use for minor illnesses. Together, we can all work to reduce the burden of AMR.
[Show abstract][Hide abstract] ABSTRACT: Predictive models to identify unknown methicillin-resistant Staphylococcus aureus (MRSA) carriage on admission may optimise targeted MRSA screening and efficient use of resources. However, common approaches to model selection can result in overconfident estimates and poor predictive performance. We aimed to compare the performance of various models to predict previously unknown MRSA carriage on admission to surgical wards.
The study analysed data collected during a prospective cohort study which enrolled consecutive adult patients admitted to 13 surgical wards in 4 European hospitals. The participating hospitals were located in Athens (Greece), Barcelona (Spain), Cremona (Italy) and Paris (France). Universal admission MRSA screening was performed in the surgical wards. Data regarding demographic characteristics and potential risk factors for MRSA carriage were prospectively collected during the study period. Four logistic regression models were used to predict probabilities of unknown MRSA carriage using risk factor data: "Stepwise" (variables selected by backward elimination); "Best BMA" (model with highest posterior probability using Bayesian model averaging which accounts for uncertainty in model choice); "BMA" (average of all models selected with BMA); and "Simple" (model including variables selected >50% of the time by both Stepwise and BMA approaches applied to repeated random sub-samples of 50% of the data). To assess model performance, cross-validation against data not used for model fitting was conducted and net reclassification improvement (NRI) was calculated.
Of 2,901 patients enrolled, 111 (3.8%) were newly identified MRSA carriers. Recent hospitalisation and presence of a wound/ulcer were significantly associated with MRSA carriage in all models. While all models demonstrated limited predictive ability (mean c-statistics <0.7) the Simple model consistently detected more MRSA-positive individuals despite screening fewer patients than the Stepwise model. Moreover, the Simple model improved reclassification of patients into appropriate risk strata compared with the Stepwise model (NRI 6.6%, P = .07).
Though commonly used, models developed using stepwise variable selection can have relatively poor predictive value. When developing MRSA risk indices, simpler models, which account for uncertainty in model selection, may better stratify patients' risk of unknown MRSA carriage.
[Show abstract][Hide abstract] ABSTRACT: Since 2010, awareness of the global threat caused by antimicrobial resistance (AMR) has risen considerably and multiple policy and research initiatives have been implemented. Research and development (R&D) of much-needed new antibiotics active against multiresistant pathogens is a key component of all programmes aiming at fighting AMR, but it has been lagging behind owing to scientific, regulatory and economic challenges. Although a few new antibiotics might be available in Switzerland in the next 5 years, these new agents are not based on new mechanisms of action and are not necessarily active against resistant pathogens for which there is the highest unmet medical need, i.e. multiresistant Gram-negative bacteria. Of the three new antibiotics with pending authorisation in Switzerland for systemic treatment of severe infections, oritavancin and tedizolid target Gram-positive pathogens, while only ceftolozane+tazobactam partially covers multiresistant Gram-negative pathogens. Among six antibiotics currently in phase III of clinical development, delafloxacin and solithromycin will also be useful mostly for Gram-positive infections. Importantly, the four other compounds are active against multiresistant Gram-negative pathogens: ceftazidime+avibactam, meropenem+RPX7009, eravacycline and plazomicin. The three last compounds are also active against carbapenem-resistant Enterobacteriaceae (CRE). A few compounds active against such pathogens are currently in earlier clinical development, but their number may decrease, considering the risk of failure over the course of clinical development. At last, through public and political awareness of pathogens with high public health impact and unmet medical need, development of innovative economic incentives and updated regulatory guidance, R&D of new antibiotics is slowly taking off again.
[Show abstract][Hide abstract] ABSTRACT: Patients in the intensive care unit (ICU) frequently receive prolonged or even unnecessary antibiotic therapy, which selects for antibiotic-resistant bacteria. Over the last decade there has been great interest in biomarkers, particularly procalcitonin, to reduce antibiotic exposure.
In this narrative review, we discuss the value of biomarkers and provide additional information beyond clinical evaluation in order to be clinically useful and review the literature on sepsis biomarkers outside the neonatal period. Both benefits and limitations of biomarkers for clinical decision-making are reviewed.
Several randomized controlled trials (RCTs) have shown the safety and efficacy of procalcitonin to discontinue antibiotic therapy in patients with severe sepsis or septic shock. In contrast, there is limited utility of procalcitonin for treatment initiation or withholding therapy initially. In addition, an algorithm using procalcitonin for treatment escalation has been ineffective and is probably associated with poorer outcomes. Little data from interventional studies are available for other biomarkers for antibiotic stewardship, except for C-reactive protein (CRP), which was recently found to be similarly effective and safe as procalcitonin in a randomized controlled trial. We finally briefly discuss biomarker-unrelated approaches to reduce antibiotic duration in the ICU, which have shown that even without biomarker guidance, most patients with sepsis can be treated with relatively short antibiotic courses of approximately 7 days.
In summary, there is an ongoing unmet need for biomarkers which can reliably and early on identify patients who require antibiotic therapy, distinguish between responders and non-responders and help to optimize antibiotic treatment decisions among critically ill patients. Available evidence needs to be better incorporated in clinical decision-making.
Intensive Care Medicine 07/2015; 41(10). DOI:10.1007/s00134-015-3978-8 · 7.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Nitrofurantoin's use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin's efficacy and toxicity in the treatment of lower UTI.
We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials.
Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin's clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare.
When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.
[Show abstract][Hide abstract] ABSTRACT: Estimates of the excess length of stay (LOS) attributable to healthcare-associated infections (HAIs) in which total LOS of patients with and without HAIs are biased because of failure to account for the timing of infection. Alternate methods that appropriately treat HAI as a time-varying exposure are multistate models and cohort studies, which match regarding the time of infection. We examined the magnitude of this time-dependent bias in published studies that compared different methodological approaches.
We conducted a systematic review of the published literature to identify studies that report attributable LOS estimates using both total LOS (time-fixed) methods and either multistate models or matching patients with and without HAIs using the timing of infection.
Of the 7 studies that compared time-fixed methods to multistate models, conventional methods resulted in estimates of the LOS to HAIs that were, on average, 9.4 days longer or 238% greater than those generated using multistate models. Of the 5 studies that compared time-fixed methods to matching on timing of infection, conventional methods resulted in estimates of the LOS to HAIs that were, on average, 12.6 days longer or 139% greater than those generated by matching on timing of infection.
Our results suggest that estimates of the attributable LOS due to HAIs depend heavily on the methods used to generate those estimates. Overestimation of this effect can lead to incorrect assumptions of the likely cost savings from HAI prevention measures.
Infection Control and Hospital Epidemiology 06/2015; -1(9):1-6. DOI:10.1017/ice.2015.129 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Previous investigations of community-associated (CA)-MRSA isolates have revealed a wide diversity of genetic backgrounds with only sporadic occurrence of ST8-USA300 in Geneva. We conducted an epidemiologic and molecular analysis to identify the origin of a sudden increase of ST8 PVL-positive isolates in Geneva during the year 2013.
Based on prospective CA-MRSA surveillance we collected isolates from colonized and infected cases with ST8-USA300 and compared them with non-ST8 CA-MRSA cases. Whole-genome sequencing (WGS) was performed for each isolate of this collection and discriminating molecular features were linked to patient data.
In 2013, 22 isolates with ST8-USA300 profile were identified among 46 cases of CA-MRSA. WGS revealed two groups of strains that differed by the type of the SCCmec IV element encoded and whether they harbored an ACME locus. ACME-negative strains were mainly isolated from patients traveling in or originating from South America. SNP positions in isolate groups were used to infer their common ancestor, determine their geographical origin and trace their relatedness.
WGS allowed the identification of transmission events and revealed that the increased prevalence of USA300 CA-MRSA isolates resulted from multiple importation events from the Americas but not from local clonal expansion of a successful clone.
[Show abstract][Hide abstract] ABSTRACT: Non-manual techniques for terminal disinfection of hospital rooms have gained increasing interest in recent years as means to reduce transmission of multidrug-resistant organisms (MDROs). A prospective crossover study by Blazejewski and colleagues in five ICUs of a French academic hospital with a high prevalence of MDRO carriers showed that two different hydrogen peroxide (H2O2)-based non-touch disinfection techniques reduced environmental contamination with MDROs after routine cleaning. This study provides further evidence of the ‘in use’ bioburden reduction offered by these techniques. Before H2O2-based non-touch disinfection can be recommended for routine clinical use outside specific outbreak situations, further studies need to show whether the environmental contamination reduction provided by these techniques is clinically relevant and results in reduced cross-infections with MDROs.
Critical Care 05/2015; 19(1). DOI:10.1186/s13054-015-0915-8 · 4.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
To investigate a nosocomial outbreak of influenza.DesignProspective outbreak investigation with active case finding and molecular typing.SettingA large academic geriatric hospital in Switzerland.ParticipantsElderly hospitalized adults.MeasurementsBased on syndromic surveillance, a nosocomial influenza outbreak was suspected in February 2012. All suspected cases were screened for respiratory viruses using real-time reverse transcription polymerase chain reaction of nasopharyngeal swabs. Infection control procedures (droplet precautions with single room isolation whenever possible) were implemented for all suspected or confirmed cases. Specimens positive for influenza viruses were processed and sequenced whenever possible to track transmission dynamics.ResultsRespiratory samples from 155 suspected cases were analyzed during the outbreak period, of which 69 (44%) were positive for influenza virus, 26 (17%) were positive for other respiratory viruses, and 60 (39%) were negative. Three other cases fulfilled clinical criteria for influenza infection but were not sampled, and one individual was admitted with an already positive test, resulting in a total of 73 influenza cases, of which 62 (85%) were classified as nosocomial. Five distinct clusters of nosocomial transmission were identified using viral sequencing, with epidemiologically unexpected in-hospital transmission dynamics. Seven of 23 patients who experienced influenza complications died. Sixteen healthcare workers experienced an influenza-like illness (overall vaccination rate, 36%).Conclusion
Nosocomial influenza transmission caused more secondary cases than repeated community importation during this polyclonal outbreak. Molecular tools revealed complex transmission dynamics. Low healthcare worker vaccination rates and gaps in recommended infection control procedures are likely to have contributed to nosocomial spread of influenza, which remains a potentially life-threatening disease in elderly adults.
Journal of the American Geriatrics Society 04/2015; 63(4). DOI:10.1111/jgs.13339 · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whilst augmented renal clearance (ARC) is associated with reduced β-lactam plasma concentrations, its impact on clinical outcomes is unclear. This single-centre prospective, observational, cohort study included non-pregnant, critically ill patients aged 18–60 years with presumed severe infection treated with imipenem, meropenem, piperacillin/tazobactam or cefepime and with creatinine clearance (CLCr) ≥60 mL/min. Peak, intermediate and trough levels of β-lactams were drawn on Days 1–3 and 5. Concentrations were deemed ‘subthreshold’ if they did not meet EUCAST-defined non-species-related breakpoints. Primary and secondary endpoints were clinical response 28 days after inclusion, and ARC prevalence (CLCr ≥ 130 mL/min) and subthreshold and undetectable concentrations, respectively. Logistic regression was used to evaluate associations between ARC, antibiotic concentrations and clinical failure. From 2010 to 2013, 100 patients were enrolled (mean age, 45 years; median CLCr at inclusion, 144.1 mL/min). ARC was present in 64 (64%) of the patients. Most patients received imipenem/cilastatin (54%). Moreover, 86% and 27% of patients had at least one subthreshold or undetectable trough level, respectively. Among imipenem and piperacillin trough levels, 77% and 61% were subthreshold, respectively, but intermediate levels of both antibiotics were largely above threshold. ARC strongly predicted undetectable trough concentrations (OR = 3.3, 95% CI 1.11–9.94). A link between ARC and clinical failure (18/98; 18%) was not observed. ARC and subthreshold β-lactam antibiotic concentrations were widespread but were not associated with clinical failure. Larger studies are necessary to determine whether standard dosing regimens in the presence of ARC impact negatively on clinical outcome and antibiotic resistance.
International Journal of Antimicrobial Agents 01/2015; 45(4). DOI:10.1016/j.ijantimicag.2014.12.017 · 4.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this review was to provide an up-to-date account of the interventions used to prevent the introduction of meticillin-resistant Staphylococcus aureus (MRSA) from the expanding community and livestock reservoirs into hospitals in the USA, Denmark, The Netherlands and Western Australia. A review of existing literature and local guidelines for the management of MRSA in hospitals was performed. In Denmark, The Netherlands and Western Australia, where the prevalence of MRSA is relatively low, targeted admission screening and isolation of predefined high-risk populations have been used for several decades to successfully control MRSA in the hospital. Furthermore, in Denmark and The Netherlands, all identified MRSA carriers undergo routine decolonisation, whereas only carriers of particularly transmissible or virulent MRSA clones are subjected to decolonisation in Western Australia. In the USA, which continues to be a high-prevalence MRSA country, policies vary by state and even by hospital, and whilst guidelines from professional organisations provide a framework for infection control practices, these guidelines lack the authority of a legislative mandate. In conclusion, the changing epidemiology of MRSA, exemplified by the recent emergence of MRSA in the community and in food animals, makes it increasingly difficult to accurately identify specific high-risk groups to screen for MRSA carriage. Understanding the changing epidemiology of MRSA in a local as well as global context is fundamental to prevent the introduction of MRSA into hospitals.
Journal of Global Antimicrobial Resistance 12/2014; 2(4). DOI:10.1016/j.jgar.2014.09.003 · 1.09 Impact Factor