Stephan Harbarth

University of Geneva, Genève, Geneva, Switzerland

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Publications (228)1571.57 Total impact

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    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.
    BMC Infectious Diseases 12/2015; 15(1):834. DOI:10.1186/s12879-015-0834-y · 2.61 Impact Factor
  • Esther Bettiol · Stephan Harbarth
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    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.
    Schweizerische medizinische Wochenschrift 08/2015; 145:w14167. DOI:10.4414/smw.2015.14167 · 2.09 Impact Factor
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    ABSTRACT: To evaluate the relative efficacy of the World Health Organization 2005 campaign (WHO-5) and other interventions to promote hand hygiene among healthcare workers in hospital settings and to summarize associated information on use of resources. Systematic review and network meta-analysis. Medline, Embase, CINAHL, NHS Economic Evaluation Database, NHS Centre for Reviews and Dissemination, Cochrane Library, and the EPOC register (December 2009 to February 2014); studies selected by the same search terms in previous systematic reviews (1980-2009). Included studies were randomised controlled trials, non-randomised trials, controlled before-after trials, and interrupted time series studies implementing an intervention to improve compliance with hand hygiene among healthcare workers in hospital settings and measuring compliance or appropriate proxies that met predefined quality inclusion criteria. When studies had not used appropriate analytical methods, primary data were re-analysed. Random effects and network meta-analyses were performed on studies reporting directly observed compliance with hand hygiene when they were considered sufficiently homogeneous with regard to interventions and participants. Information on resources required for interventions was extracted and graded into three levels. Of 3639 studies retrieved, 41 met the inclusion criteria (six randomised controlled trials, 32 interrupted time series, one non-randomised trial, and two controlled before-after studies). Meta-analysis of two randomised controlled trials showed the addition of goal setting to WHO-5 was associated with improved compliance (pooled odds ratio 1.35, 95% confidence interval 1.04 to 1.76; I(2)=81%). Of 22 pairwise comparisons from interrupted time series, 18 showed stepwise increases in compliance with hand hygiene, and all but four showed a trend for increasing compliance after the intervention. Network meta-analysis indicated considerable uncertainty in the relative effectiveness of interventions, but nonetheless provided evidence that WHO-5 is effective and that compliance can be further improved by adding interventions including goal setting, reward incentives, and accountability. Nineteen studies reported clinical outcomes; data from these were consistent with clinically important reductions in rates of infection resulting from improved hand hygiene for some but not all important hospital pathogens. Reported costs of interventions ranged from $225 to $4669 (£146-£3035; €204-€4229) per 1000 bed days. Promotion of hand hygiene with WHO-5 is effective at increasing compliance in healthcare workers. Addition of goal setting, reward incentives, and accountability strategies can lead to further improvements. Reporting of resources required for such interventions remains inadequate. © Luangasanatip et al 2015.
    BMJ (online) 07/2015; 351:h3728. DOI:10.1136/bmj.h3728 · 17.45 Impact Factor
  • Werner C Albrich · Stephan Harbarth
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    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
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    ABSTRACT: Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a 'one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the β-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with β-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing β-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
    Journal of Antimicrobial Chemotherapy 07/2015; DOI:10.1093/jac/dkv201 · 5.31 Impact Factor
  • Stephan Harbarth
    Evidence-based medicine 07/2015; 20(4). DOI:10.1136/ebmed-2015-110241
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    ICPIC 2015; 06/2015
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    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. Methods: 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. Results: 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. Conclusions: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.
    Journal of Antimicrobial Chemotherapy 06/2015; 70(9). DOI:10.1093/jac/dkv147 · 5.31 Impact Factor
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    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. METHODS 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. RESULTS 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. CONCLUSION 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
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    Benedikt D Huttner · Stephan Harbarth
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    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
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    ABSTRACT: As the number of antibacterial medicines in the pipeline remains low, we anonymously surveyed pharmaceutical industry professionals on challenges and solutions for clinical development of these agents. Challenges were reported primarily as financial and regulatory. For multi-drug resistant organisms, there are needs for rapid diagnostic tests, new regulatory guidance, and adaptation of endpoints/trial designs. Regulators and public-private initiatives are addressing these challenges, to help ensuring that proposed solutions have the support of all involved stakeholders. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 04/2015; 59(7). DOI:10.1128/AAC.00638-15 · 4.48 Impact Factor
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    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
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    ABSTRACT: The objective was to study changes in the faecal microbiota of patients with uncomplicated urinary tract infections (UTIs) treated with nitrofurantoin and of non-treated healthy controls using 16S rRNA analysis. Serial stool samples were collected from patients receiving nitrofurantoin treatment at different timepoints [before treatment (day 1; T1), within 48 h of end of treatment (days 5-15; T2) and 28 days after treatment (days 31-43; T3)], as well as from healthy controls. Direct DNA extraction (PowerSoil DNA Isolation Kit, MoBio Laboratories, Carlsbad, CA, USA) from stool samples was followed by pyrosequencing (454 GS FLX Titanium) of the V3-V5 region of the bacterial 16S rRNA gene. Among UTI patients, mean proportions of the Actinobacteria phylum increased by 19.6% in the first follow-up sample (T2) in comparison with the pretreatment baseline stool sample (T1) (P = 0.026). However, proportions of Actinobacteria reversed to 'normal' pre-antibiotic levels, with a mean difference of 1.0% compared with baseline proportions, in the second follow-up sample (T3). The increase in Actinobacteria was specifically due to an increase in the Bifidobacteriaceae family (Bifidobacterium genus), which constituted 81.0% (95% CI ±7.4%) of this phylum. No significant impact was observed other than a temporary increase in the beneficial Bifidobacterium genus following nitrofurantoin treatment, which supports its reintroduction into clinical use. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
    Journal of Antimicrobial Chemotherapy 03/2015; 70(7). DOI:10.1093/jac/dkv062 · 5.31 Impact Factor
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    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
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    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
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    Kalisvar Marimuthu · Didier Pittet · Stephan Harbarth
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    ABSTRACT: The purpose of this review is to examine studies that have assessed the association between hand hygiene enhancement and methicillin-resistant Staphylococcus aureus (MRSA) rates and to explore controversies surrounding this association. Many studies have been published confirming the link between improved hand hygiene compliance and reduction in MRSA acquisition and infections, including bacteremia. These studies have also shown the cost-beneficial nature of these programmes. Despite considerable research some issues remain unanswered still, including the temporal relationship between hand hygiene enhancement strategies and decrease in MRSA rates, association between hand hygiene enhancement and MRSA-related surgical site infections, diminishing effect of hand hygiene compliance on MRSA rates after reaching a threshold and the role of instituting contact precautions in the setting of low MRSA rates and sufficient hand hygiene compliance. In conclusion, enhancement of hand hygiene compliance has been shown to reduce MRSA rates; however, some open issues warrant further investigation.
    11/2014; 3(1):34. DOI:10.1186/2047-2994-3-34
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    ABSTRACT: The best treatment for Tropheryma whipplei infections is controversial. We report a patient who suffered from T. whipplei aortic native valve endocarditis that relapsed despite surgery and four weeks of intravenous ceftriaxone followed by several months of oral trimethoprim/sulfamethoxazole. Cure was achieved after replacement of the prosthesis with a homograft and 18 months of oral doxycycline-hydroxychloroquine. We discuss the need for a change in treatment guidelines for T. whipplei infections. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
    International Journal of Infectious Diseases 11/2014; 30C:17-19. DOI:10.1016/j.ijid.2014.11.003 · 1.86 Impact Factor
  • K Stucki · S Harbarth · M Nendaz
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    ABSTRACT: Enterococci are microorganisms with a remar- kable ability to adapt to their environment. Two species have a significant clinical implication, Enterococcus faecalis and Enterococcus faecium. The risk factors for colonization and infection must be recognized, including prior treatment with antibiotics such as cephalosporins or quinolones. Because of their native resistance to several classes of antibiotics and the increase of acquired resistance to penicillins, the initial empiric treatment of a severe infection in a patient at risk of enterococcal infection often includes a glycopeptide. A restriction in the empirical use of cephalosporins or quinolones and a targeted antibiotic therapy following receipt of the antibiogram are essential to prevent the emergence of enterococcal strains and especially vancomycin-resistant enterococci.
    Revue médicale suisse 10/2014; 10(446):1918, 1920-3.
  • Benedikt Huttner · Stephan Harbarth · Dilip Nathwani
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    ABSTRACT: It has been increasingly recognized that antimicrobial stewardship (AMS) has to be a key component of any efforts that aim to mitigate the current global antimicrobial resistance (AMR) crisis. It has also become evident that AMR is a problem that cannot be tackled by single institutions or physicians, but needs concerted actions on the regional, national and supranational level. It is, however, easy to become discouraged given the problems that are often encountered when implementing AMS. The aim of this review is to highlight some of the success stories of AMS strategies, to describe the actions that have been taken, the outcomes that have been obtained and the obstacles that have been met. While the best approach to effective AMS remains elusive and may significantly vary among settings, these diverse examples from a range of health care contexts demonstrate that effective AMS is possible. The learning from such examples will inform and encourage others to formally evaluate and share their results with the global stewardship community. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 10/2014; 20(10). DOI:10.1111/1469-0691.12803 · 5.77 Impact Factor
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    ABSTRACT: Importance The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial.Objective To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia.Design, Setting, and Participants Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation.Interventions Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm.Main Outcomes and Measures Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7.Results After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.Conclusions and Relevance We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.Trial Registration Identifier: NCT00818610
    JAMA Internal Medicine 10/2014; 174(12). DOI:10.1001/jamainternmed.2014.4887 · 13.12 Impact Factor

Publication Stats

10k Citations
1,571.57 Total Impact Points


  • 1998–2015
    • University of Geneva
      • • Faculty of Medicine
      • • Division of Infectious Diseases
      • • Department of Internal Medicine
      Genève, Geneva, Switzerland
  • 1998–2014
    • Hôpitaux Universitaires de Genève
      • Service de médecine interne générale (SMIG)
      Genève, Geneva, Switzerland
  • 2011
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
    • Royal Prince Alfred Hospital
      • Division of Infectious Diseases & Microbiology
      Camperdown, New South Wales, Australia
  • 2002–2007
    • University of Utah
      • Division of Infectious Diseases
      Salt Lake City, Utah, United States
  • 2006
    • Universitätsspital Basel
      • Klinik für Infektiologie & Spitalhygiene
      Bâle, Basel-City, Switzerland
  • 2001–2002
    • Boston Children's Hospital
      • Division of Infectious Diseases
      Boston, Massachusetts, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1999–2000
    • Harvard University
      • Department of Epidemiology
      Cambridge, Massachusetts, United States