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Optimizing antibiotic therapies to reduce the risk of bacterial resistance

  • Stefano Bassetti
    Correspondence
    Corresponding author at: Division of Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
    Affiliations
    Division of Internal Medicine, University Hospital Basel and University of Basel, Switzerland

    Department of Clinical Research, University Hospital Basel and University of Basel, Switzerland
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  • Sarah Tschudin-Sutter
    Affiliations
    Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, Switzerland

    Department of Clinical Research, University Hospital Basel and University of Basel, Switzerland
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  • Adrian Egli
    Affiliations
    Division of Clinical Bacteriology and Mycology, University Hospital Basel and University of Basel, Switzerland

    Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland
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  • Michael Osthoff
    Affiliations
    Division of Internal Medicine, University Hospital Basel and University of Basel, Switzerland

    Department of Clinical Research, University Hospital Basel and University of Basel, Switzerland
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Open AccessPublished:January 21, 2022DOI:https://doi.org/10.1016/j.ejim.2022.01.029

      Highlights

      • About 33′000 deaths yearly are caused by antibiotic resistant bacteria in Europe.
      • Up to > 50% of antibiotic treatments are inappropriate, depending on the setting.
      • To improve antibiotic prescribing a bundle of measures is necessary, based on education, clinical reasoning, and improvement of the prescribing environment.
      • Possible strategies/tools to optimize antibiotic therapies and to reduce the risk of bacterial resistance include: rapid microbiological diagnostics, inflammation markers-guided therapies, the reduction of standard durations of antibiotic courses, to consider dosing according to PK/PD targets and to avoid antibiotic classes carrying a higher risk for induction of bacterial resistance.

      Abstract

      The incidence of infections caused by bacteria that are resistant to antibiotics is constantly increasing. In Europe alone, it has been estimated that each year about 33′000 deaths are attributable to such infections. One important driver of antimicrobial resistance is the use and abuse of antibiotics in human medicine. Inappropriate prescribing of antibiotics is still very frequent: up to 50% of all antimicrobials prescribed in humans might be unnecessary and several studies show that at least 50% of antibiotic treatments are inadequate, depending on the setting. Possible strategies to optimize antibiotic use in everyday clinical practice and to reduce the risk of inducing bacterial resistance include: the implementation of rapid microbiological diagnostics for identification and antimicrobial susceptibility testing, the use of inflammation markers to guide initiation and duration of therapies, the reduction of standard durations of antibiotic courses, the individualization of antibiotic therapies and dosing considering pharmacokinetics/pharmacodynamics targets, and avoiding antibiotic classes carrying a higher risk for induction of bacterial resistance. Importantly, measures to improve antibiotic prescribing and antibiotic stewardship programs should focus on facilitating clinical reasoning and improving prescribing environment in order to remove any barriers to good prescribing.

      Key words

      Introduction

      The incidence of infections caused by bacteria that are resistant to antibiotics is constantly increasing. Infections with resistant bacteria are associated with higher morbidity, mortality and costs. It has been estimated that in Europe each year about 33′000 deaths are attributable to infections with antibiotic resistant bacteria [
      • Cassini A.
      • et al.
      Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis.
      ], and that by 2050 antimicrobial resistance will cause 10 million deaths every year worldwide (as compared to e.g. 8.2 million deaths caused annually by cancer) [
      • O’Neill J.
      Tackling drug-resistant infections globally: final report and recommendations.
      ]. In 2019, the World Health Organization (WHO) declared antimicrobial resistance as one of the top 10 global public health threats facing humanity [
      Global antimicrobial resistance and use surveillance system (GLASS) report 2021.
      ]. In the same year, a United Nations report stated that “alarming levels of resistance have been reported in countries of all income levels, with the result that common diseases are becoming untreatable, and lifesaving medical procedures riskier to perform” [

      Interagency Coordination Group (IACG) on Antimicrobial Resistance (2019). No time to wait: securing the future from drug-resistant infections. Report to the secretary-general of the United Nations. 2019, United Nations: https://www.who.int/publications/i/item/no-time-to-wait-securing-the-future-from-drug-resistant-infections (accessed July 16, 2021).

      ].
      Antibiotic resistance occurs naturally in bacteria and predates the use of antibiotics. Metagenomic analyses of ancient DNA from 30,000-year-old permafrost sediments found for example a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics [
      • D’Costa V.M.
      • et al.
      Antibiotic resistance is ancient.
      ]. Most known antibiotics are produced by microorganisms, and many organisms in the environment, including plants and animals, naturally produce antimicrobial substances [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ]. The exposure to antimicrobials selects resistant bacteria and drives the spread of antimicrobial resistance. Several factors contribute to this selective pressure: the use and abuse of antibiotics in human medicine, in veterinary medicine, in food-animal and fish production, but also environmental contamination and pollution [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ,
      • Hendriksen R.S.
      • et al.
      Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage.
      ]. As the drivers of antimicrobial resistance lie in humans, animals, plants, food and the environment and are interconnected, the problem of spreading antimicrobial resistance can only be addressed by a “One Health” approach, which is the collaborative effort of multiple health science professions to attain optimal health for people, domestic animals, wildlife, plants, and our environment [

      Interagency Coordination Group (IACG) on Antimicrobial Resistance (2019). No time to wait: securing the future from drug-resistant infections. Report to the secretary-general of the United Nations. 2019, United Nations: https://www.who.int/publications/i/item/no-time-to-wait-securing-the-future-from-drug-resistant-infections (accessed July 16, 2021).

      ,
      • McEwen S.A.
      • Collignon P.J.
      Antimicrobial resistance: a one health perspective.
      ]. Keeping this interconnectivity in mind, stakeholders should engage with issues specific to their area of competence [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ]. In the present review, we will focus on possible strategies to optimize antibiotic therapies in everyday clinical practice and reduce the risk of inducing bacterial resistance to antibiotics.

      Antibiotic use in human medicine

      Both, the overall reduction of antibiotic consumption and the reduction of inappropriate antibiotic use are essential measures to reduce the emergence of resistant bacteria and are the targets of antibiotic stewardship programs, i.e. of a collection of strategies, policies, guidelines or tools aiming at improving antibiotic use [
      • Monnier A.A.
      • et al.
      Towards a global definition of responsible antibiotic use: results of an international multidisciplinary consensus procedure.
      ,
      • Monnier A.A.
      • et al.
      Quality indicators for responsible antibiotic use in the inpatient setting: a systematic review followed by an international multidisciplinary consensus procedure.
      ]. Recent studies showed that the global use of antibiotics in human medicine is increasing, while inappropriate prescribing of antibiotics remains frequent: it has been estimated, that up to 50% of all antimicrobials prescribed in humans might be unnecessary [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ].
      An analysis of antibiotic consumption in 76 countries showed that from the year 2000 to 2015, the antibiotic consumption expressed in defined daily doses (DDD) increased by 65% and the antibiotic consumption rate (DDDs per 1′000 inhabitants per day) by 39%. The increase in antibiotic consumption was driven by low- and middle-income countries. In most of these countries, consumption rates are still lower than in high-income countries. However, their antibiotic consumption rates are rapidly aligning to the rates in high-income countries. In high-income countries overall consumption increased modestly and DDDs per 1000 inhabitants per day fell by 4%. Alarmingly, in both high-income and low- and middle-income countries, the use of last-resort antibiotics (such as glycylcyclines, oxazolidinones, carbapenems, and polymyxins) was rapidly increasing. The authors projected a 200% increase of global antibiotic consumption by 2030, assuming no policy changes would be implemented [
      • Klein E.Y.
      • et al.
      Global increase and geographic convergence in antibiotic consumption between 2000 and 2015.
      ]. There are large variations in antibiotic consumption among countries, even among countries with similar income level [
      • Klein E.Y.
      • et al.
      Global increase and geographic convergence in antibiotic consumption between 2000 and 2015.
      ,
      • Robertson J.
      • et al.
      Variations in the consumption of antimicrobial medicines in the European region, 2014-2018: findings and implications from ESAC-Net and WHO Europe.
      ]. The analysis of consumption data of antimicrobials for systemic use in 45 countries of the WHO European Region in 2018 showed for example, that the total antibiotic consumption rate was up to 3.5 times higher in the countries with highest consumption compared with the countries with lowest consumption (e.g. Greece 34.1, Turkey 30.9 versus Netherlands 9.7 DDD per 1′000 inhabitants per day). Large variations are observed not only for the total antibiotic consumption, but also for the use of parenteral antibiotics (e.g. in Romania 23.9% of total antibiotic consumption are parenteral formulations versus 2.8% in Turkey) and for the use of different antibiotic classes, including the use of antibiotics that have a higher risk of selecting for resistance and that only should be used as first- or second-line options for a limited number of indications (“Watch antibiotics” according to the WHO AWaRe classification [
      • Pauwels I.
      • et al.
      Hospital antibiotic prescribing patterns in adult patients according to the WHO Access, Watch and Reserve classification (AWaRe): results from a worldwide point prevalence survey in 69 countries.
      ]). The relative consumption of Watch antibiotics ranged from 13% of total consumption in Iceland to 61% in Slovakia and 69% in Uzbekistan [
      • Robertson J.
      • et al.
      Variations in the consumption of antimicrobial medicines in the European region, 2014-2018: findings and implications from ESAC-Net and WHO Europe.
      ].
      These large variations not only in total consumption but also in the patterns of antibiotics prescriptions are mostly unexplained and suggest opportunities for improved prescribing [
      • Klein E.Y.
      • et al.
      Global increase and geographic convergence in antibiotic consumption between 2000 and 2015.
      ,
      • Robertson J.
      • et al.
      Variations in the consumption of antimicrobial medicines in the European region, 2014-2018: findings and implications from ESAC-Net and WHO Europe.
      ]. This is confirmed by several studies reporting inappropriate prescribing in different settings (hospitals and outpatients) and different countries. A recent study analyzing antibiotic prescriptions in ambulatory patients in the USA concluded that the proportion of unnecessary antibiotic prescriptions in US physician offices and emergency departments in 2014–2015 was 28%, compared to 30% in 2010–2011. While unnecessary prescribing among adults did not change during this period, there was a decrease in children from 32% to 19% [
      • Hersh A.L.
      • et al.
      Unnecessary antibiotic prescribing in US ambulatory care settings, 2010-2015.
      ]. Also in hospitals, a substantial part of antibiotics treatments overall or in specific subgroups of patients is inappropriate. A cross-sectional study analyzed 1566 patients at 192 US hospitals. The prevalence of patients with antimicrobial medications was 49.5%. Antibiotic use was inadequate in 56% of patients treated for community-acquired pneumonia or urinary tract infection or receiving fluoroquinolones or intravenous vancomycin [
      • Magill S.S.
      • et al.
      Assessment of the appropriateness of antimicrobial use in US hospitals.
      ]. A national point prevalence survey in Germany included data from 218 acute care hospitals, more than 64′000 patients and 22′000 administered antimicrobials. Overall 26.2% of patients were treated with antibiotics. The rate of inadequate antibiotic use was 50% in patients with surgical prophylaxis, community-acquired pneumonia, pyelonephritis, asymptomatic bacteriuria and patients receiving antibiotic treatment without clear indication [
      • Aghdassi S.J.S.
      • et al.
      The quality of antimicrobial prescribing in acute care hospitals: results derived from a national point prevalence survey, Germany, 2016.
      ]. In a repeated point prevalence survey at one tertiary hospital in Switzerland evaluating all patients receiving antibiotics, 33% of prescriptions were not appropriate [
      • Gurtler N.
      • et al.
      Appropriateness of antimicrobial prescribing in a Swiss tertiary care hospital: a repeated point prevalence survey.
      ]. The main reasons for inappropriate antibiotic therapies reported in several studies include non-adherence to prescription guidelines, lack of indication for antimicrobial therapy, excessive duration of therapy, incorrect dosing and delay in the switch from intravenous to oral administration [
      • Magill S.S.
      • et al.
      Assessment of the appropriateness of antimicrobial use in US hospitals.
      ,
      • Gurtler N.
      • et al.
      Appropriateness of antimicrobial prescribing in a Swiss tertiary care hospital: a repeated point prevalence survey.
      ]. Based on these observations, several targets for interventions aiming at optimizing antibiotic use and reducing the risk of bacterial resistance can be identified (Table 1), in addition to, or as part of antibiotic stewardship measures.
      Table 1Possible measures and targets for interventions aiming at optimizing antibiotic use and reducing the risk of bacterial resistance (in addition to, or as part of antibiotic stewardship programs).
      MeasuresAims
      Reduce the use of antibiotics (and in particular of broad spectrum antibiotics)
      Implement rapid microbiological diagnostics- Rapid identification of non-bacterial infections / illnesses –> withhold or stop antibiotics

      - Rapid identification of bacteria and susceptibility testing –> de-escalate antibiotics
      Inflammation markers-guided therapies (e.g. C-reactive protein, procalcitonin)- Shorten treatment duration and withhold non indicated antibiotic treatments
      Shorter standard duration of antibiotic treatment (based on current evidence)- Reduce total amount of antibiotics per treatment course
      Reduce the risk of emergence of bacterial resistance
      Choose the antibiotic class with lowest potential for inducing resistance- Avoid / reduce the use of antibiotic classes with higher risk of selecting for bacterial resistance
      Choose the right antibiotic dosage and route of administration considering PK/PD targets- Avoid subtherapeutic concentrations and non-lethal selective pressure
      In general:
      Facilitate and promote clinical reasoning, and improve the prescribing environment (e.g. through good organization and enough time in consultations and on rounds)- Obtain the time needed for careful clinical evaluation of the patient and for thorough assessment of laboratory and microbiology results
      PK: pharmacokinetics; PD: pharmacodynamics.

      Rapid microbiological diagnostics

      The identification of bacteria in microbiological cultures is the current gold standard for the diagnosis of bacterial infections. However, culture based identification of bacteria and phenotypic antibiotic susceptibility testing usually take > 48 h. Waiting for the results of cultures, empiric antibiotic therapies are therefore frequently started in patients with fever, but eventually without bacterial infections, and patients with suspected severe infections such as sepsis are empirically treated with broad-spectrum antibiotics for several days. The long turn-around times of conventional testing hinders withholding or rapid stopping of unnecessary antibiotics in non-bacterial infections and hinders rapid escalation or de-escalation of antibiotics. This may delay optimal antimicrobial treatment of the causative pathogen [
      • Briggs N.
      • Campbell S.
      • Gupta S.
      Advances in rapid diagnostics for bloodstream infections.
      ]. Rapid methods for identification of bacteria and antimicrobial susceptibility testing such as methods based on Nucleic Acid Amplification Technology (NAAT) or on Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight mass spectrometry (MALDI-TOF) provide results within minutes to hours and can in some cases be applied directly to patient samples, thereby bypassing time demanding culture steps [
      • Vasala A.
      • Hytonen V.P.
      • Laitinen O.H.
      Modern tools for rapid diagnostics of antimicrobial resistance.
      ,
      • Osthoff M.
      • et al.
      Impact of MALDI-TOF-MS-based identification directly from positive blood cultures on patient management: a controlled clinical trial.
      ,
      • Hinic V.
      • Reist J.
      • Egli A.
      Evaluation of the rapid biochemical beta-CARBA test for detection of carbapenemase-producing Gram-negative bacteria.
      ,
      • Torres-Miranda D.
      • et al.
      Use of BioFire FilmArray gastrointestinal PCR panel associated with reductions in antibiotic use, time to optimal antibiotics, and length of stay.
      ]. The knowledge of causative bacteria and of possible presence or absence of resistance points to the possible source of infection and allows for fast optimization and optimal duration of antibiotic treatment. This affects patient outcome and costs of care. A meta-analysis including 31 studies with 5920 patients with bloodstream infections found that the use of molecular rapid diagnostic testing (polymerase chain reaction [PCR], MALDI-TOF, or peptide nucleic acid fluorescent in situ hybridization [PNA-FISH]) was associated with significant decreases of mortality risk in the presence of an antibiotic stewardship program (number needed to treat of 20), shorter time to effective therapy (- 5 h) and shorter length of stay (- 2.5 days) [
      • Timbrook T.T.
      • et al.
      The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis.
      ]. In a controlled clinical trial on 368 patients with positive blood cultures in a setting with an antibiotic stewardship program and low resistance rates, rapid identification of bacteria using MALDI-TOF directly from positive blood cultures significantly shortened the time to active treatment (- 3 h) in patients with clinically significant bloodstream infection, and decreased the duration of intravenous antibiotic treatment (- 2.7 days) in patients with contaminated blood cultures. Admission to the intensive care unit after bloodstream infection onset was significantly less frequent in the MALDI-TOF group (23.1 versus 37.2%) [
      • Osthoff M.
      • et al.
      Impact of MALDI-TOF-MS-based identification directly from positive blood cultures on patient management: a controlled clinical trial.
      ]. In another study, the use of a PCR-based test that reports the presence of bacteria, viruses, and genetic markers of antimicrobial resistance within about 75 min. was evaluated in bronchoalveolar lavage of adult hospitalized patients with lower respiratory tract infections. The authors estimated that the results of this test would have allowed for antibiotic adjustment in 71% of patients, including discontinuation or de-escalation in 48% of patients, resulting in an average saving of 6.2 antibiotic days/patient [
      • Buchan B.W.
      • et al.
      Practical comparison of the BioFire FilmArray pneumonia panel to routine diagnostic methods and potential impact on antimicrobial stewardship in adult hospitalized patients with lower respiratory tract infections.
      ]. This observation is supported by the findings of a recent randomized controlled trial investigating the effect antibiotic stewardship based on multiplex bacterial PCR performed on bronchoalveolar lavage of patients with pneumonia at risk for Gram-negative bacterial infection. For patients in the PCR group, time on inappropriate antibiotic therapy was reduced by 45% [
      • Darie A.
      • K.N Jahn K
      • Osthoff M.
      • Bassetti S.
      • Osthoff M.
      • Schumann D.
      • Albrich W.
      • Brutsche M.
      • Grize L.
      • Tamm M.
      • Stolz D.
      Fast multiplex bacterial PCR in the bronchoalveolar lavage for antibiotic stewardship in hospitalized patients with pneumonia at risk for Gram negative bacteria infection–the randomized FLAGSHIP II Study.
      ]. The proper evaluation of the impact of new technologies is crucial to quantify effects on antibiotic stewardship and patient outcomes. Whereas most studies fail to show an impact on mortality due to a low power, many studies provide clear evidence on a shorter time to optimal antibiotic treatments. It is expected that the digitalization of microbiological data will allow to further speed up the diagnostic workflows and make data more rapidly available [
      • Egli A.
      • Schrenzel J.
      • Greub G.
      Digital microbiology.
      ]. In addition, new technologies able to detect or exclude the presence of pathogens within minutes and as point-of-care tests may allow withholding antibiotics at all [
      • Rentschler S.
      • Kaiser L.
      • Deigner H.P.
      Emerging Options for the Diagnosis of Bacterial Infections and the Characterization of Antimicrobial Resistance.
      ].

      Inflammation markers–guided therapies

      In several conditions, it is very difficult or even impossible to clinically differentiate between a bacterial, a viral infection or a non-infectious inflammatory disorder. Therefore, the unnecessary prescription of antibiotics for viral infections or non-infectious inflammations is a frequent and relevant problem. This is particularly true for respiratory infections, which are one of the most frequent indication for antibiotics but are mostly of viral origin (respiratory infections are the most common infections treated with antibiotics in European hospitals, causing about 32% of antibiotic prescriptions [
      • Plachouras D.
      • et al.
      Antimicrobial use in European acute care hospitals: results from the second point prevalence survey (PPS) of healthcare-associated infections and antimicrobial use, 2016 to 2017.
      ]). Several studies have evaluated whether measurements of different biomarkers may help to discriminate acute bacterial infections from non-bacterial infections or non-infectious inflammatory states. Among the diagnostic biomarkers studied are cellular biomarkers, such as leukocyte surface markers (e.g. neutrophil CD35 or CD64 expression), and soluble biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT), markers of macrophage activation (e.g. neopterin, soluble CD163), cytokines (e.g. interleukin (IL)−2, IL-6, IL-8) and soluble receptors, including proteins involved in Toll-like receptor signaling [
      • ten Oever J.
      • Netea M.G.
      • Kullberg B.J.
      Utility of immune response-derived biomarkers in the differential diagnosis of inflammatory disorders.
      ]. New tests assessing host-response by profiling host gene expression in the peripheral blood (via measurement of host messenger RNA transcripts) seem promising for determining the likelihood of bacterial and viral infections [
      • Bauer W.
      • et al.
      A Novel 29-Messenger RNA host-response assay from whole blood accurately identifies bacterial and viral infections in patients presenting to the emergency department with suspected infections: a prospective observational study.
      ,
      • Tsalik E.L.
      • et al.
      Discriminating bacterial and viral infection using a rapid host gene expression test.
      ].
      Currently, the two most commonly used and available biomarkers are CRP, which is synthetized in the liver mainly in response to IL-6 [
      • ten Oever J.
      • Netea M.G.
      • Kullberg B.J.
      Utility of immune response-derived biomarkers in the differential diagnosis of inflammatory disorders.
      ], and PCT, a calcitonin-related gene product expressed by human epithelial cells in response to bacterial infection and downregulated during viral infections [
      • Schuetz P.
      • et al.
      Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.
      ]. Guidelines recommend interpreting results of CRP-test in patients with suspected pneumonia as follows: a CRP level of <20 mg/L at presentation, with symptoms for >24 h, makes the presence of pneumonia highly unlikely (therefore, no antibiotics are indicated), a level of >100 mg/L makes pneumonia likely (therefore: offer antibiotic therapy) [
      • Woodhead M.
      • et al.
      Guidelines for the management of adult lower respiratory tract infections–full version.
      ]. CRP use was for example shown to effectively reduce antibiotic prescribing for respiratory tract infections in primary care [
      • Little P.
      • et al.
      Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections: a multinational, cluster, randomised, factorial, controlled trial.
      ].
      PCT has a higher diagnostic accuracy in differentiating community-acquired pneumonia from other diagnoses, as compared to CRP [
      • Muller B.
      • et al.
      Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia.
      ]. Several randomized controlled trials investigated the use of PCT to guide antibiotic treatment in patients with acute respiratory infections and reported significant reductions in antibiotic exposure and duration of treatment in the PCT-guided therapy group [
      • Schuetz P.
      • et al.
      Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.
      ]. Recently, a point-of-care test for PCT became available and the use of point-of-care PCT was shown to significantly reduce antibiotic prescription rates in patients with a lower respiratory tract infection in primary care [
      • Lhopitallier L.
      • et al.
      Procalcitonin and lung ultrasonography point-of-care testing to determine antibiotic prescription in patients with lower respiratory tract infection in primary care: pragmatic cluster randomised trial.
      ]. Accordingly, in our clinical experience and in retrospective and observational studies, a negative PCT in COVID-19 patients appears to be very useful to help ruling out bacterial co-infection, and the measurement of PCT in COVID-19 patients reduces unnecessary antibiotic treatments [
      • Williams E.J.
      • et al.
      Evaluation of procalcitonin as a contribution to antimicrobial stewardship in SARS-CoV-2 infection: a retrospective cohort study.
      ,
      • Roy A.
      • et al.
      Antibiotic stewardship: early discontinuation of antibiotics based on procalcitonin level in COVID-19 pneumonia.
      ,
      • Heesom L.
      • et al.
      Procalcitonin as an antibiotic stewardship tool in COVID-19 patients in the intensive care unit.
      ,
      • Richards O.
      • et al.
      Procalcitonin Increase Is Associated with the Development of Critical Care-Acquired Infections in COVID-19 ARDS.
      ,
      • Wolfisberg S.
      • Gregoriano C.
      • Schuetz P.
      Procalcitonin for individualizing antibiotic treatment: an update with a focus on COVID-19.
      ]. In 2017, the U.S. Food and Drug Administration approved an expanded indication for PCT “to help health care providers determine if antibiotic treatment should be started or stopped in patients with lower respiratory tract infections.” [
      • Pulia M.S.
      • Lindenauer P.K.
      Web exclusive. Annals for hospitalists inpatient notes - a critical look at procalcitonin testing in pneumonia.
      ]. In 2018 a large patient level meta-analysis including patient data from 26 randomized controlled trials with 6708 patients concluded that use of PCT to guide antibiotic treatment in patients with acute respiratory infections not only significantly reduces antibiotic exposure (by 2.4 days) and side effects, but also mortality (adjusted odds ratio (OR) 0.83 (95% CI 0.70 – 0.99)) [
      • Schuetz P.
      • et al.
      Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.
      ]. Despite this robust evidence, controversy on the use of PCT persists. However, it should be noted, that criticism of PCT-guided antibiotic therapy is frequently based on results of studies looking at different outcomes and / or using different PCT-protocols. Some of these studies failed for example to find a PCT threshold clearly discriminating between community-acquired pneumonia caused by bacteria or by viruses [
      • Self W.H.
      • et al.
      Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia.
      ]. However, this is not the relevant outcome, because even in large studies performing extensive diagnostic tests, no pathogen causing community-acquired pneumonia can be identified in more than 60% of patients [
      • Bergin S.P.
      • Tsalik E.L.
      Procalcitonin: the right answer but to which question?.
      ]. Moreover, in the same study by Self et al. [
      • Self W.H.
      • et al.
      Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia.
      ], PCT was measured only once, whereas in the studies showing a benefit of PCT-algorithms, PCT was usually measured repeatedly, in order to account for the dynamic of PCT secretion in response to bacterial infection. Other studies investigated the usefulness of PCT-guided algorithms, but were not able to sufficiently enforce the use of these algorithms, so that in one such study for example the adherence of clinicians with PCT guidelines recommendations for antibiotic treatment was only 39% for community-acquired pneumonia, and 49% for exacerbations of chronic obstructive pulmonary disease (COPD) [
      • Huang D.T.
      • et al.
      Procalcitonin-guided use of antibiotics for lower respiratory tract infection.
      ].
      If used correctly to complement clinical practice, PCT is a useful tool for antibiotic stewardship and allows to safely reduce antibiotic use in patients with acute lower respiratory tract infections [
      • Pulia M.S.
      • Lindenauer P.K.
      Web exclusive. Annals for hospitalists inpatient notes - a critical look at procalcitonin testing in pneumonia.
      ].

      Shorter standard duration of antibiotic therapies

      The standard duration of antibiotic therapy for most bacterial infections is not based on evidence and is frequently unnecessarily long. A simple and safe strategy to reduce antibiotic use is therefore the reduction in length of standard antimicrobial regimens [
      • Rice L.B.
      The Maxwell Finland Lecture: for the duration-rational antibiotic administration in an era of antimicrobial resistance and clostridium difficile.
      ,
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ]. Several randomized controlled trials comparing traditional versus short courses of antibiotics for different conditions showed comparable effectiveness and often fewer adverse events with shorter antibiotic courses (Table 2) [
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ,
      • Dinh A.
      • et al.
      Discontinuing beta-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial.
      ,
      • Drekonja D.M.
      • et al.
      Effect of 7vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ,
      • von Dach E.
      • et al.
      Effect of C-reactive Protein-guided antibiotic treatment duration, 7-Day treatment, or 14-Day treatment on 30-Day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ,
      • Molina J.
      • et al.
      Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial.
      ,
      • Brindle R.
      • et al.
      Assessment of antibiotic treatment of cellulitis and erysipelas: a systematic review and meta-analysis.
      ].
      Table 2Examples of diseases for which short courses of antibiotic treatment were found to be equivalent to longer courses (adapted from
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ).
      DiseaseShort courses (days)Long courses (days)Selected references
      Community-acquired pneumonia3 or 57, 8, or 10[
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ,
      • Dinh A.
      • et al.
      Discontinuing beta-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial.
      ]
      Hospital-acquired/ventilator-associated pneumonia7–814–15
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      Complicated urinary tract infections/pyelonephritis5 or 710 or 14[
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ,
      • Drekonja D.M.
      • et al.
      Effect of 7vs 14 days of antibiotic therapy on resolution of symptoms among afebrile men with urinary tract infection: a randomized clinical trial.
      ]
      Complicated/postoperative intraabdominal infections4 or 810 or 15
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      Gram-negative bacteremia714[
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ,
      • von Dach E.
      • et al.
      Effect of C-reactive Protein-guided antibiotic treatment duration, 7-Day treatment, or 14-Day treatment on 30-Day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.
      ,
      • Molina J.
      • et al.
      Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial.
      ]
      Acute bacterial skin and skin structure infections (cellulitis/major abscess)5–610[
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".
      ,
      • Brindle R.
      • et al.
      Assessment of antibiotic treatment of cellulitis and erysipelas: a systematic review and meta-analysis.
      ]
      Empiric neutropenic feverAfebrile and stable × 72 hAfebrile and stable × 72 h and with absolute neutrophil count > 500 cells/μL
      • Wald-Dickler N.
      • Spellberg B.
      Short-course antibiotic therapy-replacing constantine units with "Shorter Is Better".

      Choose the antibiotic class with lowest potential for inducing resistance, and individualize therapies

      A too uniform use of antibiotics (few substances / antibiotic classes) might increase selective pressure and promote the spread of antimicrobial resistances [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ]. In addition, the use of particular antibiotic classes carries a higher risk for the emergence of resistant bacteria. For example, cephalosporin use has been associated with subsequent infection with vancomycin-resistant Enterococcus faecium, extended-spectrum β-lactamase (ESBL)–producing or β-lactam-resistant Gram-negative bacteria, and Clostridioides difficile. Quinolone use has been linked to infection with methicillin-resistant Staphylococcus aureus and with increasing quinolone resistance in Gram-negative bacilli, such as Pseudomonas aeruginosa [
      • Paterson D.L.
      Collateral damage" from cephalosporin or quinolone antibiotic therapy.
      ,
      • Calbo E.
      • et al.
      Risk factors for community-onset urinary tract infections due to Escherichia coli harbouring extended-spectrum beta-lactamases.
      ,
      • McKinnell J.A.
      • et al.
      Association between vancomycin-resistant Enterococci bacteremia and ceftriaxone usage.
      ,
      • Slimings C.
      • Riley T.V.
      Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis.
      ]. In 2017, the World Health Organization (WHO) introduced the Access, Watch and Reserve (AWaRe) categorization of antibiotics with the aim to provide a tool to use antibiotics safely and effectively. Following the AWaRe principles, antibiotics included in the WHO's Essential Medicines List are classified into three groups balancing benefits, harms and the potential to induce and propagate resistance. Antibiotics in the Access Group are first or second choice antibiotics that offer the best therapeutic value, while minimizing the potential for resistance. Watch Group antibiotics are first or second choice antibiotics only indicated for a specific, limited number of infective syndromes. They are more prone to be a target of antibiotic resistance and should be prioritized as targets of stewardship programs and monitoring. Notably, several very frequently used antibiotics such as cephalosporins (with the exception of cephazolin), ciprofloxacin or piperacillin-tazobactam are included in the Watch Group [
      • Sharland M.
      • et al.
      Encouraging AWaRe-ness and discouraging inappropriate antibiotic use-the new 2019 Essential Medicines List becomes a global antibiotic stewardship tool.
      ]. Finally, Reserve Group antibiotics are “last resort” antimicrobials for highly selected indications such as life-threatening infections due to multi-drug resistant bacteria. Their use needs closely monitoring and prioritization within stewardship programs [
      • Sharland M.
      • et al.
      Encouraging AWaRe-ness and discouraging inappropriate antibiotic use-the new 2019 Essential Medicines List becomes a global antibiotic stewardship tool.
      , ] . The overall goal is to reduce the use of antibiotics most crucial for human medicine and at higher risk of resistance (i.e. the Watch and Reserve Group antibiotics). The WHO recommends that by 2023, Access Group antibiotics should make up at least 60% of all antibiotics consumed at national level [

      Adoptaware. 2021.10.14]; Available from: https://adoptaware.org/.

      ]. Therefore, one potential approach to reduce the risk of insurgence of antimicrobial resistance is diversification of antibiotic prescriptions at the individual patient level, and avoiding the use of antibiotics and antibiotic classes associated with higher risk of resistance induction [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ]. Recommendations on first and second choice antibiotics to be used for the treatment of the most common and severe clinical infections according to the AWaRe principles are provided on the AWaRe portal (https://aware.essentialmeds.org/).

      Choose the right antibiotic dosage and route of administration

      Guidelines and antibiotic stewardship interventions focus mostly on antibiotic choice, and on start and duration of antibiotic therapy. However, an essential aspect to be considered for efficacious and safe antimicrobial therapy is how the antibiotic is administered in order to rapidly attain pharmacokinetics (PK)/pharmacodynamics (PD) targets for optimal effect, avoiding overdosing with toxicity. Suboptimal antibiotic concentrations are associated with poor treatment outcome, exert non-lethal selective pressure and may cause amplification of resistant bacteria [
      • Holmes A.H.
      • et al.
      Understanding the mechanisms and drivers of antimicrobial resistance.
      ,
      • Martinez M.N.
      • Papich M.G.
      • Drusano G.L.
      Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target.
      ,
      • Thabet P.
      • et al.
      Clinical and pharmacokinetic/dynamic outcomes of prolonged infusions of beta-lactam antimicrobials: an overview of systematic reviews.
      ]. To maximize therapeutic effect and for early reduction of bacterial burden, on the one hand it is important to consider starting treatment with a high dose of an antibiotic to achieve high drug concentrations as soon as possible [
      • Martinez M.N.
      • Papich M.G.
      • Drusano G.L.
      Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target.
      ]. On the other hand, several studies showed that continuous infusions (over 24 h) or prolonged infusions (over ≥3 h) of β-lactam antibiotics lead to better PK/PD targets attainment rates and patient outcomes than intermittent intravenous bolus administration (over 30–60 min, 1 to 6 times per day), particularly in critically ill patients and in patients with serious infections [
      • Thabet P.
      • et al.
      Clinical and pharmacokinetic/dynamic outcomes of prolonged infusions of beta-lactam antimicrobials: an overview of systematic reviews.
      ,
      • Abdul-Aziz M.H.
      • et al.
      Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis.
      ,
      • Vardakas K.Z.
      • et al.
      Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.
      ,
      • Rhodes N.J.
      • et al.
      Prolonged infusion piperacillin-tazobactam decreases mortality and improves outcomes in severely Ill patients: results of a systematic review and meta-analysis.
      ,
      • Fawaz S.
      • Barton S.
      • Nabhani-Gebara S.
      Comparing clinical outcomes of piperacillin-tazobactam administration and dosage strategies in critically ill adult patients: a systematic review and meta-analysis.
      ]. Administering β-lactams continuously or by prolonged infusion to achieve optimal PK/PD might slow the development of resistance and improve the outcomes of patients with sepsis and septic shock. However, the literature is not univocal and evidence from randomized-controlled trials regarding relevant clinical outcomes is still limited [
      • Thabet P.
      • et al.
      Clinical and pharmacokinetic/dynamic outcomes of prolonged infusions of beta-lactam antimicrobials: an overview of systematic reviews.
      ,
      • Osthoff M.
      • et al.
      Prolonged administration of beta-lactam antibiotics - a comprehensive review and critical appraisal.
      ]. Prolonged or continuous β-lactam infusion may benefit only high-risk patients such as critically ill patients or patients with severe, less susceptible gram-negative infections, or may be only beneficial for the administration of particular β-lactams. To optimize antibiotic therapy, PK/PD targets need to be accounted for. However, in addition, therapeutic drug monitoring may be necessary to individualize antibiotic treatment and achieve PK/PD targets, particularly in critically ill patients, where PK of β-lactams is profoundly modified because of an increased volume of distribution and the presence of altered renal function, leading to significant changes in plasma concentrations of the drugs [
      • Osthoff M.
      • et al.
      Prolonged administration of beta-lactam antibiotics - a comprehensive review and critical appraisal.
      ,
      • Moser S.
      • et al.
      Probability of pharmacological target attainment with flucloxacillin in Staphylococcus aureus bloodstream infection: a prospective cohort study of unbound plasma and individual MICs.
      ].

      Facilitate and promote clinical reasoning, and improve the prescribing environment

      The basis for optimal decisions on antibiotic therapies is careful clinical reasoning. The treating physician needs to consider history, symptoms, clinical findings and comorbidities of the patient; epidemiology; precise diagnosis and course of the infectious disease present including possible complications; results of laboratory, microbiology and radiology exams, etc.….This is the only way to optimize and individualize antibiotic treatment (right antibiotic, right dose and application, correct duration of therapy). However, in every day clinical practice there might not be sufficient time for such a careful assessment. Antibiotics are then prescribed because they are the fastest option and/or are considered the safest option. For the same reasons antibiotic therapies are often not de-escalated or timely stopped (e.g. for fear of missing some bacterial infection and/or because of the frequent reflex/bias “never change a winning team”). This problem is frequently forgotten in antibiotic stewardship recommendations, but is highlighted by interesting observations. Linder et al. found for example that primary care clinicians’ likelihood of prescribing antibiotics for acute respiratory infections increased during clinic sessions, with peaks before lunch and in the late afternoon. They postulated that decision fatigue (the erosion of self-control after making repeated decisions) progressively impairs clinicians’ ability to resist ordering inappropriate treatments [
      • Linder J.A.
      • et al.
      Time of day and the decision to prescribe antibiotics.
      ]. In a tertiary care hospital in the Netherlands, appropriateness of antimicrobial prescribing in the morning was significantly lower compared with the afternoon and evening/night. This “morning dip” in antibiotic appropriateness might be explained by the different work organization on hospital wards of a teaching hospital, where medical residents take decisions on most antibiotic treatments during morning rounds, which are frequently very busy, and when availability of diagnostic results and presence of supervisors or consulting specialties is reduced [
      • Sikkens J.J.
      • et al.
      The 'morning dip' in antimicrobial appropriateness: circumstances determining appropriateness of antimicrobial prescribing.
      ]. A national point-prevalence survey in 218 German hospitals found further that high bed occupancy significantly reduced the likelihood of adequate antimicrobial use, suggesting that with higher workload, decisions on antibiotic therapies may be more rushed and less thoughtful, leading to less adequate antimicrobial treatments [
      • Aghdassi S.J.S.
      • et al.
      The quality of antimicrobial prescribing in acute care hospitals: results derived from a national point prevalence survey, Germany, 2016.
      ].
      Therefore, measures to improve antibiotic prescribing and antibiotic stewardship programs should focus also on facilitating clinical reasoning and improving the prescribing environment in order to remove any barriers to good prescribing. Possible approaches are: increase in time available to prescribe, increased speed and availability of information (in particular microbiological results), modified schedules, shorter clinical sessions, mandatory breaks [
      • Linder J.A.
      • et al.
      Time of day and the decision to prescribe antibiotics.
      ,
      • Sikkens J.J.
      • et al.
      The 'morning dip' in antimicrobial appropriateness: circumstances determining appropriateness of antimicrobial prescribing.
      ], and the implementation of user friendly, “intelligent” clinical decision support systems based on artificial intelligence [
      • Rawson T.M.
      • et al.
      A real-world evaluation of a case-based reasoning algorithm to support antimicrobial prescribing decisions in acute care.
      ].

      Conclusions

      Inadequate antibiotic use is still very frequent and has many causes. The quality of antibiotic prescribing needs to be improved urgently in order to improve patient care and to tackle the dangerous spread of bacterial resistance to antibiotics. To reach this goal a bundle of measures is necessary (antibiotic stewardship), based on education, clinical reasoning and improvement of the prescribing environment. The local quality of antibiotic prescribing should be analyzed to identify problems and barriers impeding optimal prescribing and to choose interventions adequate to each specific setting.

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