A case study on Staphylococcus aureus bacteraemia: available treatment options, antibiotic R&D and responsible antibiotic-use strategies

Abstract Objectives This case study addresses: (i) antibiotic treatment options for Staphylococcus aureus bacteraemia (SAB), for both empirical and targeted therapy; (ii) the current status of and priorities for the antibiotic pipeline to ensure access of effective antibiotics for SAB; and (iii) strategies for responsible antibiotic use relevant to the clinical management of SAB. Methods Evidence to address the aims was extracted from the following information sources: (i) EUCAST and CLSI recommendations, summaries of product characteristics (SPCs), antibiotic treatment guidelines and the textbook Kucers' The Use of Antibiotics; (ii) the www.clinicaltrial.gov database; and (iii) quality indicators for responsible antibiotic use. Results Current monotherapy treatment options for SAB include only three drug classes (β-lactams, glycopeptides and lipopeptides), of which two also cover MRSA bacteraemia (glycopeptides and lipopeptides). The analysis of the antibiotic pipeline and ongoing clinical trials revealed that several new antibiotics with S. aureus (including MRSA) coverage were developed in the past decade (2009–19). However, none belonged to a new antibiotic class or had superior effectiveness and their added clinical value for SAB remains to be proven. Responsible antibiotic use for the treatment of SAB was illustrated using 11 quality indicators. Conclusions Awareness of the problem of a limited antibiotic arsenal, together with incentives (e.g. push incentives), is needed to steer the R&D landscape towards the development of novel and effective antibiotics for treating SAB. In the meantime, responsible antibiotic use guided by quality indicators should preserve the effectiveness of currently available antibiotics for treating SAB

Exploring the economic impact of inappropriate antibiotic use: the case of upper respiratory tract infections in Ghana.

BACKGROUND: Antibiotic consumption is increasing worldwide, particularly in low and middle-income countries (LMICs). Access to lifesaving antibiotics in LMICs is crucial while minimising inappropriate use. Studies assessing the economic impact of inappropriate antibiotic use in LMICs are lacking. We explored the economic impact of inappropriate antibiotic use using the example of upper respiratory tract infections (URIs) in Ghana, as part of the ABACUS (AntiBiotic ACcess and USe) project. METHODS: A top-down, retrospective economic impact analysis of inappropriate antibiotic use for URIs was conducted. Two inappropriate antibiotic use situations were considered: (1) URIs treated with antibiotics, against recommendations from clinical guidelines; and (2) URIs that should have been treated with antibiotics according to clinical guidelines, but were not. The analysis included data collected in Ghana during the ABACUS project (household surveys and exit-interviews among consumers buying antibiotics), scientific literature and stakeholder consultations. Included cost types related to health care seeking behaviour for URIs. Additionally, cost saving projections were computed based on potential effects of future interventions that improve antibiotic use. RESULTS: Health care costs related to inappropriate antibiotic use for URIs were estimated to be around 20 million (M) USD annually, including 18 M USD for situation 1 and 2 M USD for situation 2. Travel costs and lost income due to travel, together, were estimated to be around 44 M USD for situation 1 and 18 M USD for situation 2. Possible health care cost savings range from 2 to 12 M USD for situation 1 and from 0.2 to 1 M USD for situation 2. CONCLUSIONS: This study indicates that inappropriate antibiotic use leads to substantial economic costs in a LMIC setting that could have been prevented. We recommend investment in novel strategies to counter these unnecessary expenditures. As the projections indicate, this may result in considerable cost reductions. By tackling inappropriate use, progress can be made in combatting antibiotic resistance

Variation in antibiotic use among and within different settings: a systematic review

Objectives: Variation in antibiotic use may reflect inappropriate use. We aimed to systematically describe the variation in measures for antibiotic use among settings or providers. This study was conducted as part of the innovative medicines initiative (IMI)-funded international project DRIVE-AB. Methods: We searched for studies published in MEDLINE from January 2004 to January 2015 reporting variation in measures for systemic antibiotic use (e.g. DDDs) in inpatient and outpatient settings. The ratio between a study's reported maximumand minimumvalues of a given measure [maximum: minimumratio (MMR)] was calculated as a measure of variation. Similar measures were grouped into categories and when possible the overall median ratio and IQR were calculated. Results: One hundred and forty-three studies were included, of which 85 (59.4%) were conducted in Europe and 12 (8.4%) in low-to middle-income countries. Most studies described the variation in the quantity of antibiotic use in the inpatient setting (81/143, 56.6%), especially among hospitals (41/81, 50.6%). Themost frequentmeasure was DDDs with different denominators, reported in 23/81 (28.4%) inpatient studies and in 28/62 (45.2%) outpatient studies. For this measure, we found a median MMR of 3.7 (IQR 2.6-5.0) in 4 studies reporting antibiotic use in ICUs in DDDs/1000 patient-days and a median MMR of 2.3 (IQR 1.5-3.2) in 18 studies reporting outpatient antibiotic use in DDDs/1000 inhabitant-days. Substantial variationwas also identified in othermeasures. Conclusions: Our review confirms the large variation in antibiotic use even across similar settings and providers. Data from low-and middle-income countries are under-represented. Further studies should try to better elucidate reasons for the observed variation to facilitate interventions that reduce unwarranted practice variation. In addition, the heterogeneity of reported measures clearly shows that there is need for standardization

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

Metrics to assess the quantity of antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure

Background The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of ‘responsible’ antibiotic use. Objectives To identify consensually validated quantity metrics for antibiotic use in the outpatient setting. Methods First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics. Results A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use. Conclusions A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use

Quality indicators for responsible antibiotic use in the inpatient setting: a systematic review followed by an international multidisciplinary consensus procedure

Background This study was conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project and aimed to develop generic quality indicators (QIs) for responsible antibiotic use in the inpatient setting. Methods A RAND-modified Delphi method was applied. First, QIs were identified by a systematic review. A complementary search was performed on web sites of relevant organizations. Duplicates were removed and disease and patient-specific QIs were combined into generic indicators. The relevance of these QIs was appraised by a multidisciplinary international stakeholder panel through two questionnaires and an in-between consensus meeting. Results The systematic review retrieved 70 potential generic QIs. The QIs were appraised by 25 international stakeholders with diverse backgrounds (medical community, public health, patients, antibiotic research and development, regulators, governments). Ultimately, 51 QIs were selected in consensus. QIs with the highest relevance score included: (i) an antibiotic plan should be documented in the medical record at the start of the antibiotic treatment; (ii) the results of bacteriological susceptibility testing should be documented in the medical record; (iii) the local guidelines should correspond to the national guidelines but should be adapted based on local resistance patterns; (iv) an antibiotic stewardship programme should be in place at the healthcare facility; and (v) allergy status should be taken into account when antibiotics are prescribed. Conclusions This systematic and stepwise method combining evidence from literature and stakeholder opinion led to multidisciplinary international consensus on generic inpatient QIs that can be used globally to assess the quality of antibiotic use

Dilemmas With Restrictive Visiting Policies in Dutch Nursing Homes During the COVID-19 Pandemic: A Qualitative Analysis of an Open-Ended Questionnaire With Elderly Care Physicians

OBJECTIVES: To mitigate the spread of COVID-19, a nationwide restriction for all visitors of residents of long-term care facilities including nursing homes (NHs) was established in the Netherlands. The aim of this study was an exploration of dilemmas experienced by elderly care physicians (ECPs) as a result of the COVID-19 driven restrictive visiting policy. SETTING AND PARTICIPANTS: ECPs working in Dutch NHs. METHODS: A qualitative exploratory study was performed using an open-ended questionnaire. A thematic analysis was applied. Data were collected between April 17 and May 10, 2020. RESULTS: Seventy-six ECPs answered the questionnaire describing a total of 114 cases in which they experienced a dilemma. Thematic analysis revealed 4 major themes: (1) The need for balancing safety for all through infection prevention measures versus quality of life of the individual residents and their loved ones; (2) The challenge of assessing the dying phase and how the allowed exception to the strict visitor restriction in the dying phase could be implemented; (3) The profound emotional impact on ECPs; (4) Many alternatives for visits highlight the wish to compensate for the absence of face-to-face contact opportunities. Many alternatives for visits highlight the wish to compensate for the absence of face-to-face opportunities but given the diversity of NH residents, alternatives were often only suitable for some of them. CONCLUSIONS AND IMPLICATIONS: ECPs reported that the restrictive visitor policy deeply impacts NHs residents, their loved ones, and care professionals. The dilemmas encountered as a result of the policy highlight the wish by ECPs to offer solutions tailored to the individual residents. We identified an overview of aspects to consider when drafting future visiting policies for NHs during the COVID-19 pandemic

ECDC Round Table Report and ProMed-mail most useful international information sources for the Netherlands Early Warning Committee.

The Netherlands Early Warning Committee (NEWC) aims to identify infectious diseases causing a potential threat to Dutch public health. Threats are assessed and published as (information) alerts for public health experts. To identify threats from abroad, the NEWC screens 10 sources reporting disease outbreaks each week. To identify the sources essential for complete and timely reporting, we retrospectively analysed 178 international alerts published between 31 January 2013 and 30 January 2014. In addition, we asked the four NEWC coordinators about the required time to scan the information sources. We documented the date and source in which the signal was detected. The ECDC Round Table (RT) Report and ProMED-mail were the most complete and timely sources, reporting 140 of 178 (79%) and 121 of 178 (68%) threats respectively. The combination of both sources reported 169 (95%) of all threats in a timely manner. Adding any of the other sources resulted in minor increases in the total threats found, but considerable additional time investment per additional threat. Only three potential relevant threats (2%) would have been missed by only using the ECDC RT Report and ProMed-mail. We concluded that using only the ECDC RT Report and ProMed-mail to identify threats from abroad maintains a sensitive Early Warning System

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. Identifier: NCT 0040272

Additional file 2 of Exploring the economic impact of inappropriate antibiotic use: the case of upper respiratory tract infections in Ghana

Summary survey results associated with the paper, "Exploring the economic impact of inappropriate antibiotic use: the case of upper respiratory tract infections in Ghana"