Background
Issue | Example |
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Failure to report key ‘bug-drug’ combinations | For both CLSI and EUCAST methods, methicillin resistance in Staphylococcus aureus is determined in the laboratory using cefoxitin (or historically oxacillin) resistance as a proxy [19, 20]. The cefoxitin/oxacillin result is used to infer susceptibility for all beta-lactam drugs, except those with specific activity against methicillin-resistant S. aureus (MRSA, i.e. ceftaroline). Thus, consistent reporting of cefoxitin/oxacillin resistance is required for unambiguous comparison of MRSA proportions between studies. |
Reporting of antimicrobials tested on a subset of isolates | The issue of first- and second-line AST panels can lead to inconsistent reporting of resistance prevalence. In many instances, second-line agents (e.g. meropenem for Escherichia coli) are only tested on a subset of isolates (e.g. only those resistant to third-generation cephalosporins, such as ceftriaxone, or only in isolates from selected clinical specimens [19]) and reporting of incorrect overall resistance proportions can occur if inappropriate denominators are selected. For example, 100 E. coli isolates are tested against ceftriaxone and 10 (10%) are found to be resistant. These 10 isolates are tested subsequently against meropenem and 1 is resistant. This could be reported as 1/10 (10%) or 1/100 (1%) meropenem resistance. Neither of these percentages may be correct. |
Multi-drug resistance definition and reporting | With the exception of Mycobacterium tuberculosis (resistance to isoniazid and rifampicin), definitions of bacterial multi-drug resistance (MDR) have been poorly defined and applied. The definition of MDR often reflects local AST selection and antibiotic availability and thus rates are difficult to compare meaningfully [21]. MDR definitions for major bacterial pathogens have been proposed recently but overall consensus is lacking for many species [10, 21, 22]. |
Changes to published antimicrobial susceptibility breakpoints over time | Changes in the definition of resistance can result in misleading time trends and difficulties in inter-study comparisons, if not explicitly dealt with during analysis. For example, the CLSI penicillin minimum inhibitory concentration (MIC) breakpoints for Streptococcus pneumoniae were updated in 2008, resulting in an increased proportion of non-meningitis isolates being reported as susceptible following the change [23]. |
Classification of infections by location | |
Selection of appropriate isolates to include in analysis | Failure to account for screening specimens (e.g. swabs to determine extended spectrum beta-lactamase Enterobacteriaceae colonisation) and/or duplicate clinical isolates from discrete infection episodes can also result in significant overestimation of resistance [26]. |
Testing and reporting clinically inappropriate bug-drug combinations | The inclusion of susceptibility data for drugs with limited in vivo activity for a given pathogen (e.g. gentamicin and Salmonella Typhi) may lead to clinical confusion and could result in poor treatment outcomes. |
Methods
Aims and use of MICRO
Development of MICRO
Step | Detail |
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Initial steps | Identify the need for a guideline |
Review the literature • Identify previous relevant guidance • Seek relevant evidence on the quality of reporting in published research articles • Identify key information related to the potential sources of bias in such studies | |
Pre-meeting activities | Identify participants |
Conduct informal exercise to identify key issues | |
Generate a list of items for consideration at the face-to-face meeting | |
Plan meeting, including preparation and of dissemination of pre-meeting materials | |
Face-to-face consensus meeting | Present and discuss results of pre-meeting activities |
Discuss the rationale for including items in the checklist | |
Post-meeting activities | Finalise the guidance statement |
Prepare manuscript for publication |
Review of published microbiology datasets from LMICs in South and South East Asia
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Laboratory EQA participation
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AST methodology: scheme and version/year
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Inclusion of internal quality control information for AST testing
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Staphylococcus aureus. Forty studies reported beta-lactam (penicillin, cephalosporin and/or carbapenem) susceptibility data for S. aureus. Of these, only 15 (38%) specifically included oxacillin and/or cefoxitin results. Several studies reported discordant results for 3rd generation cephalosporins and carbapenems, which would be expected to be more or less identical given the common resistance mechanism. Of note, six studies included susceptibility data for ceftazidime, an anti-pseudomonal third-generation cephalosporin with limited anti-Gram-positive activity which would not normally be tested against S. aureus: two reported susceptible isolates despite the absence of CLSI breakpoints.
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Streptococcus pneumoniae. Two studies reported testing gentamicin and identification of susceptible isolates despite there being no breakpoints defined by either EUCAST or CLSI for this ‘bug-drug’ combination. Minimum inhibitory concentration (MIC) determination is required for confirmation of reduced susceptibility to penicillin among S. pneumoniae isolates by both CLSI and EUCAST criteria. However, of the seven studies reporting non-susceptible pneumococci, two reported this phenotype based on oxacillin disk diffusion testing alone and one confirmed penicillin MIC in only a subset of oxacillin non-susceptible isolates.
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Klebsiella pneumoniae. Isolates were reported to be ampicillin susceptible (5–62% of isolates tested) in 5/11 (45%) studies reporting the species, despite almost universal intrinsic resistance globally and CLSI guidance to report all isolates as resistant [19].
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Salmonella spp. Despite absence of in vivo activity, and a specific CLSI warning against reporting, 24/76 (32%) studies reporting Salmonella spp. included results for gentamicin. All but one study reported susceptible isolates, ranging from 33 to 100% of isolates tested.
Checklist development
Results
Item | Number | Recommendation |
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Methods | ||
Study design | 1* | Specimen types: Describe the types of specimen included, i.e. clinical (e.g. blood cultures) or non-diagnostic surveillance (e.g. admission and other screening swabs to diagnose carriage). If specimens were obtained for diagnostic reasons, clinical syndromes should be described where possible, and specimens/isolates stratified by clinical syndrome. |
2* | Sampling period: State the collection timeframe for specimens yielding isolates for which data is reported, e.g. from MM/YY to MM/YY to be able to identify variability between seasons. | |
3* | Sampling strategy: Describe the strategy for specimen collection, e.g. asymptomatic screening, sampling of all febrile patients, sampling at clinician discretion, sampling of specific patient groups and convenience sampling (e.g. use of isolates from an existing sample repository). Specify whether sampling followed routine clinical practice or was protocol driven. Classify specimens as from community-acquired (CAI) or hospital-acquired (HAI) infections. The definition of HAI used (e.g. HAI defined by specimen collection > 48 h after hospital admission) should be provided and should use ideally an international standard (e.g. US Centers for Disease Control [27, 28]). | |
4 | Target organisms: Explicitly state which organisms/organism groups were included in the report. Nomenclature should follow international standards (i.e. using approved genus/species names as summarised in the International Journal of Systematic and Evolutionary Microbiology). Lists of approved bacterial names can be downloaded from Prokaryotic Nomenclature Up-to-Date (https://www.dsmz.de/bacterial-diversity/prokaryotic-nomenclature-up-to-date.html) and the List of Prokaryotic Names with Standing in Nomenclature (http://www.bacterio.net/). Organisms considered contaminants should be listed, if appropriate (e.g. coagulase negative staphylococci or Corynebacterium spp. [29, 30]). | |
Setting | 5* | Geographical setting: Describe the geographical distribution of specimens/patients from which isolates were obtained, at least to a country level, but preferably to a sub-national level or a geoposition. |
6* | Clinical setting: Describe the type and level of the healthcare facilities (e.g. primary, secondary, tertiary) from which specimens were obtained. If stating a microbiology laboratory, the centres served by the laboratory should be specified. | |
Laboratory work | 7 | Specimen processing: If applicable, describe specimen collection and handling, processing and sub-culture methods for all types of specimen included. For example, if reporting AST results for blood culture and cerebrospinal fluid culture isolates, the processing of these specimens by the laboratory should be briefly explained, including how specimens are sub-cultured, the media used, incubation conditions and duration. A summary of specimen processing steps (e.g. pre-processing steps, nucleic acid extraction method (if applicable), amplification platform, contamination avoidance strategy) should be provided for molecular-only workflows (e.g. to detect Mycobacterium tuberculosis and rifampicin resistance using the Cepheid Xpert MTB/RIF system). |
8* | Target organism identification: Details of identification methodology should be reported briefly. Where identification databases were used (e.g. bioMerieux API/bioMerieux VITEK-MS/Bruker Biotyper), the version should be specified. In general, all pathogens should be identified to species level. In the case of Salmonella species, organisms should be identified to at least the S. Typhi, S. Paratyphi, or non-typhoidal Salmonella (NTS) level. Strain subtyping methods should be reported according to STROME-ID [15]. | |
9* | Antimicrobial susceptibility testing: Describe the antimicrobial susceptibility testing methods used, internal quality control processes and their interpretation, with reference to a recognised international standard, e.g. CLSI, EUCAST. Where an international standard was followed, the specific edition(s) of guidelines used should be referenced. Deviations from standard methodology should be described, along with evidence of validation. Handling of any changes to interpretative criteria during the sampling period should be documented. State whether the raw AST data (zone diameters and/or minimum inhibitory concentrations) were re-categorised with updated breakpoints or left as-is. | |
10 | Additional tests performed to identify resistance mechanisms: Describe the testing methods used for adjunctive/confirmatory antimicrobial susceptibility tests, such as enzymatic/molecular assays (e.g. Xpert MTB/RIF, mecA PCR) and inducible resistance assays, with reference to a recognised international standard, where available. Where an international standard was followed, the specific edition of guidelines used should be referenced. Deviations from standard methodology should be described, along with evidence of validation. | |
11* | Antimicrobial resistance definitions: Define resistance for each antimicrobial class (i.e. are isolates in the ‘intermediate’ category included within ‘susceptible’ or ‘resistant’ or analysed as a distinct category). If using the term, define MDR (e.g. ≥ 1 agent in ≥ 3 classes tested). For each organism type, an MDR test panel must be defined, consisting of the minimum panel of individual antimicrobial agents/classes against which an isolate must be tested for that isolate to be considered tested for MDR status. Antimicrobials to which an organism is intrinsically resistant cannot be part of the test panel or contribute to MDR status [10, 22]. | |
Quality assurance | 12* | External quality assurance: State whether the microbiology laboratory participates in an external quality control programme and, if so, provide scheme details. Examples include the UK National External Quality Assurance Scheme (www.ukneqasmicro.org.uk) and the American College of Pathologists External Quality Assurance/Proficiency Testing Program (https://www.cap.org/) |
13 | Accreditation: State whether the laboratory is accredited through a national or international body (e.g. the International Standards Organisation, ISO) and specify which assays are covered in the accreditation. | |
Bias | 14* | Duplicate and sequential isolates: The strategy for accounting for duplicate and sequential isolates from the same patient should be clearly detailed. Duplicate isolates are multiple isolates of the same phenotypic organism (i.e. same species and same resistance profile) from the same patient on the same date cultured either from the same clinical specimen, or from two separate clinical specimens, such as blood and CSF. Sequential isolates are isolates of the same phenotypic organism from the same patient at different dates, such as blood cultures taken on different dates. Various strategies for the handling of duplicate and sequential isolates exist [11], and the strategy used should be transparent as it will bias pooled resistance results. For example, inclusion of all isolates (the ‘all isolate strategy’) has been shown to shift pooled resistance proportions toward greater resistance, whilst inclusion of only the first isolate per patient (the ‘first isolate strategy’) or only the first isolate per infection episode (the ‘episode-based strategy’) will shift pooled results toward susceptibility. |
Results | ||
15* | Population: Describe the demographics of the population from which clinical specimens and subsequent isolates have been obtained, disaggregating age and gender data. | |
16* | Denominators: Patient and isolate denominators should be used appropriately to ensure clarity regarding the numbers included in each analysis. Of particular importance is the reporting of resistance where first- and second-line AST panels were used (i.e. not all isolates of a particular species were tested against all agents). For drugs where only a subset of isolates were tested, reporting of a percentage without the numbers of isolates tested/resistant may be highly misleading. | |
17 | Site/place of acquisition: AST data from CAI and HAI should be reported and analysed separately. | |
18* | Reporting resistance proportions for single agent and class resistance: Proportions of resistant isolates should be reported as number of isolates susceptible or resistant to a given antimicrobial agent/class out of actual number of isolates tested for susceptibility to that agent/class. | |
19 | Reporting multidrug resistance proportions: If defined, the proportion of MDR isolates should be expressed as the number of MDR isolates out of the number of isolates tested (i.e. the number undergoing the MDR test panel specific to that organism). Single agent/class resistance should be always be reported, regardless of MDR reporting. | |
Discussion | ||
Limitations | 20 | Discuss any reasons why bias may have been introduced into the reported data, due to patient/specimen selection, isolation of organisms, or otherwise. Consider factors which may have either introduced bias into the types of organisms isolated or the antimicrobial susceptibility profiles, e.g. receipt of antimicrobials prior to specimen collection will reduce the yield of certain species and also select for more resistant organisms. |
Discussion
Grade | Detail |
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A | Accreditation details provided No ID or AST errors detected |
B | Accreditation details not provided EQA participation confirmed Organism ID and AST methodology completely described No ID or AST errors detected |
C | Accreditation details not provided EQA participation not confirmed Organism ID and AST methodology completely described No ID or AST errors detected |
D | Accreditation details not provided EQA participation not confirmed Organism ID and AST methodology partially described No ID or AST errors detected |
E | Overt ID and/or AST errors detected/strongly suspected |