Scientific letter
Comparative activity of tedizolid against clinical isolates of linezolid-resistant coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus
Actividad comparativa de tedizolid frente a Staphylococcus coagulasa negativos resistentes a linezolid y Staphylococcus aureus resistentes a meticilina
Santiago Pérez-Parra
, Alejandro Peña-Monje, Juan Luis Recio, Federico García-García
Corresponding author
Complejo Hospitalario Universitario de Granada, Centro San Cecilio-PTS, Granada, Spain
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Our objective was to evaluate <span class="elsevierStyleItalic">in vitro</span> the susceptibility to tedizolid of methicillin- and linezolid-resistant coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span> (LR-CNS) and methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> (MRSA). Our secondary objective was to compare the susceptibility of our isolates to other antibiotics used as an alternative in MRSA infections.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Susceptibility <span class="elsevierStyleItalic">in vitro</span> to tedizolid was studied in 22 LR-CNS and 33 MRSA isolates in the Department of Microbiology at Hospital Universitario San Cecilio in Granada, Spain, from 2007. Nine of the LR-CNS isolates were recovered from a previous study conducted by Sorlozano et al.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> Identification was performed using MALDI-TOF (Bruker Daltonics<span class="elsevierStyleSup">®</span>, Germany) and all isolates underwent a study of the minimum inhibitory concentration (MIC) against tedizolid, linezolid, vancomycin, ceftaroline and daptomycin through the disk diffusion method with a gradient strip (Liofilchem<span class="elsevierStyleSup">®</span>, Italy). All LR isolates also underwent a study of the MIC against erythromycin, clindamycin, chloramphenicol and streptogramin A, and the different profiles of resistance linked to different mechanisms of resistance to linezolid were evaluated<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a>: point mutations in the V domain of 23S ribosomal RNA (<span class="elsevierStyleItalic">rrn</span> gene), presence of the <span class="elsevierStyleItalic">cfr</span> gene or mutations in the genes that encode the L3 and L4 proteins of the 50S ribosomal subunit. All isolates were seeded in Mueller-Hinton agar with a 0.5 McFarland inoculum and incubated for 24<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>°C. Methicillin resistance was confirmed using 5<span class="elsevierStyleHsp" style=""></span>μg cefoxitin. The MIC of the different antibiotics was interpreted according to the EUCAST recommendations (v. 6.0). All redundant isolates with a period less than 5 days for a single patient were excluded. In addition, a clonality study was conducted using pulsed-field gel electrophoresis (PFGE)<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> on the isolates that had signs of epidemiological outbreak: isolates that were grouped in time and space.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A total of 55 isolates from 30 men (54.5%) and 25 women (45.5%), from different locations, were analysed: 29 blood culture samples (13 <span class="elsevierStyleItalic">S. aureus</span>, 7 <span class="elsevierStyleItalic">Staphylococcus epidermidis</span> and 9 <span class="elsevierStyleItalic">Staphylococcus hominis</span>), 15 respiratory samples (15 <span class="elsevierStyleItalic">S. aureus</span>) and 11 samples from exudates (5 <span class="elsevierStyleItalic">S. aureus</span> and 6 <span class="elsevierStyleItalic">S. epidermidis</span>).</p><p id="par0020" class="elsevierStylePara elsevierViewall">The epidemiological relationship of the patients infected with LR-CNS was as follows: 9 of the patients infected with <span class="elsevierStyleItalic">S. hominis</span> between 2007 and 2008 were admitted to the intensive care unit (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) or the emergency department (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1). All other patients infected with LR-CNS (<span class="elsevierStyleItalic">S. epidermidis</span>, n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>13) were admitted to different departments between 2009 and 2015: general surgery (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2, 2009–2013), internal medicine (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3, 2010–2015), gastroenterology (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1, 2009), vascular medicine (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2, 2009–2014), nephrology (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3, 2011–2015), anaesthesia (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1, 2010) and emergency medicine (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1, 2013). The clonality study for the <span class="elsevierStyleItalic">S. hominis</span> isolates that had signs of epidemiological outbreak confirmed the presence of 2 different clones: clone A (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) and clone B (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> All other isolates had no signs of epidemiological outbreak.</p><p id="par0025" class="elsevierStylePara elsevierViewall">All isolates were resistant to methicillin. The susceptibility profile for the isolates is presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Tedizolid proved to have higher activity <span class="elsevierStyleItalic">in vitro</span> compared to linezolid. The MIC<span class="elsevierStyleInf">90</span> for tedizolid <span class="elsevierStyleItalic">versus</span> LR-CNS and MRSA was lower (8 and 0.5<span class="elsevierStyleHsp" style=""></span>mg/l) compared to that observed for linezolid (>256<span class="elsevierStyleHsp" style=""></span>mg/l and 2<span class="elsevierStyleHsp" style=""></span>mg/l). In addition, intervals were estimated for the MIC of tedizolid <span class="elsevierStyleItalic">versus</span> LR-CNS and MRSA from 1 to 8<span class="elsevierStyleHsp" style=""></span>mg/l and from 0.25 to 0.5<span class="elsevierStyleHsp" style=""></span>mg/l, respectively, compared to linezolid (MIC of 8 to >256<span class="elsevierStyleHsp" style=""></span>mg/l for LR-CNS and 1 to 3<span class="elsevierStyleHsp" style=""></span>mg/l for MRSA). We found resistance to tedizolid in all LR-CNS (MIC<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mg/l, the EUCAST breakpoint to consider them resistant). In addition, 4 MRSAs had a MIC of 0.5<span class="elsevierStyleHsp" style=""></span>mg/l against tedizolid. No resistance to vancomycin, ceftaroline or daptomycin was found in any of the isolates that we studied.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The resistance phenotypes of the LR-CNS isolates were consistent with the presence of a single strain carrying the <span class="elsevierStyleItalic">cfr</span> gene (cross-resistance to linezolid, amphenicols, lincosamides and streptogramin A, as well as susceptibility to macrolides), with a MIC to linezolid higher than 256<span class="elsevierStyleHsp" style=""></span>mg/l and a MIC to tedizolid higher than 3<span class="elsevierStyleHsp" style=""></span>mg/l. In addition, we found another strain consistent with the presence of mutations in the V domain of 23S ribosomal RNA (resistance to linezolid and susceptibility to amphenicols, lincosamides, streptogramin A and to macrolides), with a MIC for linezolid and tedizolid of 32 and 6<span class="elsevierStyleHsp" style=""></span>mg/l, respectively. All other isolates had phenotypes consistent with the coexistence of multiple mechanisms of resistance.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Tedizolid is presented as a highly potent drug, and in line with other series, we present data showing a MIC<span class="elsevierStyleInf">90</span> 4 to 16 times lower compared to linezolid.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">9</span></a> Although our results suggest that this antibiotic has higher activity <span class="elsevierStyleItalic">in vitro</span>, as in other studies conducted in LR Staphylococcus,<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">10,11</span></a> the MIC of tedizolid often exceeds the breakpoint established by EUCAST. In our study, the MIC<span class="elsevierStyleInf">50</span> and MIC<span class="elsevierStyleInf">90</span><span class="elsevierStyleItalic">versus</span> LR-CNS were 4 and 8<span class="elsevierStyleHsp" style=""></span>mg/l, respectively, and all were resistant.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Although some studies have demonstrated greater susceptibility to tedizolid in LR isolates carrying the <span class="elsevierStyleItalic">cfr</span> gene,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> we were unable to demonstrate this. However, we present results that demonstrate high resistance to tedizolid in isolates that often have phenotypic profiles of resistance consistent with the presence of multiple mechanisms of resistance to linezolid. In light of these facts, the existence of a new plasmid (<span class="elsevierStyleItalic">optr</span>A) conferring resistance to linezolid and to amphenicols was recently reported.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a> Therefore, new studies are needed that provide definitive data on the efficacy of tedizolid in LR isolates, which often possess multiple mechanisms of resistance to this drug.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Pérez-Parra S, Peña-Monje A, Recio JL, García-García F. Actividad comparativa de tedizolid frente a <span class="elsevierStyleItalic">Staphylococcus</span> coagulasa negativos resistentes a linezolid y <span class="elsevierStyleItalic">Staphylococcus aureus</span> resistentes a meticilina. Enferm Infecc Microbiol Clin. 2017;35:323–324.</p>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0050" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0010" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">MIC, minimum inhibitory concentration; MRSA, methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span>; LR-CNS, methicillin- and linezolid-resistant coagulase-negative <span class="elsevierStyleItalic">Staphylococcus</span>.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MIC (mg/l)</th><th class="td" title="table-head " align="left" valign="top" scope="col">Percentage of resistance<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antibiotics \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Range \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">50% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">90% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">LR-CNS (22)</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Linezolid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 to >256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tedizolid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Vancomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.5–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ceftaroline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.125–0.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Daptomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.19–0.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">MRSA (33)</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Linezolid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tedizolid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.25–0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Vancomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.38–1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ceftaroline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.25–1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Daptomycin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.125–1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1414634.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">According to the breakpoint points established by EUCAST (v 6.0).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Summary of the <span class="elsevierStyleItalic">in vitro</span> activity of different antibiotics in 22 LR-CNS and 33 MRSA isolates.</p>" ] ] 1 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 87728 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0070" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "European Medicines Agency. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 13 | 13 | 26 |
| 2024 September | 14 | 18 | 32 |
| 2024 August | 26 | 14 | 40 |
| 2024 July | 13 | 13 | 26 |
| 2024 June | 14 | 2 | 16 |
| 2024 May | 13 | 3 | 16 |
| 2024 April | 18 | 33 | 51 |
| 2024 March | 15 | 4 | 19 |
| 2024 February | 13 | 4 | 17 |
| 2024 January | 14 | 1 | 15 |
| 2023 December | 13 | 4 | 17 |
| 2023 November | 17 | 19 | 36 |
| 2023 October | 38 | 2 | 40 |
| 2023 September | 8 | 2 | 10 |
| 2023 August | 12 | 0 | 12 |
| 2023 July | 11 | 3 | 14 |
| 2023 June | 15 | 2 | 17 |
| 2023 May | 17 | 4 | 21 |
| 2023 April | 11 | 2 | 13 |
| 2023 March | 13 | 1 | 14 |
| 2023 February | 10 | 16 | 26 |
| 2023 January | 17 | 7 | 24 |
| 2022 December | 18 | 5 | 23 |
| 2022 November | 13 | 7 | 20 |
| 2022 October | 11 | 7 | 18 |
| 2022 September | 14 | 8 | 22 |
| 2022 August | 27 | 14 | 41 |
| 2022 July | 11 | 6 | 17 |
| 2022 June | 8 | 10 | 18 |
| 2022 May | 10 | 5 | 15 |
| 2022 April | 15 | 13 | 28 |
| 2022 March | 11 | 5 | 16 |
| 2022 February | 27 | 5 | 32 |
| 2022 January | 15 | 6 | 21 |
| 2021 December | 15 | 10 | 25 |
| 2021 November | 16 | 7 | 23 |
| 2021 October | 13 | 8 | 21 |
| 2021 September | 11 | 12 | 23 |
| 2021 August | 20 | 8 | 28 |
| 2021 July | 13 | 8 | 21 |
| 2021 June | 10 | 6 | 16 |
| 2021 May | 21 | 17 | 38 |
| 2021 April | 81 | 4 | 85 |
| 2021 March | 43 | 10 | 53 |
| 2021 February | 15 | 7 | 22 |
| 2021 January | 22 | 9 | 31 |
| 2020 December | 19 | 9 | 28 |
| 2020 November | 50 | 14 | 64 |
| 2020 October | 22 | 6 | 28 |
| 2020 September | 15 | 9 | 24 |
| 2020 August | 22 | 7 | 29 |
| 2020 July | 13 | 6 | 19 |
| 2020 June | 15 | 12 | 27 |
| 2020 May | 18 | 12 | 30 |
| 2020 April | 14 | 5 | 19 |
| 2020 March | 16 | 6 | 22 |
| 2020 February | 15 | 1 | 16 |
| 2020 January | 20 | 12 | 32 |
| 2019 December | 19 | 15 | 34 |
| 2019 November | 9 | 5 | 14 |
| 2019 October | 21 | 11 | 32 |
| 2019 September | 11 | 5 | 16 |
| 2019 August | 12 | 0 | 12 |
| 2019 July | 9 | 11 | 20 |
| 2019 June | 17 | 9 | 26 |
| 2019 May | 69 | 11 | 80 |
| 2019 April | 32 | 11 | 43 |
| 2019 March | 7 | 7 | 14 |
| 2019 February | 4 | 5 | 9 |
| 2019 January | 6 | 2 | 8 |
| 2018 December | 6 | 1 | 7 |
| 2018 November | 6 | 3 | 9 |
| 2018 October | 6 | 12 | 18 |
| 2018 September | 23 | 0 | 23 |
| 2018 August | 10 | 0 | 10 |
| 2018 July | 9 | 3 | 12 |
| 2018 June | 5 | 1 | 6 |
| 2018 May | 9 | 4 | 13 |
| 2018 April | 6 | 2 | 8 |
| 2018 March | 11 | 1 | 12 |
| 2018 February | 3 | 0 | 3 |
| 2018 January | 10 | 1 | 11 |
| 2017 December | 7 | 0 | 7 |
| 2017 November | 13 | 2 | 15 |
| 2017 October | 5 | 2 | 7 |
| 2017 July | 1 | 0 | 1 |
| 2017 May | 2 | 0 | 2 |
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