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After three weeks, when the patient presented septic symptoms (C-reactive protein of 23<span class="elsevierStyleHsp" style=""></span>mg/dL, 4220<span class="elsevierStyleHsp" style=""></span>leukocytes/mm<span class="elsevierStyleSup">3</span>) the drainages were replaced. The cerebrospinal fluid (CSF) biochemistry was compatible with a bacterial central nervous system (CNS) infection (glucose<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mg/dL and proteins 550<span class="elsevierStyleHsp" style=""></span>mg/dL). Broad spectrum antibiotic therapy was started with intravenous (IV) linezolid 600<span class="elsevierStyleHsp" style=""></span>mg q12h and meropenem 2000<span class="elsevierStyleHsp" style=""></span>mg q8h in a 4h extended infusion.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Five days later, a Class B carbapenemase (metallo-β-carbapenemase)-producing <span class="elsevierStyleItalic">Enterobacter cloacae</span> with intermediate susceptibility to meropenem with minimum inhibitory concentration (MIC) of 8<span class="elsevierStyleHsp" style=""></span>mg/L and susceptible to colistin (MIC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.20<span class="elsevierStyleHsp" style=""></span>mg/L) was isolated in both CSF and blood cultures (drainages were not cultured). In addition, a Class A carbapenemase (KPC)-producing <span class="elsevierStyleItalic">Klebsiella pneumoniae</span> (colistin MIC<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mg/L) and an extensively drug-resistant <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> (colistin MIC<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mg/L; meropenem MIC<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>mg/L) were isolated in blood cultures. These nosocomial microorganisms were not isolated in any other culture and they could be a consequence of an incorrect drainage manipulation in a COVID pandemic situation, with a higher prevalence of multi-drug resistant bacteria. Linezolid was stopped and intravenous colistimethate sodium (CMS) at a dose of 6 MIU q12h was added to meropenem due to the synergic effects of both antibiotics.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> In addition, intraventricular colistin (10<span class="elsevierStyleHsp" style=""></span>mg q4h administered through each CSF drainage) was added to try to ensure therapeutic concentrations into the CSF, as described in exceptional cases.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">On day 7 of CMS treatment, total colistin sulphate levels in plasma, determined by high performance liquid chromatography, were infratherapeutic (<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">ss</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mg/L). Due to severity of the infection, CSF levels of colistin were also determined and ranged between 2.5 and 5.6<span class="elsevierStyleHsp" style=""></span>mg/L, a value 10 times higher than the colistin MIC. Both IV and intraventricular CMS doses were maintained. Eight days later plasma colistin concentration were still low (see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The intraventricular and IV CMS treatments were stopped after 15 and 30 days, respectively. Finally, after 63 days in the Resuscitation Unit, the patient could be discharged to a conventional hospital ward without any signs and symptoms of an active CNS infection.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Colistin-associated nephrotoxicity<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> was not observed during CMS treatment being the estimated glomerular filtration rate greater than 120<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> during treatment. Neurotoxicity, a side effect caused by colistin,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> could not be assessed because patient's impaired status of consciousness caused by a diencephalic irritation during the previous surgery.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Meningoventriculitis caused by <span class="elsevierStyleItalic">Enterobacter</span> spp. is a rare infectious complication in neurosurgical patients but associated with a high morbidity and mortality.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> The treatment is often complex due to the isolation of bacterial strains resistant to multiple antibiotics, such as third-generation cephalosporins and even, as in the present case, to carbapenems. In these cases, colistin becomes one of the last available therapeutic options.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The achievement of adequate antibiotic concentrations at the infection site is essential in these difficult-to-treat infections. Although CNS penetration in patients with meningoventriculitis might be increased by 60% for some antimicrobials, in other cases intraventricular administration may be necessary to reach therapeutic levels.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Colistin is an antimicrobial with a very complex pharmacokinetics. Therapeutic plasma colistin concentrations are difficult to achieve, even after the administration of very high CMS doses, especially in patients with conserved renal function.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> This is due to the fact that CMS is rapidly renally excreted before it can be hydrolyzed to colistin, the active compound.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a> In addition, colistin penetration into the CSF after its IV administration has been reported to be very low and variable, ranging between 5% and 7% in some experiences and<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a> up to 25% in others.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Our patient, with preserved renal function, presented suboptimal colistin plasma levels, even after the administration of a high CMS IV dose.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> The local intraventricular administration allowed to achieve optimal colistin levels in CSF (10 times above the MIC).<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion, when using colistin for the treatment of a CNS infection, local intraventricular administration could be necessary to reach optimal levels at the infection site, especially in the case of young patients with preserved renal function and infections caused by multi-drug-resistant Gram-negative bacteria.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In addition, therapeutic drug monitoring of colistin may be a useful strategy for optimizing the treatment of these complicated infections that can help to ensure an optimal exposure while reducing the risk of nephrotoxicity.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Clinical case" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 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:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Day of CMS treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Extraction time \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Extraction site \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colistin concentration (mg/L) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trough or pre IV dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plasma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trough or pre IT dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Right CSF drain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peak (3<span class="elsevierStyleHsp" style=""></span>h after IT administration) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Right CSF drain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trough or pre IT dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Left CSF drain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peak (3<span class="elsevierStyleHsp" style=""></span>h after IT administration) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Left CSF drain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trough or pre IV dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plasma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2888379.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Colistin levels in plasma and CSF.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 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Scientific letter
Therapeutic drug monitoring of colistin in plasma and cerebrospinal fluid in meningoventriculitis caused by a carbapenem-resistant Enterobacter cloacae
Monitorización terapéutica de niveles de colistina en plasma y líquido cefalorraquídeo en meningoventriculitis causada por Enterobacter cloacae resistente a meropenem
Pablo Acína, Sonia Luquea,b,c,
, Luisa Sorlib,c,d,e, Santiago Graua,b,c,f
Autor para correspondencia
a Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
b Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
c Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
d Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
e Universitat Pompeu Fabra, Barcelona, Spain
f Universitat Autònoma de Barcelona, Barcelona, Spain