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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Multidrug-resistant tuberculosis &#40;MDR-TB&#41; represents a global challenge&#46; In 2018&#44; 186&#44;772 new cases of MDR-TB or TB resistant to rifampicin &#40;RR-TB&#41; were notified globally&#44; resulting in an estimated incidence of 484&#44;000 &#40;95&#37; confidence interval 417&#44;000&#8211;556&#44;000&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Mathematical modelling studies estimate the number of MDR-TB in children as between 25&#44;000 and 32&#44;000 annually&#44; although it is suspected that &#60;5&#37; are identified and even less are correctly treated&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Treatment outcomes for MDR-TB remain suboptimal&#46; In the last 40 years only two new drugs for TB treatment have been licensed &#40;bedaquiline and delamanid&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> However&#44; the World Health Organization &#40;WHO&#41; has recently updated its guidelines on MDR-TB treatment&#44; as well as the SEPAR guideline updated in 2017&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4&#44;5</span></a> They propose new drug combination regimens which exclude the second-line injectable agents and include bedaquiline&#44; delamanid and other repurposed drugs such as linezolid and clofazimine in order to optimize safety and efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Bedaquiline is considered highly effective and is recommended in all MDR-TB regimens for adults and children<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>6 years&#59; however&#44; it is expensive and not currently available in many European countries such as Spain&#46; Bedaquiline dosing and safety studies are yet to be done in young children &#40;&#60;6 years&#41;&#46; Linezolid is also recommended as a core agent with good activity against <span class="elsevierStyleItalic">M&#46; tuberculosis</span> including extensively drug-resistant &#40;XDR&#41; strains&#46; Fluoroquinolones &#40;levofloxacin and moxifloxacin&#41; complete the group of the most effective agents &#40;Group A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> The major advantage is that they are all-oral regimens&#44; increasing treatment feasibility and reducing severe adverse events such as ototoxicity and nephrotoxicity caused by the aminoglycosides&#46; However&#44; these new drug regimens are not exempt from adverse events and data on safety and efficacy in children are scarce&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> We present a case of probable cycloserine-associated behavioural disturbance with neuromuscular symptoms&#44; as well as intracranial hypertension secondary to levofloxacin in a child with MDR-TB&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">A previously healthy&#44; not BCG-vaccinated&#44; Spanish six-year-old girl was diagnosed with tuberculosis &#40;TB&#41; following active household contact tracing&#46; Her father&#44; diagnosed with infectious MDR pulmonary TB&#44; was the index case&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">At diagnosis she was asymptomatic&#44; with normal physical examination and a positive tuberculin skin test &#40;induration of 13<span class="elsevierStyleHsp" style=""></span>mm&#41;&#46; Left hilar enlarged lymph nodes were suspected on her chest-X-ray and bilateral enlarged mediastinal and hilar lymph nodes with bilateral lung nodules were detected on chest computed tomography &#40;CT&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Serial gastric aspirate specimens for acid-fast bacilli smear microscopy&#44; PCR and mycobacterial culture were negative in the patient&#59; however&#44; <span class="elsevierStyleItalic">M&#46; tuberculosis</span> cultures were positive in both her father and four-year old brother&#44; with isolates showing resistance to isoniazid&#44; rifampicin&#44; pyrazinamide&#44; ethionamide and streptomycin&#46; These findings were sufficient for the diagnosis of MDR pulmonary TB&#44; reserving the bronchoscopy in the event that the patient did not have a known TB contact or antimicrobial sensitivity pattern&#46; Therefore&#44; an injectable-free treatment regimen was initiated with levofloxacin &#40;18&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#44; linezolid &#40;14<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#44; clofazimine &#40;100<span class="elsevierStyleHsp" style=""></span>mg every second day&#41;&#44; cycloserine &#40;18&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41; and ethambutol &#40;18&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Three weeks later&#44; she was admitted to hospital due to vomiting and refusal to take MDR-TB drugs&#46; On admission she presented with right-sided torticollis and an adjustment disorder with mixed disturbance of emotions and conduct including insomnia and an anxiety crisis&#46; Six days later&#44; the patient also developed right peripheral facial palsy&#46; A cranial and cervical spine CT scan did not show any abnormal findings such as an intracranial tuberculoma or cervical spine TB&#46; Complete blood count &#40;CBC&#41;&#44; renal&#44; hepatic and mineral panel and thyroid function tests were normal&#46; Rheumatoid factor and anti-nuclear antibodies were negative&#46; Cycloserine was considered as likely responsible for these clinical findings and was discontinued&#58; neuro-psychiatric symptoms progressively disappeared&#46; Delamanid &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41; was added to the treatment regimen to replace cycloserine&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Two weeks later &#40;5 weeks after treatment initiation&#41;&#44; bilateral optic disc swelling was detected after performing a routine ophthalmological toxicity examination&#46; She was asymptomatic at this time and a brain magnetic resonance imaging showed a papillary protrusion and posterior flattening of both eyes &#40;indirect signs of intracranial hypertension&#41; without any other abnormal radiological findings&#46; Cytological and biochemical analysis of the cerebrospinal fluid were normal and culture was negative&#46; An increased intracranial pressure &#40;ICP&#41; &#40;34<span class="elsevierStyleHsp" style=""></span>cm H<span class="elsevierStyleInf">2</span>O&#41; confirmed the diagnosis of intracranial hypertension&#46; Levofloxacin was considered the likely cause and was discontinued&#46; To manage the raised ICP&#44; acetazolamide was added&#44; causing metabolic acidosis&#44; which was treated with oral bicarbonate&#46; Thereafter her clinical resolution was good with a progressive decrease of ICP and after six weeks the fundus examination returned to normal&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">At present&#44; she is in the 8th month of treatment and medications including linezolid&#44; clofazimine&#44; delamanid&#44; and ethambutol are well tolerated&#46; She remains asymptomatic presenting an adequate weight gain&#46; Serial chest X-ray are normal and a chest CT will be scheduled at the end of treatment at 15 months from treatment initiation&#46; Clinical follow up including CBC&#44; electrocardiogram and ophthalmologic exam is performed on a monthly basis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">This case report shows the challenges of managing MDR-TB in children&#46; The clinical evolution of this case with several adverse events related to the MDR-TB treatment&#44; highlights the potential risk of adverse effects caused by these new drug combinations and the concern that treatment interruption may compromise treatment efficacy&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Initially&#44; the patient presented with behavioural disturbance after three weeks of MDR-TB therapy&#46; The association of cycloserine with depression&#44; psychosis and neuropathy is well established&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Cycloserine-associated neuro-psychiatric effects are likely due to its binding to N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate receptors and it has been demonstrated that these adverse events are related to high drug concentrations in serum&#46; This has led to investigate the therapeutic use of cycloserine at lower doses for psychiatric disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Therapeutic drug monitoring is used to individualize treatment doses and might help to prevent toxicities caused by high drug concentrations&#59; however&#44; it was not performed in this case as it was not locally available&#46; Moreover&#44; based on the presence of right-sided torticollis and lower motor neuron facial palsy&#44; a space-occupying lesion was also ruled out&#46; We finally attributed these neuro-psychiatric symptoms to cycloserine&#44; as they progressively disappeared after the withdrawal of the drug&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The association between fluoroquinolones and intracranial hypertension has been previously described&#44; although it is rare&#44; and the pathogenic mechanism is not completely understood&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Few case reports have shown specific association of levofloxacin-induced intracranial hypertension between 5 days and 3 months after the start of the treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8&#8211;10</span></a> We decided to discontinue levofloxacin and improvement of her condition was observed in a short period of time&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Fluoroquinolones are a key component for MDR-TB treatment&#46; When contraindicated&#44; the therapeutic strategy should be planned as extensively drug-resistant tuberculosis&#46; Therefore&#44; she eventually continued with a &#8220;non-optimal&#8221; regimen with good radiological response&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Despite the improvement in therapeutic strategies for MDR-TB&#44; this case points out the need to keep searching for the most effective and least toxic drug regimen&#40;s&#41; for MDR-TB in children and in adults&#46;</p></span>"
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