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Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections
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Central nervous system (CNS) infections constitute a life-threatening condition, especially in children. Treatment limitations exist for drug-resistant CNS bacterial infections. Inadequate CNS penetration and intravenous (IV) antibiotic treatment failure represent a major clinical challenge. However, patients with antibiotic-resistant bacterial CNS infections may benefit from intrathecal (IT) or intraventricular (IVT) colistin. IT/IVT colistin therapy is safe and effective as either the primary or adjunct treatment for antibiotic-resistant cases with CNS infection.

CNS infection children colistin Acinetobacter baumannii intrathecal intraventricular
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Subjects: Neurosciences
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    1. Introduction

    Infections of the central nervous system (CNS) may develop in patients with traumatic brain injury after external ventricular drainage insertion and, broadly, after any neurosurgery procedure. Various bacteria are responsible for these infections, especially Staphylococcus epidermidis, but Gram-negative bacteria are responsible for almost 15% of CNS infections. Many patients with CNS infections develop systemic and neurologic complications, with potential sequelae in the survivors and substantial mortality. These infections require prompt diagnosis and management, which depend mainly on the local epidemiology and patterns of antibiotic resistance of common pathogens [1][2].
    It has been shown that the extensive use of antibiotics after neurosurgical CNS infections might alter their epidemiology. External ventricular drainage is one of the common procedures performed in neurosurgery associated with a variable infection rate ranging from 2% to 33% [3].
    Due to the increasing emergence of multidrug-resistant bacteria (MDR) (e.g., Acinetobacter, A. baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae) [4][5], treatment of CNS infections has become increasingly difficult. Several bacteria have become susceptible only to colistin and polymyxin B. Colistin is a complex mixture of polymyxins, mainly polymyxin E1 and polymyxin E2. It was the first antibiotic with notable in vitro activity against P. aeruginosa [1].
    Colistin began to be used in the treatment of multidrug-resistant A. baumannii infections [6]. However, since there is a limited penetration of intravenous colistin to the cerebrospinal fluid, IT or IVT treatment is commonly applied in CNS infections [7].

    2. Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections

    CNS infections are associated with high morbidity and the case fatality rate, in addition to a significant cost to the healthcare system.
    Despite colistin being introduced in clinical practice in 1947, it was not until recent years that concerns were raised regarding the low level of colistin concentration in the cerebrospinal fluid, leading to a concern for poor penetration of the blood–brain barrier, which has led to the possibility of intrathecal (IT)/intraventricular (IVT)  (IT/IVT) administration to achieve direct eradication of the causative organism [6]. It was also reported that only 5–25% of IV colistin crosses into the CSF [8]. Even in patients with meningitis, with a disrupted blood–brain barrier, this rate does not exceed 25%. On the other hand, several studies proved the efficacy of IT and IVT colistin administration [9][10]. However, the first report of intrathecal administration of colistin in a pediatric patient was back in 1990 [11] (Table 1).
    Table 1. Summary of the main studies.
    Reference Age Gender Route of Infection EVD CSF Culture Colistin (Duration) Other Antibiotics Outcome
    Kaplan & Patrick, 1990 [11] 4 years NR CSF leak after trauma Yes A. baumannii IV, IVT, and IT
    (20 days)
    -- Recovered
    Fernandez-Viladrich et al., 1999 [12] 16 years Male After neurosurgical intervention Yes A. baumannii IVT and IT
    (20 days)
    Meropenem, Tobramycin, Sulbactam Severe disability
    Ng et al., 2006 [13] 4 years Male After neurosurgical intervention No A. baumannii IV, IVT, and IT
    (24 days)
    Amikacin Severe disability
    Yagmur & Esen, 2006 [14] 16 years Male After neurosurgical intervention Yes P. aeruginosa IVT and IT
    (21 days)
    IV amikacin Recovered
    Dalgic et al., 2009 [15] 2 months Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (27 days)
    -- Recovered
    Dalgic et al., 2009 [15] 2 months Female After neurosurgical intervention Yes K. pneumoniae IV, IVT, and IT
    (14 days)
    Ciprofloxacin Recovered
    Özdemir et al., 2010 [16] 3 years Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (35 days)
    Meropenem, amikacin, ampicillin Recovered
    Cascio et al., 2010 [9] 5 years Male After neurosurgical intervention Yes Enterobacter cloacae IV, IVT, and IT
    (14 days)
    Teicoplanin, Rifampin, cefazidime Moderate disability
    Saleem et al., 2011 [17] 5 months Male After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (24 days)
    -- Died
    Saleem et al., 2011 [17] 9 months Male After neurosurgical intervention No A. baumannii IV, IVT, and IT
    (6 days)
    -- Recovered
    Saleem et al., 2011 [17] 3 months Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (11 days)
    -- Recovered
    Saleem et al., 2011 [17] 9 years Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (21 days)
    -- Recovered
    Wang et al., 2012 [18] 15 years Male After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (24 days)
    Meropenem Recovered
    Karaiskos et al., 2013 [6] 18 years Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (17 days)
    Carbapenem, Sulbactam. Recovered
    Bargiacchi et al., 2014 [19] 18 years Male After neurosurgical intervention Yes P. aeruginosa IV, IVT, and IT
    (18 days)
    Ciprofloxacin Recovered
    Tekgündüz et al., 2015 [8] <1 month Male After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (9 days)
    Vancomycin Recovered
    Santos et al., 2015 [20] 15 months Male After neurosurgical intervention Yes E. coli, K. pneumoniae IV, IVT, and IT Meropenem Recovered
    Santos et al., 2015 [20] 11 months Male After neurosurgical intervention Yes A. baumannii IV, IVT, and IT Meropenem, Amikacin Recovered
    Tekgunduz et al., 2015 [21] 2 months Male After neurosurgical intervention Yes A. baumannii IV, IVT, and IT Gentamicin, Sulbactam Moderate disability
    Mahabeer et al., 2018 [22] 1 month Male Healthcare-associated infection Yes A. baumannii IV, IVT, and IT Gentamicin Recovered
    Hiremath et al., 2018 [23] 17 years Female After neurosurgical intervention Yes A. baumannii IVT and IT
    (11 days)
    IV meropenem and teicoplanin recovered
    Abad-Restrepo et al., 2018 [24] 11 years Female After neurosurgical intervention Yes P. aeruginosa IV, IVT, and IT
    (42 days)
    Vancomycin Recovered
    AlZailaie et al., 2018 [25] 5 years Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (49 days)
    -- Recovered
    Al Yazidi et al., 2018 [26] <1 month Male After neurosurgical intervention Yes Enterobacter cloacae IV, IVT, and IT
    (9 days)
    Meropenem, Ciprofloxacin Died
    Hussain et al., 2021 [10] 1 month Female After neurosurgical intervention Yes E.coli, K. pneumoniae IV, IVT, and IT
    (7 days)
    IV meropenem, vancomycin Recovered
    Hussain et al., 2021 26] <1 month Male After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (7 days)
    IV meropenem, vancomycin Recovered
    Hussain et al., 2021 [10] < 1 month Male Healthcare-associated infection Yes A. baumannii IV, IVT, and IT
    (5 days)
    IV meropenem, vancomycin Recovered
    Hussain et al., 2021 [10] <1 month Female After neurosurgical intervention Yes A. baumannii IV, IVT, and IT
    (8 days)
    IV cefotaxime,
    Meropenem,
    amikacin,
    colistin
    Recovered
    Hussain et al., 2021 [10] <1 month Male Healthcare-associated infection Yes A. baumannii IV, IVT, and IT
    (7 days)
    IV cefotaxime,
    Meropenem,
    amikacin
    Moderate disability
    Hussain et al., 2021 [10] <1 month Male Healthcare-associated infection Yes A. baumannii IV, IVT, and IT
    (3 days)
    IV cefotaxime,
    Meropenem,
    amikacin,
    vancomycin
    Died
    Hussain et al., 2021 [10] <1 month Male After neurosurgical intervention Yes K pneumoniae, A. baumannii IV, IVT, and IT
    (8 days)
    IV meropenem,
    Ceftazidime,
    amikacin
    Recovered
    EVD: External ventricular drain, MDR: Multidrug resistant, NR: Not reported, IVT: Intraventricular therapy, and IT: Intrathecal.
    In recent years, A. baumannii has appeared as an important pathogen, especially in hospital-acquired infections [27]. The risk factors for infection are neurosurgical procedures, CSF leak, a prolonged use of intravascular devices, prior treatment with broad-spectrum antibiotics, prior colonization with Acinetobacter, prolonged mechanical ventilation, and ICU stay, as well as intracranial hemorrhage [6].
    It was reported that the incidence of CNS infections is associated with ventricular devices, with more than 50% of the episodes occurring within the first month of implant placement [19]. Therefore, it is generally advised in cases of CSF shunt infections that all components of infected shunts or external drainage devices be removed and appropriate antimicrobial therapy be administered in combinations [28].
    In the USA, there are no FDA-approved antimicrobial agents for intraventricular use [26]. Intraventricular colistin is being used off-label to sterilize the cerebrospinal fluid. Moreover, the dosages for antimicrobials have been empiric, with dose adjustments and dosing intervals mainly based on pharmacokinetic calculations to achieve adequate CNS concentrations [28].
    Polymyxins are increasingly used for the treatment of CNS infections caused by multidrug-resistant Gram-negative bacteria. Four polymyxins exhibit rapid bacterial killing against most Gram-negative microorganisms by disturbing the bacterial cell membrane and can block the biologic effects of endotoxins [10]. However, intravenously administered polymyxins do not achieve high concentrations in the CNS. Therefore, IVT and ITH have been recommended in patients with CNS device infections that are difficult to eradicate or who cannot undergo the surgical removal of infected devices [7].
    The toxicity from intrathecal or intraventricular therapy with colistin is a major challenge, especially with respect to aseptic or chemical meningitis, which is very hard to differentiate clinically from bacterial meningitis. However, the CSF parameters are the only key in differentiating the two [6]. Despite that, the three deaths that were not related directly to the intrathecal toxicity, as one child, for instance, died from consequences of hydrocephalus, and the team with the family reached the conclusion of withdrawing care after the EVD was inadvertently dislodged [26], and another child died from the consequences of sepsis [17].
    A recent study addressed the use of colistin in neonates found that six out of seven patients who received IT/IVT colistin survived, where five of them received it in combination with IV colistin, and the one that died received only IT/IVY colistin [29]. And reported three patients who had a seizure disorder on follow-up, and the only patient with moderate disability had both hearing and visual impairments [29].
    IT/IVT as a last resort of the management of serious CNS infections should be pursued without delay. However, caution throughout the treatment period should be implemented by all treating teams, which should include pediatric neurosurgeons, infectious disease specialists, neurologists, clinical pharmacologists, etc.
    There was no consistency regarding the dosage of IT/IVT used. However, a dose of 0.16–0.24 mg/kg every 24 h was most commonly used [6][17]. Some studies used up to 10 mg every 24 h, which appeared to be a high dose in, for instance, a three-year-old child; despite that, it is hard to comment on the appropriateness of the dose with the lack of data on the weight of children [16].
    IT/IVT colistin therapy is a safe and effective last resort of management as either the primary or adjunct treatment for antibiotic-resistant cases with CNS infections in the pediatric population.

    References

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    2. Brouwer, M.; van de Beek, D. Management of bacterial central nervous system infections. In Critical Care Neurology. Part I. Handbook of Clinical Neurology, 1st ed.; 3rd Series; Wijdicks, E.F.M., Kramer, A.H., Eds.; Elsevier: Amsterdam, The Netherlands, 2017; Volume 140.
    3. De Pascale, G.; Pompucci, A.; Maviglia, R.; Spanu, T.; Bello, G.; Mangiola, A.; Scoppettuolo, G. Successful treatment of multidrug-resistant Acinetobacter baumannii ventriculitis with intrathecal and intravenous colistin. Minerva Anestesiol. 2010, 76, 957–960.
    4. Tartor, Y.H.; Gharieb, R.M.A.; El-Aziz, N.K.A.; El Damaty, H.M.; Enany, S.; Khalifa, E.; Attia, A.S.A.; Abdellatif, S.S.; Ramadan, H. Virulence Determinants and Plasmid-Mediated Colistin Resistance mcr Genes in Gram-Negative Bacteria Isolated from Bovine Milk. Front. Cell. Infect. Microbiol. 2021, 11, 761417.
    5. Tartor, Y.H.; El-Aziz, N.K.A.; Gharieb, R.M.A.; El Damaty, H.M.; Enany, S.; Soliman, E.A.; Abdellatif, S.S.; Attia, A.S.A.; Bahnass, M.M.; El-Shazly, Y.A.; et al. Whole-Genome Sequencing of Gram-Negative Bacteria Isolated from Bovine Mastitis and Raw Milk: The First Emergence of Colistin mcr-10 and Fosfomycin fosA5 Resistance Genes in Klebsiella pneumoniae in Middle East. Front. Microbiol. 2021, 12, 770813.
    6. Karaiskos, I.; Galani, L.; Baziaka, F.; Giamarellou, H. Intraventricular and intrathecal colistin as the last therapeutic resort for the treatment of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii ventriculitis and meningitis: A literature review. Int. J. Antimicrob. Agents 2013, 41, 499–508.
    7. Markantonis, S.L.; Markou, N.; Fousteri, M.; Sakellaridis, N.; Karatzas, S.; Alamanos, I.; Dimopoulou, E.; Baltopoulos, G. Penetration of Colistin into Cerebrospinal Fluid. Antimicrob. Agents Chemother. 2009, 53, 4907–4910.
    8. Tekgunduz, K.S.; Kara, M.; Caner, I.; Demirelli, Y. Safety and Efficacy of Intravenous Colistin in Neonates with Culture Proven Sepsis. Iran. J. Pediatr. 2015, 25, e453.
    9. Cascio, A.; Conti, A.; Sinardi, L.; Iaria, C.; Angileri, F.F.; Stassi, G.; David, T.; Versaci, A.; Iaria, M.; David, A. Post-neurosurgical multidrug-resistant Acinetobacter baumannii meningitis successfully treated with intrathecal colistin. A new case and a systematic review of the literature. Int. J. Infect. Dis. 2010, 14, e572–e579.
    10. Falagas, M.E.; Bliziotis, I.A.; Tam, V.H. Intraventricular or intrathecal use of polymyxins in patients with Gram-negative meningitis: A systematic review of the available evidence. Int. J. Antimicrob. Agents 2007, 29, 9–25.
    11. Kaplan, S.L.; Patrick, C.C. Cefotaxime and aminoglycoside treatment of meningitis caused by Gram-negative enteric organisms. Pediatr. Infect. Dis. J. 1990, 9, 810–814.
    12. Fernandez-Viladrich, P.; Corbella, X.; Corral, L.; Tubau, F.; Mateu, A. Successful Treatment of Ventriculitis Due to Carbapenem-ResistantAcinetobacter baumanniiwith Intraventricular Colistin Sulfomethate Sodium. Clin. Infect. Dis. 1999, 28, 916–917.
    13. Ng, J.; Gosbell, I.B.; Kelly, J.A.; Boyle, M.J.; Ferguson, J.K. Cure of multiresistant Acinetobacter baumannii central nervous system infections with intraventricular or intrathecal colistin: Case series and literature review. J. Antimicrob. Chemother. 2006, 58, 1078–1081.
    14. Yagmur, R.; Esen, F. Intrathecal colistin for treatment of Pseudomonas aeruginosa ventriculitis: Report of a case with successful outcome. Crit. Care 2006, 10, 428.
    15. Dalgic, N.; Ceylan, Y.; Sancar, M.; Telhan, L.; Kafadar, I.; Cavusoglu, H.; Ceylan, O.; Hasim, O. Successful treatment of multidrug-resistant Acinetobacter baumannii ventriculitis with intravenous and intraventricular colistin. Ann. Trop. Paediatr. 2009, 29, 141–147.
    16. Özdemir, H.; Tapısız, A.; Çiftçi, E.; Ince, E.; Mokhtari, H.; Güriz, H.; Aysev, A.D.; Doğru, Ü.; Tapisiz, A. Successful treatment of three children with post-neurosurgical multidrug-resistant Acinetobacter baumannii meningitis. Infection 2010, 38, 241–244.
    17. Saleem, A.F.; Shah, M.S.; Shaikh, A.S.; Mir, F.; Zaidi, A.K.M. Acinetobacter species meningitis in children: A case series from Karachi, Pakistan. J. Infect. Dev. Ctries. 2011, 5, 809–814.
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    19. Bargiacchi, O.; Rossati, A.; Car, P.; Brustia, D.; Brondolo, R.; Rosa, F.; Garavelli, P.L.; DE Rosa, F.G. Intrathecal/intraventricular colistin in external ventricular device-related infections by multi-drug resistant Gram negative bacteria: Case reports and review. Infection 2014, 42, 801–809.
    20. Santos, A.S.; Iraneta, A.; Matos, M.; Brito, M.J. Intraventricular colistin in Gram-negative ventriculoperitoneal shunt infection in two pediatric patients. Acta Neurochir. 2015, 157, 2219–2220.
    21. Tekgündüz, K.S.; Demirelli, Y.; Caner, I.; Kara, M. Intraventricular colistin use in a premature infant with cerebral abscess and ventriculitis. J. Clin. Neonatol. 2015, 4, 132–134.
    22. Mahabeer, P.; Mzimela, B.W.; Lawler, M.A.; Singh-Moodley, A.; Singh, R.; Mlisana, K.P. Colistin-resistantAcinetobacter baumanniias a cause of neonatal ventriculitis. S. Afr. J. Infect. Dis. 2018, 33, 1–3.
    23. Rao, K.; Rangappa, P.; Jacob, I.; Hiremath, P. Cerebrospinal fluid lactate as a prognostic indicator in postneurosurgical bacterial meningitis and use of intrathecal colistin. Indian J. Crit. Care Med. 2018, 22, 297–299.
    24. Abad-Restrepo, J.; Díaz-Díaz, A.; Osorio-Cadavid, N. Post-surgical ventriculitis due to extensively resistant Pseudomonas aeruginosa treated with intrathecal colistin: Pediatric case report and literature review. Rev. Chil. Infectología 2018, 35, 321–325.
    25. Alzailaie, A.K.; Aljarie, A.A.; Abdelwahab, H.M. Successful Outcome in Treating Ventriculitis with Intrathecal Colistin in a Child. Bahrain Med. Bull. 2018, 40, 59–60.
    26. Al Yazidi, L.S.; McMullan, B.; Kohan, S.; Palasanthiran, P. Persistent Gram-negative Neurosurgical Meningitis in a Neonate, Successfully Treated with Intraventricular Colistin: Case Report and Review of the Literature. Pediatr. Infect. Dis. J. 2018, 37, e79–e81.
    27. Giamarellou, H.; Antoniadou, A.; Kanellakopoulou, K. Acinetobacter baumannii: A universal threat to public health? Int. J. Antimicrob. Agents 2008, 32, 106–119.
    28. Tunkel, A.R.; Hartman, B.J.; Kaplan, S.L.; Kaufman, B.A.; Roos, K.L.; Scheld, W.M.; Whitley, R.J. Practice Guidelines for the Management of Bacterial Meningitis. Clin. Infect. Dis. 2004, 39, 1267–1284.
    29. Hussain, K.; Salat, M.S.; Ambreen, G.; Iqbal, J. Neurodevelopment Outcome of Neonates Treated with Intraventricular Colistin for Ventriculitis Caused by Multiple Drug-Resistant Pathogens—A Case Series. Front. Pediatr. 2021, 8, 843.
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      Alnaami, I. Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections. Encyclopedia. Available online: https://encyclopedia.pub/entry/24048 (accessed on 07 February 2023).
      Alnaami I. Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections. Encyclopedia. Available at: https://encyclopedia.pub/entry/24048. Accessed February 07, 2023.
      Alnaami, Ibrahim. "Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections," Encyclopedia, https://encyclopedia.pub/entry/24048 (accessed February 07, 2023).
      Alnaami, I. (2022, June 15). Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections. In Encyclopedia. https://encyclopedia.pub/entry/24048
      Alnaami, Ibrahim. ''Intrathecal/Intraventricular Colistin for Pediatric Antibiotic-Resistant Bacterial CNS Infections.'' Encyclopedia. Web. 15 June, 2022.
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