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

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1		Ibrahim Alnaami	--	1002	2022-06-15 08:32:28	\|
2	Reference format revised.	Lindsay Dong	+ 638 word(s)	1640	2022-06-15 11:14:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/tropicalmed7030041

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

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.

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1. Introduction

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

References