Intraventricular Antibiotics in Children

Intraventricular (IVT) administration of antibiotics is a treatment option for treatment-resistant central nervous system (CNS) infections, such as meningitis and ventriculitis. IVT administration produces higher antibiotic concentrations in cerebrospinal fluid (CSF) but usually requires an access point in the form of an external ventricular drain or an Ommaya reservoir. A bacterial infection of the meninges and ventricles of the brain is an acute, life-threatening event. Ventriculitis refers to infection and inflammation of the ventricles, ventricular fluid and surrounding tissues. It usually develops secondary to meningitis, especially when there is a concurrent or preexisting obstruction to the flow of CSF. The infectious pathogen can also reach the ventricles directly through a CNS device used to drain CSF or as a postneurosurgical or posttraumatic complication. With the rise of multidrug-resistant bacteria, especially Gram-negative (GNB), the incidence of difficult-to-treat infections is rising. Recent literature has shown that in low and middle-income countries, GNB causes up to 80% of neonatal sepsis/meningitis and around 30% of pediatric meningitis.1 Gram-positive pathogens, such as Group B Streptococcus and enterococci can cause ventriculitis, and staphylococci are associated with infections in IVT devices.2 IVT antibiotic treatment for ventriculitis and meningitis not responding to conventional treatment will be outlined in this paper. ANATOMY AND RISK FACTORS FOR VENTRICULITIS/MENINGITIS The two major risk factors for ventriculitis requiring IVT antibiotics are meningitis with CSF flow hindrance and a ventricular shunt device coinciding with a highly resistant pathogen and/or poor antibiotic penetrance due to pharmacology, anatomy or biofilm formation. Prematurity increases the risk for CNS infections 10-fold, and up to 20% of neonates with meningitis may develop ventriculitis.3 In GNB meningitis, sterilization of the CSF usually takes longer compared with Group B Streptococci and may therefore increase the risk of ventriculitis as a complication.4 Germinal matrix or IVT hemorrhage and posthemorrhagic hydrocephalus increase the risk of ventriculitis because of incomplete CSF drainage.5 The risk of obstruction of CSF drainage and a relatively immature immune response, in addition to the glycogen-rich choroid plexus, significantly increases the risk of CNS infection.6 Age <6 months at the time of shunt placement and presence of CSF leak are also risk factors for shunt infection.7 IVT devices of any kind carry a risk of infection. The most common devices used are ventriculoperitoneal shunts, used for noncommunicating hydrocephalus, and external devices, such as external ventricular drain and Ommaya reservoirs, which are placed when frequent access to CSF fluid is needed. Infection risk is higher for external devices than ventriculoperitoneal shunts.8 For infants and children requiring shunt placement, the incidence of infection ranges from 8% to 15% with a median of 11% within 24 months of CSF shunt insertion.9 Preventive measures such as antibiotic-impregnated catheters and intraoperative IVT antibiotic administration have been shown to significantly reduce rates of postoperative CSF shunt infections.10–12 Despite the lack of international guidelines, this should be considered to reduce the risk of infection, in addition to a strict aseptic approach when accessing the devices. Ventriculitis Microbiology The pathogens causing infections requiring IVT antibiotic treatment differ from the typical pathogens in community-acquired CNS infections. Typical pathogens of nosocomial meningitis and ventriculitis and CNS infections requiring IVT therapy are coagulase-negative staphylococci and Staphylococcus aureus (methicillin sensitive and methicillin resistant (MSSA and MRSA)), enterococci, and Gram-negative bacteria, such as Acinetobacter species, Klebsiella species, Escherichia coli, Pseudomonas aeruginosa and other multidrug-resistant gram-negative organisms.6,13,14 A global increasing trend in GNB has been observed.1,15 Most cases of ventriculitis caused by bacteria susceptible to conventional therapy do not require IVT treatment. A review of published case reports and case series in neonatal ventriculitis requiring IVT was mostly caused by rare microorganisms resistant to conventional therapy.6 In addition, case reports of fungal ventriculitis requiring IVT have been published.16 Diagnosing Ventriculitis Diagnosis of meningitis and ventriculitis remains a challenge. Headache, nausea, lethargy, irritation and/or change in mental status are suggestive of ventriculitis/meningitis in children. In neonates and infants, the clinical signs may be more subtle. When evaluating a patient with a CSF shunt/drain, several symptoms should lead to further workup, such as signs of infection over the subcutaneous shunt, fever, signs of peritonitis or pleuritis and bacteremia without a clear primary source. The workup must consist of CSF sampling for Gram stain and culture; cell count and measurements of protein and glucose, in addition to blood cultures. Molecular diagnostics for pathogen detection can significantly enhance sensitivity.17,18 Imaging is important when suspicion of ventriculitis arises. Ultrasonography of the ventricles is a valuable diagnostic tool in neonates, although contrast magnetic resonance imaging has higher sensitivity in those with suspected ventriculitis.3,6 Normal results from CSF investigations do not rule out a CSF infection, especially in neonates.19 Some of the pathogens causing device-related ventriculitis are opportunistic organisms and may be slow growing. Cultures should therefore be continued for at least 10 days, or molecular diagnostics applied if available.20 Treatment of Ventriculitis Empiric IV treatment for suspected CNS infection should cover the most likely pathogens, both Gram-positives and Gram-negatives, according to local guidelines and adjusted according to cultures and antibiotic sensitivity. Common options for empiric therapy are third generation cephalosporins, which have good CSF penetration. Antibiotic options for IVT treatment are listed in Table 1, but the most used combination is IVT vancomycin and gentamicin combined with intravenous treatment of the same drugs or a third generation cephalosporin. The recommended treatment duration is 4–6 weeks.27 TABLE 1. - Dosages of Antimicrobial Agents Administered by the Intraventricular Route Antibiotic Daily Intraventricular Dose Infant (0–12 months) Children Amikacin21 5–10 mg 10–15 mg Amphotericin B16,22 0.1–0.2 mg* 0.2–0.5 mg Colistin21 0.16 –0.24 mg/kg 0.16–0.24 mg/kg, up to 10 mg Daptomycin23,24 2.5 mg 2.5–5 mg Gentamicin13,20 1–2 mg† , ‡ 1–2 mg† , ‡ Polymyxin B25 2 mg 2–5 mg Tobramycin13 2–5 mg 5 mg Vancomycin26 5–10 mg† , ‡ 10 mg† , ‡ *May also be given every 48 hours or once per week.†Dosage recommendations based on ventricle size/volume as follows:-Slit ventricles: 0.5 × dose.-Enlarged ventricles: 1.5–2 × dose.‡Consider adjusting doses based on external ventricular shunt flow.Doses of IVT Tigecycline in published case reports are 2–4 mg daily for infants and 2–5 mg for children.Adapted from the Infectious Diseases Society of America guidelines on healthcare-associated ventriculitis and meningitis (2017). Although there are no published guidelines available for IVT for the pediatric population, IVT treatment appears both safe and effective, especially for those with CSF shunts already in place.6,13,20,28 In 2017, the Infectious Diseases Society of America published guidelines on healthcare-associated ventriculitis and meningitis, although the guidelines do not mention children.20 These are the only formal guidelines for IVT therapy published that we are aware of. A prospective study of IVT antibiotics in GNB meningitis published in 1977 showed low mortality.27 In 1980, the only randomized controlled study on primary treatment with IVT antibiotics in meningitis and ventriculitis was published. Higher mortality in the IVT treatment group was observed, and the study was stopped before completion.29 The reasons for higher mortality in the treatment group are unknown, but the authors theorized that IVT gentamicin may cause toxin release, leading to a local inflammatory response. Subsequent review of the data from the study, however, found that if children received at least 3 days of IVT treatment, the outcomes were better in terms of morbidity and mortality.30,31 Other studies have not found increased mortality from IVT gentamicin treatment.31,32 When to Initiate IVT Treatment? The decision to initiate IVT treatment will be influenced by several factors. If the response to empiric therapy for the CNS infection is not adequate (clinically deteriorating, persistent symptoms, persistent positive CSF cultures despite appropriate antibiotic treatment [5–7days]), IVT antibiotics should be considered in combination with IV treatment. Positive cultures with multiresistant GNB may also be an indication for earlier IVT treatment. In patients without a CSF shunt, a temporary device needs to be inserted for IVT treatment. When this decision is made, the pathogen has usually been identified and the IV treatment has been adjusted according to the antibiotic sensitivity of the pathogen, sometimes with more than one antibiotic. Most IVT antibiotics are given once daily (Table 1). If a diagnosis of CSF drain-associated ventriculitis is confirmed, prompt removal of the shunt is indicated with an insertion of a temporary drain, if clinically possible. Repeat cultures and cell counts of CSF are of high importance to monitor clinical success. Removal of the proximal tube (proximal to the valve) with concurrent 3–7 days of IVT treatment will probably enhance complete and durable clearance of CSF.14 IVT administration of antibiotics leads to quick clearance of CSF fluid, and side effects are rare.14 Pharmacology Intrathecal antibiotic treatment is a generic term referring to both intralumbar and IVT administration of medication. The blood-brain barrier and blood-CSF barriers protect the central nervous system from toxins and pathogens. It, however, presents an obstacle for many anti-infective drugs to reach effective concentrations in the CNS after systemic administration. The CSF is produced by the choroid plexus located within the cerebral ventricles, and the flow is unidirectional. Intralumbar administration of antibiotics, therefore, does not lead to sufficient IVT concentration. Intracranial CSF gradually increases from 50 ml in neonates and infants to approximately 100–150 ml in teenagers and young adults.33 Most patients needing IVT therapy will have increased CSF volumes due to disrupted flow. Pharmacodynamics CSF concentrations far above the minimum inhibitory concentration of susceptible bacteria can be reached with IV administration of β-lactam and fluoroquinolones in higher doses, since they readily pass the blood-brain barrier with low toxicity profiles. IVT β-lactams can cause severe neurotoxicity, such as seizures and should not be used.28 The antibiotics used for IVT treatment are those that do not reach adequate CSF concentration after systemic administration, despite higher dosing. Table 1 shows a list of antibiotics used for IVT treatment. Dosing and Administration Most antibiotics given as IVT are dosed once per 24 hours. CSF production and total CSF volume will influence the elimination half-life of IVT antibiotics.28 Concurrent IV treatment with the same antimicrobials or another compound active against the infective agent is always recommended, except for prophylactic IVT administration in shunt placement. It is recommended to clamp the IVT drain for 15–60 minutes after antibiotic administration to allow adequate distribution. If possible, antibiotic concentration of CSF, ventricular size and daily output from the ventricular drain can be used to adjust dosing and intervals20 and this may apply particularly for neonates. The CSF trough concentration divided by the minimum inhibitory concentration should exceed 10–20 for consistent CSF sterilization.34 Aminoglycosides have a narrow therapeutic window in the blood and poor CSF penetration. They have been used for several decades for IVT. Gentamicin, tobramycin, netilmicin and amikacin are all suitable options for IVT, although most available data is from gentamicin use. Resistance to one aminoglycoside does not imply reduced susceptibility to all aminoglycosides, and testing for alternative aminoglycosides is recommended. Side effects are rare, and temporary hearing loss has only been reported in one case report in IVT gentamicin treatment.13 The ototoxicity of aminoglycosides is due to vestibular and cochlear damage, and high CSF levels should therefore carry minimal risk.35 Colistin is the cornerstone of treatment in CNS infections with carbapenemase-producing bacteria and can be used as IVT, potentially in combination with IVT polymyxin B. Vancomycin, along with aminoglycosides and colistin, is the most frequently used antibiotic for IVT administration. Few side effects have been reported, and no contraindications have been noted. Concentrations of up to 812 mg/L have been documented without adverse effects. Therapeutic monitoring of intrathecal vancomycin is therefore probably not needed.36 Daptomycin IVT is a treatment option for infections with multiresistant E. faecium and S. epidermidis.28 DISCUSSION IVT antibiotic treatment is a rare intervention but must be considered in hard-to-treat CNS infections. Trials on effectiveness and safety are however lacking. Using IVT treatment has become more relevant with larger populations of extremely prematurely born infants with a high risk of IVT hemorrhage and subsequent infections. It is likely that the incidence of multiresistant GNB CNS infections will continue to rise globally, and therefore, more patients will be considered for IVT treatment. As the safety and efficacy of IVT administration of antimicrobials have not been demonstrated in controlled trials, and this treatment is not approved by the U.S. Food and Drug Administration, there is currently insufficient evidence to recommend their general use. Nevertheless, IVT remains an option when conventional treatment fails. No guidelines exist for neonatal and pediatric ventriculitis or IVT treatment. Dosing and treatment duration are based on expert opinion and experience. Overall, the treatment seems to be well tolerated and causes few side effects, although side effects might be underreported due to the severity of illness in the patient population needing IVT therapy. In most studies, it has shown effective sterilization of CSF fluid with minimal relapses and toxicity. Clinical trials are needed to determine dosing and treatment length and adequate dosing in the pediatric population, especially for neonates. Until then, IVT for treatment-resistant meningitis and ventriculitis will remain a second-line treatment option.