Typical Symptoms and Signs

Cerebrospinal Fluid (CSF) Shunts and Drains

• New headache, nausea, lethargy and/or change in mental status are suggestive of CSF shunt infection (S-M).
• Erythema and tenderness over the subcutaneous shunt tubing are suggestive of CSF shunt infection (S-M).
• Fever, in the absence of another clear source of infection, could be suggestive of CSF shunt infection (W-L).
• Symptoms and signs of peritonitis or abdominal tenderness in patients with ventriculoperitoneal shunts, in the absence of another clear etiology, are indicative of CSF shunt infection (S-M).
• Symptoms and signs of pleuritis in patients with ventriculopleural shunts, in the absence of another clear etiology, are indicative of CSF shunt infection (S-M).
• Demonstration of bacteremia in a patient with a ventriculoatrial shunt, in the absence of another clear source of bacteremia, is evidence of CSF shunt infection (S-M).
• Demonstration of glomerulonephritis in a patient with a ventriculoatrial shunt is suggestive of CSF shunt infection (W-L).
• New or worsening altered mental status in patients with external ventricular drains is suggestive of infection (W-L).
• New fever and increased CSF white blood cell count in patients with external ventricular drains could be suggestive of infection (W-L).

Neurosurgery or Head Trauma

• New headache, fever, evidence of meningeal irritation, seizures and/or worsening mental status are suggestive of ventriculitis or meningitis in the setting of recent trauma or neurosurgery (S-M).
• Fever, in the absence of another clear source of infection, is suggestive of central nervous system (CNS) infection in the setting of recent head trauma or neurosurgery (W-L).

Intrathecal Infusion Pumps

• New fever and drainage from the surgical site in patients with intrathecal infusion pumps are suggestive of wound infection (W-L).

Typical Cerebrospinal Fluid Findings

Cell Count, Glucose and Protein

• Abnormalities of CSF cell count, glucose and/or protein may not be reliable indicators for the presence of infection in patients with healthcare-associated ventriculitis and meningitis (W-M).
• Normal CSF cell count, glucose and protein may not reliably exclude infection in patients with healthcare-associated ventriculitis and meningitis (W-M).
• A negative CSF Gram stain does not exclude the presence of infection, especially in patients who have received previous antimicrobial therapy (S-M).

Culture

• CSF cultures are the most important test to establish the diagnosis of healthcare-associated ventriculitis and meningitis (S-H).
• If initial CSF cultures are negative in patients with CSF shunts or drains with suspected infection, it is recommended that cultures should be held for at least 10 days in an attempt to identify organisms such as Propionibacterium acnes (S-H).
• If a CSF shunt or drain is removed in patients suspected of having infection, cultures of shunt and drain components are recommended (S-M).
• If a CSF shunt or drain is removed for indications other than infection, cultures of shunt or drain components are NOT recommended (S-M).
• Blood cultures are recommended in patients with suspected ventriculoatrial shunt infections (S-H).
• Blood cultures may be considered in patients with ventriculoperitoneal and ventriculopleural shunts (W-L).
• Single or multiple positive CSF cultures in patients with CSF pleocytosis and/or hypoglycorrhachia, or an increasing cell count, and clinical symptoms suspicious for ventriculitis or meningitis, is indicative of CSF drain infection (S-H).
• CSF and blood cultures in selected patients should be obtained before the administration of antimicrobial therapy. A negative CSF culture in the setting of previous antimicrobial therapy does not exclude healthcare-associated ventriculitis and meningitis (S-M).

Neurosurgery or Head Trauma

• CSF pleocytosis with a positive culture and symptoms of infection are indicative of a diagnosis of healthcare-associated ventriculitis or meningitis (S-H).
• Hypoglycorrhachia and elevated CSF protein concentrations are suggestive of the diagnosis of healthcare-associated ventriculitis or meningitis (W-L).
• Growth of an organism which is commonly considered a contaminant (e.g., coagulase-negative Staphylococcus) in enrichment broth only or on just one of multiple cultures, in a patient with normal CSF and no fever, is not indicative of healthcare-associated ventriculitis or meningitis (S-L).
• CSF cultures with multiple organisms from a single sample may be contaminants in patients with no symptoms of infection or CSF pleocytosis (W-L).
• CSF cultures that grow Staphylococcus aureus or aerobic gram-negative bacilli are indicative of infection (S-M).
• CSF cultures that grow a fungal pathogen are indicative of infection (S-M).
  

Specific CSF Tests to Confirm the Diagnosis

• An elevated CSF lactate or an elevated CSF procalcitonin, or the combination of both, may be useful in the diagnosis of healthcare-associated bacterial ventriculitis and meningitis (W-M).
• An elevated serum procalcitonin may be useful in differentiating between CSF abnormalities due to surgery or intracranial hemorrhage from those due to bacterial infection (W-L).
• Nucleic acid amplification tests, such as polymerase chain reaction (PCR), on CSF may both increase the ability to identify a pathogen and decrease the time to making a specific diagnosis (W-L).
• Detection of β–D-glucan and galactomannan in CSF may be useful in the diagnosis of fungal ventriculitis and meningitis (S-M).

Imaging

• Neuroimaging is recommended in patients with suspected healthcare-associated ventriculitis and meningitis (S-M).
• Magnetic resonance imaging (MRI) with gadolinium-enhancement and diffusion-weighted imaging is recommended for detecting abnormalities in patients with healthcare-associated ventriculitis and meningitis (S-M).
• In patients with infected ventriculoperitoneal shunts and abdominal symptoms (e.g., pain or tenderness), an ultrasound or computed tomography (CT) of the abdomen is recommended to detect CSF loculations at the shunt terminus (S-M).

Empiric Antimicrobials

• Vancomycin plus an anti-pseudomonal β-lactam (such as cefepime, ceftazidime or meropenem) is recommended as empiric therapy for healthcare-associated ventriculitis and meningitis. Choice of the empiric β-lactam agent should be based on local in vitro susceptibility patterns (S-L).
• In seriously ill adult patients with healthcare-associated ventriculitis and meningitis, the vancomycin trough concentration should be maintained at 15–20 μg/mL in those receiving intermittent bolus administration (S-L).
• For patients with healthcare-associated ventriculitis and meningitis who have experienced anaphylaxis to β-lactam antimicrobial agents and in whom meropenem is contraindicated, aztreonam or ciprofloxacin is recommended for gram-negative coverage (S-L).
• For patients with healthcare-associated ventriculitis and meningitis who are colonized or infected elsewhere with a highly antimicrobial-resistant pathogen, adjusting the empiric regimen to treat for this pathogen is recommended (S-L).

Specific Antimicrobials

• For treatment of infection caused by methicillin-susceptible Staphylococcus aureus, nafcillin or oxacillin is recommended (S-M). If the patient cannot receive β-lactam agents, the patient can be desensitized or may receive vancomycin as an alternative agent (W-M).
• For treatment of infection caused by methicillin-resistant S. aureus (MRSA), vancomycin is recommended as first line therapy (S-M), with consideration for an alternative antimicrobial agent if the vancomycin MIC is ≥1 μg/mL (S-M).
• For treatment of infection caused by coagulase-negative staphylococci, the recommended therapy should be similar to S. aureus and based on in vitro susceptibility testing (S-M).
• If the staphylococcal isolate is susceptible to rifampin, this agent may be considered in combination with other antimicrobial agents for staphylococcal ventriculitis and meningitis (W-L). Rifampin is recommended as part of combination therapy for any patient with intracranial or spinal hardware such as a CSF shunt or drain (S-L).
• For treatment of patients with healthcare-associated ventriculitis and meningitis caused by staphylococci in whom β-lactam agents or vancomycin cannot be used, linezolid (S-L), daptomycin (S-L), or trimethoprim-sulfamethoxazole (S-L) is recommended with selection of a specific agent based on in vitro susceptibility testing.
• For treatment of infection caused by P. acnes, penicillin G is recommended (S-M).
• For treatment of infection caused by gram-negative bacilli, therapy should be based on in vitro susceptibility testing with agents that achieve good CNS penetration (S-M).
• For treatment of infection caused by gram-negative bacilli susceptible to third-generation cephalosporins, ceftriaxone or cefotaxime is recommended (S-M).
• For treatment of infection caused by Pseudomonas species, the recommended therapy is cefepime, ceftazidime or meropenem (S-M). Recommended alternative antimicrobial agents are aztreonam or a fluoroquinolone with in vitro activity (S-M).
• For treatment of infection caused by extended spectrum β-lactamase (ESBL)-producing gram-negative bacilli, meropenem should be used if this isolate demonstrates in vitro susceptibility (S-M).
• For treatment of infection caused by Acinetobacter species, meropenem is recommended (S-M). For strains demonstrating carbapenem resistance, colistimethate sodium or polymyxin B (either agent administered by the intravenous and intraventricular routes) is recommended (S-M).
• Prolonged infusion of meropenem (each dose administered over 3 hours) may be successful in treating resistant gram-negative organisms (W-L).
• For treatment of infection caused by Candida species, based on in vitro susceptibility testing, liposomal amphotericin B, often combined with 5-flucytosine, is recommended (S-M). Once the patient shows clinical improvement, therapy can be changed to fluconazole if the isolated species is susceptible (W-L).
• For treatment of infection caused by Aspergillus or Exserophilum species, voriconazole is recommended (S-L).

Intraventricular Antimicrobial Therapy

• Intraventricular antimicrobial therapy should be considered for patients with healthcare-associated ventriculitis and meningitis in which the infection responds poorly to systemic antimicrobial therapy alone (S-L).
• When antimicrobial therapy is administered via a ventricular drain, the drain should be clamped for 15–60 minutes to allow the agent to equilibrate throughout the CSF (S-L).
• Dosages and intervals of intraventricular antimicrobial therapy should be adjusted based on CSF antimicrobial concentrations to 10–20 times the MIC of the causative microorganism (S-L), ventricular size (S-L), and daily output from the ventricular drain (S-L).

Optimal Duration of Antimicrobial Therapy

• Infections caused by a coagulase-negative Staphylococcus or P. acnes with no or minimal CSF pleocytosis, normal CSF glucose and few clinical symptoms or systemic features should be treated for 10 days (S-L).
• Infections caused by a coagulase negative Staphylococcus or P. acnes with significant CSF pleocytosis, CSF hypoglycorrhachia or clinical symptoms or systemic features should be treated for 10–14 days (S-L).
• Infections caused by S. aureus or gram-negative bacilli with or without significant CSF pleocytosis, CSF hypoglycorrhachia or clinical symptoms or systemic features should be treated for 10–14 days (S-L). Some experts suggest treatment of infection caused by gram-negative bacilli for 21 days (W-L).
• In patients with repeatedly positive CSF cultures on appropriate antimicrobial therapy, treatment should be continued for 10–14 after the last positive culture (S-L).

Catheter Removal

• Complete removal of an infected CSF shunt and replacement with an external ventricular drain, combined with intravenous antimicrobial therapy, is recommended in patients with infected CSF shunts (S-M).
• Removal of an infected CSF drain is recommended (S-M).
• Removal of an infected intrathecal infusion pump is recommended (S-M).
• Removal of infected hardware in patients with deep brain stimulation infections is recommended (S-M).

Patient Monitoring

• Patients with healthcare-associated ventriculitis and meningitis should be monitored for response to treatment based on clinical parameters (S-L).
• In patients with healthcare-associated ventriculitis and meningitis and an external drainage device, monitoring of CSF cultures is recommended to ensure that they become negative (S-L).
• In patients with no definitive clinical improvement, additional CSF analysis is recommended to ensure that the CSF parameters have improved and the cultures become negative (S-L).
• For external CSF drains not being used in the treatment of CSF shunt infection, daily CSF cultures and analysis are NOT recommended unless clinically indicated (S-L).

Shunt Reimplantion

• In patients with infection caused by coagulase-negative staphylococci or P. acnes, with no associated CSF abnormalities and with negative CSF cultures for 48 hours after externalization, a new shunt should be reimplanted as soon as the third day after removal (S-L).
• In patients with infection caused by a coagulase-negative Staphylococcus or P. acnes, and associated CSF abnormalities but negative repeat CSF cultures, a new shunt should be reimplanted after 7 days of antimicrobial therapy (S-L). If repeat cultures are positive, antimicrobial treatment is recommended until CSF cultures remain negative for 7–10 consecutive days before a new shunt is placed (S-L).
• In patients with infection caused by S. aureus or gram-negative bacilli, a new shunt should be reimplanted 10 days after CSF cultures are negative (S-L).
• A period off antimicrobial therapy is NOT recommended to verify clearing of the infection before shunt reimplantation (S-L).

Prevention

• Periprocedural prophylactic antimicrobial administration is recommended for patients undergoing CSF shunt or drain insertion (S-M).
• Periprocedural prophylactic antimicrobial administration is recommended for patients undergoing placement of external ventricular drains (S-M).
• Prolonged antimicrobial prophylaxis for the duration of the external ventricular drain is of uncertain benefit and NOT recommended (S-M).
• Use of antimicrobial-impregnated CSF shunts and CSF drains is recommended (S-M).
• In patients with external ventricular drains, fixed interval exchange is NOT recommended (S-M).
• Use of a standardized protocol for insertion of CSF shunts and drains is recommended (S-M).

Prophylactic Antimicrobial Therapy

• For neurosurgical patients, perioperative antimicrobial agents are recommended to prevent infections of the incision (S-H).
• In patients with basilar skull fractures and a CSF leak, prophylactic antimicrobial agents are NOT recommended (S-M).
• In patients with basilar skull fractures and a prolonged CSF leakage (>7 days), an attempt to repair the leak is recommended (S-L).
• In patients with basilar skull fractures and a CSF leak, pneumococcal vaccination is recommended (S-M).

Table 1. Recommended Antimicrobial Therapy in Patients with Healthcare-Associated Ventriculitis and Meningitis Based on Isolated Pathogen and In Vitro Susceptibility Testing

^a Add rifampin if organism is susceptible and prosthetic material is also in place.

^b Cefotaxime or ceftriaxone

^c Consider adding rifampin if the MIC to ceftriaxone is >2 μg/mL.

^d Many authorities would combine moxifloxacin with either vancomycin or a third-generation cephalosporin (cefotaxime or ceftriaxone).

^e May also need to administer via the intraventricular or intrathecal route.

^f Choice of agent based in in vitro susceptibility testing; for organisms (e.g., Enterobacter, Citrobacter, Serratia) that may hyperproduce β-lactamases, meropenem or trimethoprim-sulfamethoxazole may be preferred.

^g Candida kruzei should not be treated with fluconazole. Candida glabrata may be treated with fluconazole if it is susceptible, but many isolates will be susceptible only to high doses or will be resistant.

Table 2. Recommended Dosages of Antimicrobial Agents in Infants and Children, and Adults with Normal Renal and Hepatic Function [Total Daily Dose (Dosing Interval in Hours)]

^a Need to monitor peak and trough serum concentrations.

^b Not approved in pediatrics; dose based on trials registered with clinical trials.gov (NTC01522105) and (NTC01728376).

• 2–6 years: 12 mg/kg (24)
• 7–11 years: 9 mg/kg (24)
• 12–17 years: 7 mg/kg (24)

^c Not to exceed the adult dose.

^d Dose of 5–7.5 mg/kg every 24 hours in patients with Aspergillus infection.

^e No data on optimal dose in patients with bacterial meningitis.

^f Dose of 200 mg orally every 6 hours initially, then 400 mg orally every 12 hours. The newer formulations (ie, intravenous and extended-release tablets) of posaconazole appear to have improved pharmacokinetic properties, but there are no available data on their use in treatment of fungal infections of the central nervous system.

^g Maximum dosage of 600 mg.

^h Dosage based on trimethoprim component.

ⁱ Maintain serum trough concentrations of 15–20 μg/mL in adult patients who receive intermittent bolus administration. Some clinicians administer vancomycin with a loading dose of 15 mg/kg, followed by a continuous infusion of 60 mg/kg/day.

^j Load with 6 mg/kg intravenous every 12 hours for 2 doses in adults and 9 mg/kg every 12 hours for 2 doses in children aged 2–12 years.

^k Maintain serum trough concentrations of 2–5 μg/mL.

^l Maximum maintenance dose in children of 350 mg every 12 hours.

Table 3. Recommended Dosages of Antimicrobial Agents Administered by the Intraventricular Route

There are no specific data that define the exact dose of intraventricular antimicrobial agents that should be used in CSF shunt and drain infections; given the smaller CSF volume in infants (~50 ml) compared to adults (~125–150 ml), doses in infants should probably be decreased at least 60% or more compared to adults.

^a The usual intraventricular dose is 30 mg daily.

^b Not usually necessary but may be needed if removal of the device is too risky or the patient has not responded to systemic antifungal therapy.

^c One study used 10 mg every day for 2 days and then 10 mg every 48 hours. Another study used 5 mg
or 10 mg every 72 hours. Data are based on isolated case reports.

^d Dose is 4–8 mg in adults; 1–2 mg in children.

^e Dosage recommendations in adults based on ventricle size/volume as follows:

• Slit ventricles: 5 mg vancomycin and 2 mg gentamicin
• Normal size: 10 mg vancomycin and 3 mg gentamicin
• Enlarged ventricles: 15–20 mg vancomycin and 4–5 mg gentamicin.

^f Recommendations for frequency of administration based on external ventricular drain output over 24 hours as follows:

• <50 mL/24 hours: every third day
• 50–100 mL/24 hours: every second day
• 100–150 mL/24 hours: once daily
• 150–200 mL/24 hours: increase the dosage by 5 mg of vancomycin and 1 mg of gentamicin and give once daily.
• 200–250 mL/24 hours: increase the dosage by 10 mg of vancomycin and 2 mg of gentamicin and give once daily.

^g Dose is 2 mg/day in children.

^h Most studies used a 10 mg or 20 mg dose.