Infectious Diseases in Clinical Practice:
Current Concepts and Approach to Ventriculitis
Agrawal, Amit MCh*; Cincu, Rafael MD, PhD†; Timothy, Jake MBBS, MD, FRCS‡
*Department of Surgery, Datta Meghe Institute of Medical Sciences, Sawangi (Meghe), Wardha, India; †Department of Neurosurgery, Miguel Servet University Hospital, Zaragoza, Spain; and ‡Department of Neurosurgery, Leeds General Infirmary, Leeds, United Kingdom.
Address correspondence and reprint requests to Amit Agrawal, MCh, Department of Surgery, Datta Meghe Institute of Medical Sciences, Sawangi (Meghe), Wardha-442005, Maharashtra, India. E-mail: firstname.lastname@example.org.
Ventriculitis is a potentially life-threatening infection, and an early diagnosis is essential for the appropriate treatment of ventriculitis. With the available literature, it is difficult to document the frequency with which ventriculitis exists, and also failure to recognize this entity might account for the scant literature. A prospective study is needed to establish the true incidence of ventriculitis and its impact on outcome. In this article, we review the available literature and current concepts in the management of ventriculitis.
Pyogenic ventriculitis is an uncommon complication of intracranial infection in adults that has been variably referred to as ependymitis, ventricular empyema, pyocephalus, and ventriculitis.1-6 If not diagnosed and treated in time, it can be potentially life threatening and neurologically disabling.7 In this article, we review the available literature and current concepts of management.
There are no well-defined definitions for ventricular infection, and it is difficult to ascertain whether reports of ventriculitis, catheter-related infections, and positive cerebrospinal fluid (CSF) cultures describe the same clinical entity.8,9 In a critical review of the literature, Lozier et al9 attempted to identify true infection versus contamination, colonization, or suspected ventriculostomy-related infection on the basis of CSF culture, CSF chemistry, and clinical signs. Progressively declining CSF glucose and increasing CSF protein profiles accompanied by advancing CSF pleocytosis (defined as at least 11 leukocytes per microliter with 50% or more polymorphonuclear neutrophils) and addition of a positive CSF culture or Gram stain accompanied by high-grade fever and clinical signs of meningitis, including nuchal rigidity, photophobia, decreased mental status, seizures, or moribund appearance (clinical symptoms that could not be attributed to causes other than ventriculitis) defines ventriculitis.8-10 It is more difficult is to define catheter-related ventriculitis.10 Lyke et al11 defined "nosocomial ventriculitis" as culture of a recognized pathogen from the CSF either at the time of or 2 days after intraventricular catheter insertion. If common skin flora, such as coagulase-negative Staphylococcus, Corynebacterium, Bacillus, Micrococcus, or Propionibacterium species is isolated, then more than one of the following criteria have to be identified:
* Gram stain of the original CSF sample that produced a finding consistent with the organism cultured,
* Decrease in the CSF glucose level (<25 mg/dL),
* An increase in the CSF protein level (>50 mg/dL), or a finding of neutrophilic pleocytosis (>10 cells/μL).
Causes of ventriculitis include trauma (posttraumatic complicating CSF leak), following ventricular drains or shunts,2,12,13 ruptured abscess,14,15 or it can occur in an immunocompromised host (human immunodeficiency virus and transplant example cytomegalovirus).16-18 Ventriculitis can be complication of intraventricular surgery, intrathecal chemotherapy or meningitis.2 The incidence of ventricular catheter-related ventriculitis ranges from 0% to 22%; most commonly, the incidence is below 10%.9,19,20 Rates higher than 10% should trigger an examination of the institutional protocol.9 The most frequent type of infection associated with pyogenic ventriculitis is gram-negative meningitis followed by Staphylococcus species.4,21-23 In ventricular catheter-related ventriculitis, gram-positive cocci consistent with skin flora comprised most isolates.9,24 In ventriculitis complicating head trauma, Streptococcus pneumonia and gram-negative rods are the most common pathogens.25 Dallacasa et al26 and Galassi et al27 found that infants, specifically those aged less than 6 months, have a higher incidence of ventricular infection, and that this is related both to their immunologic deficiency and to the particular features of the residential bacterial flora in this age group.
Patients with ventriculitis may present with the clinical evidence of sepsis. Clinical features of ventriculitis include high-grade fever and clinical signs of meningitis, including nuchal rigidity, photophobia, decreased mental status, seizures, or moribund appearance.9,28,29 The onset of bacterial meningitis and/or ventriculitis after neurosurgery may be more subtle than in spontaneous meningitis, and there may be a considerable overlap of clinical data between aseptic and bacterial meningitis.9 Ventriculitis in infants can cause inflammatory aqueductal obstruction resulting in obstructive hydrocephalus.29-31 Clinical symptoms of ventriculitis can be masked by the inadequate use of antibiotics, and the condition can be misdiagnosed as aqueductal stenosis.29 Unsuspected ventriculitis might be a source of persistent infection and therapeutic failure in the management of meningitis.21,32,33
Ventriculitis can be diagnosed by microbiological tests on the CSF.34 Gram stain of the CSF sample produces a finding consistent with the organism cultured, decrease in the CSF glucose level (<25 mg/dL), an increase in the CSF protein level (>50 mg/dL), or a finding of neutrophilic pleocytosis (>10 cells/μL).11 However, microbiological examination is often not possible or can delay the diagnosis; other tests are also used.34 As most of us know, active ventriculitis may be present in the absence of a positive CSF culture after the institution of antibiotics.11 Because of high morbidity and mortality, laboratory tests have been gauged, so that they can establish an early etiologic diagnosis.7 Among these tests, the one for determination of the lactic acid levels is among the most used.35,36 The presence of oligoclonal immunoglobulin G bands, CSF immunoglobulin M, CSF lactate, and lysozyme in the CSF are used to make an early diagnosis of ventriculitis. However, a single, marginally pathological value has less diagnostic value than an increase in lysozyme detected in a series of CSF samples.34 To avoid a fatal outcome, an early diagnosis and treatment of ventriculitis is mandatory.4 At the same time, a noninvasive method for detection of ventriculitis would be highly desirable because it could potentially avoid the morbidity of invasive methods of diagnosis.4,37
Computed tomographic (CT) imaging and magnetic resonance (MR) imaging are the mainstays of noninvasive methods of neuroimaging in cases of adult meningitis, very few reports in sporadic cases have documented CT and MR imaging findings of ventriculitis.1-3,38 Recently, many investigators have tried to identify CT and MR imaging features of pyogenic ventriculitis in an effort to improve detection and effect prompt treatment.4,5,39 Ventricular uptake in radionuclide brain scintigraphy using technetium-99m pertechnetate has been reported in children40 and adults.5,39 On imaging, ventricular debris is the most characteristic finding, and it is characterized by irregular level. Hydrocephalus and ependymal enhancement are less frequent signs.1,2,4,38 This ventricular debris because of its bright signal is more conspicuous in diffusion-weighted images.4 Periventricular signal abnormality, detected in 78% of cases with MR imaging, likely reflects the periventricular infammatory change observed at pathology.39 Denuding of the ependyma, as described in infants with ventriculitis, could potentially be responsible for, or be coincident with, breakdown of the blood-brain barrier and, hence, enhancement.41 Ependymal enhancement also has been described in occasional case reports of ventriculitis,1,2 however, it is not specific for infection.4
One of the most important mainstays in the therapy for severe brain infections is the administration of antimicrobial agents that are known to reach effective concentrations in the CSF and brain tissue.42,43 Infection in immunocompromised patients needs to be treated aggressively with appropriate agents.17,44
Antimicrobial dosages have been used empirically, with dosage adjustments and dosing intervals based on the ability of the agent to achieve adequate CSF concentrations.45-47 The choice of empirical antimicrobial therapy in ventriculitis should be governed by the patient's age and by various conditions that may have predisposed the patient to ventriculitis (posttraumatic, shunt catheter-associated, etc.).43
Decisions on the choice of a specific antimicrobial agent are based on knowledge of in vitro susceptibility and relative penetration into CSF in the presence of meningeal inflammation (whether gleaned from experimental animal models or patients).43 Recommendations for antimicrobial therapy in patients with presumptive pathogen identification by positive Gram stain, based on patient's age and specific predisposing condition, and based on isolated pathogen and susceptibility testing with dosages are discussed in an excellent review by Tunkel et al.43
However, given the increasing frequency of antimicrobial resistance among gram-negative bacilli, especially in the hospital setting, in vitro susceptibility testing of isolates is critical to guide antimicrobial therapy. One agent, ceftazidime, has also shown efficacy in several studies of patients with Pseudomonas meningitis.48,49 A fourth-generation cephalosporin, cefepime, has been shown to be safe and therapeutically equivalent to cefotaxime in the treatment of bacterial meningitis in infants and children.50,51 Cefepime also has greater in vitro activity than the third-generation cephalosporins against Enterobacter species and Pseudomonas aeruginosa and has been used successfully in some patients with meningitis caused by these bacteria, making it a useful agent in the treatment of patients with bacterial meningitis.52
Recent reports suggest that amikacin, administered systemically to patients with meningitis or ventriculitis, reaches levels in CSF or ventricular fluid that will inhibit or kill many of the common gram-negative bacteria that cause central nervous system infections.53-55 Systemic therapy with amikacin may be the treatment of choice for children with ventriculitis caused by bacteria which are highly susceptible to this drug.56
On the basis of these findings, vancomycin is not recommended in the treatment of bacterial meningitis caused by isolates that are susceptible to other agents (ie, penicillins and cephalosporins).43 Even in patients with meningitis caused by highly penicillin- and cephalosporin-resistant strains, vancomycin should be combined with a third-generation cephalosporin and should not be used as a single agent.57 When used for the treatment of bacterial meningitis, vancomycin should be administered to maintain serum vancomycin trough concentrations of approximately 15 to 20 mg/mL. Intrathecal administration of vancomycin may be considered in patients who are not responding to parenteral administration.43
Rifampin has many properties that make it an excellent agent for the treatment of meningitis, including good CSF penetration and in vitro activity against many meningeal pathogens. However, when used alone, resistance rapidly develops, such that rifampin must be used in combination with other antimicrobial agents. Rifampin should only be added if the organism is shown to be susceptible and there is a delay in the expected clinical or bacteriologic response.43 Rifampin should also be combined with vancomycin in patients with CSF shunt infections caused by staphylococci, especially in cases in which the shunt cannot be removed.58
Imipenem and meropenem agents have been studied in patients with bacterial meningitis. Imipenem has been successfully used in patients with pneumococcal meningitis caused by penicillin- and cephalosporin-resistant strains and in patients with Acinetobacter meningitis, although the potential for seizure activity (which was 33% in 1 study of children with bacterial meningitis) argues against its use in most patients with bacterial meningitis.43 Meropenem, which has a broad range of in vitro activity and less seizure proclivity than imipenem, has also been studied in both children and adults with bacterial meningitis.59,60
Quinolones group antibiotics also can be used in the treatment of ventriculitis.61-66 Ciprofloxacin penetrates into the CSF of patients with bacterial meningitis and has an extremely broad range of antibacterial activity, including most organisms responsible for purulent meningitis, except Streptococcus pneumoniae. The concentrations of ciprofloxacin in CSF are equal to or higher than the reported minimal inhibitory concentrations (MICs) or minimal bacterial concentrations against most enterobacteria.62-64 Ofloxacin readily diffuses into the CSF of patients with bacterial meningitis or ventriculitis, and the concentrations in CSF exceed the MICs for most pathogens responsible for purulent meningitis.65 Pefloxacin may be useful for the treatment of gram-negative bacilli and Staphylococci meningitis or ventriculitis, and CSF concentrations exceed the MICs for most strains (except streptococci), especially when a high dosage is used.66 However, on the basis of limited published literature, these agents should only be used for meningitis caused by multidrug resistant gram-negative bacilli or when patients have not responded to or cannot receive standard antimicrobial therapy.43
Intraventricular administration of antibiotics may be considered if ventriculitis is refractory to systemic antimicrobial therapy.67,68 Recommended dosages of antimicrobial agents administered by the intraventricular route are vancomycin (5-20 mg/d), gentamicin (1-8 mg/d), tobramycin (5-20 mg/d), amikacin (5-50 mg/d), polymyxin B (5 mg/d), colistin (10 mg/d), quinupristin/dalfopristin (2-5 mg/d), and teicoplanin (5-40 mg/d).43 After administration of the first intraventricular dose, additional doses can be determined by calculation of the "inhibitory quotient." Before administration of the next intraventricular dose, a sample of CSF is withdrawn to obtain the trough CSF concentration.43 Intraventricular administration of 1 mg of gentamicin results in ventricular CSF concentrations greater than 20 μg/mL 1 hour and 5 to 14 μg/mL 36 hours after administration.69 Intraventricular vancomycin application is a safe and efficacious treatment modality in drain-associated ventriculitis, with much higher vancomycin levels being achieved in the ventricular CSF than by intravenous administration.24,67,70
MANAGEMENT OF SHUNT-ASSOCIATED VENTRICULITIS
The principles of antimicrobial therapy for CSF shunt infections are generally the same as those for the treatment of acute bacterial meningitis.43 However, direct instillation of antimicrobial agents into the ventricles through either an external ventriculostomy or shunt reservoir is occasionally necessary in patients who have shunt infections that are difficult to eradicate or who cannot undergo the surgical components of therapy.43 Removal of all components of the infected shunt and some component of external drainage, in combination with appropriate antimicrobial therapy, helps to clear the ventriculitis of the shunt infection more rapidly.45-47 The timing of shunt reimplantation is dependent upon the isolated microorganism, the extent of infection as defined by culture of samples obtained after externalization, and occasionally, on CSF findings.45,58
Antibiotic prophylaxis has been shown to be inefficient in trauma patients with CSF fistulae, and recommendations do not support the use of prophylactic antibiotics in patients with CSF fistulae or prophylaxis duration exceeding 24 to 48 hours.71,72 In patients who are undergoing craniotomy, antibiotic prophylaxis is helpful in preventing incision infections but has no effect on meningitis prevention.73-75 Although the use of prophylactic antibiotics decreases the incidence of CSF infections and systemic infections, at the same time, it predisposes the patient to infection by more resistant organisms.11,76,77 Because clinical ventriculitis can be a devastating consequence, the use of prophylactic antibiotics is recommended in all patients with ventriculostomies.9
With the available literature, it is difficult to document the frequency with which ventriculitis exists, and also failure to recognize this entity might account for the scant literature. A prospective study is needed to establish the true incidence of ventriculitis and its impact on outcome.
The authors thank Ms Jayashree PR, who helped in writing, assisted in editing the English style and grammar, and offered suggestions for the improvement of this article.
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