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Central Nervous System Infections: Updates in Literature & Treatment
Brett Van Rossum PharmD, BCPS, ENLS
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Conflicts of InterestNo financial or professional conflicts of interest to disclose
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ObjectivesIdentify antimicrobial medications commonly used in the treatment of central nervous system (CNS) infections
Compare the recommendations from the new 2017 IDSA guidelines for healthcare-associated meningitis and ventriculitis to content previously published in the 2004 meningitis guidelines
Describe ways to optimize the efficacy of pharmacologic treatment of CNS infections
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Review of Anatomy: the BrainCerebrum or Cerebral Cortex (Latin, “the brain”)Encephalon (Greek, “what is inside the head”)
Images via the Northern Brain Injury Association, http://nbia.ca/brain-structure-function/
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Anatomy: the MeningesMembranes between the brain and the skull
© 2001 Benjamin Cummings, Courtesy of Austin Peay State University, ttp://www.apsubiology.org/anatomy/2010/2010_Exam_Reviews/Exam_4_Review/CH_12_The_Meninges.htm
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Anatomy: the Meninges
© 2001 Benjamin Cummings, Courtesy of Austin Peay State University, ttp://www.apsubiology.org/anatomy/2010/2010_Exam_Reviews/Exam_4_Review/CH_12_The_Meninges.htm/
Layers of the Meninges
The subarachnoid space
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Anatomy: Ventricles and the Cerebrospinal Fluid (CSF)
Images: https://radiopaedia.org/cases/elderly-ct-brain, http://medicalterms.info/anatomy/Ventricles-Of-The-Brain/
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Anatomy: The spinal cord
Images: Medical College of Jaipur, University of Washington, https://faculty.washington.edu/chudler/spinal.html/
Subarachnoid Space
Pia Mater
Arachnoid Mater
Dura Mater
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Infections of the CNSEncephalitis: inflammation/infection of the brainMeningitis: inflammation/infection of the CNS,
centered around the meningesMeningoencephalitis: features of both the aboveVentriculitis: inflammation of the lining of the
ventricles/ventricular drainage system CNS Abscesses: Subdural, Epidural, Brain Abscesses
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Pertinent IDSA GuidelinesBacterial Meningitis (2004)Nervous System Lyme Disease (2007)Viral Encephalitis (2008)Management of Cryptococcal Disease (2010)Healthcare-Associated Ventriculitis and Meningitis (2017)
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Pertinent IDSA GuidelinesBacterial Meningitis (2004)Nervous System Lyme Disease (2007)Viral Encephalitis (2008)Management of Cryptococcal Disease (2010)Healthcare-Associated Ventriculitis and Meningitis (2017)
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Review of Bacterial MeningitisPresentation: Headache, Neck pain, Altered mental status,
nonspecific signs: Fever, WBC, malaise, etcCommon pathogens– Listeria monocytogenes– Group B Streptococci– Haemophilus influenzae– Neisseria meningitidis– Streptococcus pneumoniae
Incidence decreasing– Vaccination
Mortality – 16.4-18% (adults)– 6.3-6.9% (pediatric)
Thigpen, et al. N Engl J Med. 2011;364:2016-25
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Meningitis Diagnostic Workup1. Suspicion of Meningitis2. Blood Cultures, Lumbar puncture, CSF culture
and gram stain STAT *3. Empiric therapy4. Continue therapy if CSF findings are consistent
with meningitis or high clinical suspicion remains
* Delay LP if concern for elevated ICPand possible subsequent herniation
Tunkel, et al. CID. 2004; 39(9):1267-84
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Examining the CSF(+) Gram Stain: 60-90% sensitivity, 97% specificityTypical CSF chemistry findings
– CSF:Blood Glucose <0.4: 80% sensitive, 98% specific – CSF Lactate > 3.5 mmol/L: 93% sensitive, 96% specific in
distinguishing bacterial from aseptic meningitis
Viral MeningitisProtein: mild elevationGlucose: Normal >67% RBC: Normal (slight
elevation if HSV)WBC: 10s-100s
- lymphocytes
Fungal MeningitisProtein: ElevatedGlucose: lowRBC: NormalWBC: ~100-400
- Lymphocytes
Tunkel, et al. CID. 2004; 39(9):1267-84, Gaieski, et al. Neurocrit Care; 2015;23Suppl2:S110-8 Sakushima et al. J Infect. 2011; 62:255-62
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Meningitis; Empiric Therapy
Highest safe dosage to penetrate the blood brain barrier– Ceftriaxone 2 grams every 12 hours– Vancomycin to target troughs 15-20 mcg/mL
Tunkel, et al. CID. 2004; 39(9):1267-84
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Healthcare-associated Bacterial Meningitis; 2004 guidelines1. Empiric coverage:
– Vancomycin + (Ceftazidime OR Cefepime OR Meropenem)
2. Guidance for neurosurgical management of infections involving implanted shunts/hardware
3. Description of antibiotic therapy via the intraventricular route
Overall, limited guidance
Tunkel, et al. CID. 2004; 39(9):1267-84
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Audience ParticipationHow many of you had at least one lecture in pharmacy school focusing on bacterial meningitis?
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Audience ParticipationHow many of you had at least one lecture in pharmacy school focusing on healthcare-associatedbacterial meningitis?
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Audience ParticipationWhat percentage of all meningitis cases are healthcare-associated?
A. 10%B. 20%C. 30%D. 40%
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Audience ParticipationWhat percentage of all meningitis cases are healthcare-associated?
A. 10%B. 20%C. 30%D. 40%
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Healthcare-associated MeningitisEpidemiological data lackingInstitutional reviews of meningitis cases– Mass General, 1962-1988, 493 cases, 40% nosocomial
– South Taiwan, 1986-2003, 329 Cases: 48% nosocomialSimilar results for causative organisms
Organism Community Nosocomial
Streptococci, H. influenzae, N. meningitidis, L. monocytogenes
64 % 8 %
Staphylococci 3 % 22 %
Other Gram Negative Bacilli 0 % 46 %
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Durand ML, et al. N Eng J Med 1993; 328:21-8Tsai MH, et al.. Infection. 2006; 34:2-8
New Guidelines!
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Healthcare-associated Meningitis & Ventriculitis
Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
“Meningitis may be acquired in the community setting or associated with a variety of invasive procedures or head trauma”
Neurosurgical hardware to be considered
May become symptomatic during hospitalization, may develop after discharge or months/years later
Different pathogens predominate
23 http://raczpainmanagement.com/intrathecal-pain-pump-therapy
https://www.healthtap.com/topics/dilated-ventricles-and-sulci-of-the-brain
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Ventriculoperitoneal shunt
External ventricular Drain (EVD) Deep Brain Stimulator (DBS)
Intrathecal medication pump
https://www.healthtap.com/topics/dilated-ventricles-and-sulci-of-the-brain
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Epidemiology: PathogensDecreasing incidence of “typical” pathogens historically seen in meningitisHigher proportion of cases caused by:– Staphylococci: S. aureus, S. epidermidis– Propionibacterium acnes– Gram negative bacilli, including MDR organisms:
P. aeruginosa E. coli Klebsiella species Serratia species Citrobacter, Enterobacter, Acinetobacter species
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Castelblanco RL, et al. Lancet Infect Dis. 2014 Sep;14(9):813-9 Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Diagnostic FactorsDiagnosis MUCH less straightforward than community cases– Pathogens more indolent– Symptomatology more subtle, varying with disease state– Concomitant disease states cloud the picture
Signs of meningeal irritation typically absent– 30% of patients or less
Does it look like an infection?– Yes? Probably an infection– No? Still might be
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Images courtesy of the European Society of Critical Care Medicine and The Facebook Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Diagnosis: CSF ChemistriesAlso may be unreliable for diagnosis– Schade et al, 2006. 230 patients with external
ventricular drains (EVDs): Daily CSF sampling for chemistries and cultures22 patients developed venticulitis and/or meningitisNonsignificant: WBC count, protein, CSF : Blood glucose
Most likely to be reliable: CSF WBC count– Walti et al, 2013: WBC count >175 cells/µL predictive of infection
All other parameters showed nonsignificant results– Pfisterer et al, 2003: CSF WBC count correlates with positive CSF
culture resultsMedian values = 150 - 237 cells/µL
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Schade et al. J Neurosurg 2006; 104:101-8Walti et al. J Infect. 2013; 66:424-31
Pfisterer et al. J Neurol Neurosurg Psychiatry 2003; 74:929-32
Diagnosis: CSF CulturesMost reliable means of diagnosis, per 2017 guidelines– “Single or multiple positive CSF cultures in patients with…
other signs or symptoms…suspicious for ventriculitis or meningitis, is indicative of CSF drain infection (strong, high)
– CSF cultures usually sensitive and specific for infection
Other recommendations: – Obtain CSF cultures – Hold cultures for 10 days in case of P. acnes – If hardware infection suspected, culture shunt and drain components – Obtain CSF and blood cultures prior to giving antibiotics
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.Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Empiric TreatmentMinimal expansion on the 2004 recommendations First line empiric regimen: – Vancomycin + ceftazidime or cefepime or meropenem
Second line against GNRs: – If patient has anaphylaxis to β-lactams AND meropenem is
contraindicated: ciprofloxacin or aztreonam
Second line against gram positive bacteria:– No alternatives to vancomycin mentioned in the guidelines– Reasonable options:
Daptomycin, Linezolid, or Sulfamethoxazole-Trimethoprim (SMX-TMP)
Note: all recommendations are “strong” recommendations with “low” quality of evidence (i.e. expert consensus)
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Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Patient CasePatient X: 52 yo F, no PMH or medications– No known drug allergies
Presents to outside ED with thunderclap HA and vomiting. Head CT shows SAH with ventricular extensionTransferred to our facility, CT/angiogram confirms diagnosis, pinpoints an ACOMM aneurysm rupture
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Anterior Communicating Artery
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CT imaging32
Patient XHospital day 1: – Emergent Coiling of the ACOMM aneurysm and
placement of an EVD on hospital day 1, admitted in stable condition to Neuro ICU
Hospital day 9: – Temp 102.5oF,– WBC 17.5 K– CSF chemistries – BG 119
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Assessment Question
What is the appropriate empiric antibiotic regimen for Patient X?A. Vancomycin + CeftriaxoneB. Vancomycin + CefepimeC. Vancomycin + GentamicinD. Daptomycin + Meropenem
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Assessment Question
What is the appropriate empiric antibiotic regimen for Patient X?A. Vancomycin + CeftriaxoneB. Vancomycin + Cefepime initiated
1250 mg Q12h 2 grams Q8hC. Vancomycin + GentamicinD. Daptomycin + Meropenem
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Pathogen-Specific Treatment36
Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Note: no randomized clinical trial data available. All recommendations based on observational studies, case series, and expert opinion
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Pathogen-Specific TreatmentGram PositivesStaphylococci
– Methicillin-Sensitive: Nafcillin or Oxacillin Alternative: vancomycin– Methicillin-Resistant: Vancomycin Alternatives: daptomycin,
linezolid, SMX-TMP
P. acnes– First line therapy: Penicillin G Alternatives: ceftriaxone, vancomycin,
daptomycin, or linezolid
S. pneumoniae– If Penicillin MIC≤0.06 mcg/mL: penicillin G Alternative: ceftriaxone– If Penicillin MIC≥0.12 mcg/mL: ceftriaxone Alt. : cefepime or meropenem– If Ceftriaxone MIC ≥1 mcg/mL: vancomycin + ceftriaxone
Alternative: add moxifloxacin to ceftriaxone or vancomycin
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Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Evidence SummaryGram Positives
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Staphylococcus infections: – If vancomycin MIC≥1 mcg/mL, consider alternatives
Linezolid, daptomycin, SMX-TMPSource: IDSA guidelines for MRSA (2011), no further data cited
– Consider adding rifampinespecially when hardware involvedEnhances the bactericidal activity of the primary agentEvidence very limited and outdated
http://www.healthhype.com/staphylococcus-aureus.htmlm
Liu, et al. Clin Infect Dis 2011; 52:285-92Gombert, et al. J Neurosurg. 1981; 55:633-6
Nau, et al. J Antimicrob Chemother. 1992; 29:719-24Dunne, et al. Antimicrob Agents Chemother. 1993; 37;2522-6
Evidence SummaryGram Positives
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Other agents– Linezolid
Useful option, especially for EnterococcusFavorable kinetics/penetration of the CNSEfficacy reported in 4 case reports/case series, totaling 9 patients
– DaptomycinTypically requires aggressive dosing ~10 mg/kgSource: 2 case series, totaling 10 patients
Yilmaz, et al. J Neurosurg Pediatr. 2010; 5:443-8Maranich, et al. Mil Med. 2008; 173:927-9
Graham et al. Pediatr Infect Dis J. 2002; 21:798-800Antony, et al. Infect Dis Clin Pract. 2012; 20:161-3
Kullar et al. Antimicrob Agents Chemother. 2011; 55:3505-9
http://www.healthhype.com/staphylococcus-aureus.htmlm
Pathogen-Specific TreatmentGram NegativesP. aeruginosa
– 1st line: ceftazidime, cefepime, or meropenem Alternatives: ciprofloxacin or aztreonam
Acinetobacter baumannii– 1st line: meropenem Alternatives: colistin or polymixin B
H. influenzae– β-Lactamase ( - ): ampicillin Alternatives: ceftriaxone, cefepime, or a FQ– β-Lactamase ( +): ceftriaxone Alternatives: aztreonam, cefepime, or a FQ
ESBL-producing organisms– 1st line: meropenem Alternatives: cefepime or a FQ– For enterobacteriaceae that hyperproduce ESBLs (Enterobacter, Citrobacter,
Serratia species), meropenem or SMX-TMP may be preferred
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Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64
Evidence SummaryGram Negatives
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Enterobacter species: – Questionable efficacy of some Beta-lactam agents
1993 review of 46 enterobacter meningitis cases– 100% cure rate with SMX-TMP– 70% with beta-lactam agents
– Possible treatment-emergent resistance to ceftriaxone?2005 retrospective review of 19 cases
– 83% cure rate with SMX-TMP– 54% with 3rd generation cephalosporins
http://www.cofa.org.ar/?p=21865
Wolff et al. Clin Infect Dis. 1993; 16:772-7Foster et al. Surg Neurol. 2005; 63:533-7
Evidence SummaryGram Negatives
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Acinetobacter species– Meropenem preferred over ceftazidime and cefepime
Cef’s may not achieve adequate CNS concentrations3 hour infusions reported as successful
– Clinical cure and CSF concentration goals attained
– May require additional IV or Intraventricular agentsAminoglycosides, colistin, polymyxin B
– Carbapenem resistance: mortality of up to 60%Addition of Colistin (IV or intraventricular) improves cure rates
Kim et al. Lancet Infect Dis. 2009; 9:245-55 Capitano et al. Pharmacotherapy. 2004; 24:803-7Nicasio et al. Ann Pharmcother. 2007; 41: 1077-81. Moon et al. J Infect Chemother. 2013; 19:916-19
http://www.cofa.org.ar/?p=21865
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Patient Case, revisitedReview: – SAH s/p coiling & EVD placement for hydrocephalus/CSF drainage– Probable meningitis/ventriculitis on hospital day 9– Empiric antibiotics (Vancomycin + Cefepime) started
Hospital day 11– Persistent Fever to 102.6oF, WBC 18.4– Initial day 9 CSF Culture results: Day 11 CSF chemistries:
– Cefepime is deescalatedappropriately to Ceftriaxone,
– Vancomycin is discontinued
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Assessment questionTrue/False: Patient X is responding appropriately to sufficient antibiotic therapyA. TrueB. False
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Assessment questionTrue/False: Patient X is responding appropriately to sufficient antibiotic therapyA. TrueB. False
Clinical signs (high fever, leukocytosis) and CSF chemistries indicate suboptimal response
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Assessment questionWhat strategies could maximize bactericidal activity and patient response?A. Add Sulfamethoxazole-Trimethoprim for synergyB. Add intraventricular CeftriaxoneC. Add intraventricular GentamicinD. Go for broke and reescalate antibiotics to
Daptomycin +Meropenem + Colistin + Azithromycin
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Assessment questionWhat strategies could maximize bactericidal activity and patient response?A. Add Sulfamethoxazole-Trimethoprim for synergyB. Add intraventricular CeftriaxoneC. Add intraventricular GentamicinD. Go for broke and reescalate antibiotics to
Daptomycin +Meropenem + Colistin + Azithromycin
Intraventricular therapy appropriate, IVT Ceftriaxone contraindicated due to high incidence of seizures with intraventricular Beta-lactams
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The Blood Brain Barrier
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Image: Rochester Institute of Technology https://cias.rit.edu/faculty-staff/101/faculty/340
1. Tight junctions between vascular endothelial cells
2. Additional lipid basement membane
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Pharmacokinetic Considerations[CSF] / [Serum] ~5-20% for most agents
Factors influencing CNS Penetration– Smaller molecular size= better penetration– More lipophilic drugs = better penetration– Protein binding: higher free drug fraction = better– Meningeal inflammation = better penetration– Active transport/Active clearance
P-GP, OAT3, PEPT2 transporter proteinsNegligible effects for most commonly used agents
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Nau R, et al. Clin Microb Rev. 2010; 23:858-83
CSF Pharmacokinetics50
Nau R, et al. Clin Microb Rev. 2010; 23:858-83
Serum concentration CSF concentration
Drug Penetration into the CNS 51
Antimicrobialagent
CSF AUC/Serum AUC (%)Un-inflamed meninges
CSF AUC/Serum AUC (%)Inflamed meninges
Ceftriaxone 0.7 N/A
Penicillins 2 20
Ceftazidime 5.7 N/A
Cefepime N/A 10.3
Daptomycin 0.8-11.5 N/A
TMP-Sulfa 12-18 24-51
Vancomycin 14-18 30
Doxycycline ~20 ~20
Rifampin 22 N/A
Meropenem 5-25 39
Metronidazole N/A 87
Ciprofloxacin 24-43 92
Levofloxacin 71 N/A
Linezolid 90 N/A
Nau R, et al. Clin Microb Rev. 2010; 23:858-83
Intraventricular Drug Administration52
External Ventricular Drain (EVD) Ommaya Reservoir• Most common method of IVT • Frequently already in place
• May be preferable for longer-term therapy
Images courtesy of SUNY-Stony Brook & Memorial Sloan Kettering Cancer Center
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Benefits– Bypasses the BBB; higher CSF [drug] than IV therapy– Long CSF half-lives, once daily administration– Minimal systemic toxicity
Risks and considerations– NOT FDA-approved; off label usage– Highly invasive– Requires small volume, preservative-free formulations– Variable neurologic toxicities
Hearing loss, seizures, tinnitis, headacheTunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Nau R, et al. Clin Microb Rev. 2010; 23:858-83
Intraventricular Antimicrobials54
Dosing strategies– May target CSF Trough concentrations 10-20x the Pathogen’s MIC – May tailor dose and interval based on troughs, ventricle size, and
EVD output Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Nau R, et al. Clin Microb Rev. 2010; 23:858-83
Intraventricular AntimicrobialsAntimicrobial agent Daily Intraventricular Dose (adults)
Amikacin 5-50 mg (usual 30 mg)
Gentamicin 1-8 mg (usual 5 mg)
Tobramycin 5-20 mg (usual 5-10 mg)
Vancomycin 5-20 mg
Daptomycin 2-10 mg
Colistimethate Sodium 10 mg
Polymyxin B 5 mg
Amphotericin B deoxycholate 0.01-1 mg
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Duration of Therapy55
Depends on the pathogen– P. acnes and coagulase-negative staphylococci
10-14 days – S. aureus and Gram Negative Bacilli
10-14 days (some experts would propose 21 days for GNR)
Other considerations– If repeatedly positive CSF cultures:
10-14 days from the last positive culture– If new CSF shunts or hardware to be re-implanted:
may require 7-10 days of negative CSF cultures prior to surgery
No benefit to extended courses of treatmentTunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Simon et al. J Pediatric Infect Dis Soc. 2014; 3:15-22
Patient Case, revisitedOptimizing therapy, Hospital Day 11– Ceftriaxone dosed 2 grams IV every 12 hours (maximum dose)– Intraventricular Gentamicin was added, 5 mg daily
Clinical Course
– Total of 11 days Intraventricular gentamicin (7 days from the last positive culture) until EVD removed
– Total of 14 days IV ceftriaxone (10 days from last positive culture)
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SummaryCNS infections pose unique challenges for physicians and pharmacists
Healthcare-associated infections require specialized management
Pharmacists’ skill sets make us uniquely positioned to optimize the treatment of difficult-to-manage cases
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Questions58
Contact Info: [email protected]
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Tunkel AR, Hartman BJ, Kaplan SL, et.al. Practice Guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004:39(9)-1267-84
Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Emerging Infections Programs Network. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011;364:2016-25
Gaieski,Nathan BR, Obrien NF. Emergency neurologic life support: meningitis and encephalitis. Neurocrit Care; 2015;23Suppl 2:S110-8
Sakushima K, Hayashino Y, Kawaguchi T, et al. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial from aseptic meningitis: as systemic review and metaanalysis. J Infect. 2011; 62:255-62
Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America’s clinical practice guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis. 2017; 64:e34-64
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References:
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Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Eng J Med 1993; 328:21-8
Tsai MH, Lu CH, Huang CR, et al. Bacterial meningitis in young adults in Southern Taiwan. Infection. 2006; 34:2-8
Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997-2010: a population-based observational study. Lancet Infect Dis. 2014; 14(9):813-9.
Wiberg K, Birnbaum A, Gradon J. Causes and presentation of meningitis in a Baltimore community Hospital. South Med J. 2008; 101:1012-6.
Walti LN, Conen A, Coward J, Jost GF, et al. Characteristics of infectious assicoated with external ventricular drains of cerebroprospinal fluid. J Infect. 2013; 66:424-31
Pfisterer W, Muhlbauer M, Czech T, Reinprecht A. Early diagnosis of external ventricular drainage infection: the results of a prospective study. J Neurol Neurosurg Psychiatry. 2003; 74:929-32
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References: (continued) References: (continued)Schade RP, Schnkel J, Roelhandse FW, et al. Lack of calue of routine
analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis J Neurosurg 2006; 104:101-8.
Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: execultive summary. Clin Infect Dis 2011; 52:285-92.
Gombert ME, Landesman SH, Corrado ML, et al. Vancomycin and rifampin therapy for staphylococcus epidermidis meningitis associated with CSF shunts: report of three cases. J Neurosurg. 1981; 55:633-6.
Nau R, Pange HW, Menck S, et al. Penetration of rifampicin into the cerebrospinal fluid of adults with inflamed meninges. J Antimicrob Chemother. 1992; 29:719-24.
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References: (continued)Dunne WM Jr, Mason EO Jr, Kaplan SL. Diffusion of rifampin and
vancomycin through a Staphylococcus epidermidis biofilm. Antimicrob Agents Chemother. 1993; 37;2522-6.
Yilmaz, A, Dalgic N, Musluman M, et al. Linezolid treatment of shunt-related cerebrospinal fluid infections in children. J NeurosurgPediatr. 2010; 5:443-8.
Maranich AM, Rajnik M. Successful treatment of vancomycin-resistant enterococcal ventriculitis in a pediatric patient with linezolid Mil Med. 2008; 173:927-9.
GrahamPL, Ampofo K, Saiman L. Linezolid treatment of vancomycin-resistant Enterococcus faecium ventriculitis. Pediatr Infect Dis J.2002; 21:798-800.
Antony SJ, Hoffman-Roberts HL, Foote BS. Use of daptomycin as salvage therapy in the treatment of central nervous system infections including meningitis and shunt infections. Infect Dis ClinPract. 2012; 20:161-3.
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References: (continued)Kullar R, Chin JN, Edwards DJ, et al. Pharmacokinetics of single-dose
daptomycin in patients with suspected or confirmed neurologic infections. Antimicrob Agents Chemother. 2011; 55:3505-9.
Wolff MA, Young CL, Ramphal R. Antibiotic therapy of Enterobacter meningitis: a retrospective review of 13 cases and a review of the literature Clin Infect Dis. 1993; 16:772-7.
Foster DR, Rhoney DH. Enterobacter meningitis: organism susceptibilities, antimicrobial therapy and related outcomes. SurgNeurol. 2005; 63:533-7.
Kim BN, Peleg AY, Lodise TP, et al. Management of meningitis due to antibiotic-resisant Acinetobacter species. Lancet Infect Dis. 2009; 9:245-55.
Moon, C, Kwak YG, Kim BN, et al. Implications of postneurosurgicalmeningitis caused by carbapenem-resistant Acinetobacter baumannii. J Infect Chemother. 2013; 19:916-19
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References: (continued)Capitano B, Nicolau DP, Potoski BA, et al. Meropenem administered as
a prolonged infusion to treat serious gram-negative central nervous system infections Pharmacotherapy. 2004; 24:803-7
Nau R, Sorgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microb Rev. 2010; 23:858-883.
Simon TD, Mayer-Hamblett N, Whitlock KB, et al. Few patient, treatment, and diagnostic or microbiological factors, except complications and intermittent negative cerebrospinal fluid (CSF) cultures during first CSF shunt infection, are associated with reinfection. J Pediatric Infect Dis Soc. 2014; 3:15-22.
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