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1 2 Conflicts of Interest Central Nervous System Infections: No financial or professional conflicts of interest to Updates in Literature & Treatment disclose

Brett Van Rossum PharmD, BCPS, ENLS

3 4 Objectives Review of Anatomy: the Brain Cerebrum or Cerebral Cortex (Latin, “the brain”) Identify antimicrobial medications commonly used in Encephalon (Greek, “what is inside the head”) 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

Images via the Northern Brain Injury Association, http://nbia.ca/brain-structure-function/

5 6 Anatomy: the Meninges Anatomy: the Meninges Membranes between the brain and the skull

Layers of the Meninges The subarachnoid space

© 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 © 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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7 8 Anatomy: Ventricles and the Anatomy: The spinal cord Cerebrospinal Fluid (CSF)

Pia Mater Subarachnoid Space Arachnoid Mater Dura Mater

Images: https://radiopaedia.org/cases/elderly-ct-brain, http://medicalterms.info/anatomy/Ventricles-Of-The-Brain/ Images: Medical College of Jaipur, University of Washington, https://faculty.washington.edu/chudler/spinal.html/

9 10 Infections of the CNS Pertinent IDSA Guidelines

Encephalitis: inflammation/infection of the brain Bacterial Meningitis (2004) Meningitis: inflammation/infection of the CNS, Nervous System Lyme Disease (2007) centered around the meninges Viral Encephalitis (2008) Meningoencephalitis: features of both the above Management of Cryptococcal Disease (2010) Ventriculitis: inflammation of the lining of the ventricles/ventricular drainage system Healthcare-Associated Ventriculitis and CNS Abscesses: Subdural, Epidural, Brain Abscesses Meningitis (2017)

11 12 Pertinent IDSA Guidelines Review of Bacterial Meningitis Presentation: Headache, Neck pain, Altered mental status, Bacterial Meningitis (2004) nonspecific signs: Fever, WBC, malaise, etc Nervous System Lyme Disease (2007) Common pathogens – Listeria monocytogenes Viral Encephalitis (2008) – Group B Streptococci – Haemophilus influenzae Management of Cryptococcal Disease (2010) – Neisseria meningitidis – Streptococcus pneumoniae Healthcare-Associated Ventriculitis and Incidence decreasing Meningitis (2017) – 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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13 14 Meningitis Diagnostic Workup Examining the CSF (+) Gram Stain: 60-90% sensitivity, 97% specificity 1. Suspicion of Meningitis Typical CSF chemistry findings

2. Blood Cultures, Lumbar puncture, CSF culture Viral Meningitis Fungal Meningitis and gram stain STAT * Protein: mild elevation Protein: Elevated Glucose: Normal >67% Glucose: low 3. Empiric therapy RBC: Normal (slight RBC: Normal elevation if HSV) WBC: ~100-400 4. Continue therapy if CSF findings are consistent WBC: 10s-100s - Lymphocytes with meningitis or high clinical suspicion remains - lymphocytes – CSF:Blood Glucose <0.4: 80% sensitive, 98% specific * Delay LP if concern for elevated ICP – CSF Lactate > 3.5 mmol/L: 93% sensitive, 96% specific in and possible subsequent herniation distinguishing bacterial from aseptic meningitis

Tunkel, et al. CID. 2004; 39(9):1267-84 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

15 16 Meningitis; Empiric Therapy Healthcare-associated Bacterial Meningitis; 2004 guidelines

1. 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 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 Tunkel, et al. CID. 2004; 39(9):1267-84

17 18 Audience Participation Audience Participation How many of you had at least How many of you had at least one lecture in pharmacy school one lecture in pharmacy school focusing on bacterial meningitis? focusing on healthcare-associated bacterial meningitis?

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19 20 Audience Participation Audience Participation What percentage of all meningitis What percentage of all meningitis cases are healthcare-associated? cases are healthcare-associated? A. 10% A. 10% B. 20% B. 20% C. 30% C. 30% D. 40% D. 40%

21 22

Healthcare-associated Meningitis New Guidelines! Epidemiological data lacking Institutional reviews of meningitis cases – Mass General, 1962-1988, 493 cases, 40% nosocomial

Organism Community Nosocomial Streptococci, H. influenzae, N. 64 % 8 % meningitidis, L. monocytogenes Staphylococci 3 % 22 % Other Gram Negative Bacilli 0 % 46 %

– South Taiwan, 1986-2003, 329 Cases: 48% nosocomial Similar results for causative organisms

Durand ML, et al. N Eng J Med 1993; 328:21-8 Tsai MH, et al.. Infection. 2006; 34:2-8

23 24 http://raczpainmanagement.com/intrathecal-pain-pump-therapy Healthcare-associated Meningitis & Ventriculitis

“Meningitis may be acquired in the community

setting or associated with a variety of invasive Intrathecal medication pump procedures or head trauma”

https://www.healthtap.com/topics/dilated-ventricles-and-sulci-of-the-brain Neurosurgical hardware to be considered Ventriculoperitoneal shunt https://www.healthtap.com/topics/dilated-ventricles-and-sulci-of-the-brain May become symptomatic during hospitalization, may develop after discharge or months/years later

Different pathogens predominate

External ventricular Drain (EVD) Deep Brain Stimulator (DBS) Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64

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25 26 Epidemiology: Pathogens Diagnostic Factors

Decreasing incidence of “typical” pathogens Diagnosis MUCH less straightforward than community cases historically seen in meningitis – Pathogens more indolent – Symptomatology more subtle, varying with disease state Higher proportion of cases caused by: – Concomitant disease states cloud the picture – Staphylococci: S. aureus, S. epidermidis Signs of meningeal irritation typically absent – Propionibacterium acnes – 30% of patients or less – Gram negative bacilli, including MDR organisms: . P. aeruginosa Does it look like an infection? . E. coli –Yes?  Probably an infection . Klebsiella species –No?  Still might be . Serratia species . Citrobacter, Enterobacter, Acinetobacter species

Castelblanco RL, et al. Lancet Infect Dis. 2014 Sep;14(9):813-9 Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Images courtesy of the European Society of Critical Care Medicine and The Facebook Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64

27 28 Diagnosis: CSF Chemistries Diagnosis: CSF Cultures Also may be unreliable for diagnosis Most reliable means of diagnosis, per 2017 guidelines – Schade et al, 2006. 230 patients with external – “Single or multiple positive CSF cultures in patients with… ventricular drains (EVDs): other signs or symptoms…suspicious for ventriculitis or Daily CSF sampling for chemistries and cultures meningitis, is indicative of CSF drain infection (strong, high) 22 patients developed venticulitis and/or meningitis Nonsignificant: WBC count, protein, CSF : Blood glucose – CSF cultures usually sensitive and specific for infection

Most likely to be reliable: CSF WBC count Other recommendations: – Walti et al, 2013: WBC count >175 cells/µL predictive of infection – Obtain CSF cultures All other parameters showed nonsignificant results – Hold cultures for 10 days in case of P. acnes – Pfisterer et al, 2003: CSF WBC count correlates with positive CSF – If hardware infection suspected, culture shunt and drain components culture results – Obtain CSF and blood cultures prior to giving antibiotics

Median values = 150 - 237 cells/µL Schade et al. J Neurosurg 2006; 104:101-8 Walti et al. J Infect. 2013; 66:424-31 . Pfisterer et al. J Neurol Neurosurg Psychiatry 2003; 74:929-32 Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64

29 30 Empiric Treatment Patient Case Minimal expansion on the 2004 recommendations First line empiric regimen: Patient X: 52 yo F, no PMH or medications – Vancomycin + ceftazidime or cefepime or meropenem – No known drug allergies Second line against GNRs: Presents to outside ED with thunderclap – If patient has anaphylaxis to β-lactams AND meropenem is HA and vomiting. Head CT shows SAH contraindicated: ciprofloxacin or aztreonam with ventricular extension Second line against gram positive bacteria: – No alternatives to vancomycin mentioned in the guidelines Transferred to our facility, CT/angiogram – Reasonable options: confirms diagnosis, pinpoints an ACOMM Daptomycin, Linezolid, or Sulfamethoxazole-Trimethoprim (SMX-TMP) aneurysm rupture Note: all recommendations are “strong” recommendations with “low” quality of evidence (i.e. expert consensus)

Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64

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31 32 CT imaging Anterior Communicating Artery

33 34 Patient X Assessment Question

Hospital day 1: What is the appropriate empiric antibiotic – Emergent Coiling of the ACOMM aneurysm and placement of an EVD on hospital day 1, admitted in regimen for Patient X? stable condition to Neuro ICU A. Vancomycin + Ceftriaxone B. Vancomycin + Cefepime Hospital day 9: C. Vancomycin + Gentamicin o – Temp 102.5 F, D. Daptomycin + Meropenem – WBC 17.5 K – CSF chemistries  – BG 119

35 36 Assessment Question Pathogen-Specific Treatment

What is the appropriate empiric antibiotic regimen for Patient X? A. Vancomycin + Ceftriaxone B. Vancomycin + Cefepime initiated 1250 mg Q12h 2 grams Q8h C. Vancomycin + Gentamicin D. Daptomycin + Meropenem

Note: no randomized clinical trial data available. All recommendations based on observational studies, case series, and expert opinion

Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64

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37 38 Pathogen-Specific Treatment Gram Positives Evidence Summary Staphylococci Gram Positives – Methicillin-Sensitive: Nafcillin or Oxacillin Alternative: vancomycin http://www.healthhype.com/staphylococcus-aureus.htmlm – Methicillin-Resistant: Vancomycin Alternatives: daptomycin, Staphylococcus infections: linezolid, SMX-TMP –If vancomycin MIC≥1 mcg/mL, consider alternatives P. acnes Linezolid, daptomycin, SMX-TMP – First line therapy: Penicillin G Alternatives: ceftriaxone, vancomycin, Source: IDSA guidelines for MRSA (2011), no further data cited daptomycin, or linezolid – Consider adding rifampin especially when hardware involved S. pneumoniae Enhances the bactericidal activity of the primary agent – If Penicillin MIC≤0.06 mcg/mL: penicillin G Alternative: ceftriaxone Evidence very limited and outdated – 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 Liu, et al. Clin Infect Dis 2011; 52:285-92 Gombert, et al. J Neurosurg. 1981; 55:633-6 Nau, et al. J Antimicrob Chemother. 1992; 29:719-24 Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Dunne, et al. Antimicrob Agents Chemother. 1993; 37;2522-6

39 40 Pathogen-Specific Treatment Evidence Summary Gram Negatives Gram Positives P. aeruginosa – 1st line: ceftazidime, cefepime, or meropenem Alternatives: ciprofloxacin Other agents http://www.healthhype.com/staphylococcus-aureus.htmlm or aztreonam – Linezolid Acinetobacter baumannii – 1st line: meropenem Alternatives: colistin or polymixin B Useful option, especially for Enterococcus Favorable kinetics/penetration of the CNS H. influenzae Efficacy reported in 4 case reports/case series, totaling 9 patients – β-Lactamase ( - ): ampicillin Alternatives: ceftriaxone, cefepime, or a FQ – Daptomycin – β-Lactamase ( +): ceftriaxone Alternatives: aztreonam, cefepime, or a FQ Typically requires aggressive dosing ~10 mg/kg ESBL-producing organisms Source: 2 case series, totaling 10 patients – 1st line: meropenem Alternatives: cefepime or a FQ Yilmaz, et al. J Neurosurg Pediatr. 2010; 5:443-8 – For enterobacteriaceae that hyperproduce ESBLs (Enterobacter, Citrobacter, Maranich, et al. Mil Med. 2008; 173:927-9 Graham et al. Pediatr Infect Dis J. 2002; 21:798-800 Serratia species), meropenem or SMX-TMP may be preferred Antony, et al. Infect Dis Clin Pract. 2012; 20:161-3 Kullar et al. Antimicrob Agents Chemother. 2011; 55:3505-9 Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64

41 42 Evidence Summary Evidence Summary Gram Negatives Gram Negatives

http://www.cofa.org.ar/?p=21865 Acinetobacter species http://www.cofa.org.ar/?p=21865 Enterobacter species: – Meropenem preferred over ceftazidime and cefepime – Questionable efficacy of some Beta-lactam agents Cef’s may not achieve adequate CNS concentrations 1993 review of 46 enterobacter meningitis cases – 100% cure rate with SMX-TMP 3 hour infusions reported as successful – 70% with beta-lactam agents – Clinical cure and CSF concentration goals attained – Possible treatment-emergent resistance to ceftriaxone? – May require additional IV or Intraventricular agents 2005 retrospective review of 19 cases Aminoglycosides, colistin, polymyxin B – 83% cure rate with SMX-TMP – Carbapenem resistance: mortality of up to 60% – 54% with 3rd generation cephalosporins Addition of Colistin (IV or intraventricular) improves cure rates

Kim et al. Lancet Infect Dis. 2009; 9:245-55 Capitano et al. Pharmacotherapy. 2004; 24:803-7 Wolff et al. Clin Infect Dis. 1993; 16:772-7 Nicasio et al. Ann Pharmcother. 2007; 41: 1077-81. Moon et al. J Infect Chemother. 2013; 19:916-19 Foster et al. Surg Neurol. 2005; 63:533-7

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43 44 Patient Case, revisited Assessment question Review: – SAH s/p coiling & EVD placement for hydrocephalus/CSF drainage True/False: Patient X is responding – Probable meningitis/ventriculitis on hospital day 9 – Empiric antibiotics (Vancomycin + Cefepime) started appropriately to sufficient antibiotic therapy Hospital day 11 – Persistent Fever to 102.6oF, WBC 18.4 A. True – Initial day 9 CSF Culture results: Day 11 CSF chemistries: B. False

– Cefepime is deescalated appropriately to Ceftriaxone, – Vancomycin is discontinued

45 46 Assessment question Assessment question

True/False: Patient X is responding What strategies could maximize bactericidal appropriately to sufficient antibiotic activity and patient response? therapy A. Add Sulfamethoxazole-Trimethoprim for synergy B. Add intraventricular Ceftriaxone A. True C. Add intraventricular Gentamicin B. False D. Go for broke and reescalate antibiotics to Daptomycin +Meropenem + Colistin + Azithromycin Clinical signs (high fever, leukocytosis) and CSF chemistries indicate suboptimal response

47 48 Assessment question The What strategies could maximize bactericidal activity and patient response? Blood A. Add Sulfamethoxazole-Trimethoprim for synergy Brain B. Add intraventricular Ceftriaxone C. Add intraventricular Gentamicin Barrier D. Go for broke and reescalate antibiotics to 1. Tight junctions Daptomycin +Meropenem + Colistin + Azithromycin between vascular endothelial cells Intraventricular therapy appropriate, IVT 2. Additional lipid basement Ceftriaxone contraindicated due to high incidence membane of seizures with intraventricular Beta-lactams Image: Rochester Institute of Technology https://cias.rit.edu/faculty-staff/101/faculty/340

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49 50 Pharmacokinetic Considerations CSF Pharmacokinetics [CSF] / [Serum] ~5-20% for most agents

Factors influencing CNS Penetration – Smaller molecular size= better penetration . Serum concentration – More lipophilic drugs = better penetration . CSF concentration – Protein binding: higher free drug fraction = better – Meningeal inflammation = better penetration – Active transport/Active clearance P-GP, OAT3, PEPT2 transporter proteins Negligible effects for most commonly used agents

Nau R, et al. Clin Microb Rev. 2010; 23:858-83 Nau R, et al. Clin Microb Rev. 2010; 23:858-83

Drug Penetration into the CNS 51 52 Antimicrobial CSF AUC/Serum AUC (%) CSF AUC/Serum AUC (%) Intraventricular Drug Administration agent Un-inflamed meninges 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 External Ventricular Drain (EVD) Ommaya Reservoir Ciprofloxacin 24-43 92 • Most common method of IVT • May be preferable for Levofloxacin 71 N/A • Frequently already in place longer-term therapy Linezolid 90 N/A

Nau R, et al. Clin Microb Rev. 2010; 23:858-83 Images courtesy of SUNY-Stony Brook & Memorial Sloan Kettering Cancer Center

53 54 Intraventricular Antimicrobials

Intraventricular Antimicrobials Antimicrobial agent Daily Intraventricular Dose (adults)

Benefits Amikacin 5-50 mg (usual 30 mg)

– Bypasses the BBB; higher CSF [drug] than IV therapy Gentamicin 1-8 mg (usual 5 mg) – Long CSF half-lives, once daily administration Tobramycin 5-20 mg (usual 5-10 mg) – Minimal systemic toxicity Vancomycin 5-20 mg Daptomycin 2-10 mg Risks and considerations Colistimethate Sodium 10 mg – NOT FDA-approved; off label usage Polymyxin B 5 mg Amphotericin B deoxycholate 0.01-1 mg – Highly invasive – Requires small volume, preservative-free formulations Dosing strategies – Variable neurologic toxicities – May target CSF Trough concentrations 10-20x the Pathogen’s MIC – May tailor dose and interval based on troughs, ventricle size, and Hearing loss, seizures, tinnitis, headache EVD output Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Nau R, et al. Clin Microb Rev. 2010; 23:858-83 Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Nau R, et al. Clin Microb Rev. 2010; 23:858-83

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55 56 Duration of Therapy Patient Case, revisited Depends on the pathogen Optimizing therapy, Hospital Day 11 – P. acnes and coagulase-negative staphylococci – Ceftriaxone dosed 2 grams IV every 12 hours (maximum dose) – Intraventricular Gentamicin was added, 5 mg daily 10-14 days – S. aureus and Gram Negative Bacilli Clinical Course 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 – Total of 11 days Intraventricular gentamicin (7 days from No benefit to extended courses of treatment the last positive culture) until EVD removed – Total of 14 days IV ceftriaxone (10 days from last positive culture) Tunkel, et al. Clin Infect Dis. 2017; 64:e34-64 Simon et al. J Pediatric Infect Dis Soc. 2014; 3:15-22

57 58 Summary Questions CNS 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 Contact Info: [email protected] difficult-to-manage cases

References:

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

59 60

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62 References: (continued) References: (continued) 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 Schade RP, Schnkel J, Roelhandse FW, et al. Lack of calue of routine analysis of cerebrospinal fluid for prediction and diagnosis of Tsai MH, Lu CH, Huang CR, et al. Bacterial meningitis in young adults in external drainage-related bacterial meningitis J Neurosurg 2006; Southern Taiwan. Infection. 2006; 34:2-8 104:101-8. Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the in the USA from 1997-2010: a population-based observational study. Infectious Diseases Society of America for the treatment of Lancet Infect Dis. 2014; 14(9):813-9. methicillin-resistant Staphylococcus aureus infections in adults and Wiberg K, Birnbaum A, Gradon J. Causes and presentation of children: execultive summary. Clin Infect Dis 2011; 52:285-92. meningitis in a Baltimore community Hospital. South Med J. 2008; Gombert ME, Landesman SH, Corrado ML, et al. Vancomycin and 101:1012-6. rifampin therapy for staphylococcus epidermidis meningitis Walti LN, Conen A, Coward J, Jost GF, et al. Characteristics of infectious associated with CSF shunts: report of three cases. J Neurosurg. 1981; assicoated with external ventricular drains of cerebroprospinal fluid. 55:633-6. J Infect. 2013; 66:424-31 Nau R, Pange HW, Menck S, et al. Penetration of rifampicin into the Pfisterer W, Muhlbauer M, Czech T, Reinprecht A. Early diagnosis of cerebrospinal fluid of adults with inflamed meninges. J Antimicrob external ventricular drainage infection: the results of a prospective Chemother. 1992; 29:719-24. study. J Neurol Neurosurg Psychiatry. 2003; 74:929-32 61

63 64 References: (continued) References: (continued)

Dunne WM Jr, Mason EO Jr, Kaplan SL. Diffusion of rifampin and Kullar R, Chin JN, Edwards DJ, et al. Pharmacokinetics of single-dose vancomycin through a Staphylococcus epidermidis biofilm. daptomycin in patients with suspected or confirmed neurologic Antimicrob Agents Chemother. 1993; 37;2522-6. infections. Antimicrob Agents Chemother. 2011; 55:3505-9. Yilmaz, A, Dalgic N, Musluman M, et al. Linezolid treatment of shunt- Wolff MA, Young CL, Ramphal R. Antibiotic therapy of Enterobacter related cerebrospinal fluid infections in children. J Neurosurg meningitis: a retrospective review of 13 cases and a review of the Pediatr. 2010; 5:443-8. literature Clin Infect Dis. 1993; 16:772-7. Maranich AM, Rajnik M. Successful treatment of vancomycin-resistant Foster DR, Rhoney DH. Enterobacter meningitis: organism enterococcal ventriculitis in a pediatric patient with linezolid Mil susceptibilities, antimicrobial therapy and related outcomes. Surg Med. 2008; 173:927-9. Neurol. 2005; 63:533-7. GrahamPL, Ampofo K, Saiman L. Linezolid treatment of vancomycin- Kim BN, Peleg AY, Lodise TP, et al. Management of meningitis due to resistant Enterococcus faecium ventriculitis. Pediatr Infect Dis J. antibiotic-resisant Acinetobacter species. Lancet Infect Dis. 2009; 2002; 21:798-800. 9:245-55. Antony SJ, Hoffman-Roberts HL, Foote BS. Use of daptomycin as Moon, C, Kwak YG, Kim BN, et al. Implications of postneurosurgical salvage therapy in the treatment of central nervous system meningitis caused by carbapenem-resistant Acinetobacter infections including meningitis and shunt infections. Infect Dis Clin baumannii. J Infect Chemother. 2013; 19:916-19 Pract. 2012; 20:161-3.

65 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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