What's New From ICAAC 1999 1Meningitis & CNS InfectionsJohn C. Rotschafer, Pharm. D., FCCPProfessor Experimental Clinical PharmacologyCollege of Pharmacy University of MinnesotaIDSA Meningitis Guidelines ObjectivesMitropoulos, I et al Central Nervous System Infections. In: Pharmacotherapy: A Pathophysiologic Approach, 7th edition. Editors: JT DiPiro, McGraw-Hill. Identify basic components of CNS anatomy Identify pathogens responsible causing CNS infection Be able to identify abnormalities in CSF chemistry & cytology associated with meningitis Be able to identify specific components of a physical exam that would suggest meningitis Identify appropriate empiric antibiotic regimens for bacterial meningitisCNS Infections Meningitis Infection of the subarachnoid space with meningeal involvement Mechanical barriers intact vs. traumatic alteration Encephalitis Inflammation of brain Meningoencephalitis Inflammation of brain with meningeal involvement Shunt or Foreign Device Infections Infected VP or VA shunt CSF pressure monitoring devices Brain Abscess Pathogens may be bacterial, TB, viral, fungal, or parasiticCNS-macrophageDecreased CerebralCSF lactateBacterial ComponentsEndothelial CellsI L-1PGE2Increased BBBPermeabilityVasogenic EdemaIncreasedCSF proteinEndothelium-leukocyteTNF and IL-1PAFThrombosisBlood FlowIncreased ICPOxygen DepletionDecreasedCSF glucoseIncreasedCSF pleocytosisCSF outflowresistanceInterstitialEdemaCytotoxic EdemaMorbidity & Mortality Seizure Disorder Blindness Deafness Learning Disabilities DeathWhat's New From ICAAC 1999 2Meningitis If a physician were attempting to do a “spinal tap” to obtain CSF for analysis, where would the needle likely be inserted and what would be the anatomical target?MeningesSkullBrainPia MaterArachnoidDura MaterSubdural SpaceSubarachnoid SpaceCSF ChannelMeningitis What would be the typical profile of CSF if the meningitis were caused by bacteria in terms of WBC, glucose, & protein?Typical Patient with Bacterial Meningitis• CSF cloudy• Opening CSF pressure 200-500 mm (water)• WBC 1,000-5,000/mm3 (>80% Neutrophils)• Protein 100-500 mg/dL• Glucose < 40 mg/dL• CSF glucose/Blood glucose ratio <0.4• Gram Stain positive 60-90%• CSF culture positive 70-85%Tunkel AR et al IDSA Guidelines CID 39(November 2004)Protein GlucoseType WBC(/mm3) Differential (mg/dL)Normal < 5 >90% mono’s < 50 50-66% serumBact 400-100,000 >90% PMN's 80-500 < 50% serumViral 5-500 >50% lymphs+ 30-150 NML/lowFungal 40-400 >50% lymphs 40-150 NML/lowT.B. 100-1,000 >80% lymphs+ 40-150 NML/lowClinical Presentation and DiagnosisAbnormal CSF-findings by type of meningitis+initially CSF WBC may be PMN’s but will convert to Lymph’s over timeMeningitis What is/are the likely pathogen/s? 4 day old child 8 mo old child 30 yr old adult 85 yr old adult 25 yr old adult MVA victim in ICUWhat's New From ICAAC 1999 3 Neonatal Children < 1 month of age Pathogens acquired from birth canalz E. coliz Group B Streptococci (S. agalactiae)Meningitis Bacterial Pathogens Meningitis Bacterial Pathogens Mechanical Barriers Intact S. pneumoniae (pneumococci) N. meningitidis (meningococci, Groups A,B,C,Y, & W135) H. influenzae (type B or Hib) Immunizations may also affect likely pathogen Special situations B. anthracis Traumatic alteration or other risk factors S. aureus E. coli or P. aeruginosa May depend on circumstancesAmpicillin + Cefotaxime or Ceftriaxone or Aminoglycoside and VancomycinS. pneumoniaeGram-negative entericsL. monocytogenes> 60 yearsCefotaxime or Ceftriaxone and VancomycinS. pneumoniaeN. meningitidis30 – 60 yearsCefotaxime or Ceftriaxone and VancomycinN. meningitidisS. pneumoniaeH. influenzae5 – 29 yearsCefotaxime or Ceftriaxone and VancomycinH. influenzaeN. meningitidisS. pneumoniae1 month – 4 yearsRespiratory tract infection Otitis media MastoiditisHead TraumaAlcoholismHigh-dose steroidsSplenectomySickle cell diseaseImmunoglobulin deficiencyImmunosuppressionAmpicillin + Cefotaxime or Ceftriaxone or AminoglycosideGram-negative entericL. monocytogenesGroup B streptococcusNewborn-1monthRisk Factors for All Age GroupsEmpiric TherapyMost Likely OrganismsAge Commonly AffectedBacterial Meningitis: Most Likely and Empiric Therapy by Age GroupListeria monocytogenes Uncommon CNS pathogen in adults More commonly seen in the young, old, alcoholics, & immunocompromised Gram positive coccobacilli but can be confused as gram positive diplococcic or diphtheroid At risk patients should have empiric coverage for this pathogen Probably best treated with Penicillin G or Ampicillin plus gentamicin TMP/SMX maybe an alternativeMeningitis Most empiric regimens suggest a 3rdgeneration cephalosporin such as ceftriaxone plus vancomycin. Is there overlap on the gram positive coverage? Is there any concerning gaps in coverage?FDA Pneumonia Breakpoints for S. pneumoniae (2008)Sensitive zPCN MIC < 2 (Previously 0.06 mg/L)Non-susceptiblezPCN MIC = 4 (Previously 0.12 to 1.0 mg/L)Resistant zPCN MIC > 8 mg/L (Previously > 2 mg/L)zMeningitis breakpoint for penicillin sensitive remains at <0.06 mg/LzMechanism of resistance is alteration of penicillin binding proteins not beta-lactamase productionWhat's New From ICAAC 1999 4A consensus regarding recommended agents for the treatment of CNS infections caused by anthrax, or other biological warfare agents, has not been reached. Optimal treatment must be tailored to the particular pathogen and/or genetic variants of the pathogen.Bacillus anthracisTrimethoprim 10 mg/kg/day and sulfamethoxazole 50 mg/kg/day, q6hAmpicillin 220 – 400 mg/kg/day, q6h IV or Penicillin G max: 2 gq4h IV plus gentamicin*Listeria monocytogenesLinezolidVancomycin*Methicillin resistantVancomycin*NafcillinPenicillin resistantStaphylococcus epidermidisLinezolidVancomycin*Methicillin resistantVancomycin*Nafcillin 200 mg/kg/day q4h IV max: 2g q4h IVPenicillin resistantStaphylococcus aureusAmpicillin ± gentamicin* CefotaximeCeftriaxoneChloramphenicol*Penicillin ± gentamicin*Group B streptococcusCefepime 50 mg/kg/dose q12hbmax: adult 2g q8h IVOr Meropenem 40mg/kg q8h IV max: adults 1 g q8h IV with Vancomycin* Linezolid 600 mg q12h IVCefotaxime or Ceftriaxone and Vancomycin* 30-40 mg/kg/day IV (60 mg/kg/day IV q6hb)Penicillin resistantCefotaxime 200 mg/kg/day q4-6h IV max 2 g
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