Antibiotics for Gram Positive Meningitis Bhakti Patel M4 Medical Therapeutics Case (adapted from ID consult 8/2006) 62 yo woman with history of Hep C presenting with GBS cervical osteomyelitis refractory to initial medical management. She required a C5-7 anterior corpectomy with posterior C4-C7 spinal fusion, which was unfortunately complicated by a persistent dural leak, requiring surgical exploration with placement of a lumbar drain for repair. Postoperatively, CSF cultures grew E. Faecium sensitive to vancomycin. Despite prolonged treatment with vancomycin CSF cultures continued to grow E. faecium and the patient’s neurological status worsened. What would be your next step in the management of this patient? Choosing the Right Antibiotic Pharmacokinetics of Antibiotics in CSF Blood Brain Barrier Cerebral capillary endothelial cells have tight junctions instead of fenestrations; Consequently only water, most ions, and lipids pass freely. Glucose and other nutrients are transported via surface enzymes and transport molecules expressed by the endothelium. Pharmacokinetics The concentration of antibiotics in CSF depends on the balance between drug penetration and elimination through the blood brain barrier. Choosing the Right Antibiotic Crossing the Blood Brain Barrier Factors Influencing antibiotic concentrations in CSF Factor Example Effect Drug Lipophilicity Fluoroquinolones Rifampin Rapid entry into CSF, Relatively good CSF conc Half life similar to serum High degree of ionization Beta-lactams Low lipid solubility with poor BBB penetration High serum protein binding Ceftriaxone Delayed entry into CSF Long CSF and serum half-life Active Transport system Penicillin Relatively rapid entry into CSF Short duration of effective CSF levels Inflammation Meningitis Increased penetration of hydrophilic agents Minimal effect on lipophilic agents Infecting organism Listeria, Haemophilus E coli, Strep pneumoniae Greater antibiotic penetration Lesser antibiotic penetration (CID 1998;27:1117-29) Choosing the Right Antibiotic Pharmacodynamics of Antibiotics in CSF Pharmacodynamics: concerned with the time course of antimicrobial activity at the site of infection The CSF has poor immune response because there are very low concentrations of pathogen-specific antibodies and complement factors even during meninigitis. Therefore antibiotics should have rapid bactericidal activity for successful treatment (J Antimicrobial Chemo. 1993; 31, Suppl D, 61-70) Concentration-dependent killing: efficacy depends on high peak concentrations and prolonged recovery period after drug levels fall below MIC. The recovery period is characterized by postantibiotic effect, in which there is delayed regrowth of bacteria after exposure and removal of an antibiotic (examples:Aminoglycosides/Fluoroquinolones) Time-dependent killing: efficacy depends on the time their concentration exceeds the MIC (T>MIC) (examples: Beta-lactams, macrolides, clindamycin) Inf Dis North Am. 1999 Sep; 13(3):595-618 Choosing the Right Antibiotic Microorganism susceptibility-Current Practice Guidelines Gram Positive Organisms ClD 2004;39:1267-84 Beta-Lactams CNS penetration: Beta lactams penetrate the intact BBB poorly However in the presence of inflammation penicillins can achieve levels greater than 10x the minimal bactericidal concentration MBC90 for gram positive pathogens (Inf Dis N Am. 1999; 13 (3): 595-611) Pharmacodynamics Exhibits time-dependent bactericidal activity Vancomycin The emergence of penicillin and cephalosporin resistant strains of S. pneumo has resulted in increased use of Vancomycin for treatment of bacterial meningitis CNS Penetration: ~ 10% of serum concentration Pharmacodynamics: Studies in rabbits suggest that maximal bacterial killing rate (BKR) is achieved when vancomycin levels are 5-10x the Minimal Bactericidal Concentration (MBC) [CID 1998;27:1117-29] Vancomycin: Concerns about CNS Penetration Given that CNS penetration by hydrophilic antibiotics like Vancomycin and Beta-lactams are dependent on meningeal inflammation, concomitant use with high dose steroids may reduce vancomycin’s penetration into the CSF Pharmacodynamics of Vancomycin for treatment of experimental Penicillin-, and Cephalosporin-resistant pneumococcal meningitis (Antimicrobial agents and Chemo, Apr 1999;43: 876-81) Experiment design: Using Rabbit meningitis model, animals were given either 20 or 40mg/kg doses of vancomycin (4 and 2 times a day respectively for a total 80mg/kg/daily dose), with and without steroids to determine the penetration of vancomycin in CSF. Results: Conclusions: In the non-steroid group, for both treatment groups (20, 40mg/kg doses) the CNS penetration was 20.1%. Mean concentration of vancomycin at 24-36hr of therapy was lower than levels achieved in the first 12hours consistent with decreasing antibiotic penetration with waning meningeal inflammation. In the steroid groups, the CNS penetration was decreased to 14.3% (P=0.035). The rate of bacterial clearance during the first 6 hours in the 20mg/kg group + steroids group was significantly lowered. However in the 40mg/kg group, the rate of clearing bacteria was similar to the animals not receiving steroids for the first 6hours. In the setting of adjuvant corticosteroid therapy, larger doses of vancomycin (40mg/kg BID) may be needed to achieve and maintain therapeutic concentrations in the CSF Clinical Implications: Clinical guidelines suggest that vancomycin should be given at total daily doses of 30-45mg/kg. This study suggests a larger total daily dose similar to that used in the pediatric population can overcome the CNS penetration impairment caused by concomitant steroid use. Vancomycin: CNS penetration Levels of Vancomycin in CSF of Adults receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study (CID 2007;44:250-5) Experimental Design: 14 Adult ICU patients with suspected pneumococcal meningitis received treatment of vancomycin (15mg/kg loading dose and continuous infusion of 60mg/kg/day), cefotaxime, and dexamethasone. Vancomycin levels in CSF were measures on day 2 or day 3. Results: 13 of 14 patients had documented pneumococcal meningitis and all achieved adequate levels of vancomycin in the CSF. The vancomycin levels were between 48 fold higher than the MICs of the pneumococcal isolates. Conclusions: Possible impairment of vancomycin penetration into the CSF could be overcome with increasing the dosage of vancomycin Clinical implications: Increasing the dose of vancomycin for treatment of meningitis may improve CNS penetration; however, high serum levels may be toxic in some patients. Meropenem A carbapenem antibiotic which is active against some of the major pathogens causing meningitis Pharmacokinetics: IV, IM formulation only CNS penetration: penetrates intact BBB poorly, but with meningeal inflammation sufficiently high CSF levels are achieved for bactericidal effect Does not have epileptogenic activity like imipenem (CID 1997;24 suppl2: S266-75) Meropenem A randomised comparison of meropenem with cefotaxime or ceftriaxone for the treatment of bacterial meningitis in adults (J Antimicrobial Chemo 1995; 36 Suppl A:85-97) Experimental design: Results: 56 patients were enrolled with half receiving meropenem and the rest a cephalosporin (either ceftriaxone or cefotaxime 11 and 17 pts respectively) Pts were assessed by neuro exam, GCS score, Herson-Todd score for measure of clinical cure Clinical cure was observed in 100% of meropenem treated group and 77% of cephalosporin treatment group Conclusions: Meropenem is an effective and well-tolerated antibiotic for treatment of adult bacterial meningitis at doses of 6g/day. Linezolid Nosocomial CNS infections (as described in the case) are often caused by resistant Gram positive bacteria. Treatment with vancomycin may have some limitations given its poor penetration, nephrotoxicity, and possible resistance (VRE). Linezolid may be considered in these situations; however its not an ideal treatment of meningitis because it is bacteriostatic. Linezolid CNS penetration Serum and Cerebrospinal Fluid Concentrations for Linezolid in Neurosurgical Patients (Antimicrobial agents and Chemotherapy. 2006; (50): 3971-6) Experimental Design 14 patients received linezolid (600mg IV BID) with gram positive CNS infections or for prophylaxis. Serum and CSF was sampled and tested for linezolid concentration Results Linezolid penetration in CSF was 66% Serum and CSF concentrations exceeded the MIC of the pathogens throughout the dosing interval There was a lot of variability in linezolid serum and CSF concentrations in this critically ill population Clinical experience with linezolid in treatment of CNS infections (European J Neurology. 2005; (12): 536-542) 10 patients were treated with linezolid after failing initial medical management of their CNS infection. 6 of the 10 patients showed clinical improvement in 1-6 weeks Linezolid: more case reports on its use in CNS infections (European J Neurology. 2005; (12): 536-542) Back to the case… Pt was not responding to vancomycin despite a prolonged course. Linezolid was started and two days later the CSF cultures were negative and there was no CSF cell count When to consider Linezolid: Should not be considered a first line agent, as it has not been extensively studied and is bacteriostatic Only consider if pt is not responding to standard therapy or cannot tolerate other antibiotics.