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. Post-
operatively, 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 Rapid entry into CSF, Relatively good CSF
Rifampin 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 Greater antibiotic penetration
E coli, Strep pneumoniae 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:
 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.
 Conclusions:
 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 4-
8 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:
 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
 Results:
 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.