Table 4 PK/PD studies of beta-lactams in cerebral spinal fluid

Goldwater et al. [149]

To evaluate antibiotic CSF penetration and antimicrobial efficacy

Ceftriaxone

Cefotaxime

Randomised, open, comparative trial

120 paediatric patients with meningitis, 33 with repeated lumbar puncture at different times

CRO 100 mg/kg once daily; CTX 50 mg/kg every 6 h

All 33 repeated lumbar punctures were sterile

The lowest CSF level recorded (0.45 μg/mL for CTX) was 45 times the MIC (0.01 μg/mL). The highest levels (24–35 μg/mL for CRO) were up to 8750 times the MIC of the patient’s causative organism

Antibiotic levels achieved in CSF were therapeutic, being well above the MIC for all organisms encountered

CSF cell count had no apparent influence on antibiotic levels

Lonsdale et al. [150]

To illustrate issues in the management of CSF antibiotic concentrations

Meropenem

Case report

Neurosurgical patient with external ventricular drain-related ventriculitis

Adequate plasma through concentrations achievable after increasing dosing to 2 g, four times daily

CSF concentrations of meropenem were similar to those seen in plasma

There were variations in CSF drug penetration

Achieving CSF therapeutic antibacterial concentrations in neurosurgical critically ill patients is difficult

Standard antibacterial prescription is potentially flawed in this setting, suggesting the need for therapeutic drug monitoring

Abdul-Aziz et al. [151]

To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections

Flucloxacillin

Case report

Critical care patient with CNS infection

Trough plasma concentrations were below the MIC; CSF concentrations were undetectable (intermittent doses 2 g 6/6 h)

With continuous infusion and increasing the dose to 20 g daily, the plasma and CSF levels became detectable, albeit lower than the predefined targets

Antibiotic pharmacokinetics may be significantly altered in critically ill patients

Applying continuous infusion and monitoring plasma and CSF levels is of significance to optimize antibiotic delivery

Cies et al. [152]

To describe the pharmacokinetics of continuous-infusion of meropenem

Meropenem

Case report.

Paediatric patient with ventriculitis

Serum levels were 12 μg/mL at 2 h and “undetectable” at 4 h, with CSF levels of 1 and 0.5 μg/mL at 2 and 4 h, respectively (MIC < 0.25)

On continuous infusion, serum, and CSF levels were noted to be 13 and 0.5 μg/mL, respectively

The continuous-infusion dosing regimen allowed for 100% probability of target attainment in the serum and CSF and a successful clinical outcome

Dahyot-Fizelier et al. [153]

To describe brain distribution of cefotaxime by microdialysis in patients with acute brain injury

Cefotaxime

Observational, prospective study

5 ICU patients with acute brain injury, treated for lung infection

Cefotaxime 2 g 8/8 h

Mean AUC_brain/AUC_plasma ratio was 26.1 ± 12.1%

Unbound cefotaxime brain concentrations were much lower than corresponding plasma concentrations

Simulated brain concentration at two dosage regimens (used for treatment of meningitis) showed T > MIC higher than 90% of the dosing interval for both dosing regimens (4 g every 6 h or 8 h) for susceptible strains and only for 4 g every 6 h for resistant ones

There is limited brain distribution of cefotaxime

Higher cefotaxime dosage (4 g 6/6 h) is required to treat meningitis with resistant bacterial strains

Morita et al. [154]

To assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid

Meropenem

Observational, prospective study

5 adult ICU patients with meningitis

Meropenem 2 g 8/h (duration of infusion was variable from 0.5 to 2 h)

CSF and blood were obtained pre-treatment and on days 3, 7, 14, and 21

Concentrations in cerebrospinal fluid ranged from 0.27 to 6.40 μg/mL up to 8.47 h and were over 1 μg/mL 3 h after starting meropenem infusion

The CSF/plasma concentration ratio ranged from 0.008 to 0.013, 0.011 to 0.953, and 0.633 to 1.821, respectively, within 2 h, 2–6 h, and after 6 h from the start of drug infusion

The relationship of CSF concentration to CSF cell counts, CSF/plasma glucose ratio, and CSF protein concentration, respectively, was statistically correlated with CSF cell counts and CSF protein concentration, and inversely correlated with CSF/plasma glucose ratio

Concentration of meropenem in CSF exceeded the minimal inhibitory concentration for the pathogens involved (penicillin sensitive S. pneumoniae and S. salivarius; methicillin-sensitive Staph aureus)

No serious adverse event and no discontinuation of treatment occurred

The meropenem concentration in the CSF can be expected to be high because of the presence of inflammation

Tsumura et al. [155]

To examine PK and PD of meropenem in cerebrospinal fluid

Meropenem

Observational, prospective study

6 neurosurgical patients

Meropenem (0.5 g every 8 h) was administered during 0.5 h.

Lumbar CSF and venous blood samples were obtained at 0.5–16 h after the start of the first infusion

Penetration into the CSF with the AUC ratio was 0.10 ± 0.03 (mean ± SD)

A dosage of 0.5 g q8h achieved a > 90% PTA (50% of the T > MIC), and 1 g q8h was needed for a > 90% PTA (100% of the T > MIC) for susceptible isolates

For P. aeruginosa, 2 g q8h achieved a lower PTA

Less susceptible bacterial CNS infections may not be optimized with standard meropenem dosage

Nicasio et al. [156]

To describe the use and cerebral spinal fluid penetration of a prolonged infusion meropenem regimen in a patient with Serratia marcescens meningitis

Meropenem

Case report

Adult patient with meningitis and epidural abscess

Meropenem 2 g q8h, 3-h infusion

The prolonged (3 h) infusion regimen of 2 g 8 h resulted in concentrations in both serum and CSF above the MIC of 0.047 μg/mL, for 100% of the dosing interval

CSF penetration was 6.4%

The use of a high-dose prolonged infusion of meropenem resulted in adequate exposure at the site of infection and a successful clinical response

At follow-up, the patient had completed a 4-week course without relapse or adverse events

Frasca et al. [157]

To describe PK–PD profile of cefotaxime in the CSF

Cefotaxime

Case report

Adult ICU patient with TBI

Cefotaxime 4 g q8h, 30-min infusion

Microdialysis was performed on day 4, after the 12th dose

Unbound plasma Cmax was 118.8 μg/mL

CSF Cmax was 11.4 μg/mL

T > MIC in the brain were, respectively, 78% (6.2 h) and 46% (3.7 h) for MIC values of 2 and 4 μg/mL

ECF brain concentrations indicate that an adequate exposure to cefotaxime is achieved in prevention and treatment of most CNS infections with the standard dosage regimen

Wang et al. [158]

To explore whether there is increased CSF penetration of cefoperazone/sulbactam when thee blood–brain barrier is impaired following craniotomy; and whether extended infusion time affects drug concentrations

Cefoperazone/sulbactam

Observational, prospective study

Dosing was 3.0 g in a 3-h infusion every 6 h, after craniotomy

Venous blood and CSF were collected before the start of drug administration and at hour 1, 2, 3, 4, 6, 12, 15, 16, and 18 after administration

8 neurosurgical adult patients enrolled

CSF penetration:

Peak concentrations (CSF/serum): 8.6% ± 7.2% for cefoperazone and 13.5% ± 11.9% for sulbactam

Trough concentrations (CSF/serum): 13.4% ± 5.3% for cefoperazone and 106.5% ± 87.5% for sulbactam

Ratio of the AUC of CSF and serum: 14.5% for cefoperazone and 22.6% for sulbactam

Cefoperazone serum concentrations achieved > 50%T > MIC for Pseudomonas and Acinetobacter (MIC₉₀ 64 mg/L) and 100%T > MIC for more susceptible bacteria

CSF cefoperazone T > MIC% was almost 100% (Escherichia coli MIC50) and T > MIC% was more than 50% (Acinetobacter baumannii MIC50)

Sulbactam serum concentrations achieved > 50%T > MIC for Acinetobacter (MIC₉₀ 16 mg/L)

CSF sulbactam concentrations did not reach the level of MIC₅₀ of 8 mg/L for Acinetobacter

If cefoperazone/sulbactam single infusion time is extended to 3 h, the serum drug concentration achieved the PK/PD standard of > 50%T > MIC (MIC₉₀ 64 mg/L)

It is very difficult to achieve this PK/PD standard in the CSF, and a higher dose might be needed to treat intracranial infections

Destruction of the blood–brain barrier after craniotomy can increase the CSF concentration to a certain extent