Table 4.

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

Study	Endpoints	Antibiotic	Design	Results	Conclusions
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 AUCbrain/AUCplasma 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

AUC area under the curve, CNS central nervous system, CRO ceftriaxone, CSF cerebral spinal fluid, CTX cefotaxime, ICU intensive care unit, MIC minimal inhibitory concentration, MIC50 minimal inhibitory concentration for 50% of isolates, PTA probability of target attainment, SD standard deviation, T > MIC percentage of time above minimal inhibitory concentration, TBI trauma brain injury