What is the central nervous system (CNS) penetration of piperacillin (antibiotic) and tazobactam (beta-lactamase inhibitor) combination?

CNS Penetration of Piperacillin and Tazobactam

Piperacillin and tazobactam have limited penetration into the central nervous system, with piperacillin achieving only 3.4% penetration and tazobactam achieving approximately 10.6% penetration into cerebrospinal fluid in patients with non-inflamed meninges. 1, 2

Cerebrospinal Fluid Penetration

• Piperacillin penetration into CSF is poor in patients with non-inflamed meninges, with maximum concentrations ranging from 0.37 to 8.67 mg/L (median 3.42 mg/L) 2
• Tazobactam shows better relative penetration than piperacillin, with maximum CSF concentrations ranging from 0.11 to 1.37 mg/L (median 0.45 mg/L) 2
• The ratio of CSF to serum area under the curve (AUC) is approximately three times higher for tazobactam (10.6%) than for piperacillin (3.4%) 2
• FDA labeling confirms that "distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins" 1

Pharmacokinetics in CSF

• Peak concentrations in CSF occur later than in serum, with median time to maximum concentration of 1.5 hours for piperacillin and 2 hours for tazobactam after the end of infusion 2
• Elimination half-life is considerably longer in CSF than in serum:
  • Piperacillin: 5.9 hours in CSF versus 1.47 hours in serum 2
  • Tazobactam: 6.1 hours in CSF versus 1.34 hours in serum 2
• In experimental meningitis models with inflamed meninges, penetration rates increase to 16.6% for piperacillin and 32.5% for tazobactam 3

Clinical Implications for CNS Infections

• Due to poor penetration, piperacillin-tazobactam is not listed as a preferred agent for CNS infections in clinical practice guidelines 4

• For CNS infections, preferred agents with better CSF penetration include:

  • Linezolid (66% penetration into CSF) 4
  • Trimethoprim-sulfamethoxazole (13-53% for TMP and 17-63% for SMX) 4
  • Meropenem (recommended for nosocomial meningitis/ventriculitis) 5

• When treating CNS infections, therapeutic drug monitoring (TDM) of beta-lactams is recommended, with sampling of both blood and CSF when possible 4

• The target concentration in CSF should be above the MIC of the isolated bacteria 4

Dosing Considerations for CNS Infections

• Higher doses of piperacillin-tazobactam may be necessary when treating CNS infections to achieve therapeutic concentrations in CSF 2, 6
• Standard dosing of tazobactam (0.5g three times daily) may be inadequate for CNS infections based on observed CSF concentrations 2
• Continuous infusion does not generally increase average CSF concentrations compared to equal daily doses administered by short-term infusion 6
• Surgical drainage of focal abscesses and removal of any foreign body (such as infected shunts) should be performed whenever possible to improve treatment outcomes 4

Risk of Neurotoxicity

• Beta-lactams can cause neurotoxicity, particularly at high concentrations 4
• Piperacillin has a relatively low pro-convulsive activity (11% relative to penicillin G) compared to other beta-lactams 4
• Plasma steady-state concentration of piperacillin above 157 mg/L (when combined with tazobactam) is predictive of neurological disorders in ICU patients with a specificity of 97% and sensitivity of 52% 4
• The risk of neurotoxicity increases when free plasma concentration exceeds 8 times the MIC 4

In summary, while piperacillin-tazobactam can penetrate the CNS to some degree, its penetration is limited, particularly in non-inflamed meninges. For CNS infections, alternative agents with better CSF penetration are generally preferred unless susceptibility testing indicates that higher doses of piperacillin-tazobactam would be beneficial with appropriate therapeutic drug monitoring.