Abstract
Neurosurgical infections of the central nervous system (CNS) are not particularly common but have potentially serious consequences with poor outcomes including death. This chapter focuses on the antimicrobial treatment and prophylaxis of important infections associated with neurosurgical procedures. We highlight some basic principles of antimicrobial therapy in neurosurgery including the penetration of antibiotics across the blood–brain barrier, risks associated with administration of antibiotics, and the emerging problem of multidrug-resistant pathogens in CNS infections.
Keywords
Antimicrobial prophylaxis, Antimicrobial treatment, Blood–brain barrier, Multidrug-resistant microorganisms, Neurosurgical infections, Surgical site infections
Outline
Introduction 613
Principles of Antimicrobial Therapy in Neurosurgery 613
The Blood–Brain Barrier 614
Empirical and Targeted Treatment of Pathogens Causing Neurosurgical Central Nervous System Infections 615
Risks Associated With Administration of Antibiotics 616
Emergence of Multidrug-Resistant Pathogens 616
Treatment of Central Nervous System Infections in the Neurosurgical Patient 616
Background 616
Microorganisms 617
Diagnosis 619
Antimicrobial Treatment 619
Management of Device-Associated Central Nervous System Infections (Shunt Infections, Infections Associated With Intrathecal Drug Pumps, Deep Brain Stimulator Devices, and Peri-/Epidural Catheters) 619
Antimicrobial Prophylaxis in Neurosurgery 620
Efficacy 620
Choice of Agent 620
Administration and Timing of Antimicrobial Prophylaxis 621
Weight-Based Dosing 621
Redosing 622
Dosing in Patients With Renal Impairment 622
Duration 622
Special Situations 622
Patients Under Antibiotic Therapy 622
Antimicrobial Prophylaxis in Patients With Basilar Skull Fractures and Cerebrospinal Fluid Leakage 622
Antimicrobial Prophylaxis and Multidrug-Resistant Pathogens 622
References 623
Introduction
Neurosurgical infections of the central nervous system (CNS) are not particularly common but have potentially serious consequences with poor outcomes including death. This chapter focuses on the antimicrobial treatment and prophylaxis of important infections associated with neurosurgical procedures and highlights some basic principles for the rational use of antibiotics in neurosurgery.
Principles of Antimicrobial Therapy in Neurosurgery
The appropriate antimicrobial therapy of CNS infections remains challenging. The goal of antimicrobial therapy is to effectively eradicate pathogenic microorganisms without major drug toxicity. Antibiotics should rapidly achieve concentrations in the CNS above the minimal inhibitory concentration (MIC) of the pathogen to exert their killing effect. Penetration and disposition of the antimicrobial agent within the CNS depends on several pharmacokinetic factors of the drug and the pathophysiology of the blood–brain barrier. Pharmacodynamic characteristics of antimicrobial agents such as antimicrobial activity (resistant vs. sensitive strains) and the killing pattern [time dependent (T > MIC) or concentration dependent (Cmax > MIC)] have to be considered.
The Blood–Brain Barrier
Penetration of the antimicrobial agent across the blood–brain barrier is essential for the therapy of CNS infections. It depends on the extent of disruption of the blood–brain barrier by inflammation and the size, charge, lipophilicity, protein binding, and the interaction with efflux pumps of the antibiotic. Clinical efficacy is determined by the antibiotic concentration in the cerebrospinal fluid (CSF) and its antimicrobial activity against the causative pathogen. Inflammation of the meninges allows an increase in CNS penetration of mainly hydrophilic drugs like β-lactam antibiotics or glycopeptides. Table 35.1 gives an overview of the CSF penetration capability of some important antibiotics used in neurosurgery.
| Antimicrobial Agent | CSF Penetration a (CSF/Plasma) Uninflamed Meninges | CSF Penetration a (CSF/Plasma) Inflamed Meninges | Comments |
|---|---|---|---|
| β – Lactam antibiotics | High systemic doses are generally well tolerated and attain adequate CSF concentration despite poor CSF penetration. Continuous infusions could enhance bacterial killing | ||
| Penicillins | |||
| Benzylpenicillin | 0.02 | 0.1–0.2 | |
| Amoxicillin | 0.01 | 0.06 | |
| Cloxacillin/flucloxacillin | 0.009 | b | |
| Piperacillin | 0.034 | 0.32 | |
| Cephalosporins | |||
| Ceftriaxone | 0.007 | 0.1 | |
| Ceftazidime | 0.06 | b | |
| Cefepime | 0.1 | 0.2 | |
| Ceftaroline | 0.01–0.035 b | b | |
| Carbapenems | |||
| Meropenem | 0.1–0.2 | 0.39 | |
| Imipenem | b | 0.14 | |
| Aminoglycosides | Toxicity and poor CSF penetration impedes increase of systemic doses. Might be used intrathecally | ||
| Gentamicin | 0.01 | 0.1 | |
| Amikacin | b | 0.1 | |
| Glycopeptides | Toxicity and poor CSF penetration impedes increase of systemic doses Limited data for intrathecal administration | ||
| Vancomycin | 0.01 | 0.2–0.3 | |
| Fluoroquinolones | Good CSF penetration | ||
| Ciprofloxacin | 0.3 | 0.4–0.9 | |
| Levofloxacin | 0.7 | 0.8 | |
| Moxifloxacin | 0.5 | 0.8 | |
| Rifampicin | 0.2 | 0.3 | CSF concentrations usually exceed MIC of susceptible bacteria |
| Linezolid | 0.5 | 0.7 | Variability of clinical response, case reports of successful treatment of pneumococcal, staphylococcal, and enterococcal meningitis |
| Daptomycin | b | 0.05 | Poor CSF penetration, but CSF concentrations usually exceed MIC of susceptible bacteria |
| Tigecycline | b | 0.5 | Good CSF penetration, but current standard dose regimen might be insufficient for successful bacterial killing |
| Fosfomycin | 0.18 | b | CSF concentration above MIC of susceptible pathogen; reserve antibiotic for MDR gram-negative bacteria |
| Polymyxins | Toxicity and poor CSF penetration, CSF concentrations may be insufficient against MDR pathogens. May consider intrathecal administration in combination with other agents | ||
| Colistin | 0.03–0.05 | 0.06–0.68 | |
| Cotrimoxazole | Acceptable CSF penetration, CSF concentration above MIC of susceptible pathogen with high dose (e.g., Listeria monocytogenes ) | ||
| Trimethoprim | 0.18 | 0.42–0.51 | |
| Sulfamethoxazole | 0.12 | 0.24–0.3 | |
| Chloramphenicol | 0.6 | 0.7 | Good CSF penetration, but toxicity limits its use |
| Metronidazol | b | 0.87 | Excellent CSF penetration, standard treatment against anaerobes |
| β – lactamase inhibitors e.g., Clavulanic acid, sulbactam, tazobactam | 0.07 | 0.1 | Little experience, insufficient data to support amoxicillin/clavulanic acid in the treatment of β-lactamase-producing pathogens like Staphylococcus aureus in the CNS |
| Antimicrobial agents not recommended for treatment of CNS infections | Cefazolin Cefuroxime Clindamycin macrolides | Poor CSF penetration, inadequate CSF concentrations, or insufficient data |
a Estimated CSF penetration: quotient based on area under the curve (AUC) AUC CSF /AUC plasma or estimation of CSF penetration from paired plasma and CSF measurements.
b No or very limited clinical data (based upon case reports, animal models).
β-Lactam antibiotics are important and commonly used agents in the treatment of various CNS infections. Although they penetrate poorly into the CSF, the administration of frequent and high systemic doses results in effective bactericidal concentrations in the CSF and is generally well tolerated. Based on their time-depending killing mechanism, continuous instead of bolus infusion can further improve antimicrobial efficacy especially when treating pathogens with higher MICs.
For other antimicrobial agents like aminoglycosides, glycopeptides, or polymyxins, dose escalation is problematic due to the increase of drug toxicity. Therefore, direct infusion of antimicrobial agents into the ventricles through a catheter is occasionally necessary when infections are difficult to eradicate with intravenous antimicrobial therapy alone following neurosurgical procedures or in association with CSF catheters.
Other classes of antibacterial drugs like fluoroquinolones, rifampicin, linezolid, or metronidazole have better penetration into CSF, even in patients with no meningeal inflammation.
Empirical and Targeted Treatment of Pathogens Causing Neurosurgical Central Nervous System Infections
A wide variety of bacterial species can cause CNS infections. The pathogen spectrum and epidemiology of nosocomial-acquired CNS infections after neurosurgical procedures differ from community-acquired CNS infections. Empirical antimicrobial treatment must, therefore, be adapted to cover expected causative pathogens until identification of bacterial species becomes available ( Table 35.2 ). After identification of the bacterial species and antimicrobial susceptibility testing, therapy should be narrowed to the specific pathogen to optimize treatment and avoid unnecessary drug toxicity and selection of resistant microorganisms ( Tables 35.3 and 35.4 ).
| Pathogenesis | Common Microorganisms | Antimicrobial Therapy a |
|---|---|---|
| Postneurosurgical infection | Staphylococcus aureus , and coagulase-negative staphylococci (especially Staphylococcus epidermidis ), gram-negative bacteria (including Pseudomonas aeruginosa ), Streptococcus spp. | Vancomycin plus cefepime, ceftazidime, or meropenem |
| Ventricular or lumbar catheter, (shunt infections), implantable drug pumps, and deep brain stimulator devices | Coagulase-negative staphylococci (especially S. epidermidis ), S. aureus , Propionibacterium acnes , gram-negative bacteria (including P. aeruginosa ) | |
| Penetrating trauma | S. aureus , coagulase-negative staphylococci (especially S. epidermidis ), gram-negative bacteria (including P. aeruginosa ) | |
| Basilar skull fracture | Streptococcus pneumoniae , Haemophilus influenzae Group A β-hemolytic streptococci | Vancomycin plus third-generation cephalosporin (i.e., ceftriaxone or cefotaxime) |
a The choice of the antimicrobial agents should be based on local antimicrobial susceptibility.
| Microorganisms | Antimicrobials Usually Active With Sufficient CSF Concentrations a | Alternatives a | |
|---|---|---|---|
| Gram-positive cocci | Staphylococcus aureus MRSA | Vancomycin b | Daptomycin, linezolid, trimethoprim-sulfamethoxazole, ceftaroline |
| S. aureus MSSA | Nafcillin, oxacillin, flucloxacillin | ||
| Coagulase-negative staphylococci | Vancomycin | Daptomycin, linezolid. If methicillin-susceptible: nafcillin, oxacillin, flucloxacillin | |
| Streptococcus pneumoniae Penicillin MIC <0.1 μg/mL | Penicillin, amoxicillin, ceftriaxone, cefotaxime | Chloramphenicol | |
| Penicillin MIC 0.1–1 μg/mL | Ceftriaxone, cefotaxime | Cefepime, meropenem | |
| Penicillin MIC >1 μg/mL | Vancomycin + ceftriaxone/cefotaxime | Vancomycin + moxifloxcacin; may add rifampicin | |
| Streptococcus agalactiae , group A β-hemolytic streptococci | Penicillin, amoxicillin, ceftriaxone, cefotaxime | Vancomycin | |
| Gram-negative cocci | Neisseria meningitidis a | Penicillin, amoxicillin, ceftriaxone, cefotaxime | Meropenem, moxifloxacin |
| Gram-positive bacilli | Listeria monocytogenes | Amoxicillin (+gentamicin) | Trimethoprim-sulfamethoxazole, meropenem |
| Propionibacterium acnes | Penicillin, amoxicillin, ceftriaxone, cefotaxime | ||
| Gram-negative bacilli | Haemophilus influenza | Ceftriaxone, cefotaxime | Amoxicillin if β-lactamase negative |
| Enterobacteriaecae ( Escherichia coli , Klebsiella pneumoniae ) a | Ceftriaxone, cefotaxime | Cefepime, meropenem, aztreonam, ciprofloxacin Colistin c | |
| Pseudomonas aeruginosa a | Cefepime, ceftazidime | Meropenem, aztreonam, ciprofloxacin Colistin c | |
| Acinetobacter baumannii a | Meropenem | Colistin c | |
a Choice of specific antimicrobial agent must be guided by in vitro susceptibility test results.
b Addition of rifampicin should be considered.
c Consider using colistin in multidrug-resistant gram-negative bacteria producing carbapenemases (e.g., KPC, NDM-1).
| Antibiotic | Dosage a |
|---|---|
| Amoxicillin | 2 g every 4 h |
| Aztreonam | 2 g every 6–8 h |
| Cefepime | 2 g every 8 h |
| Cefotaxime | 2 g every 4–6 h |
| Ceftaroline | 600 mg every 8 h |
| Ceftazidime | 2 g every 8 h |
| Ceftriaxone | 2 g every 12 h |
| Ciprofloxacin | 400 mg every 8 h |
| Flucloxacillin | 2 g every 4 h |
| Meropenem | 2 g every 8 h |
| Moxifloxacin | 400 mg every 24 h |
| Nafcillin | 2 g every 4 h |
| Oxacillin | 2 g every 4 h |
| Penicillin G | 4 Mio U every 4 h |
| Vancomycin b | 15–20 mg/kg BW every 8–12 h |
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