Antibiotics: Prophylactic and Therapeutics

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.

Table 35.1

Penetration of Different Antibiotics into CSF

Adapted from van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012;380:1693–702; Nau R, Sorgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood–brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010;23:858–83; Di Paolo A, Gori G, Tascini C, Danesi R, Del Tacca M. Clinical pharmacokinetics of antibacterials in cerebrospinal fluid. Clin Pharmacokinet 2013;52:511–42.

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

CSF , cerebrospinal fluid; MIC , minimum inhibitory concentration; MDR , multidrug resistant.

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 ).

Table 35.2

Common Pathogens and Recommended Empirical Antibiotic Treatment for Neurosurgical CNS Infections

Adapted from Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267–84; van de Beek D, Drake JM, Tunkel AR. Nosocomial bacterial meningitis. N Engl J Med 2010;362:146–54.

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)

CNS , central nervous system.

a The choice of the antimicrobial agents should be based on local antimicrobial susceptibility.

Table 35.3

Pathogen-Targeted Antimicrobial Therapy of CNS Infections

Adapted from Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267–84; van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012;380:1693–702.

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
Gram-positive bacilli	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

CNS , central nervous system; CSF , cerebrospinal fluid; MIC , minimal inhibitory concentration; MRSA , methicillin-resistant S. aureus ; MSSA , methicillin-susceptible S. aureus .

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).

Table 35.4

Dosage of Intravenous Antibiotics Used in the Treatment of Central Nervous System Infections in Adults

Adapted from Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267–84.

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

BW , body weight; U , international units.

a For normal kidney function.

b Maintain serum trough level 15–20 μg/mL.

Risks Associated With Administration of Antibiotics

As antimicrobial treatment can be associated with considerable side effects and toxicity, the indication of antimicrobial treatment has to be carefully established.

High-dose penicillin, cefepime, imipenem, or fluoroquinolones can cause neurotoxicity and seizures especially in neurosurgical patients. Given the lower risk of seizures compared to imipenem, meropenem is the agent of choice if a carbapenem is used.

Other important adverse effects of antimicrobial therapy are antibiotic-associated diarrhea caused by Clostridium difficile , nephrotoxicity (e.g., aminogylcosides, colistin, vancomycin), drug–drug interactions (particularly with antiepileptic drugs), and allergic reactions.

Emergence of Multidrug-Resistant Pathogens

CNS infections caused by bacteria with reduced sensitivity to antimicrobial drugs represent an increasing challenge worldwide. Multidrug resistant (MDR) gram-negative bacteria, in particular, are an emerging problem that complicates adequate antimicrobial therapy. Extended-spectrum beta-lactamase (ESBL)–producing gram-negative bacteria are resistant to third- and fourth-generation cephalosporins and usually require treatment with carbapenems. Carbapenemases [e.g., New Delhi Metallo-betalactamse (NDM-1), Klebsiella pneumoniae carbapenemases (KPC)] are increasingly found in gram-negative bacteria (e.g., Pseudomonas aeruginosa , Acinetobacter baumanii , or K. pneumoniae ). Such MDR microorganisms are very difficult to treat because of resistance to carbapenems and most other antibiotics. Colistin might be the only active antimicrobial agent. Unfortunately, penetration of colistin into CSF is poor. High systemic doses or even additional intraventricular or intrathecal administration are required with a high rate of toxicity. Due to the rapid emergence of resistance, colistin should only be given in combination with other antibiotics, and consultation of an infectious diseases specialist for optimization of antibiotic treatment is strongly advised.

Treatment of Central Nervous System Infections in the Neurosurgical Patient

Background

Nosocomial bacterial CNS infections may result from invasive neurosurgical procedures [e.g., craniotomy, placement of internal or external ventricular drainage (EVD) catheters] or from complicated head trauma with disruption of the integrity of the skull and meninges. The clinical spectrum of nosocomial CNS infections include meningitis, ventriculitis, as well as epidural and subdural brain abscesses.

Posttraumatic meningitis or ventriculitis after open compound skull or basilar skull fractures with CSF leakage is a serious complication that occurs in about 2–11% (up to 25%) with a median time between injury and the onset of meningitis of 11 days. Persistent leakage of CSF is the major risk factor for the development of meningitis.

Postoperative neurosurgical site infection rates, including meningitis or ventriculitis, range on average between 0.8 and 1.5% after craniotomy, 1.9 and 4.4% after spinal procedures, 5 and 15% after neurosurgical shunt operations (including external and internal shunts), 4.7% after deep brain stimulator device implantation, and 0.7 and 5.2% after intrathecal drug pump implantation , and 0–0.7% after epidural catheter placement depending on various risk factors ( Table 35.5 ). The majority of neurosurgical site infections typically occur within 1–4 weeks.

Table 35.5

Risk Factors for Neurosurgical Site Infections

Contaminated or dirty procedures

ASA classification of ≥2

Postoperative monitoring of intracranial pressure or ventricular drains for ≥5 days

Cerebrospinal fluid leak

Procedure duration ≥2–4 h

Diabetes

Placement of foreign body (e.g., ventriculoperitoneal shunt)

Repeat or additional neurosurgical procedures

Concurrent (remote, incision, or shunt) or previous shunt infection

Emergency procedures

No antimicrobial prophylaxis

Colonization with MRSA or MSSA

Obesity

ASA , American Society of Anesthesiologists; MRSA , methicillin-resistant Staphylococcus aureus ; MSSA , methicillin-susceptible S. aureus .

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