The Use and Misuse of Antibiotics in Neurosurgery

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CHAPTER 42 The Use and Misuse of Antibiotics in Neurosurgery

Koijan Kainth, Matthew A. Hunt, Stephen J. Haines

The Importance of Antibiotics in Neurosurgery

Few neurosurgeons would be willing to practice modern neurosurgery without the ready availability of antibiotics. They have made it possible to treat infections of the brain, meninges, and surgical site effectively and to salvage excellent results from what would otherwise be devastating complications of neurosurgical operations. Although some still argue based on the extraordinary results of Harvey Cushing, who reported one infection in 149 patients (0.7%), that careful technique overcomes almost all sources of infection, a very special understanding of the available evidence is required to deliberately omit perioperative antibiotic prophylaxis in modern neurosurgical practice.1 Antibiotics are an integral part of the daily life of the neurosurgeon.

Antibiotics, like all other neurosurgical interventions, however, carry with them cost and risk. A superficial understanding of their use and the evidence underlying their applications can lead to excessive use, ineffective use, and other forms of misuse that should be avoided if excellence in practice is to be achieved. In this chapter we review appropriate use and discuss common misuses of antibiotics in neurosurgical practice.

Risks Associated with Antibiotic Administration

Antibiotic therapy in neurosurgical patients is implemented in various situations, including prophylaxis for procedures, empirical treatment of a presumed infection, or treatment of a specific infection. Administration of antibiotics is not without consequence, however. Adverse drug reactions that may result include central nervous system (CNS) toxicities, systemic toxicities, allergic reactions, side effects, and drug-drug interactions. Moreover, there is the potential for antibiotic resistance with careless administration. The emergence of antibiotic resistance is a growing and potentially catastrophic problem that should not be taken lightly. Drug toxicity is a consequence of either excessive dosing or impaired drug metabolism, the latter possibly being due to hepatic or renal insufficiency. An allergic drug reaction is a hypersensitivity reaction to a medication that may be immunologically mediated and can result in urticaria, bronchospasm, anaphylactic shock, or angioedema. Side effects are other adverse drug reactions that are neither due to drug toxicity or to a hypersensitivity reaction. In this section, commonly used antibiotics in neurosurgery are addressed, along with their local toxicity, systemic toxicity, side effects, drug-drug interactions, and potential for resistance. Hypersensitivity reactions are discussed briefly and only in regard to specific antibiotics. Table 42-1 summarizes the most important neurotoxicities encountered with current antibiotic use. Table 42-2 summarizes selected drug interactions of importance to the neurosurgical patient.

TABLE 42-1 Antibiotic Neurotoxicity

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TABLE 42-2 Selected Drug Interactions

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Sulfonamides

Sulfonamide neurotoxicity can occur in the premature and newborn period because sulfonamides have the potential to displace bilirubin from albumin, with the resultant free bilirubin being deposited in the basal ganglia and subthalamic nuclei and resulting in kernicterus.2 Moreover, there are reports in the literature of other CNS toxicities, including ataxia, depression, and psychosis with associated visual and auditory hallucinations.3,4

Quinolones

The incidence of neurotoxicity from quinolones ranges from 1% to 2%, and symptoms may include headache, dizziness, and insomnia.5–8 Additionally, instances of delirium, acute psychosis, and seizures have been reported.5,6,9 Moreover, there have been reports of the development of demyelinating polyneuropathy,10 exacerbation of myasthenia gravis,11–15 and peripheral sensory disturbances16 with fluoroquinolone use. Signs of pseudotumor cerebri may develop in infants and young children with high doses of nalidixic acid, the first quinolone to be introduced.17 These CNS effects should generally resolve with the discontinuation of therapy.

Penicillins

Neurotoxicity after parenteral administration of penicillin G is most likely to occur in patients with renal insufficiency, intracranial lesions, or alteration of the blood-brain barrier (BBB).18 This toxicity can occur when the concentration of penicillin G in cerebrospinal fluid (CSF) exceeds 10 µg/mL and may be manifested as lethargy, confusion, twitching, multifocal myoclonus, or seizures.18 Arachnoiditis and encephalopathy may follow the intrathecal injection of penicillin G, and therefore intraventricular and intrathecal administration should be avoided.18 The development of symptoms that may resemble panic attacks or acute psychosis with seizures or hallucinations is known as Hoigne’s syndrome and can follow the intravascular injection of penicillin.19,20 Furthermore, ampicillin may exacerbate weakness in patients with myasthenia gravis.21

Cephalosporins

Many cephalosporins have been associated with neurotoxicity, and ceftazidime, in particular, has been reported to cause hallucinations,22 confusion, encephalopathy,23 and status epilepticus.22,24 There have also been published reports of cephalosporin-associated recurrent aseptic meningitis.25

A hypersensitivity reaction is the most common side effect of cephalosporin administration and may be manifested as anaphylaxis, bronchospasm, urticaria, fever, or maculopapular rash.

Carbapenems

The most common adverse events encountered with carbapenem administration are nausea and vomiting.26 Other frequent adverse events include diarrhea, rash, fever, and laboratory abnormalities, such as elevated liver enzyme levels, eosinophilia, thrombocytopenia, and increased prothrombin time.26 Patients at risk for seizures are those with preexisting renal insufficiency or an intracranial mass lesion who are given high doses of imipenem.27 Furthermore, there are reports that concomitant administration of imipenem with theophylline, quinolones, metronidazole, ganciclovir, or cyclosporine may reduce the seizure threshold.28–30 In contrast to imipenem, meropenem is less likely to induce seizures.31–34

Aminoglycosides

The most important and serious side effects of aminoglycosides are nephrotoxicity and ototoxicity. The other dose-related adverse effect of clinical importance is neuromuscular blockade, which occurs rarely and is usually related to an underlying condition.35 The first signs of ototoxicity may be seen histologically, with the outer hair cells of the cochlea affected first, followed by the inner hair cells.36 Damage to the hair cells results in high-frequency hearing loss, followed by progressive loss of hearing at lower frequencies.35 After degeneration of the hair cells, there can also be damage to nerve fibers.37 The first clinical symptom of cochlear damage is often high-pitched and continuous tinnitus.38 In regard to the vestibular apparatus, hair cell damage occurs along with deterioration of the otoconial membrane and otolith structures.39,40 Clinical signs and symptoms of vestibular damage include disequilibrium, ataxia, transient positional vertigo, and oscillopsia.35,38 In rare instances, aminoglycosides have the potential to cause neuromuscular blockade and paralysis.35 Patients with preexisting myasthenia gravis are at a higher risk for the development of neuromuscular blockade.41 Risk factors for ototoxicity include renal insufficiency, preexisting impaired hearing, old age, sepsis, dehydration, fever, previous aminoglycoside exposure, and concomitant use of vancomycin, cisplatin, or carboplatin.35 Anosmia after aminoglycoside therapy has also been described in the literature, with the sense of smell returning after time.42,43 Intrathecal or intraventricular administration is used rarely because it may cause local inflammation and can result in aseptic meningits.44

Polymyxins

The major adverse drug effects of polymyxins are nephrotoxicity, neurotoxicity, and neuromuscular blockade. Renal insufficiency and giddiness may result when polymyxins are used parenterally, and pain, numbness, paresthesias, confusion, coma, and convulsions may result when they are used intrathecally.45–47

Neurotoxicity from parenteral polymyxin B and colistin is seen most frequently in patients with compromised renal function, with an overall incidence of approximately 7.3%.48 With increasing doses of polymyxin, patients may experience circumoral paresthesias, convulsions, apnea, distal paresthesias, ptosis, diplopia, dysphagia, dysphonia, areflexia, ataxia, and dizziness.49–51 Intrathecal dosages greater than 50,000 U/day have been reported to cause chemical meningitis.18,52

Vancomycin

Neurotoxicity with the administration of vancomycin can include both vestibular damage and cochlear damage, which can result in tinnitus and sensory hearing loss.53,54 Tinnitus may be an early symptom and can indicate the development of deafness.55 Ototoxicity in the early stages, characterized by tinnitus and dizziness, appears to be reversible.56 However, by the time that the patient experiences a noticeable hearing deficit, the toxicity is often irreversible.57 The mechanism by which vancomycin causes ototoxicity is thought to be direct damage to the auditory nerve, which leads to irreversible loss of the sensory hairs in the cochlea that initially affects high-frequency sensory hearing.57 Subsequently, lower frequencies are affected, and eventually, total hearing loss may result.58

Tetracyclines

Neurotoxicity is a well-recognized side effect of tetracycline therapy, and there are several reports in the literature documenting increased intracranial pressure with medium- to long-term use.59–62 In infants, a bulging fontanelle may be apparent but resolves on discontinuation of the therapy.63 Vestibular symptoms are also reported with tetracycline administration and may include dizziness and ataxia.64–66 Additionally, tetracyclines are thought to block the neuromuscular junction by both prejunctional and postjunctional effects that depress the sensitivity of muscle to acetylcholine.3,67 This neuromuscular blockade has been reported to exacerbate myasthenia gravis.18

Chloramphenicol

Neurotoxic effects of chloramphenicol administration are rare. Optic neuropathy and peripheral neuropathy have been cited in the literature in children with cystic fibrosis.68–71 Symptoms of visual toxicity may include blurred vision followed by loss of visual acuity and impaired red-green color discrimination, whereas peripheral nerve toxicities result in burning, tingling, or numbness of extremities.3 The aforementioned symptoms generally resolve after discontinuation of the therapy.3 Additionally, there have been reports of chloramphenicol-induced encephalopathy that can progress to delirium.72

The most feared toxicities of chloramphenicol administration include bone marrow suppression, aplastic anemia, and gray baby syndrome.73

Macrolides

Neurotoxicity is mostly associated with erythromycin and may result in neuropsychiatric symptoms or ototoxicity.74 The neuropsychiatric symptoms that have been reported in the literature include confusion, hysteria, anxiety, and nightmares, all of which disappeared after therapy was terminated.75,76 The ototoxicity that is induced by erythromycin is a result of high doses, or it can occur in patients with preexisting hepatic or renal insufficiency.74,77 In contrast to aminoglycosides, the hearing loss with macrolides is reversible with cessation of the drug.78 There are also reports cited in the literature of the potential for erythromycin to exacerbate weakness in patients with myasthenia gravis.79,80

Linezolid

Neurotoxicity can result in peripheral neuropathy with prolonged use of linezolid.81–83 Most cases of peripheral neuropathy have occurred when linezolid is used beyond the maximal recommended duration of therapy of 28 days.83 Additionally, there have been several reports documenting linezolid-associated optic neuropathy.84–86

Rifampin

The neurotoxic effects of rifampin may include ataxia, confusion, dizziness, numbness, muscular weakness, inability to concentrate, and headache.18,87

The adverse reactions most commonly reported include rash, fever, headache, general malaise, gastrointestinal symptoms, nausea, and vomiting.88,89

General Principles of Antibiotic Use

Neurosurgeons are involved in the treatment of infections not only of the CNS itself but also of the surrounding tissues. These areas encompass multiple diverse compartments, including the cranial soft tissues, skull, paranasal sinuses, paraspinal soft tissues, and the spine itself, including bones, soft tissues, and intervertebral disks, as well as the tissues and body cavities used for the insertion of prostheses such as shunt hardware, electrodes, batteries, and pumps. Fortunately, many of the infections that neurosurgeons must deal with are extradural. This fact simplifies treatment in that delivery of antibiotics does not depend on the physiology of the brain barriers: the BBB and the blood-CSF barrier (BCSFB). The BBB and BCSFB provide protection to the CNS from substances circulating through the blood and help facilitate transfer of important nutrients to the CNS. However, these brain barriers present an obstacle to the entry of antibiotics and require special consideration when contemplating how to treat an infection inside these barriers. Treating infections such as meningitis or brain abscesses requires that adequate amounts of antibiotic cross the BBB and BCSFB into the CSF or the extracellular space of the CNS.

The Blood-Brain and Blood–Cerebrospinal Fluid Barriers

The BBB is formed by endothelial cells of the cerebral vasculature, supported by astroglia and pericytes, with tight junctions between the endothelial cells and minimal fenestrations or bulk transport across the cells. For the BCSFB, this barrier is located at the epithelial layer of the choroid plexus, not at the endothelium, but is similar in character, with tight junctions between the epithelial cells. For both barriers, active influx and efflux transporters located on the endothelial/epithelial cell surface may drastically alter the distribution of an antibiotic into the desired compartment.90,91 Many factors can contribute to the permeability of any substance across the BBB:

• Molecular weight
• Lipophilicity (i.e., octanol/water partition coefficient)
• Ionization
• Presence of transport mechanisms (influx or efflux)
• Plasma protein binding
• Inflammation
• pH
• Metabolism at the barrier

Each of these factors affects a substance’s ability to cross the brain barriers and reach its intended site of action. Increasing molecular weight, ionization, plasma protein binding, and metabolism at the barrier and the presence of efflux transporters decrease the permeability of substances across the brain barriers.91,92 Increased lipophilicity, influx transporters, and inflammation can increase the permeability of the barriers to antibiotics.93 The inflammation associated with infections may decrease over the course of and in response to treatment. Antibiotics may cross into the CSF or brain parenchyma more readily at the initiation of treatment, but as the inflammatory response to the infection abates, either from the antibiotic treatment or from the administration of other medications such as dexamethasone, the ability of an antibiotic to cross the brain barriers diminishes.94,95 However, this effect may not alter outcome.96–100

The overall goal of antibiotic treatment is to deliver an adequate concentration of the drug to the proper compartment. Antibiotics that are bactericidal are generally preferred for the treatment of CNS infections as well because of the low concentration of immunologic proteins such as complement and immunoglobulins and the relatively low numbers of phagocytic cells, although this contention may be changing.101–103 This goal may be accomplished in several ways. First, the dose of the drug may be increased. This method is helpful for drugs with low systemic toxicity and relatively low permeability across the brain barriers, such as β-lactam antibiotics. Second, the choice of antibiotic may be changed to a drug that has greater penetration into the CNS, such as chloramphenicol or quinolones. Third, antibiotics may be delivered directly across the brain barriers (usually by indwelling ventricular or lumbar catheters). This method is especially helpful when using antibiotics that have higher systemic toxicity and poor permeability across the brain barriers, which may limit the systemic dose that can be administered; such drugs include vancomycin and aminoglycosides. For example, administration of chloramphenicol via an intraventricular route does not provide the same advantage that intraventricular administration of vancomycin does because chloramphenicol’s penetration of the brain barriers already exceeds that needed to provide a therapeutic concentration. In addition, bypassing the brain barriers does not provide a significant advantage because chloramphenicol also needs to be hydrolyzed to be effective, which is usually done in the liver. Although hydrolysis has been shown to occur in the CSF, intraventricular administration is probably not necessary.104 Alternatively, using higher doses of β-lactam antibiotics to reach bactericidal concentrations is easily accomplished and generally associated with minimal systemic toxicity. Intraventricular administration of β-lactams is probably more toxic than systemic administration, although whether the source of the toxicity is the antibiotic or the underlying infection is not clear.104

Pharmacokinetics of Antibiotic Delivery

To achieve effective antibiotic dosing, the pharmacokinetics of antibiotic administration must be understood. For infections occurring outside the barriers of the CNS, the principles of systemically administering antibiotics are less complicated. Peak concentrations depend on bioavailability, the amount delivered, the volume of distribution, and elimination via metabolism and excretion.103 However, the pharmacokinetics of antibiotic administration to the CNS depends on both systemic pharmacokinetics and the behavior of the antibiotic in its access to and elimination from the CNS. The sum of these factors can be ascertained by experimentally determining the proportion of antibiotic that reaches the CNS. Most data relating to antibiotic pharmacokinetics in the CNS come from studies on CSF and meningitis. Much less data exist on these parameters for the brain parenchyma itself.105,106

In determining this proportion, careful interpretation of experimental data is required. Many studies looking at the proportion of antibiotic reaching the CNS use simple plasma-CSF ratios at a single time point. These ratios can vary widely during a dosing cycle and can be quite misleading.106,107 The most useful data are derived from using plasma-CSF AUC (AUC is the area under the drug concentration–versus-time curve) ratios in intermittent dosing or steady-state concentrations during continuous infusion. For β-lactam antibiotics, the AUC ratio generally ranges from 0.01 to 0.1. Less hydrophilic antibiotics, such as rifampicin, trimethoprim-sulfamethoxazole, and the fluoroquinolones, have ratios that range from 0.1 to 0.9. Vancomycin and the aminoglycosides also exhibit low penetration into CSF, with ratios of less than 0.1.106,108 However, data suggest that these ratios may be different in the treatment of infections of the brain parenchyma (i.e., brain abscess). One study showed equivalent levels of antibiotic in abscess fluid and plasma 6 hours after administration; however, these are also point ratios, not AUC ratios.109 Whether the antibiotics are as effective in abscess fluid is a separate consideration. Concentrations of antibiotics throughout the CSF are not constant. Ventricular CSF will have a lower concentration of protein and antibiotic than will lumbar CSF because the CSF produced in the ventricles has not yet mixed with exuded extracellular fluid from the brain parenchyma. Therefore, CSF concentrations of antibiotics rely on the permeability of both the BBB and the BCSFB. Penetration of antibiotics through the blood-lesion barrier (specifically, the blood-abscess barrier) will vary with the stage of formation of the abscess, the relative vascularity of the lesion, and even the cause of the lesion. However, it is impossible to differentiate the individual contributions of the blood-lesion barrier and the surrounding BBB to antibiotic concentrations by measuring antibiotic levels within abscesses.105,109–111

The half-life of the antibiotic in CSF is also an important consideration. Most antibiotics are not metabolized in CSF. Elimination is achieved either by diffusion back through the BBB and BCSFB or from turnover of the CSF. Generally, the CSF half-life of antibiotics is significantly longer than the plasma half-life. The CSF half-life of antibiotics may also be increased in CNS infections because of decreased turnover of CSF. Conversely, in patients with CSF shunts or external CSF drains, the CSF half-life may be quite variable because the circulation of CSF is altered by the presence of the shunt or drain.112,113

Central Nervous System Toxicity of Antibiotic Therapy

Antibiotics may be toxic to the CNS when administered systemically, as discussed earlier, or when administered directly into the CNS via an intrathecal route or by means of antibiotic irrigation.

Intrathecal antibiotics may also have significant neurological toxicities, although the most commonly used intrathecal antibiotics, vancomycin and gentamicin, appear to have relatively low toxicity when administered intrathecally. Additionally, discerning these effects may be difficult in patients with a coexisting serious CNS infection. Intraventricular vancomycin appears to be relatively free of toxicity, even at high CSF levels.114 Intraventricular gentamicin may lead to CNS toxicity and cause ototoxicity or epilepsy; however, these effects are not clearly related to CSF levels of gentamicin.115,116 Other antibiotics less commonly used intraventricularly, such as the β-lactam antibiotics, may cause similar effects, especially seizures, as when they are administered systemically.117,118

Antibiotic Prophylaxis

Systemic Antibiotic Prophylaxis

Antibiotic prophylaxis should be considered in terms of the inherent risk for infection associated with the procedure being contemplated. The standard approach to estimating risk for infection at the surgical site is the classification endorsed by the Centers for Disease Control and Prevention (Table 42-3).119

TABLE 42-3 Classification of Surgical Site infection

WOUND CLASS DESCRIPTION EXAMPLES
Clean Uninflamed, uncontaminated, no trauma or infection, primarily closed with no break in sterile technique
Craniotomy for tumor
Microlumbar diskectomy

Clean-contaminated Entry into the alimentary, respiratory, or genitourinary tract under controlled circumstances; no contamination; minor break in sterile technique Transnasal hypophysectomy Contaminated Nonpurulent inflammation, recent trauma, gastrointestinal tract contamination, major break in sterile technique
Depressed skull fracture with overlying laceration
Dropped bone flap

Dirty Purulent inflammation, perforated viscus, fecal contamination, trauma with devitalized tissue, foreign bodies or other gross contamination
Open depressed skull fracture with in-driven foreign bodies
Epidural abscess
Brain abscess

Expected infection rates range from less than 1% in clean wounds with antibiotic prophylaxis to 6% to 10% in dirty wounds, even with antibiotic treatment.120

Clean wounds in neurosurgery are generally subdivided into those with and without implantation of a substantial foreign body. The prototypical neurosurgical foreign body is the shunt. Clean shunt implantations with antibiotic prophylaxis have approximately an 8% to 10% infection rate, a rate much higher than that for non–foreign body operations.121

The use of antibiotics in contaminated and dirty wounds is considered therapeutic, not prophylactic. A full therapeutic course is recommended. Limiting antibiotics to perioperative use in these wound categories would be considered misuse.

Clean Neurosurgical Procedures

The value of systemic antibiotic prophylaxis in clean neurosurgical operations is supported by level I evidence from multiple randomized clinical trials and high-quality meta-analysis.122 The same is true of systemic antibiotic prophylaxis for shunt operations.123,124 Additional meta-analyses have supported its value in preventing meningitis after craniotomy125 and in spine neurosurgery.126

The value of systemic antibiotic prophylaxis in clean-contaminated operations has not been adequately studied to allow a confident conclusion to be reached. The current accepted practice in transnasal surgery varies from limited perioperative use127 to use as though the procedure were contaminated (i.e., therapeutic doses for a therapeutic duration).128

It is not feasible to study the differential effectiveness of different antibiotics. If one antibiotic reduces the expected infection rate to 1% and another is twice as good (infection rate of 0.5%), a study consisting of more than 5000 patients would be required to have a reasonable chance (power of 0.8) of finding that result to be statistically significant (P ≤ .05). Although the duration of prophylactic antibiotic administration in neurosurgery has not been specifically studied in a randomized trial, the general principles of systemic prophylactic antibiotic administration are well established in many disciplines119:

• Use an antibiotic directed at the most common organisms implicated in postoperative infections for the specific operation in the institution in which the operation takes place.
• Administer the antibiotic intravenously and time it so that a bactericidal level is obtained at the time of incision.
• Repeat the antibiotic dose at intervals so that bactericidal serum levels are maintained during the operation.
• Do not continue the antibiotic more than a few hours after the end of the operation.
• Vancomycin should be avoided unless no other antibiotic meets the aforementioned criteria.129

The value of systemic antibiotic prophylaxis in reducing the rate of infection after neurosurgical operations is well established with evidence of the highest quality. Failure to use antibiotics in this way requires justification with evidence of similar quality.

External Ventricular Drains

There is insufficient evidence to support a firm conclusion about the value of systemic antibiotic prophylaxis in reducing infections associated with external ventricular drains.130 One underpowered trial compared systemic antibiotic prophylaxis with placebo for ventriculostomy and found no difference in the infection rate.131 A single trial compared short-term and long-term antibiotic administration and suggested that long-term use reduced infection rates but selected for resistant organisms.132 The infection rates in this study were high (extracranial infection rates of 40% with short-term use and 20% with long-term use). This is an area in which further study could be useful.

Cerebrospinal Fluid Fistula

A recent Cochrane Systematic Review examined the value of systemic antibiotic prophylaxis in preventing meningitis in patients with basilar skull fracture and confirmed the long-held view that the practice is ineffective.133

Topical Antibiotic Prophylaxis

The topical use of antibiotics during neurosurgical procedures to prevent postoperative infection has a long history but has not been studied with sufficient rigor to produce a definitive conclusion about its effectiveness. Two reviews have been published.134,135

When antibiotics first became available, they were sprinkled into the wound in powdered form. Pennybacker and coauthors reported a reduction in infection rates to modern levels (0.9%),136 but a large review of practice at Massachusetts General Hospital did not confirm this benefit.137 A report by Malis in 1979, however, renewed enthusiasm for the practice (now with antibiotic solutions rather than powder).138 Subsequent case series have supported the concept, although a randomized comparison of systemic plus topical antibiotic prophylaxis against systemic antibiotics alone has not been done.135,139,140

The principles of topical antibiotic prophylaxis are similar to those for systemic antibiotic prophylaxis:

• Bactericidal concentrations of antibiotic in solution should be used.
• The antibiotic should be active against the most likely infecting organisms in the institution in which it is used.
• Vancomycin should be avoided unless no other active antibiotic is available.
• Toxicity should be minimized.

The issue of toxicity requires special consideration for topical administration. The tendency of penicillin to produce seizures when applied to the cerebral cortex is well known, therefore topical penicillins should be avoided.141 Limited study of the effect of topical application on the cerebral cortex suggests that bacitracin and metronidazole have the lowest likelihood of producing epileptiform activity.142 pH is likely to be an important parameter, and topical solutions applied directly to the nervous system should be adjusted to physiologic pH when possible.

Cerebrospinal Fluid Shunts

Topical antibiotic prophylaxis is commonly used during CSF shunt procedures in two ways: wound irrigation plus filling the shunt with antibiotic solution and the use of antibiotic-impregnated shunt catheters. The topical use of solutions has the same quality of evidence as it does for other neurosurgical procedures (see earlier). A recent Cochrane Systematic Review of the prevention of CSF shunt infection examined the evidence regarding antibiotic-impregnated shunt catheters and concluded that the evidence did support their effectiveness in reducing shunt infection rates.123

Antibiotic Treatment

This section details the treatment of common neurosurgical infections. A review of the literature reveals that there is a lack of properly designed randomized controlled studies evaluating the different treatment regimens. Therefore, the majority of the evidence regarding the effectiveness of the different antibiotic therapies is classified as only level III evidence. The recommendations come from the experiences of individuals and groups who have found success in the way that they manage a certain infection.

Soft Tissue Infections

Initial treatment in most cases should be directed against staphylococci and streptococci. Oral antibiotic therapy with a semisynthetic penicillin, a first-generation cephalosporin, clindamycin, or erythromycin should be considered.143 If methicillin-resistant Staphylococcus aureus is suspected, vancomycin should be used until cultures prove otherwise. The duration of antimicrobial therapy is dictated by how the infection responds but should typically continue for 7 to 10 days.

Necrotizing Soft Tissue Infections

Because of the polymicrobial nature of necrotizing soft tissue infections, empirical treatment with broad-spectrum antibiotics is often initiated. A number of different regimens may be used to achieve broad-spectrum coverage, the most common of which include the following144:

1 Penicillin or ampicillin plus anaerobic coverage (clindamycin or metronidazole)
2 Vancomycin plus anaerobic and gram-negative coverage (an aminoglycoside, aztreonam, or third-generation cephalosporin)
3 Ampicillin/sulbactam with additional gram-negative coverage
4 Imipenem with additional coverage

The most common antibiotic prescribing error is inadequate coverage of Enterococcus, which optimally requires ampicillin or vancomycin plus an aminoglycoside.144

Meningitis

Antibiotic therapy for neurosurgical patients with postoperative bacterial meningitis is initially empirical. Practice guidelines for the initial empirical antimicrobial treatment of bacterial meningitis have been published by the Infectious Disease Society of America along with recommended dosages (Table 42-4). First-line empirical therapy includes a third-generation cephalosporin such as cefotaxime or ceftriaxone and vancomycin.145 In suspected cases of Pseudomonas aeruginosa, ceftazidime should be used. Unfortunately, there have been reports of the emergence of resistant gram-negative bacilli (i.e., resistant Enterobacter146–149 and Acinetobacter150–152 species) with plasmid-encoded or inducible chromosomal β-lactamases that hydrolyze extended-spectrum cephalosporins.153 In these cases, amikacin can be added, although this does not always prevent the development of resistance, as Chow and associates reported in their study.154 Therefore, for β-lactamase–producing Enterobacteriaceae or Acinetobacter species, an extended-spectrum carbapenem such as meropenem may be used because these organisms tend to be resistant to multiple antibiotics. Moreover, Parodi and coauthors reported good clinical and microbiologic responses with carbapenems for Enterobacter meningitis.155 Judicious use of this antibiotic needs to be ensured because carbapenem-resistant Enterobacter strains have been reported.156 For resistant Acinetobacter meningitis, Nguyen and colleagues demonstrated that intravenous imipenem and amikacin with or without intrathecal amikacin could be used successfully with the caveat that all patients have their ventriculostomy catheters removed as part of the treatment.151 Although their study consisted of a small number of cases, Rodriguez Guardado and coworkers demonstrated that intravenous and intrathecal colistin is an option and is as safe and effective as carbapenems for the treatment of nosocomial meningitis caused by Acinetobacter.157 Furthermore, a review by Falagas and associates documented that therapy with intraventricular and intrathecal polymyxins alone or in combination with systemic antimicrobial agents is effective against gram-negative meningitis.52

TABLE 42-4 Recommendations for Empirical Antimicrobial Therapy for Purulent Meningitis Based on Patient Age and Specific Predisposing Condition (A-III)

PREDISPOSING FACTOR COMMON BACTERIAL PATHOGENS ANTIMICROBIAL THERAPY
Age    
<1 mo Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella species Ampicillin plus cefotaxime or ampicillin plus an aminoglycoside
1-23 mo Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli Vancomycin plus a third-generation cephalosporin*†
2-50 yr N. meningitidis, S. pneumoniae Vancomycin plus a third-generation cephalosporin*†
>50 yr S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli Vancomycin plus ampicillin and a third-generation cephalosporin*†
Head trauma    
Basilar skull fracture S. pneumoniae, H. influenzae, group A β-hemolytic streptococci Vancomycin plus a third-generation cephalosporin*
Penetrating trauma Staphylococcus aureus, coagulase-negative staphylococci (especially Staphylococcus epidermidis), aerobic gram-negative bacilli (including Pseudomonas aeruginosa) Vancomycin plus cefepime, vancomycin plus ceftazidime, or vancomycin plus meropenem
Neurosurgery Aerobic gram-negative bacilli (including P. aeruginosa), S. aureus, coagulase-negative staphylococci (especially S. epidermidis) Vancomycin plus cefepime, vancomycin plus ceftazidime, or vancomycin plus meropenem
Cerebrospinal fluid shunt Coagulase-negative staphylococci (especially S. epidermidis), S. aureus, aerobic gram-negative bacilli (including P. aeruginosa), Propionibacterium acnes Vancomycin plus cefepime,‡ vancomycin plus ceftazidime,‡ or vancomycin plus meropenem‡

* Ceftriaxone or cefotaxime.

† Some experts would add rifampin if dexamethasone is also given.

‡ In infants and children, vancomycin alone is reasonable unless Gram stains reveal the presence of gram-negative bacilli.

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

As mentioned previously, gram-negative bacilli have the potential to become resistant to β-lactam antibiotics, therefore CSF needs to be sampled at regular intervals to ensure that it is being sterilized. When the response to systemic antibiotic treatment is poor during the treatment of gram-negative meningitis, the use of intraventricular antibiotics in combination with intravenous antibiotics should be considered early. The most commonly used intraventricular agents include gentamicin, amikacin, and polymyxin E (colistin) (Table 42-5).104,153

TABLE 42-5 Recommended Dosages of Antimicrobial Agents Administered by the Intraventricular Route (A-III)

ANTIMICROBIAL AGENT DAILY INTRAVENTRICULAR DOSE (mg)
Vancomycin 5-20*
Gentamicin 1-8†
Tobramycin 5-20
Amikacin 5-50‡
Polymyxin B 5§
Colistin 10
Quinupristin/dalfopristin 2-5
Teicoplanin 5-40image

NOTE: There are no specific data that define the exact dose of an antimicrobial agent that should be administered by the intraventricular route. Virtually all intrathecal use of antibiotics is considered “off label.”

* Most studies have used a 10- or 20-mg dose.

† The usual daily dose is 1 to 2 mg for infants and children and 4 to 8 mg for adults.

‡ The usual daily intraventricular dose is 30 mg.

§ The dosage in children is 2 mg daily.

image Dosage of 5 to 10 mg every 48 to 72 hours.

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

As results from cultures are confirmed for susceptibility, the antibiotic treatment should be adjusted accordingly. Practice guidelines for pathogen-specific antimicrobial treatment of bacterial meningitis have been published by the Infectious Disease Society of America along with recommended dosages (Tables 42-6 and 42-7). The length of treatment when treating gram-negative bacilli is most often 2 weeks after culture results have been negative.158,159 Other authors have recommended a treatment duration between 2 and 4 weeks.153,160,161 When treating S. aureus, 2 weeks of treatment is reasonable. However, the duration of therapy should always be individualized based on the patient’s clinical response to treatment.

TABLE 42-6 Recommendations for Specific Antimicrobial Therapy for Bacterial Meningitis Based on Isolated Pathogen and Susceptibility Testing

MICROORGANISM, SUSCEPTIBILITY STANDARD THERAPY ALTERNATIVE THERAPIES
Streptococcus pneumoniae
Penicillin MIC    
<0.1 µg/mL Penicillin G or ampicillin Third-generation cephalosporin,* chloramphenicol
0.1-1.0 µg/mL† Third-generation cephalosporin* Cefepime (B-II), meropenem (B-II)
≥2.0 µg/mL Vancomycin plus a third-generation cephalosporin*‡ Fluoroquinolone§ (B-II)
Cefotaxime or ceftriaxone MIC ≥1.0 µg/mL Vancomycin plus a third-generation cephalosporin*‡ Fluoroquinolone§ (B-II)
Neisseria meningitidis
Penicillin MIC    
<0.1 µg/mL Penicillin G or ampicillin Third-generation cephalosporin,* chloramphenicol
0.1-1.0 µg/mL Third-generation cephalosporin* Chloramphenicol, fluoroquinolone, meropenem
Listeria monocytogenes Ampicillin or penicillin Gimage Trimethoprim-sulfamethoxazole, meropenem (B-III)
Streptococcus agalactiae Ampicillin or penicillin Gimage Third-generation cephalosporin* (B-III)
Escherichia coli and other Enterobacteriaceae Third-generation cephalosporin (A-II) Aztreonam, fluoroquinolone, meropenem, trimethoprim-sulfamethoxazole, ampicillin
Pseudomonas aeruginosa Cefepimeimage or ceftazidimeimage (A-II) Aztreonam,image ciprofloxacin,image meropenemimage
Haemophilus influenzae
β-Lactamase negative Ampicillin Third-generation cephalosporin,* cefepime, chloramphenicol, fluoroquinolone
β-Lactamase positive Third-generation cephalosporin (A-I) Cefepime (A-I), chloramphenicol, fluoroquinolone
Staphylococcus aureus
Methicillin susceptible Nafcillin or oxacillin Vancomycin, meropenem (B-III)
Methicillin resistant Vancomycin** Trimethoprim-sulfamethoxazole, linezolid (B-III)
Staphylococcus epidermidis Vancomycin** Linezolid (B-III)
Enterococcus species
Ampicillin susceptible Ampicillin plus gentamicin —
Ampicillin resistant Vancomycin plus gentamicin —
Ampicillin and vancomycin resistant Linezolid (B-III) —

NOTE: All recommendations are A-III unless otherwise indicated.

MIC, minimal inhibitory concentration.

* Ceftriaxone or cefotaxime.

† Ceftriaxone/cefotaxime-susceptible isolates.

‡ Consider addition of rifampin if the MIC of ceftriaxone is greater than 2 µg/mL.

§ Gatifloxacin or moxifloxacin.

image Addition of an aminoglycoside should be considered.

Choice of a specific antimicrobial agent must be guided by in vitro susceptibility test results.

** Consider addition of rifampin.

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

TABLE 42-7 Recommended Dosages of Antimicrobial Therapy in Patients with Bacterial Meningitis (A-III)

image

Empyema

Antibiotic treatment is initially broad spectrum and is directed against streptococci, staphylococci, and anaerobes. Empirical therapy includes a third-generation cephalosporin, vancomycin, or penicillin and metronidazole, with the latter providing anaerobic coverage. The suggested duration of treatment includes 2 weeks of intravenous therapy with an additional 6 weeks of oral therapy.162,163 Nathoo and colleagues use a regimen consisting of a penicillin, chloramphenicol, and metronidazole administered intravenously for 2 weeks followed by a 4-week oral course.164 The antibiotic regimen will require appropriate modification to either narrow or broaden the coverage based on bacterial culture and susceptibility results.

Brain Abscess

Initial coverage should begin with vancomycin, a third-generation cephalosporin, and metronidazole for anaerobic coverage.165 As cultures and sensitivities are reported, the antibiotic regimen should be tailored accordingly. Proteus, Escherichia coli, and Serratia species, which are common causes of cerebral abscesses in neonates, should be covered with a combination of cefotaxime and gentamicin or amikacin. If the infection is refractory to the aforementioned management, craniotomy with eradication of the primary foci should be undertaken.

The duration of therapy is still a point of debate. In most cases, parenteral treatment for 6 to 8 weeks is recommended.166,167 Some authors advocate an additional course of oral antibiotics for 2 to 3 months to eliminate any residual foci.167

Ventriculitis

The initial antibiotic regimen should include broad-spectrum coverage for possible resistant gram-positive and gram-negative organisms. Appropriate antibiotic therapy may include vancomycin plus a cephalosporin with antipseudomonal coverage such as cefepime or ceftazidime. Alternatively, vancomycin can be combined with meropenem to achieve similar coverage. Intraventricular vancomycin has also been reported to be successful in the treatment of ventriculitis caused by Staphylococcus and Enterococcus species.168,169

Intravenous polymyxin E (colistin) may be an option for gram-negative organisms, such as Acinetobacter and Pseudomonas, that are resistant to first-line antibacterial treatments.170 There have also been case reports documenting the success of intrathecal colistin in the treatment of resistant Acinetobacter ventriculitis.171–173

Shunt Infections

Initial antibiotic selection should be broad spectrum and include coverage for methicillin-resistant S. aureus and Staphylococcus epidermidis, along with coverage for resistant gram-negative organisms such as Pseudomonas species, which have a propensity to adhere to foreign material.174 Recommended empirical antibiotic therapy should consist of vancomycin to cover gram-positive organisms along with a cephalosporin that has antipseudomonal activity, such as cefepime or ceftazidime.175–177 Rifampin can also be added for gram-positive shunt infections that fail to clear with vancomycin monotherapy.174 Intrathecal administration of vancomycin or aminoglycosides may need to be initiated for shunt infections that are difficult to eradicate and fail to clear with systemic therapy.174 For the treatment of Propionibacterium acnes, small studies have documented success with intravenous penicillin combined with shunt externalization and replacement.178

An alternative treatment of gram-positive shunt infections is intravenous linezolid, which has been demonstrated to be successful in case reports.179,180 Linezolid possesses many attractive features that may increase its use, such as excellent CSF penetration and broad-spectrum activity. Additionally, Cruciani and coworkers demonstrated that intraventricular administration of teicoplanin was effective in seven patients with staphylococcal neurosurgical shunt infections.181

The introduction of antibiotic-impregnated shunt catheters may prove beneficial. A randomized controlled study performed by Eymann and associates demonstrated that antibiotic-impregnated shunt catheters reduce the infection rate significantly in both pediatric and adult populations.182

Infection with Spinal Instrumentation

Empirical antibiotic therapy should be directed against staphylococcal species along with gram-negative organisms. Initial treatment with vancomycin and a third-generation cephalosporin until culture and susceptibility results return is appropriate. In most cases, removal of hardware is not necessary and can potentially have devastating complications because of spine instability and lack of bony fusion. Retrospective reviews of clinical practice have suggested that titanium instrumentation does not interfere with the treatment of spinal infection to the extent that stainless steel or other foreign bodies do.183 Therefore, instrumentation should be left in place.184

The duration of antibiotic therapy for postoperative infection after spinal instrumentation is still debated. Lonstein proposes intravenous antibiotics for 10 to 14 days followed by oral antibiotics for 3 to 6 months.185 Perry and coauthors recommend antibiotic treatment until the fever and leukocytosis resolve or for a minimum of 10 days.186

Vertebral Osteomyelitis

Specific antibiotic treatment should be based on culture and susceptibility results. For methicillin-resistant S. aureus, combination therapy with rifampin and intravenous vancomycin is the preferred regimen,187,188 whereas linezolid can serve as an alternative. Previous studies have recommended that antibiotics be administered for a minimum of 6 to 8 weeks.189–191 Gasbarrini and colleagues recommend that a minimum of 6 weeks of intravenous antibiotics be administered followed by 6 weeks of oral antibiotics.192 For tuberculous vertebral osteomyelitis, the current standard of practice is to initiate isoniazid and rifampin for a 6- to 9-month period.193 Nussbaum and coworkers have recommended that the course of treatment be at least 12 months in duration and consist of at least two antituberculous drugs.194

Osteomyelitis of the Skull

Initial antibiotic therapy should be directed against staphylococci with vancomycin plus a third-generation cephalosporin to cover gram-negative bacilli. If there is concern about anaerobes, metronidazole should be initiated. Once culture and susceptibility results return, the antibiotic therapy can be modified. Intravenous antibiotic treatment should be continued for at least 4 weeks and possibly followed by an additional oral course of antibiotics.195

Diskitis

For antibiotic treatment of diskitis, Cushing recommends empirical treatment directed against methicillin-resistant S. aureus for 5 to 7 days, followed by oral therapy for 1 to 2 weeks.196 An appropriate empirical regimen may include a combination of vancomycin and a third-generation cephalosporin. Jansen and associates recommend intravenous antibiotics for 4 to 6 weeks followed by oral antibiotics until the symptoms resolve.197

Conclusion

Antibiotics are essential to modern neurosurgical practice. Like all drugs, they have important risks and their misuse can lead to serious problems for individual patients. Irresponsible use by the profession can even lead to public health concerns. Judicious use and adherence to the basic principles of appropriate use optimize their value in the treatment of neurosurgical patients. Basic principles include the following:

1 Antibiotics should be used only for the prevention or treatment of susceptible infections.
2 The choice of antibiotic should be guided by the most likely infecting organisms and directed by culture results whenever possible.
3 Antibiotics should be used for their shortest effective duration.
4 The risks associated with antibiotic administration must be considered every time that they are used.
5 The dose and frequency of administration should be guided by principles of pharmacokinetics and, in serious infections, by measured antibiotic levels.

Failure to follow established basic principles can lead to antibiotic misuse ranging from embarrassing (using an antibiotic in a way that it cannot work) to harmful (superinfection with an organism resistant to all known drugs). The following is a list of a few such misuses of antibiotics in neurosurgery.

Intraventricular administration of chloramphenicol

• It penetrates the BBB very well.
• It requires hydrolysis in the liver to be active.

Routine use of vancomycin for prophylaxis

• Most infections are not caused by methicillin-resistant S. aureus.
• Vancomycin penetration into the CSF is variable and frequently poor in the absence of inflammation.
• Indiscriminant prophylactic use contributes to the emergence of vancomycin resistance, which threatens to become a major public health problem because alternative antibiotics for vancomycin-resistant organisms are not widely available.

Assuming that good CSF penetration in the presence of meningeal inflammation is equivalent to good penetration of the CNS in the absence of inflammation
It can’t hurt

• See the list of toxicities and interactions.

More is better

• Excessive use leads to selecting resistant organisms, which makes treatment more difficult.
• Superinfections hurt patients (e.g., Clostridium difficile).

Adherence to basic principles and appropriate consultation with specialists in infectious disease can optimize the use of antibiotics in neurosurgical practice.

Suggested Readings

Barker FG. Efficacy of prophylactic antibiotics against meningitis after craniotomy: a meta-analysis. Neurosurgery. 2007;60:887.

Barker FG. Efficacy of prophylactic antibiotic therapy in spinal surgery: a meta-analysis. Neurosurgery. 2002;51:391.

Barker FG. Efficacy of prophylactic antibiotics for craniotomy: a meta-analysis. Neurosurgery. 1994;35:484.

Chow KM, Hui AC, Szeto CC. Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside. Eur J Clin Microbiol Infect Dis. 2005;24:649.

Eymann R, Chehab S, Strowitzki M, et al. Clinical and economic consequences of antibiotic-impregnated cerebrospinal fluid shunt catheters. J Neurosurg Pediatr. 2008;1:444.

Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis: a systematic review of the available evidence. Int J Antimicrob Agents. 2007;29:9.

Haines SJ, Walters BC. Antibiotic prophylaxis for cerebrospinal fluid shunts: a metaanalysis. Neurosurgery. 1994;34:87.

Kearney BP, Aweeka FT. The penetration of anti-infectives into the central nervous system. Neurol Clin. 1999;17:883.

Lee MC, Wang MY, Fessler RG, et al. Instrumentation in patients with spinal infection. Neurosurg Focus. 2004;17:E7(6).

Mangram AJ, Horan TC, Pearson ML, et al. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27:97.

Nagarajan L, Lam GC. Tetracycline-induced benign intracranial hypertension. J Paediatr Child Health. 2000;36:82.

Nau R, Prange HW, Muth P, et al. Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges. Antimicrob Agents Chemother. 1993;37:1518.

Nau R, Sorgel F, Prange HW. Pharmacokinetic optimisation of the treatment of bacterial central nervous system infections. Clin Pharmacokinet. 1998;35:223.

Neuwelt EA. Mechanisms of disease: the blood-brain barrier. Neurosurgery. 2004;54:131.

Ratilal B, Costa J, Sampaio C. Antibiotic prophylaxis for surgical introduction of intracranial ventricular shunts: a systematic review. J Neurosurg Pediatr. 2008;1:48.

Ratilal B, Costa J, Sampaio C. Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures. Cochrane Database Syst Rev. 2006;1:CD004884.

Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Ann Intern Med. 1984;101:92.

Thomas RJ. Neurotoxicity of antibacterial therapy. South Med J. 1994;87:869.

Wagner C, Sauermann R, Joukhadar C. Principles of antibiotic penetration into abscess fluid. Pharmacology. 2006;78:1.

Wen DY, Bottini AG, Hall WA, et al. Infections in neurologic surgery. The intraventricular use of antibiotics. Neurosurg Clin N Am. 1992;3:343.

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