Postoperative Infections of the Head and Brain

Epidemiology and Etiology

Postoperative infections are typically categorized according to anatomic site ( Table 53.1 ). The Centers for Disease Control and Prevention defines superficial incisional infections as those limited to the skin and subcutaneous tissue, whereas deep incisional infections may involve the subgaleal space and bone flap. Deep organ space infections include subdural empyema, brain abscess, and meningitis/ventriculitis. The incidence of infection after craniotomy is difficult to estimate from the neurosurgical literature because of differences in definitions and methodology; however, several large prospective studies have reported postcraniotomy infection rates ranging from 1% to 10%, with the higher rates occurring in the absence of antibiotic prophylaxis. In a study restricted to elective procedures, McClelland and Hall reviewed the postoperative courses of 1587 patients who underwent cranial operations over a 15-year period performed by a single surgeon and found an impressively low rate (0.8%) of postoperative infection. In their 10-year retrospective study that included a cohort of 16,540 patients who underwent craniotomy at the Barrow Neurological Institute, Dashti and coworkers reported an overall incidence of 0.5% of postoperative infections that required return to the operating room for débridement and/or evacuation.

Infections after craniotomy are most commonly associated with gram-positive bacteria such as S. aureus and coagulase-negative staphylococci. Isolation of Cutibacterium (formerly Propionibacterium ) acnes, an anaerobic gram-positive bacillus, from neurosurgical specimens had been dismissed as a contaminant because it is commensal scalp flora; however, the role of C. acnes as a causative agent of postcraniotomy infections is now well established. Earlier reports likely underestimated its pathologic role owing to its often indolent clinical manifestations and the difficulties associated with microbiologic isolation of the organism, specifically the need to hold the anaerobic culture for 10 days. Other bacteria commonly isolated from postcraniotomy infections include enterococci, Streptococcus spp., Pseudomonas aeruginosa, Acinetobacter spp., Citrobacter spp., Enterobacter spp., Klebsiella pneumoniae, Escherichia coli, and miscellaneous other gram-negative bacilli. ^,

Gram-negative bacteria have been isolated in 5% to 8% of postcraniotomy infections as well as within polymicrobial infections. Although direct spread from contiguous areas of infection is common, the causative agents tend to vary according to the site of infection and the antimicrobial spectrum of administered perioperative antibiotics. Yang and colleagues retrospectively identified 31 patients with brain abscesses after neurosurgical procedures and found the most prevalent pathogens to be a single gram-negative bacillus or a polymicrobial infection, followed by infection with streptococcal and staphylococcal spp. Gram-negative bacilli are also the most common causes of postoperative meningitis, accounting for 29% to 38% of nosocomial episodes of this infection. ^,

Risk Factors for Infection and Preventative Strategies

The majority of postsurgical infections are due to contamination of the wound with bacteria from the patient’s skin. Although the magnitude of contamination and the virulence of the contaminating organism certainly contribute to the rate of infection, all surgical wounds become inoculated with bacteria to some extent at the time of surgery, but in only a small percentage of patients does this contamination lead to clinical infection. ^, Although it is unlikely that all postoperative infections can be completely prevented, many of the factors influencing the development of infection may be modifiable, particularly those attributable to the patient and others related to the surgical intervention itself.

Host defense mechanisms, which represent the primary barrier to establishment of infection, may be impaired in patients undergoing craniotomy. The brain is a relatively immune-privileged site, and low levels of antibody and complement contribute to make the brain less efficient than other organs of the body at eradicating infection. Furthermore, many of the underlying pathologies leading to neurosurgical intervention may significantly impair immune function. For example, patients with malignant gliomas express a variety of immune defects, including increased secretion of immunosuppressive cytokines. In addition, many of the adjunctive therapies necessary for treating brain tumors, such as corticosteroid administration, chemotherapy, and irradiation, may result in immune compromise and impaired wound healing. Other frequent indications for craniotomy, such as trauma, have also been shown to be profoundly immunosuppressive. General surgical and infection control studies have identified other host factors that influence the risk for SSI, including advanced age, obesity, hypoalbuminemia, diabetes mellitus, and poor functional status. ^, Gianotti and associates demonstrated the importance of nutritional status in oncologic surgery by showing that malnourished patients had improved resistance to infection after as little as 5 days of enteral nutrition.

Several factors specific to craniotomy have been identified that increase the risk of postoperative infection. In a prospective multicenter trial, Korinek identified postoperative CSF leakage and early subsequent reoperation as independent risk factors for SSI, suggesting that careful attention to closure techniques and meticulous hemostasis may potentially result in lower rates of postoperative infection. In a recent meta-analysis reported by Fang and coworkers, comprising 26 total published studies, the following risk factors that predispose to increased risk of postcraniotomy infection were identified: concurrent infection in another organ system, duration of surgery greater than 4 hours, CSF leak, and venous sinus injury. Multiple studies have established CSF leakage as a major risk factor for infection, likely related to continued CSF egress serving as a conduit for bacterial inoculation of the surgical site. ^{, ,} Valentini and colleagues observed a relative risk of 12.6 for postoperative infection in elective clean craniotomies lasting 2 hours and a relative risk of 24.3 for procedures lasting longer than 3 hours. The association between longer duration of surgery and infection has not been defined precisely, but plausible explanations include greater complexity of the surgery and prolonged exposure of the wound to bacterial contamination.

The association of a variety of other risk factors with infection after craniotomy has been less reliably demonstrated; placement of drains or intracranial pressure monitors, poor neurological status, paranasal sinus entry, diabetes mellitus, and foreign body implantation (other than shunts) have been identified as risk factors in some retrospective studies. ^{, ,} Synthetic dural substitutes are foreign bodies and might represent a potentially greater risk factor for infection than an autologous graft material such as pericranium, temporalis fascia, or fascia lata. Evidence demonstrating increased rates of infection with the use of synthetic dural substitutes, however, is limited. Malliti and colleagues reported a statistically nonsignificant higher incidence of deep wound infections after craniotomy with the use of a non-resorbable polyester urethane synthetic dural graft (Neuro-Patch; B. Braun Surgical). Postoperative CSF leaks were also significantly more frequent when the synthetic dural substitute was used, thus limiting the ability of this study to determine whether use of the dural substitute independently increased the risk for infection. The presence of a nonresorbable dural substitute may also impair successful treatment of an infected wound because a graft may become colonized and its removal may be required to eradicate the infection. A variety of nonautologous, resorbable collagen dural substitutes are currently available, and their relationship with surgical infection has not been well explored. McCall and coworkers reported the uncomplicated use of several of these materials in a small number of patients in the setting of contaminated wounds, a finding suggesting that they may not impede clearance of bacteria.

Multiple prospective randomized clinical studies and a meta-analyses have validated the effectiveness of perioperative antibiotics in reducing the incidence of SSIs after craniotomy. Cairns described the first trial of a modern prophylactic antibiotic in neurosurgery in 1947 when he reported sprinkling a “light frosting” of penicillin powder directly onto the brain in 670 patients and deemed the results superior to those of historical controls. ^, In 1979, Malis demonstrated the ability of a prophylactic antibiotic regimen (vancomycin and an aminoglycoside) to reduce the incidence of SSI after craniotomy. Since these initial reports, a variety of antibiotic regimens have been used for effective surgical prophylaxis. Guidelines for a standardized approach to antimicrobial prophylaxis in surgery have been developed and updated in an effort to prevent SSIs (and their associated morbidity, mortality, and additional health care costs and length of hospitalization) without adverse consequences to both the patient and the microbial milieu of the patient or the hospital. The Surgical Care Improvement Project outlines the following three performance measures for monitoring appropriate antimicrobial prophylaxis use: selection of an appropriate antibiotic, its administration within 1 hour before incision (2 hours to allow for the administration of vancomycin and fluoroquinolones), and discontinuation of the antibiotic within 24 hours after surgery is completed. The choice of an agent with an appropriately narrow spectrum of coverage against relevant pathogens should be guided by individual institutional data on frequently recovered pathogens and their resistance profiles. For clean neurosurgical procedures, a single dose of cefazolin is recommended. Vancomycin may be used as an alternative agent in the setting of MRSA colonization or for a patient with a documented β-lactam allergy. Antibiotics with short half-lives, such as cefazolin, should be readministered every 3 to 4 hours during prolonged surgery to ensure adequate drug levels throughout the period of potential contamination, including the time of wound closure. Use of antibiotics beyond 24 hours postoperatively has not shown a greater benefit and may increase the risk for other nosocomial infections as well as promote the emergence of multidrug-resistant pathogens. ^,

Prophylactic administration of topical antibiotics at the surgical site is a strategy that has been shown to be potentially beneficial in reducing the rate of SSI after spine surgery, but there are limited data investigating its use during craniotomy. Abdullah and colleagues performed a retrospective case-control study of patients undergoing craniotomy who received 1 gram of topical vancomycin powder in the subgaleal space at the time of closure and found that this was associated with a reduced incidence of SSIs compared to a standard intravenous antibiotic prophylaxis regimen. In a subsequent single-institution, nonblinded prospective cohort study, Mallela and coworkers evaluated the use of subgaleal topical vancomycin in 355 patients who underwent craniotomy. They reported that the application of topical vancomycin in addition to standard intravenous antibiotic prophylaxis significantly reduced the incidence of SSI from 6% to 0.49%. While the observed rate of infection for patients receiving standard intravenous prophylaxis is much higher than that in many larger studies for craniotomy, the results demonstrate that topical vancomycin for craniotomy patients should be further evaluated in well-designed prospective studies. Concerns regarding the widespread use of topical vancomycin for cases with low risk of SSI include potential selection pressure for gram-negative and/or polymicrobial species, which may be associated with increased morbidity.

With the rise of resistant pathogens, in particular MRSA, attention is being focused on the perioperative management of neurosurgical patients with MRSA colonization. A review of 1000 neurosurgical admissions identified the following risk factors for MRSA infection: male sex, malignancy, diabetes, prior MRSA infection, immunosuppressed state, and traumatic injury. Although the institution of MRSA-specific antibiotic prophylaxis appears to benefit neurosurgical patients identified with MRSA colonization or prior MRSA infection, its widespread use may lead to further development of resistance. Given the increase in prevalence of MRSA colonization, patients presenting for elective surgical procedures should be screened via nasal swab; those who are positive should have mupirocin ointment applied to their nares for 3 to 5 days before their surgical procedure. ^, Patients with known MRSA colonization should have their perioperative antibiotic regimen tailored to ensure proper coverage.

Measures to decrease bacterial contamination in the operating room environment may help to reduce SSIs, although it is difficult to ascertain the independent effects of these measures from the literature. Both the number of health care workers within the operating room and traffic throughout the procedure should be kept to a minimum because bacterial shedding increases with activity and can potentially result in increased airborne contamination. Ensuring adequate ventilation minimizes the particulates and bacteria in the perioperative environment, and the use of high-efficiency particulate air (HEPA) filters has been shown to reduce the rate of SSI development after orthopedic implant surgery. Effective cleaning and disinfection of the operating room environment is also imperative to decrease pathogen transmission. Using ultraviolet markers and environmental cultures, Munoz-Price and associates evaluated operating room contamination and cleaning practices at an academic medical center and demonstrated bacterial contamination, including by multidrug-resistant organisms, on more than half of tested surfaces. After implementation of ongoing performance feedback measures and increased attention to cleaning of high-touch areas and anesthesia equipment, the percentage of cleaned surfaces increased to 82%.

Principles of Treatment

Immune defenses within the brain are rarely adequate to control infection once it has been established. Postoperative infections tend to be particularly difficult to resolve because of the complex anatomic changes resulting from craniotomy and the frequent involvement of virulent organisms. Early and decisive intervention is critical to limit morbidity, and the keystone of successful treatment is effective source control (i.e., drainage of abscesses and infected fluid collections and débridement of necrotic tissue). Once source control has been achieved, initiation of appropriate antibiotic therapy is necessary to eliminate any residual local infection.

The antibiotic regimen and duration of treatment should be selected in consultation with infectious disease specialists and based on the capacity of the antibiotic to penetrate the infected tissue effectively and exhibit activity against the suspected pathogen. Bactericidal rather than bacteriostatic agents are generally preferred because of the inefficient opsonization and phagocytic capabilities within the brain. Most antibiotic agents enter the central nervous system (CNS) predominantly by passive diffusion down a concentration gradient, with physical barriers such as the blood-brain and blood-CSF barriers functioning as the primary determinants of drug distribution. Inflammation at the site of infection may facilitate entry of drugs across these barriers and into the brain, but not all postoperative infections are accompanied by marked inflammation, and concomitant treatment with corticosteroids may further impair drug entry. Other inherent physiochemical properties of the antimicrobial agent, including molecular weight, lipophilicity, plasma protein binding, and ionization state, may affect its penetration into the CNS. Ultimately, adequate dosing to achieve maximal bactericidal activity depends on the in vitro susceptibility of the causative organism (its minimal bactericidal concentration). Often, in the absence of data from prospective randomized clinical trials evaluating the success rates of specific antibacterial agents, recommendations for the treatment of postcraniotomy infections are based largely on the results of previous experience, along with consideration of the complex physiologic, bacteriologic, and pharmacologic factors involved.

As postoperative infections may have severe neurological sequelae or cause death, empirical treatment of postoperative infections should include coverage for the full spectrum of potential pathogens, including resistant gram-positive organisms (e.g., MRSA) and nosocomial gram-negative bacilli (e.g., Pseudomonas and Acinetobacter spp.). Infections that may have an anaerobic component (brain abscess, paranasal sinus approach) should also be treated empirically with metronidazole. Suitable empirical regimens for postcraniotomy infections typically include a combination of vancomycin and a drug such as a third- or fourth-generation cephalosporin that has antipseudomonal activity (e.g., ceftazidime, cefepime), with the addition of metronidazole when anaerobic infection is possible. Owing to activity against gram-negative and anaerobic bacteria, a carbapenem (e.g., meropenem) may be substituted for the combination of a third- or fourth-generation cephalosporin and metronidazole. Antibiotic selection should be tailored once species identification and results of susceptibility testing of a microbiologic specimen are available.

β-Lactam antibiotics (penicillins, cephalosporins, carbapenems) have poor penetration into the CSF in the absence of meningeal inflammation, but higher systemic doses can result in therapeutic CSF concentrations. Third- and fourth-generation cephalosporins (specifically cefotaxime, ceftriaxone, and ceftazidime) are often used for the treatment of CNS and postcraniotomy infections because of their low toxicity and excellent in vitro activity against many of the responsible bacterial pathogens. Administration of these agents in high doses achieves therapeutic concentrations within brain abscess cavities. The carbapenems, such as imipenem and meropenem, also cover a broad antimicrobial spectrum and have been used successfully for the treatment of bacterial brain abscesses. ^{, ,} Imipenem, however, is associated with an increased seizure risk relative to meropenem (and other β-lactams), so its use should be carefully considered for the treatment of CNS infections. ^{, ,} As a class, β-lactam antibiotics are proconvulsive and, for this reason, their use via intraventricular injection is not recommended.

Vancomycin has weaker activity against staphylococcal infections relative to β-lactams and decreased penetration into the CNS owing to its high molecular weight (1449 Da). Even in the presence of significant inflammation, concentrations of vancomycin may be critically low at the site of infection, and substitution of a β-lactamase–resistant penicillin (e.g., nafcillin, oxacillin) for vancomycin is appropriate, except in the setting of resistance or hypersensitivity.

Newer agents that may prove useful for the treatment of resistant staphylococcal infections include linezolid and daptomycin. Linezolid has bacteriostatic activity against both MRSA and vancomycin-resistant enterococci and bactericidal activity against most streptococci. Linezolid, which has excellent bioavailability, may be administered intravenously or orally. Experience with this agent for the treatment of postcraniotomy infections is limited, but it may play a role in the treatment of resistant gram-positive infections and in the setting of treatment failure. Potential side effects include myelosuppression and irreversible peripheral neuropathy. Daptomycin, a novel cyclic lipopeptide antibiotic, has shown better in vitro microbicidal activity against MRSA than either vancomycin or linezolid and has been primarily used and approved by the US Food and Drug Administration for the treatment of skin and soft tissue infections. Animal models of meningitis suggest that daptomycin may be an effective therapeutic agent in a setting of meningeal inflammation, but human studies of its efficacy in neurosurgical infections are lacking. ^,

Rifampin is a broad-spectrum antimicrobial that may have a role in the adjunctive treatment of bone flap osteomyelitis or infections associated with foreign body implantation. These types of infections are notoriously difficult to eradicate because of their resistance to host defense mechanisms and the poor penetration of antimicrobials. Most foreign body infections are caused by staphylococci growing in biofilms consisting of bacteria clustered together in an extracellular matrix attached to the foreign body. Depletion of metabolic substances within the biofilm causes the microbes to enter a slowly growing (sessile) state. Dormant microbes within the biofilm are up to 1000 times more tolerant of most antimicrobial agents than their free-living (planktonic) counterparts. Rifampin is one of just a few agents that can effectively penetrate biofilms and kill organisms in the sessile phase of growth. Because of the rapid emergence of resistance to it, rifampin must always be used in combination with a second active agent. In vitro data, experimental animal models, and several randomized clinical trials suggest that dual therapy that includes rifampin may be better than monotherapy for orthopedic hardware–related staphylococcal infections in terms of bone sterilization and cure rates. ^, This experience makes adjunctive therapy with rifampin an attractive consideration for difficult postcraniotomy staphylococcal infections associated with retained hardware or osteitis. Caution must be used with rifampin therapy because of its very large number of drug interactions. Through cytochrome P-450 enzyme induction, rifampin increases the metabolism of many substrates, including antiseizure drugs, anticoagulants, and immunosuppressive and chemotherapeutic agents.

From a pharmacokinetic viewpoint, fluoroquinolones (levofloxacin, ciprofloxacin, moxifloxacin) are attractive agents for the treatment of CNS infection because of their lipophilicity and low molecular weight. For sensitive gram-negative aerobic bacilli, fluoroquinolones (in particular, ciprofloxacin) are useful; however, their therapeutic utility is limited in other infections owing to a high rate of bacterial resistance in nosocomial infections and, albeit modestly, increased seizure potential and to limited data regarding their clinical effectiveness for postoperative CNS infections.

Aminoglycosides have excellent activity against aerobic gram-negative bacilli, including P. aeruginosa, as well as synergistic activity with β-lactams against aerobic gram-positive cocci. Systemic use of aminoglycosides is limited by their toxicity profile and a narrow therapeutic window. Furthermore, their penetration into CSF and across the blood-brain barrier is poor. Polymyxins (e.g., colistin) also have activity against a broad array of gram-negative bacilli but fell out of favor because of nephrotoxicity. As a result of the retained activity of polymyxins against multidrug-resistant gram-negative bacilli, including P. aeruginosa and Acinetobacter baumannii, this class again plays a role in CNS infections that are difficult to treat. As with the aminoglycosides, the distribution of systemically administered polymyxins to CSF is poor, and their toxicity does not allow for an increase in systemic doses.

Intraventricular antibiotic administration bypasses the blood-brain barrier, can achieve much higher CSF concentrations than systemic administration, and has been used successfully in multiple case reports. Intraventricular antibiotic dosing has been associated with neurotoxicity, however, in experimental animal models and a small number of case reports. ^, Currently, there are no well-established data to support adjunctive intraventricular administration of an antimicrobial when a systemically delivered agent can achieve adequate microbicidal concentrations in CSF and the patient has an appropriate clinical response.

Superficial Incisional Infections

Clinical Manifestations

Superficial infections after craniotomy comprise a collection of anatomically distinct infections that may extend from the skin to the epidural space. The potential for these infections to extend to the underlying bone flap and through the dura mandates rapid effective treatment with close monitoring to ensure a response to therapy and resolution of infection.

Superficial infection is the most common infectious complication after craniotomy. Although every surgical patient is at risk for postoperative infection, a variety of factors may contribute to create an environment that is suboptimal for wound healing and more favorable for infection, including repeat operative intervention, poor tissue quality, impaired vascular supply, radiation injury, nutritional deficiency, and the presence of foreign bodies. The role of foreign material in facilitating infection was first reported by Elek and Conen, who demonstrated that the presence of suture material increased the skin abscess–causing virulence of coagulase-positive staphylococci by 10,000-fold. Continuous activation of granulocytes by foreign bodies may lead to local impairment of phagocytic ability, thereby reducing the amount of bacterial contamination needed to establish infection.

Superficial infection typically manifests as local erythema, swelling, and tenderness at the craniotomy site with possible suppurative drainage ( Fig. 53.1 ). With progressive infection, systemic signs such as malaise, fever, and chills may develop. Exposure of the underlying bone flap or metallic hardware ( Fig. 53.2 ) indicates deep organ space infection, whereas the presence of neurological symptoms such as meningismus, altered mental status, and new focal deficits strongly suggests the coexistence of intracranial infection. The most common pathogenic agents of superficial wound infections are gram-positive cocci, including S. aureus, coagulase-negative staphylococci, and C. acnes. ^,

Deep Incisional Infections: Subgaleal Space and Bone Flap